FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Wang, Y Efstathiou, JA Sharp, GC Lu, HM Ciernik, IF Trofimov, AV AF Wang, Yi Efstathiou, Jason A. Sharp, Gregory C. Lu, Hsiao-Ming Ciernik, I. Frank Trofimov, Alexei V. TI Evaluation of the dosimetric impact of interfractional anatomical variations on prostate proton therapy using daily in-room CT images SO MEDICAL PHYSICS LA English DT Article DE proton therapy; prostate cancer; interfractional organ motion; daily in-room serial CT; deformable registration ID CANCER RADIOTHERAPY; PLANNING CT; IMRT; REGISTRATION; VERIFICATION; RECTUM; TISSUE; MOTION; SHIFTS; VOLUME AB Purpose: To quantify interfractional anatomical variations and their dosimetric impact during the course of fractionated proton therapy (PT) of prostate cancer and to assess the robustness of the current treatment planning techniques. Methods: Simulation and daily in-room CT scans from ten prostate carcinoma patients were analyzed. PT treatment plans (78 Gy in 39 fractions of 2 Gy) were created on the simulation CT, delivering 25 fractions to PTV1 (expanded from prostate and seminal vesicles), followed by 14 boost fractions to PTV2 (expanded from prostate). Plans were subsequently applied to daily CT, with beams aligned to the prostate center in the sagittal plane. For five patients having a sufficiently large daily imaging volume, structure contours were manually drawn, and plans were evaluated for all CT sets. For the other five patients, the plans were evaluated for six selected fractions. The daily CT was matched to the simulation CT through deformable registration. The registration accuracy was validated for each fraction, and the three patients with a large number of accurately registered fractions were used for dose accumulation. Results: In individual fractions, the coverage of the prostate, seminal vesicles, and PTV1 was generally maintained at the corresponding prescription dose. For PTV2, the volume covered by the fractional prescription dose of 2 Gy (i.e., V2) was, on average, reduced by less than 3% compared to the simulation plan. Among the 225 (39 x 5 + 6 x 5) fractions examined, 15 showed a V2 reduction larger than 5%, of which ten were caused by a large variation in rectal gas, and five were due to a prostate shift in the craniocaudal direction. The fractional dose to the anterior rectal wall was found to increase for one patient who had large rectal gas volume in 25 of the 39 fractions, and another who experienced significant prostate volume reduction during the treatment. The fractional bladder dose generally increased with decreasing fullness. In the total accumulated dose for the three patients after excluding a few fractions with inaccurate registration due to a large amount of rectal gas (a condition inconsistent with RTOG protocol), 98.5%, 96.6%, and 98.2% of the PTV2 received the prescription dose of 78 Gy. The V75 and V70 of the anterior rectal wall and bladder both remained within tolerance. Conclusions: The results confirm that the PT planning techniques and dose constraints used at our institution ensure that target coverage to the prescription dose is maintained in the presence of interfractional anatomical variations. Dose coverage in individual fractions can be compromised, and normal tissue dose increased, due to deviations in the bladder and rectal volume compared to the simulation plans or progressive changes in the prostate volume during the treatment. Deviations from the plan can be reduced with efforts aimed at maintaining consistent daily patient anatomy. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3604152] C1 [Wang, Yi; Efstathiou, Jason A.; Sharp, Gregory C.; Lu, Hsiao-Ming; Trofimov, Alexei V.] Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ciernik, I. Frank] Dessau Med Ctr, D-06847 Dessau, Germany. [Ciernik, I. Frank] Univ Zurich Hosp, Clin Res Ctr, CH-8006 Zurich, Switzerland. RP Wang, Y (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM yi.wang@mgh.harvard.edu FU Massachusetts General Hospital [C06-CA059267] FX The authors would like to express their gratitude to James R. Wong, M.D., and Scott Merrick (Morristown Memorial Hospital, Morristown, NJ) for providing the patient data. They also thank Dr. Peter Biggs for his insightful comments on this study. This study was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06-CA059267, Proton Therapy Research and Treatment Center. NR 26 TC 13 Z9 13 U1 0 U2 9 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD AUG PY 2011 VL 38 IS 8 BP 4623 EP 4633 DI 10.1118/1.3604152 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 801DV UT WOS:000293417500023 PM 21928635 ER PT J AU Duan, ZF Choy, E Harmon, D Liu, XZ Susa, M Mankin, H Hornicek, F AF Duan, Zhenfeng Choy, Edwin Harmon, David Liu, Xianzhe Susa, Michiro Mankin, Henry Hornicek, Francis TI MicroRNA-199a-3p Is Downregulated in Human Osteosarcoma and Regulates Cell Proliferation and Migration SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID RAPID COLORIMETRIC ASSAY; STEM-CELLS; CANCER; EXPRESSION; MET; SURVIVAL; GROWTH; TUMOR; SENSITIVITY; SIGNATURES AB microRNAs (miRNA, miR) play an important role in cancer cell growth andmigration; however, the potential roles of miRNAs in osteosarcoma remain largely uncharacterized. By applying a miRNA microarray platform and unsupervised hierarchical clustering analysis, we found that several miRNAs have altered expression levels in osteosarcoma cell lines and tumor tissues when compared with normal human osteoblasts. Three miRNAs, miR-199a-3p, miR-127-3p, and miR-376c, were significantly decreased in osteosarcoma cell lines, whereas miR-151-3p and miR-191 were increased in osteosarcoma cell lines in comparison with osteoblasts. Transfection of precursor miR-199a-3p into osteosarcoma cell lines significantly decreased cell growth and migration, thus indicating that the inhibition effect is associated with an increase in the G(1)-phase and a decrease of the S-phase cell population. In addition, we observed decreased mTOR and Stat3 expression in miR-199a-3p transfected cells. This study provides new insights for miRNAs in osteosarcoma and suggests that miR-199a-3p may play a functional role in osteosarcoma cell growth and proliferation. Restoring miR-199a-3p's function may provide therapeutic benefits in osteosarcoma. Mol Cancer Ther; 10(8); 1337-45. (C) 2011 AACR. C1 [Duan, Zhenfeng; Choy, Edwin; Harmon, David; Liu, Xianzhe; Susa, Michiro; Mankin, Henry; Hornicek, Francis] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, 100 Blossom St,Jackson 1115, Boston, MA 02114 USA. EM zduan@partners.org RI Susa, Michiro/L-2291-2013; OI Choy, Edwin/0000-0001-9896-8084 FU Gattegno and Wechsler funds; Kenneth Stanton Fund; Sarcoma Foundation of America (SFA); MGH Orthopaedics; Harvard Clinical and Translational Science Center [UL1 RR 025758]; Harvard University FX This project was supported, in part, by grants from the Gattegno and Wechsler funds. Support has also been provided by the Kenneth Stanton Fund. Dr. Z. Duan is supported, in part, through a grant from Sarcoma Foundation of America (SFA) and a grant from an Academic Enrichment Fund of MGH Orthopaedics. Dr. E. Choy is supported by the Harvard Catalyst | The Harvard Clinical and Translational Science Center (Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). NR 32 TC 112 Z9 123 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD AUG PY 2011 VL 10 IS 8 BP 1337 EP 1345 DI 10.1158/1535-7163.MCT-11-0096 PG 9 WC Oncology SC Oncology GA 804YR UT WOS:000293692500004 PM 21666078 ER PT J AU Ziegler, DS Keating, J Kesari, S Fast, EM Zawel, L Ramakrishna, N Barnes, J Kieran, MW van Zanten, SEMV Kung, AL AF Ziegler, David S. Keating, Joanna Kesari, Santosh Fast, Eva M. Zawel, Leigh Ramakrishna, Naren Barnes, Jessica Kieran, Mark W. van Zanten, Sophie E. M. Veldhuijzen Kung, Andrew L. TI A small-molecule IAP inhibitor overcomes resistance to cytotoxic therapies in malignant gliomas in vitro and in vivo SO NEURO-ONCOLOGY LA English DT Article DE apoptosis; glioma; Inhibitor of Apoptosis Protein; radiotherapy ID IRRADIATION-INDUCED APOPTOSIS; X-LINKED INHIBITOR; GROWTH-FACTOR; HUMAN GLIOBLASTOMA; BRAIN-TUMORS; CELLS; EXPRESSION; RECEPTORS; ASTROCYTOMA; ANTAGONISTS AB We tested the use of the small-molecule Inhibitor of Apoptosis Protein (IAP) inhibitor LBW242 in combination with the standard-of-care therapies of irradiation and temozolomide for malignant gliomas. In vitro assays demonstrated that LBW242 enhanced the cytotoxic activity of radiotherapy, and clonogenic assays showed that the combination therapy led to a synergistic anti-glioma effect in multiple cell lines. Neurosphere assays revealed that the combination of radiation and LBW242 led to a pro-apoptotic effect in these glioma-initiating cell-enriched assays, with a corresponding inhibition of primary tumor cell growth. Athymic mice bearing established human malignant glioma tumor xenografts treated with LBW242 plus radiation and temozolomide demonstrated a synergistic suppression of tumor growth. Taken together, these experiments show that the pro-apoptotic and anti-glioma effects of radiotherapy and chemotherapy can be enhanced by the addition of a small-molecule IAP inhibitor. These results are readily translatable to clinical trial and offer the potential for improved treatment outcomes for patients with glioma. C1 [Ziegler, David S.; Kieran, Mark W.; van Zanten, Sophie E. M. Veldhuijzen; Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Kesari, Santosh; Fast, Eva M.; Ramakrishna, Naren] Dana Farber Canc Inst, Dept Med Oncol & Canc Biol, Boston, MA 02215 USA. [Kesari, Santosh; Fast, Eva M.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Ramakrishna, Naren] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Barnes, Jessica; Kieran, Mark W.] Childrens Hosp Boston, Vasc Biol Program, Boston, MA USA. [Barnes, Jessica; Kieran, Mark W.] Childrens Hosp Boston, Dept Surg, Boston, MA USA. [Kieran, Mark W.; Kung, Andrew L.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. [Zawel, Leigh] Novartis Inst BioMed Res, Cambridge, MA USA. [Ziegler, David S.; Keating, Joanna] Univ New S Wales, Childrens Canc Inst Australia Med Res, Randwick, NSW 2031, Australia. RP Kung, AL (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave,Dana 630D, Boston, MA 02215 USA. EM andrew_kung@dfci.harvard.edu RI Kesari, Santosh/E-8461-2013; OI Kieran, Mark/0000-0003-2184-7692; Kung, Andrew/0000-0002-9091-488X FU DFCI-Novartis; Royal Australasian College of Physicians; Hagerty Fund Research Award; Leonard Florence and Joanna Bruner Brain Tumor Research Funds; Australian-American Fulbright Commission; Balnaves Foundation FX Funding provided by the DFCI-Novartis Drug Discovery Program (A.L.K.), the Royal Australasian College of Physicians Rowden White Fellowship (D.S.Z.), the Hagerty Fund Research Award (D.S.Z., A.L.K.), the Leonard Florence and Joanna Bruner Brain Tumor Research Funds (S.K.), the Australian-American Fulbright Commission (D.S.Z.), and the Balnaves Foundation (D.S.Z., J.K.). We thank Renee Wright for her assistance with the in vivo experiments. NR 39 TC 16 Z9 17 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD AUG PY 2011 VL 13 IS 8 BP 820 EP 829 DI 10.1093/neuonc/nor066 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 806PU UT WOS:000293820900003 PM 21724651 ER PT J AU Sano, M Bell, KL Galasko, D Galvin, JE Thomas, RG van Dyck, CH Aisen, PS AF Sano, M. Bell, K. L. Galasko, D. Galvin, J. E. Thomas, R. G. van Dyck, C. H. Aisen, P. S. TI A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease SO NEUROLOGY LA English DT Article ID C-REACTIVE PROTEIN; CLINICAL-TRIALS; COGNITIVE FUNCTION; MOUSE MODEL; STATINS; RISK; DEMENTIA; HEALTH; IMMUNOREACTIVITY; ATORVASTATIN AB Background: Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD. Objective: To determine if the lipid-lowering agent simvastatin slows the progression of symptoms in AD. Methods: This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer's Disease Assessment Scale-cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior. Results: A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment. Conclusion: Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. Classification of evidence: This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog. Neurology (R) 2011;77:556-563 C1 [Sano, M.] Mt Sinai Sch Med, New York, NY USA. [Sano, M.] James J Peters VAMC, Bronx, NY 10468 USA. [Bell, K. L.] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Galasko, D.; Aisen, P. S.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Galvin, J. E.] NYU, Langone Med Ctr, Ctr Excellence Brain Aging, New York, NY USA. [Galvin, J. E.] NYU, Langone Med Ctr, Alzheimer Dis Ctr, New York, NY USA. [Thomas, R. G.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [van Dyck, C. H.] Yale Univ, Sch Med, Alzheimers Dis Res Unit, New Haven, CT USA. RP Sano, M (reprint author), Mt Sinai Sch Med, 130 W Kingsbridge Rd,Code 150,Rm 1F01, Bronx, NY 10468 USA. EM mary.sano@mssm.edu FU NIH (NIA/NCRR); Baxter International Inc.; Wyeth; Pfizer Inc; Janssen Alzheimer Immunotherapy Research & Development, LLC; NIH/NIA; Eli Lilly and Company; Avid Radiopharmaceuticals, Inc.; Novartis; Elan Corporation; Bristol-Myers Squibb; Alzheimer Association; US Department of Defense; Medivation, Inc.; Bayer Schering Pharma; Abbott; GlaxoSmithKline; Myriad Genetics, Inc.; Neurochem Inc; Sanofi-Synthelabo Research; Janssen; Eisai Inc.; Merck Serono; Mitsubishi Tanabe Pharma Corporation; NIH (NIA, NIMH); Alzheimer's Association; American Health Assistance Foundation; National Alliance for Research on Schizophrenia and Affective Disorders (NARSAD); Shire plc; NIH (NIA, NINDS); Kavli Neuroscience Institute at Yale; Merck; NIA [U01AG10483]; Forest Laboratories, Inc. FX This work was supported by NIA grant U01AG10483. The ADCS received an unrestricted educational grant from Merck who also supplied drug and placebo. Merck did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation of the manuscript. Authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.; Dr. Sano serves on a scientific advisory board for Medivation, Inc.; serves as a consultant for Bayer Schering Pharma, Bristol-Meyers Squibb, Elan Corporation, Genentech, Inc., Medivation, Inc., Medpace Inc., Pfizer Inc, Janssen, Takeda Pharmaceutical Company Limited, and United Biosource Corporation; and receives research support from the NIH (NIA/NCRR). Dr. Bell serves on speakers' bureaus for and has received speaker honoraria from Eisai Inc. and Forest Laboratories, Inc.; and receives research support from Baxter International Inc., Wyeth, Pfizer Inc, Janssen Alzheimer Immunotherapy Research & Development, LLC, and the NIH/NIA. Dr. Galasko serves on a scientific advisory board for Janssen/Elan Corporation; serves as Co-Editor for Alzheimer's Research and Therapy; serves as a consultant for United BioSource Corporation; and receives research support from Eli Lilly and Company, Avid Radiopharmaceuticals, Inc., and the NIH/NIA. Dr. Galvin serves on a scientific advisory board for the American Federation for Aging Research and on the Board of Directors and the Scientific Advisory Council for the Lewy Body Dementia Association; serves on the editorial boards of Alzheimer's Disease and Associated Disorders and Acta Neuropathologica; serves on speakers' bureaus for Pfizer Inc, Eisai Inc., Novartis, and Forest Laboratories, Inc.; has served as a consultant for Novartis, Forest Laboratories, Inc., Pfizer Inc, Eisai Inc., Janssen, and Medivation, Inc.; has received license fee payments for AD8 dementia screening test (copyrighted): license agreements between Washington University and Pfizer Inc, Eisai Inc., and Novartis; and receives research support from Novartis, Eli Lilly and Company, Elan Corporation, Wyeth, Bristol-Myers Squibb, the NIH/NIA, and the Alzheimer Association. Dr. Thomas has served on a scientific advisory board for Myriad Genetics, Inc.; has served as a consultant for Medivation, Inc., Myriad Genetics, Inc., Bristol-Meyers Squibb, and Neurochem Inc.; and receives research support from the US Department of Defense and the NIH/NIA. Dr. van Dyck has served on scientific advisory boards for Elan Corporation, Pfizer Inc, GlaxoSmithKline, Bristol-Myers Squibb, and Forest Laboratories, Inc.; has received funding for travel and speaker honoraria from Forest Laboratories, Inc.; his spouse owns or has applied for patents re: Use of guanfacine in the treatment of behavioral disorders, Use of lofexidine in the treatment of behavioral disorders, Chelerythrine, analogs thereof and their use in the treatment of bipolar disorder and other cognitive disorders (formerly licensed to Marinus Pharmaceuticals, Inc.); his spouse receives publishing royalties for The Neuropharmacology of Stimulant Drugs: Implications for AD/HD (Oxford University Press, 2000); serves as a consultant for Elan Corporation, Pfizer Inc, GlaxoSmithKline, Bristol-Myers Squibb, Forest Laboratories, Inc., and Merck Serono, and his spouse serves as a consultant for Shire plc; served on the speakers' bureau for Forest Laboratories, Inc.; receives/has received research support from Wyeth, Eli Lilly and Company, Pfizer Inc, Bristol-Myers Squibb, Medivation, Inc., Bayer Schering Pharma, Abbott, Elan Corporation, GlaxoSmithKline, Myriad Genetics, Inc., Neurochem Inc, Sanofi-Synthelabo Research, Janssen, Eisai Inc.; , Merck Serono, Mitsubishi Tanabe Pharma Corporation, the NIH (NIA, NIMH), Alzheimer's Association, American Health Assistance Foundation, and the National Alliance for Research on Schizophrenia and Affective Disorders (NARSAD); his spouse receives research support fro Shire plc, the NIH (NIA, NINDS), the Kavli Neuroscience Institute at Yale, and NARSAD; and his spouse has received license fee payments and receives royalties from Shire plc for a patent re: Use of guanfacine in the treatment of behavioral disorders. Dr. Aisen serves on a scientific advisory board for NeuroPhage and Novartis; serves on the editorial boards of BMC Medicine and Alzheimer's Research & Therapy; is listed as inventor on a patent re: DHA therapy for apolipoprotein E4 negative Alzheimer's disease (potential royalties assigned in full to UCSD); serves as a consultant to Elan Corporation, Wyeth, Eisai Inc., Schering-Plough Corp., Bristol-Myers Squibb, Eli Lilly and Company, NeuroPhage, Merck & Co., Roche, Amgen, Genentech, Inc., Abbott, Pfizer Inc, Novartis, Bayer Schering Pharma, Astellas Pharma Inc., Dainippon Sumitomo Pharma, BioMarin Pharmaceutical Inc., Solvay Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo, AstraZeneca, Janssen, and Medivation, Inc.; receives research support from Pfizer Inc, Bayer Schering Pharma, Baxter International Inc., and the NIH/NIA; and has received stock options from Medivation, Inc. and NeuroPhage. NR 38 TC 106 Z9 111 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 2011 VL 77 IS 6 BP 556 EP 563 DI 10.1212/WNL.0b013e318228bf11 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 804MW UT WOS:000293658900011 PM 21795660 ER PT J AU Messlinger, K Fischer, MJM Lennerz, JK AF Messlinger, K. Fischer, M. J. M. Lennerz, J. K. TI Neuropeptide effects on the trigeminal system SO SCHMERZ LA German DT Article DE CGRP; Headache; Dura mater; Trigeminal ganglion; Trigeminal nucleus ID GENE-RELATED PEPTIDE; RAT DURA-MATER; ACTIVITY-MODIFYING PROTEIN-1; RECEPTOR ANTAGONIST; SUBSTANCE-P; BLOOD-FLOW; NEUROGENIC INFLAMMATION; MIGRAINE HEADACHE; CGRP ANTAGONISTS; NITRIC-OXIDE AB Neuropeptides, such as calcitonin gene-related peptide (CGRP), substance P and vasoactive intestinal polypeptide (VIP) are considered important mediators in primary headaches. Increased concentrations of CGRP have been found in jugular venous plasma during attacks of migraine and, concomitant with VIP elevation, during cluster headache. Substance P and CGRP are produced from subsets of trigeminal afferents whereas VIP derives from parasympathetic efferents. Release of these neuropeptides in the meninges causes arterial vasodilatation, mast cell degranulation and plasma extravasation in animal experiments. Particularly CGRP seems to be important, as receptor antagonists have recently been shown to have a therapeutic effect on migraine. Animal models have confirmed the role of CGRP in meningeal nociception. The activity of spinal trigeminal neurons is a sensitive integrative measure of trigeminal activity and CGRP released from central terminals of trigeminal afferents in the spinal trigeminal nucleus has been shown to facilitate nociceptive transmission, most likely by a presynaptic action. The proposed CGRP functions are supported by the distribution of CGRP receptor components localized in the rat cranial dura mater, the trigeminal ganglion and the spinal trigeminal nucleus. The currently available data indicate multiple sites of CGRP action in trigeminal nociception and the pathogenesis of migraine but central CGRP receptors are probably the essential targets in the treatment of migraine using CGRP receptor antagonists. C1 [Messlinger, K.] Univ Erlangen Nurnberg, Inst Physiol & Pathophysiol, D-91054 Erlangen, Germany. [Fischer, M. J. M.] Univ Cambridge, Dept Pharmacol, Cambridge CB2 1TN, England. [Lennerz, J. K.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Messlinger, K (reprint author), Univ Erlangen Nurnberg, Inst Physiol & Pathophysiol, Univ Str 17, D-91054 Erlangen, Germany. EM Messlinger@physiologie1.uni-erlangen.de NR 40 TC 1 Z9 1 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0932-433X J9 SCHMERZ JI Schmerz PD AUG PY 2011 VL 25 IS 4 BP 393 EP + DI 10.1007/s00482-011-1069-5 PG 8 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 804DO UT WOS:000293634600004 PM 21818718 ER PT J AU Gala, M Chung, DC AF Gala, Manish Chung, Daniel C. TI Hereditary Colon Cancer Syndromes SO SEMINARS IN ONCOLOGY LA English DT Review ID FAMILIAL ADENOMATOUS POLYPOSIS; NONPOLYPOSIS COLORECTAL-CANCER; PEUTZ-JEGHERS-SYNDROME; DNA MISMATCH REPAIR; MSH2 MUTATION CARRIERS; GERM-LINE MUTATIONS; LYNCH-SYNDROME; APC GENE; MICROSATELLITE-INSTABILITY; JUVENILE POLYPOSIS C1 [Chung, Daniel C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Boston, MA 02114 USA. [Chung, Daniel C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Chung, DC (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, 50 Blossom St,GRJ 825, Boston, MA 02114 USA. EM dchung@partners.org NR 117 TC 20 Z9 21 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2011 VL 38 IS 4 BP 490 EP 499 DI 10.1053/j.seminoncol.2011.05.003 PG 10 WC Oncology SC Oncology GA 806KG UT WOS:000293805700004 PM 21810508 ER PT J AU Meyerhardt, JA AF Meyerhardt, Jeffrey A. TI Beyond Standard Adjuvant Therapy for Colon Cancer: Role of Nonstandard Interventions SO SEMINARS IN ONCOLOGY LA English DT Review ID BODY-MASS INDEX; QUALITY-OF-LIFE; GROWTH-FACTOR-I; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PREVENT COLORECTAL ADENOMAS; TREATMENT-RELATED TOXICITY; STAGE BREAST-CANCER; CARCINOMA CELL-LINE; VITAMIN-D STATUS; PHYSICAL-ACTIVITY C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM jmeyerhardt@partners.org FU NCI [R01 CA149222, R01 CA118553, P50 CA127003, P01CA87969, P01 CA55075] FX Jeffrey Meyerhardt receives research support from NCI grants R01 CA149222, R01 CA118553, P50 CA127003. P01CA87969 and P01 CA55075. NR 78 TC 15 Z9 15 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2011 VL 38 IS 4 BP 533 EP 541 DI 10.1053/j.seminoncol.2011.05.007 PG 9 WC Oncology SC Oncology GA 806KG UT WOS:000293805700008 PM 21810512 ER PT J AU Eiseman, B AF Eiseman, Ben TI SUS Lifetime Achievement Award Lecture The elder surgeon's role in academia SO SURGERY LA Latin DT Editorial Material C1 Denver VA Med Ctr, Denver, CO 80220 USA. RP Eiseman, B (reprint author), Denver VA Med Ctr, 1055 Clermont St, Denver, CO 80220 USA. EM ben.eiseman@va.gov NR 12 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 2011 VL 150 IS 2 BP 141 EP 145 DI 10.1016/j.surg.2011.05.002 PG 5 WC Surgery SC Surgery GA 806KI UT WOS:000293805900001 PM 21723577 ER PT J AU Bettencourt-Dias, M Hildebrandt, F Pellman, D Woods, G Godinho, SA AF Bettencourt-Dias, Monica Hildebrandt, Friedhelm Pellman, David Woods, Geoff Godinho, Susana A. TI Centrosomes and cilia in human disease SO TRENDS IN GENETICS LA English DT Review ID POLYCYSTIC KIDNEY-DISEASE; PLANAR CELL POLARITY; SENIOR-LOKEN-SYNDROME; CHROMOSOMAL INSTABILITY; DROSOPHILA NEUROBLASTS; CYST FORMATION; CANCER-CELLS; SPINDLE POLE; DAUGHTER CENTROSOME; GENETIC INSTABILITY AB Centrioles are microtubule-derived structures that are essential for the formation of centrosomes, cilia and flagella. The centrosome is the major microtubule organiser in animal cells, participating in a variety of processes, from cell polarisation to cell division, whereas cilia and flagella contribute to several mechanisms in eukaryotic cells, from motility to sensing. Although it was suggested more than a century ago that these microtubule-derived structures are involved in human disease, the molecular bases of this association have only recently been discovered. Surprisingly, there is very little overlap between the genes affected in the different diseases, suggesting that there are tissue-specific requirements for these microtubule-derived structures. Knowledge of these requirements and disease mechanisms has opened new avenues for therapeutical strategies. Here, we give an overview of recent developments in this field, focusing on cancer, diseases of brain development and ciliopathies. C1 [Bettencourt-Dias, Monica] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Hildebrandt, Friedhelm] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Hildebrandt, Friedhelm] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Hildebrandt, Friedhelm] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Pellman, David; Godinho, Susana A.] Harvard Univ, Dept Pediat Oncol, Howard Hughes Med Inst, Dana Farber Canc Inst,Childrens Hosp,Med Sch, Boston, MA 02115 USA. [Woods, Geoff] Univ Cambridge, Dept Med Genet, Cambridge Inst Med Res, Cambridge CB2 0XY, England. RP Bettencourt-Dias, M (reprint author), Inst Gulbenkian Ciencias, Oeiras, Portugal. EM mdias@igc.gulbenkian.pt; susana_godinho@dfci.harvard.edu RI Bettencourt-Dias, Monica/B-5176-2015 OI Bettencourt-Dias, Monica/0000-0003-1987-5598 FU Fundacao para a Ciencia e Tecnologia; Fundacao Calouste Gulbenkian; European Molecular Biology Organization; European Research Council; MBD laboratory; DP laboratory; NIH [DK068306, DK090917] FX We would like to thank Zita Carvalho-Santos and Ofelia Carvalho for help with figures and Gaelle Marteil for discussing the manuscript. Research in MBD's lab is funded by Fundacao para a Ciencia e Tecnologia, Fundacao Calouste Gulbenkian, European Molecular Biology Organization and the European Research Council. SG is funded by a postdoctoral fellowship from the Harvard-Portugal programme (FCT) for a collaborative grant between the MBD and the DP laboratories. FH is an Investigator of the Howard Hughes Medical Institute, the Frederick G. L. Huetwell Professor and a Doris Duke Distinguished Clinical Scientist. FH was supported by grants from the NIH (DK068306, DK090917). DP is a Howard Hughes Medical Institute Investigator. We would like to thank Michel Bornens for his permission to use Figure 1a'. NR 96 TC 139 Z9 140 U1 3 U2 28 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD AUG PY 2011 VL 27 IS 8 BP 307 EP 315 DI 10.1016/j.tig.2011.05.004 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 805HL UT WOS:000293717400002 PM 21680046 ER PT J AU Anger, JT Scott, VCS Sevilla, C Wang, MM Yano, EM AF Anger, Jennifer T. Scott, Victoria C. S. Sevilla, Claudia Wang, Mingming Yano, Elizabeth M. TI Patterns of Management of Urethral Stricture Disease in the Veterans Affairs System SO UROLOGY LA English DT Article ID TERM-FOLLOW-UP; INTERNAL URETHROTOMY; HEALTH-CARE; URETHROPLASTY; DILATION; ANASTOMOSIS; GRAFT AB OBJECTIVES To describe the number of urethral dilations, urethrotomies, and urethroplasties performed on men with a diagnosis of urethral stricture disease seeking care in the Veterans Affairs (VA) health care system in southern California and southern Nevada over a 5-year period. To date, few health services research studies have evaluated patterns of care for urethral stricture disease using national datasets. METHODS We analyzed stricture treatment for male veterans with an ICD-9 diagnosis code for urethral stricture in the National Patient Care Database (NPCD). Encounters for urethral stricture procedures performed were identified based on the presence of Physicians Current Procedural Terminology Coding System (4th edition, CPT-4) codes for treatments performed during the fiscal years 2002-2006. RESULTS A total of 1457 men carried a diagnosis of urethral stricture disease during the index time period. Of these, 333 men (23%) underwent 431 procedures. Of the 216 men who underwent urethral dilations, 170 (79%) underwent only 1 procedure and 26 (12%) underwent 2 procedures. Of the 79 men who underwent urethrotomy, 76 (96%) underwent 1 procedure. Sixteen men (5%) underwent a urethroplasty, 8 of whom underwent a perineal urethrostomy. CONCLUSIONS The vast majority of men treated for stricture disease underwent only 1 such procedure over a 5-year time period. Further research is required to investigate whether this is a quality-of-care issue or patients refusing intervention. It is possible that some patients may be temporized for a significant period with dilation/urethrotomy, whereas those with rapid recurrence require early urethroplasty. UROLOGY 78: 454-458, 2011. (C) 2011 Published by Elsevier Inc. C1 Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. Cedars Sinai Med Ctr, Dept Surg, Div Urol, Los Angeles, CA 90048 USA. VA Greater Los Angeles Healthcare Syst, Vet Affairs Hlth Serv Res & Dev Ctr Excellence St, Sepulveda, CA USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA USA. RP Anger, JT (reprint author), 99 La Cienega Blvd,Suite 307, Beverly Hills, CA 90211 USA. EM angerj@cshs.org FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development (HSRD) [65-106]; VA Greater Lost Angeles HSR&D Center of Excellence for the Study of Healthcare Provider Behavior FX This material was based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development (HSR&D) Service through a Locally Initiated Project (Project # 65-106) funded by the VA Greater Lost Angeles HSR&D Center of Excellence for the Study of Healthcare Provider Behavior. NR 20 TC 10 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD AUG PY 2011 VL 78 IS 2 BP 454 EP 458 DI 10.1016/j.urology.2010.12.081 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 803JH UT WOS:000293577100064 PM 21689845 ER PT J AU Powell, TM Glynn, RJ Buring, JE Creager, MA Ridker, PM Pradhan, AD AF Powell, Tiffany M. Glynn, Robert J. Buring, Julie E. Creager, Mark A. Ridker, Paul M. Pradhan, Aruna D. TI The relative importance of systolic versus diastolic blood pressure control and incident symptomatic peripheral artery disease in women SO VASCULAR MEDICINE LA English DT Article DE hypertension; peripheral artery disease; women ID ANKLE-BRACHIAL INDEX; RANDOMIZED CONTROLLED-TRIAL; LOW-DOSE ASPIRIN; INTERMITTENT CLAUDICATION; RISK-FACTORS; PRIMARY PREVENTION; PROSPECTIVE COHORT; CARDIOVASCULAR-DISEASE; HEALTH; MEN AB Prospective data regarding risk factors for peripheral artery disease (PAD) are sparse, especially among women; the relative contribution of systolic versus diastolic blood pressure control for incident PAD has not been well studied. We evaluated the association of self-reported blood pressure control with incident symptomatic PAD in middle-aged and older women. We examined the relationship between reported hypertension and incident confirmed symptomatic PAD (n = 178) in 39,260 female health professionals aged = 45 years without known vascular disease at baseline. Median follow-up was 13.3 years. Women were grouped according to presence of reported isolated diastolic (IDH), isolated systolic (ISH), or combined systolic-diastolic hypertension (SDH) using cut-points of 90 and 140 mmHg for diastolic and systolic blood pressure, respectively. SBP and DBP were modeled as continuous and categorical exposures. Multivariable-adjusted hazard ratios (HRs), including adjustment for cardiovascular risk factors, were derived from Cox proportional hazards models. Adjusted HRs compared to women without reported hypertension were 1.0 (0.4-2.8) for IDH, 2.0 (1.3-3.1) for ISH, and 2.8 (1.8-4.5) for SDH. There was a 43% increased adjusted risk per 10 mmHg of reported SBP (95% CI 27-62%) and a gradient in risk according to SBP category (< 120, 120-139, 140-159, and >= 160 mmHg); HRs were 1.0, 2.3, 4.3, and 6.6 (p-trend < 0.001), respectively. Reported DBP, while individually predictive in models excluding SBP, was not predictive after adjustment for SBP. In conclusion, these prospective data suggest a strong prognostic role for uncontrolled blood pressure and, particularly, uncontrolled systolic blood pressure in the development of peripheral atherosclerosis in women. C1 [Powell, Tiffany M.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dept Internal Med, Dallas, TX 75390 USA. [Glynn, Robert J.; Buring, Julie E.; Ridker, Paul M.; Pradhan, Aruna D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Creager, Mark A.; Ridker, Paul M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Pradhan, Aruna D.] VA Boston Hlth Care Syst, Div Cardiovasc Med, Boston, MA USA. RP Powell, TM (reprint author), Univ Texas SW Med Ctr Dallas, Div Cardiol, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM powtiff@yahoo.com FU National Heart, Lung, and Blood Institute (Bethesda, MD) [HL43851, HL58755, HL75771, HL 082740]; National Cancer Institute (Bethesda, MD) [CA47988]; Donald W Reynolds Foundation (Las Vegas, NV) FX This work was supported by the National Heart, Lung, and Blood Institute (Bethesda, MD) [HL43851, HL58755, HL75771, and HL 082740], the National Cancer Institute (Bethesda, MD) [CA47988], and the Donald W Reynolds Foundation (Las Vegas, NV). NR 30 TC 1 Z9 1 U1 1 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD AUG PY 2011 VL 16 IS 4 BP 239 EP 246 DI 10.1177/1358863X11413166 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 805AW UT WOS:000293699400001 PM 21730007 ER PT J AU Tsao, CW Gona, P Salton, C Murabito, JM Oyama, N Danias, PG O'Donnell, CJ Manning, WJ Yeon, SB AF Tsao, Connie W. Gona, Philimon Salton, Carol Murabito, Joanne M. Oyama, Noriko Danias, Peter G. O'Donnell, Christopher J. Manning, Warren J. Yeon, Susan B. TI Relationship between central and peripheral atherosclerosis and left ventricular dysfunction in a community population SO VASCULAR MEDICINE LA English DT Article DE aortic atherosclerosis; epidemiology; left ventricular wall motion abnormality; MRI; peripheral artery disease ID ANKLE-BRACHIAL INDEX; CORONARY-ARTERY-DISEASE; CARDIOVASCULAR MAGNETIC-RESONANCE; WALL-MOTION ABNORMALITIES; HEART-DISEASE; ARM INDEX; PROGNOSTIC-SIGNIFICANCE; MYOCARDIAL-INFARCTION; MORTALITY; RISK AB We aimed to determine the relationships between resting left ventricular (LV) wall motion abnormalities (WMAs), aortic plaque, and peripheral artery disease (PAD) in a community cohort. A total of 1726 Framingham Heart Study Offspring Cohort participants (806 males, 65 +/- 9 years) underwent cardiovascular magnetic resonance with quantification of aortic plaque volume and assessment of regional left ventricular systolic function. Claudication, lower extremity revascularization, and ankle-brachial index (ABI) were recorded at the most contemporaneous examination visit. WMAs were associated with greater aortic plaque burden, decreased ABI, and claudication in age-and sex-adjusted analyses (all p < 0.001), which were not significant after adjustment for cardiovascular risk factors. In age-and sex-adjusted analyses, both the presence (p < 0.001) and volume of aortic plaque were associated with decreased ABI (p < 0.001). After multivariable adjustment, an ABI <= 0.9 or prior revascularization was associated with a threefold odds of aortic plaque (p = 0.0083). Plaque volume significantly increased with decreasing ABI in multivariable-adjusted analyses (p < 0.0001). In this free-living population, associations of WMAs with aortic plaque burden and clinical measures of PAD were attenuated after adjustment for coronary heart disease risk factors. Aortic plaque volume and ABI remained strongly negatively correlated after multivariable adjustment. Our findings suggest that the association between coronary heart disease and non-coronary atherosclerosis is explained by cardiovascular risk factors. Aortic atherosclerosis and PAD remain strongly associated after multivariable adjustment, suggesting shared mechanisms beyond those captured by traditional risk factors. C1 [Yeon, Susan B.] Beth Israel Deaconess Med Ctr, Div Cardiol, Harvard Thorndike Lab, Boston, MA 02215 USA. [Tsao, Connie W.; Salton, Carol; Oyama, Noriko; Danias, Peter G.; Manning, Warren J.; Yeon, Susan B.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Cardiovasc Div, Boston, MA USA. [Gona, Philimon] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Gona, Philimon; Murabito, Joanne M.; O'Donnell, Christopher J.] NHLBI, NIH, Framingham Heart Study, Framingham, MA USA. [Murabito, Joanne M.] Boston Univ, Dept Med, Gen Internal Med Sect, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Yeon, SB (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiol, Harvard Thorndike Lab, 330 Brookline Ave, Boston, MA 02215 USA. EM syeon@bidmc.harvard.edu RI Oyama-Manabe, Noriko/A-5212-2012; OI Murabito, Joanne/0000-0002-0192-7516 FU National Heart, Lung and Blood Institute, Bethesda, Maryland, USA [N01-HC-25195]; National Institutes of Health [RO1 HL70279, T32 HL07374] FX The Framingham Heart Study is supported by Grant N01-HC-25195 from the National Heart, Lung and Blood Institute, Bethesda, Maryland, USA. This work is also partially supported by a grant from the National Institutes of Health (RO1 HL70279) and a National Institutes of Health training grant (T32 HL07374 to CWT). NR 35 TC 2 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD AUG PY 2011 VL 16 IS 4 BP 253 EP 259 DI 10.1177/1358863X11408640 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 805AW UT WOS:000293699400003 PM 21708875 ER PT J AU Sher, L AF Sher, Leo TI Brain-derived neurotrophic factor and suicidal behavior in adolescents SO WORLD JOURNAL OF PEDIATRICS LA English DT Editorial Material ID RISK-FACTORS; BDNF; CHILDREN C1 [Sher, Leo] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Sher, Leo] James J Peters Vet Adm Med Ctr, Dept Psychiat, New York, NY USA. RP Sher, L (reprint author), James J Peters Vet Adm Med Ctr, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM drleosher@gmail.com NR 18 TC 1 Z9 3 U1 1 U2 2 PU ZHEJIANG UNIV SCH MEDICINE PI HANGZHOU PA CHILDRENS HOSPITAL, 57 ZHUGAN XIANG, HANGZHOU, 310003, PEOPLES R CHINA SN 1708-8569 J9 WORLD J PEDIATR JI World Journal of Pediatrics PD AUG PY 2011 VL 7 IS 3 BP 197 EP 198 DI 10.1007/s12519-011-0316-2 PG 2 WC Pediatrics SC Pediatrics GA 804FX UT WOS:000293640800001 PM 21822986 ER PT J AU Reiner, CS Fischer, MA Hany, T Stolzmann, P Nanz, D Donati, OF Weishaupt, D von Schulthess, GK Scheffel, H AF Reiner, Caecilia S. Fischer, Michael A. Hany, Thomas Stolzmann, Paul Nanz, Daniel Donati, Olivio F. Weishaupt, Dominik von Schulthess, Gustav K. Scheffel, Hans TI Molecular Imaging of Malignant Tumor Metabolism: Whole-Body Image Fusion of DWI/CT vs. PET/CT SO ACADEMIC RADIOLOGY LA English DT Article DE Whole-body imaging; molecular imaging; diffusion weighted imaging; positron emission tomography; tumor metabolism; image fusion ID POSITRON-EMISSION-TOMOGRAPHY; DIFFUSION-WEIGHTED MRI; DUAL-MODALITY PET/CT; CELL LUNG-CANCER; FDG-PET; LYMPH-NODES; COMPUTED-TOMOGRAPHY; DIAGNOSTIC-ACCURACY; METASTASES; CT AB Purpose: To prospectively investigate the technical feasibility and performance of image fusion for whole-body diffusion-weighted imaging (wbDWI) and computed tomography (CT) to detect metastases using hybrid positron emission tomography/computed tomography (PET/CT) as reference standard. Material and Methods: Fifty-two patients (60 +/- 14 years; 18 women) with different malignant tumor disease examined by PET/CT for clinical reasons consented to undergo additional wbDWI at 1.5 Tesla. WbDWI was performed using a diffusion-weighted single-shot echoplanar imaging during free breathing. Images at b = 0 s/mm(2) and b = 700 s/mm(2) were acquired and apparent diffusion coefficient (ADC) maps were generated. Image fusion of wbDWI and CT (from PET/CT scan) was performed yielding for wbDWI/CT fused image data. One radiologist rated the success of image fusion and diagnostic image quality. The presence or absence of metastases on wbDWI/CT fused images was evaluated together with the separate wbDWI and CT images by two different, independent radiologists blinded to results from PET/CT. Detection rate and positive predictive values for diagnosing metastases was calculated. PET/CT examinations mere used as reference standard. Results: PET/CT identified 305 malignant lesions in 39 of 52 (75%) patients. WbDWI/CT image fusion was technically successful and yielded diagnostic image quality in 73% and 92% of patients, respectively. Interobserver agreement for the evaluation of wbDWI/CT images was kappa = 0.78. WbDWI/CT identified 270 metastases in 43 of 52 (83%) patients. Overall detection rate and positive predictive value of wbDWI/CT was 89% (95% CI, 0.85-0.92) and 94% (95% CI, 0.92-0.97), respectively. Conclusion: WbDWI/CT image fusion is technically feasible in a clinical setting and allows the diagnostic assessment of metastatic tumor disease detecting nine of 10 lesions as compared with PET/CT. C1 [Reiner, Caecilia S.; Fischer, Michael A.; Stolzmann, Paul; Nanz, Daniel; Donati, Olivio F.; Scheffel, Hans] Univ Hosp, Dept Med Radiol, Inst Diagnost & Intervent Radiol, Zurich, Switzerland. [Weishaupt, Dominik] Triemli Hosp, Inst Radiol, Zurich, Switzerland. [Stolzmann, Paul; Scheffel, Hans] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Stolzmann, Paul; Scheffel, Hans] Harvard Univ, Sch Med, Boston, MA USA. RP Scheffel, H (reprint author), Univ Hosp, Dept Med Radiol, Inst Diagnost & Intervent Radiol, Zurich, Switzerland. EM hans.scheffel@usz.ch RI Nanz, Daniel/A-9889-2012 NR 36 TC 4 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2011 VL 18 IS 8 BP 940 EP 946 DI 10.1016/j.acra.2011.03.010 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 797EK UT WOS:000293107100003 PM 21718953 ER PT J AU Castillo, JJ Sinclair, N Stachurski, D Jacobsen, ED AF Castillo, Jorge J. Sinclair, Natalie Stachurski, Dariusz Jacobsen, Eric D. TI Positive HIV ELISA test, autoimmune hemolytic anemia, and generalized lymphadenopathy: A unifying diagnosis SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID T-CELL LYMPHOMA; HIGH-DOSE CHEMOTHERAPY; NON-HODGKINS-LYMPHOMA; MARROW-TRANSPLANTATION; EUROPEAN GROUP; WORKING PARTY; SURVIVAL; DISEASE; BLOOD; MODEL C1 [Castillo, Jorge J.; Sinclair, Natalie] Brown Univ, Miriam Hosp, Warren Alpert Med Sch, Div Hematol & Oncol, Providence, RI USA. [Stachurski, Dariusz] Brown Univ, Dept Pathol, Warren Alpert Med Sch, Miriam Hosp, Providence, RI 02912 USA. [Jacobsen, Eric D.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Castillo, JJ (reprint author), 164 Summit Ave, Providence, RI 02906 USA. EM jcastillo@lifespan.org OI Castillo, Jorge/0000-0001-9490-7532 NR 22 TC 1 Z9 1 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2011 VL 86 IS 8 BP 690 EP 693 DI 10.1002/ajh.22049 PG 4 WC Hematology SC Hematology GA 802KE UT WOS:000293508600011 PM 21630306 ER PT J AU Addington, J Cornblatt, BA Cadenhead, KS Cannon, TD McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Heinssen, R AF Addington, Jean Cornblatt, Barbara A. Cadenhead, Kristin S. Cannon, Tyrone D. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Heinssen, Robert TI At Clinical High Risk for Psychosis: Outcome for Nonconverters SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ULTRA-HIGH RISK; INTERRATER RELIABILITY; PREDICTIVE-VALIDITY; PRODROMAL SYNDROMES; INITIAL PRODROME; FOLLOW-UP; SCHIZOPHRENIA; INTERVIEW AB Objective: A major focus of early intervention research is determining the risk of conversion to psychosis and developing optimal algorithms of prediction. Although reported rates of nonconversion vary in the literature, the nonconversion rate always encompasses a majority (50%-85%) of the sample participants. Less is known about the outcome among this group, referred to as false positive individuals. Method: A longitudinal study was conducted of more than 300 prospectively identified treatment-seeking individuals meeting criteria for a psychosis-risk syndrome. Participants were recruited and evaluated across eight clinical research centers as part of the North American Prodrome Longitudinal Study. Over a 2.5-year follow-up assessment period, 214 (71%) participants had not made the transition to psychosis. Results: The sample examined included 111 individuals who had at least 1 year of follow-up data available and did not transition to psychosis within the study duration. In year 1, there was significant improvement in ratings for attenuated positive and negative symptoms. However, at least one attenuated positive symptom was still present for 43% of the sample at 1 year and for 41% at 2 years. At the follow-up timepoints, social and role functioning were significantly poorer in the clinical sample relative to nonpsychiatric comparison subjects. Conclusions: Help-seeking individuals who meet prodromal criteria appear to represent those who are truly at risk for psychosis and are showing the first signs of illness, those who remit in terms of the symptoms used to index clinical high-risk status, and those who continue to have attenuated positive symptoms. C1 [Addington, Jean] Univ Calgary, Ctr Mental Hlth Res & Educ, Dept Psychiat, Calgary, AB T2N 4Z6, Canada. Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Psychiat, Sch Med, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory Univ, Dept Psychiat & Psychol, Atlanta, GA 30322 USA. NIMH, Schizophrenia Spectrum Res Program, Div Adult Translat Res, Bethesda, MD 20892 USA. RP Addington, J (reprint author), Univ Calgary, Ctr Mental Hlth Res & Educ, Dept Psychiat, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM jmadding@ucalgary.ca FU National Institute of Mental Health [U01 MH-066160, U01 MH0-66134, R01 MH-60720, K24 MH-76191, R01 MH-065079, R01 MH-061523, R01 MH-066069, K23 MH-01905, R18 MH-43518, R01 MH-065562, P50 MH-080272, R21MH-075027, RO1MH-062066, K05MH01654]; Donaghue Foundation; Eli Lilly FX Supported by the National Institute of Mental Health (grants U01 MH-066160 [Dr. Woods], U01 MH0-66134 [Dr. Addington], R01 MH-60720 and K24 MH-76191 [Dr. Cadenhead], R01 MH-065079 [Dr. Cannon], R01 MH-061523 [Dr. Cornblatt], R01 MH-066069 and K23 MH-01905 [Dr. Perkins], R18 MH-43518 [Drs. Tsuang and Seidman], R01 MH-065562 and P50 MH-080272 [Dr. Seidman], R21MH-075027 [Dr. Tsuang], RO1MH-062066 [Dr. Walker], and K05MH01654 [Dr. McGlashan]); the Donaghue Foundation (Dr. Woods); and Eli Lilly (Drs. McGlashan, Addington, and Perkins). NR 17 TC 170 Z9 173 U1 3 U2 18 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2011 VL 168 IS 8 BP 800 EP 805 DI 10.1176/appi.ajp.2011.10081191 PG 6 WC Psychiatry SC Psychiatry GA 800SQ UT WOS:000293387600010 PM 21498462 ER PT J AU Vigen, CLP Mack, WJ Keefe, RSE Sano, M Sultzer, DL Stroup, TS Dagerman, KS Hsiao, JK Lebowitz, BD Lyketsos, CG Tariot, PN Zheng, L Schneider, LS AF Vigen, Cheryl L. P. Mack, Wendy J. Keefe, Richard S. E. Sano, Mary Sultzer, David L. Stroup, T. Scott Dagerman, Karen S. Hsiao, John K. Lebowitz, Barry D. Lyketsos, Constantine G. Tariot, Pierre N. Zheng, Ling Schneider, Lon S. TI Cognitive Effects of Atypical Antipsychotic Medications in Patients With Alzheimer's Disease: Outcomes From CATIE-AD SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID RATING-SCALE BPRS; DEMENTIA; SCHIZOPHRENIA; TRIAL; METAANALYSIS; OLANZAPINE; QUETIAPINE; SYMPTOMS; DRUGS; RISPERIDONE AB Objective: The impact of the atypical antipsychotics olanzapine, quetiapine, and risperidone on cognition in patients with Alzheimer's disease is unclear. The authors assessed the effects of time and treatment on neuropsychological functioning during the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study (CATIE-AD). Method: CATIE-AD included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior who were randomly assigned to receive masked, flexible-dose olanzapine, quetiapine, risperidone, or placebo. Based on their clinicians' judgment, patients could discontinue the originally assigned medication and receive another randomly assigned medication. Patients were followed for 36 weeks, and cognitive assessments were obtained at baseline and at 12, 24, and 36 weeks. Outcomes were compared for 357 patients for whom data were available for at least one cognitive measure at baseline and one follow-up assessment that took place after they had been on their prescribed medication or placebo for at least 2 weeks. Results: Overall, patients showed steady, significant declines over time in most cognitive areas, including in scores on the Mini-Mental State Examination (MMSE; -2.4 points over 36 weeks) and the cognitive subscale of the Alzheimer's Disease Assessment Scale (-4.4 points). Cognitive function declined more in patients receiving antipsychotics than in those given placebo on multiple cognitive measures, including the MMSE, the cognitive subscale of the Brief Psychiatric Rating Scale, and a cognitive summary score summarizing change on 18 cognitive tests. Conclusions: In CATIE-AD, atypical antipsychotics were associated with worsening cognitive function at a magnitude consistent with 1 year's deterioration compared with placebo. Further cognitive impairment is an additional risk of treatment with atypical antipsychotics that should be considered when treating patients with Alzheimer's disease. C1 [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Gerontol, Los Angeles, CA 90033 USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Columbia Univ, Dept Psychiat, Sch Med, New York, NY USA. Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Banner Hlth Ctr, Phoenix, AZ USA. Univ Calif San Diego, VA Greater Los Angeles Healthcare Syst, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. RP Schneider, LS (reprint author), Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, 1510 San Pablo St,HCC 600, Los Angeles, CA 90033 USA. EM lschneid@usc.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU AstraZeneca; Eli Lilly; Forest; Pfizer; Ad-lyfe; Associated Jewish Federation of Baltimore; Bristol-Myers Squibb; Eisai; GlaxoSmithKline; Ortho-McNeil; Monitor; Novartis; National Institute on Aging; Supernus; Takeda; Wyeth; Abbott; AC Immune; Alzheimer's Association; Arizona Department of Health Services; Avid; Baxter Healthcare; Elan; Epix; Institute for Mental Health Research; Lundbeck; Memory; Merck; Merz; Mitsubishi Pharma; Myriad; Neurochem; Ono; Sanofi-Aventis; Janssen; NIMH [N01 MH-9001]; USC Alzheimer's Disease Research Center NIH [P50 AG05142]; Department of Veterans Affairs FX Dr. Schneider has been a consultant for Pfizer, Eli Lilly, Johnson & Johnson, AstraZeneca, and Bristol-Myers Squibb. Dr. Keefe has received research support from AstraZeneca, Eli Lilly, and NIMH and has served as a consultant, adviser, or speaker for Abbott, Acadia, BiolineRx, Bristol-Myers Squibb, Cephalon, Cortex, Dainippon Sumitomo Pharma, Eli Lilly, Johnson & Johnson, Lundbeck, Memory Pharmaceuticals, Merck, Orexigen, Organon, Pfizer, Sanofi/Aventis, Schering-Plough, Wyeth, and Xenoport. Dr. Sano has served as a consultant or adviser for Aventis, Bayer, Bristol-Myers Squibb, Eisai, Elan, Forest, Genentech, GlaxoSmithKline, Janssen, Martek, Medivation, Novartis, Ortho-McNeil, Pfizer, Takeda, United BioSource, and Voyager. Dr. Sultzer has received research funding or lecture honoraria from or served as a consultant to AstraZeneca, Eli Lilly, Forest, and Pfizer. Dr. Lyketsos has received research funding, lecture honoraria, or travel support from or served as a consultant or adviser to Ad-lyfe, Associated Jewish Federation of Baltimore, AstraZeneca, Bristol-Myers Squibb, Eisai, Eli Lilly, Forest, GlaxoSmithKline, Ortho-McNeil, Monitor, Novartis, NIMH, National Institute on Aging, Pfizer, Supernus, Takeda, and Wyeth. Dr. Tariot has received research support or consulting or educational fees from Abbott, AC Immune, Alzheimer's Association, Arizona Department of Health Services, AstraZeneca, Avid, Baxter Healthcare, Eisai, Elan, Epix, Forest, GlaxoSmithKline, Institute for Mental Health Research, Lundbeck, Memory, Merck, Merz, Mitsubishi Pharma, Myriad, National Institute on Aging, Neurochem, NIMH, Ono, Pfizer, Sanofi-Aventis, Takeda, and Wyeth; he is also a contributor to the patent "Biomarkers of Alzheimer's Disease." Dr. Stroup has received speaking or consulting fees from Eli Lilly, Janssen, and Lundbeck. The other authors report no financial relationships with commercial interests.; Supported in part by NIMH research contract N01 MH-9001, USC Alzheimer's Disease Research Center NIH P50 AG05142, and the Department of Veterans Affairs. Medications for this study were provided by AstraZeneca, Forest, Janssen, and Eli Lilly. NR 32 TC 82 Z9 83 U1 8 U2 24 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2011 VL 168 IS 8 BP 831 EP 839 DI 10.1176/appi.ajp.2011.08121844 PG 9 WC Psychiatry SC Psychiatry GA 800SQ UT WOS:000293387600014 PM 21572163 ER PT J AU Yoo, DC Dupuy, DE Hillman, SL Fernando, HC Rilling, WS Shepard, JAO Siegel, BA AF Yoo, Don C. Dupuy, Damian E. Hillman, Shauna L. Fernando, Hiran C. Rilling, William S. Shepard, Jo-Anne O. Siegel, Barry A. TI Radiofrequency Ablation of Medically Inoperable Stage IA Non-Small Cell Lung Cancer: Are Early Posttreatment PET Findings Predictive of Treatment Outcome? SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE non-small cell lung cancer; PET/CT; radiofrequency ablation ID TUMOR ABLATION; FOLLOW-UP; FDG-PET; CT; OPPORTUNITIES; MALIGNANCIES; METASTASES; CHALLENGES; LESIONS AB OBJECTIVE. The purpose of this study was to evaluate initial experience with (18)F-FDG PET/CT after pulmonary radiofrequency ablation of stage IA non-small cell lung cancer to determine whether treatment success or residual disease can be predicted with early postablation PET. SUBJECTS AND METHODS. Thirty patients with medically inoperable stage IA non-small cell lung cancer (12 men, 18 women; median age, 76 years; range, 60-87 years) underwent outpatient CT-guided radiofrequency ablation over a 33-month period. Mean tumor size was 2.0 cm (range, 1.3-2.9 cm). PET/CT was performed within 60 days before radiofrequency ablation (RFA), within 4 days after RFA, and 6 months after RFA. Metabolic response was categorized as complete response or partial or no response at early post-RFA PET/CT and complete response, partial response, or progressive metabolic disease at 6-month post-RFA PET/CT and was compared with the 1-year clinical event rate (death, disease progression at contrast-enhanced CT, or repeat ablation). RESULTS. Early PET/CT images, obtained within 4 days of RFA, were evaluable for 26 patients (23 at 6 months). Patients with a complete metabolic response at early PET/CT had a 1-year event rate of 43%, whereas those with partial or no response or disease progression had a 1-year event rate of 67% (p = 0.27). Patients with a complete metabolic response at 6-month PET/CT had a 1-year event rate of 0%. Those with a partial response and those with disease progression had an overall event rate of 75% (p = 0.001). CONCLUSION. Early post-RFA PET/CT is not necessary and 6-month post-RFA PET/CT findings correlate better with clinical outcome at 1 year. C1 [Yoo, Don C.; Dupuy, Damian E.] Rhode Isl Hosp, Warren Alpert Med Sch, Dept Diagnost Imaging, Providence, RI 02903 USA. [Hillman, Shauna L.] Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. [Fernando, Hiran C.] Boston Univ, Med Ctr, Dept Surg, Boston, MA USA. [Rilling, William S.] Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. [Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Siegel, Barry A.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Siegel, Barry A.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA. RP Yoo, DC (reprint author), Rhode Isl Hosp, Warren Alpert Med Sch, Dept Diagnost Imaging, 593 Eddy St, Providence, RI 02903 USA. EM dyoo@lifespan.org OI Fernando, Hiran/0000-0002-5330-7036; Dupuy, Damian/0000-0003-0524-5982 FU NCI NIH HHS [U10 CA 76001, U10 CA076001] NR 19 TC 21 Z9 21 U1 2 U2 7 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2011 VL 197 IS 2 BP 334 EP 340 DI 10.2214/AJR.10.6108 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 796OY UT WOS:000293062600039 PM 21785078 ER PT J AU Kanal, KM Chung, JH Wang, J Bhargava, P Kohr, JR Shuman, WP Stewart, BK AF Kanal, Kalpana M. Chung, Jonathan H. Wang, Jin Bhargava, Puneet Kohr, Jennifer R. Shuman, William P. Stewart, Brent K. TI Image Noise and Liver Lesion Detection With MDCT: A Phantom Study SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE automatic tube current modulation; liver phantom; low-contrast lesion detection; MDCT; noise index ID PHASE HELICAL CT; HEPATOCELLULAR-CARCINOMA; REDUCTION FILTERS; CONTRAST MATERIAL; ABDOMEN AB OBJECTIVE. The purpose of this study was to determine the upper limit of noise for detection of small low-contrast lesions in a liver phantom. MATERIALS AND METHODS. A CT liver phantom containing 21 low-contrast, low-attenuation, circular simulated lesions ranging in size from 2.4 to 10 mm was scanned 23 times at different tube current ranges (varying noise index) on a 64-MDCT scanner with automatic tube current modulation. The attenuation of the simulated lesions was 20 HU less than that of the liver-equivalent background. Three radiologists independently reviewed the resultant CT images, which contained either a low-contrast lesion or no lesion and scored certainty of lesion detection using a 4-point Likert scale. Overall performance was evaluated by sensitivity analysis with receiver operator curve and area under the curve (A(z)) computation for ranges of noise index. RESULTS. The reviewers achieved 100% sensitivity with a noise index of 15 or less for lesions measuring 6.3-10.0 mm (A(z) = 0.96). Increasing noise index to the 17-21 range resulted in a minor decrease in sensitivity and overall performance (sensitivity, 92.3%; A(z) = 0.93). A further increase in noise index to the 23-27 range resulted in a moderate decrease in sensitivity (sensitivity, 81.4%; A(z) = 0.77). Beyond the noise index 23-27 range, sensitivity dropped markedly from 81.4% to 39%. Agreement between the three readers in assessing the image sets was moderate. CONCLUSION. For detection of small low-contrast lesions in the liver phantom model used in this study, the upper limit of noise index may be in the 15-21 range for sensitivity greater than 90%. C1 [Kanal, Kalpana M.; Bhargava, Puneet] Univ Washington, Dept Radiol, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Wang, Jin] Univ Washington, Dept Surg, Seattle, WA 98195 USA. RP Kanal, KM (reprint author), Univ Washington, Dept Radiol, VA Puget Sound Hlth Care Syst, Box 357987,1959 NE Pacific St, Seattle, WA 98195 USA. EM kkanal@u.washington.edu RI Bhargava, Puneet /F-1330-2011; OI Bhargava, Puneet/0000-0002-3849-9666 FU GE Healthcare FX K. M. Kanal has received an honorarium from GE Healthcare for participation in a symposium. W. P. Shuman has received a research grant from GE Healthcare. NR 11 TC 8 Z9 8 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2011 VL 197 IS 2 BP 437 EP 441 DI 10.2214/AJR.10.5726 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 796OY UT WOS:000293062600052 PM 21785091 ER PT J AU O'Regan, KN Jagannathan, JP Ramaiya, N Hodi, FS AF O'Regan, Kevin N. Jagannathan, Jyothipriya P. Ramaiya, Nikhil Hodi, F. Stephen TI Radiologic Aspects of Immune-Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE adverse drug effects; immune response criteria; ipilimumab; melanoma; oncologic imaging; therapy ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; SOLID TUMORS; AUTOIMMUNE HYPOPHYSITIS; METASTATIC MELANOMA; CANCER; GUIDELINES AB OBJECTIVE. The objective of this article is to illustrate examples of radiologic immune-related response criteria and toxicity in patients with advanced melanoma treated with the immunotherapeutic agent ipilimumab. CONCLUSION. Novel immune-related tumor response criteria should be applied to patients undergoing therapy with ipilimumab for advanced melanoma. Ipilimumab also produces a spectrum of immune-related adverse effects that can be recognized radiologically. C1 [O'Regan, Kevin N.; Jagannathan, Jyothipriya P.; Ramaiya, Nikhil] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [O'Regan, Kevin N.; Jagannathan, Jyothipriya P.; Ramaiya, Nikhil; Hodi, F. Stephen] Dana Farber Brigham & Womens Canc Ctr, Melanoma Dis Ctr, Boston, MA 02115 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Ramaiya, N (reprint author), Dana Farber Canc Inst, Dept Radiol, 44 Binney St, Boston, MA 02115 USA. EM nramaiya@partners.org NR 15 TC 21 Z9 22 U1 0 U2 4 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2011 VL 197 IS 2 BP W241 EP W246 DI 10.2214/AJR.10.6032 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 796OY UT WOS:000293062600005 PM 21785048 ER PT J AU Baylor, C Hula, W Donovan, NJ Doyle, PJ Kendall, D Yorkston, K AF Baylor, Carolyn Hula, William Donovan, Neila J. Doyle, Patrick J. Kendall, Diane Yorkston, Kathryn TI An Introduction to Item Response Theory and Rasch Models for Speech-Language Pathologists SO AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY LA English DT Article DE item response theory; outcomes measurement; Rasch model ID COMMUNICATIVE EFFECTIVENESS SURVEY; PATIENT-REPORTED OUTCOMES; CONSTRUCT-VALIDITY; HEALTH OUTCOMES; REHABILITATION; RELIABILITY; PERFORMANCE; DEPENDENCE; RECOVERY; MULTILOG AB Purpose: To present a primarily conceptual introduction to item response theory (IRT) and Rasch models for speech-language pathologists (SLPs). Method: This tutorial introduces SLPs to basic concepts and terminology related to IRT as well as the most common IRT models. The article then continues with an overview of how instruments are developed using IRT and some basic principles of adaptive testing. Conclusion: IRT is a set of statistical methods that are increasingly used for developing instruments in speech-language pathology. While IRT is not new, its application in speech-language pathology to date has been relatively limited in scope. Several new IRT-based instruments are currently emerging. IRT differs from traditional methods for test development, typically referred to as classical test theory (CTT), in several theoretical and practical ways. Administration, scoring, and interpretation of IRT instruments are different from methods used for most traditional CTT instruments. SLPs will need to understand the basic concepts of IRT instruments to use these tools in their clinical and research work. This article provides an introduction to IRT concepts drawing on examples from speech-language pathology. C1 [Baylor, Carolyn; Kendall, Diane; Yorkston, Kathryn] Univ Washington, Seattle, WA 98195 USA. [Hula, William; Doyle, Patrick J.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Hula, William; Doyle, Patrick J.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Donovan, Neila J.] Louisiana State Univ, Baton Rouge, LA 70803 USA. [Kendall, Diane] VA Puget Sound Med Ctr, Seattle, WA USA. RP Baylor, C (reprint author), Univ Washington, Seattle, WA 98195 USA. EM cbaylor@u.washington.edu FU NIDCD NIH HHS [1R03DC010044] NR 60 TC 20 Z9 20 U1 0 U2 5 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1058-0360 J9 AM J SPEECH-LANG PAT JI Am. J. Speech-Lang. Pathol. PD AUG 1 PY 2011 VL 20 IS 3 BP 243 EP 259 DI 10.1044/1058-0360(2011/10-0079) PG 17 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 800RI UT WOS:000293382000008 PM 21622595 ER PT J AU Ehrenfeld, JM Epstein, RH Bader, S Kheterpal, S Sandberg, WS AF Ehrenfeld, Jesse M. Epstein, Richard H. Bader, Stephen Kheterpal, Sachin Sandberg, Warren S. TI Automatic Notifications Mediated by Anesthesia Information Management Systems Reduce the Frequency of Prolonged Gaps in Blood Pressure Documentation SO ANESTHESIA AND ANALGESIA LA English DT Article ID TIMELINESS; PREVENTION; ACCIDENTS; FEEDBACK; FAILURE; RECORDS; HUMANS; INJURY; SAFETY; MISUSE AB BACKGROUND: Arterial blood pressure (BP) measurement at least every 5 minutes is part of the American Society of Anesthesiologists' monitoring standard, but prolonged BP gaps in electronic anesthesia records have been noted. We undertook multicenter studies to determine the frequency of cases with at least 1 interval >= 10 minutes between successive BP measurements and then to ascertain whether educational feedback via an electronic, near real-time notification system alerting providers to the presence of such gaps would reduce their incidence. METHODS: We evaluated 212,706 electronic anesthesia records from 3 large academic centers. We determined the fraction of cases with >= 10-minute BP monitoring gaps at baseline and did a root cause analysis to determine common causes for these lapses. We then designed and implemented automated systems at 2 of the hospitals to notify point-of-care providers immediately after such 10-minute gaps occurred and determined the subsequent impact of this feedback on BP gap incidence, compared with baseline. RESULTS: At Hospital A, the notification system reduced the incidence of cases with at least 1 BP gap (1.48% +/- 0.19% SD vs 0.79% +/- 0.36% SD, P < 0.0001). At Hospital B, the gap incidence was not significantly altered when notification was provided after a 10-minute gap had already occurred (2.72% +/- 0.60% SD vs 2.45% +/- 0.48% SD, P = 0.27), but the incidence was reduced when such notification was provided after 6 minutes without a BP reading (2.72% +/- 0.60% SD vs 1.54% +/- 0.19% SD, P < 0.0001). At Hospital C, where notification was not implemented, the baseline rate of BP gaps was consistent across the preintervention and follow-up periods (7.03% +/- 1.27% SD vs 7.13% +/- 0.11% SD, P = 0.74). Although monitors disconnected during position change was the most common identifiable cause of BP gaps, reasons for the missing BP measurements were often not documented. During a week when the electronic charting system was temporarily inoperable, no BP gaps were noted on a convenience sample of 500 paper records from Hospital A (99% upper confidence limit = 0.83%). CONCLUSIONS: BP gaps of >= 10 minutes were common in electronic anesthesia records, and their incidence was reduced but not eliminated by near real-time feedback to providers. The American Society of Anesthesiologists' standard for BP documentation every 5 minutes might not be achievable with current practices and technology. Anesthesia information management systems users need to be cognizant of the potential for gaps in BP measurement, take steps to minimize their occurrence, and document an explanation when such failures occur. (Anesth Analg 2011;113:356-63) C1 [Ehrenfeld, Jesse M.; Sandberg, Warren S.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Epstein, Richard H.; Bader, Stephen] Thomas Jefferson Univ, Jefferson Med Coll, Dept Anesthesiol, Philadelphia, PA 19107 USA. [Kheterpal, Sachin] Univ Michigan, Dept Anesthesiol, Sch Med, Ann Arbor, MI 48109 USA. RP Ehrenfeld, JM (reprint author), Vanderbilt Univ, 1301 Med Ctr Dr,Suite 4648 TVC, Nashville, TN 37232 USA. EM jehrenfe@post.harvard.edu OI Ehrenfeld, Jesse/0000-0003-3427-0140; Epstein, Richard/0000-0001-8466-3845; Sandberg, Warren/0000-0002-9246-777X FU Foundation for Anesthesia Education and Research; National Institutes of Health [5T32GM007592]; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital FX Supported by a research fellowship grant from the Foundation for Anesthesia Education and Research, grant 5T32GM007592 from the National Institutes of Health, and by funds from the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital. NR 30 TC 35 Z9 35 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2011 VL 113 IS 2 BP 356 EP 363 DI 10.1213/ANE.0b013e31820d95e7 PG 8 WC Anesthesiology SC Anesthesiology GA 796PQ UT WOS:000293064500024 PM 21415437 ER PT J AU Yang, SH Kimmelman, AC AF Yang, Shenghong Kimmelman, Alec C. TI A critical role for autophagy in pancreatic cancer SO AUTOPHAGY LA English DT Editorial Material DE pancreatic cancer; autophagy; metabolism; chloroquine; ROS; tumor C1 [Yang, Shenghong; Kimmelman, Alec C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair,Dept Radiat Oncol, Boston, MA 02115 USA. RP Kimmelman, AC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair,Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM Alec_Kimmelman@dfci.harvard.edu NR 0 TC 28 Z9 30 U1 1 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD AUG PY 2011 VL 7 IS 8 BP 912 EP 913 DI 10.4161/auto.7.8.15762 PG 2 WC Cell Biology SC Cell Biology GA 800AU UT WOS:000293329800014 PM 21494085 ER PT J AU Ho, VT AF Ho, Vincent T. TI Ex Vivo T Cell Depletion of Allogeneic PBSC as Acute and Chronic GVHD Prophylaxis after Myeloablative HCT: Time to Reconsider? SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material ID VERSUS-HOST-DISEASE; DONOR BONE-MARROW; TRIAL; MULTICENTER C1 Dana Farber Canc Inst, Boston, MA 02215 USA. RP Ho, VT (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM vincent_ho@dfci.harvard.edu NR 6 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2011 VL 17 IS 8 BP 1112 EP 1113 DI 10.1016/j.bbmt.2011.02.005 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 801HQ UT WOS:000293429600002 PM 21382501 ER PT J AU Lee, SJ Flowers, MED Martin, PJ Carpenter, P Hansen, J Chai, X Kurland, B Storer, B Arai, S Johnston, L Miklos, D Weisdorf, D Arora, M Majhail, N Cutler, C Jagasia, M Palmer, J Pidala, J Westervelt, P Pusic, I Giralt, S Goldberg, J Couriel, D Kitko, C Pavletic, SZ Vogelsang, GB Gilman, A Schultz, K AF Lee, Stephanie J. Flowers, Mary E. D. Martin, Paul J. Carpenter, Paul Hansen, John Chai, Xiaoyu Kurland, Brenda Storer, Barry Arai, Sally Johnston, Laura Miklos, David Weisdorf, Daniel Arora, Mukta Majhail, Navneet Cutler, Corey Jagasia, Madan Palmer, Jeanne Pidala, Joseph Westervelt, Peter Pusic, Iskra Giralt, Sergio Goldberg, Jenna Couriel, Daniel Kitko, Carrie Pavletic, Steven Z. Vogelsang, Georgia B. Gilman, Andrew Schultz, Kirk CA Chronic GVHD Consortium TI Rationale and Design of the Chronic GVHD Cohort Study: Improving Outcomes Assessment in Chronic GVHD SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material DE Chronic graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Outcomes research; Observational clinical study ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; BONE-MARROW-TRANSPLANTATION; CHRONIC GRAFT; CLINICAL-TRIALS; CELL TRANSPLANTATION; COMORBIDITY INDEX; HEALTH; CRITERIA AB In 2005, the National Institutes of Health sponsored a Consensus Development Project on Criteria for Clinical Trials in chronic graft-versus-host (cGVHD) to achieve consensus about key elements of cGVHD research, including definitions for diagnosis, severity scoring, and response measures. To test these proposed definitions, a multicenter prospective cohort study of people with cGVHD is ongoing. This study will evaluate the performance of proposed prognostic factors, measures of disease activity, and surrogate endpoints for therapeutic response. Data are collected at 6-month intervals in a heterogeneous population of patients reflecting modern transplant techniques and posttransplantation clinical management (target enrollment 672 with cGVHD from I 0 transplantation centers). This report describes the rationale, design, and methods of the cGVHD cohort study, and invites other investigators to collaborate with the Consortium to analyze data or specimens. Biol Blood Marrow Transplant 17: 1114-1120 (2011) (C) 2011 American Society for Blood and Mal-row Transplantation. C1 [Lee, Stephanie J.; Flowers, Mary E. D.; Martin, Paul J.; Carpenter, Paul; Hansen, John; Chai, Xiaoyu; Kurland, Brenda; Storer, Barry] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Arai, Sally; Johnston, Laura; Miklos, David] Stanford Univ, Stanford, CA 94305 USA. [Weisdorf, Daniel; Arora, Mukta; Majhail, Navneet] Univ Minnesota, Minneapolis, MN 55455 USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Palmer, Jeanne] Med Coll Wisconsin, Milwaukee, WI USA. [Pidala, Joseph] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Westervelt, Peter; Pusic, Iskra] Washington Univ, St Louis, MO 63130 USA. [Giralt, Sergio; Goldberg, Jenna] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Couriel, Daniel; Kitko, Carrie] Univ Michigan, Ann Arbor, MI 48109 USA. [Pavletic, Steven Z.; Vogelsang, Georgia B.; Gilman, Andrew; Schultz, Kirk] Northwestern Univ, Evanston, IL 60208 USA. RP Lee, SJ (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,D5-290, Seattle, WA 98109 USA. EM sjlee@fhcrc.org NR 34 TC 15 Z9 16 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2011 VL 17 IS 8 BP 1114 EP 1120 DI 10.1016/j.bbmt.2011.05.007 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 801HQ UT WOS:000293429600003 ER PT J AU Ho, VT Kim, HT Aldridge, J Liney, D Kao, G Armand, P Koreth, J Cutler, C Ritz, J Antin, JH Soiffer, RJ Alyea, EP AF Ho, Vincent T. Kim, Haesook T. Aldridge, Julie Liney, Deborah Kao, Grace Armand, Philippe Koreth, John Cutler, Corey Ritz, Jerome Antin, Joseph H. Soiffer, Robert J. Alyea, Edwin P. TI Use of Matched Unrelated Donors Compared with Matched Related Donors Is Associated with Lower Relapse and Superior Progression-Free Survival after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Transplant; GVHD; Donor; Reduced intensity; Leukemia; Lymphoma ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; HOST-DISEASE PROPHYLAXIS; HLA-IDENTICAL SIBLINGS; GRAFT-VERSUS-LEUKEMIA; HEMATOLOGIC MALIGNANCIES; COMPETING RISK; TOTAL-BODY; THERAPY; AGE AB As success of reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) relies primarily on graft-versus-leukemia (GVL) activity, increased minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent GVL in RIC HSCT compared to matched related donors (MRD), we retrospectively studied 433 consecutive T-replete 6/6 HLA matched URD (n = 246) and MRD (n = 187) RIC HSCT for hematologic malignancies at our institution. Diseases included: acute myelogenous leukemia (AML) (127), non-Hodgkin lymphoma (NHL) (71), chronic lymphocytic leukemia (CLL) (68), myelodysplastic syndrome (MDS) (64), Hodgkin disease (HD) (40), chronic myeloid leukemia (CML) (25), multiple myeloma (MM) (23), myeloproliferative disorder (MPD) (12), acute lymphoblastic leukemia (ALL) (7), and other leukemia (1). All received uniform fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/mini-methroxate (mini-MTX) or tacrolimus/sirolimus +/- mini-MTX. Unrelated donors were younger compared to MRD (median donor age: 33 years versus 52 years, P <.0001), and provided larger CD34(+) products (median CD34(+) cells infused: 8.7 x 10(6)/kg versus 7.5 x 10(6)/kg, P = .002). Distribution of diseases, disease risk, prior transplant, and cytomegalovirus (CMV) status was similar in both cohorts. Cumulative incidence of grade II-IV acute GVHD (at day +180), 2-year chronic GVHD, and 2-year nonrelapse mortality (NRM) were 20% versus 16%, 55% versus 50%, and 8% versus 6% in URD and MRD, respectively (P = NS). Cumulative incidence of relapse at 2 years was lower in URD, 52% versus 65% (P = .005). With median follow-up of 26.5 and 35.8 months, 2-year progression-free survival (PFS) was significantly better in unrelated donor transplants, 39.5% for URD, and 29% for MRD (P = .01). Overall survival (OS) at 2 years were 56% for URD versus 50% for MRD (P = .53). In multivariable analysis, URD was associated with a lower risk of relapse (hazard ratio [FIR] 0.67, P = .002) and superior PFS (HR 0.69, P = .002). These results suggest that URD is associated with greater GVL activity than MRD, and could have practice changing impact on future donor selection in RIC HSCT. Biol Blood Marrow Transplant 17: 1196-1204 (2011) 2011 (C) American Society for Blood and Marrow) Transplantation C1 [Ho, Vincent T.; Liney, Deborah; Kao, Grace; Armand, Philippe; Koreth, John; Cutler, Corey; Ritz, Jerome; Antin, Joseph H.; Soiffer, Robert J.; Alyea, Edwin P.] Harvard Univ, Ctr Hematol Oncol, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. RP Ho, VT (reprint author), Harvard Univ, Ctr Hematol Oncol, Dana Farber Canc Inst, Sch Med, 44 Binney St,D1B30, Boston, MA 02115 USA. EM Vincent_ho@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU Ted and Eileen Pasquarello Research Fund; NIH [CA142106, PO1HL070149-02]; Jock and Bunny Adams Education and Research Fund FX This study was supported, in part, by the Ted and Eileen Pasquarello Research Fund, NIH Grants CA142106, PO1HL070149-02, and the Jock and Bunny Adams Education and Research Fund. NR 31 TC 31 Z9 33 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2011 VL 17 IS 8 BP 1196 EP 1204 DI 10.1016/j.bbmt.2010.12.702 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 801HQ UT WOS:000293429600012 PM 21193054 ER PT J AU Weisdorf, D Weinstock, D Case, C Chao, N Confer, DL AF Weisdorf, Daniel Weinstock, David Case, Cullen Chao, Nelson Confer, Dennis L. TI Planning and Response to Radiation Exposures SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Letter ID HEMATOPOIETIC-CELL TRANSPLANTATION C1 [Weisdorf, Daniel] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Weinstock, David] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chao, Nelson] Duke Univ, Med Ctr, Durham, NC USA. [Case, Cullen; Confer, Dennis L.] Natl Marrow Donor Program, Minneapolis, MN USA. RP Weisdorf, D (reprint author), Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. FU NIAID NIH HHS [U19 AI067798] NR 9 TC 1 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2011 VL 17 IS 8 BP 1262 EP 1263 DI 10.1016/j.bbmt.2011.06.002 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 801HQ UT WOS:000293429600022 PM 21723406 ER PT J AU Argiris, A Ghebremichael, M Burtness, B Axelrod, RS Deconti, RC Forastiere, AA AF Argiris, Athanassios Ghebremichael, Musie Burtness, Barbara Axelrod, Rita S. Deconti, Ronald C. Forastiere, Arlene A. TI A Phase 2 Trial of Bortezomib Followed by the Addition of Doxorubicin at Progression in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma of the Head and Neck A Trial of the Eastern Cooperative Oncology Group (E1303) SO CANCER LA English DT Article DE head and neck cancer; adenoid cystic carcinoma; bortezomib; doxorubicin ID PROTEASOME INHIBITOR PS-341; SALIVARY-GLAND CARCINOMAS; KAPPA-B-ALPHA; MULTIPLE-MYELOMA; CHEMOTHERAPEUTIC-AGENTS; GROWTH-FACTOR; II TRIAL; CELLS; CISPLATIN; CANCER AB BACKGROUND: Bortezomib, an inhibitor of the 26S proteasome and NF-kappa B, may have antitumor activity in adenoid cystic carcinoma (ACC). Preclinical studies have shown synergy between bortezomib and doxorubicin. METHODS: Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and ejection fraction within normal limits. Patients with stable disease for >= 9 months were excluded. Patients received bortezomib 1.3 mg/m(2) by intravenous (IV) push on Days 1, 4, 8, and 11, every 21 days until progression. Doxorubicin 20 mg/m(2) IV on Days 1 and 8 was added at the time of progression. RESULTS: Twenty-five patients were enrolled, of whom 24 were eligible; the most common distant metastatic sites were the lung (n = 22) and the liver (n = 7). There was no objective response with single-agent bortezomib; best response was stable disease in 15 (71%) of 21 evaluable patients. The median progression-free survival and overall survival were 6.4 months and 21 months, respectively. Of 10 evaluable patients who received bortezomib plus doxorubicin, 1 had a partial response, and 6 had stable disease. The most frequent toxicity with bortezomib was grade 3 sensory neuropathy (16%). With bortezomib plus doxorubicin, serious toxicities seen more than once were grade 3-4 neutropenia (n = 3) and grade 3 anorexia (n = 2). CONCLUSIONS: Bortezomib was well tolerated and resulted in disease stabilization in a high percentage of patients but no objective responses. The combination of bortezomib and doxorubicin was also well tolerated and may warrant further investigation in ACC. Cancer 2011;117:3374-82. (C) 2011 American Cancer Society C1 [Argiris, Athanassios] Univ Pittsburgh, Div Hematol Oncol, Dept Med, Sch Med,UPMC Canc Pavil, Pittsburgh, PA 15232 USA. [Ghebremichael, Musie] Harvard Univ, Boston, MA 02115 USA. [Ghebremichael, Musie] Dana Farber Canc Inst, Boston, MA 02115 USA. [Burtness, Barbara] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Axelrod, Rita S.] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Deconti, Ronald C.] H Lee Moffitt Canc Inst, Tampa, FL USA. [Forastiere, Arlene A.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Argiris, A (reprint author), Univ Pittsburgh, Div Hematol Oncol, Dept Med, Sch Med,UPMC Canc Pavil, 5th Floor, Pittsburgh, PA 15232 USA. EM argirisae@upmc.edu FU National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Millennium Pharmaceuticals, Inc.; [CA23318]; [CA66636]; [CA21115]; [CA39229]; [CA17145]; [CA27525]; [CA13650]; [CA16116] FX This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA39229, CA17145, CA27525, CA13650, and CA16116 and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Dr. Argiris has received research support from Millennium Pharmaceuticals, Inc. NR 29 TC 21 Z9 21 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 1 PY 2011 VL 117 IS 15 BP 3374 EP 3382 DI 10.1002/cncr.25852 PG 9 WC Oncology SC Oncology GA 797DD UT WOS:000293103800011 PM 21246525 ER PT J AU Martin, MY Pisu, M Oster, RA Urmie, JM Schrag, D Huskamp, HA Lee, J Kiefe, CI Fouad, MN AF Martin, Michelle Y. Pisu, Maria Oster, Robert A. Urmie, Julie M. Schrag, Deborah Huskamp, Haiden A. Lee, Jeannette Kiefe, Catarina I. Fouad, Mona N. TI Racial Variation in Willingness to Trade Financial Resources for Life-Prolonging Cancer Treatment SO CANCER LA English DT Article DE treatment; preferences; cancer; race; financial resources; tradeoffs ID CARE OUTCOMES RESEARCH; OF-LIFE; TREATMENT PREFERENCES; ETHNIC-DIFFERENCES; AFRICAN-AMERICAN; ADVANCE DIRECTIVES; WHITE PATIENTS; END; ATTITUDES; SUPPORT AB BACKGROUND: Minority patients receive more aggressive care at the end of life, but it is unclear whether this trend is consistent with their preferences. We compared the willingness to use personal financial resources to extend life among white, black, Hispanic, and Asian cancer patients. METHODS: Patients with newly diagnosed lung or colorectal cancer participating in the Cancer Care Outcomes Research and Surveillance observational study were interviewed about myriad aspects of their care, including their willingness to expend personal financial resources to prolong life. We evaluated the association of race/ethnicity with preference for life-extending treatment controlling for clinical, sociodemographic, and psychosocial factors using logistic regression. RESULTS: Among patients (N = 4214), 80% of blacks reported a willingness to spend all resources to extend life, versus 54% of whites, 69% of Hispanics, and 72% of Asians (P<.001). In multivariate analyses, blacks were more likely to opt for expending all financial resources to extend life than whites (odds ratio, 2.41; 95% confidence interval, 1.84-3.17; P < .001). CONCLUSIONS: Black cancer patients are more willing to exhaust personal financial resources to extend life. Delivering quality cancer care requires an understanding of how these preferences impact cancer care and outcomes. Cancer 2011;117:3476-84. (C) 2011 American Cancer Society. C1 [Martin, Michelle Y.] Univ Alabama, Dept Med, Div Prevent Med, Sch Med, Birmingham, AL 35294 USA. [Urmie, Julie M.] Univ Iowa, Coll Pharm, Iowa City, IA 52242 USA. [Schrag, Deborah] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Huskamp, Haiden A.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Lee, Jeannette] Univ Arkansas, Dept Biostat, Little Rock, AR 72204 USA. [Kiefe, Catarina I.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. RP Martin, MY (reprint author), Univ Alabama, Dept Med, Div Prevent Med, Sch Med, 1530 3rd Ave S,MT 617, Birmingham, AL 35294 USA. EM mymartin@uab.edu FU National Cancer Institute (NCI) [U01 CA093344]; Dana-Farber Cancer Institute/Cancer Research Network [U01 CA093332]; Harvard Medical School/Northern California Cancer Center [U01 CA093324]; RAND/University of California at Los Angeles [U01 CA093348]; University of Alabama at Birmingham [U01 CA093329]; University of Iowa [U01 CA09339]; University of North Carolina [U01 CA 093,326]; Department of Veterans Affairs (VA) [CRS 02-164] FX CanCORS was supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01 CA093344) and primary data collection and research centers (Dana-Farber Cancer Institute/Cancer Research Network [U01 CA093332], Harvard Medical School/Northern California Cancer Center [U01 CA093324], RAND/University of California at Los Angeles [U01 CA093348], University of Alabama at Birmingham [U01 CA093329], University of Iowa [U01 CA09339], and University of North Carolina [U01 CA 093,326]), and by a Department of Veterans Affairs (VA) grant to the Durham VA Medical Center (CRS 02-164). NR 37 TC 8 Z9 8 U1 3 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 1 PY 2011 VL 117 IS 15 BP 3476 EP 3484 DI 10.1002/cncr.25839 PG 9 WC Oncology SC Oncology GA 797DD UT WOS:000293103800021 PM 21523759 ER PT J AU Forghanifard, MM Gholamin, M Farshchian, M Moaven, O Memar, B Forghani, MN Dadkhah, E Naseh, H Moghbeli, M Raeisossadati, R Abbaszadegan, MR AF Forghanifard, Mohammad Mahdi Gholamin, Mehran Farshchian, Moein Moaven, Omeed Memar, Bahram Forghani, Mohammad Naser Dadkhah, Ezzat Naseh, Hossein Moghbeli, Meysam Raeisossadati, Reza Abbaszadegan, Mohammad Reza TI Cancer-testis gene expression profiling in esophageal squamous cell carcinoma Identification of specific tumor marker and potential targets for immunotherapy SO CANCER BIOLOGY & THERAPY LA English DT Article DE esophageal squamous cell carcinoma; cancer testis antigens; real-time PCR; tumor marker; cancer vaccine ID PROTEIN-PROTEIN INTERACTION; MAGE GENES; IMMUNOHISTOCHEMICAL EXPRESSION; HETEROGENEOUS EXPRESSION; CANCER/TESTIS ANTIGENS; NY-ESO-1 EXPRESSION; ANDROGEN RECEPTOR; GROWTH-FACTOR; LUNG-CANCER; STEM-CELLS AB Cancer-testis antigens (CTAs) are often specifically expressed in cancer cells and under normal conditions are only considered to be expressed in the germ line cells and the placenta. CTAs are potential targets for cancer immunotherapy and therefore necessitates their expression profiling. The expression profile of LAGE1, MAGE-A4 and NY-ESO1, their possible correlations and interaction, and the clinicopathological associations of each marker were studied. RNA was extracted from fresh esophagectomy tissues of 41 esophageal squamous cell carcinoma (ESCC) patients prior to any other therapeutic intervention. The relative mRNA expression of LAGE1, MAGE-A4 and NY-ESO1 was assessed with the real-time reverse transcription-polymerase chain reaction (RT-PCR) 5' nuclease assay. The overexpression of LAGE1, MAGE-A4 and NY-ESO1 was found in 39, 90.2 and 41.4% of ESCC samples respectively. Of the patients, 97.5% showed an overexpression of at least one CTA. The relative expression of MAGE-A4 was directly associated with lymph node metastasis and the stage of the tumor (p < 0.05). A significant direct correlation was also detected between the MAGE-A4/LAGE1 and MAGE-A4/NY-ESO1 levels of gene expression. MAGE-A4 is identified as a specific biomarker of ESCC with a possible oncogenic role contributing to tumor progression. Interactions between MAGE-A4, LAGE1 and NY-ESO1 and their significant clinical consequences introduce these CTAs as appropriate targets for a polyvalent cancer vaccine. C1 [Forghanifard, Mohammad Mahdi; Gholamin, Mehran; Farshchian, Moein; Moaven, Omeed; Dadkhah, Ezzat; Moghbeli, Meysam; Raeisossadati, Reza; Abbaszadegan, Mohammad Reza] Mashhad Univ Med Sci, Div Human Genet, Immunol Res Ctr, Avicenna Res Inst, Mashhad, Iran. [Forghanifard, Mohammad Mahdi] Islamic Azad Univ, Dept Biol, Sci & Res Branch, Tehran, Iran. [Moaven, Omeed] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Memar, Bahram; Naseh, Hossein] MUMS, Omid Hosp, Dept Pathol, Mashhad, Iran. [Forghani, Mohammad Naser] MUMS, Omid Hosp, Dept Surg, Mashhad, Iran. RP Abbaszadegan, MR (reprint author), Mashhad Univ Med Sci, Div Human Genet, Immunol Res Ctr, Avicenna Res Inst, Mashhad, Iran. EM Forghanifard@gmail.com; abbaszadeganmr@mums.ac.ir RI Memar, Bahram/F-6572-2012; Moghbeli, Meysam/Q-6582-2016; OI Moghbeli, Meysam/0000-0001-9680-0309; Moaven, Omeed/0000-0002-0560-0457 FU Mashhad University of Medical Sciences [88098] FX The authors gratefully acknowledge Azadeh A'rabi and Martha Ghahraman in the Division of Human Genetics for their technical assistance, and also the colleagues from the departments of surgery and pathology at Omid Hospital for their help in gathering and preparing the tissue specimens. This study was supported by a grant from Mashhad University of Medical Sciences (#88098). The results described in this paper were part of a Ph.D. dissertation. NR 52 TC 19 Z9 21 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG 1 PY 2011 VL 12 IS 3 BP 191 EP 197 DI 10.4161/cbt.12.3.15949 PG 7 WC Oncology SC Oncology GA 800II UT WOS:000293352600004 PM 21613820 ER PT J AU Wu, H Zhang, Y AF Wu, Hao Zhang, Yi TI Tet1 and 5-hydroxymethylation A genome-wide view in mouse embryonic stem cells SO CELL CYCLE LA English DT Article DE Tet1; 5-hydroxymethylcytosine; DNA methylation; embryonic stem cells; pluripotency; cell differentiation; polycomb repression; epigenomics ID DNA METHYLATION; CPG ISLANDS; CHROMATIN-STRUCTURE; MYELOID CANCERS; BINDING PROTEIN; TRANSCRIPTION; 5-METHYLCYTOSINE; SPECIFICATION; CONVERSION; MUTATIONS AB Inner cell mass (ICM) cells of a blastocyst, the source of embryonic stem (ES) cells, are characterized by their unique ability to give rise to all cell types in adult organisms. The epigenomes of germ cells and developing zygotes undergo extensive reprogramming to acquire such a pluripotent state. A major reprogramming event during early embryonic development is the erasure and subsequent re-establishment of patterns of methylation at the 5-position of cytosine (5mC). The recent demonstration that Ten-eleven translocation family proteins, Tet1-3 have the capacity to convert 5mC to 5-hydroxymethylcytosine (5hmC) raises the possibility that 5hmC may act as an distinct epigenetic state contributing to dynamic changes in DNA methylation and transcriptional regulation during embryonic development. In ES cells, Tet1 is highly expressed and 5hmC is present at relatively high levels compared to most differentiated cells, but the functional significance of Tet1 and 5hmC in these pluripotent cells are not clear. Recently, a flurry of papers that profile the distribution of Tet1 and/or 5hmC across the genome of mouse ES cells provide new insights into the role of Tet proteins and 5hmC in regulating expression of genes related to pluripotency and cellular differentiation. Through integrative analyses of datasets from different groups, we reveal the common Tet1 and 5hmC targets in undifferentiated mouse ES cells, which suggest that Tet1 may play a key role in orchestrating the balance between pluripotent and lineage committed states. C1 [Wu, Hao] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Wu, Hao] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Zhang, Yi] Univ N Carolina, Howard Hughes Med Inst, Chapel Hill, NC USA. [Zhang, Yi] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RP Wu, H (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM haowu7@gmail.com; yi_zhang@med.unc.edu RI Wu, Hao/G-4145-2013; Waha, Andreas/J-2950-2014 OI Wu, Hao/0000-0002-1256-6891; FU NIH [GM68804]; Jane Coffin Childs postdoctoral fellowship FX We thank Susan Wu for critical reading of the manuscript. This work was supported by NIH grants GM68804 (to Y.Z.). H. W. is supported by a Jane Coffin Childs postdoctoral fellowship. Y.Z. is an Investigator of the Howard Hughes Medical Institute. NR 34 TC 75 Z9 80 U1 1 U2 21 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD AUG 1 PY 2011 VL 10 IS 15 BP 2428 EP 2436 DI 10.4161/cc.10.15.16930 PG 9 WC Cell Biology SC Cell Biology GA 800GD UT WOS:000293346900016 PM 21750410 ER PT J AU van der Vos, KE Balaj, L Skog, J Breakefield, XO AF van der Vos, Kristan E. Balaj, Leonora Skog, Johan Breakefield, Xandra O. TI Brain Tumor Microvesicles: Insights into Intercellular Communication in the Nervous System SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE Microvesicles; Glioblastoma; Biomarkers; Gene transfer; Tumor microenvironment; Non-coding RNAs; Retrotransposons; MicroRNAs ID CELL-DERIVED MICROVESICLES; STEM-CELL; HORIZONTAL TRANSFER; PROSTATE-CANCER; NONCODING RNAS; MESSENGER-RNA; LUNG-CANCER; DIAGNOSTIC BIOMARKERS; ENDOTHELIAL-CELLS; APOPTOTIC BODIES AB Brain tumors are heterogeneous tumors composed of differentiated tumor cells that resemble various neural cells and a small number of multipotent cancer stem cells. These tumors modify normal cells in their environment to promote tumor growth, invasion and metastases by various ways. Recent publications show that glioblastoma cells release microvesicles that contain a select subset of cellular proteins and RNAs. These microvesicles are avidly taken up by normal cells in cell culture and can change the translational profile of these cells through delivery of tumor-derived mRNAs, which are translated into functional proteins. In addition to mRNA and proteins, microvesicles have been shown to contain microRNAs, non-coding RNAs and DNA. This commentary explores the recent advances in this novel intercellular communication route and discusses the potential physiological role of microvesicles in brain tumorigenesis. C1 [Breakefield, Xandra O.] Massachusetts Gen Hosp E, Mol Neurogenet Unit, Charlestown, MA 02129 USA. [van der Vos, Kristan E.; Balaj, Leonora; Skog, Johan; Breakefield, Xandra O.] Dept Neurol, Boston, MA USA. [van der Vos, Kristan E.; Balaj, Leonora; Skog, Johan; Breakefield, Xandra O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [van der Vos, Kristan E.; Balaj, Leonora; Skog, Johan; Breakefield, Xandra O.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02114 USA. [Skog, Johan] Exosome Diagnost Inc, New York, NY 10032 USA. RP Breakefield, XO (reprint author), Massachusetts Gen Hosp E, Mol Neurogenet Unit, 13th St,Bldg 149, Charlestown, MA 02129 USA. EM breakefield@hms.harvard.edu FU NINDS; NCI; American Brain Tumor Association (ABTA) FX This commentary is written in deep appreciation of the inspiring mentorship of Dr. Marshall Nirenberg. The authors have tried to include exciting new scientific ideas, which he always relished. The authors would like to thank Ms. Suzanne McDavitt for skilled editorial assistance and Drs. Charles Lai and David Corey for contributing figures. The Breakefield laboratory is funded by NINDS and NCI. Dr. Skog has a grant from the American Brain Tumor Association (ABTA). NR 93 TC 45 Z9 45 U1 1 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD AUG PY 2011 VL 31 IS 6 SI SI BP 949 EP 959 DI 10.1007/s10571-011-9697-y PG 11 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 799ZF UT WOS:000293325300017 PM 21553248 ER PT J AU Leung, DT Rahman, MA Mohasin, M Riyadh, MA Patel, SM Alam, MM Chowdhury, F Khan, AI Kalivoda, EJ Aktar, A Bhuiyan, MS LaRocque, RC Harris, JB Calderwood, SB Qadri, F Ryan, ET AF Leung, Daniel T. Rahman, Mohammad Arif Mohasin, M. Riyadh, M. Asrafuzzaman Patel, Sweta M. Alam, Mohammad Murshid Chowdhury, Fahima Khan, Ashraful Islam Kalivoda, Eric J. Aktar, Amena Bhuiyan, M. Saruar LaRocque, Regina C. Harris, Jason B. Calderwood, Stephen B. Qadri, Firdausi Ryan, Edward T. TI Comparison of Memory B Cell, Antibody-Secreting Cell, and Plasma Antibody Responses in Young Children, Older Children, and Adults with Infection Caused by Vibrio cholerae O1 El Tor Ogawa in Bangladesh SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID IMMUNE-RESPONSES; ORAL IMMUNIZATION; ESCHERICHIA-COLI; SPATIAL-ANALYSIS; FIELD-TRIAL; MUCOSAL; TOXIN; EPIDEMIOLOGY; PROTECTION; PREVENTION AB Children bear a large component of the global burden of cholera. Despite this, little is known about immune responses to cholera in children, especially those under 5 years of age. Cholera vaccine studies have demonstrated lower long-term protective efficacy in young children than in older children and adults. Memory B cell (MBC) responses may correlate with duration of protection following infection and vaccination. Here we report a comparison of immune responses in young children (3 to 5 years of age; n = 17), older children (6 to 17 years of age; n = 17), and adults (18 to 60 years of age; n = 68) hospitalized with cholera in Dhaka, Bangladesh. We found that young children had lower baseline vibriocidal antibody titers and higher fold increases in titer between day 2 and day 7 than adults. Young children had higher baseline IgG plasma antibody levels to Vibrio cholerae antigens, although the magnitudes of responses at days 7 and 30 were similar across age groups. As a surrogate marker for mucosal immune responses, we assessed day 7 antibody-secreting cell (ASC) responses. These were comparable across age groups, although there was a trend for older age groups to have higher levels of lipopolysaccharide-specific IgA ASC responses. All age groups developed comparable MBC responses to V. cholerae lipopolysaccharide and cholera toxin B subunit at day 30. These findings suggest that young children are able to mount robust vibriocidal, plasma antibody, ASC, and MBC responses against V. cholerae O1, suggesting that under an optimal vaccination strategy, young children could achieve protective efficacy comparable to that induced in adults. C1 [Leung, Daniel T.; Patel, Sweta M.; LaRocque, Regina C.; Harris, Jason B.; Calderwood, Stephen B.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Leung, Daniel T.; Rahman, Mohammad Arif; Mohasin, M.; Riyadh, M. Asrafuzzaman; Patel, Sweta M.; Alam, Mohammad Murshid; Chowdhury, Fahima; Khan, Ashraful Islam; Kalivoda, Eric J.; Aktar, Amena; Bhuiyan, M. Saruar; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Leung, Daniel T.; LaRocque, Regina C.; Calderwood, Stephen B.; Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Leung, DT (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Jackson 504,55 Fruit St, Boston, MA 02114 USA. EM dleung@partners.org OI leung, daniel/0000-0001-8401-0801 FU ICDDR,B; National Institutes of Health, National Institute of Allergy & Infectious Diseases [U01 AI058935, R03 AI063079, U01 AI077883]; Fogarty International Center [TW05572, TW007409, TW07144]; American Recovery and Reinvestment Act (ARRA) [TW05572]; American Society of Tropical Medicine and Hygiene; Howard Hughes Medical Institute; Harvard Initiative for Global Health FX This work was supported by the ICDDR,B and grants from the National Institutes of Health, including the National Institute of Allergy & Infectious Diseases (U01 AI058935 [S. B. C. and E. T. R.], R03 AI063079 [F. Q.[, and U01 AI077883 [E. T. R.]), a Training Grant in Vaccine Development from the Fogarty International Center (TW05572 [M. M. A., M. S. B., and F. Q.]), an American Recovery and Reinvestment Act (ARRA) FIC Postdoctoral Fellowship in Global Infectious Diseases (TW05572 [D. T. L.]), Career Development awards (K01) from the Fogarty International Center (TW007409 [J.B.H.] and TW07144 [R. C. L.]), the Infectious Diseases Society of America Medical Scholars Program (E.J.K.), the American Society of Tropical Medicine and Hygiene Benjamin H. Kean Traveling Fellowship in Tropical Medicine (E.J.K.), a Physician Scientist Early Career Award from the Howard Hughes Medical Institute (R. C. L.), and the Harvard Initiative for Global Health Postdoctoral Fellowship in Global Infectious Diseases (D.T.L.). NR 41 TC 19 Z9 19 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD AUG PY 2011 VL 18 IS 8 BP 1317 EP 1325 DI 10.1128/CVI.05124-11 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 800ID UT WOS:000293352100016 PM 21697337 ER PT J AU Kuchta, A Rahman, T Sennott, EL Bhuyian, TR Uddin, T Rashu, R Chowdhury, F Kahn, AI Arifuzzaman, M Weil, AA Podolsky, M LaRocque, RC Ryan, ET Calderwood, SB Qadri, F Harris, JB AF Kuchta, Alison Rahman, Taibur Sennott, Erica L. Bhuyian, Taufiqur R. Uddin, Taher Rashu, Rasheduzzaman Chowdhury, Fahima Kahn, Ashraf I. Arifuzzaman, Mohammad Weil, Ana A. Podolsky, Michael LaRocque, Regina C. Ryan, Edward T. Calderwood, Stephen B. Qadri, Firdausi Harris, Jason B. TI Vibrio cholerae O1 Infection Induces Proinflammatory CD4(+) T-Cell Responses in Blood and Intestinal Mucosa of Infected Humans SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID NEISSERIA-MENINGITIDIS; FIELD TRIAL; FOLLOW-UP; B-CELL; IMMUNITY; TOXIN; VACCINES; BANGLADESH; DISEASE; MEMORY AB Vibrio cholerae O1 is a noninvasive enteric pathogen and serves as a model for studies of mucosal immunity. Although symptomatic V. cholerae infection induces durable protection against subsequent disease, vaccination with oral killed whole-cell V. cholerae stimulates less long-lasting protection against cholera. In this study, we demonstrated that cholera induces an early proinflammatory cellular immune response that results in priming of Th1- and Th17-type cytokine responses to ex vivo antigenic stimulation and an increase in the ratio of Th1 to Th2 CD4(+) T-cell responses. Comparable priming of Th1 and Th17 responses, with an increased ratio of Th1 to Th2 CD4(+) T-cell responses, was not observed in subjects who received two doses of the oral cholera vaccine Dukoral (a whole-cell cholera toxin B subunit containing [WC-CTB] vaccine). These findings suggest that natural V. cholerae infection induces an early, proinflammatory cellular immune response, despite the apparent lack of clinical signs of inflammation. The failure of the WC-CTB vaccine to activate equivalent, CD4(+) T-cell responses is a potential explanation for the shorter duration of protection following immunization with this vaccine. Additional studies are needed to determine whether these early T-cell-mediated events predict the subsequent duration of immunologic memory. C1 [Sennott, Erica L.; Podolsky, Michael; LaRocque, Regina C.; Ryan, Edward T.; Calderwood, Stephen B.; Harris, Jason B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Kuchta, Alison; Rahman, Taibur; Bhuyian, Taufiqur R.; Uddin, Taher; Rashu, Rasheduzzaman; Chowdhury, Fahima; Kahn, Ashraf I.; Arifuzzaman, Mohammad; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [LaRocque, Regina C.; Ryan, Edward T.; Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Harris, JB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. EM jbharris@partners.org FU ICDDR,B Centre for Health and Population Research; International Research Scientist Development Award [KO1 TW07409, U01 AI058935, RO3 AI063079, U01 AI077883, KO1 TW07144]; Charles H. Hood Foundation; Howard Hughes Medical Institute; Fogarty International Center [D43 TW05572]; Fogarty International Center at the National Institutes of Health [D43 TW005572, R24 TW007988]; Swedish Agency for International Development and Cooperation (Sida) FX This research was supported by the ICDDR,B Centre for Health and Population Research and by the following grants: International Research Scientist Development Award KO1 TW07409 (to J.B.H.), U01 AI058935 (to S. B. C.), RO3 AI063079 (to F. Q.), and U01 AI077883 (to E. T. R.); International Research Scientist Development Award KO1 TW07144 (to R. C. L.); a Charles H. Hood Foundation award (to J.B.H.); a Howard Hughes Medical Institute Physician Scientist Early Career Award (to R. C. L.); and Fogarty International Center Global Infectious Disease Research Training Program Award in Vaccine Development D43 TW05572 (to M. A.). A. K., A. A. W., F. C., and A. I. K. are recipients of Fogarty International Clinical Research Scholars awards from the Fogarty International Center at the National Institutes of Health (D43 TW005572 and R24 TW007988). F. Q. and T. R. B. are recipients of funds from the Swedish Agency for International Development and Cooperation (Sida). NR 36 TC 14 Z9 15 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD AUG PY 2011 VL 18 IS 8 BP 1371 EP 1377 DI 10.1128/CVI.05088-11 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 800ID UT WOS:000293352100023 PM 21697339 ER PT J AU Ben-Menachem, T Dominitz, JA AF Ben-Menachem, Tamir Dominitz, Jason A. TI Acute Upper Gastrointestinal Hemorrhage in an Elderly Woman Taking Aspirin and Clopidogrel SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Editorial Material ID ACUTE CORONARY SYNDROMES; ANTIPLATELET THERAPY; MYOCARDIAL-INFARCTION; MANAGEMENT; ULCERS; TRIAL; BLIND; RISK C1 [Ben-Menachem, Tamir] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Dominitz, Jason A.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Ben-Menachem, T (reprint author), Summit Med Grp, 1 Diamond Hill Rd, Berkeley Hts, NJ 07922 USA. EM tbenmenachem@smgnj.com OI Dominitz, Jason/0000-0002-8070-7086 NR 17 TC 0 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD AUG PY 2011 VL 9 IS 8 BP 649 EP 652 DI 10.1016/j.cgh.2011.03.022 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 803OW UT WOS:000293591600011 PM 21440673 ER PT J AU Urayama, A Morales, R Niehoff, ML Banks, WA Soto, C AF Urayama, Akihiko Morales, Rodrigo Niehoff, Michael L. Banks, William A. Soto, Claudio TI Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake SO FASEB JOURNAL LA English DT Article DE PrP(Sc); pharmacokinetics; blood-brain barrier ID BLOOD-BRAIN-BARRIER; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; MISFOLDING CYCLIC AMPLIFICATION; MANNOSE 6-PHOSPHATE RECEPTOR; IN-VITRO; PRESYMPTOMATIC DETECTION; SCRAPIE INFECTIVITY; MEDIATED TRANSPORT; LYSOSOMAL-ENZYME; AMYLOID-BETA AB Prion diseases are infectious neurodegenerative disorders associated with the misfolded prion protein (PrP(Sc)), which appears to be the sole component of the infectious agent (termed prion). To produce disease, prions have to be absorbed into the body and reach sufficient quantities in the brain. Very little is known about the biological mechanisms controlling the initial fate of prions. Here, we studied the systemic pharmacokinetics and biodistribution of PrP(Sc) in vivo. After an intravenous injection of highly purified radiolabeled or native unlabeled PrP(Sc), the protein was eliminated rapidly from the serum (half-life of 3.24 h), mostly through tissue uptake. The quantity of intact PrP(Sc) reaching the brain was similar to 0.2% of the injected dose per gram of brain tissue (ID/g). The highest levels were found in liver (similar to 20% ID/g), spleen (similar to 13% ID/g), and kidney (similar to 7.4% ID/g). Cell surface PrP(C) does not appear to play a role in PrP(Sc) pharmacokinetics, since the infectious protein distributed similarly in wild-type and PrP-null mice. To measure tissue uptake kinetics and biodistribution accurately, vascular space in tissues was measured with radioactively labeled albumin coinjected with radioactively labeled PrP(Sc). Our results provide a fundamental pharmacokinetic characterization of PrP(Sc) in vivo, which may be relevant to estimate tissue risks and mechanisms of prion neuroinvasion and to identify novel therapeutic strategies.-Urayama, A., Morales, R., Niehoff, M. L., Banks, W. A., Soto, C. Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake FASEB J. 25, 2792-2803 (2011). www.fasebj.org C1 [Urayama, Akihiko; Morales, Rodrigo; Soto, Claudio] Univ Texas Houston, Med Sch Houston, Dept Neurol, Mitchell Ctr Alzheimers Dis & Related Brain Disor, Houston, TX 77030 USA. [Niehoff, Michael L.] Vet Affairs Med Ctr St Louis, GRECC, St Louis, MO USA. [Niehoff, Michael L.] St Louis Univ, Sch Med, Dept Internal Med, Div Geriatr, St Louis, MO USA. [Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Banks, William A.] Univ Washington, Sch Med, Dept Internal Med, Div Gerontol & Geriatr Med, Seattle, WA USA. RP Urayama, A (reprint author), Univ Texas Houston, Med Sch Houston, Dept Neurol, Mitchell Ctr Alzheimers Dis & Related Brain Disor, MSE R468,6431 Fannin St, Houston, TX 77030 USA. EM akihiko.urayama@uth.tmc.edu; claudio.soto@uth.tmc.edu FU U.S. National Institutes of Health [R01 NS050547, P01 AI77774] FX This study was supported by U.S. National Institutes of Health grant R01 NS050547 (to W.A.B. and C.S.) and P01 AI77774 (to C.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A.U. designed the study, performed the bulk of the experiments, analyzed all data, wrote the manuscript, and managed the peer review process. R.M.L. helped on the characterization of iodinated PrPSc. M.L.N. contributed to HPLC analysis. W.A.B. analyzed all data and critically reviewed the manuscript. C.S. developed the hypothesis, wrote the manuscript, and supervised the entire research project and the peer review process. NR 51 TC 5 Z9 5 U1 1 U2 17 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2011 VL 25 IS 8 BP 2792 EP 2803 DI 10.1096/fj.11-180729 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 800CV UT WOS:000293337800027 PM 21555356 ER PT J AU Okechukwu, CA Krieger, N Sorensen, G Li, Y Barbeau, EM AF Okechukwu, Cassandra A. Krieger, Nancy Sorensen, Glorian Li, Yi Barbeau, Elizabeth M. TI Testing Hypothesized Psychosocial Mediators: Lessons Learned in the MassBUILT Study SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE smoking cessation; blue-collar workers; social contextual model ID BLUE-COLLAR WORKERS; SMOKING-CESSATION; INTERVENTION; DISPARITIES; WORKING; TOBACCO; MODEL AB Only a few of the interventions that target blue-collar workers have conducted formal analysis to evaluate the specific attributes of their intervention that are associated with success or failure. This study examined the role of dual hazard and decisional balance in the MassBUILT smoking cessation intervention. The authors conducted sets of multivariable linear and logistic regressions that examined if (a) the intervention was associated with changes in the psychosocial variables and (b) increase in psychosocial variables was associated with increase in smoking cessation. As hypothesized by the theoretical basis of the study, higher scores on both of the psychosocial variables were significantly associated with smoking cessation. However, the intervention did not change decisional balance and decreased dual hazard. The variables examined were important but were not mediators of the MassBUILT intervention and this could have contributed to the significant relapse in smoking among study participants. C1 [Okechukwu, Cassandra A.; Krieger, Nancy; Sorensen, Glorian; Barbeau, Elizabeth M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Li, Yi] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Li, Yi] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Barbeau, Elizabeth M.] Healthrageous, Boston, MA USA. RP Okechukwu, CA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 665 Huntington Ave,,Floor 7, Boston, MA 02115 USA. EM cassandrao@post.harvard.edu FU NCCDPHP CDC HHS [1R01 DP000097, R01 DP000097]; NCI NIH HHS [K05 CA108663]; NIMHD NIH HHS [L60 MD003645] NR 29 TC 8 Z9 8 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD AUG PY 2011 VL 38 IS 4 BP 404 EP 411 DI 10.1177/1090198110380544 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 800HM UT WOS:000293350400008 PM 21474634 ER PT J AU Ross, JR Case, C Confer, D Weisdorf, DJ Weinstock, D Krawisz, R Chute, J Wilhauk, J Navarro, W Hartzman, R Coleman, CN Hatchett, R Chao, N AF Ross, Joel R. Case, Cullen Confer, Dennis Weisdorf, Daniel J. Weinstock, David Krawisz, Robert Chute, John Wilhauk, Julie Navarro, Willis Hartzman, Robert Coleman, C. Norman Hatchett, Richard Chao, Nelson TI Radiation Injury Treatment Network (RITN): Healthcare professionals preparing for a mass casualty radiological or nuclear incident SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article DE radiation accidents; cell therapy; haematology - radiation; radiation injury; emergency response; emergency preparedness ID MEDICAL-MANAGEMENT; BIODOSIMETRY; TERRORISM; TRIAGE AB Purpose: To describe the history, composition, and activities of the Radiation Injury Treatment Network (RITN). The Radiation Injury Treatment Network (R) is a cooperative effort of the National Marrow Donor Program and the American Society for Blood and Marrow Transplantation. The goals of RITN are to educate hematologists, oncologists, and stem cell transplant practitioners about their potential involvement in the response to a radiation incident and provide treatment expertise. Injuries to the marrow system readily occur when a victim is exposed to ionising radiation. This focus therefore leverages the expertise of these specialists who are accustomed to providing the intensive supportive care required by patients with a suppressed marrow function. Following a radiological incident, RITN centres may be asked to: Accept patient transfers to their institutions; provide treatment expertise to practitioners caring for victims at other centres; travel to other centres to provide medical expertise; or provide data on victims treated at their centres. Moving forward, it is crucial that we develop a coordinated interdisciplinary approach in planning for and responding to radiological and nuclear incidents. The ongoing efforts of radiation biologists, radiation oncologists, and health physicists can and should complement the efforts of RITN and government agencies. Conclusion: RITN serves as a vital partner in preparedness and response efforts for potential radiological and nuclear incidents. C1 [Case, Cullen; Confer, Dennis; Krawisz, Robert; Navarro, Willis; Hartzman, Robert] Natl Marrow Donor Program, Minneapolis, MN USA. [Weisdorf, Daniel J.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Weinstock, David] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wilhauk, Julie] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Coleman, C. Norman] NCI, Bethesda, MD 20892 USA. [Hatchett, Richard] NIAID, NIH, Bethesda, MD 20892 USA. [Ross, Joel R.; Chute, John; Chao, Nelson] Duke Univ, Div Cellular Therapy, Durham, NC 27710 USA. RP Chao, N (reprint author), Duke Univ, Div Cellular Therapy BMT, 2400 Pratt St,Suite 9011,Box 3961, Durham, NC 27710 USA. EM chao0002@mc.duke.edu FU NIH [U19 AI 067798]; Department of the Navy, Office of Naval Research [N00014-10-1-0204] FX This study was supported in part by NIH U19 AI 067798 and Department of the Navy, Office of Naval Research Grant #N00014-10-1-0204 to the National Marrow Donor Program. NR 26 TC 9 Z9 9 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0955-3002 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD AUG PY 2011 VL 87 IS 8 SI SI BP 748 EP 753 DI 10.3109/09553002.2011.556176 PG 6 WC Biology; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 800HG UT WOS:000293349800002 PM 21801106 ER PT J AU Hirsh, JM Boyle, DJ Collier, DH Oxenfeld, AJ Nash, A Quinzanos, I Caplan, L AF Hirsh, Joel M. Boyle, Dennis J. Collier, David H. Oxenfeld, Abbey J. Nash, Alyssa Quinzanos, Itziar Caplan, Liron TI Limited Health Literacy Is a Common Finding in a Public Health Hospital's Rheumatology Clinic and Is Predictive of Disease Severity SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Article DE rheumatoid arthritis; health literacy; patient outcome assessment ID SELF-MANAGEMENT SUPPORT; DIABETES PATIENTS; IDENTIFY PATIENTS; ARTHRITIS; ASSOCIATION; OUTCOMES; CARE; COMMUNICATION; KNOWLEDGE AB Background: Health literacy (HL) is associated with outcomes in many conditions, but little is known about its impact on arthritic diseases. Objectives: We sought to determine whether HL is related to disease activity and severity in patients with rheumatoid arthritis (RA). Methods: English-speaking adult RA patients were recruited for this cross-sectional study. Background information was ascertained by medical record review; Disease Activity Score 28 (DAS-28) scores were determined by providers; subjects completed the Multidimensional Health Assessment Questionnaire (MDHAQ), demographic questionnaires, and validated HL instruments, including the Short Test of Functional Health Literacy in Adults, Rapid Estimate of Adult Literacy in Medicine, and the single-item literacy screener. We used linear regression to assess whether HL was associated with MDHAQ and DAS-28 scores. Results: One hundred ten subjects participated in the study. Limited HL was a common finding, especially among ethnic minorities. The single-item literacy screener results were predictive of lower MDHAQ scores by univariate regression analysis. Similar trends were observed for the Short Test of Functional Health Literacy in Adults and Rapid Estimate of Adult Literacy in Medicine. The relationship between the single-item literacy screener and MDHAQ remained statistically significant in multivariate analysis that controlled for the impact of demographic features and RA disease characteristics. Health literacy scores were not associated with DAS-28 scores. Conclusions: Health literacy was independently associated with functional impairment in English-speaking RA patients at an urban safety-net clinic. This new finding suggests that RA functional status might be improved by strategies that target limited HL's causal pathways. C1 [Hirsh, Joel M.; Boyle, Dennis J.; Collier, David H.; Oxenfeld, Abbey J.; Nash, Alyssa] Denver Hlth Med Ctr, Dept Med, Div Rheumatol, Denver, CO 80204 USA. [Hirsh, Joel M.; Boyle, Dennis J.; Collier, David H.; Caplan, Liron] Univ Colorado, Sch Med, Dept Med, Div Rheumatol, Denver, CO USA. [Quinzanos, Itziar] Denver Hlth Med Ctr, Dept Gen Internal Med, Denver, CO 80204 USA. [Caplan, Liron] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO USA. RP Hirsh, JM (reprint author), Denver Hlth Med Ctr, Dept Med, Div Rheumatol, 777 Bannock St,Mail Code 4000, Denver, CO 80204 USA. EM joel.hirshMD@dhha.org FU Denver Health Department of Medicine; VA HSRD [07-221] FX Project support provided by the Denver Health Department of Medicine. Dr. Caplan is supported by a VA HSR&D Career Development Award (07-221). NR 44 TC 18 Z9 19 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 EI 1536-7355 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD AUG PY 2011 VL 17 IS 5 BP 236 EP 241 DI 10.1097/RHU.0b013e318226a01f PG 6 WC Rheumatology SC Rheumatology GA 800PS UT WOS:000293376000003 PM 21778910 ER PT J AU Zhang, LY Schumacher, HR Su, HH Lie, D Dinnella, J Baker, JF Von Feldt, JM AF Zhang, Li Yun Schumacher, H. Ralph Su, Hou Heng Lie, Dai Dinnella, Janet Baker, Joshua F. Von Feldt, Joan M. TI Development and Evaluation of a Survey of Gout Patients Concerning Their Knowledge About Gout SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Article DE gout; patient's knowledge; questionnaire; survey ID EVIDENCE BASED RECOMMENDATIONS; ANTIHYPERURICEMIC THERAPY; RHEUMATIC SYMPTOMS; TOPHACEOUS GOUT; TASK-FORCE; MANAGEMENT; HYPERURICEMIA; DIAGNOSIS; PREVALENCE; ARTHRITIS AB Objective: The objective of the study was to develop and test a survey of gout patients regarding their level of disease-related knowledge, to identify potential targets for patient education. Methods: A 10-item questionnaire with readability at a Flesch-Kincaid grade level of 4.6 and Flesch reading ease of 83.9% was designed to address parameters considered important for patient participation in the management of gout. The questionnaire was primarily evaluated at the Veterans Affairs (VA) Medical Center in Philadelphia, but was also secondarily performed at 2 Chinese hospitals, the Sun Yat-sen Memorial Hospital of Zhong Shan University, Guangdong Province (GZ), and the Qingdao Municipal Hospital, Qingdao City, Shandong Province (QD). Demographic and questionnaire data by institution were evaluated using descriptive statistics, and significant differences were identified by W 2 and Fisher exact tests. Patient responses were displayed by each individual question and by the distribution of total scores. Kruskal-Wallis tests of significance were used for nonparametric or skewed data. Intraclass correlations (ICCs) were performed within the VA population to determine internal consistency of the individual questions. A high score was defined as greater than 7 (the median value). Multivariate regression models using demographic and clinical characteristics attempted to identify factors associated with correct answers to each question. Results: Total correct score for individual patients varied widely at each institution with a mean (SD) and median (interquartile range [IQR]) scores in all 3 hospitals of 6.15 (2.25) and 7 (5-8), respectively. The average numbers of correct responses for each institution were 4.38 (SD, 3.04) (median, 4 [IQR, 2-7]) at GZ; 7.05 (SD, 1.37) (median, 8 [IQR, 6-8]) at QD; 6.21 (SD, 1.74) (median, 7 [IQR, 6-7]) at VA; P = 0.0010. Two questions (Q4 and Q10) were identified as difficult to understand by patients and showed poor ICC (ICC = 0.0000, P > 0.5) at the VA. Questions that were more difficult to answer were (1) Q3: What inside the joint causes attacks of gout? (GZ, 28.6%; QD, 7.7%; VA, 72.4%; P = 0.000); (2) Q8: How long should patients continue with serum uric acid-lowering drugs? (GZ, 19.1%; QD, 10.3%; VA, 82.7%; P = 0.000); (3) Q6: The ideal serum uric acid to aim at during treatment? (GZ, 42.8%; QD, 89.7%; and VA, 17.2%; P = 0.000); and (4) Q5: Which drugs can lower serum uric acid? (GZ, 61.9%; QD, 89.7%; VA, 51.7%; P = 0.002). Conclusions: This study describes an easy-to-read 10-item questionnaire that can identify important knowledge gaps in patients with gout. This can be the first step in designing educational interventions to improve patient understanding and improve clinical care. C1 [Zhang, Li Yun] Shanxi Med Univ, Hosp 2, Div Rheumatol, Taiyuan 030001, Shanxi Province, Peoples R China. [Zhang, Li Yun; Schumacher, H. Ralph; Dinnella, Janet; Baker, Joshua F.; Von Feldt, Joan M.] Univ Penn, Vet Affairs Med Ctr, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. [Su, Hou Heng] Qingdao Municipal Hosp, Dept Rheumatol, Qingdao, Shandong, Peoples R China. [Lie, Dai] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Rheumatol, Guangzhou 510275, Guangdong, Peoples R China. RP Zhang, LY (reprint author), Shanxi Med Univ, Hosp 2, Div Rheumatol, 382 Wuyi Rd, Taiyuan 030001, Shanxi Province, Peoples R China. EM zhangly2006@sina.com NR 32 TC 12 Z9 12 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD AUG PY 2011 VL 17 IS 5 BP 242 EP 248 DI 10.1097/RHU.0b013e318228b4e2 PG 7 WC Rheumatology SC Rheumatology GA 800PS UT WOS:000293376000004 PM 21778899 ER PT J AU Pinals, RS AF Pinals, Robert S. TI Lupus in the Mid-20th Century The Life and Death of Flannery O'Connor SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Article ID ERYTHEMATOSUS C1 [Pinals, Robert S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Pinals, RS (reprint author), 18 Pickman Dr, Bedford, MA USA. EM bob@pinals.com NR 17 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD AUG PY 2011 VL 17 IS 5 BP 266 EP 268 PG 3 WC Rheumatology SC Rheumatology GA 800PS UT WOS:000293376000007 PM 21778907 ER PT J AU Fernandez-Rebollo, E de Nanclares, GP Lecumberri, B Turan, S Anda, E Perez-Nanclares, G Feig, D Nik-Zainal, S Bastepe, M Juppner, H AF Fernandez-Rebollo, Eduardo Perez de Nanclares, Guiomar Lecumberri, Beatriz Turan, Serap Anda, Emma Perez-Nanclares, Gustavo Feig, Denice Nik-Zainal, Serena Bastepe, Murat Jueppner, Harald TI Exclusion of the GNAS Locus in PHP-Ib Patients With Broad GNAS Methylation Changes: Evidence for an Autosomal Recessive Form of PHP-Ib? SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE PARATHYROID HORMONE; PSEUDOHYPOPARATHYROIDISM IB; GNAS LOCUS; METHYLATION; AUTOSOMAL RECESSIVE ID PSEUDOHYPOPARATHYROIDISM TYPE-IB; ALBRIGHTS HEREDITARY OSTEODYSTROPHY; BECKWITH-WIEDEMANN-SYNDROME; IMPRINTING CONTROL ELEMENT; FETAL-GROWTH DISORDERS; EPIGENETIC DEFECTS; HORMONE RESISTANCE; MUTATIONS; DELETION; DOMINANT AB Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. (C) 2011 American Society for Bone and Mineral Research. C1 [Fernandez-Rebollo, Eduardo; Turan, Serap; Bastepe, Murat; Jueppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Fernandez-Rebollo, Eduardo; Turan, Serap; Bastepe, Murat; Jueppner, Harald] Harvard Univ, Sch Med, Boston, MA USA. [Perez de Nanclares, Guiomar] Hosp Txagorritxu, Res Unit, Mol Genet Lab, Vitoria, Basque Country, Spain. [Lecumberri, Beatriz] Hosp La Paz, Serv Endocrinol, Madrid, Spain. [Anda, Emma] Hosp Navarra, Serv Endocrinol, Navarra, Spain. [Perez-Nanclares, Gustavo] Hosp Cruces, Endocrinol & Diabet Res Grp, Baracaldo, Basque Country, Spain. [Feig, Denice] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Feig, Denice] Univ Toronto, Toronto, ON, Canada. [Nik-Zainal, Serena] Addenbrookes Hosp NHS Trust, Dept Med Genet, Cambridge, England. [Jueppner, Harald] Massachusetts Gen Hosp, Dept Pediat, Pediat Nephrol Unit, Boston, MA 02114 USA. RP Juppner, H (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Thier 10,50 Blossom St, Boston, MA 02114 USA. EM hjueppner@partners.org RI Feig, Denice/C-4606-2015; OI FERNANDEZ-REBOLLO, EDUARDO/0000-0002-4378-7590; Perez de Nanclares, Guiomar/0000-0002-2424-5294 FU National Institutes of Health [R37DK46718-19, R01DK073911]; Basque Department of Health [GV2008, BIO08/ER/001]; Instituto de Salud Carlos III [CP03/0064, SIVI 1395/09] FX We thank the patients and their families for participation in this study. This work was supported by grants from the National Institutes of Health (R37DK46718-19 to HJ and R01DK073911 to MB) and Grants GV2008/111035 from the Basque Department of Health and BIO08/ER/001 to GPN. GPN is furthermore cofunded by the Instituto de Salud Carlos III I3SNS Program (CP03/0064, SIVI 1395/09). NR 44 TC 17 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD AUG PY 2011 VL 26 IS 8 BP 1854 EP 1863 DI 10.1002/jbmr.408 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 800RL UT WOS:000293382600021 PM 21523828 ER PT J AU Zazo, C Thiele, S Martin, C Fernandez-Rebollo, E Martinez-Indart, L Werner, R Garin, I Hiort, O de Nanclares, GP AF Zazo, Celia Thiele, Susanne Martin, Cesar Fernandez-Rebollo, Eduardo Martinez-Indart, Lorea Werner, Ralf Garin, Intza Hiort, Olaf Perez de Nanclares, Guiomar CA Spanish PHP Gp TI Gs alpha Activity Is Reduced in Erythrocyte Membranes of Patients With Psedohypoparathyroidism Due to Epigenetic Alterations at the GNAS Locus SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE PSEUDOHYPOPARATHYROIDISM; Gs alpha PROTEIN; GNAS; METHYLATION DEFECTS; AHO PHENOTYPE ID PSEUDOHYPOPARATHYROIDISM TYPE-IB; ALBRIGHTS HEREDITARY OSTEODYSTROPHY; NUCLEOTIDE REGULATORY PROTEIN; IMPRINTING CONTROL ELEMENT; HORMONE-RELEASING-HORMONE; AUTOSOMAL-DOMINANT; DEFICIENT ACTIVITY; RESISTANCE; GENE; DELETION AB In pseudohypoparathyroidism (PHP), PTH resistance results from impairment of signal transduction of G protein-coupled receptors caused by a deficiency of the Gs alpha-cAMP signaling cascade due to diminished Gs alpha activity in maternally imprinted tissues. In PHP-Ia, inactivating mutations of the GNAS gene lead to haploinsufficiency in some tissues with biallelic expression, so in addition to PHP, Albright's hereditary osteodystrophy (AHO) is also present. In PHP-Ib, caused by methylation defects at the GNAS locus, diminished Gs alpha activity was thought to be limited to maternally imprinted tissues, such as the renal proximal tubule and the thyroid, leading to a lack of AHO. Recently, we demonstrated methylation defects in patients with AHO signs, indicating a connection between epigenetic changes and AHO. Our objective was to determine Gs alpha activity in erythrocyte membranes in patients with epigenetic defects at the GNAS locus compared to normal controls and patients with inactivating GNAS mutations. Gs alpha activity and expression, mutation of the GNAS locus, and methylation status were studied in patients with PHP and mild signs of AHO (PHP-Ia: 12; PHP-Ib: 17, of which 8 had some features of AHO). Then, we statistically compared the Gs alpha activity of the different PHP subtypes. Patients with methylation defects at the GNAS locus show a significant decrease in erythrocyte Gs alpha activity compared to normal controls (PHP-Ib versus controls, p<.001). This was significantly lower in patients with AHO signs (PHP-Ib+mild-AHO versus PHP-Ib, p<.05). Our research shows that PHP-Ia and PHP-Ib classification is not only overlapped genetically, as reported, but also in terms of Gs alpha activity. Reduced expression of GNAS due to methylation defects could downregulate Gs alpha activity in other tissues beyond those described and could also be causative of AHO. (C) 2011 American Society for Bone and Mineral Research. C1 [Zazo, Celia; Garin, Intza; Perez de Nanclares, Guiomar; Spanish PHP Gp] Hosp Txagorritxu, Mol Genet Lab, Res Unit, Vitoria 01009, Alava, Spain. [Thiele, Susanne; Werner, Ralf; Hiort, Olaf] Univ Lubeck, Dept Pediat & Adolescent Med, Lubeck, Germany. [Martin, Cesar] Univ Basque Country, Unidad Biofis, Dept Bioquim, Ctr Mixto CSIC UPV EHU, E-48080 Bilbao, Spain. [Fernandez-Rebollo, Eduardo] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Martinez-Indart, Lorea] CAIBER Hosp Cruces, Res Unit, Clin Epidemiol Unit, Barakaldo Bizkaia, Spain. RP de Nanclares, GP (reprint author), Hosp Txagorritxu, Mol Genet Lab, Res Unit, Vitoria 01009, Alava, Spain. EM gnanclares@osakidetza.net RI Audiparera, Laura/H-7291-2012; Menendez Torre, Edelmiro/G-1547-2013; Argente , Jesus /K-1167-2014; Luque, Inmaculada/K-9464-2014; OI Menendez Torre, Edelmiro/0000-0002-9548-7821; Argente , Jesus /0000-0001-5826-0276; Luque, Inmaculada/0000-0003-1838-2636; FERNANDEZ-REBOLLO, EDUARDO/0000-0002-4378-7590 FU Carlos III Health Institute [CP03/0064, SIVI 1395/09]; Basque Department of Health [GV2008/111035]; Eugenio Rodriguez Pascual foundation; German Ministry for Research and Education (BMBF) [GMG 01GM0315]; [BIO08/ER/001] FX GPN receives funding from the Carlos III Health Institute I3SNS Programme (CP03/0064; SIVI 1395/09). This work was partially supported by grants GV2008/111035 from the Basque Department of Health, BIO08/ER/001, and the Eugenio Rodriguez Pascual foundation (awarded to GPN), as well as grants from the German Ministry for Research and Education (BMBF No: GMG 01GM0315, awarded to OH, RW, and ST). This group is founded by the Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII. NR 32 TC 30 Z9 32 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD AUG PY 2011 VL 26 IS 8 BP 1864 EP 1870 DI 10.1002/jbmr.369 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 800RL UT WOS:000293382600022 PM 21351142 ER PT J AU Bloch, MJ Basile, JN AF Bloch, Michael J. Basile, Jan N. TI SPIRONOLACTONE IS MORE EFFECTIVE THAN EPLERENONE AT LOWERING BLOOD PRESSURE IN PATIENTS WITH PRIMARY ALDOSTERONISM SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Editorial Material C1 [Bloch, Michael J.] Univ Nevada, St Marys Reg Med Ctr, Risk Reduct Ctr, Dept Internal Med,Sch Med, Reno, NV 89503 USA. [Basile, Jan N.] Med Univ S Carolina, Seinsheimer Cardiovasc Hlth Program, Div Gen Internal Med Geriatr, Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. RP Bloch, MJ (reprint author), Univ Nevada, St Marys Reg Med Ctr, Risk Reduct Ctr, Dept Internal Med,Sch Med, 645 N Arlington St,Suite 460, Reno, NV 89503 USA. EM mbloch@aol.com NR 0 TC 0 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1524-6175 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD AUG PY 2011 VL 13 IS 8 BP 629 EP 631 DI 10.1111/j.1751-7176.2011.00495.x PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 800HE UT WOS:000293349600014 PM 21806775 ER PT J AU Kofler, MJ McCart, MR Zajac, K Ruggiero, KJ Saunders, BE Kilpatrick, DG AF Kofler, Michael J. McCart, Michael R. Zajac, Kristyn Ruggiero, Kenneth J. Saunders, Benjamin E. Kilpatrick, Dean G. TI Depression and Delinquency Covariation in an Accelerated Longitudinal Sample of Adolescents SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE adolescents; depression; delinquency; acting out theory; failure theory ID CONDUCT PROBLEMS; ENVIRONMENTAL-INFLUENCES; MODELING APPROACH; MAJOR DEPRESSION; SUBSTANCE-ABUSE; CHILDHOOD; DISORDERS; SYMPTOMS; COMORBIDITY; BOYS AB Objectives: The current study tested opposing predictions stemming from the failure and acting out theories of depression-delinquency covariation. Method: Participants included a nationwide longitudinal sample of adolescents (N = 3,604) ages 12 to 17. Competing models were tested with cohort-sequential latent growth curve modeling to determine whether depressive symptoms at age 12 (baseline) predicted concurrent and age-related changes in delinquent behavior, whether the opposite pattern was apparent (delinquency predicting depression), and whether initial levels of depression predict changes in delinquency significantly better than vice versa. Results: Early depressive symptoms predicted age-related changes in delinquent behavior significantly better than early delinquency predicted changes in depressive symptoms. In addition, the impact of gender on age-related changes in delinquent symptoms was mediated by gender differences in depressive symptom changes, indicating that depressive symptoms are a particularly salient risk factor for delinquent behavior in girls. Conclusion: Early depressive symptoms represent a significant risk factor for later delinquent behavior-especially for girls-and appear to be a better predictor of later delinquency than early delinquency is of later depression. These findings provide support for the acting out theory and contradict failure theory predictions. C1 [McCart, Michael R.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Family Serv Res Ctr, Charleston, SC 29425 USA. [Kofler, Michael J.] Univ Cent Florida, Dept Psychol, Orlando, FL 32816 USA. [Ruggiero, Kenneth J.; Saunders, Benjamin E.; Kilpatrick, Dean G.] Med Univ S Carolina, Natl Crime Victims Res & Treatment Ctr, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP McCart, MR (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, Family Serv Res Ctr, Charleston, SC 29425 USA. EM mccartm@musc.edu FU NICHD NIH HHS [R01 HD046830, R01HD046830] NR 46 TC 31 Z9 32 U1 3 U2 23 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD AUG PY 2011 VL 79 IS 4 BP 458 EP 469 DI 10.1037/a0024108 PG 12 WC Psychology, Clinical SC Psychology GA 800PZ UT WOS:000293376900005 PM 21787049 ER PT J AU Gutierrez, A Grebliunaite, R Feng, H Kozakewich, E Zhu, SZ Guo, F Payne, E Mansour, M Dahlberg, SE Neuberg, DS den Hertog, J Prochownik, EV Testa, JR Harris, M Kanki, JP Look, AT AF Gutierrez, Alejandro Grebliunaite, Ruta Feng, Hui Kozakewich, Elena Zhu, Shizhen Guo, Feng Payne, Elspeth Mansour, Marc Dahlberg, Suzanne E. Neuberg, Donna S. den Hertog, Jeroen Prochownik, Edward V. Testa, Joseph R. Harris, Marian Kanki, John P. Look, A. Thomas TI Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3; C-MYC; TRANSGENIC ZEBRAFISH; IN-VIVO; GENETIC DISSECTION; TUMOR-REGRESSION; NUCLEAR PTEN; PATHWAY; NOTCH1; AKT AB The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN-PI3K-AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene. C1 [Gutierrez, Alejandro; Grebliunaite, Ruta; Feng, Hui; Kozakewich, Elena; Zhu, Shizhen; Guo, Feng; Payne, Elspeth; Mansour, Marc; Kanki, John P.; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Dahlberg, Suzanne E.; Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Gutierrez, Alejandro; Look, A. Thomas] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA. [den Hertog, Jeroen] Hubrecht Inst, NL-3584 CT Utrecht, Netherlands. [Prochownik, Edward V.] Childrens Hosp Pittsburgh, Div Hematol Oncol, Pittsburgh, PA 15215 USA. [Testa, Joseph R.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Harris, Marian] Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA. RP Gutierrez, A (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM alejandro_gutierrez@dfci.harvard.edu; thomas_look@dfci.harvard.edu OI Feng, Hui/0000-0003-1318-821X; Gutierrez, Alejandro/0000-0002-0249-9007 FU National Institutes of Health [NCI 5P01CA68484, NCI 1K08CA133103]; William Lawrence Foundation; National Cancer Institute (NCI)/National Institutes of Health [K99CA134743, P30 CA-06927]; Commonwealth of Pennsylvania FX This work was supported by National Institutes of Health grants NCI 5P01CA68484 and NCI 1K08CA133103 and by the William Lawrence Foundation. A. Gutierrez is a Scholar of the American Society of Hematology-Harold Amos Medical Faculty Development Program. H. Feng is supported by an award from the National Cancer Institute (NCI)/National Institutes of Health (K99CA134743). This work was also supported in part by grant P30 CA-06927 from the National Cancer Institute and by an appropriation from the Commonwealth of Pennsylvania. NR 52 TC 43 Z9 47 U1 2 U2 5 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 AUG 1 PY 2011 VL 208 IS 8 BP 1595 EP 1603 DI 10.1084/jem.20101691 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 801LX UT WOS:000293441500005 PM 21727187 ER PT J AU Jeevan-Raj, BP Robert, I Heyer, V Page, A Wang, JH Cammas, F Alt, FW Losson, R Reina-San-Martin, B AF Jeevan-Raj, Beena Patricia Robert, Isabelle Heyer, Vincent Page, Adeline Wang, Jing H. Cammas, Florence Alt, Frederick W. Losson, Regine Reina-San-Martin, Bernardo TI Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INDUCED CYTIDINE DEAMINASE; ACTIVATION-INDUCED DEAMINASE; RNA-POLYMERASE-II; SOMATIC HYPERMUTATION; DNA BREAKS; HISTONE H3; IN-VIVO; ANTIBODY DIVERSIFICATION; NUCLEAR-EXPORT; CHAIN LOCUS AB Immunoglobulin class switch recombination (CSR) is initiated by double-stranded DNA breaks (DSBs) in switch regions triggered by activation-induced cytidine deaminase (AID). Although CSR correlates with epigenetic modifications at the IgH locus, the relationship between these modifications and AID remains unknown. In this study, we show that during CSR, AID forms a complex with KAP1 (KRAB domain-associated protein 1) and HP1 (heterochromatin protein 1) that is tethered to the donor switch region (S mu) bearing H3K9me3 (trimethylated histone H3 at lysine 9) in vivo. Furthermore, in vivo disruption of this complex results in impaired AID recruitment to S mu, inefficient DSB formation, and a concomitant defect in CSR but not in somatic hypermutation. We propose that KAP1 and HP1 tether AID to H3K9me3 residues at the donor switch region, thus providing a mechanism linking AID to epigenetic modifications during CSR. C1 [Jeevan-Raj, Beena Patricia; Robert, Isabelle; Heyer, Vincent; Page, Adeline; Cammas, Florence; Losson, Regine; Reina-San-Martin, Bernardo] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, INSERM, U964,CNRS,Unite Mixte Rech 7104, F-67404 Illkirch Graffenstaden, France. [Wang, Jing H.; Alt, Frederick W.] Immune Dis Inst, Boston, MA 02115 USA. [Wang, Jing H.; Alt, Frederick W.] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Alt, Frederick W.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet & Pediat, Boston, MA 02115 USA. RP Reina-San-Martin, B (reprint author), Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, INSERM, U964,CNRS,Unite Mixte Rech 7104, F-67404 Illkirch Graffenstaden, France. EM reinab@igbmc.fr RI Heyer, Vincent/M-6540-2016; ROBERT, Isabelle/M-6520-2016; Wang, Jing/M-7813-2015; Reina-San-Martin, Bernardo/I-9484-2016 OI Wang, Jing/0000-0003-4343-2527; Reina-San-Martin, Bernardo/0000-0003-2083-6166 FU Association pour la Recherche sur le Cancer (ARC); Fondation pour la Recherche Medicale; Agence Nationale pour la Recherche [ANR-07-MIME-004-01]; Institut National de la Sante et de la Recherche Medicale (INSERM) FX B.P. Jeevan-Raj was supported by fellowships from the Association pour la Recherche sur le Cancer (ARC) and the Fondation pour la Recherche Medicale. F.W. Alt is an investigator of the Howard Hughes Medical Institute. This work was supported by grants to B. Reina-San-Martin from the Agence Nationale pour la Recherche (ANR-07-MIME-004-01), the ARC, and the Institut National de la Sante et de la Recherche Medicale (INSERM). B. Reina-San-Martin is an AVENIR-INSERM young investigator. NR 57 TC 53 Z9 53 U1 3 U2 12 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 AUG 1 PY 2011 VL 208 IS 8 BP 1649 EP 1660 DI 10.1084/jem.20110118 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 801LX UT WOS:000293441500009 PM 21746811 ER PT J AU Mintzopoulos, D Ackerman, JL Song, YQ AF Mintzopoulos, Dionyssios Ackerman, Jerome L. Song, Yi-Qiao TI MRI of Trabecular Bone Using a Decay Due to Diffusion in the Internal Field Contrast Imaging Sequence SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE trabecular bone; imaging; DDIF; diffusion; MRI contrast ID MAGNETIC-RESONANCE IMAGES; X-RAY ABSORPTIOMETRY; AGE-RELATED-CHANGES; IN-VIVO; CANCELLOUS BONE; TRANSVERSE-RELAXATION; POROUS-MEDIA; STRUCTURAL DETERMINANTS; PULSE SEQUENCE; PROXIMAL FEMUR AB Purpose: To characterize the DDIF (Decay due to Diffusion in the Internal Field) method using intact animal trabecular bone specimens of varying trabecular structure and porosity, under ex vivo conditions closely resembling in vivo physiological conditions. The DDIF method provides a diffusion contrast which is related to the surface-to-volume ratio of the porous structure of bones. DDIF has previously been used successfully to study marrow-free trabecular bone, but the DDIF contrast hitherto had not been tested in intact specimens containing marrow and surrounded by soft tissue. Materials and Methods: DDIF imaging was implemented on a 4.7 Tesla (T) small-bore, horizontal, animal scanner. Ex vivo results on fresh bone specimens containing marrow were obtained at body temperature. Control measurements were carried out in surrounding tissue and saline. Results: Significant DDIF effect was observed for trabecular bone samples, while it was considerably smaller for soft tissue outside the bone and for lipids. Additionally, significant differences were observed between specimens of different trabecular structure. Conclusion: The DDIF contrast is feasible despite the reduction of the diffusion constant and of T(1) in such conditions, increasing our confidence that DDIF imaging in vivo may be clinically viable for bone characterization. C1 [Mintzopoulos, Dionyssios; Ackerman, Jerome L.; Song, Yi-Qiao] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Song, Yi-Qiao] Schlumberger Doll Res Ctr, Cambridge, MA USA. RP Mintzopoulos, D (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, MGH Bldg 149,13th St,5th Ave, Charlestown, MA 02129 USA. EM dionyssi@nmr.mgh.harvard.edu RI Ackerman, Jerome/E-2646-2015 OI Ackerman, Jerome/0000-0001-5176-7496 FU Schlumberger-Doll Research; National Institutes of Health [S10-RR16811, P41-RR14075]; Athinoula A. Martinos Center for Biomedical Imaging; MIND Institute FX Contract grant sponsor: Schlumberger-Doll Research; Contract grant sponsor: National Institutes of Health; Contract grant number: S10-RR16811, Contract grant number: P41-RR14075; Contract grant sponsor: Athinoula A. Martinos Center for Biomedical Imaging; Contract grant sponsor: the MIND Institute. NR 73 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD AUG PY 2011 VL 34 IS 2 BP 361 EP 371 DI 10.1002/jmri.22612 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 800LM UT WOS:000293361300014 PM 21780229 ER PT J AU Feke, GT Hazin, R Grosskreutz, CL Pasquale, LR AF Feke, Gilbert T. Hazin, Ribhi Grosskreutz, Cynthia L. Pasquale, Louis R. TI Effect of Brimonidine on Retinal Blood Flow Autoregulation in Primary Open-Angle Glaucoma SO JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID NORMAL-PRESSURE GLAUCOMA; NORMAL-TENSION GLAUCOMA; OCULAR HYPERTENSION TREATMENT; OPTIC DISC HEMORRHAGES; VASCULAR DYSREGULATION; VITREOUS CONCENTRATION; INTRAOCULAR-PRESSURE; PERFUSION-PRESSURE; RANDOMIZED-TRIAL; POSTURAL CHANGES AB Purpose: To determine whether topically applied brimonidine affects the retinal hemodynamic autoregulatory response to posture change in patients with normal tension glaucoma. Methods: Six patients with normal tension glaucoma (primary open-angle glaucoma and maximum untreated intraocular pressure < 22 mmHg) in each eye were studied. We retrospectively reviewed retinal hemodynamic data acquired when the patients were off and on treatment with brimonidine 0.15% (twice a day, both eyes) during the course of their care. At each testing session, vessel diameter and blood speed at the same site along the inferior temporal retinal artery of 1 eye were measured while sitting, while reclining for 30 min, and again while sitting using a retinal laser Doppler instrument. Blood flow was computed automatically. Brachial artery blood pressure and heart rate were also measured. The Wilcoxon signed rank test was used to assess the statistical significance of the differences in each measured parameter while subjects were on and off brimonidine. Results: Off brimonidine, the mean blood flow rate increased by 68.0% +/- 34.3% (range: + 17% to + 108%) after 30 min in reclined posture compared to baseline-seated measures. On brimonidine, the mean blood flow rate increased by 8.9% +/- 16.8% (range: - 9.7 to + 28.0%) after 30 min in reclined posture compared to baseline-seated measures. The difference in the posture-induced changes for blood flow rate while on brimonidine compared to off brimonidine was statistically significant (P = 0.027). Conclusions: Off brimonidine, the patients exhibited marked increases in retinal blood flow while reclining. On brimonidine, the hemodynamic changes were consistent with normal autoregulatory control of retinal blood flow. C1 [Feke, Gilbert T.; Hazin, Ribhi; Grosskreutz, Cynthia L.; Pasquale, Louis R.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Pasquale, LR (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM louis_pasquale@meei.harvard.edu FU Research to Prevent Blindness; Margolis Fund; Harvard Glaucoma Center for Excellence; Allergan, Inc. FX This work was supported by a Research to Prevent Blindness Award and the Margolis Fund (both to Dr. Pasquale) and by the Harvard Glaucoma Center for Excellence. Dr. Pasquale has received research funding from Allergan, Inc. on healthcare economics research, but no pharmaceutical company sponsored this investigator-initiated research. The Glaucoma Service at Massachusetts Eye and Ear Infirmary is a recipient of a Horizon Grant from Allergan, Inc. NR 48 TC 9 Z9 9 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1080-7683 J9 J OCUL PHARMACOL TH JI J. Ocular Pharmacol. Ther. PD AUG PY 2011 VL 27 IS 4 BP 347 EP 352 DI 10.1089/jop.2011.0014 PG 6 WC Ophthalmology; Pharmacology & Pharmacy SC Ophthalmology; Pharmacology & Pharmacy GA 800TC UT WOS:000293388900007 PM 21631365 ER PT J AU Shazly, TA Latina, MA AF Shazly, Tarek A. Latina, Mark A. TI Comparison of Intraocular Pressure-Lowering Effect of Every Night Versus Every Other Night Dosing of Bimatoprost 0.03% SO JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID OCULAR HYPERTENSION; GLAUCOMA; LATANOPROST; TRAVOPROST; EFFICACY; TRIAL AB Purpose: To compare intraocular pressure (IOP) reduction profiles of bimatoprost 0.03% administered every other night (QOD-HS) compared with every night (QHS) in patients with primary open angle glaucoma and pseudoexfoliation glaucoma. Methods: A retrospective chart review of 68 eyes of 45 consecutive patients who were switched from QHS to QOD-HS bimatoprost due to intolerable conjunctival hyperemia between May 2005 and May 2008. IOP in the morning (AM) and afternoon (PM) of the next day after administration (day 1) and the day after (day 2) on QOD-HS regimen was compared with IOP in the AM and PM when they were on QHS regimen, 4-6 weeks after switching to QOD-HS. Results: Mean IOPs on QHS bimatoprost were 15.9 +/- 3.4mm Hg in the AM and 15.5 +/- 2.7mm Hg in the PM, whereas mean IOPs on QOD-HS were 14 +/- 2mm Hg (AM) and 14.2 +/- 2.5mm Hg (PM) on day 1, and 14.7 +/- 2.6mm Hg (AM) and 14.4 +/- 2.4mm Hg (PM) on day 2 after administration. Differences between IOP fluctuation on QHS and QOD-HS days 1 and 2, respectively, were not significant (P = 0.87 and 0.94). Conclusion: Every other night dosing of bimatoprost was effective in controlling IOP in this select group of patients with primary open angle glaucoma and pseudoexfoliation glaucoma who had troublesome side effects on bimatoprost 0.03% QHS regimen, and may be considered as an alternative to every day treatment. C1 [Shazly, Tarek A.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 01867 USA. [Latina, Mark A.] Reading Hlth Ctr, Reading, MA USA. RP Shazly, TA (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 20 Pondmeadow Dr,Ste 203, Boston, MA 01867 USA. EM shazlyt@gmail.com OI A Shazly, Tarek/0000-0002-4561-1871 NR 16 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1080-7683 J9 J OCUL PHARMACOL TH JI J. Ocular Pharmacol. Ther. PD AUG PY 2011 VL 27 IS 4 BP 369 EP 371 DI 10.1089/jop.2011.0028 PG 3 WC Ophthalmology; Pharmacology & Pharmacy SC Ophthalmology; Pharmacology & Pharmacy GA 800TC UT WOS:000293388900010 PM 21663517 ER PT J AU Reinke, LF Slatore, CG Uman, J Udris, EM Moss, BR Engelberg, RA Au, DH AF Reinke, Lynn F. Slatore, Christopher G. Uman, Jane Udris, Edmunds M. Moss, Brianna R. Engelberg, Ruth A. Au, David H. TI Patient-Clinician Communication about End-of-Life Care Topics: Is Anyone Talking to Patients with Chronic Obstructive Pulmonary Disease? SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID ADVANCE DIRECTIVE EDUCATION; PALLIATIVE CARE; PHYSICIANS; HEALTH; CANCER; REHABILITATION; SPIRITUALITY; DISCUSSIONS; FAMILIES; OUTCOMES AB Background: Reports describe patient and health care system benefits when clinicians engage in end-of-life conversations with patients diagnosed with life-limiting illnesses, yet most clinicians focus on life-preserving treatments and avoid conversations about end-of-life care. We describe patient-clinician communication practices about end-of-life care in patients with chronic obstructive pulmonary disease (COPD) using self-report questionnaires to: (1) characterize the content of patient-clinician communication about end-of-life care from the patient perspective, including topics that were not addressed and ratings of the quality of the communication for topics discussed and (2) determine whether clinician characteristics was associated with the absence of specific communication items addressed. Methods: Cross-sectional study of outpatients (n = 376) who completed the Quality of Communication (QOC) questionnaire (outcome measure). The primary exposure was clinician training. We used logistic regression. All tests were two-tailed and p < 0.05 was considered significant. Results: Clinicians (n = 92) were staff physicians (33.7%), physician trainees (35.9%), and advanced practice nurses (30.4%). Patients were older (mean age, 69.4 years, standard deviation [SD] 10.0); white (86%) men (97%) with severe COPD (mean forced expiraory volume in 1 second [FEV(1)] percent predicted 50%, SD 20). All end-of-life topics were underaddressed. Four topics were not addressed 77%-94% of the time. None of the QOC items varied significantly by clinician type in adjusted logistic regression. Conclusions: All end-of-life communication topics were underaddressed by clinicians, regardless of training, with four topics particularly unlikely to be discussed. End-of-life topics that are important to patients should be targeted for an intervention to facilitate improvement in clinicians' communication skills and practice and may improve patient satisfaction with clinician communication. C1 [Reinke, Lynn F.; Uman, Jane; Udris, Edmunds M.; Moss, Brianna R.; Au, David H.] VA Puget Sound Hlth Care Syst, Hlth Serv R&D, Seattle, WA 98101 USA. [Slatore, Christopher G.] Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland VA Med Ctr Hlth Serv Res & Dev, Portland, OR 97201 USA. [Engelberg, Ruth A.; Au, David H.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Seattle, WA USA. RP Reinke, LF (reprint author), VA Puget Sound Hlth Care Syst, Hlth Serv R&D, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM reinkl@u.washington.edu RI Oliveira, Joana\/A-8373-2012; OI Slatore, Christopher/0000-0003-0958-8122 FU Health Services Research and Development, Department of Veterans Affairs [IIR 02-292]; Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; Health Services Research and Development; VA HSRD Career Development Award; Portland VA Medical Center FX Funded by Health Services Research and Development, Department of Veterans Affairs. IIR 02-292.; This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and Health Services Research and Development.; Dr. Slatore is a recipient of a VA HSRD Career Development Award and is supported by resources from the Portland VA Medical Center. NR 36 TC 23 Z9 23 U1 0 U2 15 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD AUG PY 2011 VL 14 IS 8 BP 923 EP 928 DI 10.1089/jpm.2010.0509 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 800TN UT WOS:000293390200008 PM 21631367 ER PT J AU Saito, AM Landrum, MB Neville, BA Ayanian, JZ Weeks, JC Earle, CC AF Saito, Akiko M. Landrum, Mary Beth Neville, Bridget A. Ayanian, John Z. Weeks, Jane C. Earle, Craig C. TI Hospice Care and Survival among Elderly Patients with Lung Cancer SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID INSTRUMENTAL VARIABLES; GEOGRAPHIC-VARIATION; COMORBIDITY INDEX; PROPENSITY SCORE; TERMINAL CARE; CLAIMS DATA; LIFE; END; CHEMOTHERAPY; DEATH AB Background: Recently observed trends toward increasingly aggressive end-of-life care may reflect providers' concerns that hospice may hasten death. Methods: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 7879 patients aged 65 years or older who died of advanced non-small-cell lung cancer from 1991 through 1999 after surviving for at least 3 months from their cancer diagnoses. Length of hospice admission post-cancer diagnosis and indicators of aggressive end-of-life care were ascertained based on claims data. We evaluated overall survival and care near death after controlling for baseline characteristics by using propensity score (PS) and instrumental variable analyses (IVA). Results: Hospice patients were older, more likely to be non-Hispanic white and female, more likely to reside in urban areas with high hospice availability and higher socioeconomic status, more likely to be treated in a teaching hospital, and received less aggressive end-of-life care compared to nonhospice patients. Among hospice patients, those experiencing short-term hospice admissions within 3 days of death were more likely to be male, reside in urban areas, be treated in a teaching hospital, and receive more aggressive end-of-life care. PS analysis found that survival favored hospice patients slightly relative to nonhospice patients by 5.0 percentage points (25.7% versus 20.7%) at 1 year and 1.4 percentage points (6.9% versus 5.5%) at 2 years postdiagnosis (p < 0.001), while there was no significant difference between those with short-and longer duration hospice stays (p = 1.00). IVA confirmed these findings. Conclusions: Hospice enrollment did not compromise length of survival following advanced lung cancer diagnosis. C1 [Earle, Craig C.] Sunnybrook Hlth Sci Ctr, Inst Clin Evaluat Sci, Toronto, ON M4N 3M5, Canada. [Earle, Craig C.] Canc Care Ontario, Ontario Inst Canc Res, Toronto, ON M4N 3M5, Canada. [Ayanian, John Z.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Neville, Bridget A.; Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. [Landrum, Mary Beth; Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Saito, Akiko M.] Natl Hosp Org, Nagoya Med Ctr, Clin Res Ctr, Lab Clin Epidemiol & Hlth Serv Res, Aichi, Japan. RP Earle, CC (reprint author), Sunnybrook Hlth Sci Ctr, Inst Clin Evaluat Sci, 2075 Bayview Ave,Room G-106, Toronto, ON M4N 3M5, Canada. EM craig.earle@ices.on.ca FU National Cancer Institute [CA 91753-02] FX This research was supported by a grant CA 91753-02 from the National Cancer Institute. NR 49 TC 39 Z9 39 U1 0 U2 11 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD AUG PY 2011 VL 14 IS 8 BP 929 EP 939 DI 10.1089/jpm.2010.0522 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 800TN UT WOS:000293390200009 PM 21767153 ER PT J AU Molis, MR Leek, MR AF Molis, Michelle R. Leek, Marjorie R. TI Vowel Identification by Listeners With Hearing Impairment in Response to Variation in Formant Frequencies SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE sensorineural hearing loss; speech perception; speech sound ID FALSE DISCOVERY RATE; SPECTRAL CONTRAST; NOTCHED-NOISE; SPEECH; DISCRIMINATION; PERCEPTION; RECOGNITION; SELECTIVITY; YOUNG; RESOLUTION AB Purpose: This study examined the influence of presentation level and mild-to-moderate hearing loss on the identification of a set of vowel tokens systematically varying in the frequency locations of their second and third formants. Method: Five listeners with normal hearing (NH listeners) and five listeners with hearing impairment (HI listeners) identified synthesized vowels that represented both highly identifiable and ambiguous examples of /I/, /U/, and /(sic)/. Results: Response patterns of NH listeners showed significant changes, with an increase in presentation level from 75 dB SPL to 95 dB SPL, including increased category overlap. HI listeners, listening only at the higher level, showed greater category overlap than normal and overall identification patterns that differed significantly from those of NH listeners. Excitation patterns based on estimates of auditory filters suggested smoothing of the internal representations, resulting in impaired formant resolution. Conclusions: Both increased presentation level for NH listeners and the presence of hearing loss produced a significant change in vowel identification for this stimulus set. Major differences were observed between NH listeners and HI listeners in vowel category overlap and in the sharpness of boundaries between vowel tokens. It is likely that these findings reflect imprecise internal spectral representations due to reduced frequency selectivity. C1 [Molis, Michelle R.; Leek, Marjorie R.] Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, Portland, OR USA. RP Molis, MR (reprint author), Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, Portland, OR USA. EM michelle.molis@va.gov FU NIDCD NIH HHS [R01DC 00626, R01 DC000626-23, R01 DC000626] NR 43 TC 4 Z9 4 U1 0 U2 2 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD AUG 1 PY 2011 VL 54 IS 4 BP 1211 EP 1223 DI 10.1044/1092-4388(2010/09-0218) PG 13 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 800RB UT WOS:000293380900017 PM 21297168 ER PT J AU Ajani, JA Barthel, JS Bentrem, DJ D'Amico, TA Das, P Denlinger, CS Fuchs, CS Gerdes, H Glasgow, RE Hayman, JA Hofstetter, WL Ilson, DH Keswani, RN Kleinberg, LR Korn, M Lockhart, AC Mulcahy, MF Orringer, MB Osarogiagbon, RU Posey, JA Sasson, AR Scott, WJ Shibata, S Strong, VEM Varghese, TK Warren, G Washington, MK Willett, C Wright, CD AF Ajani, Jaffer A. Barthel, James S. Bentrem, David J. D'Amico, Thomas A. Das, Prajnan Denlinger, Crystal S. Fuchs, Charles S. Gerdes, Hans Glasgow, Robert E. Hayman, James A. Hofstetter, Wayne L. Ilson, David H. Keswani, Rajesh N. Kleinberg, Lawrence R. Korn, Michael Lockhart, A. Craig Mulcahy, Mary F. Orringer, Mark B. Osarogiagbon, Raymond U. Posey, James A. Sasson, Aaron R. Scott, Walter J. Shibata, Stephen Strong, Vivian E. M. Varghese, Thomas K. Warren, Graham Washington, Mary Kay Willett, Christopher Wright, Cameron D. TI Esophageal and Esophagogastric Junction Cancers SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review DE NCCN Clinical Practice Guidelines; NCCN Guidelines; esophageal carcinoma; chemotherapy; chemoradiation; combined modality therapy; surgery; resection; multidisciplinary care; biologic therapy; organ preservation ID PHASE-II TRIAL; POSITRON-EMISSION-TOMOGRAPHY; SQUAMOUS-CELL CARCINOMA; HIGH-GRADE DYSPLASIA; ENDOSCOPIC MUCOSAL RESECTION; COMBINED-MODALITY THERAPY; ARBEITSGEMEINSCHAFT INTERNISTISCHE ONKOLOGIE; TERM-FOLLOW-UP; INTENSITY-MODULATED RADIOTHERAPY; MINIMALLY INVASIVE ESOPHAGECTOMY C1 [Ajani, Jaffer A.; Das, Prajnan; Hofstetter, Wayne L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Barthel, James S.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Bentrem, David J.; Keswani, Rajesh N.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Denlinger, Crystal S.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Fuchs, Charles S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Gerdes, Hans; Ilson, David H.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Glasgow, Robert E.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Hayman, James A.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kleinberg, Lawrence R.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, New York, NY USA. [Korn, Michael] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Lockhart, A. Craig] Washington Univ, Siteman Canc Ctr, Barnes Jewish Hosp, St Louis, MO 63130 USA. [Mulcahy, Mary F.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Osarogiagbon, Raymond U.] Univ Tennessee, St Jude Childrens Hosp, Knoxville, TN 37996 USA. [Posey, James A.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Shibata, Stephen] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Warren, Graham] Roswell Pk Canc Inst, Buffalo, NY USA. [Washington, Mary Kay] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Wright, Cameron D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Ajani, JA (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 275 TC 74 Z9 89 U1 3 U2 13 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD AUG PY 2011 VL 9 IS 8 BP 830 EP + PG 32 WC Oncology SC Oncology GA 803LT UT WOS:000293583500004 PM 21900218 ER PT J AU Crawford, J Allen, J Armitage, J Blayney, DW Cataland, SR Heaney, ML Htoy, S Hudock, S Kloth, DD Kuter, DJ Lyman, GH McMahon, B Steensma, DP Vadhan-Raj, S Westervelt, P Westmoreland, M AF Crawford, Jeffrey Allen, Jeffrey Armitage, James Blayney, Douglas W. Cataland, Spero R. Heaney, Mark L. Htoy, Sally Hudock, Susan Kloth, Dwight D. Kuter, David J. Lyman, Gary H. McMahon, Brandon Steensma, David P. Vadhan-Raj, Saroj Westervelt, Peter Westmoreland, Michael TI Myeloid Growth Factors SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review DE NCCN Clinical Practice Guidelines; NCCN Guidelines; myeloid growth factors; neutropenia; fever; chemotherapy ID COLONY-STIMULATING FACTOR; NON-HODGKINS-LYMPHOMA; CHEMOTHERAPY-INDUCED NEUTROPENIA; PATIENTS RECEIVING CHEMOTHERAPY; INDUCED FEBRILE NEUTROPENIA; CONTROLLED PHASE-III; CELL LUNG-CANCER; BREAST-CANCER; RANDOMIZED-TRIAL; ELDERLY-PATIENTS C1 [Crawford, Jeffrey] Duke Canc Inst, Durham, NC USA. [Allen, Jeffrey] Univ Tennessee, St Jude Childrens Res Hosp, Inst Canc, Knoxville, TN 37996 USA. [Armitage, James] Nebraska Med Ctr, UNMC Eppley Canc Ctr, Omaha, NE USA. [Blayney, Douglas W.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Cataland, Spero R.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Htoy, Sally] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Hudock, Susan] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Kuter, David J.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Kuter, David J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [McMahon, Brandon] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Vadhan-Raj, Saroj] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Westervelt, Peter] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. RP Crawford, J (reprint author), Duke Canc Inst, Durham, NC USA. OI Kloth, Dwight/0000-0001-7220-2830; Steensma, David/0000-0001-5130-9284 NR 58 TC 16 Z9 16 U1 0 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD AUG PY 2011 VL 9 IS 8 BP 914 EP + PG 10 WC Oncology SC Oncology GA 803LT UT WOS:000293583500007 PM 21900221 ER PT J AU Walsh, CJ Sapkota, BH Kalra, MK Hanumara, NC Liu, B Shepard, JAO Gupta, R AF Walsh, Conor J. Sapkota, Bishnu H. Kalra, Mannudeep K. Hanumara, Nevan C. Liu, Bob Shepard, Jo-Anne O. Gupta, Rajiv TI Smaller and Deeper Lesions Increase the Number of Acquired Scan Series in Computed Tomography-guided Lung Biopsy SO JOURNAL OF THORACIC IMAGING LA English DT Article DE computed tomography-guided lung biopsy; lesion size; radiation dose; subtask ID NEEDLE ASPIRATION BIOPSY; PULMONARY-LESIONS; INTERVENTIONAL PROCEDURES; PNEUMOTHORAX RATE; PATIENT; NODULES; RISK; DOSIMETRY; DIAGNOSIS; SKIN AB Purpose: To determine factors influencing the number of acquired scan series and subsequently the radiation dose and time during computed tomography (CT)-guided lung biopsies. Materials and Methods: This Health Insurance Portability and Accountability Act-compliant, institutional review board-approved, retrospective study reviewed 50 consecutive procedures. Each procedure was separated into the following steps: trajectory planning, needle placement, needle insertion (extrapulmonary and intrapulmonary), and sampling and follow-up. The number of scan series, time, and radiation dose were calculated for each procedure and its steps. The effects of patient characteristics (age, sex, history of surgery that violated the pleura), procedure characteristics (needle-pleural angle, patient position), and lesion characteristics (size, depth, lobar location) on the number of scan series for the procedure and each step were evaluated using stepwise linear regression. The overall diagnostic accuracy, pneumothorax rate, and chest tube insertion rate were also calculated. Results: The mean number of total CT scans was 21, the mean effective dose was 14 mSv, and the mean entrance skin dose was 249 mGy. On average, trajectory planning and needle insertion contributed most to the number of scan series (18.5% and 52.9%, respectively). For trajectory planning, a smaller lesion size and shallower needle-pleural angle were associated with an increased number of scans (R(2)=0.200, P=0.005). During needle insertion, smaller lesions were associated with increased scanning (R(2)=0.296, P<0.001), with both smaller and deeper lesions associated with an increased number of scans during the intrapulmonary component (R(2)=0.372, P<0.001). For the entire procedure, smaller lesions were associated with an increased number of scans (R(2)=0.12, P=0.01). Conclusion: Lesions that are smaller or deeper in the lung result in a higher number of CT scans, resulting in increased radiation dose and procedure time, with most of these performed during the needle insertion step. C1 [Walsh, Conor J.; Hanumara, Nevan C.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Walsh, Conor J.; Kalra, Mannudeep K.; Liu, Bob; Shepard, Jo-Anne O.; Gupta, Rajiv] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sapkota, Bishnu H.] Univ Mississippi, Dept Neurol, Med Ctr, University, MS 38677 USA. RP Walsh, CJ (reprint author), MIT, Dept Mech Engn, 77 Massachusetts Ave,Room 3-470, Cambridge, MA 02139 USA. EM walshcj@mit.edu FU Center for Integration of Medicine and Innovative Technology (CIMIT) FX The authors thank the Center for Integration of Medicine and Innovative Technology (CIMIT) for supporting this study. They also acknowledge Dr Eric Macklin for his guidance with the statistical analysis, Dr Ammar Sarwar for his assistance with data collection, and Professor Alexander Slocum for his valuable feedback. NR 26 TC 5 Z9 5 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0883-5993 J9 J THORAC IMAG JI J. Thorac. Imaging PD AUG PY 2011 VL 26 IS 3 BP 196 EP 203 DI 10.1097/RTI.0b013e3182018576 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 796UW UT WOS:000293079600013 PM 21263356 ER PT J AU Sun, L Xie, HM Mori, MA Alexander, R Yuan, BB Hattangadi, SM Liu, QQ Kahn, CR Lodish, HF AF Sun, Lei Xie, Huangming Mori, Marcelo A. Alexander, Ryan Yuan, Bingbing Hattangadi, Shilpa M. Liu, Qingqing Kahn, C. Ronald Lodish, Harvey F. TI Mir193b-365 is essential for brown fat differentiation SO NATURE CELL BIOLOGY LA English DT Article ID ADIPOSE-TISSUE; MYOGENIC DIFFERENTIATION; TRANSCRIPTIONAL COMPLEX; TRANSGENIC MICE; PPAR-ALPHA; OBESITY; CELL; EXPRESSION; RECEPTOR; GENE AB Mammals have two principal types of fat. White adipose tissue primarily serves to store extra energy as triglycerides, whereas brown adipose tissue is specialized to burn lipids for heat generation and energy expenditure as a defence against cold and obesity(1,2). Recent studies have demonstrated that brown adipocytes arise in vivo from a Myf5-positive, myoblastic progenitor by the action of Prdm16 (PR domain containing 16). Here, we identified a brown-fat-enriched miRNA cluster, MiR-193b-365, as a key regulator of brown fat development. Blocking miR-193b and/or miR-365 in primary brown preadipocytes markedly impaired brown adipocyte adipogenesis by enhancing Runx1t1 (runt-related transcription factor 1; translocated to, 1) expression, whereas myogenic markers were significantly induced. Forced expression of Mir193b and/or Mir365 in C2C12 myoblasts blocked the entire programme of myogenesis, and, in adipogenic conditions, miR-193b induced myoblasts to differentiate into brown adipocytes. Mir193b-365 was upregulated by Prdm16 partially through Ppar alpha. Our results demonstrate that Mir193b-365 serves as an essential regulator for brown fat differentiation, in part by repressing myogenesis. C1 [Sun, Lei; Xie, Huangming; Alexander, Ryan; Yuan, Bingbing; Hattangadi, Shilpa M.; Liu, Qingqing; Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Xie, Huangming] Natl Univ Singapore, Singapore MIT Alliance, Singapore 117576, Singapore. [Mori, Marcelo A.; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res,Sect Integrat Physiol & Metab, Boston, MA 02115 USA. [Alexander, Ryan; Lodish, Harvey F.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Hattangadi, Shilpa M.] Boston Childrens Hosp, Dept Hematol, Boston, MA 02115 USA. [Lodish, Harvey F.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. RP Lodish, HF (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM lodish@wi.mit.edu RI Xie, Huangming/B-2260-2012 FU NIH [DK047618, DK 068348, DK076848, 5P01 HL066105]; Singapore-MIT Alliance (SMA) [C-382-641-001-091] FX This work is supported by NIH grants DK047618, DK 068348, DK076848 and 5P01 HL066105, grant C-382-641-001-091 from the Singapore-MIT Alliance (SMA) and a graduate fellowship from SMA. Thanks for intellectual support, materials and advice from members of the laboratories of Drs P. Seale, D. Bartel and C. Emerson, and from all members of the Lodish laboratory. Thanks to Rochford's laboratory for their generous gifts of Runx1t1 plasmid. NR 40 TC 132 Z9 146 U1 3 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2011 VL 13 IS 8 BP 958 EP U198 DI 10.1038/ncb2286 PG 22 WC Cell Biology SC Cell Biology GA 800OW UT WOS:000293373700014 PM 21743466 ER PT J AU Wei, CL El Hindi, S Li, J Fornoni, A Goes, N Sageshima, J Maiguel, D Karumanchi, SA Yap, HK Saleem, M Zhang, QY Nikolic, B Chaudhuri, A Daftarian, P Salido, E Torres, A Salifu, M Sarwal, MM Schaefer, F Morath, C Schwenger, V Zeier, M Gupta, V Roth, D Rastaldi, MP Burke, G Ruiz, P Reiser, J AF Wei, Changli El Hindi, Shafic Li, Jing Fornoni, Alessia Goes, Nelson Sageshima, Junichiro Maiguel, Dony Karumanchi, S. Ananth Yap, Hui-Kim Saleem, Moin Zhang, Qingyin Nikolic, Boris Chaudhuri, Abanti Daftarian, Pirouz Salido, Eduardo Torres, Armando Salifu, Moro Sarwal, Minnie M. Schaefer, Franz Morath, Christian Schwenger, Vedat Zeier, Martin Gupta, Vineet Roth, David Rastaldi, Maria Pia Burke, George Ruiz, Phillip Reiser, Jochen TI Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis SO NATURE MEDICINE LA English DT Article ID PLASMINOGEN-ACTIVATOR RECEPTOR; IDIOPATHIC NEPHROTIC SYNDROME; RENAL-TRANSPLANTATION; GLOMERULAR-PERMEABILITY; PL(A2) POLYMORPHISM; RECURRENCE; PROTEINURIA; PLASMA; SERUM; FSGS AB Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte beta(3) integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte beta(3) integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-beta(3) integrin interaction through antibodies and small molecules targeting either uPAR or beta(3) integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS. C1 [Wei, Changli; El Hindi, Shafic; Li, Jing; Fornoni, Alessia; Maiguel, Dony; Gupta, Vineet; Roth, David; Reiser, Jochen] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Fornoni, Alessia] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Goes, Nelson] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Goes, Nelson; Karumanchi, S. Ananth; Nikolic, Boris] Harvard Univ, Sch Med, Boston, MA USA. [Sageshima, Junichiro; Burke, George; Ruiz, Phillip] Univ Miami, Miller Sch Med, Dept Surg, Miami, FL 33136 USA. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Yap, Hui-Kim] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pediat, Singapore 117595, Singapore. [Saleem, Moin] Univ Bristol, Childrens Renal Unit, Bristol Royal Hosp Children, Bristol, Avon, England. [Zhang, Qingyin] Columbia Univ, Dept Surg, New York, NY USA. [Chaudhuri, Abanti; Sarwal, Minnie M.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Daftarian, Pirouz] Univ Miami, Miller Sch Med, Wallace H Coulter Ctr Translat Res, Miami, FL 33136 USA. [Daftarian, Pirouz] Univ Miami, Miller Sch Med, Dept Ophthalmol, Miami, FL 33136 USA. [Salido, Eduardo; Torres, Armando] Hosp Univ Canarias, Serv Nefrol, Canary Isl, Spain. [Salido, Eduardo; Torres, Armando] Hosp Univ Canarias, Ctr Biomed Res Rare Dis CIBERER, Canary Isl, Spain. [Salifu, Moro] Suny Downstate Med Ctr, Div Nephrol, Brooklyn, NY 11203 USA. [Schaefer, Franz] Heidelberg Univ, Ctr Pediat & Adolescent Med, Heidelberg, Germany. [Morath, Christian; Schwenger, Vedat; Zeier, Martin] Heidelberg Univ, Dept Nephrol & Endocrinol, Heidelberg, Germany. [Rastaldi, Maria Pia] Fdn IRCCS Osped Maggiore Policlin, Renal Res Lab, Milan, Italy. [Rastaldi, Maria Pia] Fdn Amico Ric Malattie Renali, Milan, Italy. [Ruiz, Phillip] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. RP Reiser, J (reprint author), Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. EM jreiser@med.miami.edu RI Schaefer, Franz/G-4365-2010; Fornoni, Alessia/F-8350-2013; Salido, Eduardo/I-2232-2015; Yap, Hui Kim/S-2934-2016; OI Salido, Eduardo/0000-0001-9599-9854; Gupta, Vineet/0000-0001-6987-2550 FU US National Institutes of Health [DK073495, DK089394, DK-82636, DK070011]; Halpin Foundation-American Society of Nephrology; American Diabetes Association [7-09-JF-23]; Diabetes Research Institute Foundation FX We thank N. Sidenius (Foundation FIRC Institute of Molecular Oncology, Italy) for help with the suPAR assay in mouse samples. We are grateful to L. H. Beck, Jr. and D. Salant (Boston University Medical Center) for providing the membranous nephropathy patient cohort. We thank S. Hsiesh for help with sample collection. We thank G. Hoyer-Hansen (the Finsen Laboratory, Denmark) for additional suPAR assays and discussions. The authors are grateful to P.J. Goldschmidt for helpful scientific discussions regarding the manuscript and to M.J. Tracy for critical reading of the manuscript. This work was supported in part by the US National Institutes of Health (grants DK073495 and DK089394 to J.R., DK-82636 to A. F., DK070011 to G. B.), the Halpin Foundation-American Society of Nephrology Research Grant (to C. W.), a grant from the American Diabetes Association (7-09-JF-23 to A. F.), and a grant from the Diabetes Research Institute Foundation (to A. F.). The authors also wish to acknowledge the generous support of the Katz Family Fund. NR 47 TC 298 Z9 316 U1 3 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD AUG PY 2011 VL 17 IS 8 BP 952 EP U70 DI 10.1038/nm.2411 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 802JW UT WOS:000293507400028 PM 21804539 ER PT J AU Liu, LB Gardecki, JA Nadkarni, SK Toussaint, JD Yagi, Y Bouma, BE Tearney, GJ AF Liu, Linbo Gardecki, Joseph A. Nadkarni, Seemantini K. Toussaint, Jimmy D. Yagi, Yukako Bouma, Brett E. Tearney, Guillermo J. TI Imaging the subcellular structure of human coronary atherosclerosis using micro-optical coherence tomography SO NATURE MEDICINE LA English DT Article ID SCANNING-ELECTRON-MICROSCOPY; PLAQUE RUPTURE; VULNERABLE PLAQUE; IN-VIVO; CLASSIFICATION; THROMBOSIS; LESIONS; RANGE; DEPTH AB Progress in understanding, diagnosis, and treatment of coronary artery disease (CAD) has been hindered by our inability to observe cells and extracellular components associated with human coronary atherosclerosis in situ. The current standards for microstructural investigation, histology and electron microscopy are destructive and prone to artifacts. The highest-resolution intracoronary imaging modality, optical coherence tomography (OCT), has a resolution of similar to 10 mu m, which is too coarse for visualizing most cells. Here we report a new form of OCT, termed micro-optical coherence tomography (mu OCT), whose resolution is improved by an order of magnitude. We show that mu OCT images of cadaver coronary arteries provide clear pictures of cellular and subcellular features associated with atherogenesis, thrombosis and responses to interventional therapy. These results suggest that mu OCT can complement existing diagnostic techniques for investigating atherosclerotic specimens, and that mu OCT may eventually become a useful tool for cellular and subcellular characterization of the human coronary wall in vivo. C1 [Liu, Linbo; Gardecki, Joseph A.; Nadkarni, Seemantini K.; Toussaint, Jimmy D.; Yagi, Yukako; Bouma, Brett E.; Tearney, Guillermo J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02115 USA. [Liu, Linbo; Gardecki, Joseph A.; Nadkarni, Seemantini K.; Toussaint, Jimmy D.; Bouma, Brett E.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Nadkarni, Seemantini K.; Bouma, Brett E.; Tearney, Guillermo J.] Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. [Yagi, Yukako; Tearney, Guillermo J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Tearney, GJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02115 USA. EM gtearney@partners.org FU US National Institutes of Health [R01HL076398, R01HL093717]; Cystic Fibrosis Foundation [TEARNE07XX0] FX We wish to acknowledge contributions from D. Winsor-Hines of Boston Scientific for providing the stents that were used to create Supplementary Figure 4, G. Veytsman of Capital Biosciences for providing explanted human hearts, and J. Zhao and the Wellman Center Photopathology Laboratory staff for expert histology processing. Swine arterial tissue was obtained from the Massachusetts General Hospital Knight Surgical Laboratory. Human tissue was provided by the National Disease Research Interchange and Capital Biosciences. Endothelial cells were supplied by the Schepens Eye Research Institute. This research was supported in part by the US National Institutes of Health (contracts R01HL076398 and R01HL093717) and the Cystic Fibrosis Foundation (contract TEARNE07XX0). NR 27 TC 148 Z9 151 U1 3 U2 42 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2011 VL 17 IS 8 BP 1010 EP U132 DI 10.1038/nm.2409 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 802JW UT WOS:000293507400036 PM 21743452 ER PT J AU Nigwekar, SU Bhan, I Thadhani, R AF Nigwekar, Sagar U. Bhan, Ishir Thadhani, Ravi TI Statins and resistance to erythropoiesis-stimulating agents: are the two associated? Reply SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Letter C1 [Nigwekar, Sagar U.; Bhan, Ishir; Thadhani, Ravi] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. RP Nigwekar, SU (reprint author), Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. EM sagarnigs@gmail.com NR 6 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD AUG PY 2011 VL 26 IS 8 BP 2717 EP 2717 DI 10.1093/ndt/gfr286 PG 1 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 800CM UT WOS:000293336500051 ER PT J AU Quiroz, YT Ally, BA Celone, K McKeever, J Ruiz-Rizzo, AL Lopera, F Stern, CE Budson, AE AF Quiroz, Y. T. Ally, B. A. Celone, K. McKeever, J. Ruiz-Rizzo, A. L. Lopera, F. Stern, C. E. Budson, A. E. TI Event-related potential markers of brain changes in preclinical familial Alzheimer disease SO NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; E280A PRESENILIN-1 MUTATION; PRESYMPTOMATIC CARRIERS; MEMORY; ABNORMALITIES; DIAGNOSIS; PICTURES; DECLINE; ATROPHY; ONSET AB Objectives: Event-related potentials (ERPs) can reflect differences in brain electrophysiology underlying cognitive functions in brain disorders such as dementia and mild cognitive impairment. To identify individuals at risk for Alzheimer disease (AD) we used high-density ERPs to examine brain physiology in young presymptomatic individuals (average age 34.2 years) who carry the E280A mutation in the presenilin-1 (PSEN1) gene and will go on to develop AD around the age of 45. Methods: Twenty-one subjects from a Colombian population with familial AD participated: 10 presymptomatic subjects positive for the PSEN1 mutation (carriers) and 11 siblings without the mutation (controls). Subjects performed a visual recognition memory test while 128-channel ERPs were recorded. Results: Despite identical behavioral performance, PSEN1 mutation carriers showed less positivity in frontal regions and more positivity in occipital regions, compared to controls. These differences were more pronounced during the 200-300 msec period. Discriminant analysis at this time interval showed promising sensitivity (72.7%) and specificity (81.8%) of the ERP measures to predict the presence of AD pathology. Conclusions: Presymptomatic PSEN1 mutation carriers show changes in brain physiology that can be detected by high-density ERPs. The relative differences observed showing greater frontal positivity in controls and greater occipital positivity in carriers indicates that control subjects may use frontally mediated processes to distinguish between studied and unstudied visual items, whereas carriers appear to rely more upon perceptual details of the items to distinguish between them. These findings also demonstrate the potential usefulness of ERP brain correlates as preclinical markers of AD. Neurology (R) 2011;77:469-475 C1 [Quiroz, Y. T.; Celone, K.; Stern, C. E.] Boston Univ, Ctr Memory & Brain, Dept Psychol, Boston, MA 02215 USA. [Quiroz, Y. T.; Ruiz-Rizzo, A. L.; Lopera, F.] Univ Antioquia, Grp Neurociencias, Medellin, Colombia. [Ally, B. A.] Vanderbilt Univ, Dept Neurol, Nashville, TN USA. [Ally, B. A.] Vanderbilt Univ, Dept Psychiat, Nashville, TN USA. [Ally, B. A.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [McKeever, J.; Budson, A. E.] Boston VA Healthcare Syst, Geriatr Res Educ Clin Ctr, Ctr Translat Cognit Neurosci, Boston, MA USA. [McKeever, J.; Budson, A. E.] Boston Univ, Dept Neurol, Alzheimers Dis Ctr, Sch Med, Boston, MA 02215 USA. RP Quiroz, YT (reprint author), Boston Univ, Ctr Memory & Brain, Dept Psychol, 2 Cummington St,Suite 109, Boston, MA 02215 USA. EM yquiroz@bu.edu OI Ally, Brandon/0000-0002-6034-7968 FU NIH/NIA [R01 AG025815, P30 AG13846, K23 AG031925]; COLCIENCIAS-Colombia [1115-343-19127, 1115-519-29028]; Boston University Department of Psychology; Vanderbilt University; NIH (NINDS/NIMH); Office of Naval Research; National Science Foundation FX Supported by the NIH/NIA (R01 AG025815, P30 AG13846 and K23 AG031925, COLCIENCIAS-Colombia [projects: 1115-343-19127; 1115-519-29028]) and the Boston University Department of Psychology. Dr. Budson's time was supported through the resources of VA Boston.; Y.T. Quiroz reports no disclosures. Dr. Ally receives research support from the NIH/NIA and Vanderbilt University. K. Celone, J. McKeever, A. L. Ruiz-Rizzo, and Dr. Lopera report no disclosures. Prof. Stern serves on the editorial boards of Frontiers in Neuroscience, Behavioral Neuroscience, and Hippocampus; and receives research support from the NIH (NINDS/NIMH), the Office of Naval Research, and the National Science Foundation. Dr. Budson serves on the editorial boards of Reviews in Neurological Diseases, the Journal of Medicine, and the International Journal of Alzheimer's Disease; serves as Deputy Chief of Staff for the VA Boston Healthcare System; and receives research support from the NIH/NIA. NR 36 TC 17 Z9 18 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 2011 VL 77 IS 5 BP 469 EP 475 DI 10.1212/WNL.0b013e318227b1b0 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 800RO UT WOS:000293383100015 PM 21775732 ER PT J AU Pearson, PA Comstock, TL Ip, M Callanan, D Morse, LS Ashton, P Levy, B Mann, ES Eliott, D AF Pearson, P. Andrew Comstock, Timothy L. Ip, Michael Callanan, David Morse, Lawrence S. Ashton, Paul Levy, Brian Mann, Eric S. Eliott, Dean TI Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: A 3-Year Multicenter, Randomized, Controlled Clinical Trial SO OPHTHALMOLOGY LA English DT Article ID TRIAMCINOLONE ACETONIDE; POSTERIOR UVEITIS; RETINAL THICKNESS; LASER TREATMENT; VISUAL-ACUITY; LONG-TERM; FOLLOW-UP; PHOTOCOAGULATION; RETINOPATHY; BEVACIZUMAB AB Purpose: We studied the 3-year efficacy and safety results of a 4-year study evaluating fluocinolone acetonide (FA) intravitreal implants in eyes with persistent or recurrent diabetic macular edema (DME). Design: Prospective, evaluator-masked, controlled, multicenter clinical trial. Participants: We included 196 eyes with refractory DME. Methods: Patients were randomized 2: 1 to receive 0.59-mg FA implant (n = 127) or standard of care (SOC additional laser or observation; n = 69). The implant was inserted through a pars plana incision. Visits were scheduled on day 2, weeks 1, 3, 6, 12, and 26, and thereafter every 13 weeks through 3 years postimplantation. Main Outcome Measures: The primary efficacy outcome was >= 15-letter improvement in visual acuity (VA) at 6 months. Secondary outcomes included resolution of macular retinal thickening and Diabetic Retinopathy Severity Score (DRSS). Safety measures included incidence of adverse events (AEs). Results: Overall, VA improved >= 3 lines in 16.8% of implanted eyes at 6 months (P = 0.0012; SOC, 1.4%); in 16.4% at 1 year (P = 0.1191; SOC, 8.1%); in 31.8% at 2 years (P = 0.0016; SOC, 9.3%); and in 31.1% at 3 years (P = 0.1566; SOC, 20.0%). The number of implanted eyes with no evidence of retinal thickening at the center of the macula was higher than SOC eyes at 6 months (P < 0.0001), 1 year (P < 0.0001; 72% vs 22%), 2 years (P = 0.016), and 3 years (P = 0.861). A higher rate of improvement and lower rate of decline in DRSS occurred in the implanted group versus the SOC group at 6 months (P = 0.0006), 1 year (P = 0.0016), 2 years (P = 0.012), and 3 years (P = 0.0207). Intraocular pressure (IOP) >= 30 mmHg was recorded in 61.4% of implanted eyes (SOC, 5.8%) at any time and 33.8% required surgery for ocular hypertension by 4 years. Of implanted phakic eyes, 91% (SOC, 20%) had cataract extraction by 4 years. Conclusions: The FA intravitreal implant met the primary and secondary outcomes, with significantly improved VA and DRSS and reduced DME. The most common AEs included cataract progression and elevated IOP. The 0.59-mg FA intravitreal implant may be an effective treatment for eyes with persistent or recurrent DME. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011; 118: 1580-1587 (C) 2011 by the American Academy of Ophthalmology. C1 [Eliott, Dean] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Mann, Eric S.] Retina Grp Ltd, Fairview Hts, IL USA. [Ashton, Paul] pSivida, Watertown, MA USA. [Morse, Lawrence S.] Univ Calif Davis, Med Ctr, Davis, CA 95616 USA. [Callanan, David] Texas Retina Associates, Arlington, TX USA. [Ip, Michael] Univ Wisconsin, Sch Med, Madison, WI USA. [Comstock, Timothy L.; Levy, Brian] Bausch & Lomb Inc, Rochester, NY 14604 USA. [Pearson, P. Andrew] Univ Kentucky, Dept Ophthalmol & Visual Sci, Lexington, KY USA. RP Eliott, D (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM dean_eliott@meei.harvard.edu OI Morse, Lawrence/0000-0002-1758-2348 FU Bausch & Lomb Incorporated, Rochester, New York FX Financial support for this research was provided by Bausch & Lomb Incorporated, Rochester, New York. The sponsor participated in the design of the study; conducting the study; data collection, management, and analysis; interpretation of the data; and preparation, review, and approval of the manuscript. NR 28 TC 84 Z9 88 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2011 VL 118 IS 8 BP 1580 EP 1587 DI 10.1016/j.ophtha.2011.02.048 PG 8 WC Ophthalmology SC Ophthalmology GA 800TT UT WOS:000293390900015 PM 21813090 ER PT J AU Coghill, M Ambalavanan, N Chatburn, RL Hibberd, PL Wright, LL Carlo, WA AF Coghill, Matthew Ambalavanan, Namasivayam Chatburn, Robert L. Hibberd, Patricia L. Wright, Linda L. Carlo, Waldemar A. CA Eunice Kennedy Shriver Natl Inst Global Network Womens Childrens TI Accuracy of a Novel System for Oxygen Delivery to Small Children SO PEDIATRICS LA English DT Article DE Venturi; infants; mortality; pneumonia; developing countries; entrainment ID EMERGENCY CARDIOVASCULAR CARE; PAPUA-NEW-GUINEA; CARDIOPULMONARY-RESUSCITATION; DEVELOPING-COUNTRIES; PERINATAL-MORTALITY; RESPIRATORY FAILURE; NASAL CANNULA; INFANTS; AIR; PERFORMANCE AB OBJECTIVE: Oxygen therapy for infants and small children in developing countries is often not available. Entrainment devices may provide an accurate and precise concentration of oxygen when used at the flow rates appropriate for infants and small children. METHODS: A continuously adjustable entrainment device was tested to determine the concentrations and flows of oxygen delivered by using low inlet flow rates suitable for therapy for infants and small children and 3 distinct oxygen delivery systems that varied in their resistive load. RESULTS: The use of long and large bore, low resistance tubing (similar to a mask) resulted in the delivery of oxygen concentrations that tracked closely (accurate and precise) to values indicated by the entrainment device. The directly connected system with lower resistance (similar to a hood) produced a similar profile of concentrations and flow rates to the large bore tubing but with even greater accuracy. The use of a long and narrow tubing with higher resistance (similar to a cannula) did not deliver accurate oxygen concentrations. In fact, this high-resistance system failed to work as intended, and instead of entraining air, a large proportion (sometimes >50%) of the oxygen delivered to the entrainment device was ejected through its vents. CONCLUSIONS: Entrainment devices can deliver accurate oxygen concentrations at low flow rates if used with low resistance delivery systems; however, entrainment devices are not suitable for use with high resistance delivery systems such as a standard nasal cannula. Pediatrics 2011;128:e382-e387 C1 [Coghill, Matthew; Ambalavanan, Namasivayam; Carlo, Waldemar A.] Univ Alabama, Dept Pediat, Birmingham, AL 35233 USA. [Chatburn, Robert L.] Cleveland Clin, Cleveland, OH 44106 USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Carlo, WA (reprint author), Univ Alabama, Dept Pediat, 1700 6th Ave S,176F Suite 9380R, Birmingham, AL 35233 USA. EM wcarlo@peds.uab.edu OI Ambalavanan, Namasivayam/0000-0003-0731-9092 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research [HD43475, HD40636] FX This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research (HD43475 and HD40636). NR 38 TC 1 Z9 1 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 AUG PY 2011 VL 128 IS 2 BP E382 EP E387 DI 10.1542/peds.2010-3745 PG 6 WC Pediatrics SC Pediatrics GA 800CK UT WOS:000293336200015 PM 21727103 ER PT J AU Cooper, JB Singer, SJ Hayes, J Sales, M Vogt, JW Raemer, D Meyer, GS AF Cooper, Jeffrey B. Singer, Sara J. Hayes, Jennifer Sales, Michael Vogt, Jay W. Raemer, Daniel Meyer, Gregg S. TI Design and Evaluation of Simulation Scenarios for a Program Introducing Patient Safety, Teamwork, Safety Leadership, and Simulation to Healthcare Leaders and Managers SO SIMULATION IN HEALTHCARE LA English DT Article DE Teamwork; Patient safety; Management; Leadership AB We developed a training program to introduce managers and informal leaders of healthcare organizations to key concepts of teamwork, safety leadership, and simulation to motivate them to act as leaders to improve safety within their sphere of influence. This report describes the simulation scenario and debriefing that are core elements of that program. Twelve teams of clinician and nonclinician managers were selected from a larger set of volunteers to participate in a 1-day, multielement training program. Two simulation exercises were developed: one for teams of nonclinicians and the other for clinicians or mixed groups. The scenarios represented two different clinical situations, each designed to engage participants in discussions of their safety leadership and teamwork issues immediately after the experience. In the scenarios for nonclinicians, participants conducted an anesthetic induction and then managed an ethical situation. The scenario for clinicians simulated a consulting visit to an emergency room that evolved into a problem-solving challenge. Participants in this scenario had a limited time to prepare advice for hospital leadership on how to improve observed safety and cultural deficiencies. Debriefings after both types of scenarios were conducted using principles of "debriefing with good judgment." We assessed the relevance and impact of the program by analyzing participant reactions to the simulation through transcript data and facilitator observations as well as a postcourse questionnaire. The teams generally reported positive perceptions of the relevance and quality of the simulation with varying types and degrees of impact on their leadership and teamwork behaviors. These kinds of clinical simulation exercises can be used to teach healthcare leaders and managers safety leadership and teamwork skills and behaviors. (Sim Healthcare 6: 231-238, 2011) C1 [Cooper, Jeffrey B.; Raemer, Daniel] Ctr Med Simulat, Cambridge, MA 02139 USA. [Cooper, Jeffrey B.; Raemer, Daniel] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Meyer, Gregg S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hayes, Jennifer; Meyer, Gregg S.] Massachusetts Gen Hosp, Edward P Lawrence Ctr Qual & Safety, Boston, MA 02114 USA. [Singer, Sara J.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. Massachusetts Gen Phys Org, Boston, MA USA. [Singer, Sara J.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Sales, Michael] Art Future, Newburyport, MA USA. [Vogt, Jay W.] Peoplesworth, Concord, MA USA. RP Cooper, JB (reprint author), Ctr Med Simulat, 65 Landsdowne St,Rm 142, Cambridge, MA 02139 USA. EM jcooper@partners.org FU Patrick; Catherine Weldon Donaghue Medical Research Foundation FX Supported in part by a grant from the Patrick and Catherine Weldon Donaghue Medical Research Foundation. NR 17 TC 17 Z9 18 U1 6 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-2332 J9 SIMUL HEALTHC JI Simul. Healthc. PD AUG PY 2011 VL 6 IS 4 BP 231 EP 238 DI 10.1097/SIH.0b013e31821da9ec PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 803JI UT WOS:000293577200007 PM 21642906 ER PT J AU Khan, B Bauman, WA Sinha, AK Kahn, NN AF Khan, B. Bauman, W. A. Sinha, A. K. Kahn, N. N. TI Non-conventional hemostatic risk factors for coronary heart disease in individuals with spinal cord injury SO SPINAL CORD LA English DT Review DE coronary heart disease; prostacyclin; insulin; antibody; platelets ID PROSTACYCLIN RECEPTOR ANTIBODY; PLATELET-STIMULATED THROMBIN; PHYSICAL-ACTIVITY; PROSTAGLANDIN ENDOPEROXIDES; ATHEROSCLEROTIC PLAQUES; ADENYLATE-CYCLASE; GROWTH-FACTOR; NITRIC-OXIDE; INSULIN; BLOOD AB Study design: Review. Objectives: In subjects with spinal cord injury (SCI), there is strong evidence for platelet hyperactivity, which may stimulate atherosclerosis and coronary heart disease (CHD). The literature was reviewed. Background: Individuals with SCI develop premature CHD. In addition to the conventional risk factors associated with CHD, there are pathologic hematological factors involved in atherogenesis that are similar to those that have been demonstrated in individuals with diabetes, and these hematological factors might affect individuals with SCI. One such hematological factor, platelet aggregation, is essential for the development of CHD, which results from thrombus formation in the coronary vasculature. Prostacyclin (PGI(2)) is a potent inhibitor of platelet aggregation and is thought to have a beneficial role in inhibiting atherogenesis; therefore, it is possible that individuals with SCI have impaired PGI(2) receptor function. Methods: We reviewed the literature by conducting a search using PubMed (1970-2007). Results: Acute thrombosis is emerging as an important factor in the etiology of CHD and therefore could mediate the risk of CHD in persons with SCI, in addition to previously known risk factors such as hyperlipidemia, hypertension, hyperlipidemia, diabetes mellitus and hyperinsulinemia. Because PGI(2) may retard atherogenesis through its inhibitory effects on platelet function, we discuss the effects of PGI(2) on platelets in persons with SCI in this review. Conclusions Subjects with chronic SCI develop abnormal platelet function, resulting in the production of atherogenic and thrombogenic factors for the following reasons: (1) the PGI(2) and insulin receptors on their platelets are impaired; (2) thrombin generation and platelet-derived growth factor release are elevated; (3) insulin-induced nitric oxide production by platelets is markedly impaired; and (4) a circulating antibody (immunoglobulin G (IgG)) blocks the antithrombotic effect of both insulin and PGI(2) receptors. Thus, this IgG molecule is thought to be one of the pathological mediators of the increased incidence of CHD in individuals with SCI. Spinal Cord (2011) 49, 858-866; doi:10.1038/sc.2011.33; published online 24 May 2011 C1 [Bauman, W. A.; Kahn, N. N.] James J Peters Vet Affairs Med Ctr, Dept Med & Res Serv, Bronx, NY 10468 USA. [Khan, B.] Amer Univ Antigua COM, New York, NY USA. [Bauman, W. A.; Kahn, N. N.] Ctr Excellence Consequences Spinal Cord Injury, Dept Vet Affairs Rehabil Res & Dev Serv, Bronx, NY USA. [Bauman, W. A.; Sinha, A. K.; Kahn, N. N.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Bauman, W. A.; Kahn, N. N.] Dept Rehabil Med, New York, NY USA. RP Kahn, NN (reprint author), James J Peters Vet Affairs Med Ctr, Dept Med & Res Serv, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM nighat.kahn@med.va.gov FU Veterans Affairs Rehabilitation Research and Development Service, Center of Excellence for the Consequences of Spinal Cord Injury [B4162]; James J. Peters Veterans Affairs Medical Center FX This work was supported by the Veterans Affairs Rehabilitation Research and Development Service, Center of Excellence for the Consequences of Spinal Cord Injury (#B4162), James J. Peters Veterans Affairs Medical Center. NR 55 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 EI 1476-5624 J9 SPINAL CORD JI Spinal Cord PD AUG PY 2011 VL 49 IS 8 BP 858 EP 866 DI 10.1038/sc.2011.33 PG 9 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 803HS UT WOS:000293573000002 PM 21606930 ER PT J AU Wu, Y Hou, J Collier, L Pan, J Hou, L Qin, W Bauman, WA Cardozo, CP AF Wu, Y. Hou, J. Collier, L. Pan, J. Hou, L. Qin, W. Bauman, W. A. Cardozo, C. P. TI The administration of high-dose methylprednisolone for 24 h reduced muscle size and increased atrophy-related gene expression in spinal cord-injured rats SO SPINAL CORD LA English DT Article DE spinal cord injury; methylprednisolone; muscle atrophy; muscle ubiquitin ligases; REDD1; FOXO1 ID SKELETAL-MUSCLE; PROTEIN; TESTOSTERONE; TRANSECTION; INVOLVE AB Objective: Administration after spinal cord injury (SCI) of methylprednisolone (MP) for 24-48h has been suggested to improve functional outcome. The safety of this approach has been questioned because of the known adverse effects of glucocorticoids on skeletal muscle and the immune system. The purpose of this study was to explicitly test adverse effects of regimen of MP administration on skeletal muscle. Study design: Male rats underwent spinal cord transection at T9-T10, followed by an intravenous injection of MP and subsequent infusion of MP for 24 h. Results: MP significantly reduced the weight of the triceps, soleus, plantaris and gastrocnemius muscles, with the greatest effect being a 63% decrease in triceps weight (for example, muscle above the level of lesion) at 7 days; below the level of lesion, gastrocnemius weight was reduced by 33% by SCI alone, and by 45% by SCI and MP. Centralized nuclei were found in myofibers of the gastrocnemius and triceps from the MP-SCI group, but not other groups. MP increased expression in the triceps, soleus and plantaris of FOXO1, MAFbx, MuRF1 and REDD1 at 1 day, and, in plantaris, at 7 days. Conclusions: Thus, 1 day of MP at a dose comparable to those routinely employed in clinical practice immediately after SCI resulted in marked atrophy of functionally intact muscle above the level of lesion, and worsened atrophy of paralyzed muscle below the level of lesion, associated with elevations in expression of four genes involved in pathways associated with muscle atrophy. Spinal Cord (2011) 49, 867-873; doi:10.1038/sc.2011.28; published online 29 March 2011 C1 [Wu, Y.; Hou, J.; Collier, L.; Pan, J.; Hou, L.; Qin, W.; Bauman, W. A.; Cardozo, C. P.] James J Peters VA Med Ctr, Dept Vet Affairs, Ctr Excellence Med Consequences Spinal Cord Injur, Bronx, NY 10468 USA. [Qin, W.; Bauman, W. A.; Cardozo, C. P.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Bauman, W. A.; Cardozo, C. P.] Mt Sinai Sch Med, Dept Med & Rehabil Med, New York, NY USA. RP Cardozo, CP (reprint author), James J Peters VA Med Ctr, Dept Vet Affairs, Ctr Excellence Med Consequences Spinal Cord Injur, Room 1E-02,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM Chris.Cardozo@mssm.edu FU Veterans Health Administration, Rehabilitation Research and Development Service [B4162C, B3347K] FX The research reported here was supported by the Veterans Health Administration, Rehabilitation Research and Development Service (B4162C and B3347K). NR 16 TC 5 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 EI 1476-5624 J9 SPINAL CORD JI Spinal Cord PD AUG PY 2011 VL 49 IS 8 BP 867 EP 873 DI 10.1038/sc.2011.28 PG 7 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 803HS UT WOS:000293573000003 PM 21445080 ER PT J AU Arsava, EM Furie, KL Schwamm, LH Sorensen, AG Ay, H AF Arsava, E. Murat Furie, Karen L. Schwamm, Lee H. Sorensen, A. Gregory Ay, Hakan TI Prediction of Early Stroke Risk in Transient Symptoms With Infarction Relevance to the New Tissue-Based Definition SO STROKE LA English DT Article DE brain infarction; diffusion-weighted imaging; MRI; transient ischemic attack; stroke risk ID ISCHEMIC ATTACK; MINOR STROKE; POPULATION; RECURRENCE; SCORE; VALIDATION AB Background and Purpose-The risk of stroke shortly after transient ischemic attack with infarction on diffusion-weighted images, also known as transient symptoms with infarction (TSI), is substantially higher than is the risk after imaging-normal transient ischemic attack. We sought to assess the utility of a Web-based recurrence risk estimator (RRE; http://www.nmr.mgh.harvard.edu/RRE/) originally developed for use in patients with ischemic stroke for predicting 7-day risk of stroke in patients with TSI. Methods-We calculated RRE and ABCD(2) scores in a retrospective series of 257 consecutive patients with TSI diagnosed by diffusion-weighted images within 24 hours of symptom onset. We defined subsequent stroke as clinical deterioration associated with new infarction spatially distinct from the index lesion. We assessed the predictive performance of each model by computing the area under receiver-operating characteristics curve. Results-Over 7-day follow-up, 16 patients developed a recurrent stroke (6.2%). The sensitivity and specificity of an RRE score of >= 2 for predicting 7-day stroke risk were 87% and 73%, respectively. The area under the receiver-operating characteristics curve was 0.85 (95% CI, 0.78-0.92) for RRE and 0.57 (95% CI, 0.45-0.69) for ABCD(2) score (z-test; P<0.001). Conclusions-The RRE score seems to predict 7-day risk of stroke after a TSI. If further validated in larger data sets, the RRE score could be useful in identifying high-risk patients with TSI who may benefit from early intervention with targeted stroke prevention strategies. (Stroke. 2011;42:2186-2190.) C1 [Arsava, E. Murat; Sorensen, A. Gregory; Ay, Hakan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging,Dept Radiol, Charlestown, MA 02129 USA. [Furie, Karen L.; Schwamm, Lee H.; Ay, Hakan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke Serv,Dept Neurol, Charlestown, MA 02129 USA. RP Ay, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging,Dept Radiol, 13th St,149-2301, Charlestown, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013; OI Arsava, Ethem Murat/0000-0002-6527-4139; Schwamm, Lee/0000-0003-0592-9145 FU NIH [P50-NS051343, R01-NS038477, R01-NS063925, R01-NS059710] FX This study was funded by NIH grant P50-NS051343 (K.L.F.); NIH grant P50-NS051343 (L.H.S.); NIH grant R01-NS038477, NIH grant R01-NS063925 (A.G.S.); NIH grant R01-NS059710 (H.A.). NR 23 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2011 VL 42 IS 8 BP 2186 EP 2190 DI 10.1161/STROKEAHA.110.604280 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 796UE UT WOS:000293077400021 PM 21680907 ER PT J AU Ross, JS Arling, G Ofner, S Roumie, CL Keyhani, S Williams, LS Ordin, DL Bravata, DM AF Ross, Joseph S. Arling, Greg Ofner, Susan Roumie, Christianne L. Keyhani, Salomeh Williams, Linda S. Ordin, Diana L. Bravata, Dawn M. TI Correlation of Inpatient and Outpatient Measures of Stroke Care Quality Within Veterans Health Administration Hospitals SO STROKE LA English DT Article DE acute stroke; healthcare; outcomes; quality of care; stroke care ID ACUTE MYOCARDIAL-INFARCTION; MORTALITY-RATES; PERFORMANCE; OUTCOMES; COMPARE AB Background and Purpose-Quality of care delivered in the inpatient and ambulatory settings may be correlated within an integrated health system such as the Veterans Health Administration. We examined the correlation between stroke care quality at hospital discharge and within 6 months postdischarge. Methods-We conducted a cross-sectional hospital-level correlation analyses of chart-abstracted data for 3467 veterans discharged alive after an acute ischemic stroke from 108 Veterans Health Administration medical centers and 2380 veterans with postdischarge follow-up within 6 months in fiscal year 2007. Four risk-standardized processes of care represented discharge care quality: prescription of antithrombotic and antilipidmic therapy, anticoagulation for atrial fibrillation, and tobacco cessation counseling along with a composite measure of defect-free care. Five risk-standardized intermediate outcomes represented postdischarge care quality: achievement of blood pressure, low-density lipoprotein, international normalized ratio, and glycosylated hemoglobin target levels, and delivery of appropriate treatment for poststroke depression along with a composite measure of achieved outcomes. Results-Median risk-standardized composite rate of defect-free care at discharge was 79%. Median risk-standardized postdischarge rates of achieving goal were 56% for blood pressure, 36% for low-density lipoprotein, 41% for international normalized ratio, 40% for glycosylated hemoglobin, and 39% for depression management and the median risk-standardized composite 6-month outcome rate was 44%. The hospital composite rate of defect-free care at discharge was correlated with meeting the low-density lipoprotein goal (r = 0.31; P = 0.007) and depression management (r = 0.27; P = 0.03) goal but was not correlated with blood pressure, international normalized ratio, glycosylated hemoglobin goals, nor with the composite measure of achieved postdischarge outcomes (probability values >0.13). Conclusions-Hospital discharge care quality was not consistently correlated with ambulatory care quality. (Stroke. 2011;42:2269-2275.) C1 [Ross, Joseph S.] Yale Univ, Sch Med, Gen Internal Med Sect, Dept Med, New Haven, CT 06520 USA. Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. [Arling, Greg] Indiana Univ, Ctr Aging Res, Indianapolis, IN 46204 USA. [Arling, Greg; Williams, Linda S.; Bravata, Dawn M.] Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. [Ofner, Susan] Indiana Univ Sch Med, Dept Med, IUPUI, Div Biostat, Indianapolis, IN USA. [Roumie, Christianne L.] Vanderbilt Univ, Med Ctr, Targeted Res Enhancement Program Ctr, VHA,HSR&D,GRECC, Nashville, TN USA. Vanderbilt Univ, Med Ctr, Clin Res Training Ctr Excellence, Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN USA. Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Keyhani, Salomeh] James J Peters Vet Affairs Med Ctr, VHA HSR&D Res Enhancement Award Program, Bronx, NY USA. James J Peters Vet Affairs Med Ctr, GRECC, Bronx, NY USA. Mt Sinai Sch Med, Dept Hlth Evidence & Policy, New York, NY USA. [Williams, Linda S.; Bravata, Dawn M.] Richard L Roudebush Vet Affairs Med Ctr, VHA HSR&D Stroke Qual Enhancement Res Initiat QUE, Indianapolis, IN 46202 USA. [Williams, Linda S.; Bravata, Dawn M.] Richard L Roudebush Vet Affairs Med Ctr, HSR&D Ctr Excellence Implementing Evidence Based, Indianapolis, IN 46202 USA. [Williams, Linda S.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN USA. [Ordin, Diana L.] VHA Off Qual & Performance OQP, Washington, DC USA. [Bravata, Dawn M.] Indiana Univ Sch Med, Dept Med, Div Gen Internal Med, Indianapolis, IN USA. RP Ross, JS (reprint author), Yale Univ, Sch Med, Gen Internal Med Sect, Dept Med, POB 208093, New Haven, CT 06520 USA. EM joseph.ross@yale.edu FU VHA HSR&D Research Enhancement; Veterans Affairs (VA) Office of Quality and Performance (OQP); VA Health Services Research and Development (HSR&D) Stroke Quality Enhancement Research Initiative (QUERI) [RRP 09-184]; National Institute on Aging and by the American Federation of Aging Research [K08 AG032886] FX From the Section of General Internal Medicine (J.S.R.), Department of Medicine, Yale University School of Medicine and Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT; Indiana University Centers for Aging Research (G. A.), Indianapolis, IN; Regenstrief Institute (G. A., L. S. W., D. M. B.), Indianapolis, IN; the Division of Biostatistics (S.O.), Department of Medicine, Indiana University School of Medicine, IUPUI, Indianapolis, IN; Veterans Health Administration (VHA) Health Services Research and Development (HSR&D) Targeted Research Enhancement Program Center (C. L. R.), Geriatrics Research, Education, and Clinical Center (GRECC), and Clinical Research Training Center of Excellence, Veterans Affairs-Tennessee Valley Healthcare System and the Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; VHA HSR&D Research Enhancement Award Program and GRECC (S. K.), James J. Peters Veterans Affairs Medical Center, Bronx, NY, and the Department of Health Evidence and Policy, Mount Sinai School of Medicine, New York, NY; VHA HSR&D Stroke Quality Enhancement Research Initiative (QUERI) and the HSR&D Center of Excellence for Implementing Evidence-Based Practice (CIEBP; L. S. W., D. M. B.), Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN; the Department of Neurology, Indiana University School of Medicine (L. S. W.), Indianapolis, IN; the VHA Office of Quality and Performance (OQP; D.L.O.), Washington, DC; and the Division of General Internal Medicine (D. M. B.), Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.; This project was supported by the Veterans Affairs (VA) Office of Quality and Performance (OQP) and the VA Health Services Research and Development (HSR&D) Stroke Quality Enhancement Research Initiative (QUERI; RRP 09-184). J.S.R. is currently supported by the National Institute on Aging and by the American Federation of Aging Research through the Paul B. Beeson Career Development Award Program (K08 AG032886). NR 20 TC 8 Z9 8 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2011 VL 42 IS 8 BP 2269 EP 2275 DI 10.1161/STROKEAHA.110.611913 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 796UE UT WOS:000293077400036 PM 21719771 ER PT J AU Kakinohana, M Kida, K Minamishima, S Atochin, DN Huang, PL Kaneki, M Ichinose, F AF Kakinohana, Manabu Kida, Kotaro Minamishima, Shizuka Atochin, Dmitriy N. Huang, Paul L. Kaneki, Masao Ichinose, Fumito TI Delayed Paraplegia After Spinal Cord Ischemic Injury Requires Caspase-3 Activation in Mice SO STROKE LA English DT Article DE apoptosis; cleaved caspase-3; delayed neuronal death; delayed paraplegia; spinal cord ischemia ID AORTIC-ANEURYSM REPAIR; BLOOD-FLOW; MOTOR-NEURONS; APOPTOSIS; DEFICITS; INHIBITOR; INDUCTION; RABBITS; STROKE; MOUSE AB Background and Purpose-Delayed paraplegia remains a devastating complication after ischemic spinal cord injury associated with aortic surgery and trauma. Although apoptosis has been implicated in the pathogenesis of delayed neurodegeneration, mechanisms responsible for the delayed paraplegia remain incompletely understood. The aim of this study was to elucidate the role of apoptosis in delayed motor neuron degeneration after spinal cord ischemia. Methods-Mice were subjected to spinal cord ischemia induced by occlusion of the aortic arch and left subclavian artery for 5 or 9 minutes. Motor function in the hind limb was evaluated up to 72 hours after spinal cord ischemia. Histological studies were performed to detect caspase-3 activation, glial activation, and motor neuron survival in the serial spinal cord sections. To investigate the impact of caspase-3 activation on spinal cord ischemia, outcome of the spinal cord ischemia was examined in mice deficient for caspase-3. Results-In wild-type mice, 9 minutes of spinal cord ischemia caused immediate paraplegia, whereas 5 minutes of ischemia caused delayed paraplegia. Delayed paraplegia after 5 minutes of spinal cord ischemia was associated with histological evidence of caspase-3 activation, reactive astrogliosis, microglial activation, and motor neuron loss starting at approximately 24 to 48 hours after spinal cord ischemia. Caspase-3 deficiency prevented delayed paraplegia and motor neuron loss after 5 minutes of spinal cord ischemia, but not immediate paraplegia after 9 minutes of ischemia. Conclusions-The present results suggest that caspase-3 activation is required for delayed paraplegia and motor neuron degeneration after spinal cord ischemia. (Stroke. 2011;42:2302-2307.) C1 [Kakinohana, Manabu; Kida, Kotaro; Minamishima, Shizuka; Kaneki, Masao; Ichinose, Fumito] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02129 USA. [Atochin, Dmitriy N.; Huang, Paul L.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Dept Med, Boston, MA 02129 USA. [Kaneki, Masao] Univ Ryukyus, Dept Anesthesiol, Fac Med, Okinawa, Japan. RP Ichinose, F (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 149 13th St,4315, Boston, MA 02129 USA. EM fichinose@partners.org RI Atochin, Dmitriy/Q-3150-2016 FU Ministry of Education of Japan [22390299]; National Institutes of Health [R01HL101930] FX This work was supported by grant-in-aid for scientific research from the Ministry of Education of Japan (B) 22390299 to M.K. and National Institutes of Health grant R01HL101930 to F.I. NR 23 TC 14 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2011 VL 42 IS 8 BP 2302 EP U430 DI 10.1161/STROKEAHA.110.600429 PG 14 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 796UE UT WOS:000293077400041 PM 21700940 ER PT J AU Reisner, SL Falb, KL Mimiaga, MJ AF Reisner, Sari L. Falb, Kathryn L. Mimiaga, Matthew J. TI Early Life Traumatic Stressors and the Mediating Role of PTSD in Incident HIV Infection Among US Men, Comparisons by Sexual Orientation and Race/Ethnicity: Results From the NESARC, 2004-2005 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; MSM; violence ID PSYCHIATRIC DIAGNOSTIC MODULES; GENERAL-POPULATION SAMPLE; ALCOHOL-USE DISORDERS; IV AUDADIS-IV; RISK BEHAVIOR; HOUSEHOLD DYSFUNCTION; CHILD MALTREATMENT; COMMUNITY VIOLENCE; DOMESTIC VIOLENCE; ABUSE AB Background: Stressful life events in childhood during critical periods of development have long-term psychological and neurobiological sequelae, which may affect risk for HIV infection across the life course. Methods: Data were from a nationally representative sample of 13,274 US men (National Epidemiologic Survey on Alcohol and Related Conditions, 2004-2005). Weighted multivariable logistic regression models examined (1) the association of childhood violent events before age 18 on 12-month incident HIV infection and (2) whether posttraumatic stress disorder (PTSD) diagnosis (clinical interview) mediated the association between early life events and HIV. Results: Overall, the 12-month HIV incidence was,1% (0.35%); 44% of new infections were among racial/ethnic minorities and 31% among men who have sex with men). One-third of the sample (33.5%) reported one or more early life stressors (physical abuse, sexual abuse, neglect, verbal violence, or witnessed violence). In a weighted multivariable logistic regression model adjusted for age, education, family's socioeconomic position, and sexual behaviors, each additional early life violent event was associated with an elevated odds of HIV infection [adjusted odds ratio (aOR) = 1.32; 95% confidence interval (CI): 1.16 to 1.50]. Adding PTSD to this adjusted model, PTSD was highly associated with incident HIV infection (aOR = 5.75; 95% CI: 4.76 to 6.95). There was evidence that PTSD partially mediated the relationship between early life events and HIV (aOR = 1.14; 95% CI: 1.02 to 1.28). Conclusions: Experiencing early life violent family stressors was associated with HIV infection among men. Early life events and HIV infection were mediated by PTSD, which has implications for understanding disparities in HIV infection. Interventions are urgently needed that address the long-term sequelae of childhood violence. C1 [Reisner, Sari L.; Mimiaga, Matthew J.] Fenway Hlth, Fenway Inst, Boston, MA 02215 USA. [Reisner, Sari L.; Falb, Kathryn L.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Reisner, SL (reprint author), Fenway Hlth, Fenway Inst, 1340 Boylston St,8th Floor, Boston, MA 02215 USA. EM sreisner@fenwayhealth.org NR 55 TC 7 Z9 7 U1 7 U2 24 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 1 PY 2011 VL 57 IS 4 BP 340 EP 350 DI 10.1097/QAI.0b013e31821d36b4 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 782TD UT WOS:000292033500019 PM 21499111 ER PT J AU Boland, GWL AF Boland, Giles W. L. TI Adrenal imaging SO ABDOMINAL IMAGING LA English DT Article DE Adrenal; Characterization; Diagnosis; Computed tomography; PET; PET/CT ID DELAYED ENHANCED CT; F-18-FDG PET/CT; UNENHANCED CT; MASSES; ADENOMAS; LESIONS; NONADENOMAS; PROTOCOL; BENIGN; PHEOCHROMOCYTOMA AB Adrenal masses are frequently encountered in imaging practices. Simple detection by radiologists is insufficient as many of these masses can now be characterized by imaging alone. Some masses can be characterized by their simple appearances, but most cannot. This article will describe the different principles used by imagers to lead them to the correct diagnosis for the overwhelming majority of lesions. Imagers should be familiar with these techniques to expedite treatment, especially in cancer patients and so prevent unnecessary biopsies, costs, and anxiety. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Boland, GWL (reprint author), Massachusetts Gen Hosp, Dept Radiol, White Bldg 270C,55 Fruit St, Boston, MA 02114 USA. EM gboland@partners.org NR 33 TC 8 Z9 9 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 J9 ABDOM IMAGING JI Abdom. Imaging PD AUG PY 2011 VL 36 IS 4 BP 472 EP 482 DI 10.1007/s00261-010-9647-z PG 11 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA 799KG UT WOS:000293285000015 PM 21052665 ER PT J AU Cox, M Kupersmith, J Jesse, RL Petzel, RA AF Cox, Malcolm Kupersmith, Joel Jesse, Robert L. Petzel, Robert A. TI Commentary: Building Human Capital: Discovery, Learning, and Professional Satisfaction SO ACADEMIC MEDICINE LA English DT Editorial Material ID CARE AB Physician satisfaction is an important contributor to a well-functioning health system. Mohr and Burgess report that physicians in the Veterans Health Administration (VA) who spend time in research have greater overall job satisfaction, that satisfaction tracks with aggregate facility research funding, and that satisfaction is higher among physicians working in VA facilities located on the same campus or within walking distance of an affiliated medical school. An environment conducive to research therefore not only advances science but also seems to be a key element of physician satisfaction. In addition to advancing scientific discovery and promoting greater physician satisfaction, these findings suggest that an environment of discovery and learning may yield benefits beyond specific academic endeavors and contribute more broadly to supporting health system performance. C1 [Cox, Malcolm] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Jesse, Robert L.] Virginia Commonwealth Univ Hlth Syst, Richmond, VA USA. [Cox, Malcolm; Kupersmith, Joel; Jesse, Robert L.; Petzel, Robert A.] US Dept Vet Affairs, Washington, DC USA. RP Cox, M (reprint author), US Dept Vet Affairs 10A4D, 810 Vermont Ave NW, Washington, DC 20420 USA. EM malcolm.cox@va.gov NR 6 TC 5 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD AUG PY 2011 VL 86 IS 8 BP 923 EP 924 DI 10.1097/ACM.0b013e3182223b8e PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 798NK UT WOS:000293215200008 PM 21795900 ER PT J AU Mohr, DC Burgess, JF AF Mohr, David C. Burgess, James F., Jr. TI Job Characteristics and Job Satisfaction Among Physicians Involved With Research in the Veterans Health Administration SO ACADEMIC MEDICINE LA English DT Article ID PATIENT; CARE; OUTCOMES; DISSATISFACTION; MOTIVATION; FACULTY; BURNOUT; WORK AB Purpose Research conducted by physicians generates knowledge and has led to important advances and changes in the health care system. Physician retention is a concern facing many health care systems, and job satisfaction and attitudes play a role in retention. This study examined whether physicians who are involved with research have greater job satisfaction and more positive job characteristics perceptions. Method Cross-sectional analysis examined this research question using a sample of 7,734 physicians across 135 medical centers in the Department of Veterans Affairs (VA) in 2008. Using existing survey results, ratings on job characteristics (job autonomy, skill development opportunities, work and family balance, and performance feedback) and job satisfaction were regressed on research involvement in a multilevel hierarchical generalized linear model. The model controlled for physician-level characteristics and organization-level characteristics related to research activities. Results Analyses revealed that physicians who spent part of their time involved with research activities were more likely to report favorable job characteristics ratings. Physicians involved with research were also more likely to be satisfied with their job. Physicians who worked in medical centers with greater levels of research funding were more likely to report favorable ratings for job characteristics and job satisfaction. Conclusions Involvement with research was associated with more favorable job characteristics and job satisfaction perceptions among physicians in VA. Although there is a time and opportunity cost involved with research, medical centers that provide physicians with the opportunity to conduct research may have a more satisfied workforce. C1 [Mohr, David C.; Burgess, James F., Jr.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. [Mohr, David C.; Burgess, James F., Jr.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. RP Mohr, DC (reprint author), VA Boston Healthcare Syst 152M, 150 S Huntington Ave, Boston, MA 02130 USA. EM david.mohr2@va.gov OI Burgess, James/0000-0002-6646-7071 FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development for IIR [05-221] FX This material is based on work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development for IIR 05-221. NR 37 TC 12 Z9 12 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD AUG PY 2011 VL 86 IS 8 BP 938 EP 945 DI 10.1097/ACM.0b013e3182223b76 PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 798NK UT WOS:000293215200012 PM 21694559 ER PT J AU Choi, AI Weekley, CC Chen, SC Li, SY Tamura, MK Norris, KC Shlipak, MG AF Choi, Andy I. Weekley, Cristin C. Chen, Shu-Cheng Li, Suying Tamura, Manjula Kurella Norris, Keith C. Shlipak, Michael G. TI Association of Educational Attainment With Chronic Disease and Mortality: The Kidney Early Evaluation Program (KEEP) SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Education; mortality; chronic kidney disease ID UNITED-STATES; RISK-FACTORS; LIFE EXPECTANCY; HEALTH; US; DISPARITIES; SURVIVAL; LITERACY; ADULTS; INCOME AB Background: Recent reports have suggested a close relationship between education and health, including mortality, in the United States. Study Design: Observational cohort. Setting & Participants: We studied 61,457 participants enrolled in a national health screening initiative, the National Kidney Foundation's Kidney Early Evaluation Program (KEEP). Predictor: Self-reported educational attainment. Outcomes: Chronic diseases (hypertension, diabetes, cardiovascular disease, reduced kidney function, and albuminuria) and mortality. Measurements: We evaluated cross-sectional associations between self-reported educational attainment with the chronic diseases listed using logistic regression models adjusted for demographics, access to care, behaviors, and comorbid conditions. The association of educational attainment with survival was determined using multivariable Cox proportional hazards regression. Results: Higher educational attainment was associated with a lower prevalence of each of the chronic conditions listed. In multivariable models, compared with persons not completing high school, college graduates had a lower risk of each chronic condition, ranging from 11% lower odds of decreased kidney function to 37% lower odds of cardiovascular disease. During a mean follow-up of 3.9 (median, 3.7) years, 2,384 (4%) deaths occurred. In the fully adjusted Cox model, those who had completed college had 24% lower mortality compared with participants who had completed at least some high school. Limitations: Lack of income data does not allow us to disentangle the independent effects of education from income. Conclusions: In this diverse contemporary cohort, higher educational attainment was associated independently with a lower prevalence of chronic diseases and short-term mortality in all age and race/ethnicity groups. Am J Kidney Dis. 58(2): 228-234. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Choi, Andy I.; Weekley, Cristin C.; Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Choi, Andy I.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Chen, Shu-Cheng; Li, Suying] Minneapolis Med Res Fdn Inc, Chron Dis Res Grp, Minneapolis, MN USA. [Tamura, Manjula Kurella] Stanford Univ, Sch Med, Div Nephrol, Palo Alto, CA 94304 USA. [Norris, Keith C.] Charles R Drew Univ Med & Sci, Dept Internal Med, Los Angeles, CA 90059 USA. RP Shlipak, MG (reprint author), San Francisco VA Med Ctr, Dept Med, Box 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM michael.shlipak@ucsf.edu RI Kurella Tamura, Manjula/C-8284-2014 OI Kurella Tamura, Manjula/0000-0001-5227-2479 FU Amgen; Abbott; Novartis; Siemens; Genentech; Genzyme; Nephroceuticals; Pfizer; Lifescan; Suplena; National Institutes of Health [MD00148, 1U54RR026138] FX KEEP is a program of the National Kidney Foundation and is supported by Amgen, Abbott, Novartis, Siemens, Genentech, Genzyme, Nephroceuticals, Pfizer, Lifescan, and Suplena. These funding sources were not involved in the design or conduct of the study. Dr Norris is supported by National Institutes of Health grants MD00148 and 1U54RR026138. NR 24 TC 16 Z9 16 U1 2 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2011 VL 58 IS 2 BP 228 EP 234 DI 10.1053/j.ajkd.2011.02.388 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 795WU UT WOS:000293010000012 PM 21601328 ER PT J AU Kloek, CE Andreoli, MT Andreoli, CM AF Kloek, Carolyn E. Andreoli, Michael T. Andreoli, Christopher M. TI Characteristics of Traumatic Cataract Wound Dehiscence SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID RELATIVE STRENGTH; CADAVER EYES; OLDER-PEOPLE; SURGERY; CORNEAL; FALLS; RISK; PHACOEMULSIFICATION; INTERVENTION; COMMUNITY AB PURPOSE: To characterize the clinical course of cataract wound dehiscence. DESIGN: Retrospective, comparative case series. METHODS: Charts of open globe injuries (848 injuries in 846 patients) treated surgically at the Massachusetts Eye and Ear Infirmary between 2000 and 2009 were retrospectively reviewed. Time from original surgery to wound dehiscence, type of initial surgery, Ocular Trauma Score, age, gender, mechanism of injury, and visual acuity were analyzed. RESULTS: Of 846 patients with 848 open globe injuries, 63 experienced cataract wound dehiscence. The majority of these cataract wounds (89%) were extracapsular cataract extraction (ECCE), with only 7 (11%) phacoemulsification wounds. The mean patient age in the wound rupture group was 78.2 years. Female patients comprised the majority (67%) of this subpopulation. The most common mechanisms of injury were fall (65%), blunt trauma (23%), and motor vehicle accident (7%). The median raw ocular trauma score was 47 in wound dehiscence patients. Visual acuity at presentation was light perception in the wound dehiscence group. The best postoperative visual acuity was significantly worse in the wound dehiscence group (hand motion) than in the remaining patients (20/40; P = .0002). When considering the phacoemulsification patients alone, these patients fared much better, with a median postoperative vision of 20/60. CONCLUSIONS: Despite recent advances in cataract surgery, wound dehiscence remains a significant source of visual disability, mainly in the geriatric population. Rupture ECCE wound patients have a poor visual prognosis. Fortunately, patients with phacoemulsification site dehiscence appear to regain the majority of their vision after open globe repair (Am J Ophthalmol 2011;152: 229-233. (C) 2011 by Elsevier Inc. All rights reserved.) C1 [Kloek, Carolyn E.; Andreoli, Michael T.; Andreoli, Christopher M.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Kloek, Carolyn E.; Andreoli, Michael T.; Andreoli, Christopher M.] Harvard Univ, Sch Med, Boston, MA USA. [Andreoli, Michael T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Andreoli, Christopher M.] Harvard Vanguard Med Associates, Boston, MA USA. RP Andreoli, CM (reprint author), 133 Brookline Ave, Boston, MA 02215 USA. EM christopher_andreoli@meei.harvard.edu NR 28 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD AUG PY 2011 VL 152 IS 2 BP 229 EP 233 DI 10.1016/j.ajo.2011.01.044 PG 5 WC Ophthalmology SC Ophthalmology GA 799WW UT WOS:000293317900013 PM 21621188 ER PT J AU Gladden, JD Ahmed, MI Litovsky, SH Schiros, CG Lloyd, SG Gupta, H Denney, TS Darley-Usmar, V McGiffin, DC Dell'Italia, LJ AF Gladden, James D. Ahmed, Mustafa I. Litovsky, Silvio H. Schiros, Chun G. Lloyd, Steven G. Gupta, Himanshu Denney, Thomas S., Jr. Darley-Usmar, Victor McGiffin, David C. Dell'Italia, Louis J. TI Oxidative Stress and Myocardial Remodeling in Chronic Mitral Regurgitation SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT Conference on Southern-Society-for-Clinical-Investigation-Cardiovascular-Club Session CY FEB 18, 2011 CL New Orleans, LA SP So Soc Clin Invest Cardiovasc Club DE Oxidative stress; Xanthine oxidase; Mitral regurgitation; Left ventricular function ID XANTHINE-OXIDASE INHIBITION; INDUCED HEART-FAILURE; NITRIC-OXIDE; VOLUME-OVERLOAD; MATRIX METALLOPROTEINASES; REACTIVE OXYGEN; CARDIOMYOCYTE FUNCTION; CARDIAC-HYPERTROPHY; SIGNAL-TRANSDUCTION; EJECTION FRACTION AB Mechanisms of left ventricular (LV) dysfunction in isolated mitral regurgitation (MR) are not well understood. Vasodilator therapy in other forms of LV dysfunction reduces LV wall stress and improves LV function; however, studies in isolated MR show no beneficial effect on LV remodeling using vasodilator drugs or renin-angiotensin system blockade. Therefore, the search for new therapies that improve LV remodeling and function in isolated MR is clinically significant. Recent work in the authors' laboratory has demonstrated increased oxidants from a number of sources including the enzyme xanthine oxidase (XO) in the LV of patients with isolated MR. In addition to being a major source of reactive oxygen species, XO is linked to bioenergetic dysfunction because its substrates derive from adenosine triphosphate catabolism. Correspondingly, there was also evidence of aggregates of small mitochondria in cardiomyocytes, which is generally considered a response to bioenergetic deficit in cells. Future studies are required to determine whether XO and persistent oxidative stress are causative in maladaptive LV remodeling and offer potential therapeutic targets in ameliorating LV damage in patients with isolated MR. C1 [Gladden, James D.; Ahmed, Mustafa I.; Litovsky, Silvio H.; Lloyd, Steven G.; Gupta, Himanshu; Darley-Usmar, Victor; McGiffin, David C.; Dell'Italia, Louis J.] Univ Alabama, Dept Med, Ctr Heart Failure Res, Birmingham, AL 35294 USA. [Gladden, James D.; Ahmed, Mustafa I.; Litovsky, Silvio H.; Lloyd, Steven G.; Gupta, Himanshu; Darley-Usmar, Victor; McGiffin, David C.; Dell'Italia, Louis J.] Univ Alabama, Dept Pathol, Ctr Heart Failure Res, Birmingham, AL 35294 USA. [Gladden, James D.; Ahmed, Mustafa I.; Litovsky, Silvio H.; Lloyd, Steven G.; Gupta, Himanshu; Darley-Usmar, Victor; McGiffin, David C.; Dell'Italia, Louis J.] Univ Alabama, Dept Biostat, Ctr Heart Failure Res, Birmingham, AL 35294 USA. [Gladden, James D.; Ahmed, Mustafa I.; Litovsky, Silvio H.; Lloyd, Steven G.; Gupta, Himanshu; Darley-Usmar, Victor; McGiffin, David C.; Dell'Italia, Louis J.] Univ Alabama, Div Cardiovasc Dis, Ctr Heart Failure Res, Birmingham, AL 35294 USA. [Gladden, James D.; Ahmed, Mustafa I.; Litovsky, Silvio H.; Lloyd, Steven G.; Gupta, Himanshu; Darley-Usmar, Victor; McGiffin, David C.; Dell'Italia, Louis J.] Univ Alabama, Div Cardiovasc Surg, Ctr Heart Failure Res, Birmingham, AL USA. [Lloyd, Steven G.; Gupta, Himanshu; Dell'Italia, Louis J.] Birmingham Vet Affairs Med Ctr, Dept Med, Birmingham, AL USA. [Lloyd, Steven G.; Gupta, Himanshu; Dell'Italia, Louis J.] Birmingham Vet Affairs Med Ctr, Div Cardiol, Birmingham, AL USA. [Schiros, Chun G.; Denney, Thomas S., Jr.] Auburn Univ, Samuel Ginn Coll Engn, Dept Elect & Comp Engn, Birmingham, AL USA. RP Dell'Italia, LJ (reprint author), UAB Ctr Heart Failure Res, Div Cardiol, 434 BMR2,901 19th St S, Birmingham, AL 35294 USA. EM loudell@uab.edu NR 64 TC 10 Z9 11 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD AUG PY 2011 VL 342 IS 2 BP 114 EP 119 DI 10.1097/MAJ.0b013e318224ab93 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 798MS UT WOS:000293212200003 PM 21795957 ER PT J AU Ashby, VB Port, FK Wolfe, RA Wynn, JJ Williams, WW Roberts, JP Leichtman, AB AF Ashby, V. B. Port, F. K. Wolfe, R. A. Wynn, J. J. Williams, W. W. Roberts, J. P. Leichtman, A. B. TI Transplanting Kidneys Without Points for HLA-B Matching: Consequences of the Policy Change SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Access to transplantation; allocation; HLA matching; kidney graft survival; kidney transplantation; minorities; policy; racial and ethnic disparities ID CADAVERIC RENAL-TRANSPLANTATION; UNITED-STATES; RACIAL-DIFFERENCES; ACCESS; ALLOCATION; IMPACT; RATES; RACE AB In 2003, the US kidney allocation system was changed to eliminate priority for HLA-B similarity. We report outcomes from before and after this change using data from the Scientific Registry of Transplant Recipients (SRTR). Analyses were based on 108 701 solitary deceased donor kidney recipients during the 6 years before and after the policy change. Racial/ethnic distributions of recipients in the two periods were compared (chi-square); graft failures were analyzed using Cox models. In the 6 years before and after the policy change, the overall number of deceased donor transplants rose 23%, with a larger increase for minorities (40%) and a smaller increase for non-Hispanic whites (whites) (8%). The increase in the proportion of transplants for non-whites versus whites was highly significant (p < 0.0001). Two-year graft survival improved for all racial/ethnic groups after implementation of this new policy. Findings confirmed prior SRTR predictions. Following elimination of allocation priority for HLA-B similarity, the deficit in transplantation rates among minorities compared with that for whites was reduced but not eliminated; furthermore, there was no adverse effect on graft survival. C1 [Ashby, V. B.] Univ Michigan, Dept Biostat, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA. [Port, F. K.; Wolfe, R. A.] Arbor Res Collaborat Hlth, Ann Arbor, MI USA. [Wynn, J. J.] Georgia Hlth Sci Univ, Dept Surg, Augusta, GA USA. [Williams, W. W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Boston, MA USA. [Williams, W. W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Unit, Boston, MA USA. [Roberts, J. P.] Univ Calif San Francisco, Liver & Kidney Transplant Serv, San Francisco, CA 94143 USA. [Leichtman, A. B.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. RP Ashby, VB (reprint author), Univ Michigan, Dept Biostat, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA. EM valarieb@umich.edu FU Scientific Registry of Transplant Recipients [234-2005-37009C]; Health Resources and Services Administration, US Department of Health and Human Services FX This research was funded through the Scientific Registry of Transplant Recipients, contract number 234-2005-37009C, from the Health Resources and Services Administration, US Department of Health and Human Services. The views expressed herein are those of the authors and not necessarily those of the US Government. NR 16 TC 20 Z9 20 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2011 VL 11 IS 8 BP 1712 EP 1718 DI 10.1111/j.1600-6143.2011.03606.x PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 800DV UT WOS:000293340900025 PM 21672159 ER PT J AU Eikermann, M Schmidt, U AF Eikermann, Matthias Schmidt, Ulrich TI Does Adrenal Size Matter? SO ANESTHESIOLOGY LA English DT Editorial Material ID INSUFFICIENCY; DIAGNOSIS; INFLAMMATION; MEDICINE; AXIS C1 [Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM meikermann@partners.org NR 11 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2011 VL 115 IS 2 BP 223 EP 225 DI 10.1097/ALN.0b013e318225d0b2 PG 3 WC Anesthesiology SC Anesthesiology GA 797ZI UT WOS:000293168800001 PM 21694575 ER PT J AU Wasan, AD Loggia, ML Chen, LQ Napadow, V Kong, J Gollub, RL AF Wasan, Ajay D. Loggia, Marco L. Chen, Li Q. Napadow, Vitaly Kong, Jian Gollub, Randy L. TI Neural Correlates of Chronic Low Back Pain Measured by Arterial Spin Labeling SO ANESTHESIOLOGY LA English DT Article ID CEREBRAL-BLOOD-FLOW; NEUROPATHIC PAIN; BRAIN; INTENSITY; ANALGESIA; CANCER; FMRI; REGISTRATION; VALIDATION; PERCEPTION AB Background: The varying nature of chronic pain (CP) is difficult to correlate to neural activity using typical functional magnetic resonance imaging methods. Arterial spin labeling is a perfusion-based imaging technique allowing the absolute quantification of regional cerebral blood flow, which is a surrogate measure of neuronal activity. Methods: Subjects with chronic low back and radicular pain and matched healthy normal subjects, undergoing identical procedures, participated in three sessions: a characterization and training session and two arterial spin labeling sessions. In the first imaging session, CP (if any) was exacerbated using clinical maneuvers; in the second session, noxious heat was applied to the affected leg dermatome, the intensity of which was matched to the pain intensity level of the CP exacerbations for each back pain subject. Results: The clinically significant worsening of ongoing CP (<= 30%, n = 16) was associated with significant regional blood flow increases (6-10 mm/100 g of tissue/min, P less than 0.01) within brain regions known to activate with experimental pain (somatosensory, prefrontal, and insular cortices) and in other structures observed less frequently in experimental pain studies, such as the superior parietal lobule (part of the dorsal attention network). This effect is specific to changes in ongoing CP as it is observed during worsening CP, but it is not observed after thermal pain application, or in matched, pain-free healthy controls. Conclusions: Study findings demonstrate the use of arterial spin labeling to investigate the neural processing of CP, and these findings are a step forward in the quest for objective biomarkers of the chronic pain experience. C1 [Chen, Li Q.; Napadow, Vitaly] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Wasan, Ajay D.; Loggia, Marco L.; Gollub, Randy L.] Harvard Univ, Sch Med, Boston, MA USA. [Kong, Jian] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Napadow, Vitaly] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Wasan, AD (reprint author), Pain Management Ctr, 850 Boylston St,Suite 320, Chestnut Hill, MA 02467 USA. EM awasan@partners.org OI Gollub, Randy L./0000-0002-9434-4044 FU National Institute of Drug Abuse of the National Institutes of Health (Bethesda, Maryland) [K23 DA020682]; Arthritis Foundation (Atlanta, Georgia); National Center for Complementary and Alternative Medicine (NCCAM) (Bethesda, Maryland) [R01AT005280]; NCCAM [KO1AT003883, R21AT004497, R01AT004714] FX Received from the Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Submitted for publication December 21, 2010. Accepted for publication March 25, 2011. Supported by the National Institute of Drug Abuse of the National Institutes of Health (Bethesda, Maryland, K23 DA020682, Dr. Wasan, primary investigator [PI]) and the Arthritis Foundation (Atlanta, Georgia, Investigator Award; Dr. Wasan, PI). Additional support provided by National Center for Complementary and Alternative Medicine (NCCAM) R01AT005280 (Bethesda, Maryland, Dr. Gollub, PI), NCCAM KO1AT003883 and R21AT004497 (Dr. Kong, PI), and NCCAM R01AT004714 (Dr. Napadow, PI). Drs. Wasan and Loggia contributed equally to the conduct of this study and the preparation of the manuscript. NR 44 TC 31 Z9 31 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2011 VL 115 IS 2 BP 364 EP 374 DI 10.1097/ALN.0b013e318220e880 PG 11 WC Anesthesiology SC Anesthesiology GA 797ZI UT WOS:000293168800017 PM 21720241 ER PT J AU Tanaka, N Abe-Dohmae, S Iwamoto, N Fitzgerald, ML Yokoyama, S AF Tanaka, Nobukiyo Abe-Dohmae, Sumiko Iwamoto, Noriyuki Fitzgerald, Michael L. Yokoyama, Shinji TI HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7 SO ATHEROSCLEROSIS LA English DT Article DE HMG-CoA reductase inhibitor; Statin; Phagocytosis; ABCA7; Cholesterol; Atherosclerosis ID CORONARY-HEART-DISEASE; SCANDINAVIAN SIMVASTATIN SURVIVAL; APOPTOTIC CELLS; DENSITY-LIPOPROTEIN; TANGIER-DISEASE; ERYTHROCYTE-MEMBRANES; CELLULAR CHOLESTEROL; TRIAL; PRAVASTATIN; EVENTS AB We recently reported that the endogenous ATP-binding cassette transporter (ABC) A7 strongly associates with phagocytosis, being regulated by sterol regulatory element binding protein 2. We therefore examined the effect of statins on phagocytosis in vitro and in vivo through the SREBP-ABCA7. Phagocytosis was found to be enhanced by pravastatin, rosuvastatin and simvastatin and cyclodextrin in J774 macrophages, as cellular cholesterol was reduced and expressions of the cholesterol-related genes were modulated, including an increase of ABCA7 mRNA and decrease of ABCA1 mRNA. Conversely, knockdown of ABCA7 expression by siRNA ablated enhancement of phagocytosis by statins. In vivo, pravastatin enhanced phagocytosis in wild-type mice, but not in ABCA7-knockout mice. We thus concluded that statins enhance phagocytosis through the SREBP-ABCA7 pathway. These findings provide a molecular basis for enhancement of the host-defense system by statins showing that one of their "pleiotropic" effects is in fact achieved through their reaction to a primary target. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Tanaka, Nobukiyo; Abe-Dohmae, Sumiko; Iwamoto, Noriyuki; Yokoyama, Shinji] Nagoya City Univ, Grad Sch Med Sci, Nagoya, Aichi 4678601, Japan. [Tanaka, Nobukiyo] Ichinomiya Nishi Hosp, Dept Cardiovasc Med, Ichinomiya 4940001, Japan. [Fitzgerald, Michael L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Fitzgerald, Michael L.] Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. [Fitzgerald, Michael L.] Massachusetts Gen Hosp, Partners Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Abe-Dohmae, S (reprint author), Nagoya City Univ, Grad Sch Med Sci, Nagoya, Aichi 4678601, Japan. EM bc.abedo@med.nagoya-cu.ac.jp; syokoyam@med.nagoya-cu.ac.jp FU The Ministry of Education, Culture, Science, Sports and Technology; The Ministry of Health, Welfare and Labor of Japan; NIH [HL074136] FX This study was supported by grants-in-aids from The Ministries of Education, Culture, Science, Sports and Technology, and of Health, Welfare and Labor of Japan, and by NIH grants to M. L. F. (HL074136). NR 43 TC 17 Z9 17 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2011 VL 217 IS 2 BP 407 EP 414 DI 10.1016/j.atherosclerosis.2011.06.031 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 798MT UT WOS:000293212400016 PM 21762915 ER PT J AU Fitch, KV Stavrou, E Looby, SE Hemphill, L Jaff, MR Grinspoon, SK AF Fitch, Kathleen V. Stavrou, Eleni Looby, Sara E. Hemphill, Linda Jaff, Michael R. Grinspoon, Steven K. TI Associations of cardiovascular risk factors with two surrogate markers of subclinical atherosclerosis: Endothelial function and carotid intima media thickness SO ATHEROSCLEROSIS LA English DT Article DE Endothelial function; Carotid intima media thickness; Atherosclerosis ID DYSFUNCTION; ARTERY; EXPRESSION; IMPACT; MEAL AB Objective: Endothelial function and carotid intima media thickness (cIMT) were investigated in a cohort of 54 healthy adults without known cardiovascular disease. Methods: Pulse wave amplitude was determined with peripheral arterial tonometry (PAT) to obtain the reactive hyperemia (RH)-PAT ratio. Ultrasound was used to determine cIMT. Results: cIMT and RH-PAT were significantly associated (rho = -0.35, P = 0.02) in univariate analysis. RH-PAT was significantly associated with age, triglycerides, fasting glucose, HDL, WHR, waist circumference and VAT. cIMT was associated with age, smoking history, fasting glucose, systolic blood pressure, diastolic blood pressure and LDL. In multivariate regression analyses, triglyceride level (P = 0.04) remained a significant determinant of RH-PAT whereas systolic blood pressure (P = 0.02) and smoking pack-year history (P = 0.046) were significant determinants of cIMT. Conclusion: Determinants of cIMT and RH-PAT were different, dominated by triglyceride and abdominal adiposity measures for RH-PAT but traditional risk factors including blood pressure, glucose, smoking and LDL for cIMT. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Fitch, Kathleen V.; Stavrou, Eleni; Looby, Sara E.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Fitch, Kathleen V.; Stavrou, Eleni; Looby, Sara E.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Fitch, Kathleen V.; Stavrou, Eleni; Looby, Sara E.; Grinspoon, Steven K.] Harvard Univ, Sch Med, Boston, MA USA. [Hemphill, Linda] Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02114 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. RP Grinspoon, SK (reprint author), LON5-207,55 Fruit St, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NIH [R01 DK049302, K24 DK064545-08, M01-RR-01066, 1 UL1 RR025758-01, K23 NR011833-01A1]; Harvard Clinical and Translational Science Center, from the National Center for Research Resources FX The authors have no relevant conflicts to disclose. Funding was provided by NIH R01 DK049302 and K24 DK064545-08 to S. K. G. and by NIH M01-RR-01066 and 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. NIH funding also provided through K23 NR011833-01A1 to S. E. L. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 15 TC 18 Z9 19 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2011 VL 217 IS 2 BP 437 EP 440 DI 10.1016/j.atherosclerosis.2011.04.009 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 798MT UT WOS:000293212400021 PM 21570076 ER PT J AU Ku, IA Farzaneh-Far, R Vittinghoff, E Zhang, MH Na, B Whooley, MA AF Ku, Ivy A. Farzaneh-Far, Ramin Vittinghoff, Eric Zhang, Mary H. Na, Beeya Whooley, Mary A. TI Association of low leptin with cardiovascular events and mortality in patients with stable coronary artery disease: The Heart and Soul Study SO ATHEROSCLEROSIS LA English DT Article DE Leptin; Coronary artery disease (CAD); Adipokine; Reverse epidemiology ID PLASMA LEPTIN; SERUM LEPTIN; MYOCARDIAL-INFARCTION; DEPRESSIVE SYMPTOMS; RISK-FACTOR; OBESITY; WOMEN; EPIDEMIOLOGY; ADIPONECTIN; PREVENTION AB Objective: Leptin is an adipokine with both protective and harmful effects on the cardiovascular (CV) system. Prior studies evaluating the association between leptin and CV outcomes have yielded conflicting results. Thus, we sought to investigate the relationship between leptin and CV events and mortality in patients with chronic stable coronary artery disease (CAD). Methods: We performed a prospective cohort study of 981 outpatients with stable CAD. Leptin levels were measured in fasting venous samples at baseline. We used proportional hazards models to evaluate the association of baseline leptin with subsequent CV events (myocardial infarction, stroke, transient ischemic attack) and death. Results: During a mean follow-up of 6.2 +/- 2.1 years, there were 304 deaths, 112 myocardial infarctions, and 52 strokes/TIAs. In models adjusted for age, sex, and race, low leptin was associated with a 30% increased risk of the combined outcome (HR 1.30, CI 1.05-1.59, p = 0.01). After further adjustment for obesity, traditional CV risk factors and biomarkers, low leptin remained associated with a 37% increased risk of events (HR 1.37, CI 1.06-1.76, p = 0.02). Conclusions: Low leptin is associated with increased CV events and mortality in patients with stable coronary artery disease. This association is independent of known factors affecting leptin levels, including gender and obesity. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Ku, Ivy A.] San Francisco Gen Hosp, Div Cardiol, San Francisco, CA 94110 USA. [Ku, Ivy A.; Farzaneh-Far, Ramin; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Na, Beeya; Whooley, Mary A.] VA Med Ctr, San Francisco, CA 94121 USA. [Vittinghoff, Eric; Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Zhang, Mary H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Ku, IA (reprint author), San Francisco Gen Hosp, Div Cardiol, 1001 Potrero Ave,Room 5G1, San Francisco, CA 94110 USA. EM ivy.ku@ucsf.edu FU NIH National Research Service [HL097461]; Department of Veterans Affairs; National Heart Lung and Blood Institute [R01 HL079235]; American Federation for Aging Research; Robert Wood Johnson Foundation; Ischemia Research and Education Foundation FX Dr. Ivy Ku was supported by the NIH National Research Service Award # HL097461. The Heart and Soul Study was supported by the Department of Veterans Affairs; the National Heart Lung and Blood Institute (R01 HL079235); the American Federation for Aging Research (Paul Beeson Scholars Program); the Robert Wood Johnson Foundation (Generalist Physician Faculty Scholars Program); and the Ischemia Research and Education Foundation. None of these funding sources had any role in the collection of data, interpretation of results, or preparation of this manuscript. Dr. Ku had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 27 TC 32 Z9 38 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2011 VL 217 IS 2 BP 503 EP 508 DI 10.1016/j.atherosclerosis.2010.10.047 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 798MT UT WOS:000293212400032 PM 21176905 ER PT J AU Kulke, MH Chan, JA Meyerhardt, JA Zhu, AX Abrams, TA Blaszkowsky, LS Regan, E Sidor, C Fuchs, CS AF Kulke, Matthew H. Chan, Jennifer A. Meyerhardt, Jeffrey A. Zhu, Andrew X. Abrams, Thomas A. Blaszkowsky, Lawrence S. Regan, Eileen Sidor, Carolyn Fuchs, Charles S. TI A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Carcinoid; Neuroendocrine Tumors; Bevacizumab; Sorafenib ID ENDOTHELIAL GROWTH-FACTOR; ADVANCED NEUROENDOCRINE TUMORS; RENAL-CELL CARCINOMA; ORAL 2-METHOXYESTRADIOL; LOW-GRADE; TRIAL; THERAPY; ANGIOGENESIS; TEMOZOLOMIDE; MULTICENTER AB Angiogenesis inhibition has emerged as a potentially promising treatment strategy for neuroendocrine tumors. 2-Methoxyestradiol (2ME2; Panzem(A (R))) is a natural derivative of estradiol with demonstrated anti-angiogenic activity in animal models. We performed a prospective, phase II study of 2ME2, administered in combination with bevacizumab, in patients with advanced carcinoid tumors. Thirty-one patients with advanced carcinoid tumors were treated with 2ME2, administered orally at a dose of 1,000 mg four times daily. Patients also received bevacizumab 5 mg/kg intravenously every 2 weeks. Patients were observed for evidence of toxicity, tumor response, and survival. The combination of 2ME2 and bevacizumab was relatively easily tolerated and was associated with anticipated toxicities for these two agents. No confirmed radiologic responses (by RECIST) were observed. However, 68% of the radiologically evaluable patients experienced at least some degree of tumor reduction, and the median progression-free survival (PFS) time was 11.3 months. 2ME2 and bevacizumab can be safely administered to patients with advanced carcinoid tumors. While major tumor regression was not observed with this regimen, the encouraging median progression-free survival time suggests that this regimen has some degree of antitumor activity and supports the further investigation of angiogenesis inhibitors in this disease. C1 [Kulke, Matthew H.; Chan, Jennifer A.; Meyerhardt, Jeffrey A.; Abrams, Thomas A.; Regan, Eileen; Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhu, Andrew X.; Blaszkowsky, Lawrence S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sidor, Carolyn] EntreMed Inc, Rockville, MD USA. RP Kulke, MH (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM matthew_kulke@dfci.harvard.edu FU Entremed, Inc; NCI [CA093401, P50 CA127003]; Saul and Gitta Kurlat fund for neuroendocrine tumor research FX Support for this study was provided by Entremed, Inc, NCI grants CA093401 (MHK) and P50 CA127003 (DF/HCC SPORE in Gastrointestinal Cancer). The authors gratefully acknowledge support from the Saul and Gitta Kurlat fund for neuroendocrine tumor research. NR 28 TC 41 Z9 42 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD AUG PY 2011 VL 68 IS 2 BP 293 EP 300 DI 10.1007/s00280-010-1478-7 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 797NC UT WOS:000293133600004 PM 20960192 ER PT J AU Norde, WJ Maas, F Hobo, W Korman, A Quigley, M Kester, MGD Hebeda, K Falkenburg, JHF Schaap, N de Witte, TM van der Voort, R Dolstra, H AF Norde, Wieger J. Maas, Frans Hobo, Willemijn Korman, Alan Quigley, Michael Kester, Michel G. D. Hebeda, Konnie Falkenburg, J. H. Frederik Schaap, Nicolaas de Witte, Theo M. van der Voort, Robbert Dolstra, Harry TI PD-1/PD-L1 Interactions Contribute to Functional T-Cell Impairment in Patients Who Relapse with Cancer After Allogeneic Stem Cell Transplantation SO CANCER RESEARCH LA English DT Article ID CHRONIC VIRAL-INFECTION; PROGRAMMED DEATH-1; MYELOID-LEUKEMIA; TUMOR; EXHAUSTION; EXPRESSION; PATHWAY; PD-1; IMMUNOTHERAPY; VACCINATION AB Tumor relapses remain a serious problem after allogeneic stem cell transplantation (alloSCT), despite the long-term persistence of minor histocompatibility antigen (MiHA)-specific memory CD8(+) T cells specific for the tumor. We hypothesized that these memory T cells may lose their function over time in transplanted patients. Here, we offer functional and mechanistic support for this hypothesis, based on immune inhibition by programmed death-1 (PD-1) expressed on MiHA-specific CD8(+) T cells and the associated role of the PD-1 ligand PD-L1 on myeloid leukemia cells, especially under inflammatory conditions. PD-L1 was highly upregulated on immature human leukemic progenitor cells, whereas costimulatory molecules such as CD80 and CD86 were not expressed. Thus, immature leukemic progenitor cells seemed to evade the immune system by inhibiting T-cell function via the PD-1/PD-L1 pathway. Blocking PD-1 signaling using human antibodies led to elevated proliferation and IFN-gamma production of MiHA-specific T cells cocultured with PD-L1-expressing leukemia cells. Moreover, patients with relapsed leukemia after initial MiHA-specific T-cell responses displayed high PD-L1 expression on CD34(+) leukemia cells and increased PD-1 levels on MiHA-specific CD8(+) T cells. Importantly, blocking PD-1/PD-L1 interactions augment proliferation of MiHA-specific CD8(+) memory T cells from relapsed patients. Taken together, our findings indicate that the PD-1/PD-L pathway can be hijacked as an immune escape mechanism in hematological malignancies. Furthermore, they suggest that blocking the PD-1 immune checkpoint offers an appealing immunotherapeutic strategy following alloSCT in patients with recurrent or relapsed disease. Cancer Res; 71(15); 5111-22. (c) 2011 AACR. C1 [Norde, Wieger J.; Maas, Frans; Hobo, Willemijn; van der Voort, Robbert; Dolstra, Harry] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Hematol Lab, NL-6500 HB Nijmegen, Netherlands. [Schaap, Nicolaas] Radboud Univ Nijmegen, Med Ctr, Dept Hematol, NL-6500 HB Nijmegen, Netherlands. [de Witte, Theo M.] Radboud Univ Nijmegen, Med Ctr, Dept Tumor Immunol, NL-6500 HB Nijmegen, Netherlands. [Hebeda, Konnie] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6500 HB Nijmegen, Netherlands. [Kester, Michel G. D.; Falkenburg, J. H. Frederik] Leiden Univ, Med Ctr, Dept Hematol, Leiden, Netherlands. [Korman, Alan] Bristol Myers Squibb Co, Dept Biol Discovery Calif, Milpitas, CA USA. [Quigley, Michael] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Dolstra, H (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Hematol Lab, Geert Grootepl 8,POB 9101, NL-6500 HB Nijmegen, Netherlands. EM h.dolstra@labgk.umcn.nl RI Dolstra, H./L-4276-2015; Witte, T.J.M./L-4762-2015; Hebeda, K.M./L-4354-2015; Schaap, N.P.M./L-4625-2015; Hobo, Willemijn/O-1667-2015 OI Hobo, Willemijn/0000-0002-8206-8185 FU RUNMC [2007-34]; Dutch Cancer Society [KWF 2008-4018] FX This work was supported by grants from the RUNMC (2007-34) and Dutch Cancer Society (KWF 2008-4018). Human antibodies to human PD-1 and PD-L1 and a matching IgG4 isotype control were kindly provided by Dr. A. Korman (Biologics Discovery California, Bristol-Myers Squibb). NR 26 TC 41 Z9 41 U1 0 U2 7 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 AUG 1 PY 2011 VL 71 IS 15 BP 5111 EP 5122 DI 10.1158/0008-5472.CAN-11-0108 PG 12 WC Oncology SC Oncology GA 799ET UT WOS:000293267600008 PM 21659460 ER PT J AU Wilson, BJ Schatton, T Zhan, Q Gasser, M Ma, J Saab, KR Schanche, R Waaga-Gasser, AM Gold, JS Huang, Q Murphy, GF Frank, MH Frank, NY AF Wilson, Brian J. Schatton, Tobias Zhan, Qian Gasser, Martin Ma, Jie Saab, Karim R. Schanche, Robin Waaga-Gasser, Ana-Maria Gold, Jason S. Huang, Qin Murphy, George F. Frank, Markus H. Frank, Natasha Y. TI ABCB5 Identifies a Therapy-Refractory Tumor Cell Population in Colorectal Cancer Patients SO CANCER RESEARCH LA English DT Article ID STEM-CELLS; MALIGNANT-MELANOMA; INITIATING CELLS; CD133 EXPRESSION; P-GLYCOPROTEIN; CHEMORESISTANCE; GROWTH; PROLIFERATION; RESISTANCE; PHENOTYPE AB Identification and reversal of treatment resistance mechanisms of clinically refractory tumor cells is critical for successful cancer therapy. Here we show that ATP-binding cassette member B5 (ABCB5) identifies therapy-refractory tumor cells in colorectal cancer patients following fluorouracil (5-FU)-based chemoradiation therapy and provide evidence for a functional role of ABCB5 in colorectal cancer 5-FU resistance. Examination of human colon and colorectal cancer specimens revealed ABCB5 to be expressed only on rare cells within healthy intestinal tissue, whereas clinical colorectal cancers exhibited substantially increased levels of ABCB5 expression. Analysis of successive, patient-matched biopsy specimens obtained prior to and following neoadjuvant 5-FU-based chemoradiation therapy in a series of colorectal cancer patients revealed markedly enhanced abundance of ABCB5-positive tumor cells when residual disease was detected. Consistent with this finding, the ABCB5-expressing tumor cell population was also treatment refractory and exhibited resistance to 5-FU-induced apoptosis in a colorectal cancer xenograft model of 5-FU monotherapy. Mechanistically, short hairpin RNA-mediated ABCB5 knockdown significantly inhibited tumorigenic xenograft growth and sensitized colorectal cancer cells to 5-FU-induced cell killing. Our results identify ABCB5 as a novel molecular marker of therapy-refractory tumor cells in colorectal cancer patients and point to a need for consistent eradication of ABCB5-positive resistant tumor cell populations for more effective colorectal cancer therapy. Cancer Res; 71(15); 5307-16. (C) 2011 AACR. C1 [Wilson, Brian J.; Schatton, Tobias; Ma, Jie; Saab, Karim R.; Frank, Markus H.; Frank, Natasha Y.] Harvard Univ, Sch Med, Childrens Hosp Boston, Transplantat Res Ctr, Boston, MA 02115 USA. [Wilson, Brian J.; Schatton, Tobias; Ma, Jie; Saab, Karim R.; Frank, Markus H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Zhan, Qian; Schanche, Robin; Murphy, George F.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Gold, Jason S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Frank, Natasha Y.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Gold, Jason S.] VA Boston Healthcare Syst, Surg Serv, Boston, MA 02132 USA. [Huang, Qin] VA Boston Healthcare Syst, Dept Pathol, Boston, MA 02132 USA. [Frank, Natasha Y.] VA Boston Healthcare Syst, Dept Med, Boston, MA 02132 USA. [Gasser, Martin; Waaga-Gasser, Ana-Maria] Univ Wurzburg, Dept Surg, Wurzburg, Germany. RP Frank, MH (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Transplantat Res Ctr, 300 Longwood Ave, Boston, MA 02115 USA. EM markus.frank@childrens.harvard.edu; nfrank@partners.org RI Gold, Jason/O-5112-2014; Frank, Markus/O-1625-2014 OI Gold, Jason/0000-0002-2925-4755; Frank, Markus/0000-0002-1312-0488 FU NIH/NCI [1RO1CA113796, 1R01CA138231]; U.S. Department of Veterans Affairs [10688354] FX This work was supported by funds provided by the NIH/NCI (grants 1RO1CA113796 and 1R01CA138231 to M.H. Frank) and the U.S. Department of Veterans Affairs (BLR&D VA CDA-2 Award to J.S. Gold and BLR&D VA Merit Award 10688354 to N.Y. Frank). NR 40 TC 47 Z9 50 U1 1 U2 9 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 AUG 1 PY 2011 VL 71 IS 15 BP 5307 EP 5316 DI 10.1158/0008-5472.CAN-11-0221 PG 10 WC Oncology SC Oncology GA 799ET UT WOS:000293267600027 PM 21652540 ER PT J AU Agarwal, S Daley, GQ AF Agarwal, Suneet Daley, George Q. TI Telomere dynamics in dyskeratosis congenita: the long and the short of iPS SO CELL RESEARCH LA English DT Editorial Material ID PLURIPOTENT STEM-CELLS; HUMAN FIBROBLASTS; COPY NUMBER C1 [Agarwal, Suneet; Daley, George Q.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Agarwal, Suneet; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Agarwal, Suneet; Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Agarwal, Suneet; Daley, George Q.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Agarwal, Suneet; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Agarwal, Suneet; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Agarwal, Suneet; Daley, George Q.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Div Hematol Oncol, 1 Blackfan Circle, Boston, MA 02115 USA. EM George.Daley@childrens.harvard.edu FU NHLBI NIH HHS [K08 HL089150] NR 15 TC 12 Z9 12 U1 0 U2 7 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD AUG PY 2011 VL 21 IS 8 BP 1157 EP 1160 DI 10.1038/cr.2011.120 PG 4 WC Cell Biology SC Cell Biology GA 800DX UT WOS:000293341100002 PM 21788988 ER PT J AU Flaherty, KT Fisher, DE AF Flaherty, Keith T. Fisher, David E. TI New Strategies in Metastatic Melanoma: Oncogene-Defined Taxonomy Leads to Therapeutic Advances SO CLINICAL CANCER RESEARCH LA English DT Article ID MALIGNANT-MELANOMA; CELL-LINES; BRAF; INHIBITION; MUTATIONS; MITF; RAF; RESISTANCE; SURVIVAL; CANCER AB The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease. Clin Cancer Res; 17(15); 4922-8. (C)2011 AACR. C1 [Flaherty, Keith T.; Fisher, David E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Fisher, DE (reprint author), Massachusetts Gen Hosp, Room 3232,Bldg 149,13th St, Charlestown, MA 02129 USA. EM dfisher3@partners.org NR 52 TC 22 Z9 25 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2011 VL 17 IS 15 BP 4922 EP 4928 DI 10.1158/1078-0432.CCR-10-2612 PG 7 WC Oncology SC Oncology GA 800CH UT WOS:000293335800002 PM 21670085 ER PT J AU DuBois, SG Shusterman, S Ingle, AM Ahern, CH Reid, JM Wu, B Baruchel, S Glade-Bender, J Ivy, P Grier, HE Adamson, PC Blaney, SM AF DuBois, Steven G. Shusterman, Suzanne Ingle, Ashish M. Ahern, Charlotte H. Reid, Joel M. Wu, Bing Baruchel, Sylvain Glade-Bender, Julia Ivy, Percy Grier, Holcombe E. Adamson, Peter C. Blaney, Susan M. TI Phase I and Pharmacokinetic Study of Sunitinib in Pediatric Patients with Refractory Solid Tumors: A Children's Oncology Group Study SO CLINICAL CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITOR; RENAL-CELL CARCINOMA; GASTROINTESTINAL STROMAL TUMORS; CIRCULATING ENDOTHELIAL-CELLS; GROWTH-FACTOR RECEPTOR; ANTITUMOR-ACTIVITY; INTERFERON-ALPHA; MALATE SU11248; VIVO ANTITUMOR; CANCER AB Purpose: Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary antitumor activity of sunitinib in a pediatric population. Experimental Design: Patients who were 2 to 21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m(2)/d were evaluated, with dose escalation based on a 3 + 3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle. Results: Twenty-three patients were treated (median age 13.9 years; range, 3.9-20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with previous exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose (MTD) was 15 mg/m(2)/d. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 to 9 cycles. Conclusions: Cardiac toxicity precluded determination of a recommended dose for pediatric patients with previous anthracycline or cardiac radiation exposure. The MTD of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m(2)/d for 28 days followed by a 14-day break. Clin Cancer Res; 17(15); 5113-22. (C)2011 AACR. C1 [DuBois, Steven G.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Shusterman, Suzanne; Grier, Holcombe E.] Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat, Boston, MA USA. [Shusterman, Suzanne; Grier, Holcombe E.] Harvard Univ, Sch Med, Boston, MA USA. [Ingle, Ashish M.] Childrens Oncol Grp Operat Ctr, Arcadia, CA USA. [Ahern, Charlotte H.] Dan L Duncan Canc Ctr, Div Biostat, Houston, TX USA. [Ahern, Charlotte H.; Blaney, Susan M.] Baylor Coll Med, Houston, TX 77030 USA. [Blaney, Susan M.] Texas Childrens Canc Ctr, Dept Pediat, Houston, TX USA. [Reid, Joel M.] Mayo Coll Med, Dept Pharmacol, Rochester, MN USA. [Wu, Bing; Baruchel, Sylvain] Hosp Sick Children, Dept Hematol Oncol, Toronto, ON M5G 1X8, Canada. [Glade-Bender, Julia] Morgan Stanley Childrens Hosp, Dept Pediat, New York, NY USA. [Glade-Bender, Julia] Columbia Univ, Sch Med, New York, NY USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Dept Oncol, Philadelphia, PA 19104 USA. [Adamson, Peter C.] Univ Penn, Philadelphia, PA 19104 USA. RP DuBois, SG (reprint author), Univ Calif San Francisco, Sch Med, Dept Pediat, 505 Parnassus Ave,M646, San Francisco, CA 94143 USA. EM duboiss@peds.ucsf.edu FU Campini Foundation; Pfizer; NIH/NCRR/OD [KL2 RR024130]; NCI [U01 CA97452] FX This work was supported by the Campini Foundation, Pfizer, NIH/NCRR/OD UCSF-CTSI grant number KL2 RR024130, and NCI U01 CA97452. NR 45 TC 43 Z9 46 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2011 VL 17 IS 15 BP 5113 EP 5122 DI 10.1158/1078-0432.CCR-11-0237 PG 10 WC Oncology SC Oncology GA 800CH UT WOS:000293335800023 PM 21690570 ER PT J AU Lara, JF Thor, AD Dressler, LG Broadwater, G Bleiweiss, IJ Edgerton, S Cowan, D Goldstein, LJ Martino, S Ingle, JN Henderson, IC Norton, L Winer, EP Hudis, CA Ellis, MJ Berry, DA Hayes, DF AF Lara, Jonathan F. Thor, Ann D. Dressler, Lynn G. Broadwater, Gloria Bleiweiss, Ira J. Edgerton, Susan Cowan, David Goldstein, Lori J. Martino, Silvana Ingle, James N. Henderson, I. Craig Norton, Larry Winer, Eric P. Hudis, Clifford A. Ellis, Matthew J. Berry, Donald A. Hayes, Daniel F. CA Canc Leukemia Grp B TI p53 Expression in Node-Positive Breast Cancer Patients: Results from the Cancer and Leukemia Group B 9344 Trial (159905) SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; PROGNOSTIC-SIGNIFICANCE; ADJUVANT CHEMOTHERAPY; PREDICTIVE-VALUE; TP53 MUTATION; BCL-2; RESISTANCE; CARCINOMA; SURVIVAL; THERAPY AB Purpose: p53 as a prognostic and predictive factor in early-stage breast cancer has had mixed results. We studied p53 protein expression, by immunohistochemistry, in a randomized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel [Cancer and Leukemia Group B (CALGB) 9344, INT0148]. Patients and Methods: Epithelial p53 expression was evaluated using two immunohistochemical antibodies (DO7 and 1801) in formalin-fixed, paraffin-embedded tissue from patients with node-positive breast cancer who were randomized to four cycles of cyclophosphamide and one of three doses of doxorubicin (60, 75, or 90 mg/m(2); AC) and to receive four subsequent cycles of paclitaxel (T) or not. Prognostic and predictive value of p53 protein expression was assessed, independent of treatment assignment, for escalating doses of doxorubicin or addition of T with endpoints of relapse-free (RFS) and overall survival (OS). Results: Of 3,121 patients, 1,887 patient specimens treated on C9344 were obtained, passed quality control, and evaluated for p53 expression. Expression was 23% and 27% for mAbs 1801 and D07, respectively, with 92% concordance. In univariate analysis, p53 positivity was associated with worse OS with either antibody, but only p53 staining with monoclonal antibody 1801 had significantly worse RFS. In multivariate analysis, p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody. Conclusion: Nuclear staining of p53 by immunohistochemistry is associated with worse prognosis in node-positive patients treated with adjuvant doxorubicin-based chemotherapy but is not a useful predictor of benefit from doxorubicin dose escalation or the addition of paclitaxel. Clin Cancer Res; 17(15); 5170-8. (C) 2011 AACR. C1 [Lara, Jonathan F.] St Barnabas Hosp, Dept Pathol, Livingston, NJ 07039 USA. [Thor, Ann D.; Edgerton, Susan] Univ Colorado, Dept Pathol, Denver, CO 80202 USA. [Dressler, Lynn G.] Univ N Carolina, Eshelman Sch Pharm, Inst Pharmacogen & Individualized Therapy, Chapel Hill, NC USA. [Cowan, David] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Broadwater, Gloria] Duke Univ, Med Ctr, Cancer & Leukemia Grp B, Ctr Stat, Durham, NC USA. [Bleiweiss, Ira J.] Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA. [Norton, Larry; Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Goldstein, Lori J.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Martino, Silvana] Angeles Clin & Res Inst, Dept Med Oncol, Santa Monica, CA USA. [Ingle, James N.] Mayo Clin, Dept Med Oncol, Rochester, MN USA. [Henderson, I. Craig] Univ Calif San Francisco, Dept Med Oncol, San Francisco, CA 94143 USA. [Winer, Eric P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ellis, Matthew J.] Washington Univ, Dept Med Oncol, Sch Med, St Louis, MO USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Ctr Stat, Dept Biostat, Houston, TX 77030 USA. [Hayes, Daniel F.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Lara, JF (reprint author), St Barnabas Hosp, Dept Pathol, 94 Old Short Hills Rd, Livingston, NJ 07039 USA. EM jlara@sbhcs.com OI Norton, Larry/0000-0003-3701-9250 FU National Cancer Institute [CA31946]; CALGB Statistical Center [CA33601]; NIH [CA33601, CA092461, CA25224]; Breast Cancer Research Foundation; Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale; Dana-Farber Cancer Institute, Boston, MA [CA32291]; Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH [CA04326]; Duke University Medical Center, Durham, NC [CA47577]; Long Island Jewish Medical Center, Lake Success, NY [CA35279]; Massachusetts General Hospital, Boston, MA [CA32291]; Medical University of South Carolina, Charleston, SC [CA03927]; Memorial Sloan-Kettering Cancer Center, New York, NY; Mount Sinai School of Medicine, New York, NY [CA04457]; North Shore-Long Island Jewish Health System, New Hyde Park, NY [CA35279]; Rhode Island Hospital, Providence [CA08025]; Roswell Park Cancer Institute, Buffalo, NY [CA59518]; State University of New York Upstate Medical University, Syracuse, NY [CA21060]; University of Alabama, Birmingham, Birmingham, AL [CA47545]; University of California at San Diego, San Diego, CA [CA11789]; University of California at San Francisco, San Francisco, CA [CA60138]; University of Chicago, Chicago, IL [CA41287]; University of Illinois MBCCOP, Chicago, IL [CA74811]; University of Iowa, Iowa City, IA [CA47642]; University of Maryland Greenebaum Cancer Center, Baltimore, MD [CA31983]; University of Massachusetts Medical School, Worcester, MA [CA37135]; University of Minnesota, Minneapolis, MN [CA16450]; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO [CA12046]; University of North Carolina at Chapel Hill, Chapel Hill, NC [CA47559]; University of Nebraska Medical Center, Omaha, NE [CA77298]; University of Tennessee Memphis, Memphis, TN [CA47555]; University of Vermont, Burlington, VT [CA77406]; Wake Forest University School of Medicine, Winston-Salem, NC [CA03927]; Walter Reed Army Medical Center, Washington, DC [CA26806]; Washington University School of Medicine, St. Louis, MO [CA77440]; Weill Medical College of Cornell University, New York, NY [CA07968]; [CA77651] FX The research for CALGB 9344 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Monica M. Bertagnolli, MD, Chair) and to the CALGB Statistical Center (Daniel J. Sargent, PhD, CA33601). The work was supported by NIH grants CA092461 (D. F. Hayes), CA33601 (D. A. Berry), and CA25224 (J.N. Ingle) from the Breast Cancer Research Foundation and the Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale (D. F. Hayes).; The following institutions participated in this study: Harold J. Burstein (MD PhD) from Dana-Farber Cancer Institute, Boston, MA, supported by CA32291; Konstantin Dragnev (MD) from Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH, supported by CA04326; Jeffrey Crawford (MD) from Duke University Medical Center, Durham, NC, supported by CA47577; Kanti R. Rai (MD) from Long Island Jewish Medical Center, Lake Success, NY, supported by CA35279; Jeffrey W. Clark, (MD) from Massachusetts General Hospital, Boston, MA, supported by CA32291; Mark Green (MD) from Medical University of South Carolina, Charleston, SC, supported by CA03927; Clifford A. Hudis (MD) from Memorial Sloan-Kettering Cancer Center, New York, NY, supported by CA77651; Lewis R. Silverman (MD) from Mount Sinai School of Medicine, New York, NY, supported by CA04457; Daniel Budman (MD) from North Shore-Long Island Jewish Health System, New Hyde Park, NY, supported by CA35279; RI William Sikov (MD) Rhode Island Hospital, Providence, supported by CA08025; Ellis Levine (MD) from Roswell Park Cancer Institute, Buffalo, NY, supported by CA59518; Stephen L. Graziano (MD) from State University of New York Upstate Medical University, Syracuse, NY, supported by CA21060; Robert Diasio (MD) from University of Alabama, Birmingham, Birmingham, AL, supported by CA47545; Barbara A. Parker (MD) from University of California at San Diego, San Diego, CA, supported by CA11789; Charles J. Ryan (MD) from University of California at San Francisco, San Francisco, CA, supported by CA60138; Hedy L. Kindler (MD) from University of Chicago, Chicago, IL, supported by CA41287; David J. Peace (MD) from University of Illinois MBCCOP, Chicago, IL, supported by CA74811; Daniel A. Vaena (MD) from University of Iowa, Iowa City, IA, supported by CA47642; Martin Edelman (MD) from University of Maryland Greenebaum Cancer Center, Baltimore, MD, supported by CA31983; William V. Walsh (MD) from University of Massachusetts Medical School, Worcester, MA, supported by CA37135; Bruce A. Peterson (MD) from University of Minnesota, Minneapolis, MN, supported by CA16450; Michael C. Perry (MD) from University of Missouri/Ellis Fischel Cancer Center, Columbia, MO, supported by CA12046; Thomas C. Shea (MD) from University of North Carolina at Chapel Hill, Chapel Hill, NC, supported by CA47559; Anne Kessinger (MD) from University of Nebraska Medical Center, Omaha, NE, supported by CA77298; Harvey B. Niell (MD) from University of Tennessee Memphis, Memphis, TN, supported by CA47555; Steven M. Grunberg (MD) from University of Vermont, Burlington, VT, supported by CA77406; David D. Hurd (MD) from Wake Forest University School of Medicine, Winston-Salem, NC, supported by CA03927; Brendan M. Weiss (MD) from Walter Reed Army Medical Center, Washington, DC, supported by CA26806; Nancy Bartlett (MD) from Washington University School of Medicine, St. Louis, MO, supported by CA77440; and John Leonard (MD) from Weill Medical College of Cornell University, New York, NY, supported by CA07968. NR 35 TC 16 Z9 16 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2011 VL 17 IS 15 BP 5170 EP 5178 DI 10.1158/1078-0432.CCR-11-0484 PG 9 WC Oncology SC Oncology GA 800CH UT WOS:000293335800029 PM 21693655 ER PT J AU Karakas, M Januzzi, JL Meyer, J Lee, H Schlett, CL Truong, QA Rottbauer, W Bamberg, F Dasdemir, S Hoffmann, U Koenig, W AF Karakas, Mahir Januzzi, James L., Jr. Meyer, Julia Lee, Hang Schlett, Christopher L. Truong, Quynh A. Rottbauer, Wolfgang Bamberg, Fabian Dasdemir, Selcuk Hoffmann, Udo Koenig, Wolfgang TI Copeptin Does Not Add Diagnostic Information to High-Sensitivity Troponin T in Low- to Intermediate-Risk Patients with Acute Chest Pain: Results from the Rule Out Myocardial Infarction by Computed Tomography (ROMICAT) Study SO CLINICAL CHEMISTRY LA English DT Article ID TERMINAL PROVASOPRESSIN COPEPTIN; EMERGENCY-DEPARTMENT; STABLE PEPTIDE; HEART-FAILURE; PRACTICAL IMPLEMENTATION; VASOPRESSIN PRECURSOR; PROGNOSTIC MARKER; GUIDELINES; SURVIVORS; ISCHEMIA AB PURPOSE: Copeptin, a stable peptide derived from the AVP precursor, has been linked to presence and severity of myocardial ischemia. We sought to evaluate the predictive value of copeptin and its incremental value beyond that of high-sensitivity cardiac troponin T (hs-cTnT) in patients with acute chest pain and low to intermediate risk for acute coronary syndrome (ACS). METHODS: We recruited patients who presented with acute chest pain to the emergency department and had a negative initial conventional troponin T test (<0.03 mu g/L). In all patients, hs-cTnT and copeptin measurements were taken. Each patient also underwent cardiac computed tomography (CT) and coronary angiography. RESULTS: Baseline copeptin concentrations, in contrast to hs-cTnT, were not significantly higher in patients with ACS than in those without (P = 0.24). hs-cTnT showed an earlier rise in patients with ACS than copeptin, when analyses were stratified by time. A copeptin concentration >= 7.38 pmol/L had a negative predictive value (NPV) of 94% and a sensitivity of 51%, whereas hs-cTnT (>= 13.0 pg/mL) had a NPV of 96% and a sensitivity of 63%. The combination of copeptin and hs-cTnT resulted in a lower diagnostic accuracy than hs-cTnT alone. Finally, on cardiac CT, copeptin concentrations were not associated with coronary artery morphology, although they were related to the presence of left ventricular dysfunction (P = 0.02). CONCLUSIONS: Among patients with acute chest pain and low to intermediate risk for ACS, copeptin concentrations are not independently predictive of ACS and do not add diagnostic value beyond that of hs-cTnT measurements. (C) 2011 American Association for Clinical Chemistry C1 [Karakas, Mahir; Rottbauer, Wolfgang; Dasdemir, Selcuk; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89081 Ulm, Germany. [Januzzi, James L., Jr.; Truong, Quynh A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Schlett, Christopher L.; Truong, Quynh A.; Bamberg, Fabian; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Meyer, Julia] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. RP Koenig, W (reprint author), Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Albert Einstein Allee 23, D-89081 Ulm, Germany. EM wolfgang.koenig@uniklinik-ulm.de FU Roche Diagnostics; NIH [RO1 HL080053]; University of Ulm FX J. Januzzi, Siemens, Critical Diagnostics, Balson Scholar Award, significant (>$ 10 000) research grant support from Roche Diagnostics; C. L. Schlett, German National Merit Foundation. This study was supported by research grants from the NIH (RO1 HL080053) and by additional funds provided by the University of Ulm. We are grateful to Brahms AG for providing copeptin measurements free of charge, and Roche for providing reagents for hs-cTnT testing. NR 25 TC 41 Z9 41 U1 0 U2 6 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 2011 VL 57 IS 8 BP 1137 EP 1145 DI 10.1373/clinchem.2010.160192 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 798PN UT WOS:000293222900010 PM 21673277 ER PT J AU Field, JJ Nathan, DG Linden, J AF Field, Joshua J. Nathan, David G. Linden, Joel TI Targeting iNKT cells for the treatment of sickle cell disease SO CLINICAL IMMUNOLOGY LA English DT Review DE iNKT cells; Sickle cell disease; Regadenoson ID ADENOSINE A(2A) RECEPTOR; ISCHEMIA-REPERFUSION INJURY; MARROW-DERIVED CELLS; ACUTE CHEST SYNDROME; SPINAL-CORD TRAUMA; NKT CELLS; ISCHEMIA/REPERFUSION INJURY; LUNG INJURY; AIRWAY HYPERREACTIVITY; LEUKOCYTE ACTIVATION AB Sickle cell disease (SCD) causes widely disseminated vaso-occlusive episodes. Building on evidence implicating invariant NKT (iNKT) cells in the pathogenesis of ischemia/reperfusion injury, recent studies demonstrate that blockade of iNKT cell activation in mice with SCD reduces pulmonary inflammation and injury. In patients with SCD, iNKT cells in blood are increased in absolute number and activated in comparison to healthy controls. iNKT cell activation is reduced by agonists of adenosine 2A receptors (A(2A)Rs) such as the clinically approved coronary vasodilator, regadenoson. An ongoing multi-center, dose-finding and safety trial of infused regadenoson, has been initiated and is providing preliminary data about its safety and efficacy to treat SCD. Very high accumulation of adenosine may have deleterious effects in SCD through activation of adenosine 2B receptors that are insensitive to regadenoson. Future possible therapeutic approaches for treating SCD include selective A(2B)R antagonists and antibodies that deplete iNKT cells. (C) 2011 Elsevier Inc. All rights reserved. C1 [Linden, Joel] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Field, Joshua J.] BloodCtr Wisconsin, Blood Res Inst, Milwaukee, WI USA. [Nathan, David G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Childrens Hosp, Boston, MA 02115 USA. RP Linden, J (reprint author), La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. EM jlinden@liai.org FU National Heart, Lung, and Blood Institute [R01HL095704, RC2HL101367] FX This work is supported in part by the National Heart, Lung, and Blood Institute award R01HL095704 (JL) and RC2HL101367 (JL and DN). NR 58 TC 25 Z9 25 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 2011 VL 140 IS 2 SI SI BP 177 EP 183 DI 10.1016/j.clim.2011.03.002 PG 7 WC Immunology SC Immunology GA 799SR UT WOS:000293306900008 PM 21429807 ER PT J AU Singal, AK Jampana, SC Anand, BS AF Singal, Ashwani K. Jampana, Sarat C. Anand, Bhupinderjit S. TI Peginterferon Alfa-2a Is Superior to Peginterferon Alfa-2b in the Treatment of Naive Patients with Hepatitis C Virus Infection: Meta-Analysis of Randomized Controlled Trials SO DIGESTIVE DISEASES AND SCIENCES LA English DT Review DE Hepatitis C virus; HCV; Pegylated interferon alfa-2a; Pegylated interferon alfa-2b; Antiviral therapy; Meta-analysis ID SUSTAINED VIROLOGICAL RESPONSE; RIBAVIRIN COMBINATION THERAPY; PEGYLATED INTERFERON ALPHA-2A; PLUS RIBAVIRIN; UNITED-STATES; MORTALITY AB Background Pegylated interferon (PEGIFN) and ribavirin combination is the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. Studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-na < ve HCV-infected patients have shown conflicting results. Aim We performed a systematic review and meta-analysis of studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in HCV-infected patients na < ve to treatment. Methods Nine studies (five abstracts) with 3,546 patients (1,771 treated with PEGIFN alfa-2a) comparing PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-na < ve HCV patients were analyzed. Efficacy outcomes were sustained virologic response (SVR) and treatment discontinuation rates due to serious adverse effects (SAE). Results Pooled data on outcomes (reported as odds ratios [ORs] with 95% confidence intervals [CIs]: [OR (95% CI)]) showed higher SVR in patients treated with PEGIFN alfa-2a as compared to treatment with PEGIFN alfa-2b [1.36 (1.07-1.73); P = 0.01]. Subgroup analysis of good quality studies on SVR in genotypes 2 and 3 also favored PEGIFN alfa-2a over PEGIFN alfa-2b (1.91 [1.09-3.37]; P = 0.02). SVR results obtained with the two types of IFN showed no impact of viral load and the presence or absence of cirrhosis. Treatment discontinuation rates due to SAE, reported in six studies (two abstracts) on 3,211 patients (1,604 treated with PEGIFN alfa-2a), were similar in the two types of PEGIFN [0.66 (0.37-1.16); P = 0.15]. Conclusions PEGIFN alfa-2a has superior efficacy with higher SVR as compared to PEGIFN alfa-2b in treatment-na < ve HCV-infected patients. The safety profile of the two types of PEGIFN was similar. C1 [Singal, Ashwani K.] Univ Texas Med Branch, Div Gastroenterol, Galveston, TX 77555 USA. [Singal, Ashwani K.; Jampana, Sarat C.] Univ Texas Med Branch, Dept Internal Med, Galveston, TX 77555 USA. [Anand, Bhupinderjit S.] Baylor Coll Med, Dept Gastroenterol & Hepatol, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Singal, AK (reprint author), Univ Texas Med Branch, Div Gastroenterol, Galveston, TX 77555 USA. EM aksingal@utmb.edu NR 25 TC 18 Z9 19 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2011 VL 56 IS 8 BP 2221 EP 2226 DI 10.1007/s10620-011-1765-0 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 799ON UT WOS:000293296100004 PM 21643737 ER PT J AU Merino, J Aller, MA Rubio, S Arias, N Nava, MP Loscertales, M Arias, J Arias, JL AF Merino, Joaquin Aller, Maria-Angeles Rubio, Sandra Arias, Natalia Nava, Maria-Paz Loscertales, Maria Arias, Jaime Arias, Jorge-Luis TI Gut-Brain Chemokine Changes in Portal Hypertensive Rats SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Chemokines; Hepatic encephalopathy; Neuroinflammation; CXCR4/SDF1-alpha; CXCR1/Fractalkine; Rat ID MINIMAL HEPATIC-ENCEPHALOPATHY; MAST-CELLS; MEMORY IMPAIRMENT; DENTATE GYRUS; HIPPOCAMPAL; INFLAMMATION; EXPRESSION; RECEPTORS; CIRRHOSIS; PATHOGENESIS AB Background Hepatic encephalopathy is a syndrome whose physiopathology is poorly understood; therefore, current diagnostic tests are imperfect and modern therapy is nonspecific. Particularly, it has been suggested that inflammation plays an important role in the pathogenesis of portal hypertensive encephalopathy in the rat. Aim We have studied an experimental model of portal hypertension based on a triple partial portal vein ligation in the rat to verify this hypothesis. Methods One month after portal hypertension we assayed in the splanchnic area (liver, small bowel and mesenteric lymph nodes) and in the central nervous system (hippocampus and cerebellum) fractalkine (CX3CL1) and stromal cell-derived factor alpha (SDF1-alpha) as well as their respective receptors (CX3CR1 and CXCR4) because of their key role in inflammatory processes. Results The significant increase of fractalkine in mesenteric lymph nodes (P < 0.05) and its receptor (CX3CR1) in the small bowel (P < 0.05) and hippocampus (P < 0.01), associated with the increased expression of SDF1-alpha in the hippocampus (P < 0.01) and the cerebellum (P < 0.01) suggest that prehepatic portal hypertension in the rat induces important alterations in the expression of chemokines in the gut-brain axis. Conclusion The present study revealed that portal hypertension is associated with splanchnic-brain inflammatory alterations mediated by chemokines. C1 [Merino, Joaquin; Aller, Maria-Angeles; Arias, Jaime] Univ Complutense Madrid, Dept Surg 1, Sch Med, E-28040 Madrid, Spain. [Rubio, Sandra] Autonomous Univ Madrid, Dept Psychobiol, Sch Psychol, E-28049 Madrid, Spain. [Arias, Natalia; Arias, Jorge-Luis] Univ Oviedo, Neurosci Lab, Sch Psychol, Oviedo 33003, Asturias, Spain. [Nava, Maria-Paz] Univ Complutense Madrid, Dept Physiol Anim Physiol 2, Sch Biol, E-28040 Madrid, Spain. [Loscertales, Maria] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Aller, MA (reprint author), Univ Complutense Madrid, Dept Surg 1, Sch Med, Plaza Ramon & Cajal S-N, E-28040 Madrid, Spain. EM josem2005@yahooo.es; maaller@med.ucm.es; sandra.rubio@uam.es; UO172871@uniovi.es; mpaznava@bio.ucm.es; mloscertales@partners.org; jariasp@med.ucm.es; jarias@uniovi.es RI Congregado, Miguel/B-9062-2009; OI Congregado, Miguel/0000-0002-2404-0176; Arias Perez, Jorge Luis/0000-0003-0983-8654 FU "Mutua Madrilena" Research Foundation (FMM) [AP69772009, AP59662009] FX We are indebted to Maria Elena Vicente for her invaluable assistance in preparing the manuscript and Elizabeth Mascola for translating it. This study was supported in part with grants from the "Mutua Madrilena" Research Foundation (FMM Ref. No. AP69772009 and Ref. No. AP59662009). NR 63 TC 4 Z9 4 U1 0 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2011 VL 56 IS 8 BP 2309 EP 2317 DI 10.1007/s10620-011-1625-y PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 799ON UT WOS:000293296100015 PM 21347560 ER PT J AU Silberman, DM Mostoslavsky, R AF Silberman, Dafne M. Mostoslavsky, Raul TI SIRT3 deacetylase: the Jekyll and Hyde sirtuin SO EMBO REPORTS LA English DT Editorial Material ID ALDEHYDE DEHYDROGENASE; ACETAMINOPHEN; PROTEIN; BIOLOGY; BINDING C1 [Silberman, Dafne M.; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Silberman, Dafne M.] Consejo Nacl Invest Cient & Tecn, CEFyBO UBA, Sch Med, Dept Human Biochem, RA-1033 Buenos Aires, DF, Argentina. RP Silberman, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. EM rmostoslavsky@mgh.harvard.edu NR 11 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD AUG PY 2011 VL 12 IS 8 BP 746 EP 747 DI 10.1038/embor.2011.147 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 799ZP UT WOS:000293326500004 PM 21738223 ER PT J AU Guzman, MP Jellinek, M George, M Hartley, M Squicciarini, AM Canenguez, KM Kuhlthau, KA Yucel, R White, GW Guzman, J Murphy, JM AF Guzman, Maria Paz Jellinek, Michael George, Myriam Hartley, Marcela Squicciarini, Ana Maria Canenguez, Katia M. Kuhlthau, Karen A. Yucel, Recai White, Gwyne W. Guzman, Javier Murphy, J. Michael TI Mental health matters in elementary school: first-grade screening predicts fourth grade achievement test scores SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Article DE Child mental health; Psychosocial screening; Academic achievement; Risk factors ID PEDIATRIC SYMPTOM CHECKLIST; TOCA-R SCORES; PSYCHOSOCIAL PROBLEMS; GLOBAL BURDEN; BEHAVIOR; UTILITY; CARE; ENVIRONMENT; MANAGEMENT; DISORDERS AB The objective of the study was to evaluate whether mental health problems identified through screens administered in first grade are related to poorer academic achievement test scores in the fourth grade. The government of Chile uses brief teacher- and parent-completed measures [Teacher Observation of Classroom Adaptation-Revised (TOCA-RR) and Pediatric Symptom Checklist (PSC-Cl)] to screen for mental health problems in about one-fifth of the country's elementary schools. In fourth grade, students take the national achievement tests (SIMCE) of language, mathematics and science. This study examined whether mental health problems identified through either or both screens predicted achievement test scores after controlling for student and family risk factors. A total of 17,252 students had complete first grade teacher forms and these were matched with fourth grade SIMCE data for 11,185 students, 7,903 of whom also had complete parent form data from the first grade. Students at risk on either the TOCA-RR or the PSC-Cl or both performed significantly worse on all SIMCE subtests. Even after controlling for covariates and adjusting for missing data, students with mental health problems on one screen in first grade had fourth grade achievement scores that were 14-18 points (similar to 1/3 SD) lower than students screened as not at risk. Students at risk on both screens had scores that were on average 33 points lower than students at risk on either screen. Mental health problems in first grade were one of the strongest predictors of lower achievement test scores 3 years later, supporting the premise that for children mental health matters in the real world. C1 [Murphy, J. Michael] Massachusetts Gen Hosp, Child Psychiat Serv, Boston, MA 02114 USA. [Guzman, Maria Paz; George, Myriam; Hartley, Marcela; Squicciarini, Ana Maria; Guzman, Javier] Junta Nacl Auxillo Escolar & Becas, Dept Sch Hlth, Santiago, Chile. [George, Myriam] Univ Chile, Fac Psychol, Santiago, Chile. [Jellinek, Michael; Murphy, J. Michael] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Jellinek, Michael; Murphy, J. Michael] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Jellinek, Michael] Newton Wellesley Hosp, Newton, MA USA. [Canenguez, Katia M.] Univ Massachusetts, Dept Psychol, Boston, MA 02125 USA. [Kuhlthau, Karen A.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Yucel, Recai] SUNY Albany, Dept Epidemiol & Biostat, New York, NY USA. [White, Gwyne W.] Rutgers State Univ, Dept Psychol, Piscataway, NJ 08855 USA. RP Murphy, JM (reprint author), Massachusetts Gen Hosp, Child Psychiat Serv, Yawkey 6A, Boston, MA 02114 USA. EM mariapaz@americasolidaria.org; mjellinek@partners.org; mpgeorge@junaeb.cl; asquicciarini@junaeb.cl; kcanenguez@partners.org; kkuhlthau@partners.org; ryucel@uamail.albany.edu; gwyneage@gmail.com; jguzman@junaeb.cl; mmurphy6@partners.org RI Guzman, Javier /E-8170-2016 OI Guzman, Javier /0000-0002-8194-039X FU The MGH Department of Psychiatry; Fuss Family Fund; Chilean government FX We wish to thank Iris Delgado and Lilian Jadue for their help in preparing the dataset and Haley Kamin for her help in preparing the manuscript. The MGH Department of Psychiatry and a Fuss Family Fund grant to Newton Wellesley Hospital made the current data analysis and paper writing possible. Correspondence should be addressed to Michael Murphy, Ed.D.; All of the Chilean authors received salary support from the Chilean government for administering the mental health program. All US authors except Dr. Jellinek received salary or consultation support for data analysis or report writing. Drs. Jellinek and Murphy are the authors of the PSC, but they received no income from this since it is available free in the public domain. No other authors reported any financial disclosures or conflict of interest. NR 50 TC 11 Z9 13 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD AUG PY 2011 VL 20 IS 8 BP 401 EP 411 DI 10.1007/s00787-011-0191-3 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 796AI UT WOS:000293022100004 PM 21647553 ER PT J AU Hoerning, A Koss, K Datta, D Boneschansker, L Jones, CN Wong, IY Irimia, D Calzadilla, K Benitez, F Hoyer, PF Harmon, WE Briscoe, DM AF Hoerning, Andre Koss, Kerith Datta, Dipak Boneschansker, Leonard Jones, Caroline N. Wong, Ian Y. Irimia, Daniel Calzadilla, Katiana Benitez, Fanny Hoyer, Peter F. Harmon, William E. Briscoe, David M. TI Subsets of human CD4(+) regulatory T cells express the peripheral homing receptor CXCR3 SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Chemokine receptors; Chemokines; CXCR3; Immunoregulation; Tregs ID ACUTE ALLOGRAFT-REJECTION; HUMAN CARDIAC ALLOGRAFTS; CHEMOKINE RECEPTOR; IN-VITRO; TRANSPLANT ARTERIOSCLEROSIS; CXCR3-BINDING CHEMOKINES; INTESTINAL INFLAMMATION; NONINVASIVE DETECTION; MAMMALIAN TARGET; MESSENGER-RNA AB Regulatory T cells (Tregs) migrate into peripheral sites of inflammation such as allografts undergoing rejection, where they serve to suppress the immune response. In this study, we find that similar to 30-40% of human CD25(hi) FOXP3(+) CD4(+) Tregs express the peripheral CXC chemokine receptor 3 (CXCR3) and that this subset has potent immunoregulatory properties. Consistently, we observed that proliferative responses as well as IFN-gamma production were significantly higher using CXCR3-depleted versus undepleted responders in the mixed lymphocyte reaction, as well as following mitogen-dependent activation of T cells. Using microfluidics, we also found that CXCR3 was functional on CXCR3(pos) Tregs, in as much as chemotaxis and directional persistence towards interferon-gamma-inducible protein of 10kDa (IP-10) was significantly greater for CXCR3(pos) than CXCR3(neg) Tregs. Following activation, CXCR3-expressing CD4(+) Tregs were maintained in vitro in cell culture in the presence of the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and we detected higher numbers of circulating CXCR3(+) FOXP3(+) T cells in adult and pediatric recipients of renal transplants who were treated with mTOR-inhibitor immunosuppressive therapy. Collectively, these results demonstrate that the peripheral homing receptor CXCR3 is expressed on subset(s) of circulating human Tregs and suggest a role for CXCR3 in their recruitment into peripheral sites of inflammation. C1 [Hoerning, Andre; Koss, Kerith; Datta, Dipak; Boneschansker, Leonard; Calzadilla, Katiana; Benitez, Fanny; Harmon, William E.; Briscoe, David M.] Childrens Hosp Boston, Dept Med, Div Nephrol, Boston, MA 02115 USA. [Hoerning, Andre; Koss, Kerith; Datta, Dipak; Boneschansker, Leonard; Calzadilla, Katiana; Benitez, Fanny; Harmon, William E.; Briscoe, David M.] Brigham & Womens Hosp, Childrens Hosp Boston, Transplantat Res Ctr, Boston, MA 02115 USA. [Hoerning, Andre; Koss, Kerith; Datta, Dipak; Boneschansker, Leonard; Calzadilla, Katiana; Harmon, William E.; Briscoe, David M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Jones, Caroline N.; Wong, Ian Y.; Irimia, Daniel] Shriners Hosp Children, Massachusetts Gen Hosp, Dept Surg, BioMEMS Resource Ctr, Boston, MA USA. [Hoyer, Peter F.] Univ Duisburg Essen, Childrens Hosp Essen, Dept Pediat 2, Essen, Germany. RP Briscoe, DM (reprint author), Childrens Hosp Boston, Dept Med, Div Nephrol, Boston, MA 02115 USA. EM david.briscoe@childrens.harvard.edu RI Wong, Ian/G-1611-2012; OI Wong, Ian/0000-0002-9439-2548; Irimia, Daniel/0000-0001-7347-2082 FU National Institutes of Health [U01 AI46135, PO1 AI50157, R01 GM092804]; Deutsche Forschungsgemeinschaft [HO2581/3-1]; Damon Runyon Cancer Research Foundation; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by National Institutes of Health Grants U01 AI46135 (To W. E. H and D. M. B) and PO1 AI50157 (to D. M. B.), R01 GM092804 (to D. I.), and by research grants from the Deutsche Forschungsgemeinschaft (HO2581/3-1 to A. H.) and the Damon Runyon Cancer Research Foundation (to I. W.). Adult patients evaluated in this study were managed by Dr. Oliver Witzke, Department of Nephrology, University Hospital Essen, Essen, Germany. Pediatric patients evaluated in this study were under the auspices of the Cooperative Clinical Trials in Pediatric Transplantation (CCTPT) of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The authors thank Leslie Spaneas RN for help with pediatric patient data analysis. NR 53 TC 32 Z9 35 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2011 VL 41 IS 8 BP 2291 EP 2302 DI 10.1002/eji.201041095 PG 12 WC Immunology SC Immunology GA 799DS UT WOS:000293264300020 PM 21538345 ER PT J AU Eschbach, C Bach, MP Fidler, I Pelanda, R Kohler, F Rajewsky, K Jumaa, H AF Eschbach, Cathrin Bach, Martina P. Fidler, Ingrid Pelanda, Roberta Koehler, Fabian Rajewsky, Klaus Jumaa, Hassan TI Efficient generation of B lymphocytes by recognition of self-antigens SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Autoimmune; Proliferation; Self-reactive; Selection ID CELL-DEVELOPMENT; MOUSE MODEL; PRO-B; RECEPTOR; DIFFERENTIATION; TRANSITION; EXPRESSION; MICE; TOLERANCE; EXPANSION AB Antibody diversity is generated by a random gene recombination process with the inherent risk of the production of autoreactive specificities. The current view suggests that B cells expressing such specificities are negatively selected at an early developmental stage. Using the knock-in model system of the 3-83 autoreactive B-cell antigen receptor (BCR) in combination with precursor-BCR (pre-BCR) deficiency, we show here that the 3-83 BCR mediates efficient generation of B cells in the presence, but not the absence, of a strongly recognized auto-antigen. Experiments with mixed bone marrow chimeras showed that combining the 3-83 BCR with the corresponding auto-antigen resulted in efficient reconstitution of B-cell development in immune-deficient mice. These results suggest that B cells are positively selected by recognition of self-antigens during developmental stages that precede receptor editing. Moreover, the data indicate that the pre-BCR functions as a specialized autoreactive BCR to initiate positive selection at a stage where the cells express immunoglobulin heavy but not light chains. C1 [Eschbach, Cathrin; Bach, Martina P.; Fidler, Ingrid; Koehler, Fabian; Jumaa, Hassan] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany. [Eschbach, Cathrin; Bach, Martina P.; Fidler, Ingrid; Koehler, Fabian; Jumaa, Hassan] Univ Freiburg, Ctr Biol Signalling Studies Bioss, Freiburg, Germany. [Eschbach, Cathrin; Bach, Martina P.; Fidler, Ingrid; Koehler, Fabian; Jumaa, Hassan] Univ Freiburg, Dept Mol Immunol, Fac Biol, Freiburg, Germany. [Pelanda, Roberta] Natl Jewish Hlth, Integrated Dept Immunobiol, Denver, CO USA. [Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. RP Jumaa, H (reprint author), Max Planck Inst Immunobiol & Epigenet, Stuebeweg 51, D-79108 Freiburg, Germany. EM jumaa@immunbio.mpg.de FU Deutsche Forschungsgemeinschaft [SFB620, SFB746] FX The authors thank U. Stauffer, N. Joswig and C. Johner for mouse work and further assistance. They thank E. Hobeika for the mb1-lox-GFP mice, P. Nielsen, D. Nemazee and M. Reth for critical reading of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (SFB620 and SFB746). NR 31 TC 15 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2011 VL 41 IS 8 BP 2397 EP 2403 DI 10.1002/eji.201041344 PG 7 WC Immunology SC Immunology GA 799DS UT WOS:000293264300031 PM 21604259 ER PT J AU Janssen, DJA Curtis, JR Au, DH Spruit, MA Downey, L Schols, JMGA Wouters, EFM Engelberg, RA AF Janssen, D. J. A. Curtis, J. R. Au, D. H. Spruit, M. A. Downey, L. Schols, J. M. G. A. Wouters, E. F. M. Engelberg, R. A. TI Patient-clinician communication about end-of-life care for Dutch and US patients with COPD SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article DE Advance care planning; chronic obstructive pulmonary disease; communication; end-of-life care; palliative care ID OBSTRUCTIVE PULMONARY-DISEASE; CRITICALLY-ILL PATIENTS; QUALITY; HEALTH; ASSOCIATIONS; DISCUSSIONS; QUESTIONNAIRE; PERSPECTIVE; CANCER; DEATH AB Improving patient-clinician communication about end-of-life care is important in order to enhance quality of care for patients with chronic obstructive pulmonary disease (COPD). Our objective was to compare quality of patient-clinician communication about end-of-life care, and endorsement of barriers and facilitators to this communication in the Netherlands and the USA. The present study was an analysis of survey data from 122 Dutch and 391 US outpatients with COPD. We compared quality of patient-clinician communication about end-of-life care (Quality of Communication questionnaire) and barriers and facilitators to communication about end-of-life care (Barriers and Facilitators Questionnaire) between the Netherlands and the USA, controlling for patients' demographic and illness characteristics. Although Dutch patients in this study had worse lung function and disease-specific health status than US patients, Dutch patients reported lower quality of communication about end-of-life care (median score 0.0 (interquartile range 0.0-2.0) versus 1.4 (0.0-3.6); adjusted p < 0.005). Clinicians in both countries rarely discussed life-sustaining treatment preferences, prognoses, dying processes or spiritual issues. Quality of communication about end-of-life care needs to improve in the Netherlands and the USA. Future studies to improve this communication should be designed to take into account international differences and patient-specific barriers and facilitators to communication about end-of-life care. C1 [Janssen, D. J. A.; Spruit, M. A.; Wouters, E. F. M.] CIRO Ctr Expertise Chron Organ Failure, Program Dev Ctr, NL-6085 NM Horn, Netherlands. [Janssen, D. J. A.] Proteion Thuis, Horn, Netherlands. [Janssen, D. J. A.] CAPHRI, Maastricht, Netherlands. [Schols, J. M. G. A.] Maastricht Univ, Fac Hlth Med & Life Sci CAPHRI, Dept Gen Practice, Maastricht, Netherlands. [Wouters, E. F. M.] Maastricht Univ Med Ctr, Dept Resp Med, Maastricht, Netherlands. [Curtis, J. R.; Downey, L.; Engelberg, R. A.] Univ Washington, Harborview Med Ctr, Dept Med, Div Pulm & Crit Care Med, Seattle, WA 98104 USA. [Au, D. H.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. RP Janssen, DJA (reprint author), CIRO Ctr Expertise Chron Organ Failure, Program Dev Ctr, Hornerheide 1, NL-6085 NM Horn, Netherlands. EM daisyjanssen@proteion.nl FU CIRO+ (Centre of Expertise for Chronic Organ Failure, Horn, the Netherlands); Proteion Thuis (Horn, the Netherlands); Netherlands Asthma Foundation (Leusden, the Netherlands) [3.4.06.082]; Stichting Wetenschapsbevordering Verpleeghuiszorg (Utrecht, The Netherlands); Health Services Research and Development, Dept of Veterans Affairs [IIR 02-292]; American Lung Association; National Heart, Lung, and Blood Institute [K24 HL068593] FX This project was part of an international research fellowship supported by CIRO+ (Centre of Expertise for Chronic Organ Failure, Horn, the Netherlands). The original Dutch study was supported by: Proteion Thuis (Horn, the Netherlands); CIRO+; grant 3.4.06.082 from the Netherlands Asthma Foundation (Leusden, the Netherlands); and Stichting Wetenschapsbevordering Verpleeghuiszorg (Utrecht, The Netherlands). The original US studies were supported by the Health Services Research and Development, Dept of Veterans Affairs (grant IIR 02-292) and the American Lung Association. J.R. Curtis was funded by a K24 Award from the National Heart, Lung, and Blood Institute (grant K24 HL068593). No funding source had any role in design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. NR 35 TC 21 Z9 21 U1 5 U2 13 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 J9 EUR RESPIR J JI Eur. Resp. J. PD AUG PY 2011 VL 38 IS 2 BP 268 EP 276 DI 10.1183/09031936.00157710 PG 9 WC Respiratory System SC Respiratory System GA 799IM UT WOS:000293280400009 PM 21233263 ER PT J AU Wang, YN Lee, K Ledoux, WR AF Wang, Yak-Nam Lee, Kara Ledoux, William R. TI Histomorphological Evaluation of Diabetic and Non-Diabetic Plantar Soft Tissue SO FOOT & ANKLE INTERNATIONAL LA English DT Article DE Plantar Soft Tissue; Diabetes; Skin; Elastic Septae; Adipocyte ID STEREOLOGICAL METHODS; VERTICAL SECTIONS; SURFACE-AREA; FOOT ULCER; FAT PADS; SKIN; THICKNESS; MELLITUS; RISK; NEUROPATHY AB Background: Diabetic foot ulceration has a complex and multifactorial etiology and can involve changes in the pathophysiology of the plantar soft tissue. In the current study, histomorphological analyses of diabetic and non-diabetic plantar tissue were performed. It was hypothesized that the diabetic tissue would have thicker skin (epidermis and dermis), less interdigitation between the dermis and epidermis, thicker elastic septa and decreased adipose cell size. Materials and Methods: Two locations of the foot (the heel and the first metatarsal) were examined, both of which have been reported to be locations with a high incidence of ulceration. Stereo logical methods and quantitative morphological techniques were used to evaluate the skin thickness, interdigitation index, elastic septae thickness and adipocyte cell size. Results: The diabetic donors had a greater body mass index (BMI) than the non-diabetic donors. The diabetic tissue had significantly thicker elastic septae and dermis. However, no significant difference was observed in the interdigitation index or adipocyte size. Conclusion: These findings demonstrate that morphological changes can be evaluated histologically to give a better understanding of the pathological changes in the plantar soft tissue with diabetes. These evaluations can then be associated with biomechanical changes that occur in diabetes to provide new insight into how microstructural changes can alter macroscopic properties. Clinical Relevance: An understanding of the histomorphological changes in the soft tissue in relationship to the location on the foot could help to explain the biomechanical changes that occur in diabetes and the subsequent increase in susceptibility to breakdown. C1 [Ledoux, William R.] RR&D Ctr Excellence Limb Loss Prevent & Prosthet, VA Puget Sound, Seattle, WA 98108 USA. RP Ledoux, WR (reprint author), RR&D Ctr Excellence Limb Loss Prevent & Prosthet, VA Puget Sound, MS 151,1660 S Columbian Way, Seattle, WA 98108 USA. EM wrledoux@u.washington.edu RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 FU NIH [IR01 DK75633-03]; Department of Veterans Affairs; RRD Service grant [A4843C]; NIDDK [P30DK017047] FX This study was supported by NIH grant IR01 DK75633-03, the Department of Veterans Affairs, RR&D Service grant A4843C, and in part by NIDDK grant P30DK017047. NR 45 TC 9 Z9 9 U1 1 U2 2 PU AMER ORTHOPAEDIC FOOT & ANKLE SOC, INC PI SEATTLE PA 2517 EASTLAKE AVE EAST, STE 200, SEATTLE, WA 98102 USA SN 1071-1007 J9 FOOT ANKLE INT JI Foot Ankle Int. PD AUG PY 2011 VL 32 IS 8 BP 802 EP 810 DI 10.3113/FAI.2011.0802 PG 9 WC Orthopedics SC Orthopedics GA 799VM UT WOS:000293314200010 PM 22049867 ER PT J AU Chan, SSC Viswanath, K Au, DWH Ma, CMS Lam, WWT Fielding, R Leung, GM Lam, TH AF Chan, Sophia S. C. Viswanath, K. Au, Doreen W. H. Ma, C. M. S. Lam, W. W. T. Fielding, R. Leung, G. M. Lam, Tai-Hing TI Hong Kong Chinese community leaders' perspectives on family health, happiness and harmony: a qualitative study SO HEALTH EDUCATION RESEARCH LA English DT Article ID FALL; RISE AB This paper examines the views of Hong Kong community leaders on the underlying issues that affect family health, happiness and harmony (3Hs) in Hong Kong. Using a community reconnaissance method, a series of individual in-depth interviews with 26 leaders that represent neighbourhoods of diverse socio-economic status (SES) from June to August 2008 were conducted. Participants considered that changing family structure, economic situation and strong work ethic are the most salient factors that affect family 3Hs. The deprived comprehensive social security assistance recipients, single-parent families and migrant women were considered to be the most vulnerable groups to breakdown in family 3Hs and particularly, they lack family resources. Families from different SES have to overcome different challenges in order to achieve and sustain family 3Hs. Leaders from low SES neighbourhood were concerned more about providing tangible help such as child care facilities to improve family resources, whereas leaders from high SES neighbourhood focused more on preventive interventions such as education on relationship skills to achieve better family well-being. The findings offer insights in designing effective social marketing education campaigns and family-friendly workplace policy to promote social harmony through the maintenance of 3Hs families. C1 [Chan, Sophia S. C.] Univ Hong Kong, Li Ka Shing Fac Med, Sch Nursing, Hong Kong, Hong Kong, Peoples R China. [Viswanath, K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Viswanath, K.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Au, Doreen W. H.; Ma, C. M. S.; Lam, W. W. T.; Fielding, R.; Leung, G. M.; Lam, Tai-Hing] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. RP Chan, SSC (reprint author), Univ Hong Kong, Li Ka Shing Fac Med, Sch Nursing, Hong Kong, Hong Kong, Peoples R China. EM nssophia@hku.hk RI Au, Doreen/Q-7988-2016; Ma, Cecilia/E-7830-2013; OI Au, Doreen/0000-0002-3793-5331; Ma, Cecilia/0000-0001-7092-7715; Leung, Gabriel/0000-0002-2503-6283 NR 27 TC 9 Z9 9 U1 3 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD AUG PY 2011 VL 26 IS 4 BP 664 EP 674 DI 10.1093/her/cyr026 PG 11 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 796BZ UT WOS:000293026500008 PM 21536713 ER PT J AU Buxton, AE AF Buxton, Alfred E. TI Sudden cardiac death won't go away: What are we to do? SO HEART RHYTHM LA English DT Editorial Material ID LEFT-VENTRICULAR HYPERTROPHY; CORONARY-ARTERY-DISEASE; RISK; REGRESSION; MORTALITY; HYPERTENSION; ARRHYTHMIAS; PREDICTION; MYOCARDIUM; REDUCTION C1 Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02215 USA. RP Buxton, AE (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, 185 Pilgrim Rd,W Campus Baker,4 Suite, Boston, MA 02215 USA. EM abuxton@bidmc.harvard.edu NR 21 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD AUG PY 2011 VL 8 IS 8 BP 1183 EP 1184 DI 10.1016/j.hrthm.2011.04.016 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 795XX UT WOS:000293013600008 PM 21699829 ER PT J AU Ackerman, MJ Priori, SG Willems, S Berul, C Brugada, R Calkins, H Camm, AJ Ellinor, PT Gollob, M Hamilton, R Hershberger, RE Judge, DP Le Marec, H McKenna, WJ Schulze-Bahr, E Semsarian, C Towbin, JA Watkins, H Wilde, A Wolpert, C Zipes, DP AF Ackerman, Michael J. Priori, Silvia G. Willems, Stephan Berul, Charles Brugada, Ramon Calkins, Hugh Camm, A. John Ellinor, Patrick T. Gollob, Michael Hamilton, Robert Hershberger, Ray E. Judge, Daniel P. Le Marec, Herve McKenna, William J. Schulze-Bahr, Eric Semsarian, Chris Towbin, Jeffrey A. Watkins, Hugh Wilde, Arthur Wolpert, Christian Zipes, Douglas P. TI HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies SO HEART RHYTHM LA English DT Article DE Genetics; Cardiomyopathies; Channelopathies ID LONG-QT SYNDROME; RIGHT-VENTRICULAR CARDIOMYOPATHY; INFANT-DEATH-SYNDROME; SUDDEN CARDIAC DEATH; FAMILIAL ATRIAL-FIBRILLATION; OF-FUNCTION MUTATION; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; GENOTYPE-PHENOTYPE CORRELATION; CAUSE HYPERTROPHIC CARDIOMYOPATHY; RYANODINE RECEPTOR GENE C1 [Ackerman, Michael J.] Mayo Clin, Rochester, MN USA. [Priori, Silvia G.] Univ Pavia, Fdn Salvatore Maugeri, I-27100 Pavia, Italy. [Priori, Silvia G.] NYU, New York, NY USA. [Willems, Stephan] Univ Hosp Hamburg Eppendorf, Hamburg, Germany. [Berul, Charles] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Berul, Charles] George Washington Sch Med, Washington, DC USA. [Brugada, Ramon] Girona Inst Biomed Res, Girona, Spain. [Brugada, Ramon] Univ Girona, Sch Med, Girona, Spain. [Calkins, Hugh; Judge, Daniel P.] Johns Hopkins Univ, Baltimore, MD USA. [Camm, A. John] St Georges Univ London, London, England. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Gollob, Michael] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. [Hamilton, Robert] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Hershberger, Ray E.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Judge, Daniel P.] Univ Paris 05, Paris, France. [Le Marec, Herve] Inst Thorax, Nantes, France. [McKenna, William J.] UCL, Inst Cardiovasc Sci, London, England. [Schulze-Bahr, Eric] Univ Hosp Muenster, Munster, Germany. [Semsarian, Chris] Univ Sydney, Sydney, NSW 2006, Australia. [Towbin, Jeffrey A.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Oxford OX3 9DU, England. [Wilde, Arthur] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Wolpert, Christian] Ludwigsburg Clin, Ludwigsburg, Germany. [Zipes, Douglas P.] Indiana Univ Sch Med, Krannert Inst Cardiol, Indianapolis, IN USA. RP Ackerman, MJ (reprint author), Care of Olson S, Heart Rhythm Soc, 1400 K St NW, Washington, DC 20005 USA. EM solson@hrsonline.org RI McKenna, William/C-3243-2008; OI McKenna, William/0000-0001-7994-2460; Zipes, Douglas/0000-0001-7141-6829 FU Wellcome Trust [090532] NR 272 TC 300 Z9 320 U1 0 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD AUG PY 2011 VL 8 IS 8 BP 1308 EP 1339 DI 10.1016/j.hrthm.2011.05.020 PG 32 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 795XX UT WOS:000293013600032 PM 21787999 ER PT J AU Link, MS Exner, DV Anderson, M Ackerman, M Al-Ahmad, A Knight, BP Markowitz, SM Kaufman, ES Haines, D Asirvatham, SJ Callans, DJ Mounsey, JP Bogun, F Narayan, SM Krahn, AD Mittal, S Singh, J Fisher, JD Chugh, SS AF Link, Mark S. Exner, Derek V. Anderson, Mark Ackerman, Michael Al-Ahmad, Amin Knight, Bradley P. Markowitz, Steven M. Kaufman, Elizabeth S. Haines, David Asirvatham, Samuel J. Callans, David J. Mounsey, J. Paul Bogun, Frank Narayan, Sanjiv M. Krahn, Andrew D. Mittal, Suneet Singh, Jagmeet Fisher, John D. Chugh, Sumeet S. TI HRS Policy Statement: Clinical Cardiac Electrophysiology Fellowship Curriculum: Update 2011 SO HEART RHYTHM LA English DT Article ID AMERICAN-HEART-ASSOCIATION; RADIOFREQUENCY CATHETER ABLATION; LONG-QT SYNDROME; PERSISTENT ATRIAL-FIBRILLATION; PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; COLLEGE-OF-CARDIOLOGY; RIGHT-VENTRICULAR CARDIOMYOPATHY/DYSPLASIA; EMERGENCY CARDIOVASCULAR CARE; ANTIARRHYTHMIC-DRUG THERAPY C1 [Link, Mark S.] Tufts Med Ctr, Boston, MA USA. [Exner, Derek V.] Univ Calgary, Libin Cardiovasc Inst Alberta, Calgary, AB T2N 1N4, Canada. [Anderson, Mark] Univ Iowa, Iowa City, IA USA. [Ackerman, Michael; Asirvatham, Samuel J.] Mayo Clin, Rochester, MN USA. [Al-Ahmad, Amin] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Knight, Bradley P.] Northwestern Univ, Evanston, IL USA. [Markowitz, Steven M.] Weill Cornell Med Coll, New York, NY USA. [Kaufman, Elizabeth S.] Case Western Reserve Univ, Heart & Vasc Ctr, Cleveland, OH 44106 USA. [Haines, David] Oakland Univ, Beaumont Hosp, William Beaumont Sch Med, Rochester, MI 48063 USA. [Callans, David J.] Univ Penn, Philadelphia, PA 19104 USA. [Mounsey, J. Paul] Univ N Carolina, Chapel Hill, NC USA. [Bogun, Frank] Univ Michigan, Ann Arbor, MI 48109 USA. [Narayan, Sanjiv M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Narayan, Sanjiv M.] VA Med Ctr San Diego, San Diego, CA USA. [Krahn, Andrew D.] Univ Western Ontario, London, ON N6A 3K7, Canada. [Mittal, Suneet] St Lukes & Roosevelt Hosp Ctr, New York, NY USA. [Singh, Jagmeet] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fisher, John D.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Chugh, Sumeet S.] Cedars Sinai Med Ctr, Inst Heart, Los Angeles, CA 90048 USA. RP Link, MS (reprint author), Care of Olson S, Heart Rhythm Soc, 1400 K St NW,Suite 500, Washington, DC 20005 USA. EM solson@hrsonline.org OI Fisher, John/0000-0003-2748-8715 FU NHLBI NIH HHS [K24 HL103800] NR 191 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD AUG PY 2011 VL 8 IS 8 BP 1340 EP 1356 DI 10.1016/j.hrthm.2011.06.008 PG 17 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 795XX UT WOS:000293013600033 PM 21699868 ER PT J AU Dienstag, JL Ghany, MG Morgan, TR Di Bisceglie, AM Bonkovsky, HL Kim, HY Seeff, LB Szabo, G Wright, EC Sterling, RK Everson, GT Lindsay, KL Lee, WM Lok, AS Morishima, C Stoddard, AM Everhart, JE AF Dienstag, Jules L. Ghany, Marc G. Morgan, Timothy R. Di Bisceglie, Adrian M. Bonkovsky, Herbert L. Kim, Hae-Young Seeff, Leonard B. Szabo, Gyongyi Wright, Elizabeth C. Sterling, Richard K. Everson, Gregory T. Lindsay, Karen L. Lee, William M. Lok, Anna S. Morishima, Chihiro Stoddard, Anne M. Everhart, James E. CA HALT-C Trial Grp TI A Prospective Study of the Rate of Progression in Compensated, Histologically Advanced Chronic Hepatitis C SO HEPATOLOGY LA English DT Article ID VIRUS-RELATED CIRRHOSIS; NATURAL-HISTORY; UNITED-STATES; INFECTION; COHORT; PEGINTERFERON; SURVIVAL; FIBROSIS; OUTCOMES; THERAPY AB The incidence of liver disease progression among subjects with histologically advanced but compensated chronic hepatitis C is incomplete. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes over 8 years. Among patients with fibrosis, the incidence of cirrhosis was 9.9% per year. Six hundred seventy-nine clinical outcomes occurred among 329 subjects. Initial clinical outcomes occurred more frequently among subjects with cirrhosis (7.5% per year) than subjects with fibrosis (3.3% per year) (P < 0.0001). Child-Turcotte-Pugh (CTP) score >= 7 was the most common first outcome, followed by hepatocellular carcinoma. Following occurrence of a CTP score >= 7, the rate of subsequent events increased to 12.9% per year, including a death rate of 10% per year. Age and sex did not influence outcome rates. Baseline platelet count was a strong predictor of all clinical outcomes. During the 8 years of follow-up, death or liver transplantation occurred among 12.2% of patients with advanced fibrosis and 31.5% of those with cirrhosis. Conclusion: Among patients with advanced hepatitis C who failed peginterferon and ribavirin therapy, the rate of liver-related outcomes, including death and liver transplantation, is high, especially once the CTP score reaches at least 7. (HEPATOLOGY 2011;54:396-405) C1 [Dienstag, Jules L.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Seeff, Leonard B.; Everhart, James E.] NIDDK, Div Digest Dis & Nutr, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Seeff, Leonard B.; Wright, Elizabeth C.] NIDDK, Off Director, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Morgan, Timothy R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Di Bisceglie, Adrian M.] St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, St Louis, MO USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Kim, Hae-Young; Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. [Szabo, Gyongyi] Univ Massachusetts, Sch Med, Dept Med, Div Gastroenterol,Hepatol & Liver Ctr, Worcester, MA USA. [Sterling, Richard K.] Virginia Commonwealth Univ, Med Ctr, Hepatol Sect, Richmond, VA USA. [Everson, Gregory T.] Univ Colorado Denver, Sch Med, Sect Hepatol, Div Gastroenterol & Hepatol, Aurora, CO USA. [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Div Digest & Liver Dis, Dallas, TX 75390 USA. [Lok, Anna S.] Univ Michigan, Sch Med, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI USA. [Morishima, Chihiro] Univ Washington, Dept Lab Med, Div Virol, Seattle, WA 98195 USA. RP Dienstag, JL (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St, Boston, MA 02114 USA. EM jdienstag@partners.org OI Yang, Shuman/0000-0002-9638-0890 FU National Institute of Diabetes & Digestive & Kidney Diseases; National Center for Research Resources, National Institutes of Health; Hoffmann-La Roche, Inc. FX Supported by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed in the Appendix). Additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed in the Appendix). Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc. (now Genentech) through a Cooperative Research and Development Agreement with the National Institutes of Health. NR 21 TC 61 Z9 62 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 AUG PY 2011 VL 54 IS 2 BP 396 EP 405 DI 10.1002/hep.24370 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 800BT UT WOS:000293333300004 PM 21520194 ER PT J AU Thakur, PC Stuckenholz, C Rivera, MR Davison, JM Yao, JK Amsterdam, A Sadler, KC Bahary, N AF Thakur, Prakash C. Stuckenholz, Carsten Rivera, Marcus R. Davison, Jon M. Yao, Jeffrey K. Amsterdam, Adam Sadler, Kirsten C. Bahary, Nathan TI Lack of De Novo Phosphatidylinositol Synthesis Leads to Endoplasmic Reticulum Stress and Hepatic Steatosis in cdipt-Deficient Zebrafish SO HEPATOLOGY LA English DT Article ID FATTY LIVER-DISEASE; GENE-EXPRESSION; ER STRESS; CANCER; RESPONSES; LIPIDS AB Hepatic steatosis is the initial stage of nonalcoholic fatty liver disease (NAFLD) and may predispose to more severe hepatic disease, including hepatocellular carcinoma. Endoplasmic reticulum (ER) stress has been recently implicated as a novel mechanism that may lead to NAFLD, although the genetic factors invoking ER stress are largely unknown. During a screen for liver defects from a zebrafish insertional mutant library, we isolated the mutant cdipt(hi559Tg-/+) (hi559). CDIPT is known to play an indispensable role in phosphatidylinositol (PtdIns) synthesis. Here we show that cdipt is expressed in the developing liver, and its disruption in hi559 mutants abrogates de novo PtdIns synthesis, resulting in hepatomegaly at 5 days postfertilization. The hi559 hepatocytes display features of NAFLD, including macrovesicular steatosis, ballooning, and necroapoptosis. Gene set enrichment of microarray profiling revealed significant enrichment of endoplasmic reticulum stress response (ERSR) genes in hi559 mutants. ER stress markers, including atf6, hspa5, calr, and xbp1, are selectively up-regulated in the mutant liver. The hi559 expression profile showed significant overlap with that of mammalian hepatic ER stress and NAFLD. Ultrastructurally, the hi559 hepatocytes display marked disruption of ER architecture with hallmarks of chronic unresolved ER stress. Induction of ER stress by tunicamycin in wild-type larvae results in a fatty liver similar to hi559, suggesting that ER stress could be a fundamental mechanism contributing to hepatic steatosis. Conclusion: cdipt-deficient zebrafish exhibit hepatic ER stress and NAFLD pathologies, implicating a novel link between PtdIns, ER stress, and steatosis. The tractability of hi559 mutant provides a valuable tool to dissect ERSR components, their contribution to molecular pathogenesis, and evaluation of novel therapeutics of NAFLD. (HEPATOLOGY 2011; 54:452-462) C1 [Thakur, Prakash C.; Stuckenholz, Carsten; Bahary, Nathan] Univ Pittsburgh, Div Hematol Oncol, Dept Med, Pittsburgh, PA 15260 USA. [Rivera, Marcus R.] Univ Pittsburgh, Childrens Hosp, Div Pediat Gastroenterol, Pittsburgh, PA 15260 USA. [Davison, Jon M.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Med, Med Res Serv, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Med, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA. [Bahary, Nathan] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15260 USA. [Amsterdam, Adam] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Sadler, Kirsten C.] Mt Sinai Sch Med, Dept Med Liver Dis, New York, NY USA. RP Bahary, N (reprint author), Univ Pittsburgh, Div Hematol Oncol, Dept Med, Biomed Sci Tower 3,Room 5058,3501 5th Ave, Pittsburgh, PA 15260 USA. EM bahary@pitt.edu RI Thakur, Prakash/H-7398-2012 FU Department of Veterans Affairs Senior Research; Cancer Center Support [P30CA047904]; National Institutes of Health [R21DK073177] FX Supported by a Department of Veterans Affairs Senior Research Career Scientist Award (to J. K. Y.), Cancer Center Support Grant P30CA047904, and National Institutes of Health Grant R21DK073177 (to N.B.). NR 38 TC 31 Z9 34 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2011 VL 54 IS 2 BP 452 EP 462 DI 10.1002/hep.24349 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 800BT UT WOS:000293333300010 PM 21488074 ER PT J AU Zhang, J Handy, DE Wang, YF Bouchard, G Selhub, J Loscalzo, J Carey, MC AF Zhang, Ji Handy, Diane E. Wang, Yufang Bouchard, Guylaine Selhub, Jacob Loscalzo, Joseph Carey, Martin C. TI Hyperhomocysteinemia from Trimethylation of Hepatic Phosphatidylethanolamine During Cholesterol Cholelithogenesis in Inbred Mice SO HEPATOLOGY LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; BILIARY LIPID SECRETION; N-METHYLTRANSFERASE; PHOSPHOLIPID METHYLATION; LITH GENES; FOLIC-ACID; PHENOTYPIC CHARACTERIZATION; DETERMINE SUSCEPTIBILITY; HOMOCYSTEINE METABOLISM; CANALICULAR MEMBRANE AB Because hyperhomocysteinemia can occur in cholesterol gallstone disease, we hypothesized that this may result from trimethylation of phosphatidylethanolamine (PE), which partakes in biliary phosphatidylcholine (PC) hypersecretion during cholesterol cholelithogenesis. We fed murine strains C57L/J, C57BL/6J, SWR/J, AKR/J, PE N-methyltransferase (PEMT) knockout (KO), PEMT heterozygous (HET), and wildtype (WT) mice a cholesterol/cholic acid lithogenic diet (LD) for up to 56 days and documented biliary lipid phase transitions and secretion rates. We quantified plasma total homocysteine (tHcy), folate, and vitamin B(12) in plasma and liver, as well as biliary tHcy and cysteine secretion rates. Rate-limiting enzyme activities of PC synthesis, PEMT and cytidine triphosphate: phosphocholine cytidylyltransferase (PCT), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured in liver homogenates. Other potential sources of plasma tHcy, glycine N-methyltransferase (GNMT) and guanidinoacetate N-methyltransferase (GAMT), were assayed by gene expression. Plasma tHcy and PEMT activities became elevated during cholelithogenesis in gallstone-susceptible C57L, C57BL/6, and SWR mice but not in the gallstone-resistant AKR mice. Persisting in C57L mice, which exhibit the greatest Lith gene burden, these increases were accompanied by elevated hepatic SAM/SAH ratios and augmented biliary tHcy secretion rates. Counter-regulation included remethylation of Hcy to methionine concurrent with decreased folate and vitamin B(12) levels and Hcy transsulfuration to cysteine. Concomitantly, methylenetetrahydrofolate reductase (Mthfr), betaine-homocysteine methyltransferase (Bhmt), and cystathionine-beta-synthase (Cbs) were up-regulated, but Gnmt and Gamt genes were down-regulated. PEMT KO and HET mice displayed biliary lipid secretion rates and high gallstone prevalence rates similar to WT mice without any elevation in plasma tHcy levels. Conclusion: This work implicates up-regulation of PC synthesis by the PEMT pathway as a source of elevated plasma and bile tHcy during cholesterol cholelithogenesis. (HEPATOLOGY 2011;54:697-706) C1 [Zhang, Ji; Bouchard, Guylaine; Carey, Martin C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol,Dept Med, Boston, MA 02115 USA. [Handy, Diane E.; Loscalzo, Joseph] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc,Dept Med, Boston, MA 02115 USA. [Wang, Yufang] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc Res,Mol Pathol Unit, Charlestown, MA USA. [Wang, Yufang] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA USA. [Selhub, Jacob] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Vitamin Metab Lab, Boston, MA 02111 USA. RP Carey, MC (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol,Dept Med, 75 Francis St, Boston, MA 02115 USA. EM mccarey@rics.bwh.harvard.edu RI Zhang, Ji /C-7583-2013 FU NIH (USPHS) [DK36588, HL61795, HL81587, HL70819, HL48743, HL89734]; USDA [1950-51520-008-00D, 58-1950-9-001] FX Supported in part by NIH (USPHS) grants: DK36588, HL61795, HL81587, HL70819, HL48743, HL89734; and USDA agreements: 1950-51520-008-00D and 58-1950-9-001. NR 49 TC 2 Z9 3 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2011 VL 54 IS 2 BP 697 EP 706 DI 10.1002/hep.24428 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 800BT UT WOS:000293333300032 PM 21567442 ER PT J AU Schutzer, WE Beard, DR Reed, JF Mader, SL AF Schutzer, William E. Beard, Douglas R. Reed, John F. Mader, Scott L. TI Characterization of Clonal Vascular Smooth Muscle Cell Lines Derived from Young and Old Fischer 344 Rats SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Article DE Aging; Adrenergic, beta; Fischer 344; Clonal Selection; cAMP; Cell culture; Isoproterenol; Vascular; G protein-coupled receptor kinase ID BETA-ADRENERGIC RESPONSIVENESS; AGE-RELATED-CHANGES; RECEPTOR KINASES; GENE-EXPRESSION; AORTA AB A significant finding with aging humans (and aging animal models) is that blood vessels lose their ability to respond to beta-adrenergic receptor stimuli. Therefore, they produce less cyclic adenosine monophosphate (cAMP) and have decreased vasorelaxation with advancing age. This change likely contributes to hypertension, insufficient blood flow, and atherosclerosis. Our goal was to develop a vascular smooth muscle cell culture model that replicates the molecular and biochemical changes observed in blood vessels with advancing age. A clonal selection strategy was used to produce cell lines from 2-, 6-, 12-, and 24-month-old male Fischer 344 rat aortae. Cultures were validated as smooth muscle cells with immunocytochemistry positive for alpha-actin and negative for von Willebrand factor VIII. Positive staining for G protein-coupled receptor kinase 2 indicated presence of this adrenergic receptor regulator. A total of n = 5 clones from n = 7 animals for each age group were initially analyzed for cAMP accumulation under three conditions: basal, isoproterenol stimulated, and forskolin stimulated. Results found that at passage 3, there was a significant reduction in cAMP accumulation to isoproterenol. However, this reduction disappeared by passage 6. Secondary analysis segregated clones into phenotypic age groups independent of donor animal age. Segregation identified n = 3 clones per group. At passage 3, the age-related change in the beta-adrenergic change was magnified. However, even with segregation, the adrenergic response was lost by passage 6. Our results show that early passaged clonal vascular smooth muscle cell cultures maintain their aging, adrenergic phenotype. Two separate strategies to identify age-representative phenotypes into later passage were unsuccessful. C1 [Schutzer, William E.; Beard, Douglas R.; Reed, John F.; Mader, Scott L.] Portland VA Med Ctr, Res Serv, Portland, OR 97201 USA. [Schutzer, William E.; Mader, Scott L.] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97239 USA. RP Mader, SL (reprint author), Portland VA Med Ctr, Res Serv, R&D 26,3710 SW US Vet Hosp Rd, Portland, OR 97201 USA. EM scott.mader@va.gov FU Research Service, Department of Veterans Affairs; Northwest Health Foundation FX This work was supported by the Research Service, Department of Veterans Affairs, and the Northwest Health Foundation. NR 22 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD AUG PY 2011 VL 47 IS 7 BP 445 EP 450 DI 10.1007/s11626-011-9430-7 PG 6 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 797OI UT WOS:000293136800005 ER PT J AU Engelmann, P Farkas, K Kis, J Richman, G Zhang, ZY Liew, CW Borowiec, M Niewczas, MA Jalahej, H Orban, T AF Engelmann, Peter Farkas, Klara Kis, Janos Richman, Geoffrey Zhang, Zhaoyun Liew, Chong Wee Borowiec, Maciej Niewczas, Monika A. Jalahej, Heyam Orban, Tihamer TI Characterization of human invariant natural killer T cells expressing FoxP3 SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE cytokines; human iNKT cells; immune regulation; regulatory T cells ID HUMAN PERIPHERAL-BLOOD; HUMAN INKT CELLS; TCR ALPHA-CHAIN; NKT CELLS; TRANSCRIPTIONAL REPRESSOR; REGULATORY-CELLS; IMMUNE-SYSTEM; CANCER; SUBSETS; MICE AB Recently described forkhead box protein 3 (FoxP3) transcription factor is a key molecule in CD4+ CD25hi+ T-cell characterization. Invariant NK T (iNKT) cells are also characterized as regulatory cells modulating the immune response by rapidly producing T(h)1 and T(h)2 cytokines. We aimed to analyze cellular markers important in regulatory features of human iNKT cells and to study their role in functional assays. iNKT cells were single cell sorted from peripheral mononuclear cells of healthy individuals after immunostaining of invariant TCR alpha-chain. We found FoxP3 expression in human iNKT clones. Randomly selected iNKT cell clones (CD4+, double negative, CD8+) expressed FoxP3 mRNA and protein at different levels upon stimulation as supported by various approaches. FoxP3 mRNA and protein expression was detected in unstimulated iNKT cells as well. Furthermore, different stimulations changed the FoxP3 expression in iNKT cells over time and the most dramatic changes were observed upon anti-CD3 stimulation. Both the supernatant of iNKT cells and iNKT cells themselves exerted similar stimulation effects on PBMC proliferation in functional assays and these stimulations showed a negative correlation with FoxP3 expression. Our data indicate that the FoxP3 expression in iNKT cells may be a key transcriptional factor in controlling the regulatory function of the iNKT cells. C1 [Engelmann, Peter; Farkas, Klara; Kis, Janos; Richman, Geoffrey; Jalahej, Heyam; Orban, Tihamer] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02115 USA. [Engelmann, Peter] Univ Pecs, Ctr Clin, Dept Immunol & Biotechnol, Pecs, Hungary. [Farkas, Klara] Bajcsy Zsilinszky Hosp, Dept Med, Budapest, Hungary. [Kis, Janos] Polyclin Hosp Bros St John, Dept Internal Med, Budapest, Hungary. [Zhang, Zhaoyun] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Vasc Cell Biol, Boston, MA 02115 USA. [Liew, Chong Wee] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Med, Boston, MA 02115 USA. [Borowiec, Maciej; Niewczas, Monika A.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02115 USA. [Borowiec, Maciej] Med Univ Lodz, Dept Pediat, PL-91738 Lodz, Poland. RP Orban, T (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Immunol & Immunogenet, 1 Joslin Pl, Boston, MA 02115 USA. EM tihamer.orban@joslin.harvard.edu RI Borowiec, Maciej/S-9220-2016 NR 68 TC 12 Z9 12 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD AUG PY 2011 VL 23 IS 8 BP 473 EP 484 DI 10.1093/intimm/dxr040 PG 12 WC Immunology SC Immunology GA 796SX UT WOS:000293073600002 PM 21708895 ER PT J AU Esselen, KM Boruta, DM del Carmen, M Schorge, JO Goodman, A Growdon, WB AF Esselen, Katharine M. Boruta, David M. del Carmen, Marcela Schorge, John O. Goodman, Annekathryn Growdon, Whitfield B. TI Defining Prognostic Variables in Recurrent Endometrioid Endometrial Cancer A 15-Year Single-Institution Review SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Endometrioid endometrial cancer; Recurrence; Survival ID GYNECOLOGIC-ONCOLOGY-GROUP; CLINICAL STAGE-I; RANDOMIZED-TRIAL; RISK-FACTORS; FOLLOW-UP; CARCINOMA; RADIOTHERAPY; MANAGEMENT; SURGERY; ADENOCARCINOMA AB Objective: This study aimed to examine the pattern of recurrence in patients with endometrioid endometrial cancer and to identify clinically important prognostic factors in the recurrent population. Methods: With institutional review board approval, a retrospective review identified 1061 patients who underwent primary surgery and treatment of endometrioid endometrial cancer at our institution from 1994 to 2007. Of this cohort, 77 (7.2%) patients developed a recurrence. Clinical factors were recorded, and Spearman correlation coefficients and chi(2) test were used to determine associations between groups. Kaplan-Meier survival estimates and Cox proportional-hazards model were used to determine how prognostic variables affected survival after recurrence (RS) and overall survival (OS). Results: Of 77 patients, site of recurrence was not available in 5 patients. The distribution of recurrence in the remaining 72 patients was as follows: isolated vaginal 18% (13/72), nonvaginal pelvic 12% (9/72), distant 31% (22/72), abdominal 24% (17/72), and nodal 15% (11/72). There was an overrepresentation of advanced stage (P < 0.001) and high-grade (P < 0.003) at presentation in the recurrent group. Median OS was 3.4 years and median RS was 1.3 years. Low-grade tumors, early stage, and those with less than 50% myometrial invasion were associated with a significant OS and RS advantage. Age-adjusted isolated vaginal recurrence presented with a 1.2-year RS survival advantage (P < 0.03). An age-adjusted Cox proportional hazard ratio model incorporating significant prognostic variables demonstrated that the only independent variable associated with worse OS and RS was increased histologic grade with a hazard ratio of 2.31 (95% confidence interval, 1.25Y3.97) for RS and 2.44 (95% confidence interval, 1.41-4.62) for OS. Conclusions: Those patients with high-grade histology at the time of initial diagnosis manifest a decreased OS and RS, suggesting that the intrinsic biology of the tumor has the greatest prognostic importance. C1 [Esselen, Katharine M.; Boruta, David M.; del Carmen, Marcela; Schorge, John O.; Goodman, Annekathryn; Growdon, Whitfield B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept OB GYN,Div Gynecol Oncol, Boston, MA USA. RP Growdon, WB (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, Boston, MA 02114 USA. EM wgrowdon@partners.org NR 20 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD AUG PY 2011 VL 21 IS 6 BP 1078 EP 1083 DI 10.1097/IGC.0b013e31821872f4 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 797ZO UT WOS:000293169500018 PM 21633304 ER PT J AU Arvold, ND Niemierko, A Mamon, HJ Fernandez-del Castillo, C Hong, TS AF Arvold, Nils D. Niemierko, Andrzej Mamon, Harvey J. Fernandez-del Castillo, Carlos Hong, Theodore S. TI PANCREATIC CANCER TUMOR SIZE ON CT SCAN VERSUS PATHOLOGIC SPECIMEN: IMPLICATIONS FOR RADIATION TREATMENT PLANNING SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Pancreatic cancer; CT; Pathology; Radiation; CTV formula ID STEREOTACTIC BODY RADIOTHERAPY; PHASE-II; CURATIVE RESECTION; ADENOCARCINOMA; GEMCITABINE; CARCINOMA; PATTERNS; FAILURE; RADIOSURGERY; SURVIVAL AB Purpose: Pancreatic cancer primary tumor size measurements are often discordant between computed tomography (CT) and pathologic specimen after resection. Dimensions of the primary tumor are increasingly relevant in an era of highly conformal radiotherapy. Methods and Materials: We retrospectively evaluated 97 consecutive patients with resected pancreatic cancer at two Boston hospitals. All patients had CT scans before surgical resection. Primary endpoints were maximum dimension (in millimeters) of the primary tumor in any direction as reported by the radiologist on CT and by the pathologist for the resected gross fresh specimen. Endoscopic ultrasound (EUS) findings were analyzed if available. Results: Of the patients, 87 (90%) had preoperative CT scans available for review and 46 (47%) had EUS. Among proximal tumors (n = 69), 40 (58%) had pathologic duodenal invasion, which was seen on CT in only 3 cases. The pathologic tumor size was a median of 7 mm larger compared with CT size for the same patient (range, 15 to 43 mm; p < 0.0001), with 73 patients (84%) having a primary tumor larger on pathology than CT. Endoscopic ultrasound was somewhat more accurate, with pathologic tumor size being a median of only 5 mm larger compared with EUS size (range, 15 to 35 mm; p = 0.0003). Conclusions: Computed tomography scans significantly under-represent pancreatic cancer tumor size compared with pathologic specimens in resectable cases. We propose a clinical target volume expansion formula for the primary tumor based on our data. The high rate of pathologic duodenal invasion suggests a risk of duodenal under-coverage with highly conformal radiotherapy. (C) 2011 Elsevier Inc. C1 [Niemierko, Andrzej; Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Arvold, Nils D.] Harvard Radiat Oncol Program, Boston, MA USA. [Fernandez-del Castillo, Carlos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mamon, Harvey J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM Tshong1@partners.org FU NCI NIH HHS [P01 CA021239] NR 30 TC 21 Z9 23 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2011 VL 80 IS 5 BP 1383 EP 1390 DI 10.1016/j.ijrobp.2010.04.058 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 798LL UT WOS:000293207600016 PM 20708856 ER PT J AU Sher, DJ Balboni, TA Haddad, RI Norris, CM Posner, MR Wirth, LJ Goguen, LA Annino, D Tishler, RB AF Sher, David J. Balboni, Tracy A. Haddad, Robert I. Norris, Charles M., Jr. Posner, Marshall R. Wirth, Lori J. Goguen, Laura A. Annino, Donald Tishler, Roy B. TI EFFICACY AND TOXICITY OF CHEMORADIOTHERAPY USING INTENSITY-MODULATED RADIOTHERAPY FOR UNKNOWN PRIMARY OF HEAD AND NECK SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Head and neck cancer; Intensity-modulated radiotherapy; IMRT; Unknown primary; Combined modality therapy ID SQUAMOUS-CELL CARCINOMA; LYMPH-NODE METASTASES; HUMAN-PAPILLOMAVIRUS; RADIATION-THERAPY; PRIMARY SITE; RISK-FACTOR; CANCER; MANAGEMENT AB Purpose: No single standard treatment paradigm is available for head-and-neck squamous cell carcinoma of an unknown primary (HNCUP). Bilateral neck radiotherapy with mucosal axis irradiation is widely used, with or without chemotherapy and/or surgical resection. Intensity-modulated radiotherapy (IMRT) is a highly conformal method for delivering radiation that is becoming the standard of care and might reduce the long-term treatment-related sequelae. We report the Dana-Farber Cancer Institute experience with IMRT-based treatment for HNCUP. Patients and Materials: A retrospective study of all patients treated at the Dana-Farber Cancer Institute for HNCUP with IMRT between August 2004 and January 2009. The primary endpoint was overall survival; the secondary endpoints were locoregional and distant control, and acute and chronic toxicity. Results: A total of 24 patients with HNCUP were included. Of these patients, 22 had Stage N2 disease or greater. All patients underwent neck computed tomography, positron emission tomography-computed tomography, and examination under anesthesia with directed biopsies. Of the 24 patients, 22 received concurrent chemotherapy, and 7 (29%) also underwent induction chemotherapy. The median involved nodal dose was 70 Gy, and the median mucosal dose was 60 Gy. With a median follow-up of 2.1 years, the 2-year actuarial overall survival and locoregional control rate was 92% and 100%, respectively. Only 25% of the patients had Grade 2 xerostomia, although 11 patients (46%) required esophageal dilation for stricture. Conclusion: In a single-institution series, IMRT-based chemoradiotherapy for HNCUP was associated with superb overall survival and locoregional control. The xerostomia rates were promising, but the aggressive therapy was associated with significant rates of esophageal stenosis. (C) 2011 Elsevier Inc. C1 [Sher, David J.; Balboni, Tracy A.; Tishler, Roy B.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Haddad, Robert I.; Posner, Marshall R.] Brigham & Womens Hosp, Dept Med, Div Otolaryngol, Boston, MA 02115 USA. [Haddad, Robert I.; Posner, Marshall R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Norris, Charles M., Jr.; Goguen, Laura A.; Annino, Donald] Brigham & Womens Hosp, Dept Surg, Div Otolaryngol, Boston, MA 02115 USA. [Wirth, Lori J.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. RP Sher, DJ (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM dsher@lroc.harvard.edu NR 25 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2011 VL 80 IS 5 BP 1405 EP 1411 DI 10.1016/j.ijrobp.2010.04.029 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 798LL UT WOS:000293207600019 PM 21177045 ER PT J AU Grassberger, C Trofimov, A Lomax, A Paganetti, H AF Grassberger, Clemens Trofimov, Alexei Lomax, Anthony Paganetti, Harald TI VARIATIONS IN LINEAR ENERGY TRANSFER WITHIN CLINICAL PROTON THERAPY FIELDS AND THE POTENTIAL FOR BIOLOGICAL TREATMENT PLANNING SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Protons; Monte Carlo; Linear energy transfer (LET); Relative biological effectiveness (RBE); IMPT ID TREATMENT UNCERTAINTIES; DOSE DISTRIBUTION; BEAM THERAPY; V79 CELLS; RBE; DISTRIBUTIONS; SENSITIVITY; FACILITY AB Purpose: To calculate the linear energy transfer (LET) distributions in patients undergoing proton therapy. These distributions can be used to identify areas of elevated or diminished biological effect. The location of such areas might be influenced in intensity-modulated proton therapy (IMPT) optimization. Methods and Materials: Because Monte Carlo studies to investigate the LET distribution in patients have not been undertaken so far, the code is first validated with simulations in water. The code was used in five patients, for each of them three planning and delivery techniques were simulated: passive scattering, three-dimensional modulation IMPT (3D-IMPT), and distal edge tracking IMPT (DET-IMPT). Results: The inclusion of secondary particles led to significant differences compared with analytical techniques. In addition, passive scattering and 3D-IMPT led to largely comparable LET distributions, whereas the DET-IMPT plans resulted in considerably increased LET values in normal tissues and critical structures. In the brainstem, dose-averaged LET values exceeding 5 keV/mu m were observed in areas with significant dose (>70% of prescribed dose). In noncritical normal tissues, even values >8 keV/mu m occurred. Conclusion: This work demonstrates that active scanning offers the possibility of influencing the distribution of dose-averaged LET (i.e., the biological effect) without significantly altering the distribution of physical dose. On the basis of this finding, we propose a method to alter deliberately the LET distribution of a treatment plan in such a manner that the LET is maximized within certain target areas and minimized in normal tissues, while maintaining the prescribed target dose and dose constraints for organs at risk. (C) 2011 Elsevier Inc. C1 [Grassberger, Clemens] Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Dept Radiat Oncol, Boston, MA 02114 USA. [Grassberger, Clemens; Trofimov, Alexei; Paganetti, Harald] Harvard Univ, Sch Med, Boston, MA USA. [Grassberger, Clemens; Lomax, Anthony] Paul Scherrer Inst, Ctr Proton Radiotherapy, Villigen, Switzerland. RP Grassberger, C (reprint author), Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Dept Radiat Oncol, Boston, MA 02114 USA. EM cgrassberger@partners.org FU Massachusetts General Hospital [C06 CA059267] FX The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. NR 26 TC 51 Z9 51 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2011 VL 80 IS 5 BP 1559 EP 1566 DI 10.1016/j.ijrobp.2010.10.027 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 798LL UT WOS:000293207600039 PM 21163588 ER PT J AU Peng, RD Paigen, B Eggleston, PA Hagberg, KA Krevans, M Curtin-Brosnan, J Benson, C Shreffler, WG Matsui, EC AF Peng, Roger D. Paigen, Beverly Eggleston, Peyton A. Hagberg, Karol A. Krevans, Mary Curtin-Brosnan, Jean Benson, Cristy Shreffler, Wayne G. Matsui, Elizabeth C. TI Both the variability and level of mouse allergen exposure influence the phenotype of the immune response in workers at a mouse facility SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Mouse allergen; IgE; IgG(4); laboratory animal allergy ID LABORATORY-ANIMAL WORKERS; RAT URINARY ALLERGENS; UNITED-STATES; CAT ALLERGEN; SENSITIZATION; ASTHMA; ANTIBODIES; CHILDREN; IGE; PREVALENCE AB Background: The role of natural aeroallergen exposure in modulating allergen-specific immune responses is not well understood. Objective: We sought to examine relationships between mouse allergen exposure and mouse-specific immune responses. Methods: New employees (n = 179) at a mouse facility underwent repeated assessment of mouse allergen exposure, skin prick tests (SPTs), and measurement of mouse-specific IgG levels. Relationships between the mean level of exposure, variability of exposure (calculated as log deviation), and time to development of immunologic outcomes were examined by using Cox proportional hazards models. Results: By 24 months, 32 (23%) participants had experienced a positive SPT response, and 10 (8%) had mouse-specific IgG(4). The incidence of a positive SPT response increased as levels of exposure increased from low to moderate, peaking at 1.2 ng/m(3), and decreased beyond this point (P = .04). The more variable the exposure was across visits, the lower the incidence of a positive SPT response (hazard ratio [HR], 0.17; 95% CI, 0.07-0.41). Variability of exposure was an independent predictor of a positive SPT response in a model that included both exposure metrics. In contrast, the incidence of mouse-specific IgG(4) increased with increasing levels of mouse allergen exposure (HR, 2.9; 95% CI, 1.4-6.0), and there was evidence of a higher risk of mouse-specific IgG(4) with greater variability of exposure (HR, 6.3; 95% CI, 0.4-95.2). Conclusion: Both the level and variability of mouse allergen exposure influence the humoral immune response, with specific patterns of exposure associated with specific immunophenotypes. Exposure variability might be a more important predictor of a positive SPT response, whereas the average exposure level might be a more important predictor of mouse-specific IgG(4). (J Allergy Clin Immunol 2011;128:390-6.) C1 [Peng, Roger D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Paigen, Beverly; Hagberg, Karol A.; Krevans, Mary; Benson, Cristy] Jackson Lab, Bar Harbor, ME 04609 USA. [Eggleston, Peyton A.; Curtin-Brosnan, Jean; Matsui, Elizabeth C.] Johns Hopkins Sch Med, Div Pediat Allergy & Immunol, Baltimore, MD USA. [Shreffler, Wayne G.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. RP Matsui, EC (reprint author), Johns Hopkins Univ Hosp, CMSC 1102,600 N Wolfe St, Baltimore, MD 21287 USA. EM ematsui@jhmi.edu FU National Institute of Allergy and Infectious Disease [R01AI070630, R01AI0818451, R03AI0629745, K23AI060955]; National Institutes of Health; Environmental Protection Agency FX Supported by the National Institute of Allergy and Infectious Disease (R01AI070630, R01AI0818451, R03AI0629745, and K23AI060955).; R. D. Peng receives research support from the National Institutes of Health and the Environmental Protection Agency. E. C. Matsui receives research support from the National Institutes of Health and the Environmental Protection Agency. The rest of the authors have declared that they have no conflict of interest. NR 35 TC 18 Z9 18 U1 2 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2011 VL 128 IS 2 BP 390 EP U414 DI 10.1016/j.jaci.2011.04.050 PG 14 WC Allergy; Immunology SC Allergy; Immunology GA 799IQ UT WOS:000293280800021 PM 21696812 ER PT J AU Kim, BG Park, YJ Libermann, TA Cho, JY AF Kim, Byung-Gyu Park, Youn-Je Libermann, Towia A. Cho, Je-Yoel TI PTH Regulates Myleoid ELF-1-Like Factor (MEF)-Induced MAB-21-Like-1 (MAB21L1) Expression Through the JNK1 Pathway SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE ETS TRANSCRIPTION FACTOR; OSTEOBLAST; PARATHYROID HORMONE; MASS SPECTROMETRY; MAB21; JNK ID ETS TRANSCRIPTION FACTORS; SIGNAL-TRANSDUCTION PATHWAYS; PARATHYROID-HORMONE 1-34; OSTEOBLASTIC CELLS; MATRIX MINERALIZATION; PROTEIN EXPRESSION; TERMINAL KINASE; UP-REGULATION; NEURAL-TUBE; MAP-KINASE AB Continuous treatment with parathyroid hormone (PTH) or excess endogenous PTH due to primary hyperparathyroidism causes increased bone resorption and, subsequently, decreased bone volume. Our previous studies showed that myeloid Elf-1-like factor (MEF) not only suppresses osteoblast differentiation through inhibition of Runx2 activity and other osteogenesis-related genes but also specifically increases the expression of Mab21, a potential transcriptional repressor of osteoblast differentiation. Here we show that the JNK1 pathway is involved in the MEF-mediated up-regulation of Mab21 expression due to PTH stimulation. PTH increased the transcription level of Mab21 in MG63 human osteoblastic cells, in contrast to the suppressive effect of TGF beta 1. PTH phosphorylates serine residues of MEF as well as c-Jun, a known substrate of JNK1. By in vitro kinase assay, we confirmed that MEF is phosphorylated by JNK1, but not by ERK. Co-transfection of MEF with both MKK4 and JNK1 increased the promoter activity of Mab21 in CV1 cells significantly more than MEF alone. We also identified the phosphorylation of MEF serine 641 by in vitro and in vivo JNK1 kinase assays combined with a proteomics approach. In conclusion, our findings indicate that MEF is involved in PTH suppression of osteoblasts through activating the MKK4/JNK1 pathway and subsequently up-regulating Mab21 expression. J. Cell. Biochem. 112: 2051-2061, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Kim, Byung-Gyu; Cho, Je-Yoel] Kyungpook Natl Univ, Sch Dent, Dept Biochem, Taegu 700422, South Korea. [Park, Youn-Je] CHA Univ, Dept Appl Biosci, Seoul 135081, South Korea. [Libermann, Towia A.] Harvard Univ, Sch Med, BIDMC Genom Ctr, Boston, MA USA. RP Cho, JY (reprint author), Kyungpook Natl Univ, Sch Dent, Dept Biochem, 101 Dong In Dong, Taegu 700422, South Korea. EM tliberma@bidmc.harvard.edu; jeycho@knu.ac.kr OI Libermann, Towia/0000-0002-4006-8179 FU Korea government [2010-0020544, 2010-0029494] FX Grant sponsor: National Research Foundation of Korea (NRF) grant funded by the Korea government; Grant numbers: 2010-0020544, 2010-0029494. NR 49 TC 1 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD AUG PY 2011 VL 112 IS 8 BP 2051 EP 2061 DI 10.1002/jcb.23124 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 800AP UT WOS:000293329300012 PM 21465527 ER PT J AU Lauer, A Schlunk, F van Cott, EM Steinmetz, H Lo, EH Foerch, C AF Lauer, Arne Schlunk, Frieder van Cott, Elizabeth M. Steinmetz, Helmuth Lo, Eng H. Foerch, Christian TI Antiplatelet pretreatment does not increase hematoma volume in experimental intracerebral hemorrhage SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE aspirin; clopidogrel; intracerebral hemorrhage; mice; platelets ID INDEPENDENT PREDICTOR; PLATELET-AGGREGATION; THROMBUS FORMATION; ASPIRIN; THERAPY; MOUSE; CLOPIDOGREL; HEMOSTASIS; ACTIVATION; EXPANSION AB While oral anticoagulants are associated with greater hematoma expansion and higher mortality rates in patients with intracerebral hemorrhage (ICH), there is ongoing discussion whether pretreatment with antiplatelet drugs also worsens prognosis. Using an experimental model of ICH, we investigated the effects of antiplatelet pretreatment on hematoma volume and functional outcome. CD-1 mice were treated with acetyl-salicylic acid (ASA, 60 mg/kg per 24 hours), clopidogrel (22.5 mg/kg per 24 hours), or both (ASA + clopidogrel) through drinking water for 3 days (n = 20 per group). Thereafter, platelet aggregation was found to be significantly reduced. Untreated mice and mice pretreated with warfarin served as controls. A stereotactic injection of collagenase into the right striatum was used to induce ICH. Twenty-four hours after ICH induction, hematoma volume was measured to be 15.0 +/- 4.4 mu L in controls, 14.1 +/- 5.3 mu L in ASA mice, 16.8 +/- 5.1 mu L in clopidogrel mice, and 16.4 +/- 5.1 mu L in ASA + clopidogrel animals. These differences were not statistically significant. However, mice pretreated with warfarin revealed largely increased hematoma volumes (25.0 +/- 7.4 mu L versus controls, P = 0.001). Neurologic outcome was not different between antiplatelet-pretreated animals and untreated controls. Our results suggest that plasmatic coagulation rather than platelet function is the most critical element for preventing hematoma expansion in acute ICH. Future therapeutic strategies may take these findings into account. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1736-1742; doi:10.1038/jcbfm.2011.22; published online 9 March 2011 C1 [Lauer, Arne; Schlunk, Frieder; Steinmetz, Helmuth; Foerch, Christian] Goethe Univ Frankfurt, Dept Neurol, D-60528 Frankfurt, Germany. [van Cott, Elizabeth M.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Lauer, Arne; Schlunk, Frieder; Lo, Eng H.; Foerch, Christian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab, Boston, MA USA. RP Foerch, C (reprint author), Goethe Univ Frankfurt, Dept Neurol, Schleusenweg 2-16, D-60528 Frankfurt, Germany. EM foerch@em.uni-frankfurt.de FU NIH [R37-NS37074, R01-NS56458, P01-NS55104] FX This study was supported in part by NIH grants R37-NS37074, R01-NS56458, P01-NS55104. NR 29 TC 10 Z9 11 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 2011 VL 31 IS 8 BP 1736 EP 1742 DI 10.1038/jcbfm.2011.22 PG 7 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 800EH UT WOS:000293342100010 PM 21386857 ER PT J AU Sun, PZ Cheung, JS Wang, EF Lo, EH AF Sun, Phillip Zhe Cheung, Jerry S. Wang, Enfeng Lo, Eng H. TI Association between pH-weighted endogenous amide proton chemical exchange saturation transfer MRI and tissue lactic acidosis during acute ischemic stroke SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE acute stroke; animal studies; brain ischemia; diffusion-weighted MRI; MRI ID MAGNETIC-RESONANCE-SPECTROSCOPY; EXPERIMENTAL CEREBRAL-ISCHEMIA; BLOOD-FLOW; TRANSFER CEST; SPREADING DEPRESSION; ENERGY METABOLITES; NMR-SPECTROSCOPY; INTRACELLULAR PH; EXTRACELLULAR PH; DIFFUSION AB The ischemic tissue becomes acidic after initiation of anaerobic respiration, which may result in impaired tissue metabolism and, ultimately, in severe tissue damage. Although changes in the major cerebral metabolites can be studied using magnetic resonance (MR) spectroscopy (MRS)-based techniques, their spatiotemporal resolution is often not sufficient for routine examination of fast-evolving and heterogeneous acute stroke lesions. Recently, pH-weighted MR imaging (MRI) has been proposed as a means to assess tissue acidosis by probing the pH-dependent chemical exchange of amide protons from endogenous proteins and peptides. In this study, we characterized acute ischemic tissue damage using localized proton MRS and multiparametric imaging techniques that included perfusion, diffusion, pH, and relaxation MRI. Our study showed that pH-weighted MRI can detect ischemic lesions and strongly correlates with tissue lactate content measured by (1)H MRS, indicating lactic acidosis. Our results also confirmed the correlation between apparent diffusion coefficient and lactate; however, no significant relationship was found for perfusion, T(1), and T(2). In summary, our study showed that optimized endogenous pH-weighted MRI, by sensitizing to local tissue pH, remains a promising tool for providing a surrogate imaging marker of lactic acidosis and altered tissue metabolism, and augments conventional techniques for stroke diagnosis. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1743-1750; doi:10.1038/jcbfm.2011.23; published online 9 March 2011 C1 [Sun, Phillip Zhe; Cheung, Jerry S.; Wang, Enfeng] MGH, Dept Radiol, Athinoula A Martinos Ctr Biomed, Charlestown, MA 02129 USA. [Sun, Phillip Zhe; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroprotect Res Lab,Dept Radiol & Neurol, Charlestown, MA 02129 USA. RP Sun, PZ (reprint author), MGH, Dept Radiol, Athinoula A Martinos Ctr Biomed, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM pzhesun@nmr.mgh.harvard.edu FU [AHA/SDG 0835384N]; [NIH/NIBIB 1K01EB009771-01]; [NIH/1R21NS061119]; [NIH/NCRR-P41RR14075] FX This study was supported in part by grants from AHA/SDG 0835384N, NIH/NIBIB 1K01EB009771-01, NIH/1R21NS061119, and NIH/NCRR-P41RR14075. This work has been presented at the Gordon Research Conference of in vivo MR in 2010. NR 52 TC 35 Z9 36 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 2011 VL 31 IS 8 BP 1743 EP 1750 DI 10.1038/jcbfm.2011.23 PG 8 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 800EH UT WOS:000293342100011 PM 21386856 ER PT J AU Jorgensen, JH McElmeel, ML Fulcher, LC McGee, L Richter, SS Heilmann, KP Ferraro, MJ Spargo, J Glennen, A AF Jorgensen, James H. McElmeel, M. Leticia Fulcher, Letitia C. McGee, Lesley Richter, Sandra S. Heilmann, K. P. Ferraro, Mary Jane Spargo, Jean Glennen, Anita TI Collaborative Evaluation of an Erythromycin-Clindamycin Combination Well for Detection of Inducible Clindamycin Resistance in Beta-Hemolytic Streptococci by Use of the CLSI Broth Microdilution Method SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID MECHANISMS AB Constitutive or inducible clindamycin resistance can occur in beta-hemolytic streptococci due to the presence of an erm gene. The Clinical and Laboratory Standards Institute (CLSI) has recommended a disk approximation test (D-zone test) with erythromycin and clindamycin disks and a single-well broth test combining erythromycin and clindamycin for detection of inducible clindamycin resistance in staphylococci, but only a disk approximation test for the beta-hemolytic streptococci. This collaborative study assessed two different erythromycin and clindamycin concentration combinations in single wells (1 mu g/ml + 0.25 mu g/ml [erythromycin plus clindamycin] and 1 mu g/ml + 0.5 mu g/ml) with three different brands of Mueller-Hinton broth supplemented with 3% lysed horse blood for testing of frozen panels prepared for this study. All labs performed the D-zone test as described by the CLSI. A total of 155 nonduplicate streptococcal isolates (50 group A, 48 group B, 28 group C, and 29 group G isolates) were tested; 99 isolates showed inducible resistance by the D-zone test. There were some differences noted based upon the test medium. The sensitivity of the erythromycin plus clindamycin combination of 1 mu g/ml + 0.25 mu g/ml was 91 to 100%, while the sensitivity of the combination of 1 mu g/ml + 0.5 mu g/ml was 95 to 100%. Specificity overall was 98%. The slightly higher sensitivity of the combination of 1 mu g/ml + 0.5 mu g/ml is recommended. This study has demonstrated that a single-well microdilution test incorporating erythromycin and clindamycin in combination is a sensitive and specific indicator of inducible clindamycin resistance and could be included in routine test panels. C1 [Jorgensen, James H.; McElmeel, M. Leticia; Fulcher, Letitia C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [McGee, Lesley] Ctr Dis Control & Prevent, Resp Dis Branch, Atlanta, GA USA. [Richter, Sandra S.; Heilmann, K. P.] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. [Ferraro, Mary Jane; Spargo, Jean] Massachusetts Gen Hosp, Microbiol Lab, Boston, MA 02114 USA. [Glennen, Anita] Minnesota Dept Hlth, St Paul, MN USA. RP Jorgensen, JH (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM jorgensen@uthscsa.edu NR 12 TC 1 Z9 2 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2011 VL 49 IS 8 BP 2884 EP 2886 DI 10.1128/JCM.00912-11 PG 3 WC Microbiology SC Microbiology GA 798PE UT WOS:000293221900016 PM 21697321 ER PT J AU Budde, LE Guthrie, KA Till, BG Press, OW Chauncey, TR Pagel, JM Petersdorf, SH Bensinger, WI Holmberg, LA Shustov, AR Green, DJ Maloney, DG Gopal, AK AF Budde, Lihua E. Guthrie, Katherine A. Till, Brian G. Press, Oliver W. Chauncey, Thomas R. Pagel, John M. Petersdorf, Steven H. Bensinger, William I. Holmberg, Leona A. Shustov, Andrei R. Green, Damian J. Maloney, David G. Gopal, Ajay K. TI Mantle Cell Lymphoma International Prognostic Index but Not Pretransplantation Induction Regimen Predicts Survival for Patients With Mantle-Cell Lymphoma Receiving High-Dose Therapy and Autologous Stem-Cell Transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROGRESSION-FREE SURVIVAL; 1ST REMISSION; HYPER-CVAD; IMMUNOCHEMOTHERAPY; RITUXIMAB; RESCUE; TRIAL; MIPI; MCL AB Purpose High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of intensive induction regimens before transplantation is unknown. Patients and Methods To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers. Results The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio [HR], 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients <= 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT. Conclusion An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis. C1 [Budde, Lihua E.; Guthrie, Katherine A.; Till, Brian G.; Press, Oliver W.; Chauncey, Thomas R.; Pagel, John M.; Petersdorf, Steven H.; Bensinger, William I.; Holmberg, Leona A.; Shustov, Andrei R.; Green, Damian J.; Maloney, David G.; Gopal, Ajay K.] Univ Washington, Seattle, WA 98195 USA. [Budde, Lihua E.; Guthrie, Katherine A.; Till, Brian G.; Press, Oliver W.; Chauncey, Thomas R.; Pagel, John M.; Petersdorf, Steven H.; Bensinger, William I.; Holmberg, Leona A.; Shustov, Andrei R.; Green, Damian J.; Maloney, David G.; Gopal, Ajay K.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Chauncey, Thomas R.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. RP Gopal, AK (reprint author), 825 Eastlake Ave E,G3-200, Seattle, WA 98109 USA. EM agopal@u.washington.edu FU National Institutes of Health [PO1CA44991]; Lymphoma Research Foundation Mantle Cell Lymphoma Initiative; Leukemia and Lymphoma Society; Mary A. Wright Memorial Research Fund FX Supported by National Institutes of Health Grant No. PO1CA44991, the Lymphoma Research Foundation Mantle Cell Lymphoma Initiative, Specialized Center of Research Grant No. 7040 from the Leukemia and Lymphoma Society, the Mary A. Wright Memorial Research Fund, and a donation from Frank and Betty Vandermeer. L.E.B. is a Special Fellow in Clinical Research of the Leukemia and Lymphoma Society. A.K.G. is a Scholar in Clinical Research of the Leukemia and Lymphoma Society. NR 19 TC 41 Z9 44 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2011 VL 29 IS 22 BP 3023 EP 3029 DI 10.1200/JCO.2010.33.7055 PG 7 WC Oncology SC Oncology GA 798PG UT WOS:000293222200021 PM 21730271 ER PT J AU Fourney, DR Frangou, EM Ryken, TC DiPaola, CP Shaffrey, CI Berven, SH Bilsky, MH Harrop, JS Fehlings, MG Boriani, S Chou, D Schmidt, MH Polly, DW Biagini, R Burch, S Dekutoski, MB Ganju, A Gerszten, PC Gokaslan, ZL Groff, MW Liebsch, NJ Mendel, E Okuno, SH Patel, S Rhines, LD Rose, PS Sciubba, DM Sundaresan, N Tomita, K Varga, PP Vialle, LR Vrionis, FD Yamada, Y Fisher, CG AF Fourney, Daryl R. Frangou, Evan M. Ryken, Timothy C. DiPaola, Christian P. Shaffrey, Christopher I. Berven, Sigurd H. Bilsky, Mark H. Harrop, James S. Fehlings, Michael G. Boriani, Stefano Chou, Dean Schmidt, Meic H. Polly, David W. Biagini, Roberto Burch, Shane Dekutoski, Mark B. Ganju, Aruna Gerszten, Peter C. Gokaslan, Ziya L. Groff, Michael W. Liebsch, Norbert J. Mendel, Ehud Okuno, Scott H. Patel, Shreyaskumar Rhines, Laurence D. Rose, Peter S. Sciubba, Daniel M. Sundaresan, Narayan Tomita, Katsuro Varga, Peter P. Vialle, Luiz R. Vrionis, Frank D. Yamada, Yoshiya Fisher, Charles G. TI Spinal Instability Neoplastic Score: An Analysis of Reliability and Validity From the Spine Oncology Study Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VERTEBRAL BODY; CORD COMPRESSION; METASTATIC-DISEASE; CANCER; AGREEMENT; SURGERY; PEDICLE; DEFECTS; TUMORS AB Purpose Standardized indications for treatment of tumor-related spinal instability are hampered by the lack of a valid and reliable classification system. The objective of this study was to determine the interobserver reliability, intraobserver reliability, and predictive validity of the Spinal Instability Neoplastic Score (SINS). Methods Clinical and radiographic data from 30 patients with spinal tumors were classified as stable, potentially unstable, and unstable by members of the Spine Oncology Study Group. The median category for each patient case (consensus opinion) was used as the gold standard for predictive validity testing. On two occasions at least 6 weeks apart, each rater also scored each patient using SINS. Each total score was converted into a three-category data field, with 0 to 6 as stable, 7 to 12 as potentially unstable, and 13 to 18 as unstable. Results The kappa statistics for interobserver reliability were 0.790, 0.841, 0.244, 0.456, 0.462, and 0.492 for the fields of location, pain, bone quality, alignment, vertebral body collapse, and posterolateral involvement, respectively. The kappa statistics for intraobserver reliability were 0.806, 0.859, 0.528, 0.614, 0.590, and 0.662 for the same respective fields. Intraclass correlation coefficients for inter-and intraobserver reliability of total SINS score were 0.846 (95% CI, 0.773 to 0.911) and 0.886 (95% CI, 0.868 to 0.902), respectively. The kappa statistic for predictive validity was 0.712 (95% CI, 0.676 to 0.766). Conclusion SINS demonstrated near-perfect inter- and intraobserver reliability in determining three clinically relevant categories of stability. The sensitivity and specificity of SINS for potentially unstable or unstable lesions were 95.7% and 79.5%, respectively. J Clin Oncol 29: 3072-3077. (C) 2011 by American Society of Clinical Oncology C1 [Fourney, Daryl R.] Univ Saskatchewan, Royal Univ Hosp, Neurosurg Residency Training Program, Saskatoon, SK S7N 0W8, Canada. [DiPaola, Christian P.; Fisher, Charles G.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Fehlings, Michael G.] Univ Toronto, Toronto, ON, Canada. [Ryken, Timothy C.] Iowa Spine & Brain Inst, Waterloo, IA USA. [Shaffrey, Christopher I.] Univ Virginia, Med Ctr, Charlottesville, VA USA. [Berven, Sigurd H.; Chou, Dean; Burch, Shane] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bilsky, Mark H.; Yamada, Yoshiya] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sundaresan, Narayan] Mt Sinai Hosp, New York, NY 10029 USA. [Harrop, James S.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Gerszten, Peter C.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Boriani, Stefano] Ausl Bologna, Osped Maggiore, Bologna, Italy. [Biagini, Roberto] Regina Elena Inst Canc Res, Rome, Italy. [Schmidt, Meic H.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Schmidt, Meic H.] Univ Utah, Clin Neurosci Ctr, Salt Lake City, UT USA. [Polly, David W.] Univ Minnesota, Minneapolis, MN USA. [Dekutoski, Mark B.; Okuno, Scott H.; Rose, Peter S.] Mayo Clin, Rochester, MN USA. [Ganju, Aruna] Northwestern Univ, Chicago, IL 60611 USA. [Gokaslan, Ziya L.; Sciubba, Daniel M.] Johns Hopkins Univ, Baltimore, MD USA. [Groff, Michael W.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Liebsch, Norbert J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mendel, Ehud] Ohio State Univ, Columbus, OH 43210 USA. [Patel, Shreyaskumar; Rhines, Laurence D.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Tomita, Katsuro] Kanazawa Univ, Sch Med, Kanazawa, Ishikawa 920, Japan. [Varga, Peter P.] Natl Ctr Spinal Disorders, Budapest, Hungary. [Vialle, Luiz R.] Catholic Univ Parana, Curitiba, Parana, Brazil. [Vrionis, Frank D.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. RP Fourney, DR (reprint author), Univ Saskatchewan, Royal Univ Hosp, Neurosurg Residency Training Program, 103 Hosp Dr, Saskatoon, SK S7N 0W8, Canada. EM daryl.fourney@usask.ca OI Biagini, Roberto/0000-0002-6819-2841; Bilsky, Mark/0000-0001-6091-0709 NR 31 TC 94 Z9 101 U1 2 U2 14 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2011 VL 29 IS 22 BP 3072 EP 3077 DI 10.1200/JCO.2010.34.3897 PG 6 WC Oncology SC Oncology GA 798PG UT WOS:000293222200028 PM 21709187 ER PT J AU Wagle, N Emery, C Berger, MF Davis, MJ Sawyer, A Pochanard, P Kehoe, SM Johannessen, CM MacConaill, LE Hahn, WC Meyerson, M Garraway, LA AF Wagle, Nikhil Emery, Caroline Berger, Michael F. Davis, Matthew J. Sawyer, Allison Pochanard, Panisa Kehoe, Sarah M. Johannessen, Cory M. MacConaill, Laura E. Hahn, William C. Meyerson, Matthew Garraway, Levi A. TI Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; GASTROINTESTINAL STROMAL TUMORS; CHRONIC MYELOGENOUS LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; IRREVERSIBLE EGFR INHIBITOR; METASTATIC BREAST-CANCER; FACIO-CUTANEOUS SYNDROME AB A detailed understanding of the mechanisms by which tumors acquire resistance to targeted anticancer agents should speed the development of treatment strategies with lasting clinical efficacy. RAF inhibition in BRAF-mutant melanoma exemplifies the promise and challenge of many targeted drugs; although response rates are high, resistance invariably develops. Here, we articulate overarching principles of resistance to kinase inhibitors, as well as a translational approach to characterize resistance in the clinical setting through tumor mutation profiling. As a proof of principle, we performed targeted, massively parallel sequencing of 138 cancer genes in a tumor obtained from a patient with melanoma who developed resistance to PLX4032 after an initial dramatic response. The resulting profile identified an activating mutation at codon 121 in the downstream kinase MEK1 that was absent in the corresponding pretreatment tumor. The MEK1(C121S) mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro. Thus, MEK1(C121S) or functionally similar mutations are predicted to confer resistance to combined MEK/RAF inhibition. These results provide an instructive framework for assessing mechanisms of acquired resistance to kinase inhibition and illustrate the use of emerging technologies in a manner that may accelerate personalized cancer medicine. J Clin Oncol 29: 3085-3096. (C) 2011 by American Society of Clinical Oncology C1 [Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. RP Garraway, LA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,D1542, Boston, MA 02115 USA. EM levi_garraway@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; Davis, Matt/F-9045-2012 FU National Institutes of Health [DP2OD002750]; National Cancer Institute [R33CA126674, U24CA143867]; Starr Cancer Consortium; Melanoma Research Alliance; Novartis Institutes for BioMedical Research; Burroughs-Wellcome Fund FX Supported by the National Institutes of Health Director's New Innovator Award, Grant No. DP2OD002750 (L.A.G.), Grants No. R33CA126674 and U24CA143867 from the National Cancer Institute (L.A.G., M.M., W.C.H.), the Starr Cancer Consortium (L.A.G., M.M.), the Melanoma Research Alliance (L.A.G.), the Novartis Institutes for BioMedical Research (L.A.G., M.M.), and the Burroughs-Wellcome Fund (L.A.G.). NR 125 TC 449 Z9 461 U1 5 U2 60 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2011 VL 29 IS 22 BP 3085 EP 3096 DI 10.1200/JCO.2010.33.2312 PG 12 WC Oncology SC Oncology GA 798PG UT WOS:000293222200030 PM 21383288 ER PT J AU Tomatis, C Taramona, C Rizo-Patron, E Hernandez, F Rodriguez, P Piscoya, A Gonzales, E Gotuzzo, E Heudebert, G Centor, RM Estrada, CA AF Tomatis, Cristina Taramona, Claudia Rizo-Patron, Emiliana Hernandez, Fiorela Rodriguez, Patricia Piscoya, Alejandro Gonzales, Elsa Gotuzzo, Eduardo Heudebert, Gustavo Centor, Robert M. Estrada, Carlos A. TI Evidence-based medicine training in a resource-poor country, the importance of leveraging personal and institutional relationships SO JOURNAL OF EVALUATION IN CLINICAL PRACTICE LA English DT Article DE developing countries; education; evidence-based medicine; evidence-based practice; international cooperation ID PUBLIC-HEALTH; CLINICAL-PRACTICE; DEVELOPING-WORLD; SELF-ASSESSMENT; CAPACITY; PRACTITIONERS; KNOWLEDGE; ATTITUDES; SETTINGS; PROGRAMS AB Rationale, aims and objectives Efforts to implement evidence-based medicine (EBM) training in developing countries are limited. We describe the results of an international effort to improve research capacity in a developing country; we conducted a course aimed at improving basic EBM attitudes and identified challenges. Method Between 2005 and 2009, we conducted an annual 3-day course in Peru consisting of interactive lectures and case-based workshops. We assessed self-reported competence and importance in EBM using a Likert scale (1 = low, 5 = high). Results Totally 220 clinicians participated. For phase I (2005-2007), self-reported EBM competence increased from a median of 2 to 3 (P < 0.001) and the perceived importance of EBM did not change (median = 5). For phase II (2008-2009), before the course, 8-72% graded their competence very low (score of 1-2). After the course, 67-92% of subjects graded their increase in knowledge very high (score of 4-5). The challenges included limited availability of studies relevant to the local reality written in Spanish, participants' limited time and lack of long-term follow-up on practice change. Informal discussion and written evaluation from participants were universally in agreement that more training in EBM is needed. Conclusions In an EBM course in a resource-poor country, the baseline self-reported competence and experience on EBM were low, and the course had measurable improvements of self-reported competence, perceived utility and readiness to incorporate EBM into their practices. Similar to developed countries, translational research and building the research capacity in developing countries is critical for translating best available evidence into practice. C1 [Estrada, Carlos A.] Birmingham Vet Affairs Med Ctr, REAP Ctr Surg Med Acute Care Res & Transit, Deep S Ctr Effectiveness, Vet Affairs Natl Qual Scholars Program, Birmingham, AL 35294 USA. [Tomatis, Cristina; Taramona, Claudia; Rizo-Patron, Emiliana; Hernandez, Fiorela; Rodriguez, Patricia] Univ Peruana Cayetano Heredia, Lima, Peru. [Piscoya, Alejandro] Hosp Nacl Cayetano Heredia, Lima, Peru. [Gonzales, Elsa; Gotuzzo, Eduardo] Alexander von Humboldt Univ Peruana Cayetano Here, Inst Med Trop, Lima, Peru. [Heudebert, Gustavo] Univ Alabama, Internal Med Residency Program, Birmingham, AL USA. [Heudebert, Gustavo] Univ Alabama, Fac Dev, Birmingham, AL USA. [Heudebert, Gustavo; Centor, Robert M.; Estrada, Carlos A.] Univ Alabama, Div Gen Internal Med, Birmingham, AL USA. RP Estrada, CA (reprint author), Birmingham Vet Affairs Med Ctr, REAP Ctr Surg Med Acute Care Res & Transit, Deep S Ctr Effectiveness, Vet Affairs Natl Qual Scholars Program, Birmingham, AL 35294 USA. EM cestrada@uab.edu OI Piscoya, Alejandro/0000-0002-4420-2419 FU Peru ICOHRTA Network for AIDS/TB Research Training; Fogarty International Center [1U2RTW007368-01A1] FX We thank Dr Pedro Legua for providing logistical support and funding from Peru ICOHRTA Network for AIDS/TB Research Training. Grant 1U2RTW007368-01A1 - Fogarty International Center to Dr Gotuzzo. NR 54 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1356-1294 J9 J EVAL CLIN PRACT JI J. Eval. Clin. Pract. PD AUG PY 2011 VL 17 IS 4 BP 644 EP 650 DI 10.1111/j.1365-2753.2011.01635.x PG 7 WC Health Care Sciences & Services; Medical Informatics; Medicine, General & Internal SC Health Care Sciences & Services; Medical Informatics; General & Internal Medicine GA 798SO UT WOS:000293232400017 PM 21276140 ER PT J AU Goldberg, JI Rich, DR Muruganathan, SP Liu, MB Pon, JR Tam, R Diefenbach, TJ Kuang, SH AF Goldberg, Jeffrey I. Rich, Darren R. Muruganathan, Siva P. Liu, Maple B. Pon, Julia R. Tam, Rose Diefenbach, Thomas J. Kuang, Shihuan TI Identification and evolutionary implications of neurotransmitter-ciliary interactions underlying the behavioral response to hypoxia in Lymnaea stagnalis embryos SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE dopamine; gastropod; hypoxia; serotonin ID HELISOMA-TRIVOLVIS EMBRYOS; POND SNAIL EMBRYOS; SEROTONIN-LIKE IMMUNOREACTIVITY; APICAL SENSORY ORGAN; PROTEIN-KINASE-C; EGG MASSES; ANTIBACTERIAL ACTIVITY; ROTATIONAL BEHAVIOR; GAS-EXCHANGE; RECEPTORS AB Acceleration of embryonic rotation is a common response to hypoxia among pond snails. It was first characterized in Helisoma trivolvis embryos, which have a pair of sensorimotor neurons that detect hypoxia and release serotonin onto postsynaptic ciliary cells. The objective of the present study was to determine how the hypoxia response is mediated in Lymnaea stagnalis, which differ from H. trivolvis by having both serotonergic and dopaminergic neurons, and morphologically distinct ciliated structures at comparative stages of embryonic development. Time-lapse video recordings of the rotational behavior in L. stagnalis revealed similar rotational features to those previously observed in H. trivolvis, including rotational surges and rotational responses to hypoxia. Serotonin and dopamine increased the rate of rotation with similar potency. In contrast, serotonin was more potent than dopamine in stimulating the ciliary beat frequency of isolated pedal cilia. Isolated apical plate cilia displayed an irregular pattern of ciliary beating that precluded the measurement of ciliary beat frequency. A qualitative assessment of ciliary beating revealed that both serotonin and dopamine were able to stimulate apical plate cilia. The ciliary responses to dopamine were reversible in both pedal and apical plate cilia, whereas the responses to serotonin were only reversible at concentrations below 100 mu mol l(-1). Mianserin, a serotonin receptor antagonist, and SKF83566, a dopamine receptor antagonist, effectively blocked the rotational responses to serotonin and dopamine, respectively. The rotational response to hypoxia was only partially blocked by mianserin, but was fully blocked by SKF83566. These data suggest that, despite the ability of serotonin to stimulate ciliary beating in L. stagnalis embryos, the rotational response to hypoxia is primarily mediated by the transient apical catecholaminergic neurons that innervate the ciliated apical plate. C1 [Goldberg, Jeffrey I.; Rich, Darren R.; Muruganathan, Siva P.; Liu, Maple B.; Pon, Julia R.; Tam, Rose; Diefenbach, Thomas J.; Kuang, Shihuan] Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada. [Diefenbach, Thomas J.] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Charlestown, MA 02129 USA. [Kuang, Shihuan] Purdue Univ, Ctr Canc Res, W Lafayette, IN 47907 USA. [Kuang, Shihuan] Purdue Univ, Dept Anim Sci, W Lafayette, IN 47907 USA. RP Goldberg, JI (reprint author), Univ Calgary, Dept Biol Sci, 2500 Univ Dr NW, Calgary, AB T2N 1N4, Canada. EM jeff.goldberg@ucalgary.ca OI Kuang, Shihuan/0000-0001-9180-3180 FU Natural Sciences and Engineering Research Council of Canada (NSERC) FX This research was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant to J.I.G. NR 56 TC 4 Z9 4 U1 3 U2 26 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD AUG PY 2011 VL 214 IS 16 BP 2660 EP 2670 DI 10.1242/jeb.053009 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 797YW UT WOS:000293167300007 PM 21795561 ER PT J AU Lillemoe, KD AF Lillemoe, Keith D. TI Prevention, Evaluation, and Treatment of Leaks after Gastrointestinal Surgery Prevention of Leaks After Pancreatic Surgery SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Pancreatic surgery; Pancreatic fistula; Pancreaticoduodenectomy ID PROSPECTIVE RANDOMIZED-TRIAL; PANCREATICODUODENECTOMY; PANCREATICOJEJUNOSTOMY; FISTULA AB Pancreatic fistula remains a frequent and serious complication following pancreatic surgery. The incidence ranges from 10-20% in most series, with pancreatic texture being the most common predictor of the complication. There is little level 1 evidence to support any potential measures to reduce the incidence of pancreatic fistula. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Lillemoe, KD (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,WHT506, Boston, MA 02114 USA. EM klillemoe@partners.org NR 5 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD AUG PY 2011 VL 15 IS 8 BP 1325 EP 1326 DI 10.1007/s11605-011-1514-x PG 2 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 798WP UT WOS:000293243200010 PM 21633869 ER PT J AU Feng, CG Zhang, L Almulki, L Faez, S Whitford, M Hafezi-Moghadam, A Cross, AS AF Feng, Chiguang Zhang, Lei Almulki, Lama Faez, Sepideh Whitford, Melissa Hafezi-Moghadam, Ali Cross, Alan S. TI Endogenous PMN sialidase activity exposes activation epitope on CD11b/CD18 which enhances its binding interaction with ICAM-1 SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE beta 2 integrin; polymorphonuclear leukocyte; endothelial cell; leukocyte trafficking ID FUNCTION-ASSOCIATED ANTIGEN-1; HUMAN NEUTROPHILS; MOLECULAR-CLONING; CELL INTERACTIONS; MAC-1 CD11B/CD18; LEUKOCYTE; ADHESION; SURFACE; RECEPTOR; INTEGRINS AB Diapedesis is a dynamic, highly regulated process by which leukocytes are recruited to inflammatory sites. We reported previously that removal of sialyl residues from PMNs enables these cells to become more adherent to EC monolayers and that sialidase activity within intracellular compartments of resting PMNs translocates to the plasma membrane following activation. We did not identify which surface adhesion molecules were targeted by endogenous sialidase. Upon activation, beta 2 integrin (CD11b/CD18) on the PMN surface undergoes conformational change, which allows it to bind more tightly to the ICAM-1 and ICAM-2 on the EC surface. Removal of sialyl residues from CD18 and CD11b, by exogenous neuraminidase or mobilization of PMN sialidase, unmasked activation epitopes, as detected by flow cytometry and enhanced binding to ICAM-1. One sialidase isoform, Neu1, colocalized with CD18 on confocal microscopy. Using an autoperfused microflow chamber, desialylation of immobilized ICAM-1 enhanced leukocyte arrest in vivo. Further, treatment with a sialidase inhibitor in vivo reversed endotoxin-induced binding of leukocytes to ICAM-1, thereby suggesting a role for leukocyte sialidase in the cellular arrest. These data suggest that PMN sialidase could be a physiologic source of the enzymatic activity that removes sialyl residues on beta 2 integrin and ICAM-1, resulting in their enhanced interaction. Thus, PMN sialidase may be an important regulator of the recruitment of these cells to inflamed sites. J. Leukoc. Biol. 90: 313-321; 2011. C1 [Feng, Chiguang; Zhang, Lei; Whitford, Melissa; Cross, Alan S.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Dept Med, Baltimore, MD 21201 USA. [Almulki, Lama; Faez, Sepideh; Hafezi-Moghadam, Ali] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Almulki, Lama; Faez, Sepideh; Hafezi-Moghadam, Ali] Harvard Univ, Sch Med, Boston, MA USA. RP Cross, AS (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Dept Med, 685 W Baltimore St, Baltimore, MD 21201 USA. EM across@medicine.umaryland.edu OI Hafezi-Moghadam, Ali/0000-0002-5336-0697 FU NIH [HL0869 33-01A1] FX This work was supported by NIH grant HL0869 33-01A1 to A.S.C. NR 32 TC 18 Z9 20 U1 1 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG PY 2011 VL 90 IS 2 BP 313 EP 321 DI 10.1189/jlb.1210708 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 800DA UT WOS:000293338500011 PM 21551251 ER PT J AU Reeves, RK Gillis, J Evans, T Johnson, RP AF Reeves, R. Keith Gillis, Jacqueline Evans, Tristan Johnson, R. Paul TI CHRONIC SIV INFECTION INDUCES AN EXPANSION OF GUT-HOMING AND CYTOTOXIC NK CELLS SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Reeves, R. Keith; Gillis, Jacqueline; Evans, Tristan; Johnson, R. Paul] Harvard Univ, Sch Med, Div Immunol, New England Primate Res Ctr, Southborough, MA 01772 USA. [Johnson, R. Paul] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Boston, MA 02114 USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 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 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2011 VL 40 IS 4 MA 10 BP 251 EP 252 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 795YL UT WOS:000293015700017 ER PT J AU Salisch, NC Kaufmann, DE Tighe, DP Evans, D Pereyra, F Johnson, RP AF Salisch, Nadine C. Kaufmann, Daniel E. Tighe, Daniel P. Evans, DavidC. Pereyra, Florencia Johnson, R. Paul TI BALANCED EXPRESSION OF THE TCR CO-RECEPTORS CD28 AND PD-1 ON VIRUS-SPECIFIC CD8+T CELLS IS A COMMON FEATURE OF CONTROLLED SIV AND HIV-1 INFECTION SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Salisch, Nadine C.; Evans, DavidC.; Johnson, R. Paul] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Charlestown, MA USA. [Salisch, Nadine C.; Evans, DavidC.; Johnson, R. Paul] Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA USA. [Kaufmann, Daniel E.; Tighe, Daniel P.; Pereyra, Florencia; Johnson, R. Paul] Dana Farber Canc Inst, Boston, MA 02115 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 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2011 VL 40 IS 4 MA 7 BP 251 EP 251 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 795YL UT WOS:000293015700014 ER PT J AU Klatt, NR Harris, LD Vinton, CL Tabb, B Morcock, D Hirsch, VM Lifson, JD Alter, G Estes, JD Brenchley, JM AF Klatt, Nichole R. Harris, Levelle D. Vinton, Carol L. Tabb, Brian Morcock, David Hirsch, Vanessa M. Lifson, Jeffrey D. Alter, Galit Estes, Jacob D. Brenchley, Jason M. TI SIV INFECTION RESULTS IN LOSS OF IL-17-PRODUCING NK CELLS IN MUCOSAL TISSUES, WHICH CONTRIBUTES TO DAMAGE TO THE MUCOSAL BARRIER AND IMMUNE ACTIVATION SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Klatt, Nichole R.; Harris, Levelle D.; Vinton, Carol L.; Hirsch, Vanessa M.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Tabb, Brian; Morcock, David; Lifson, Jeffrey D.; Estes, Jacob D.] NCI, AIDS & Canc Virus Program, SAICF Inc, Frederick, MD 21701 USA. [Alter, Galit] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, Boston, MA 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 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2011 VL 40 IS 4 MA 23 BP 256 EP 256 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 795YL UT WOS:000293015700030 ER PT J AU Colantonio, AD Bimber, BN Neidermyer, WJ Reeves, RK Alter, G Altfeld, M Johnson, RP Carrington, M O'Connor, DH Evans, DT AF Colantonio, Arnaud D. Bimber, Benjamin N. Neidermyer, William J., Jr. Reeves, R. Keith Alter, Galit Altfeld, Marcus Johnson, R. Paul Carrington, Mary O'Connor, David H. Evans, David T. TI KIR POLYMORPHISMS MODULATE PEPTIDE-SPECIFIC BINDING TO A COMMON MHC CLASS I MOLECULE IN THE RHESUS MACAQUE SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Colantonio, Arnaud D.; Neidermyer, William J., Jr.; Evans, David T.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, New England Primate Res Ctr, Southborough, MA 01772 USA. [Bimber, Benjamin N.; O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Reeves, R. Keith; Johnson, R. Paul] New England Reg Primate Res Ctr, Div Immunol, Southborough, MA 01772 USA. [Alter, Galit; Altfeld, Marcus; Johnson, R. Paul; Carrington, Mary] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02114 USA. [Carrington, Mary] NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, 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 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2011 VL 40 IS 4 MA 26 BP 257 EP 257 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 795YL UT WOS:000293015700033 ER PT J AU Campbell, JH Burdo, TH Autissier, P Bombardier, JP Westmoreland, SV Soulas, C Gonzalez, RG Ratai, EM Williams, KC AF Campbell, Jennifer H. Burdo, Tricia H. Autissier, Patrick Bombardier, Jeffrey P. Westmoreland, Susan V. Soulas, Caroline Gonzalez, R. Gilberto Ratai, Eva-Maria Williams, Kenneth C. TI PREVENTION OF MONOCYTE ACTIVATION WITH MINOCYCLINE TREATMENT CORRELATES WITH NEURONAL PROTECTION IN SIV-INDUCED NEURAL AIDS SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Campbell, Jennifer H.; Burdo, Tricia H.; Autissier, Patrick; Soulas, Caroline; Williams, Kenneth C.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. [Bombardier, Jeffrey P.; Gonzalez, R. Gilberto; Ratai, Eva-Maria] Harvard Univ, Sch Med, Boston, MA USA. [Westmoreland, Susan V.] New England Reg Primate Res Ctr, Southborough, MA 01772 USA. [Gonzalez, R. Gilberto; Ratai, Eva-Maria] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Gonzalez, R. Gilberto; Ratai, Eva-Maria] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2011 VL 40 IS 4 MA 35 BP 260 EP 260 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 795YL UT WOS:000293015700042 ER PT J AU Lakhashe, SK Wang, WD Siddappa, NB Hemashettar, G Polacino, P Hu, SL Villinger, F Else, JG Novembre, FJ Yoon, JK Lee, SJ Montefiori, DC Ruprecht, RM Rasmussen, RA AF Lakhashe, Samir K. Wang, Wendy Siddappa, Nagadenahalli B. Hemashettar, Girish Polacino, Patricia Hu, Shiu-Lok Villinger, Francois Else, James G. Novembre, Francis J. Yoon, John K. Lee, Sandra J. Montefiori, David C. Ruprecht, Ruth M. Rasmussen, Robert A. TI VACCINATION AGAINST MUCOSAL CHALLENGES WITH HETEROLOGOUS R5 CLADE C SHIV: PREVENTION OF INFECTION AND CORRELATES OF PROTECTION SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Lakhashe, Samir K.; Wang, Wendy; Siddappa, Nagadenahalli B.; Hemashettar, Girish; Yoon, John K.; Lee, Sandra J.; Ruprecht, Ruth M.; Rasmussen, Robert A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lakhashe, Samir K.; Siddappa, Nagadenahalli B.; Lee, Sandra J.; Ruprecht, Ruth M.; Rasmussen, Robert A.] Harvard Univ, Sch Med, Boston, MA USA. [Polacino, Patricia; Hu, Shiu-Lok] Univ Washington, Seattle, WA 98195 USA. [Villinger, Francois; Else, James G.; Novembre, Francis J.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Montefiori, David C.] Duke Univ, Durham, NC USA. RI Hu, Shiu-Lok/A-3196-2008 OI Hu, Shiu-Lok/0000-0003-4336-7964 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 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2011 VL 40 IS 4 MA 58 BP 267 EP 268 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 795YL UT WOS:000293015700065 ER PT J AU Kuzmichev, YV Hong, HS Glickman, RL Rajakumar, PA Johnson, RP AF Kuzmichev, Yury V. Hong, Henoch S. Glickman, Rhona L. Rajakumar, Premeela A. Johnson, R. Paul TI MOLECULAR CLONING AND CHARACTERIZATION OF NKG2D LIGANDS IN RHESUS MACAQUES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Kuzmichev, Yury V.; Hong, Henoch S.; Glickman, Rhona L.; Rajakumar, Premeela A.; Johnson, R. Paul] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. [Johnson, R. Paul] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Charlestown, MA USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 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 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2011 VL 40 IS 4 MA 103 BP 281 EP 281 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 795YL UT WOS:000293015700110 ER PT J AU Shea, MK O'Donnell, CJ Vermeer, C Magdeleyns, EJP Crosier, MD Gundberg, CM Ordovas, JM Kritchevsky, SB Booth, SL AF Shea, M. Kyla O'Donnell, Christopher J. Vermeer, Cees Magdeleyns, Elke J. P. Crosier, Michael D. Gundberg, Caren M. Ordovas, Jose M. Kritchevsky, Stephen B. Booth, Sarah L. TI Circulating Uncarboxylated Matrix Gla Protein Is Associated with Vitamin K Nutritional Status, but Not Coronary Artery Calcium, in Older Adults SO JOURNAL OF NUTRITION LA English DT Article ID HEART-DISEASE EVENTS; VASCULAR CALCIFICATION; RISK-FACTORS; BIOCHEMICAL MEASURES; COMPUTED-TOMOGRAPHY; MEN; WOMEN; ATHEROSCLEROSIS; SUPPLEMENTATION; CARBOXYLASE AB Matrix Gla protein (MGP) is a calcification inhibitor in vascular tissue that must be carboxylated by vitamin K to function. Evidence suggests circulating uncarboxylated MGP (ucMGP) is elevated in persons with disease characterized by vascular calcification. The primary purpose of this study was to determine cross-sectional and longitudinal associations between plasma ucMGP, vitamin K status, and coronary artery calcium (CAC) in older adults without coronary heart disease. Genetic determinants of ucMGP were also explored. Cross-sectional associations among baseline plasma ucMGP, vitamin K status biomarkers [plasma phylloquinone, uncarboxylated prothrombin (PIVKA-II), serum uncarboxylated osteocalcin (%ucOC)], CAC, and plausible genetic polymorphisms were examined in 438 community-dwelling adults (60-80 y, 59% women). The effect of phylloquinone supplementation (500 mu g/d) for 3 y on plasma ucMGP was determined among 374 participants. At baseline, plasma phylloquinone was lower and %ucOC and PIVKA-II were greater across higher plasma ucMGP quartiles (all P < 0.001, age-adjusted). Major allele homozygotes for MGP rs1800801 and rs4236 had higher plasma ucMGP than heterozygotes or minor allele homozygotes. (P <= 0.004). The decrease in plasma ucMGP was greater in the 190 participants who received phylloquinone (mean +/- SD) (-345 +/- 251 pmol/L) than in the 184 who did not (-40 +/- 196 pmol/L) (P < 0.0001). CAC did not differ according to ucMGP quartile (P = 0.35, age-adjusted). In the phylloquinone-supplemented group, the 3-y change in ucMGP was not associated with the 3-y change in CAC [unstandard beta (SE) = -0.02 (0.02); P = 0.44]. Plasma ucMGP was associated with vitamin K status biomarkers and was reduced following phylloquinone supplementation, suggesting it may be a useful marker of vitamin K status in vascular tissue. Plasma ucMGP did not reflect CAC in healthy older adults. J. Nutr. 141: 1529-1534, 2011. C1 [Ordovas, Jose M.; Booth, Sarah L.] Tufts Univ, USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Shea, M. Kyla; Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [Vermeer, Cees; Magdeleyns, Elke J. P.] Maastricht Univ, NL-6200 Maastricht, Netherlands. [Crosier, Michael D.] Framingham State Univ, Framingham, MA 01702 USA. [Gundberg, Caren M.] Yale Univ, Sch Med, New Haven, CT 06511 USA. [Ordovas, Jose M.] Ctr Nacl Invest Cardiovasc, Madrid 28029, Spain. RP Booth, SL (reprint author), Tufts Univ, USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM sarah.booth@tufts.edu OI Vermeer, Cees/0000-0002-2300-8561; Kritchevsky, Stephen/0000-0003-3336-6781 FU USDA, Agricultural Research Service under Cooperative Agreement [58-1950-7-707]; NIH [AG14759, AG23914, HL69272, T32HL69772, P30AG021332-08]; AHA [09CRP2070013, 0515605T] FX Supported by the USDA, Agricultural Research Service under Cooperative Agreement No. 58-1950-7-707, the NIH (AG14759, AG23914, HL69272, T32HL69772, and P30AG021332-08), and the AHA (09CRP2070013 and 0515605T). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the USDA. NR 32 TC 39 Z9 39 U1 0 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD AUG PY 2011 VL 141 IS 8 BP 1529 EP 1534 DI 10.3945/jn.111.139634 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 796KE UT WOS:000293049400018 PM 21628633 ER PT J AU Xiao, HD Yamaguchi, H Dias-Santagata, D Kuboki, Y Akhavanfard, S Hatori, T Yamamoto, M Shiratori, K Kobayashi, M Shimizu, M Fernandez-del Castillo, C Mino-Kenudson, M Furukawa, T AF Xiao, Hong D. Yamaguchi, Hiroshi Dias-Santagata, Dora Kuboki, Yuko Akhavanfard, Sara Hatori, Takashi Yamamoto, Masakazu Shiratori, Keiko Kobayashi, Makio Shimizu, Michio Fernandez-del Castillo, Carlos Mino-Kenudson, Mari Furukawa, Toru TI Molecular characteristics and biological behaviours of the oncocytic and pancreatobiliary subtypes of intraductal papillary mucinous neoplasms SO JOURNAL OF PATHOLOGY LA English DT Article DE intraductal papillary mucinous neoplasm; pancreas; cystic; oncocytic; pancreatobiliary; molecular; survival ID K-RAS MUTATIONS; DUCTAL ADENOCARCINOMA; CLINICOPATHOLOGICAL FEATURES; EVOLUTIONARY STAGES; INVASIVE-CARCINOMA; INTESTINAL PATHWAY; CYSTIC NEOPLASMS; PANCREAS; TUMORS; DISTINCT AB Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes. Of those, pancreatobiliary and oncocytic types are recently recognized and relatively uncommon, and usually exhibit high-grade dysplasia. The biological properties and molecular characteristics of these two types have not been well documented. The few molecular studies of the oncocytic type showed absence of KRAS mutations commonly seen in the other subtypes, raising the possibility that the oncocytic type is distinct from the other subtypes. Thus, we examined clinicopathological features and molecular alterations of the two subtypes. The study cohort consisted of 12 pancreatobiliary and 18 oncocytic IPMN cases. KRAS, BRAF, and PIK3CA mutations and TP53, SMAD4, and beta-catenin expression were analysed, and the results of molecular and clinicopathological profiles were compared between the two subtypes. KRAS mutations were identified in the oncocytic type, but less frequently than the pancreatobiliary type (17% versus 58%, p = 0.048). BRAF mutation was found in a single oncocytic tumour, and no PIK3CA mutations were seen in any of the study cohort. TP53 overexpression was less frequent in the oncocytic type than in the pancreatobiliary type (11% versus 58%, p = 0.013). Invasive components were present in 50% of the oncocytic and 92% of the pancreatobiliary types, with lymph node metastasis more frequently seen in the latter, corresponding to better outcomes in the former (5-year survival rates: 93% versus 32%, p = 0.014). Our demonstration of KRAS and BRAF mutations in the oncocytic-type IPMN supports a role for the activation of the RAS-MAPK pathway in this tumour type. However, the less frequent TP53 overexpression associated with the significantly lower rates of invasion and nodal disease in the oncocytic type correlates with better outcomes compared to the pancreatobiliary type. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Xiao, Hong D.; Dias-Santagata, Dora; Akhavanfard, Sara; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Xiao, Hong D.; Dias-Santagata, Dora; Akhavanfard, Sara; Fernandez-del Castillo, Carlos; Mino-Kenudson, Mari] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yamaguchi, Hiroshi; Kuboki, Yuko; Furukawa, Toru] Tokyo Womens Med Univ, Inst Integrated Med Sci, Tokyo, Japan. [Yamaguchi, Hiroshi; Shimizu, Michio] Saitama Med Univ, Saitama Int Med Ctr, Dept Pathol, Saitama, Japan. [Kuboki, Yuko; Hatori, Takashi; Yamamoto, Masakazu; Shiratori, Keiko] Tokyo Womens Med Univ, Inst Gastroenterol, Tokyo, Japan. [Kobayashi, Makio] Tokyo Womens Med Univ, Dept Pathol, Tokyo, Japan. [Fernandez-del Castillo, Carlos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM mminokenudson@partners.org; toru.furukawa@twmu.ac.jp NR 51 TC 22 Z9 23 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3417 J9 J PATHOL JI J. Pathol. PD AUG PY 2011 VL 224 IS 4 BP 508 EP 516 DI 10.1002/path.2875 PG 9 WC Oncology; Pathology SC Oncology; Pathology GA 799HE UT WOS:000293276600009 PM 21547907 ER PT J AU Kasinath, BS Feliers, D AF Kasinath, Balakuntalam S. Feliers, Denis TI The complex world of kidney microRNAs SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID GROWTH-FACTOR-BETA; DIABETIC-NEPHROPATHY; TRANSLATION; EXPRESSION AB MicroRNAs are short noncoding RNAs that usually reduce translation of messenger RNAs. Changes in microRNA-192 (miR-192) are reported in states of renal fibrosis. New evidence supports a role for miR-192 and its target miR-200b/c in transforming growth factor-beta 1 regulation of its own expression and that of collagens in mesangial cells, with a possible role in diabetic nephropathy. As there is controversy on the role of these microRNAs in diabetic nephropathy, more work is needed. Kidney International (2011) 80, 334-337. doi:10.1038/ki.2011.165 C1 [Kasinath, Balakuntalam S.; Feliers, Denis] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Kasinath, BS (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, S Texas Vet Hlth Care Syst, MC 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM Kasinath@uthscsa.edu FU NIA NIH HHS [RC2 AG036613]; NIDDK NIH HHS [R01 DK077295, DK077295] NR 11 TC 16 Z9 17 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2011 VL 80 IS 4 BP 334 EP 337 DI 10.1038/ki.2011.165 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 799DX UT WOS:000293264900004 PM 21799505 ER PT J AU Hess, AT Tisdall, MD Andronesi, OC Meintjes, EM van der Kouwe, AJW AF Hess, Aaron T. Tisdall, M. Dylan Andronesi, Ovidiu C. Meintjes, Ernesta M. van der Kouwe, Andre J. W. TI Real-Time Motion and B-0 Corrected Single Voxel Spectroscopy Using Volumetric Navigators SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE single voxel spectroscopy; motion correction; shim correction; navigator ID MAGNETIC-RESONANCE-SPECTROSCOPY; IMAGE-BASED TRACKING; COMPENSATION; ALGORITHM; SPECTRA; ECHOES; WATER; MRI AB In population groups where head pose cannot be assumed to be constant during a magnetic resonance spectroscopy examination or in difficult-to-shim regions of the brain, real-time volume of interest, frequency, and shim optimization may be necessary. We investigate the effect of pose change on the B-0 homogeneity of a (2 cm)(3) volume and observe typical first-order shim changes of 1 mu T/m per 1 degrees rotation (chin down to up) in four different volumes of interest in a single volunteer. An echo planar imaging volume navigator was constructed to measure and apply in real-time within each pulse repetition time: volume of interest positioning, frequency adjustment, and first-order shim adjustment. This volume navigator is demonstrated in six healthy volunteers and achieved a mean linewidth of 4.4 Hz, similar to that obtained by manual shim adjustment of 4.9 Hz. Furthermore, this linewidth is maintained by the volume navigator at 4.9 Hz in the presence of pose change. By comparison, a mean linewidth of 7.5 Hz was observed, when no correction was applied. Magn Reson Med 66:314-323,2011. (C)2011 Wiley-Liss, Inc. C1 [Hess, Aaron T.] Univ Cape Town, Fac Hlth Sci, Dept Human Biol, MRC UCT Med Imaging Res Unit, ZA-7925 Observatory, South Africa. [Tisdall, M. Dylan; Andronesi, Ovidiu C.; van der Kouwe, Andre J. W.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Tisdall, M. Dylan; Andronesi, Ovidiu C.; van der Kouwe, Andre J. W.] Harvard Univ, Sch Med, Dept Radiol, Brookline, MA USA. RP Hess, AT (reprint author), Univ Cape Town, Fac Hlth Sci, Dept Human Biol, MRC UCT Med Imaging Res Unit, ZA-7925 Observatory, South Africa. EM aaron.hess@gmail.com OI Hess, Aaron/0000-0002-9289-5619 FU South African Research Chairs Initiative of the Department of Science and Technology; National Research Foundation of South Africa; University of Cape Town; Medical Research Council of South Africa; Ellison Medical Foundation; NIH [R21AA017410, R33DA026104, R21EB008547, R01NS055754, P41RR014075] FX Grant sponsors: South African Research Chairs Initiative of the Department of Science and Technology, National Research Foundation of South Africa, University of Cape Town, Medical Research Council of South Africa, and The Ellison Medical Foundation; Grant sponsor: NIH; Grant numbers: R21AA017410, R33DA026104, R21EB008547, R01NS055754, and P41RR014075. NR 20 TC 37 Z9 37 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD AUG PY 2011 VL 66 IS 2 BP 314 EP 323 DI 10.1002/mrm.22805 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 799AV UT WOS:000293256800002 PM 21381101 ER PT J AU Keil, B Wiggins, GC Triantafyllou, C Wald, LL Meise, FM Schreiber, LM Klose, KJ Heverhagen, JT AF Keil, Boris Wiggins, Graham C. Triantafyllou, Christina Wald, Lawrence L. Meise, Florian M. Schreiber, Laura M. Klose, Klaus J. Heverhagen, Johannes T. TI A 20-Channel Receive-Only Mouse Array Coil for a 3 T Clinical MRI System SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; phased-array coil; small animal imaging; parallel imaging ID IN-VIVO; PHASED-ARRAY; FIELD MRI; DESIGN; TESLA; NMR; MICROSCOPY; EFFICIENT; MODEL; SENSE AB A 20-channel phased-array coil for MRI of mice has been designed, constructed, and validated with bench measurements and high-resolution accelerated imaging. The technical challenges of designing a small, high density array have been overcome using individual small-diameter coil elements arranged on a cylinder in a hexagonal overlapping design with adjacent low impedance preamplifiers to further decouple the array elements. Signal-to-noise ratio (SNR) and noise amplification in accelerated imaging were simulated and quantitatively evaluated in phantoms and in vivo mouse images. Comparison between the 20-channel mouse array and a length-matched quadrature driven small animal birdcage coil showed an SNR increase at the periphery and in the center of the phantom of 3- and 1.3-fold, respectively. Comparison with a shorter but SNR-optimized birdcage coil (aspect ratio 1:1 and only half mouse coverage) showed an SNR gain of twofold at the edge of the phantom and similar SNR in the center. G-factor measurements indicate that the coil is well suited to acquire highly accelerated images. Magn Reson Med 66:584-595, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Keil, Boris; Klose, Klaus J.; Heverhagen, Johannes T.] Univ Marburg, Univ Hosp, Dept Diagnost Radiol, Marburg, Germany. [Wiggins, Graham C.] NYU Langone Med Ctr, Ctr Biomed Imaging, New York, NY USA. [Triantafyllou, Christina] MIT, McGovern Inst Brain Res, AA Martinos Imaging Ctr, Cambridge, MA 02139 USA. [Wald, Lawrence L.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Meise, Florian M.; Schreiber, Laura M.] Johannes Gutenberg Univ Mainz, Dept Radiol, Sect Med Phys, Univ Med Ctr, Mainz, Germany. [Keil, Boris; Triantafyllou, Christina; Wald, Lawrence L.] Harvard Univ, Sch Med, AA Martinos Ctr Biomed Imaging, MGH Dept Radiol, Charlestown, MA 02129 USA. RP Keil, B (reprint author), Harvard Univ, Sch Med, AA Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp,Dept Radiol, 149 13th St, Charlestown, MA 02129 USA. EM keil@nmr.mgh.harvard.edu RI Triantafyllou, Christina/E-7724-2011; Keil, Boris/P-1411-2014; Schreiber, Laura/E-1902-2011; Wald, Lawrence/D-4151-2009 OI Schreiber, Laura/0000-0002-8827-1838; FU Von-Behring-Roentgen Foundation; NIH [P41RR14075, R01EB006847] FX Grant sponsor: Von-Behring-Roentgen Foundation; Grant sponsor: NIH; Grant numbers: P41RR14075, R01EB006847. NR 42 TC 8 Z9 8 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD AUG PY 2011 VL 66 IS 2 BP 584 EP 595 DI 10.1002/mrm.22791 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 799AV UT WOS:000293256800031 PM 21433066 ER PT J AU Bonora, E Kiechl, S Zoppini, G Targher, G Meigs, JB Willeit, J Oberhollenzer, F Bonadonna, RC Muggeo, M AF Bonora, Enzo Kiechl, Stefan Zoppini, Giacomo Targher, Giovanni Meigs, James B. Willeit, Johann Oberhollenzer, Friedrich Bonadonna, Riccardo C. Muggeo, Michele TI Impact of Reference Category and Number of Traits in the Cluster on Risk of Coronary Heart Disease in Metabolic Syndrome: Prospective Data from the Bruneck Study SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID CHOLESTEROL EDUCATION-PROGRAM; HOMEOSTASIS MODEL ASSESSMENT; INSULIN-RESISTANCE SYNDROME; SAN-ANTONIO HEART; CARDIOVASCULAR-DISEASE; ALL-CAUSE; MORTALITY; PREVALENCE; ATHEROSCLEROSIS; PLASMA AB Background: We assessed the risk of coronary heart disease (CHD) in subjects with metabolic syndrome using different reference categories and focusing on the number of traits in the cluster. Methods: For 15 years, we followed 840 subjects from the general population living in Bruneck, northeastern Italy, aged 40-79 years, without CHD at baseline. Metabolic syndrome was diagnosed at baseline using American Heart Association/National Heart, Lung, and Blood Institute criteria. Subjects with the syndrome were compared to subjects without, as well as to subjects without any metabolic abnormality, using Cox models adjusted for sex, age, smoking, and low-density lipoprotein-cholesterol. There were 89 incident CHD cases. Results: In subjects with the metabolic syndrome, the risk of CHD was < approx sign > 1.5-fold higher when subjects without the syndrome were the reference category. CHD risk, however, was 12.5-fold higher (95% confidence interval [CI], 1.7-92.7, P = 0.014) when subjects without any metabolic abnormality composed the reference category. As compared to subjects with no abnormalities (who had a trivial number of CHD events), the risk increased from subjects with one (hazard ratio 7.6, 95% CI 1.0-56.5, P = 0.047) to those with 2, 3, and 4/5 abnormalities (11.6, 1.6-84.9, P = 0.016; 12.9, 1.7-96.0, P = 0.013; and 10.1, 1.3-79.2, P = 0.028), respectively. Conclusions: When compared to the reference category of people without any metabolic abnormality, those with the metabolic syndrome had high cardiovascular risk. However, in the Bruneck population, the risk of CHD seems to be similar in subjects having two or three to five clinical features of metabolic syndrome. Therefore, the clinical utility of identifying subjects with the syndrome using current diagnostic criteria remains uncertain and might be the focus of further specific studies. C1 [Bonora, Enzo; Zoppini, Giacomo; Targher, Giovanni; Bonadonna, Riccardo C.; Muggeo, Michele] Univ Verona, Dept Med, Sect Endocrinol Diabet & Metab, I-37100 Verona, Italy. [Bonora, Enzo; Zoppini, Giacomo; Targher, Giovanni; Bonadonna, Riccardo C.; Muggeo, Michele] Univ Hosp, Dept Gen Med, Div Endocrinol & Metab Dis, Verona, Italy. [Kiechl, Stefan; Willeit, Johann] Univ Innsbruck, Dept Neurol, A-6020 Innsbruck, Austria. [Meigs, James B.] Harvard Univ, Dept Internal Med, Boston, MA 02115 USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Oberhollenzer, Friedrich] Bruneck Hosp, Div Internal Med, Brunico, Italy. RP Bonora, E (reprint author), Osped Maggiore, Piazzale Stefani 1, I-37126 Verona, Italy. EM enzo.bonora@univr.it OI BONORA, Enzo/0000-0003-1074-5164; Bonadonna, Riccardo/0000-0002-9809-1005 FU Italian Ministry of the Public Education, University and Research; University of Verona; Veneto Region; American Diabetes Association FX This study was supported by grants from the Italian Ministry of the Public Education, University and Research, the University of Verona, and the Veneto Region. Prof. J.B. Meigs was supported by an American Diabetes Association Career Development Award. The skillful technical assistance of Lorenza Santi, Federica Moschetta and Monica Zardini is gratefully acknowledged. NR 34 TC 1 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD AUG PY 2011 VL 9 IS 4 BP 313 EP 318 DI 10.1089/met.2010.0130 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 798OM UT WOS:000293219200010 PM 21491992 ER PT J AU Wang, SY Kamat, A Pergola, P Swamy, A Tio, F Cusi, K AF Wang, Shaoyun Kamat, Amrita Pergola, Pablo Swamy, Anita Tio, Fermin Cusi, Kenneth TI Metabolic factors in the development of hepatic steatosis and altered mitochondrial gene expression in vivo SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID FATTY LIVER-DISEASE; INTRAHEPATIC TRIGLYCERIDE CONTENT; TISSUE INSULIN-RESISTANCE; PLACEBO-CONTROLLED TRIAL; NONALCOHOLIC STEATOHEPATITIS; ADIPOSE-TISSUE; COACTIVATOR PGC-1; PPAR-ALPHA; ADIPONECTIN RECEPTORS; DIABETES-MELLITUS AB The objective of the study was to understand the role in vivo of elevated plasma free fatty acids (FFA), insulin, and glucose levels in the development of steatosis and altered mitochondrial gene/protein expression. We studied 4 groups of Sprague-Dawley rats: (1) high-fat diet (HFD), (2) high-dose streptozotocin-induced diabetes (T1DM), (3) low-dose streptozotocin-induced diabetic rats on an HFD (T2DM), and (4) controls. Liver histology and expression of genes/proteins related to mitochondrial fatty acid oxidation and biogenesis were analyzed. Despite an attempt to compensate by increasing expression of genes of fatty acid oxidation (carnitine palmitoyl transferase-l/medium chain acyl-CoA dehydrogenase), the HFD and diabetic groups developed marked steatosis and suffered a significant reduction in mitochondrial biogenesis gene expression (nuclear respiratory factor 11 transcriptional factor A, mitochondrial). In T2DM rats, the combination of high glucose and FFA unexpectedly did not lead to greater fat accumulation than HFD alone. Greater steatosis in HFD vs T2DM (P < .001) correlated with impairment in the gene expression of PPAR-alpha (ie, fatty acid oxidation) and PGCl alpha, a major coactivator for mitochondrial biogenesis. Steatosis was not severe in insulin-deficient T1DM rats despite very elevated FFA and glucose levels. Increased carnitine palmitoyl transferase-1/medium chain acyl-CoA dehydrogenase/PPAR-alpha gene expression suggested inadequate adaptation to high FFA in both T1DW/T2DM rats. Hyperinsulinemia combined with elevated FFA is the key metabolic factor driving hepatic lipogenesis in vivo (HFD rats). Mitochondrial biogenesis (nuclear respiratory factor 1; transcriptional factor A, mitochondrial) is highly susceptible to FFA-induced steatosis. In contrast, hyperglycemia does not have an additive effect (T2DM) and leads to only a modest degree of steatosis in the absence of hyperinsulinemia, even when FFA are extremely elevated as in T1DM rats. (C) 2011 Elsevier Inc. All rights reserved. C1 [Cusi, Kenneth] Univ Texas Hlth Sci Ctr San Antonio, Diabet Div, Dept Med, Audie L Murphy Vet Adm Med Ctr, San Antonio, TX 78229 USA. RP Cusi, K (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Diabet Div, Dept Med, Audie L Murphy Vet Adm Med Ctr, San Antonio, TX 78229 USA. EM cusi@uthscsa.edu FU Burroughs Wellcome Fund; American Diabetes Association; Veterans Affairs Medical Research Fund; American Heart Association; South Central Affiliate; National Center for Research Resources [UL 1RR025767] FX We would like to thank Sergio Garcia for his assistance with the animal work. The project described was supported by the Burroughs Wellcome Fund, the American Diabetes Association, and the Veterans Affairs Medical Research Fund (Kenneth Cusi); by a Grant in Aid Award from the American Heart Association, South Central Affiliate (Pablo Pergola, MD, and Amrita Kamat, PhD); and by Award Number UL 1RR025767 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources of the National Institutes of Health. NR 62 TC 28 Z9 28 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2011 VL 60 IS 8 BP 1090 EP 1099 DI 10.1016/j.metabol.2010.12.001 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799AW UT WOS:000293256900006 PM 21310443 ER PT J AU Petridou, ET Sergentanis, TN Antonopoulos, CN Dessypris, N Matsoukis, IL Aronis, K Efremidis, A Syrigos, C Mantzoros, CS AF Petridou, Eleni Th. Sergentanis, Theodoros N. Antonopoulos, Constantine N. Dessypris, Nick Matsoukis, Ioannis L. Aronis, Konstantinos Efremidis, Anna Syrigos, Constantinos Mantzoros, Christos S. TI Insulin resistance: an independent risk factor for lung cancer? SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID PLASMA ADIPONECTIN CONCENTRATIONS; HOMEOSTASIS MODEL ASSESSMENT; DIABETES-MELLITUS; GROWTH-FACTOR; LEPTIN LEVELS; FOOD-INTAKE; US ADULTS; MORTALITY; EXPRESSION; WOMEN AB Insulin resistance is closely associated with numerous metabolic disorders. Although studies have supported the importance of insulin resistance in carcinogenesis, the existing data have not established its relevance in the context of lung cancer. The aim of the present case-control study was to evaluate the association between insulin resistance and lung cancer after adjusting for possible confounders. Homeostasis model assessment of insulin resistance (HOMA-IR) and serum leptin and adiponectin levels were determined in 81 lung cancer cases and 162 age-and sex-matched controls; anthropometric and lifestyle variables were recorded. Mean HOMA-IR in the cases was more than 2-fold higher compared with the mean value of controls (P < .001). Among controls, HOMA-IR correlated positively with serum leptin (r = 0.16; P = .04), body mass index (r = 0.43; 13 = .0001), and waist-to-hip ratio (r = 0.21; P = .01) but negatively with serum adiponectin (r = -0.29; P = .0002). As expected, smoking was associated with an approximately 10-fold increase in lung cancer risk in multiple logistic regression models. A positive association between HOMA-IR, treated as continuous variable, and lung cancer (odds ratio [OR] = 1.52, 95% confidence interval [CI]: 1.16-1.99, P = .002, model 1) was demonstrated, which persisted after adjustment for somatometric and lifestyle variables (OR = 2.36, 95% CI: 1.00-5.55, P =.05, model 2). When serum adiponectin was also taken into account, the association seemed fairly robust (OR = 2.58, 95% CI: 1.11-6.01, P = .03, model 3); on the contrary, when serum leptin was added, the association remained positive, but lost its statistical significance (OR = 1.76, 95% CI: 0.78-3.98, P = .17, model 4). In the fully adjusted model, HOMA-IR was still positively, but only marginally, associated with lung cancer risk (OR = 2.02, 95% CI: 0.88-4.65, P = .10, model 5). Insulin resistance may represent a meaningful risk factor for lung cancer. (C) 2011 Elsevier Inc. All rights reserved. C1 [Petridou, Eleni Th.; Sergentanis, Theodoros N.; Antonopoulos, Constantine N.; Dessypris, Nick; Matsoukis, Ioannis L.] Univ Athens, Dept Hyg Epidemiol & Med Stat, Sch Med, Athens 11527, Greece. [Aronis, Konstantinos; Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Dept Internal Med,Med Sch, Boston, MA 02215 USA. [Efremidis, Anna] St Savvas Anticancer Hosp, Pathol Oncol Clin 2, Athens, Greece. [Syrigos, Constantinos] Univ Athens, Oncol Unit, Dept Internal Med 3, Sotiria Gen Hosp,Med Sch, Athens 11527, Greece. [Mantzoros, Christos S.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA USA. RP Petridou, ET (reprint author), Univ Athens, Dept Hyg Epidemiol & Med Stat, Sch Med, Athens 11527, Greece. EM epetrid@med.uoa.gr RI Aronis, Konstantinos/F-3586-2012; OI Aronis, Konstantinos/0000-0001-7189-8434; Antonopoulos, Constantine N./0000-0003-0696-695X; Sergentanis, Theodoros N./0000-0002-9355-5528 NR 55 TC 22 Z9 26 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2011 VL 60 IS 8 BP 1100 EP 1106 DI 10.1016/j.metabol.2010.12.002 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799AW UT WOS:000293256900007 PM 21251684 ER PT J AU Gold, MC Lewinsohn, DM AF Gold, Marielle C. Lewinsohn, David M. TI Mucosal associated invariant T cells and the immune response to infection SO MICROBES AND INFECTION LA English DT Review DE Mucosal associated invariant T (MAIT) cells; iNKT cells; MR1; MHC-I; Mucosal immunity; Mycobacterium tuberculosis ID MR1 ANTIGEN PRESENTATION; MAIT CELLS; CRYSTAL-STRUCTURE; ALPHA-CHAIN; GENES; TCR; RECOGNITION; EXPRESSION; MOLECULES; SYMBIOSIS AB Mucosal associated invariant T cells are unique T cells localized at high frequencies at the portals of entry for many pathogens. Mucosal associated invariant T cells display a variety of characteristics that suggest their function is to act as effectors in the initial control of microbial infection at mucosal sites. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Gold, Marielle C.; Lewinsohn, David M.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Gold, Marielle C.; Lewinsohn, David M.] Portland VA Med Ctr, Portland, OR 97239 USA. RP Gold, MC (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code VA R&D 11, Portland, OR 97239 USA. EM goldm@ohsu.edu RI Lewinsohn, David/I-4936-2013; OI Lewinsohn, David/0000-0001-9906-9494; Gold, Marielle/0000-0003-2505-3291 FU NIAID NIH HHS [R01 AI078965-01A2, R01 AI078965, U01 AI095776] NR 42 TC 10 Z9 10 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD AUG PY 2011 VL 13 IS 8-9 BP 742 EP 748 DI 10.1016/j.micinf.2011.03.007 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 797IS UT WOS:000293118300003 PM 21458588 ER PT J AU Milane, L Duan, ZF Amiji, M AF Milane, Lara Duan, Zhen-feng Amiji, Mansoor TI Pharmacokinetics and biodistribution of lonidamine/paclitaxel loaded, EGFR-targeted nanoparticles in an orthotopic animal model of multi-drug resistant breast cancer SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE Pharmacokinetics; Multidrug-resistant cancer; Nanoparticles; Lonidamine; Paclitaxel ID DRUG-RESISTANCE; POLY(EPSILON-CAPROLACTONE) NANOPARTICLES; PEPTIDE LIGAND; DELIVERY; NANOTECHNOLOGY; THERAPEUTICS; NANOCARRIERS; TAMOXIFEN; RECEPTOR AB The aim of this study was to assess the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)-targeted polymer-blend nanoparticles loaded with the anticancer drugs lonidamine and paclitaxel. Plasma, tumor, and tissue distribution profiles were quantified in an orthotopic animal model of multidrug-resistant breast cancer and were compared to treatment with nontargeted nanoparticles and to treatment with drug solution. A poly(d, l-lactide-co-glycolide)-poly(ethylene glycol)-EGFR targeting peptide (PLGA-PEG-EFGR peptide) construct was synthesized for incorporation in poly(epsilon-caprolactone) particles to achieve active EGFR targeting. An isocratic high-pressure liquid chromatography method was developed to quantify lonidamine and paclitaxel in mice plasma, tumors, and vital organs. The targeted nanoparticles demonstrated a superior pharmacokinetic profile relative to drug solution and nontargeted nanoparticles, particularly for lonidamine delivery. The first target site of accumulation was the liver, followed by the kidneys, and then the tumor mass; maximal tumor accumulation occured at 3 hours after administration. Lonidamine-paclitaxel combination therapy administered via EGFR-targeted polymer-blend nanocarriers may become a viable platform for the future treatment of multidrug-resistant cancer. From the Clinical Editor: In this study the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)-targeted polymer-blend nanoparticles loaded with lonidamine and paclitaxel were assessed. The targeted nanoparticles demonstrated a superior pharmacokinetic profile relative to drug solution and nontargeted nanoparticles, paving the way to new therapeutic approaches for multidrug-resistant malignancies. (C) 2011 Elsevier Inc. All rights reserved. C1 [Milane, Lara; Amiji, Mansoor] Northeastern Univ, Dept Pharmaceut Sci, Sch Pharm, Boston, MA 02115 USA. [Duan, Zhen-feng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Duan, Zhen-feng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. RP Amiji, M (reprint author), Northeastern Univ, Dept Pharmaceut Sci, Sch Pharm, Boston, MA 02115 USA. EM m.amiji@neu.edu RI Amiji, Mansoor/A-4365-2014 OI Amiji, Mansoor/0000-0001-6170-881X FU National Cancer Institute, National Institutes of Health [R01 CA-119617, R01 CA-119617S1, R21 CA-135594] FX This study was supported by the National Cancer Institute, National Institutes of Health through grants R01 CA-119617 and R01 CA-119617S1 (ARRA Supplement), and R21 CA-135594. NR 21 TC 35 Z9 36 U1 2 U2 31 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 EI 1549-9642 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD AUG PY 2011 VL 7 IS 4 BP 435 EP 444 DI 10.1016/j.nano.2010.12.009 PG 10 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 798OJ UT WOS:000293218800008 PM 21220050 ER PT J AU Kilpelainen, TO Zillikens, MC Stancakova, A Finucane, FM Ried, JS Langenberg, C Zhang, WH Beckmann, JS Luan, JA Vandenput, L Styrkarsdottir, U Zhou, YH Smith, AV Zhao, JH Amin, N Vedantam, S Shin, SY Haritunians, T Fu, M Feitosa, MF Kumari, M Halldorsson, BV Tikkanen, E Mangino, M Hayward, C Song, C Arnold, AM Aulchenko, YS Oostra, BA Campbell, H Cupples, LA Davis, KE Doring, A Eiriksdottir, G Estrada, K Fernandez-Real, JM Garcia, M Gieger, C Glazer, NL Guiducci, C Hofman, A Humphries, SE Isomaa, B Jacobs, LC Jula, A Karasik, D Karlsson, MK Khaw, KT Kim, LJ Kivimaki, M Klopp, N Kuhnel, B Kuusisto, J Liu, YM Ljunggren, O Lorentzon, M Luben, RN McKnight, B Mellstrom, D Mitchell, BD Mooser, V Moreno, JM Mannisto, S O'Connell, JR Pascoe, L Peltonen, L Peral, B Perola, M Psaty, BM Salomaa, V Savage, DB Semple, RK Skaric-Juric, T Sigurdsson, G Song, KS Spector, TD Syvanen, AC Talmud, PJ Thorleifsson, G Thorsteinsdottir, U Uitterlinden, AG van Duijn, CM Vidal-Puig, A Wild, SH Wright, AF Clegg, DJ Schadt, E Wilson, JF Rudan, I Ripatti, S Borecki, IB Shuldiner, AR Ingelsson, E Jansson, JO Kaplan, RC Gudnason, V Harris, TB Groop, L Kiel, DP Rivadeneira, F Walker, M Barroso, I Vollenweider, P Waeber, G Chambers, JC Kooner, JS Soranzo, N Hirschhorn, JN Stefansson, K Wichmann, HE Ohlsson, C O'Rahilly, S Wareham, NJ Speliotes, EK Fox, CS Laakso, M Loos, RJF AF Kilpelainen, Tuomas O. Zillikens, M. Carola Stancakova, Alena Finucane, Francis M. Ried, Janina S. Langenberg, Claudia Zhang, Weihua Beckmann, Jacques S. Luan, Jian'an Vandenput, Liesbeth Styrkarsdottir, Unnur Zhou, Yanhua Smith, Albert Vernon Zhao, Jing-Hua Amin, Najaf Vedantam, Sailaja Shin, So-Youn Haritunians, Talin Fu, Mao Feitosa, Mary F. Kumari, Meena Halldorsson, Bjarni V. Tikkanen, Emmi Mangino, Massimo Hayward, Caroline Song, Ci Arnold, Alice M. Aulchenko, Yurii S. Oostra, Ben A. Campbell, Harry Cupples, L. Adrienne Davis, Kathryn E. Doering, Angela Eiriksdottir, Gudny Estrada, Karol Manuel Fernandez-Real, Jose Garcia, Melissa Gieger, Christian Glazer, Nicole L. Guiducci, Candace Hofman, Albert Humphries, Steve E. Isomaa, Bo Jacobs, Leonie C. Jula, Antti Karasik, David Karlsson, Magnus K. Khaw, Kay-Tee Kim, Lauren J. Kivimaeki, Mika Klopp, Norman Kuehnel, Brigitte Kuusisto, Johanna Liu, Yongmei Ljunggren, Osten Lorentzon, Mattias Luben, Robert N. McKnight, Barbara Mellstrom, Dan Mitchell, Braxton D. Mooser, Vincent Maria Moreno, Jose Mannisto, Satu O'Connell, Jeffery R. Pascoe, Laura Peltonen, Leena Peral, Belen Perola, Markus Psaty, Bruce M. Salomaa, Veikko Savage, David B. Semple, Robert K. Skaric-Juric, Tatjana Sigurdsson, Gunnar Song, Kijoung S. Spector, Timothy D. Syvanen, Ann-Christine Talmud, Philippa J. Thorleifsson, Gudmar Thorsteinsdottir, Unnur Uitterlinden, Andre G. van Duijn, Cornelia M. Vidal-Puig, Antonio Wild, Sarah H. Wright, Alan F. Clegg, Deborah J. Schadt, Eric Wilson, James F. Rudan, Igor Ripatti, Samuli Borecki, Ingrid B. Shuldiner, Alan R. Ingelsson, Erik Jansson, John-Olov Kaplan, Robert C. Gudnason, Vilmundur Harris, Tamara B. Groop, Leif Kiel, Douglas P. Rivadeneira, Fernando Walker, Mark Barroso, Ines Vollenweider, Peter Waeber, Gerard Chambers, John C. Kooner, Jaspal S. Soranzo, Nicole Hirschhorn, Joel N. Stefansson, Kari Wichmann, H-Erich Ohlsson, Claes O'Rahilly, Stephen Wareham, Nicholas J. Speliotes, Elizabeth K. Fox, Caroline S. Laakso, Markku Loos, Ruth J. F. TI Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; INSULIN-RECEPTOR SUBSTRATE-1; BODY-MASS INDEX; ADIPOCYTE DIFFERENTIATION; ADULT OBESITY; FTO GENE; LOCI; RESISTANCE; EXPRESSION; MIGRATION AB Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. C1 [Kilpelainen, Tuomas O.; Finucane, Francis M.; Langenberg, Claudia; Luan, Jian'an; Zhao, Jing-Hua; Wareham, Nicholas J.; Loos, Ruth J. F.] MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Zillikens, M. Carola; Estrada, Karol; Jacobs, Leonie C.; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Zillikens, M. Carola; Estrada, Karol; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Rivadeneira, Fernando] NGI, NCHA, Leiden, Netherlands. [Stancakova, Alena; Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Stancakova, Alena; Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Ried, Janina S.; Doering, Angela; Gieger, Christian; Klopp, Norman; Kuehnel, Brigitte; Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Zhang, Weihua; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. [Beckmann, Jacques S.] Univ Lausanne Hosp, Dept Med Genet, Lausanne, Switzerland. [Vandenput, Liesbeth; Lorentzon, Mattias; Mellstrom, Dan; Ohlsson, Claes] Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden. [Styrkarsdottir, Unnur; Halldorsson, Bjarni V.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] DeCODE Genet, Reykjavik, Iceland. [Zhou, Yanhua; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Smith, Albert Vernon; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Heart Prevent Clin, Kopavogur, Iceland. [Smith, Albert Vernon; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland. [Amin, Najaf; Aulchenko, Yurii S.; Oostra, Ben A.; Estrada, Karol; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Rivadeneira, Fernando] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Vedantam, Sailaja; Guiducci, Candace; Hirschhorn, Joel N.; Speliotes, Elizabeth K.] Broad Inst, Metab Initiat, Cambridge, MA USA. [Vedantam, Sailaja; Guiducci, Candace; Hirschhorn, Joel N.; Speliotes, Elizabeth K.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [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. [Shin, So-Youn; Peltonen, Leena; Barroso, Ines; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge, England. [Haritunians, Talin] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Fu, Mao; Mitchell, Braxton D.; O'Connell, Jeffery R.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. [Kumari, Meena] UCL, Dept Epidemiol, Genet Epidemiol Grp, London, England. [Halldorsson, Bjarni V.] Reykjavik Univ, Reykjavik, Iceland. [Tikkanen, Emmi; Peltonen, Leena; Perola, Markus; Ripatti, Samuli] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Mangino, Massimo; Spector, Timothy D.] Kings Coll London, London WC2R 2LS, England. [Hayward, Caroline; Wright, Alan F.] MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Song, Ci; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Arnold, Alice M.; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Campbell, Harry; Wild, Sarah H.; Wilson, James F.; Rudan, Igor] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Davis, Kathryn E.; Clegg, Deborah J.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Touchstone Diabet Ctr, Dallas, TX 75390 USA. [Manuel Fernandez-Real, Jose; Maria Moreno, Jose] Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Inst Invest Biomed Girona, Dept Diabet Endocrinol & Nutr, Girona, Spain. [Garcia, Melissa; Kim, Lauren J.; Harris, Tamara B.] NIA, Intramural Res Program, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Glazer, Nicole L.; McKnight, Barbara; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Glazer, Nicole L.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Humphries, Steve E.; Talmud, Philippa J.] UCL, Dept Med, Ctr Cardiovasc Genet, London, England. [Isomaa, Bo] Folkhalsan Res Ctr, Helsinki, Finland. [Isomaa, Bo] Dept Social Serv & Hlth Care, Pietarsaari, Finland. [Jula, Antti] Natl Inst Hlth & Welf, Populat Studies Unit, Helsinki, Finland. [Karasik, David; Kiel, Douglas P.] Hebrew SeniorLife, Inst Aging Res, Boston, MA USA. [Karlsson, Magnus K.] Malmo Univ Hosp, Dept Orthopaed, Malmo, Sweden. [Khaw, Kay-Tee; Luben, Robert N.] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Kivimaeki, Mika] UCL, Dept Epidemiol & Publ Hlth, London, England. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Ljunggren, Osten] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Mooser, Vincent; Song, Kijoung S.] GlaxoSmithKline, Genet Res & Dev, King Of Prussia, PA USA. [Mannisto, Satu; Salomaa, Veikko] Natl Inst Hlth & Welf, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland. [Pascoe, Laura; Walker, Mark] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Peral, Belen] CSIC, Inst Invest Biomed, Madrid, Spain. [Peral, Belen] Univ Autonoma Madrid, Madrid, Spain. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Savage, David B.; Semple, Robert K.; Vidal-Puig, Antonio; Barroso, Ines; O'Rahilly, Stephen] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England. [Skaric-Juric, Tatjana] Inst Anthropol Res, Zagreb, Croatia. [Sigurdsson, Gunnar] Univ Hosp, Dept Endocrinol & Metab, Reykjavik, Iceland. [Sigurdsson, Gunnar; Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden. [van Duijn, Cornelia M.] CMSB, NGI, Leiden, Netherlands. [Schadt, Eric] Pacific Biosci, Menlo Pk, CA USA. [Schadt, Eric] Sage Bionetworks, Seattle, WA USA. [Rudan, Igor] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia. [Rudan, Igor] Gen Info Ltd, Zagreb, Croatia. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Ingelsson, Erik] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Jansson, John-Olov] Univ Gothenburg, Dept Physiol, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Groop, Leif] Lund Univ, Dept Clin Sci, Ctr Diabet, Malmo, Sweden. [Vollenweider, Peter; Waeber, Gerard] Univ Lausanne Hosp, Dept Internal Med, Lausanne, Switzerland. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Speliotes, Elizabeth K.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Fox, Caroline S.] NHLBI, Boston, MA USA. RP Loos, RJF (reprint author), MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. EM ruth.loos@mrc-epid.cam.ac.uk RI Wilson, James F/A-5704-2009; Rivadeneira, Fernando/O-5385-2015; Beckmann, Jacques S /A-9772-2008; Skaric-Juric, Tatjana/H-5997-2011; Kivimaki, Mika/B-3607-2012; Kilpelainen, Tuomas/F-8569-2012; Rudan, Igor/I-1467-2012; Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; Moreno-Navarrete, Jose Maria/H-9772-2015; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Smith, Albert/K-5150-2015; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Feitosa, Mary/K-8044-2012; OI Wilson, James F/0000-0001-5751-9178; Rivadeneira, Fernando/0000-0001-9435-9441; Beckmann, Jacques S /0000-0002-9741-1900; Rudan, Igor/0000-0001-6993-6884; Aulchenko, Yurii/0000-0002-7899-1575; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Smith, Albert/0000-0003-1942-5845; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Feitosa, Mary/0000-0002-0933-2410; Cupples, L. Adrienne/0000-0003-0273-7965; Soranzo, Nicole/0000-0003-1095-3852; Song, Ci/0000-0002-0947-9068; Kivimaki, Mika/0000-0002-4699-5627; Talmud, Philippa/0000-0002-5560-1933; Halldorsson, Bjarni/0000-0003-0756-0767; Vandenput, Liesbeth/0000-0002-1712-6131; Mitchell, Braxton/0000-0003-4920-4744; Fernandez-Real, Jose Manuel/0000-0002-7442-9323; Mannisto, Satu/0000-0002-8668-3046; Luben, Robert/0000-0002-5088-6343; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Semple, Robert/0000-0001-6539-3069; Kiel, Douglas/0000-0001-8474-0310; PERAL, BELEN/0000-0003-4984-4020; Karasik, David/0000-0002-8826-0530 FU Academy of Finland [10404, 124243, 129680, 129494, 141005, 213506]; Agency for Health Care Policy Research [HS06516]; Althingi (the Icelandic Parliament); American Heart Association [10SDG269004]; AstraZeneca; Baltimore Geriatric Research Education and Clinical Centers; Biocentrum Helsinki Foundation; Biotechnology and Biological Sciences Research Council [G20234]; British Heart Foundation [PG/07/133/24260, RG/08/008, SP/04/002, SP/07/007/23671]; CamStrad; Cancer Research UK; Cedars-Sinai Board of Governors' Chair in Medical Genetics; Centre for Medical Systems Biology (The Netherlands); Centre Hospitalier Universitaire Vaudois (Lausanne); Croatian Ministry of Science, Education and Sport [196-1962766-2747, 216-1080315-0302, 309-0061194-2023]; Department of Health (UK); Department of Veterans Affairs (USA); Emil and Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus University (Rotterdam); European Commission [FP7/2007-2013, FP7-KBBE-2010-4-266408, HEALTH-F2-2007-201681, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2003-503041, LSHM-CT-2004-512013, QLG1-CT-2001-01252, QLG2-CT-2002-01254]; Finnish Diabetes Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Heart Foundation; Finnish Medical Society; Folkhalsan Research Foundation; Food Standards Agency (UK); Foundation for Life and Health in Finland; German Bundesministerium fur Forschung und Technology [01AK803A-H, 01IG07015G]; German Federal Ministry of Education and Research; German National Genome Research Network [NGFN-2, NGFNPlus: 01GS0823]; Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Goteborg Medical Society; Gyllenberg Foundation; Health and Safety Executive (UK); Health Care Center in Vasa; Health Care Center in Narpes; Health Care Center in Korsholm; Hjartavernd (the Icelandic Heart Association); John D. and Catherine T. MacArthur Foundation; Knut and Alice Wallenberg Foundation; Leenaards Foundation; Ludwig-Maximilians Universitat Munchen; Lundberg Foundation; Medical Research Council (UK); Men's Associates of Hebrew SeniorLife; Ministerio de Ciencia e Innovacion (Spain) [SAF-2009, SAF-2008-02073]; Ministry for Health, Welfare and Sports (The Netherlands); Ministry of Education (Finland); Ministry of Education, Culture and Science (The Netherlands); Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Narpes Health Care Foundation; National Institute for Health Research (UK); 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; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Robert Dawson Evans Endowment; Royal Society (UK); Sahlgrenska Center for Cardiovascular and Metabolic Research [A305:188]; Sahlgrenska University Hospital Foundation (ALF/LUA); Science Funding programme (UK); Scottish Executive Health Department; Sigrid Juselius Foundation; State of Bavaria; Stroke Association (UK); Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Research Council [K2010-54X-09894-19-3, K2010-52X-20229-05-3, 2006-3832]; Swedish Strategic Foundation; Swiss Institute of Bioinformatics; Swiss National Science Foundation [3100AO-116323/1, 310000-112552, 33CSCO-122661]; TEKES [1510/31/06]; Torsten and Ragnar Soderberg's Foundation; United Kingdom NIHR Cambridge Biomedical Research Centre; University of Lausanne; University of Maryland General Clinical Research Center [M01 RR 16500]; Uppsala University FX A full list of Acknowledgments appears in the Supplementary Note. Funding was provided by Academy of Finland (10404, 124243, 129680, 129494, 141005 and 213506); Agency for Health Care Policy Research (HS06516); Althingi (the Icelandic Parliament); American Heart Association (10SDG269004); AstraZeneca; Baltimore Geriatric Research Education and Clinical Centers; Biocentrum Helsinki Foundation; Biotechnology and Biological Sciences Research Council (G20234); British Heart Foundation (PG/07/133/24260, RG/08/008, SP/04/002, SP/07/007/23671); CamStrad; Cancer Research UK; Cedars-Sinai Board of Governors' Chair in Medical Genetics; Centre for Medical Systems Biology (The Netherlands); Centre Hospitalier Universitaire Vaudois (Lausanne); Croatian Ministry of Science, Education and Sport (196-1962766-2747, 216-1080315-0302 and 309-0061194-2023); Department of Health (UK); Department of Veterans Affairs (USA); Emil and Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus University (Rotterdam); European Commission (DG XII, FP7/2007-2013, FP7-KBBE-2010-4-266408, HEALTH-F2-2007-201681, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2003-503041, LSHM-CT-2004-512013, QLG1-CT-2001-01252 and QLG2-CT-2002-01254); Finnish Diabetes Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Heart Foundation; Finnish Medical Society; Folkhalsan Research Foundation; Food Standards Agency (UK); Foundation for Life and Health in Finland; German Bundesministerium fur Forschung und Technology (01AK803A-H and 01IG07015G); German Federal Ministry of Education and Research; German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823); Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Goteborg Medical Society; Gyllenberg Foundation; Health and Safety Executive (UK); Health Care Centers in Vasa, Narpes and Korsholm; Hjartavernd (the Icelandic Heart Association); John D. and Catherine T. MacArthur Foundation; Knut and Alice Wallenberg Foundation; Leenaards Foundation; Ludwig-Maximilians Universitat Munchen; Lundberg Foundation; Medical Research Council (UK); Men's Associates of Hebrew SeniorLife; Ministerio de Ciencia e Innovacion (Spain) (SAF-2009 and SAF-2008-02073); Ministry for Health, Welfare and Sports (The Netherlands); Ministry of Education (Finland); Ministry of Education, Culture and Science (The Netherlands); Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Narpes Health Care Foundation; National Institute for Health Research (UK); US National Institutes of Health (USA) (AG13196, DK063491, K23-DK080145, M01-RR00425, N01-AG12100, N01-AG62101, N01-AG62103, N01-AG62106, N01-HC15103, N01-HC25195, N01-HC35129, N01-HC45133, N01-HC55222, N01-HC75150, N01-HC85079 through N01-HC85086, P30-DK072488, R01-AG031890-01, R01-AG18728, R01-AG032098-01A1, R01-AR/AG41398, R01-AR046838, R01-DK06833603, R01-DK075787, R01-DK07568102, R01-HL036310-20A2, R01-HL087652, R01-HL08770003, R01-HL088119, U01-HL080295, U01-HL72515 and U01-HL84756); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (175.010.2005.; 011 and 911-03-012); Netherlands Organization for the Health Research and Development; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Research Institute for Diseases in the Elderly (01-93-015; RIDE2); Robert Dawson Evans Endowment; Royal Society (UK); Sahlgrenska Center for Cardiovascular and Metabolic Research (A305:188); Sahlgrenska University Hospital Foundation (ALF/LUA); Science Funding programme (UK); Scottish Executive Health Department; Sigrid Juselius Foundation; State of Bavaria; Stroke Association (UK); Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Research Council (K2010-54X-09894-19-3, K2010-52X-20229-05-3 and 2006-3832); Swedish Strategic Foundation; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 310000-112552 and 33CSCO-122661); TEKES (1510/31/06); Torsten and Ragnar Soderberg's Foundation; United Kingdom NIHR Cambridge Biomedical Research Centre; University of Lausanne; University of Maryland General Clinical Research Center (M01 RR 16500); Uppsala University; Vastra Gotaland Foundation; and Wellcome Trust (077016/Z/05/Z, 084723/Z/08/Z and 091746/Z/10/Z). NR 51 TC 120 Z9 124 U1 3 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2011 VL 43 IS 8 BP 753 EP U58 DI 10.1038/ng.866 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 798CD UT WOS:000293178300011 PM 21706003 ER PT J AU Shea, J Agarwala, V Philippakis, AA Maguire, J Banks, E DePristo, M Thomson, B Guiducci, C Onofrio, RC Kathiresan, S Gabriel, S Burtt, NP Daly, MJ Groop, L Altshuler, D AF Shea, Jessica Agarwala, Vineeta Philippakis, Anthony A. Maguire, Jared Banks, Eric DePristo, Mark Thomson, Brian Guiducci, Candace Onofrio, Robert C. Kathiresan, Sekar Gabriel, Stacey Burtt, Noel P. Daly, Mark J. Groop, Leif Altshuler, David CA Myocardial Infarction Genetics Con TI Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; DNA-SEQUENCING DATA; SUSCEPTIBILITY LOCI; IDENTIFIES 5; VARIANTS; RISK; REPLICATION; IMPUTATION; FRAMEWORK; GLIOMA AB Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes(1-4), myocardial infarction(5-7), aneurysm(8), vertical cup disc ratio(9) and at least five cancers(10-16). Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing and from 1000 Genomes Project low-coverage data. Polymorphisms with frequency >5% were captured well by all strategies. Imputation of intermediate-frequency polymorphisms required a higher density of tag SNPs in disease samples than is available on first-generation genome-wide association study (GWAS) arrays. Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals. C1 [Shea, Jessica; Agarwala, Vineeta; Philippakis, Anthony A.; Maguire, Jared; Banks, Eric; DePristo, Mark; Thomson, Brian; Guiducci, Candace; Kathiresan, Sekar; Gabriel, Stacey; Burtt, Noel P.; Daly, Mark J.; Altshuler, David] Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA. [Shea, Jessica] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA USA. [Shea, Jessica; Agarwala, Vineeta; Philippakis, Anthony A.; Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Agarwala, Vineeta; Philippakis, Anthony A.] Harvard Univ, Program Biophys, Cambridge, MA 02138 USA. [Agarwala, Vineeta; Philippakis, Anthony A.] Harvard Univ, Sch Med, Harvard Massachusetts Inst Technol Div Hlth Sci &, Boston, MA USA. [Philippakis, Anthony A.; Kathiresan, Sekar; Daly, Mark J.; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Philippakis, Anthony A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Kathiresan, Sekar; Daly, Mark J.; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar; Daly, Mark J.; Altshuler, David] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Groop, Leif] Lund Univ, Malmo Univ Hosp, Diabet & Endocrinol Res Unit, Dept Clin Sci, Malmo, Sweden. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Altshuler, D (reprint author), Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA. EM altshuler@molbio.mgh.harvard.edu RI Altshuler, David/A-4476-2009 OI Altshuler, David/0000-0002-7250-4107 FU Sigrid Juselius foundation; Folkhalsan foundation; Swedish Research Council; Novartis; US National Institutes of Health (NIH); US National Heart, Lung, and Blood Institute [R01 HL087676]; Doris Duke Charitable Foundation; NIH; Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital; US National Human Genome Research Institute; Broad Institute FX Sample collections in the DGI study were funded by grants from the Sigrid Juselius and Folkhalsan foundations and from the Swedish Research Council (L. G.). The DGI GWAS study was supported by a grant from Novartis. The MIGen study was funded by the US National Institutes of Health (NIH) and the US National Heart, Lung, and Blood Institute's STAMPEED genomics research program through a grant to D. A. (R01 HL087676). S. K. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a charitable gift from the Fannie E. Rippel Foundation, the Donovan Family Foundation, a career development award from the NIH and the Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital. D. A. and J. S. are supported in part by a Distinguished Clinical Scholar Award from the Doris Duke Charitable Foundation (to D. A.). Next-generation sequencing for this work was carried out by the Broad Institute Sequencing Platform, and genotyping was carried out by the Broad Institute Genetic Analysis Platform. We acknowledge their excellence and collaboration on this study. Sequencing was supported in part by a grant from the US National Human Genome Research Institute and by the Broad Institute. We thank M. Rivas, A. Sivachenco and K. Garimella for helpful discussions on sequencing, and B. Voight, S. Ripke and R. Do for helpful discussions on imputation. NR 30 TC 54 Z9 54 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2011 VL 43 IS 8 BP 801 EP U114 DI 10.1038/ng.871 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 798CD UT WOS:000293178300018 PM 21775993 ER PT J AU Yang, XP Boehm, JS Yang, XP Salehi-Ashtiani, K Hao, T Shen, Y Lubonja, R Thomas, SR Alkan, O Bhimdi, T Green, TM Johannessen, CM Silver, SJ Nguyen, C Murray, RR Hieronymus, H Balcha, D Fan, CY Lin, CW Ghamsari, L Vidal, M Hahn, WC Hill, DE Root, DE AF Yang, Xiaoping Boehm, Jesse S. Yang, Xinping Salehi-Ashtiani, Kourosh Hao, Tong Shen, Yun Lubonja, Rakela Thomas, Sapana R. Alkan, Ozan Bhimdi, Tashfeen Green, Thomas M. Johannessen, Cory M. Silver, Serena J. Cindy Nguyen Murray, Ryan R. Hieronymus, Haley Balcha, Dawit Fan, Changyu Lin, Chenwei Ghamsari, Lila Vidal, Marc Hahn, William C. Hill, David E. Root, David E. TI A public genome-scale lentiviral expression library of human ORFs SO NATURE METHODS LA English DT Article ID OPEN READING FRAMES; CLONING; MAP; COLLECTION; DISCOVERY; RESOURCE; PROTEOME; GENES AB Functional characterization of the human genome requires tools for systematically modulating gene expression in both loss-of-function and gain-of-function experiments. We describe the production of a sequence-confirmed, clonal collection of over 16,100 human open-reading frames (ORFs) encoded in a versatile Gateway vector system. Using this ORFeome resource, we created a genome-scale expression collection in a lentiviral vector, thereby enabling both targeted experiments and high-throughput screens in diverse cell types. C1 [Yang, Xinping; Salehi-Ashtiani, Kourosh; Hao, Tong; Shen, Yun; Murray, Ryan R.; Balcha, Dawit; Fan, Changyu; Lin, Chenwei; Ghamsari, Lila; Vidal, Marc; Hahn, William C.; Hill, David E.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Yang, Xiaoping; Lubonja, Rakela; Alkan, Ozan; Bhimdi, Tashfeen; Green, Thomas M.; Silver, Serena J.; Cindy Nguyen; Root, David E.] Broad Inst Harvard & Massachusetts Inst Technol M, RNA Interference RNAi Platform, Cambridge, MA USA. [Boehm, Jesse S.; Thomas, Sapana R.; Johannessen, Cory M.; Hieronymus, Haley; Hahn, William C.] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA USA. [Yang, Xinping; Salehi-Ashtiani, Kourosh; Hao, Tong; Shen, Yun; Murray, Ryan R.; Balcha, Dawit; Fan, Changyu; Lin, Chenwei; Ghamsari, Lila; Vidal, Marc; Hill, David E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Yang, Xinping; Salehi-Ashtiani, Kourosh; Hao, Tong; Shen, Yun; Murray, Ryan R.; Balcha, Dawit; Fan, Changyu; Lin, Chenwei; Ghamsari, Lila; Vidal, Marc; Hill, David E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Johannessen, Cory M.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Johannessen, Cory M.; Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Hieronymus, Haley] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Vidal, M (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM arc_vidal@dfci.harvard.edu; william_hahn@dfci.harvard.edu; david_hill@dfci.harvard.edu; droot@broadinstitute.org RI Hill, David/B-6617-2011; OI Boehm, Jesse/0000-0002-6795-6336; Salehi-Ashtiani, Kourosh/0000-0002-6521-5243 FU Broad Institute Scientific Planning and Allocation of Resources Committee; The Ellison Foundation; Dana-Farber Cancer Institute; Center for Cancer Genome Discovery; US National Institutes of Health [R33 CA128625] FX We thank B. Piqani, I. Budianto, D. Szeto, T. Hirozane-Kishikawa, V. Swearingen, A. MacWilliams, T. Nieland, S. Hoang, J. Bochicchio, S. Young, A. Berlin, C. Russ, M. Garber and members of the Broad Institute Genetic Sequencing Platform who provided technical assistance or advice throughout this project, and J. Zhao, T. Roberts and T. Golub for participation in kinase ORFs subcollection generation. This work was supported by Broad Institute Scientific Planning and Allocation of Resources Committee funding, The Ellison Foundation (D.E.H. and M.V.), Dana-Farber Cancer Institute sponsored research funds to CCSB and Center for Cancer Genome Discovery and US National Institutes of Health R33 CA128625 (W.C.H., D.E.R. and D.E.H.). NR 19 TC 126 Z9 126 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD AUG PY 2011 VL 8 IS 8 BP 659 EP U80 DI 10.1038/NMETH.1638 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 798OV UT WOS:000293220600021 PM 21706014 ER PT J AU Weinberg, MD Lau, JF Rosenfield, K Olin, JW AF Weinberg, Mitchell D. Lau, Joe F. Rosenfield, Kenneth Olin, Jeffrey W. TI Peripheral artery disease. Part 2: medical and endovascular treatment SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID SUPERFICIAL FEMORAL-ARTERY; CRITICAL LIMB ISCHEMIA; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; RANDOMIZED CONTROLLED-TRIALS; SWEDISH-TICLOPIDINE-MULTICENTER; INFRAINGUINAL BYPASS-SURGERY; NITINOL STENT IMPLANTATION; PLACEBO-CONTROLLED TRIAL; INTER-SOCIETY-CONSENSUS; CORONARY-HEART-DISEASE AB The treatment of peripheral artery disease (PAD) focuses on risk factor modification, cardiovascular event reduction, limb viability, and symptom improvement. Hypertension, hyperlipidemia, and diabetes mellitus should all be controlled to recommended target levels, and smoking cessation is vital. Antiplatelet therapies, such as aspirin or clopidogrel, should be administered in all patients unless contraindicated. Whenever possible, patients who present with claudication should be offered a regimen comprised of both medical and exercise therapy, which often results in substantial improvement in symptoms. For patients presenting with more-advanced disease, such as acute limb ischemia, critical limb ischemia, and severely-limiting symptoms of PAD, revascularization is often necessary. As a result of the rapid evolution in endovascular revascularization technology and expertise, many patients with PAD can be treated percutaneously. Therefore, in this Review, we will focus on medical therapy and endovascular revascularization of patients with PAD, with reference to surgical bypass in specific clinical scenarios. C1 [Weinberg, Mitchell D.; Lau, Joe F.; Olin, Jeffrey W.] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Weinberg, Mitchell D.; Lau, Joe F.; Olin, Jeffrey W.] Mt Sinai Sch Med, Marie Josee & Henry R Kravis Cardiovasc Hlth Ctr, New York, NY 10029 USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Sect Vasc Med & Intervent, Div Cardiol, Boston, MA 02114 USA. RP Olin, JW (reprint author), Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, 1 Gustave L Levy Pl,Box 1033, New York, NY 10029 USA. EM jeffrey.olin@msnyuhealth.org NR 126 TC 16 Z9 18 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD AUG PY 2011 VL 8 IS 8 BP 429 EP 441 DI 10.1038/nrcardio.2011.81 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 797ZR UT WOS:000293169900003 PM 21670746 ER PT J AU Bartzokis, G AF Bartzokis, George TI Alzheimer's disease as homeostatic responses to age-related myelin breakdown SO NEUROBIOLOGY OF AGING LA English DT Review DE Aging; Oligodendrocyte; Peroxisome; BACE; Neuregulin; Apolipoprotein; Prevention; Ubiquitin; alpha-Synuclein; TDP-43; FTLD ID AMYLOID PRECURSOR PROTEIN; GROWTH-FACTOR-I; CENTRAL-NERVOUS-SYSTEM; AMYOTROPHIC-LATERAL-SCLEROSIS; FAST AXONAL-TRANSPORT; FRONTOTEMPORAL LOBAR DEGENERATION; 2',3'-CYCLIC NUCLEOTIDE 3'-PHOSPHODIESTERASE; ETHANOLAMINE PLASMALOGEN DEFICIENCY; MYELOGENETIC CORTICAL LOCALIZATION; POLYUNSATURATED FATTY-ACIDS AB The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta(A beta) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase A beta production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing A beta deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as A beta and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides" upstream" treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin. (C) 2009 Elsevier Inc. All rights reserved. C1 [Bartzokis, George] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Bartzokis, George] Univ Calif Los Angeles, David Geffen Sch Med, Lab Neuroimaging, Dept Neurol,Div Brain Mapping, Los Angeles, CA 90095 USA. [Bartzokis, George] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA 90073 USA. RP Bartzokis, G (reprint author), 300 UCLA Med Plaza,Suite 2200, Los Angeles, CA 90095 USA. EM gbar@ucla.edu RI Bartzokis, George/K-2409-2013 FU NIH [MH066029, AG027342]; RCS Alzheimer's Foundation; Department of Veterans Affairs Research and Psychiatry Services FX Part of this work was supported by NIH grants (MH066029 and AG027342); the RCS Alzheimer's Foundation; and the Department of Veterans Affairs Research and Psychiatry Services. NR 437 TC 148 Z9 152 U1 7 U2 49 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2011 VL 32 IS 8 BP 1341 EP 1371 DI 10.1016/j.neurobiolaging.2009.08.007 PG 31 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 796CT UT WOS:000293028500001 PM 19775776 ER PT J AU Arterburn, DE Westbrook, EO Bogart, TA Sepucha, KR Bock, SN Weppner, WG AF Arterburn, David E. Westbrook, Emily O. Bogart, T. Andy Sepucha, Karen R. Bock, Steven N. Weppner, William G. TI Randomized Trial of a Video-Based Patient Decision Aid for Bariatric Surgery SO OBESITY LA English DT Article ID WEIGHT-LOSS; MORTALITY; OBESITY; METAANALYSIS; QUALITY; SAFETY; CHOICE; RATES AB The decision to have bariatric surgery should be based on accurate information on possible risks and benefits of all treatment options. The goal of this study was to determine whether a video-based bariatric decision aid intervention results in superior decision quality compared to an educational booklet. We conducted a prospective, randomized controlled trial among adult patients in a single health plan who met standard criteria for bariatric surgery. Patients were randomly assigned to review either a video-based decision aid (intervention) or an educational booklet on bariatric surgery (control). Changes in patient decision quality were assessed using bariatric-specific measures of knowledge, values, and treatment preference after 3 months. Of 152 eligible participants, 75 were randomly assigned to the intervention and 77 to the control. The 3-month follow-up rate was 95%. Among all participants, significant improvements were observed in knowledge (P < 0.001), values concordance (P = 0.009), decisional conflict (P < 0.001), decisional self-efficacy (P < 0.001), and in the proportion who were "unsure" of their treatment choice (P < 0.001). The intervention group had larger improvements in knowledge (P = 0.03), decisional conflict (P = 0.03), and outcome expectancies (P = 0.001). The proportion of participants choosing bariatric surgery did not differ significantly between groups, although there was a trend toward decreased surgical choice in the intervention group (59% booklet vs. 42% video at 3 months; P = 0.16). The use of bariatric surgery decision aids was followed by improved decision quality and reduced uncertainty about treatment at 3 months. The video-based decision aid appeared to have a greater impact than the educational booklet on patient knowledge, decisional conflict, and outcome expectancies. C1 [Arterburn, David E.; Westbrook, Emily O.; Bogart, T. Andy] Grp Hlth Res Inst, Seattle, WA USA. [Sepucha, Karen R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Bock, Steven N.] Grp Hlth Permanente, Seattle, WA USA. [Weppner, William G.] Univ Washington, Boise, ID USA. RP Arterburn, DE (reprint author), Grp Hlth Res Inst, Seattle, WA USA. EM arterburn.d@ghc.org FU Foundation for Informed Medical Decision Making Inc. [0077-4, 0094-1]; Foundation for Informed Medical Decision Making FX The authors acknowledge the contributions of the following individuals in the conduct of this study: For their help with subject recruitment and data collection, we thank Mary Shea, Melissa Parson, Kristin Delaney, Christi Hanson, Jessica Ridpath, Ellen Schartz, Julie Grimm, RN CBN, Jeffery Landers, MD, and Candace Carroll of Group Health, Seattle, WA. We thank Stephen Kearing of Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire for his advice regarding our statistical analyses; and we thank Dan Cherkin, PhD of Group Health, Seattle for his critical review of the original proposal and manuscript. This work was funded by the Foundation for Informed Medical Decision Making Inc., Grant nos. 0077-4 and 0094-1. The sponsor did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.; D.E.A., E.O.W., T.A.B., and K.R.S. have support from the Foundation for Informed Medical Decision Making for the submitted work. D.E.A. receives research funding and has received salary support as a medical editor for the not-for profit (501[3]c) Foundation for Informed Medical Decision Making (http://www.fimdm.org), which develops content for patient education programs-including the bariatric surgery program that is the subject of this study. K. R. S. has also received research and salary support from the foundation. The Foundation has an arrangement with a for-profit company, Health Dialog, to coproduce and market these programs to health-care organizations. D. E. A. and K. R. S. have no relationship with any company making products for the treatment of obesity. The authors' spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and authors have no nonfinancial interests that may be relevant to the submitted work. NR 27 TC 21 Z9 21 U1 1 U2 6 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 AUG PY 2011 VL 19 IS 8 BP 1669 EP 1675 DI 10.1038/oby.2011.65 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 797XI UT WOS:000293163000019 PM 21475138 ER PT J AU Chen, T Markmann, J Sachs, D Poznansky, M AF Chen, Tao Markmann, James Sachs, David Poznansky, Mark TI CXCL12 COATING CAUSES EFFECTOR T CELL CHEMOREPULSION FROM AND T REGULATORY CELL CHEMOATTRACTION TO ALLO-ISLET GRAFTS AND SIGNIFICANTLY DELAYS THEIR REJECTION SO PEDIATRIC TRANSPLANTATION LA English DT Meeting Abstract C1 [Chen, Tao; Poznansky, Mark] Massachusetts Gen Hosp, VIC, Charlestown, MA USA. [Sachs, David] MGH, TBRC, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1397-3142 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD AUG PY 2011 VL 15 SU 1 SI SI MA 399 BP 139 EP 139 PG 1 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA 798ZJ UT WOS:000293251100408 ER PT J AU Nahrendorf, M Sosnovik, DE AF Nahrendorf, Matthias Sosnovik, David E. TI Science to Practice: Will Magnetic Guidance of Microbubbles Play a Role in Clinical Molecular Imaging? SO RADIOLOGY LA English DT Article ID ATHEROSCLEROSIS; EXPRESSION AB The elegant study by Wu et al (1) presents additional evidence that vascular cell adhesion molecule-1 (VCAM-1) imaging in atherosclerotic mice is feasible and of substantial preclinical value. The current study is well performed and enhances the diagnostic armamentarium of ultrasonography (US) in molecular imaging of the endothelium. The technique is likely to have a substantial impact in the preclinical arena, where it will assist in the elucidation of endothelial biology and the assessment of new therapies in mice. The impact of the technique in the clinical arena, however, is likely to be more limited. Although final judgment will need to be held until large animal studies are performed with this approach, it is likely that more tomographic and quantitative techniques that are capable of imaging the coronary arteries, such as magnetic resonance (MR) imaging and positron emission tomography (PET), will be of greatest value in the clinical setting. C1 [Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA 02129 USA. [Nahrendorf, Matthias; Sosnovik, David E.] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. [Sosnovik, David E.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Nahrendorf, M (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 149 13th St, Charlestown, MA 02129 USA. EM sosnovik@nmr.mgh.harvard.edu FU Siemens Medical FX M.N. No potential conflicts of interest to disclose. D. E. S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: receives research support from Siemens Medical. Other relationships: none to disclose. NR 5 TC 2 Z9 2 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2011 VL 260 IS 2 BP 309 EP 310 DI 10.1148/radiol.11111017 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 795TU UT WOS:000292999600001 PM 21778448 ER PT J AU Nasis, A Meredith, IT Nerlekar, N Cameron, JD Antonis, PR Mottram, PM Leung, MC Troupis, JM Crossett, M Kambourakis, AG Braitberg, G Hoffmann, U Seneviratne, SK AF Nasis, Arthur Meredith, Ian T. Nerlekar, Nitesh Cameron, James D. Antonis, Paul R. Mottram, Philip M. Leung, Michael C. Troupis, John M. Crossett, Marcus Kambourakis, Anthony G. Braitberg, George Hoffmann, Udo Seneviratne, Sujith K. TI Acute Chest Pain Investigation: Utility of Cardiac CT Angiography in Guiding Troponin Measurement SO RADIOLOGY LA English DT Article ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; ACUTE CORONARY SYNDROMES; EMERGENCY-DEPARTMENT PATIENTS; FRACTIONAL FLOW RESERVE; TIMI RISK SCORE; MYOCARDIAL-INFARCTION; DIAGNOSTIC-ACCURACY; ARTERY-DISEASE; COST-EFFECTIVENESS; ISCHEMIA AB Purpose: To assess the impact on length of stay and rate of major adverse cardiovascular events of a cardiac computed tomographic (CT) angiography-guided algorithm to examine patients who present to the emergency department (ED) with low-to intermediate-risk chest pain. Materials and Methods: The study was approved by the institutional review board, and all patients gave written informed consent. Two hundred three consecutive patients (mean age, 55 years +/- 11 [standard deviation]; 123 men) with low-to intermediate-risk ischemic-type chest pain were prospectively enrolled. Patients underwent initial cardiac CT angiography with subsequent treatment determined by reference to findings at cardiac CT angiography; patients without overt plaque were immediately discharged from the hospital, patients with nonobstructive plaque and mild-to-moderate stenoses were discharged after a negative 6-hour troponin level, and patients with severe stenoses were admitted to the hospital. Discharged patients were followed up for a mean of 14.2 months. Additionally, length of stay and safety outcomes among these patients were compared with those in 102 consecutive patients with low-to intermediate-risk chest pain who presented to the ED and underwent a standard of care (SOC) work-up without cardiac CT angiography. One-way analysis of variance with Bonferroni correction was used to compare length of stay between groups. Results: Cardiac CT angiography findings in the 203 patients who underwent cardiac CT angiography were as follows: Sixty-five (32%) patients had no plaque, 107 (53%) had nonobstructive plaque, and 31 (15%) had severe stenoses. At follow-up, there were no deaths or cases of acute coronary syndrome (cardiac CT angiography, 0%, 95% confidence interval [CI]: 0%, 1.85%; SOC, 0%, 95% CI: 0%, 3.63%), and the rate of readmission to the hospital because of chest pain was higher with the SOC approach (9% vs 1%, P = .01). Mean ED length of stay was lower with cardiac CT angiography (6.62 hours +/- 0.38 after a single troponin level and 9.15 hours +/- 0.30 after serial troponin levels) than with the SOC approach (11.62 hours +/- 0.47, P < .001). Conclusion: Tailoring troponin measurement to cardiac CT angiography findings is safe and allows early discharge of patients with low-to intermediate-risk chest pain, resulting in reduced length of stay. (C) RSNA, 2011 C1 [Nasis, Arthur; Meredith, Ian T.; Nerlekar, Nitesh; Cameron, James D.; Antonis, Paul R.; Mottram, Philip M.; Leung, Michael C.; Crossett, Marcus; Seneviratne, Sujith K.] MonashHEART, Monash Cardiovasc Res Ctr, Clayton, Vic 3168, Australia. [Nasis, Arthur; Meredith, Ian T.; Nerlekar, Nitesh; Cameron, James D.; Antonis, Paul R.; Mottram, Philip M.; Leung, Michael C.; Crossett, Marcus; Seneviratne, Sujith K.] Monash Univ, Dept Med, Melbourne, Vic, Australia. [Troupis, John M.] So Hlth, Dept Diagnost Imaging, Melbourne, Vic, Australia. [Kambourakis, Anthony G.; Braitberg, George] So Hlth, Dept Emergency Med, Melbourne, Vic, Australia. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. RP Seneviratne, SK (reprint author), MonashHEART, Monash Cardiovasc Res Ctr, 246 Clayton Rd, Clayton, Vic 3168, Australia. EM sujith.seneviratne@southernhealth.org.au RI Troupis, John/I-1784-2013 OI Troupis, John/0000-0003-3225-7153 NR 37 TC 14 Z9 14 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2011 VL 260 IS 2 BP 381 EP 389 DI 10.1148/radiol.11110013 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 795TU UT WOS:000292999600008 PM 21673228 ER PT J AU Renker, M Nance, JW Schoepf, UJ O'Brien, TX Zwerner, PL Meyer, M Kerl, JM Bauer, RW Fink, C Vogl, TJ Henzler, T AF Renker, Matthias Nance, John W., Jr. Schoepf, U. Joseph O'Brien, Terrence X. Zwerner, Peter L. Meyer, Mathias Kerl, J. Matthias Bauer, Ralf W. Fink, Christian Vogl, Thomas J. Henzler, Thomas TI Evaluation of Heavily Calcified Vessels with Coronary CT Angiography: Comparison of Iterative and Filtered Back Projection Image Reconstruction SO RADIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; DUAL-SOURCE CT; HEART-RATE-VARIABILITY; EX-VIVO MODEL; DIAGNOSTIC-ACCURACY; ARTERY-DISEASE; QUALITY; METAANALYSIS; PERFORMANCE; MORTALITY AB Purpose: To prospectively compare traditional filtered back projection (FBP) and iterative image reconstruction for the evaluation of heavily calcified arteries with coronary computed tomography (CT) angiography. Materials and Methods: The study had institutional review board approval and was HIPAA compliant. Written informed consent was obtained from all patients. Fifty-five consecutive patients (35 men, 20 women; mean age, 58 years +/- 12 [standard deviation]) with Agatston scores of at least 400 underwent coronary CT angiography and cardiac catheterization. Image data were reconstructed with both FBP and iterative reconstruction techniques with corresponding cardiac algorithms. Image noise and subjective image quality were compared. To objectively assess the effect of FBP and iterative reconstruction on blooming artifacts, volumes of circumscribed calcifications were measured with dedicated volume analysis software. FBP and iterative reconstruction series were independently evaluated for coronary artery stenosis greater than 50%, and their diagnostic accuracy was compared, with cardiac catheterization as the reference standard. Statistical analyses included paired t tests, Kruskal-Wallis analysis of variance, and a modified McNemar test. Results: Image noise measured significantly lower (P = .011-.035) with iterative reconstruction instead of FBP. Image quality was rated significantly higher (P = .031 and .042) with iterative reconstruction series than with FBP. Calcification volumes measured significantly lower (P = .019 and .026) with iterative reconstruction (44.3 mm(3) +/- 64.7 and 46.2 mm(3) +/- 68.8) than with FBP (54.5 mm(3) +/- 69.5 and 56.3 mm(3) +/- 72.5). Iterative reconstruction significantly improved some measures of per-segment diagnostic accuracy of coronary CT angiography for the detection of significant stenosis compared with FBP (accuracy: 95.9% vs 91.8%, P = .0001; specificity: 95.8% vs 91.2%, P = .0001; positive predictive value: 76.9% vs 61.1%, P = .0001). Conclusion: Iterative reconstruction reduces image noise and blooming artifacts from calcifications, leading to improved diagnostic accuracy of coronary CT angiography in patients with heavily calcified coronary arteries. (C) RSNA, 2011 C1 [Renker, Matthias; Nance, John W., Jr.; Schoepf, U. Joseph; O'Brien, Terrence X.; Zwerner, Peter L.; Meyer, Mathias; Kerl, J. Matthias; Bauer, Ralf W.; Fink, Christian; Henzler, Thomas] Med Univ S Carolina, Heart & Vasc Ctr, Charleston, SC 29425 USA. [Renker, Matthias; Kerl, J. Matthias; Bauer, Ralf W.; Vogl, Thomas J.] Goethe Univ Frankfurt, Dept Radiol, Frankfurt, Germany. [O'Brien, Terrence X.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Meyer, Mathias; Fink, Christian; Henzler, Thomas] Univ Heidelberg, Inst Clin Radiol & Nucl Med, Univ Med Ctr Mannheim, D-6800 Mannheim, Germany. RP Schoepf, UJ (reprint author), Med Univ S Carolina, Heart & Vasc Ctr, Ashley River Tower,25 Courtenay Dr, Charleston, SC 29425 USA. EM schoepf@musc.edu RI Meyer, Mathias/G-6791-2015 FU Department of Veterans Affairs FX From the Heart and Vascular Center, Medical University of South Carolina, Ashley River Tower, 25 Courtenay Dr, Charleston, SC 29425-2260 (M. R., J.W.N., U.J.S., T.X.O., P.L.Z., M. M., J.M.K., R. W. B., C. F., T. H.); Department of Radiology, Johann Wolfgang Goethe University, Frankfurt, Germany (M. R., J.M.K., R. W. B., T.J.V.); Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC (T.X.O.); and Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany (M. M., C. F., T. H.). Received December 30, 2010; revision requested February 28, 2011; revision received March 18; accepted April 2; final version accepted April 20. Supported in part by the Research and Development Program of the Department of Veterans Affairs. Address correspondence to U.J.S. (e-mail: schoepf@musc.edu). NR 38 TC 89 Z9 96 U1 0 U2 8 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2011 VL 260 IS 2 BP 390 EP 399 DI 10.1148/radiol.11103574 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 795TU UT WOS:000292999600009 PM 21693660 ER PT J AU Boland, GWL Dwamena, BA AF Boland, Giles W. L. Dwamena, Ben A. TI Preferred Diagnostic Tools for the Evaluation of Adrenal Masses: CT and MR Imaging Response SO RADIOLOGY LA English DT Letter ID LESIONS; PET/CT C1 [Boland, Giles W. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Dwamena, Ben A.] Univ Michigan, Dept Radiol, Sch Med, Ann Arbor, MI 48109 USA. RP Boland, GWL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St,White Bldg 270C, Boston, MA 02114 USA. EM gboland@partners.org NR 7 TC 1 Z9 1 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2011 VL 260 IS 2 BP 610 EP 611 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 795TU UT WOS:000292999600043 ER PT J AU Alonso-Alonso, M Ziemke, F Magkos, F Barrios, FA Brinkoetter, M Boyd, I Rifkin-Graboi, A Yannakoulia, M Rojas, R Pascual-Leone, A Mantzoros, CS AF Alonso-Alonso, Miguel Ziemke, Florencia Magkos, Faidon Barrios, Fernando A. Brinkoetter, Mary Boyd, Ingrid Rifkin-Graboi, Anne Yannakoulia, Mary Rojas, Rafael Pascual-Leone, Alvaro Mantzoros, Christos S. TI Brain responses to food images during the early and late follicular phase of the menstrual cycle in healthy young women: relation to fasting and feeding SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; EFFECTIVE CONNECTIVITY; ORBITOFRONTAL CORTEX; FACE PERCEPTION; SEX-DIFFERENCES; ESTROGEN; ACTIVATION; HUNGER; FMRI; APPETITE AB Background: Food intake fluctuates throughout the menstrual cycle; it is greater during the early follicular and luteal phases than in the late follicular (periovulatory) phase. Ovarian steroids can influence brain areas that process food-related information, but the specific contribution of individual hormones and the importance of the prandial state remain unknown. Objective: The objective was to examine whether brain activation during food visualization is affected by changes in estradiol concentration in the fasted and fed conditions. Design: Nine eumenorrheic, lean young women [mean (+/- SD) age: 26.2 +/- 3.2 y; body mass index (in kg/m(2)): 22.4 +/- 1.2] completed 2 visits, one in the early (low estradiol) and one in the late (high estradiol) follicular phase of their menstrual cycle. At each visit, subjects underwent functional magnetic resonance imaging while they viewed food and nonfood images, before and after a standardized meal. Region-of-interest analysis was used to examine the effect of follicular phase and prandial state on brain activation (food > nonfood contrast) and its association with estradiol concentration. Results: Differences were identified in the inferior frontal and fusiform gyri. In these areas, visualization of food elicited greater activation in the fed state than during fasting but only in the late follicular phase, when estradiol concentration was high. The change in estradiol concentration across the follicular phase (late minus early) was inversely correlated with the change in fusiform gyrus activation in the fasted state but not in the fed state. Conclusion: Our findings suggest that estradiol may reduce food intake by decreasing sensitivity to food cues in the ventral visual pathway under conditions of energy deprivation. This trial was registered at clinicaltrials.gov as NCT00130117. Am J Clin Nutr 2011;94:377-84. C1 [Alonso-Alonso, Miguel] Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Div Cognit Neurol, Boston, MA 02215 USA. [Ziemke, Florencia; Magkos, Faidon; Brinkoetter, Mary; Boyd, Ingrid; Rifkin-Graboi, Anne; Yannakoulia, Mary; Mantzoros, Christos S.] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Rojas, Rafael] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Endocrinol Sect, Boston VA Healthcare Syst, Boston, MA USA. [Barrios, Fernando A.] Univ Nacl Autonoma Mexico, Inst Neurobiol, Queretaro, Mexico. [Magkos, Faidon; Yannakoulia, Mary] Harokopio Univ, Dept Nutr & Dietet, Athens, Greece. RP Alonso-Alonso, M (reprint author), Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Div Cognit Neurol, 330 Brookline Ave,Ks 158, Boston, MA 02215 USA. EM malonso@bidmc.harvard.edu RI Barrios, Fernando/B-4295-2012; Barrios, Fernando/D-1591-2016 OI Barrios, Fernando/0000-0002-5699-4222 FU Harvard Clinical and Translational Science Center, from the National Center for Research Resources [UL1 RR025758, M01-RR-01032]; National Institute of Diabetes and Digestive and Kidney Diseases [DK58785, DK79929, DK81913, AG032030]; Beth Israel Deaconess Medical Center; Davis Foundation of the Klarman Family Foundation FX Supported by grants UL1 RR025758 and M01-RR-01032-Harvard Clinical and Translational Science Center, from the National Center for Research Resources. Funding was also received from the National Institute of Diabetes and Digestive and Kidney Diseases (grants DK58785, DK79929, DK81913, and AG032030). The Mantzoros Laboratory is supported by a discretionary grant from Beth Israel Deaconess Medical Center. MA-A and AP-L were supported by a Davis Foundation Award of the Klarman Family Foundation Grants Program in Eating Disorders. NR 56 TC 19 Z9 19 U1 0 U2 9 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2011 VL 94 IS 2 BP 377 EP 384 DI 10.3945/ajcn.110.010736 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 794TT UT WOS:000292924900004 PM 21593494 ER PT J AU Rich-Edwards, JW Ganmaa, D Kleinman, K Sumberzul, N Holick, MF Lkhagvasuren, T Dulguun, B Burke, A Frazier, AL AF Rich-Edwards, Janet W. Ganmaa, Davaasambuu Kleinman, Ken Sumberzul, Namjav Holick, Michael F. Lkhagvasuren, Tserenkhuu Dulguun, Batbaatar Burke, Anne Frazier, A. Lindsay TI Randomized trial of fortified milk and supplements to raise 25-hydroxyvitamin D concentrations in schoolchildren in Mongolia SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID VITAMIN-D SUPPLEMENTATION; D DEFICIENCY; SERUM CONCENTRATIONS; D METABOLITES; D PROPHYLAXIS; CHILDREN; GIRLS; INTERVENTION; ADOLESCENTS; PREVALENCE AB Background: The optimal public health strategy for maintaining 25-hydroxyvitamin D [25(OH) D] concentrations in schoolchildren in Mongolia is unknown. Objective: The objective was to compare the effectiveness of different supplement and fortified milk regimens to increase 25(OH) D concentrations in Mongolian schoolchildren. Design: Twenty-one classrooms of 579 children aged 9-11 y were randomized to interventions with an equivalent content of vitamin D-3: 1) a one-time seasonal supplement of 13,700 IU, 2) 300 IU/d from supplements, 3) 300 IU/d from fortified ultra-high-temperature pasteurized milk from the United States, 4) 300 IU/d from fortified pasteurized Mongolian milk, or 5) unfortified pasteurized Mongolian milk (control). Results: In January, the mean (+/- SD) serum 25(OH) D concentration was 8 +/- 4 ng/mL (20 +/- 10 nmol/L), and 98% of the children had a concentration <20 ng/mL (50 nmol/L). In March, concentrations were 8 +/- 4 ng/mL after unfortified milk, 20 +/- 6 ng/mL after fortified Mongolian milk, 29 +/- 10 ng/mL after fortified US milk, 21 +/- 6 ng/mL after daily supplements, and 12 +/- 4 ng/mL after seasonal supplements (each greater than unfortified milk, P < 0.01). Seasonal supplementation was less effective than was daily supplementation (P < 0.0001). Despite consuming daily supplements or fortified milk, 41% of the children still had concentrations <20 ng/mL (50 nmol/L). Children with lower baseline 25(OH) D concentrations experienced slightly larger 25(OH) D responses to intervention than did children with higher concentrations (P = 0.002). Conclusions: In this population with extremely low vitamin D concentrations, delivery of 300 IU vitamin D/d via supplements or in fortified milk improved 25(OH) D concentrations but failed to raise concentrations uniformly to >20 ng/mL (50 nmol/L). The daily low-dose intervention was superior to the seasonal larger-dose intervention. Higher doses may be needed to prevent deficiency in schoolchildren in Mongolia and at other northern latitudes. This trial is registered at clinicaltrials.gov as NCT00886379. Am J Clin Nutr 2011; 94: 578-84. C1 [Rich-Edwards, Janet W.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. [Rich-Edwards, Janet W.; Ganmaa, Davaasambuu; Kleinman, Ken] Harvard Univ, Sch Med, Boston, MA USA. [Rich-Edwards, Janet W.; Frazier, A. Lindsay] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ganmaa, Davaasambuu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ganmaa, Davaasambuu] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Kleinman, Ken] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Sumberzul, Namjav; Lkhagvasuren, Tserenkhuu; Dulguun, Batbaatar] Univ Mongolia, Ulaanbaatar, Mongol Peo Rep. [Holick, Michael F.] Boston Univ, Med Ctr, Dept Med, Endocrine Diabet & Nutr Sect, Boston, MA USA. [Burke, Anne] Univ Rochester, Dept Clin Psychol, Rochester, NY USA. [Frazier, A. Lindsay] Dana Farber Canc Inst, Boston, MA 02115 USA. [Frazier, A. Lindsay] Boston Childrens Hosp, Boston, MA USA. RP Rich-Edwards, JW (reprint author), 1620 Tremont St,3rd Floor, Boston, MA 02120 USA. EM jr33@partners.org NR 37 TC 18 Z9 18 U1 0 U2 5 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2011 VL 94 IS 2 BP 578 EP 584 DI 10.3945/ajcn.110.008771 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 794TT UT WOS:000292924900028 PM 21697075 ER PT J AU Cavusoglu, E Marmur, JD Hojjati, MR Chopra, V Butala, M Subnani, R Huda, MS Yanamadala, S Ruwende, C Eng, C Pinsky, DJ AF Cavusoglu, Erdal Marmur, Jonathan D. Hojjati, Mohammad R. Chopra, Vineet Butala, Mitul Subnani, Rakesh Huda, Mohammad S. Yanamadala, Sunitha Ruwende, Cyril Eng, Calvin Pinsky, David J. TI Plasma Interleukin-10 Levels and Adverse Outcomes in Acute Coronary Syndrome SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Acute coronary syndrome; Biomarker; Inflammation; Interleukin-10; Prognosis ID ANTIINFLAMMATORY CYTOKINE INTERLEUKIN-10; C-REACTIVE PROTEIN; MYOCARDIAL-INFARCTION; INDEPENDENT PREDICTOR; CARDIAC MORTALITY; ADIPONECTIN; DISEASE AB PURPOSE OR BACKGROUND: Interleukin (IL)-10 is an immunoregulatory cytokine that is produced by a variety of cell types, such as macrophages and activated monocytes. IL-10 possesses numerous anti-inflammatory, anti-thrombotic and anti-atherosclerotic properties. Furthermore, patients with acute coronary syndrome have been demonstrated to have reduced levels of IL-10 compared to their stable counterparts. For these reasons, it has been proposed that IL-10 plays a protective role in both atherogenesis and plaque vulnerability. However, 2 short-term studies on the prognostic utility of IL-10 in patients with acute coronary syndrome have provided conflicting results, with one study showing that reduced levels of IL-10 were predictors of adverse outcomes and another showing that elevated levels predicted poor outcomes. The objective of the present study was to investigate the long-term prognostic significance of baseline IL-10 levels in patients with acute coronary syndrome. METHODS: Baseline plasma IL-10 levels were measured in 193 well-characterized male patients with acute coronary syndrome who were referred for coronary angiography and followed prospectively for 5 years for the development of major adverse cardiovascular events. RESULTS: After controlling for a variety of baseline variables (including established biomarkers such as high-sensitivity C-reactive protein and N-terminal-pro-B-type natriuretic peptide), plasma IL-10 levels (whether analyzed as a continuous variable or as a categorical variable using receiver operating characteristic-derived cut point) were a strong and independent predictor of the composite outcome of death or non-fatal myocardial infarction when using a Cox proportional hazards model. CONCLUSIONS: These data demonstrate that, despite biologic plausibility for IL-10 as being a cardioprotective cytokine, elevated baseline plasma levels of IL-10 are a strong and independent predictor of long-term adverse cardiovascular outcomes in patients with acute coronary syndrome. Published by Elsevier Inc. The American Journal of Medicine (2011) 124, 724-730 C1 [Cavusoglu, Erdal; Marmur, Jonathan D.; Hojjati, Mohammad R.; Butala, Mitul; Subnani, Rakesh; Huda, Mohammad S.] Suny Downstate Med Ctr, Div Cardiol, Dept Med, Brooklyn, NY 11203 USA. [Cavusoglu, Erdal; Chopra, Vineet; Eng, Calvin] Bronx Vet Affairs Med Ctr, Dept Med, Div Cardiol, Bronx, NY USA. [Yanamadala, Sunitha; Ruwende, Cyril; Pinsky, David J.] Univ Michigan, Dept Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. RP Cavusoglu, E (reprint author), Suny Downstate Med Ctr, Div Cardiol, Dept Med, 450 Clarkson Ave,Box 1257, Brooklyn, NY 11203 USA. EM ECavusoglu@aol.com NR 18 TC 30 Z9 33 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG PY 2011 VL 124 IS 8 BP 724 EP 730 DI 10.1016/j.amjmed.2011.02.040 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 795WV UT WOS:000293010100024 PM 21787901 ER PT J AU Haaf, P Balmelli, C Reichlin, T Twerenbold, R Reiter, M Meissner, J Schaub, N Stelzig, C Freese, M Paniz, P Meune, C Drexler, B Freidank, H Winkler, K Hochholzer, W Mueller, C AF Haaf, Philip Balmelli, Cathrin Reichlin, Tobias Twerenbold, Raphael Reiter, Miriam Meissner, Julia Schaub, Nora Stelzig, Claudia Freese, Michael Paniz, Patricia Meune, Christophe Drexler, Beatrice Freidank, Heike Winkler, Katrin Hochholzer, Willibald Mueller, Christian TI N-terminal Pro B-type Natriuretic Peptide in the Early Evaluation of Suspected Acute Myocardial Infarction SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Acute chest pain; Early diagnosis; NT-proBNP; Risk stratification ID ACUTE CORONARY SYNDROMES; EMERGENCY DIAGNOSIS; ARTERY-DISEASE; HEART-FAILURE; BNP; ELEVATION; EUROPE; COSTS AB BACKGROUND: Myocardial ischemia is a strong trigger of N-terminal pro-B-type natriuretic peptide (NT-proBNP) release. As ischemia precedes necrosis in acute myocardial infarction, we hypothesized that NT-proBNP might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction. METHODS: In a prospective multicenter study, NT-proBNP was measured at presentation in 658 consecutive patients with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long term regarding mortality. RESULTS: Acute myocardial infarction was the adjudicated final diagnosis in 117 patients (18%). NT-proBNP levels at presentation were significantly higher in acute myocardial infarction as compared with patients with other final diagnoses (median 886 pg/mL vs 135 pg/mL, P <.001). The diagnostic accuracy of NT-proBNP for acute myocardial infarction as quantified by the area under the receiver operating characteristic curve (AUC) was 0.79 (95% confidence interval [CI], 0.75-0.83). When added to cardiac troponin T, NT-proBNP significantly increased the AUC from 0.89 (95% CI, 0.84-0.93) to 0.91 (95% CI, 0.88-0.94; P = .033). Cumulative 24-month mortality rates were 0% in the first, 1.3% in the second, 8.3% in the third, and 23.3% in the fourth quartile of NT-proBNP (P <.001). NT-proBNP (AUC 0.85, 95% CI, 0.81-0.89) predicted all-cause mortality independently of and more accurately than both cardiac troponin T (AUC 0.66, 95% CI, 0.58-0.74; P <.001) and the Thrombolysis in Myocardial Infarction risk score (AUC 0.79, 95% CI, 0.74-0.84; P <.001). Net reclassification improvement (Thrombolysis in Myocardial Infarction vs additionally NT-proBNP) was 0.188 (P <.009), and integrated discrimination improvement was 0.100 (P <.001). CONCLUSIONS: Use of NT-proBNP improves the early diagnosis and risk stratification of patients with suspected acute myocardial infarction. (C) 2011 Elsevier Inc. All rights reserved. The American Journal of Medicine (2011) 124, 731-739 C1 [Haaf, Philip; Balmelli, Cathrin; Reichlin, Tobias; Twerenbold, Raphael; Reiter, Miriam; Meissner, Julia; Schaub, Nora; Stelzig, Claudia; Freese, Michael; Paniz, Patricia; Meune, Christophe; Drexler, Beatrice; Hochholzer, Willibald; Mueller, Christian] Univ Basel Hosp, Dept Internal Med, CH-4031 Basel, Switzerland. [Reichlin, Tobias; Mueller, Christian] Univ Basel Hosp, Dept Cardiol, CH-4031 Basel, Switzerland. [Meune, Christophe] Paris Descartes Univ, Cochin Hosp, APHP, Dept Cardiol, Paris, France. [Freidank, Heike] Univ Basel Hosp, Dept Lab Med, CH-4031 Basel, Switzerland. [Winkler, Katrin] Hosp del Mar, IMIM UPF, CIBERES, ISC III,Serv Pneumol, Barcelona, Spain. [Winkler, Katrin] Hosp del Mar, IMIM UPF, CIBERES, ISC III,Serv Urgencias, Barcelona, Spain. [Hochholzer, Willibald] Harvard Univ, Brigham & Womens Hosp, TIMI Study Grp, Sch Med,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. RP Mueller, C (reprint author), Univ Basel Hosp, Dept Internal Med, Petersgraben 4, CH-4031 Basel, Switzerland. EM chmueller@uhbs.ch OI Twerenbold, Raphael/0000-0003-3814-6542 FU Swiss National Science Foundation [PP00B-102853]; Swiss Heart Foundation, Roche; Department of Internal Medicine, University Hospital Basel; Swiss Heart Foundation; Stanley Thomas Johnson Foundation; Abbott; ALERE; Brahms; Nanosphere; Roche; Siemens; University of Basel; Freie Akademische Gesellschaft Basel (FAG) FX The study was supported by research grants from the Swiss National Science Foundation (PP00B-102853), the Swiss Heart Foundation, Roche, and the Department of Internal Medicine, University Hospital Basel.; We disclose that Dr. Mueller has received research support from the Swiss National Science Foundation (PP00B-102853), the Swiss Heart Foundation, the Stanley Thomas Johnson Foundation, Abbott, ALERE, Brahms, Nanosphere, Roche, Siemens, and the Department of Internal Medicine, University Hospital Basel, as well as speaker honoraria from Abbott, ALERE, Brahms, Roche, and Siemens. Dr. Reichlin has received research grants from the University of Basel and the Department of Internal Medicine, University Hospital Basel, as well as speaker honoraria from Brahms and Roche. Dr. Meune was supported by a grant from the Freie Akademische Gesellschaft Basel (FAG). All other authors declare that they have no conflict of interest. NR 24 TC 14 Z9 19 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG PY 2011 VL 124 IS 8 BP 731 EP 739 DI 10.1016/j.amjmed.2011.02.035 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 795WV UT WOS:000293010100025 PM 21787902 ER PT J AU Brondolo, E Hausmann, LRM Jhalani, J Pencille, M Atencio-Bacayon, J Kumar, A Kwok, J Ullah, J Roth, A Chen, D Crupi, R Schwartz, J AF Brondolo, Elizabeth Hausmann, Leslie R. M. Jhalani, Juhee Pencille, Melissa Atencio-Bacayon, Jennifer Kumar, Asha Kwok, Jasmin Ullah, Jahanara Roth, Alan Chen, Daniel Crupi, Robert Schwartz, Joseph TI Dimensions of Perceived Racism and Self-Reported Health: Examination of Racial/Ethnic Differences and Potential Mediators SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Racism; Ethnic discrimination; Self-reported health; Health; Social exclusion; Meditation; Depression ID MEXICAN-ORIGIN ADULTS; AFRICAN-AMERICAN ADULTS; MEDLEY HOSTILITY SCALE; PHYSICAL HEALTH; ETHNIC DISCRIMINATION; COMMUNITY SAMPLE; RESIDENTIAL SEGREGATION; COLLEGE-STUDENTS; WHITE AMERICANS; BLOOD-PRESSURE AB Background Many details of the negative relationship between perceived racial/ethnic discrimination and health are poorly understood. Purpose The purpose of this study was to examine racial/ethnic differences in the relationship between perceived discrimination and self-reported health, identify dimensions of discrimination that drive this relationship, and explore psychological mediators. Methods Asian, Black, and Latino(a) adults (N = 734) completed measures of perceived racial/ethnic discrimination, self-reported health, depression, anxiety, and cynical hostility. Results The association between perceived discrimination and poor self-reported health was significant and did not differ across racial/ethnic subgroups. Race-related social exclusion and threat/harassment uniquely contributed to poor health for all groups. Depression, anxiety, and cynical hostility fully mediated the effect of social exclusion on health, but did not fully explain the effect of threat. Conclusions Our results suggest that noxious effects of race-related exclusion and threat transcend between-group differences in discriminatory experiences. The effects of race-related exclusion and threat on health, however, may operate through different mechanisms. C1 [Brondolo, Elizabeth; Jhalani, Juhee; Pencille, Melissa; Atencio-Bacayon, Jennifer; Kumar, Asha; Kwok, Jasmin; Ullah, Jahanara] St Johns Univ, Dept Psychol, Jamaica, NY 11439 USA. [Hausmann, Leslie R. M.] Vet Affairs Pittsburgh Hlth Care Syst, Hlth Serv Res & Dev Serv, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Roth, Alan] Jamaica Hosp Med Ctr, Jamaica, NY USA. [Chen, Daniel; Crupi, Robert] Flushing Hosp Med Ctr, Flushing, NY USA. [Schwartz, Joseph] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. RP Brondolo, E (reprint author), St Johns Univ, Dept Psychol, Jamaica, NY 11439 USA. EM brondole@stjohns.edu OI Brondolo, Elizabeth/0000-0002-7110-956X FU NHLBI NIH HHS [R01 HL065890, R01 HL068590, R01 HL068590-01A1] NR 100 TC 46 Z9 46 U1 1 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD AUG PY 2011 VL 42 IS 1 BP 14 EP 28 DI 10.1007/s12160-011-9265-1 PG 15 WC Psychology, Multidisciplinary SC Psychology GA 794UK UT WOS:000292926600002 PM 21374099 ER PT J AU Gonzalez, JS Psaros, C Batchelder, A Applebaum, A Newville, H Safren, SA AF Gonzalez, Jeffrey S. Psaros, Christina Batchelder, Abigail Applebaum, Allison Newville, Howard Safren, Steven A. TI Clinician-Assessed Depression and HAART Adherence in HIV-Infected Individuals in Methadone Maintenance Treatment SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE HIV; Depression; Adherence; Assessment; Methadone maintenance; HAART ID ACTIVE ANTIRETROVIRAL THERAPY; SOCIAL SUPPORT; DRUG-USERS; SHORT FORM; NONADHERENCE; VALIDATION; PREDICTORS; INVENTORY; HIV/AIDS; FAILURE AB Background The impact of measurement methods on the relationship between depression and HIV treatment adherence has not been adequately examined. Purpose The purpose of this paper is to examine the relationship between clinician- and patient-rated depression and HIV medication adherence. Methods The participants were 91 HIV-infected individuals in methadone maintenance. Depression was assessed via clinician ratings (Clinical Global Impression Scale and Montgomery Asberg Depression Rating Scale) and self-report (Beck Depression Inventory-Short Form). Clinicians rated substance abuse using the Clinical Global Impression Scale and a structured interview. HIV medication adherence was measured over the following 2 weeks using electronic caps. Results Each unit increase in the Clinical Global Impression Scale was associated with 75% increased odds of nonadherence (OR = 1.75, p = 0.002, 95% CI = 1.23-2.48). Similarly, for each standard deviation Montgomery Asberg Depression Rating Scale increase, there was a 2.6-fold increased odds of nonadherence (OR = 2.60, p = 0.001, 95% CI = 1.45-4.67). Substance abuse and self-reported depression severity were not significantly related to adherence. Conclusions Clinician-rated depression severity was a strong predictor of nonadherence. Assessment methods may influence the relationship between depression and HIV nonadherence. C1 [Gonzalez, Jeffrey S.] Yeshiva Univ, Albert Einstein Coll Med, Bronx, NY 10461 USA. [Gonzalez, Jeffrey S.; Batchelder, Abigail; Newville, Howard] Yeshiva Univ, Ferkauf Grad Sch Psychol, Bronx, NY 10461 USA. [Gonzalez, Jeffrey S.; Psaros, Christina; Safren, Steven A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Psaros, Christina; Safren, Steven A.] Harvard Univ, Sch Med, Boston, MA USA. [Applebaum, Allison] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Gonzalez, JS (reprint author), Yeshiva Univ, Albert Einstein Coll Med, Rousso Bldg,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM jeffrey.gonzalez@einstein.yu.edu RI Newville, Howard/H-3175-2014 OI Newville, Howard/0000-0001-7694-9368 FU NCI NIH HHS [P30 CA008748]; NIDA NIH HHS [R01 DA018603] NR 25 TC 12 Z9 12 U1 6 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD AUG PY 2011 VL 42 IS 1 BP 120 EP 126 DI 10.1007/s12160-011-9268-y PG 7 WC Psychology, Multidisciplinary SC Psychology GA 794UK UT WOS:000292926600011 PM 21503833 ER PT J AU Greenberg, CC Lipsitz, SR Hughes, ME Edge, SB Theriault, R Wilson, JL Carter, WB Blayney, DW Niland, J Weeks, JC AF Greenberg, Caprice C. Lipsitz, Stuart R. Hughes, Melissa E. Edge, Stephen B. Theriault, Richard Wilson, John L. Carter, W. Bradford Blayney, Douglas W. Niland, Joyce Weeks, Jane C. TI Institutional Variation in the Surgical Treatment of Breast Cancer A Study of the NCCN SO ANNALS OF SURGERY LA English DT Article ID COMPARING TOTAL MASTECTOMY; 20-YEAR FOLLOW-UP; GEOGRAPHIC-VARIATION; RADICAL-MASTECTOMY; CONSERVING SURGERY; RADIATION-THERAPY; LIFE; RECONSTRUCTION; CARCINOMA; DECISION AB Objective: To investigate the relationship between supply of subspecialty care and type of procedure preferentially performed for early stage breast cancer. Background: Three surgical options exist for early stage breast cancer: (1) breast conserving surgery (BCS), (2) mastectomy with reconstruction (RECON), and (3) mastectomy alone. Current guidelines recommend that surgical treatment decisions should be based on patient preference if a patient is eligible for all 3. However, studies demonstrate persistent variation in the use of BCS and RECON. Methods: Patients undergoing an operation for DCIS or stage I or II breast cancer at NCCN institutions between 2000 and 2006 were identified. Institutional procedure rates were determined. Spearman correlations measured the association between procedure types. Patient-level logistic regression models investigated predictors of procedure type and association with institutional supply of subspecialty care. Results: Among 10,607 patients, 19% had mastectomy alone, 60% BCS, and 21% RECON. The institutional rate of BCS and RECON were strongly correlated (r = -0.80, P = 0.02). Institution was more important than all patient factors except age in predicting receipt of RECON or BCS. RECON was more likely for patients treated at an institution with a greater supply of reconstructive surgeons or where patients live further from radiation facilities. RECON was less likely at institutions with longer waiting times for surgery with reconstruction. Conclusions: Even within the NCCN, a consortium of multidisciplinary cancer centers, the use of BCS and mastectomy with reconstruction substantially varies by institution and correlates with the supply of subspecialty care. C1 [Greenberg, Caprice C.; Lipsitz, Stuart R.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Dept Surg, Boston, MA 02120 USA. [Greenberg, Caprice C.; Hughes, Melissa E.; Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Edge, Stephen B.] Roswell Pk Canc Ctr, Dept Breast & Soft Tissue Surg, Buffalo, NY USA. [Theriault, Richard] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Wilson, John L.] Ohio State Univ, Ctr Comprehens Canc, Dept Surg, Columbus, OH 43210 USA. [Carter, W. Bradford] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Blayney, Douglas W.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Niland, Joyce] City Hope Med Ctr, Dept Biostat, Duarte, CA USA. RP Greenberg, CC (reprint author), Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Dept Surg, 1 Brigham Circle,1620 Tremont St, Boston, MA 02120 USA. EM ccgreenberg@partners.org FU National Cancer Institute [P50 CA092203]; American Surgical Association FX Supported in part by grant P50 CA092203 from the National Cancer Institute to Dana-Farber Cancer Institute. Dr.Greenberg receives support from the American Surgical Association Foundation Fellowship. NR 40 TC 43 Z9 46 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD AUG PY 2011 VL 254 IS 2 BP 339 EP 345 DI 10.1097/SLA.0b013e3182263bb0 PG 7 WC Surgery SC Surgery GA 794OC UT WOS:000292908700023 PM 21725233 ER PT J AU Qi, YM Liu, J Wu, XW Brakebusch, C Leitges, M Han, YL Corbett, SA Lowry, SF Graham, AM Li, SH AF Qi, Yanmei Liu, Jie Wu, Xunwei Brakebusch, Cord Leitges, Michael Han, Yaling Corbett, Siobhan A. Lowry, Stephen F. Graham, Alan M. Li, Shaohua TI Cdc42 Controls Vascular Network Assembly Through Protein Kinase C iota During Embryonic Vasculogenesis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE angiogenesis; endothelium; signal transduction; vascular biology ID CELL-POLARITY; LUMEN FORMATION; BRANCHING MORPHOGENESIS; SHEAR-STRESS; STEM-CELLS; RAC1; GENE; PKC; BETA-1-INTEGRIN; ANGIOGENESIS AB Objective-The goal of this study was to determine the role of Cdc42 in embryonic vasculogenesis and the underlying mechanisms. Methods and Results-By using genetically modified mouse embryonic stem (ES) cells, we demonstrate that ablation of the Rho GTPase Cdc42 blocks vascular network assembly during embryoid body (EB) vasculogenesis without affecting endothelial lineage differentiation. Reexpression of Cdc42 in mutant EBs rescues the mutant phenotype, establishing an essential role for Cdc42 in vasculogenesis. Chimeric analysis revealed that the vascular phenotype is caused by inactivation of Cdc42 in endothelial cells rather than surrounding cells. Endothelial cells isolated from Cdc42-null EBs are defective in directional migration and network assembly. In addition, activation of atypical protein kinase C iota (PKC iota) is abolished in Cdc42-null endothelial cells, and PKC iota ablation phenocopies the vascular abnormalities of the Cdc42-null EBs. Moreover, the inhibitory phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) at Ser9 depends on Cdc42 and PKC iota, and expression of kinase-dead GSK-3 beta in Cdc42-null EBs promotes the formation of linear endothelial segments without branches. These results suggest that PKC iota and GSK-3 beta are downstream effectors of Cdc42 during vascular morphogenesis. Conclusion-Cdc42 controls vascular network assembly but not endothelial lineage differentiation by activating PKC iota during embryonic vasculogenesis. (Arterioscler Thromb Vasc Biol. 2011;31:1861-1870.) C1 [Li, Shaohua] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Surg, Div Vasc Surg, New Brunswick, NJ 08903 USA. [Wu, Xunwei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Charlestown, MA USA. [Brakebusch, Cord] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark. [Leitges, Michael] Univ Oslo, Biotechnol Ctr Oslo, Oslo, Norway. [Han, Yaling] Shenyang No Hosp, Shenyang, Peoples R China. RP Li, SH (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Surg, Div Vasc Surg, 1 Robert Wood Johnson Pl,MEB-541, New Brunswick, NJ 08903 USA. EM shaohua.li@umdnj.edu FU New Jersey Commission on Science and Technology [07-2042-014-84]; National Institute of General Medical Sciences [R01GM081674] FX This study was supported by research funding from the New Jersey Commission on Science and Technology (Grant 07-2042-014-84) and the National Institute of General Medical Sciences (Grant R01GM081674) (to S.L.). NR 39 TC 11 Z9 11 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD AUG PY 2011 VL 31 IS 8 BP 1861 EP U342 DI 10.1161/ATVBAHA.111.230144 PG 12 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 794RH UT WOS:000292918500022 PM 21659643 ER PT J AU Newfell, BG Iyer, LK Mohammad, NN McGraw, AP Ehsan, A Rosano, G Huang, PL Mendelsohn, ME Jaffe, IZ AF Newfell, Brenna G. Iyer, Lakshmanan K. Mohammad, Najwa N. McGraw, Adam P. Ehsan, Afshin Rosano, Giuseppe Huang, Paul L. Mendelsohn, Michael E. Jaffe, Iris Z. TI Aldosterone Regulates Vascular Gene Transcription via Oxidative Stress-Dependent and -Independent Pathways SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE gene expression; vascular biology; aldosterone; mineralocorticoid receptor antagonists ID SMOOTH-MUSCLE-CELLS; ENDOTHELIAL-CELLS; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; MINERALOCORTICOID RECEPTORS; LEUKOCYTE ADHESION; ESTROGEN-RECEPTOR; CORONARY EVENTS; ANGIOTENSIN-II; GROWTH-FACTOR; RAT-HEART AB Objective-Aldosterone (Aldo) antagonism prevents cardiovascular mortality by unclear mechanisms. Aldo binds to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, which is expressed in human vascular cells. Here we define the early Aldo-regulated vascular transcriptome and investigate the mechanisms of gene regulation by Aldo in the vasculature that may contribute to vascular disease. Methods and Results-Gene expression profiling of Aldo-treated mouse aortas identified 72 genes regulated by Aldo. These genes are overrepresented in Gene Ontology categories involved in vascular function and disease. Quantitative reverse transcription-polymerase chain reaction was used to confirm and further explore mechanisms of vascular gene regulation by Aldo. Aldo-regulated vascular gene expression was inhibited by actinomycin D and MR antagonists supporting a transcriptional MR-dependent mechanism. Aldo regulation of a subset of genes was enhanced in the setting of vascular endothelial denudation and blocked by the free radical scavenger Tempol, supporting synergy between Aldo and vascular injury that is oxidative stress dependent. In the aortic arch, a region predisposed to atherosclerosis, the injury-enhanced genes also demonstrated enhanced expression compared with the descending aorta, both at baseline and after Aldo exposure. Furthermore, the clinically beneficial MR antagonist spironolactone inhibited expression of the identified genes in aortic tissue from humans with atherosclerosis. Conclusion-This study defines the Aldo-regulated vascular transcriptome and characterizes a subset of proatherogenic genes with enhanced Aldo-stimulated, oxidative stress-dependent expression in the setting of vascular injury and in areas predisposed to atherosclerosis. Inhibition of MR regulation of these genes may play a role in the protective effects of Aldo antagonists in patients with vascular disease, and these pathways may provide novel drug targets to prevent atherosclerosis in humans. (Arterioscler Thromb Vasc Biol. 2011;31:1871-1880.) C1 [Newfell, Brenna G.; Iyer, Lakshmanan K.; Mohammad, Najwa N.; McGraw, Adam P.; Ehsan, Afshin; Mendelsohn, Michael E.; Jaffe, Iris Z.] Tufts Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA. [Ehsan, Afshin] Tufts Med Ctr, Div Cardiothorac Surg, Boston, MA 02111 USA. [Iyer, Lakshmanan K.] Tufts Univ, Sch Med, Neurosci Res Ctr, Boston, MA 02111 USA. [Rosano, Giuseppe] Inst Ricovero & Cura Carattere Sci San Raffaele P, Rome, Italy. [Huang, Paul L.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Huang, Paul L.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Huang, Paul L.] Harvard Univ, Sch Med, Boston, MA USA. [Mendelsohn, Michael E.] Merck Res Labs, Rahway, NJ USA. RP Jaffe, IZ (reprint author), Tufts Med Ctr, Mol Cardiol Res Inst, 800 Washington St,Box 80, Boston, MA 02111 USA. EM ijaffe@tuftsmedicalcenter.org OI Iyer, Lakshmanan/0000-0001-9167-6396; Ehsan, Afshin/0000-0003-1470-6760 FU National Institutes of Health [HL74892, HL095590, HL069770]; American Heart Association [0855920D] FX This work was supported by National Institutes of Health Grants HL74892 and HL095590 (to I.Z.J.) and HL069770 (to M. E. M.), and American Heart Association Grant 0855920D (to I.Z.J.). NR 44 TC 33 Z9 33 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD AUG PY 2011 VL 31 IS 8 BP 1871 EP U365 DI 10.1161/ATVBAHA.111.229070 PG 22 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 794RH UT WOS:000292918500023 PM 21617142 ER PT J AU Johansen, CT Wang, J Lanktree, MB McIntyre, AD Ban, MR Martins, RA Kennedy, BA Hassell, RG Visser, ME Schwartz, SM Voight, BF Elosua, R Salomaa, V O'Donnell, CJ Dallinga-Thie, GM Anand, SS Yusuf, S Huff, MW Kathiresan, S Cao, H Hegele, RA AF Johansen, Christopher T. Wang, Jian Lanktree, Matthew B. McIntyre, Adam D. Ban, Matthew R. Martins, Rebecca A. Kennedy, Brooke A. Hassell, Reina G. Visser, Maartje E. Schwartz, Stephen M. Voight, Benjamin F. Elosua, Roberto Salomaa, Veikko O'Donnell, Christopher J. Dallinga-Thie, Geesje M. Anand, Sonia S. Yusuf, Salim Huff, Murray W. Kathiresan, Sekar Cao, Henian Hegele, Robert A. TI An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE lipoproteins; genetic risk scores; genetic variation; hypertriglyceridemia; pleiotropy ID GENOME-WIDE ASSOCIATION; NONFASTING TRIGLYCERIDES; HYPERLIPOPROTEINEMIA PHENOTYPES; MYOCARDIAL-INFARCTION; LIPOPROTEIN-LIPASE; HEART-DISEASE; POPULATION; DEFICIENCY; VARIANTS; DETERMINANTS AB Objective-Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity. Methods and Results-First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes. Conclusion-HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants. (Arterioscler Thromb Vasc Biol. 2011; 31: 1916-1926.) C1 [Hegele, Robert A.] Univ Western Ontario, Blackburn Cardiovasc Genet Lab, Robarts Res Inst, Dept Biochem, London, ON N6A 5K8, Canada. [Johansen, Christopher T.; Huff, Murray W.; Hegele, Robert A.] Univ Western Ontario, Dept Med, Schulich Sch Med & Dent, London, ON N6A 5K8, Canada. [Visser, Maartje E.; Dallinga-Thie, Geesje M.] Acad Med Ctr Amsterdam, Dept Expt Vasc Med, Amsterdam, Netherlands. [Visser, Maartje E.; Dallinga-Thie, Geesje M.] Acad Med Ctr Amsterdam, Dept Vasc Med, Amsterdam, Netherlands. [Schwartz, Stephen M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Voight, Benjamin F.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Cardiovasc Res Ctr, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Voight, Benjamin F.; Kathiresan, Sekar] Broad Inst Massachusetts Inst Technol & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Elosua, Roberto] Inst Municipal Invest Med, E-08003 Barcelona, Spain. [Elosua, Roberto] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Salomaa, Veikko] Natl Inst Hlth & Welf, Chron Dis Epidemiol Unit, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Anand, Sonia S.; Yusuf, Salim] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. RP Hegele, RA (reprint author), Univ Western Ontario, Blackburn Cardiovasc Genet Lab, Robarts Res Inst, Dept Biochem, London, ON N6A 5K8, Canada. EM hegele@robarts.ca RI Voight, Benjamin/F-1775-2011; Hegele, Robert/G-3301-2011; OI Lanktree, Matthew/0000-0002-5750-6286; ELOSUA, ROBERTO/0000-0001-8235-0095 FU Canadian Institutes of Health Research (CIHR) [MOP-13430, MOP-79523, CTP-79853]; University of Western Ontario; Jacob J. Wolfe Distinguished Medical Research Chair at the University of Western Ontario; Edith Schulich Vinet Canada Research Chair in Human Genetics (Tier I); Martha G. Blackburn Chair in Cardiovascular Research; Heart and Stroke Foundation of Ontario [NA-6059, T-6018, PRG-4854]; Pfizer; Genome Canada through the Ontario Genomics Institute FX Dr Johansen is supported by the Canadian Institutes of Health Research (CIHR) Banting and Best Canada Graduate Scholarship Doctoral Research Award and the University of Western Ontario MD/PhD program, and is a CIHR fellow in Vascular Research. Dr Hegele is supported by the Jacob J. Wolfe Distinguished Medical Research Chair at the University of Western Ontario; the Edith Schulich Vinet Canada Research Chair in Human Genetics (Tier I); the Martha G. Blackburn Chair in Cardiovascular Research; and operating grants from the CIHR (MOP-13430, MOP-79523, CTP-79853), the Heart and Stroke Foundation of Ontario (NA-6059, T-6018, PRG-4854), the Pfizer Jean Davignon Distinguished Cardiovascular and Metabolic Research Award, and Genome Canada through the Ontario Genomics Institute. NR 29 TC 31 Z9 32 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD AUG PY 2011 VL 31 IS 8 BP 1916 EP U460 DI 10.1161/ATVBAHA.111.226365 PG 21 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 794RH UT WOS:000292918500028 PM 21597005 ER PT J AU Ozanne, EM Shieh, Y Barnes, J Bouzan, C Hwang, ES Esserman, LJ AF Ozanne, Elissa M. Shieh, Yiwey Barnes, James Bouzan, Colleen Hwang, E. Shelley Esserman, Laura J. TI Characterizing the impact of 25 years of DCIS treatment SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Ductal carcinoma in situ; Screening mammography; Incidence trends ID CARCINOMA IN-SITU; INVASIVE BREAST-CANCER; SERVICES TASK-FORCE; SCREENING MAMMOGRAPHY; NATURAL-HISTORY; UNITED-STATES; PROSPECTIVE COHORT; COLORECTAL-CANCER; PHYSICAL-ACTIVITY; HORMONE-THERAPY AB The significant increase in the detection and treatment of ductal carcinoma in situ (DCIS) since the introduction of screening mammography has not been accompanied by the anticipated reduction in invasive breast cancer (IBC) incidence. The prevalence of DCIS requires a reexamination of the population level effects of detecting and treating DCIS. To further our understanding of the possible impact of DCIS diagnosis and treatment on IBC incidence in the U.S., we simulated breast cancer incidence over 25 years under various assumptions regarding the baseline incidence of IBC and the progression of DCIS to IBC. The simulations demonstrate a tradeoff between the expected increased incidence of IBC absent any DCIS detection and treatment and the rate of progression of DCIS to IBC. Our analyses indicate that a high progression of DCIS to IBC implies a significant increase in incidence of IBC over what is observed had we not detected and treated DCIS. Conversely, if we assume that there would not have been a significant increase over and above the observed incidence evident in SEER, then our model indicates that the rate of DCIS progression to clinically significant IBC is low. Given the tradeoff illustrated by our model, we must reevaluate the assumption that DCIS is a short-term obligate precursor of invasive cancer and instead focus on further exploration of the true natural history of DCIS. C1 [Ozanne, Elissa M.; Bouzan, Colleen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA 02114 USA. [Hwang, E. Shelley] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Barnes, James] Univ Illinois, Chicago, IL USA. [Esserman, Laura J.] Univ Calif San Francisco, Dept Surg & Radiol, San Francisco, CA 94143 USA. RP Ozanne, EM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM elissa@mgh-ita.org OI Shieh, Yiwey/0000-0002-0159-7748 NR 44 TC 34 Z9 34 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2011 VL 129 IS 1 BP 165 EP 173 DI 10.1007/s10549-011-1430-5 PG 9 WC Oncology SC Oncology GA 794EQ UT WOS:000292878700016 PM 21390494 ER PT J AU Bauer, C Dauer, M Saraj, S Schnurr, M Bauernfeind, F Sterzik, A Junkmann, J Jakl, V Kiefl, R Oduncu, F Emmerich, B Mayr, D Mussack, T Bruns, C Ruttinger, D Conrad, C Jauch, KW Endres, S Eigler, A AF Bauer, Christian Dauer, Marc Saraj, Samira Schnurr, Maximilian Bauernfeind, Franz Sterzik, Alexander Junkmann, Jana Jakl, Veronika Kiefl, Rosemarie Oduncu, Fuat Emmerich, Bertold Mayr, Doris Mussack, Thomas Bruns, Christiane Ruettinger, Dominik Conrad, Claudius Jauch, Karl-Walter Endres, Stefan Eigler, Andreas TI Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Immunotherapy; Pancreatic cancer; Dendritic cell; Vaccination ID CANCER-CHEMOTHERAPY; T-CELLS; GEMCITABINE; COMBINATION; INCREASES; MODEL; TRIAL; ADENOCARCINOMA; IMMUNOTHERAPY; EXPRESSION AB Dendritic cell (DC)-based vaccination can induce antitumor T cell responses in vivo. This clinical pilot study examined feasibility and outcome of DC-based tumor vaccination for patients with advanced pancreatic adenocarcinoma. Tumor lysate of patients with pancreatic carcinoma was generated by repeated freeze-thaw cycles of surgically obtained tissue specimens. Patients were eligible for DC vaccination after recurrence of pancreatic carcinoma or in a primarily palliative situation. DC were generated from peripheral blood mononuclear cells (PBMC), loaded with autologous tumor lysate, stimulated with TNF-alpha and PGE(2) and injected intradermally. All patients received concomitant chemotherapy with gemcitabine. Disease response was the primary endpoint. Individual immunological responses to DC vaccination were analyzed by T cell-based immunoassays using pre- and post-vaccination samples of non-adherent PBMC. Twelve patients received DC vaccination and concomitant chemotherapy. One patient developed a partial remission, and two patients remained in stable disease. Median survival was 10.5 months. No severe side effects were observed. Tumor-reactive T cells could be detected prior to vaccination. DC vaccination increased the frequency of tumor-reactive cells in all patients tested; however, the degree of this increase varied. To quantify the presence of tumor-reactive T cells, stimulatory indices (SI) were calculated as the ratio of proliferation-inducing capacity of lysate-loaded versus -unloaded DC. The patient with longest overall survival of 56 months had a high SI of 6.49, indicating that the presence of a pre-vaccination antitumor T cell response might be associated with prolonged survival. Five patients survived 1 year or more. DC-based vaccination can stimulate an antitumoral T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment. C1 [Eigler, Andreas] Univ Munich, Dept Internal Med 1, Klinikum Dritter Orden, Teaching Hosp, D-80638 Munich, Germany. [Endres, Stefan] Univ Munich, Med Klin Innenstadt, Div Clin Pharmacol, D-80638 Munich, Germany. [Bruns, Christiane; Ruettinger, Dominik; Conrad, Claudius; Jauch, Karl-Walter] Univ Munich, Chirurg Klin & Poliklin Grosshadern, D-80638 Munich, Germany. [Mussack, Thomas] Univ Munich, Chirurg Klin & Poliklin Innenstadt, D-80638 Munich, Germany. [Dauer, Marc] Univ Saarland, Saarland Univ Hosp, Dept Med 2, D-6650 Homburg, Germany. [Conrad, Claudius] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Mayr, Doris] Univ Munich, Inst Pathol, D-80638 Munich, Germany. RP Eigler, A (reprint author), Univ Munich, Dept Internal Med 1, Klinikum Dritter Orden, Teaching Hosp, Menzinger Str 44, D-80638 Munich, Germany. EM a.eigler@dritter-orden.de FU Gravenhorst Stiftung; Forderprogramm fur Forschung und Lehre (FoFoLe) of the University of Munich; Deutsche Forschungsgemeinschaft [Ba 3824/1-1, Graduiertenkolleg 1202]; Deutsche Krebshilfe; University of Munich FX This work was supported by grants from the Gravenhorst Stiftung (M. D.), the Forderprogramm fur Forschung und Lehre (FoFoLe) of the University of Munich (C. B.), the Deutsche Forschungsgemeinschaft (Ba 3824/1-1 to C. B. and Graduiertenkolleg 1202 to M. S., S.E.), and the Deutsche Krebshilfe (M. S.). This work is part of the doctoral thesis of S.S. at the University of Munich. NR 29 TC 26 Z9 29 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD AUG PY 2011 VL 60 IS 8 BP 1097 EP 1107 DI 10.1007/s00262-011-1023-5 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA 795KP UT WOS:000292973400004 PM 21547597 ER PT J AU Simon, T Bhatt, DL Bergougnan, L Farenc, C Pearson, K Perrin, L Vicaut, E LaCreta, F Hurbin, F Dubar, M AF Simon, T. Bhatt, D. L. Bergougnan, L. Farenc, C. Pearson, K. Perrin, L. Vicaut, E. LaCreta, F. Hurbin, F. Dubar, M. TI Genetic Polymorphisms and the Impact of a Higher Clopidogrel Dose Regimen on Active Metabolite Exposure and Antiplatelet Response in Healthy Subjects SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; OF-FUNCTION POLYMORPHISM; INDUCED PLATELET-AGGREGATION; HAPLOTYPE RECONSTRUCTION; ADENOSINE DIPHOSPHATE; CARDIOVASCULAR EVENTS; MAJOR DETERMINANT; STENT PLACEMENT; ARTERY-DISEASE; CYP2C19 AB A double-blind crossover study was conducted in four CYP2C19 genotype-defined metabolizer groups to assess whether increase in clopidogrel dosing can overcome reduced pharmacodynamic response in CYP2C19 poor metabolizers (PMs). Ten healthy subjects in each of four metabolizer groups were randomized to a clopidogrel regimen of a 300-mg loading dose (LD) and a 75-mg/day maintenance dose (MD) for 4 days followed by 600-mg LD and 150 mg/day MD, or vice versa. The exposure levels of clopidogrel's active metabolite H4 (clopi-H4) in PMs were 71% lower on the 75-mg/day regimen and 64% lower on the 150-mg/day regimen than the corresponding exposure levels in extensive metabolizers (EMs). In PMs, the maximal platelet aggregation (MPA) induced by adenosine diphosphate (ADP) 5 mu mol/l was 10.5% lower on the 75-mg/day regimen and 7.9% lower on the 150-mg/day regimen than the corresponding values in EMs. PMs who were on the clopidogrel regimen of 600-mg LD/150 mg/day MD showed clopi-H4 exposure and MPA levels similar to those in EMs who were on the regimen of 300-mg LD/75 mg/day MD. In a pooled analysis evaluating CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A5, CYP2D6, ABCB1, and P2RY12 polymorphisms (N = 396 healthy subjects), only CYP2C19 had a significant impact on antiplatelet response. In healthy CYP2C19 PMs, a clopidogrel regimen of 600-mg LD/150 mg/day MD largely overcomes diminished clopi-H4 exposure and antiplatelet response, as assessed by MPA levels. C1 [Simon, T.] CHU St Antoine, Assistance Publ Hop Paris, Dept Clin Pharmacol, Paris, France. [Simon, T.] Univ Paris 06, Paris, France. [Bhatt, D. L.] VA Boston Healthcare Syst, Dept Cardiovasc Med, Boston, MA USA. [Bhatt, D. L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bergougnan, L.; Dubar, M.] Sanofi Aventis Rech Dev, Clin Pharmacol & Exploratory Dept, Chilly Mazarin, France. [Farenc, C.; Hurbin, F.] Sanofi Aventis Rech Dev, Global Metab & Pharmacokinet Dept, Montpellier, France. [Pearson, K.] Sanofi Aventis Rech Dev, Global Metab & Pharmacokinet Dept, Great Valley, PA USA. [Perrin, L.] Sanofi Aventis Rech Dev, Dept Biostat, Montpellier, France. [Vicaut, E.] Hop Fernand Widal, Clin Res Unit Lariboisiere St Louis, Paris, France. [LaCreta, F.] Bristol Myers Squibb, Discovery Med & Clin Pharmacol, Princeton, NJ USA. RP Simon, T (reprint author), CHU St Antoine, Assistance Publ Hop Paris, Dept Clin Pharmacol, Paris, France. EM tabassome.simon@sat.aphp.fr FU Eli Lilly; Merck; sanofi-aventis; AstraZeneca; Bristol-Myers Squibb; Eisai; Medicines Company; Pfizer FX T.S. has received grants from Eli Lilly, Merck, and sanofi-aventis and consulting and lecture fees from AstraZeneca, Eli Lilly, and sanofi-aventis. D.L.B. has received research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, sanofi-aventis, and The Medicines Company. E.V. has received grant support from Pfizer and sanofi-aventis and serves as a consultant or advisory board member for Pfizer, sanofi-aventis, and Servier. L.B., C.F., K.P., L.P., F.H., and M.D. are employees of sanofi-aventis. F.L. is an employee of Bristol-Myers Squibb.; All the studies, editorial support, and academic statistical verification were funded by sanofi-aventis and Bristol-Myers Squibb. The authors acknowledge Andreas Schrodter, of FOCUS Clinical Drug Development (Neuss, Germany), for support in conducting the study; Melanie Leiby, of inScience Communications, a Wolters Kluwer business, for editorial assistance in creating tables and figures, coordinating revisions, ensuring language accuracy, and styling references for submission; and Nicolas Bonnet, Xavier Boulenc, William Brian, and Silvia Saitmacher of sanofi-aventis for their role in the design, operational aspects of the study, and data analysis. NR 50 TC 42 Z9 48 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2011 VL 90 IS 2 BP 287 EP 295 DI 10.1038/clpt.2011.127 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 795LE UT WOS:000292974900022 PM 21716274 ER PT J AU Christoforidis, D Bordeianou, L Rockwood, TH Lowry, AC Parker, S Mellgren, AF AF Christoforidis, D. Bordeianou, L. Rockwood, T. H. Lowry, A. C. Parker, S. Mellgren, A. F. TI Faecal incontinence in men SO COLORECTAL DISEASE LA English DT Article; Proceedings Paper CT Annual Meeting of the European-Society-of-Colon-and-Rectal-Surgeons CY SEP 26-29, 2007 CL MALTA DE Faecal incontinence; male; anus; faecal incontinence quality of life; sphincter defect; soiling ID ANAL RESTING PRESSURES; QUALITY-OF-LIFE; ANORECTAL MANOMETRY; SEVERITY INDEX; SEEPAGE; PREVALENCE; INSTRUMENT; ULTRASOUND; COMMUNITY; CORRELATE AB Aim A few studies have specifically addressed faecal incontinence (FI) in men. We sought to describe patterns of male FI, assess treatment outcome and compare some aspects of FI between men and women, including quality of life. Method Prospectively recorded data on 85 consecutive male patients evaluated for FI at our pelvic floor centre in 2004 and 2005 were reviewed and compared with a cohort of 408 female patients. Treatment outcome in men was assessed by questionnaire. Results The aetiology of FI could be determined in 61 (72%) men and was most commonly related to anal surgery (n = 23), prostate cancer therapy (n = 9) and spinal injury (n = 9). Eight patients had idiopathic soiling only. Mean age, Fecal Incontinence Severity Index (FISI) and quality of life scores were similar between men and women. Maximal mean resting pressure (MRP) and squeeze pressure (MSP) were on average higher in men than in women [MRP 56.9 (26.2) vs 40 (20.4) mmHg; P < 0.0001]; [MSP 98.1 (67.3) vs 39.4 (28.5) mmHg; P < 0.0001]. Sphincter defects involved the external sphincter less often in men (35 vs 70%, P = 0.004). Differences in faecal incontinence quality of life (FIQL) and SF-36 scores between men and women were minimal. After a median follow up of 2 years, complete resolution of symptoms was reported in 17% and improvement of symptoms in another 48% of men. Conclusion Although physiological and anatomical features of FI differ between men and women, its severity and impact on quality of life are similar. External sphincter defects are less common in men; hence, direct sphincter repair is less frequently an option. Evaluation and treatment improves symptoms in more than half of male patients. C1 [Christoforidis, D.; Lowry, A. C.; Parker, S.; Mellgren, A. F.] Univ Minnesota, Dept Surg, Div Colon & Rectal Surg, Minneapolis, MN 55455 USA. [Christoforidis, D.] Ctr Hosp Univ Vaudois CHUV, Dept Visceral Surg, Lausanne, Switzerland. [Bordeianou, L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastrointestinal Surg, Boston, MA USA. [Rockwood, T. H.] Univ Minnesota, Div Hlth Policy & Management, Minneapolis, MN USA. RP Christoforidis, D (reprint author), Serv Chirurg Viscerale, BH 15, CH-1011 Lausanne Chuv, Switzerland. EM christoforidis@chuv.ch NR 23 TC 10 Z9 11 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1462-8910 J9 COLORECTAL DIS JI Colorectal Dis. PD AUG PY 2011 VL 13 IS 8 BP 906 EP 913 DI 10.1111/j.1463-1318.2010.02276.x PG 8 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 793SU UT WOS:000292844200028 PM 20402738 ER PT J AU Gault, CR Obeid, LM AF Gault, Christopher R. Obeid, Lina M. TI Still benched on its way to the bedside: sphingosine kinase 1 as an emerging target in cancer chemotherapy SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Sphingolipids; sphingosine-1-phosphate; ceramide; chemoresistance; angiogenesis; oncogene ID PROTEIN-COUPLED RECEPTOR; HUMAN COLON-CANCER; SPHINGOLIPID METABOLISM; CELL-DEATH; ENDOTHELIAL-CELLS; PROSTATE-CANCER; BREAST-CANCER; SPHINGOSINE-1-PHOSPHATE LYASE; VASCULAR MATURATION; DEPENDENT MECHANISM AB For several decades, lipid biologists have investigated how sphingolipids contribute to physiology, cell biology, and cell fate. Foremost among these discoveries is the finding that the bioactive sphingolipids ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have diverse and often opposing effects on cell fate. Interestingly, these bioactive sphingolipids can be interconverted by just a few enzymatic reactions. Therefore, much attention has been paid to the enzymes which govern these reactions with a disproportionate amount of focus on the enzyme sphingosine kinase 1 (SK1). Several studies have found that tissue expression of SK1 correlates with cancer stage, chemotherapy response, and tumor aggressiveness. In addition, overexpression of SK1 in multiple cancer cell lines increases their resistance to chemotherapy, promotes proliferation, allows for anchorage independent growth, and increases local angiogenesis. Inhibition of SK1 using either pharmacological inhibitors or by crossing SK1 null mice has shown promise in many xenograft models of cancer, as well as several genetic and chemically induced mouse models of carcinogenesis. Here, we review the majority of the evidence that suggests SK1 is a promising target for the prevention and/or treatment of various cancers. Also, we strongly advocate for further research into basic mechanisms of bioactive sphingolipid signaling, and an increased focus on the efficacy of SK inhibitors in non-xenograft models of cancer progression. C1 [Obeid, Lina M.] Med Univ S Carolina, Dept Med, Div Gen Internal Med, Charleston, SC 29425 USA. Ralph H Johnson Vet Adm, Charleston, SC USA. [Obeid, Lina M.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. RP Obeid, LM (reprint author), Med Univ S Carolina, Dept Med, Div Gen Internal Med, 114 Doughty St,MSC 779, Charleston, SC 29425 USA. EM obeidl@musc.edu OI obeid, lina/0000-0002-0734-0847 FU NIH [R01AG16583, GM062887, P01 CA097132, NIH NRSA 5F3-HL093991]; VA MERIT Award [BX000156-01A1] FX This work was supported in part by: NIH grants R01AG16583, GM062887, and P01 CA097132 (LMO); NIH NRSA 5F3-HL093991 (CRG). VA MERIT Award BX000156-01A1 (LMO). NR 80 TC 16 Z9 19 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-9238 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD AUG PY 2011 VL 46 IS 4 BP 342 EP 351 DI 10.3109/10409238.2011.597737 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 797JQ UT WOS:000293121100006 PM 21787121 ER PT J AU Fisher, FM Estall, JL Adams, AC Antonellis, PJ Bina, HA Flier, JS Kharitonenkov, A Spiegelman, BM Maratos-Flier, E AF Fisher, Ffolliott M. Estall, Jennifer L. Adams, Andrew C. Antonellis, Patrick J. Bina, Holly A. Flier, Jeffrey S. Kharitonenkov, Alexei Spiegelman, Bruce M. Maratos-Flier, Eleftheria TI Integrated Regulation of Hepatic Metabolism by Fibroblast Growth Factor 21 (FGF21) in Vivo SO ENDOCRINOLOGY LA English DT Article ID BETA-KLOTHO; PPAR-ALPHA; INSULIN SENSITIVITY; ENERGY-METABOLISM; LIPID-METABOLISM; THYROID-HORMONE; EXPRESSION; FIBROBLAST-GROWTH-FACTOR-21; PGC-1-ALPHA; STATE AB Fibroblast growth factor (FGF21) plays an important role in regulating hepatic oxidation of fatty acids and gluconeogenesis in response to fasting and during consumption of a ketogenic diet. However, the metabolic pathways through which FGF21 regulates hepatic function are not well defined. To identify the effects of FGF21 on the liver in vivo, we administered FGF21 to mice and analyzed acute effects on signaling and gene expression. We found that FGF21 acts directly on the liver to stimulate phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1 alpha. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha), suggesting that PGC-1 alpha may play a role in regulating FGF21 action. However, studies using mice with liver-specific ablation of PGC-1 alpha revealed the same regulation of gluconeogenic gene expression by FGF21 as seen in wild-type mice, indicating that PGC-1 alpha is not necessary for the effect of FGF21 on glucose metabolism. These data demonstrate that FGF21 acts directly on the liver to modulate hepatic metabolism. The direct effects we examined are not dependent on PGC-1 alpha. In addition, FGF21 treatment is associated with decreased serum insulin levels that my affect hepatic function. (Endocrinology 152: 2996-3004, 2011) C1 [Maratos-Flier, Eleftheria] Beth Israel Deaconess Med Ctr, Div Endocrinol, Dept Med, Boston, MA 02215 USA. [Estall, Jennifer L.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Cell Biol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Metab & Chron Dis, Boston, MA 02215 USA. [Bina, Holly A.; Kharitonenkov, Alexei] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Maratos-Flier, E (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrinol, Dept Med, Boston, MA 02215 USA. EM emaratos@bidmc.harvard.edu FU National Institutes of Health [DK028082]; Picower Foundation; Obesity Society FX This work was supported in part by National Institutes of Health Grant DK028082 as well a Picower Foundation grant and a Young Investigator award from the Obesity Society. NR 27 TC 100 Z9 104 U1 1 U2 16 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2011 VL 152 IS 8 BP 2996 EP 3004 DI 10.1210/en.2011-0281 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 795XA UT WOS:000293010700010 PM 21712364 ER PT J AU Karimov, CB Moragianni, VA Cronister, A Srouji, S Petrozza, J Racowsky, C Ginsburg, E Thornton, KL Welt, CK AF Karimov, C. B. Moragianni, V. A. Cronister, A. Srouji, S. Petrozza, J. Racowsky, C. Ginsburg, E. Thornton, K. L. Welt, C. K. TI Increased frequency of occult fragile X-associated primary ovarian insufficiency in infertile women with evidence of impaired ovarian function SO HUMAN REPRODUCTION LA English DT Article DE fragile X syndrome; primary ovarian insufficiency; intermediate repeat; infertility; ovarian aging ID FMR1 PREMUTATION CARRIERS; ANTI-MULLERIAN HORMONE; CGG REPEAT; FAILURE; AGE; INTERMEDIATE; GENE; FSH; EXPANSIONS; PHENOTYPE AB BACKGROUND: The FMR1 premutation is associated with overt primary ovarian insufficiency (POI). However, its prevalence in women with occult POI (i.e. menstrual cycles, but impaired ovarian response) has not been examined. We hypothesized that both the FMR1 premutation and intermediate allele is more frequent in infertile women with occult POI than in controls, and that a repeat length cutoff might predict occult POI. METHODS: All subjects were menstruating women,42 years old and with no family history of unexplained mental retardation, autism or fragile X syndrome. Cases had occult POI defined by elevated FSH or poor response to gonadotrophin therapy (n = 535). Control subjects (n = 521) had infertility from other causes or were oocyte donors. Prevalence of the FMR1 premutation and intermediate alleles was examined and allele length was compared between controls and women with occult POI. RESULTS: The frequency of the premutation (7/535 versus 1/521; P < 0.05) and intermediate alleles (17/535 versus 7/521; P < 0.05) was higher in women with occult POI than in controls. The allele with the greatest number of CGG repeats was longer in women with occult POI compared with controls (32.7 +/- 7.1 versus 31.6 +/- 4.3; P < 0.01). A receiver operating characteristic curve examining repeat length as a test for occult POI had an area of 0.56 +/- 0.02 (P < 0.01). A repeat cutoff of 45 had a specificity of 98%, but a sensitivity of only 5% to identify occult POI. The positive predictive value was only 21% for a fertility population that has similar to 22% of its patients with occult POI. CONCLUSIONS: The data suggest that FMR1 premutations and intermediate alleles are increased in women with occult POI. Thus, FMR1 testing should be performed in these women as some will have fragile X-associated POI. Although the FMR1 repeat lengths were longer in women with occult POI, the data do not support the use of a repeat length cutoff to predict occult POI. C1 [Karimov, C. B.; Welt, C. K.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Moragianni, V. A.; Thornton, K. L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Moragianni, V. A.] Boston IVF, Waltham, MA USA. [Cronister, A.] Esoterix Genet Labs LLC, Phoenix, AZ USA. [Srouji, S.; Racowsky, C.; Ginsburg, E.] Brigham & Womens Hosp, Ctr Reprod Med, Boston, MA 02115 USA. RP Welt, CK (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, BHX 511,55 Fruit St, Boston, MA 02114 USA. EM cwelt@partners.org OI Welt, Corrine/0000-0002-8219-5504 FU Schering Plough; MERCK-EMD-Serono; Gene Security Network; Harvard University FX A.C. is an employee of Esoterix Genetic Laboratories, LLC, owned by Laboratory Corporation of America Holdings. The company performs DNA testing for fragile X. C. R. is on the board at Origio and received speaker funding from the SMART Conference on behalf of Schering Plough. Both are unrelated to the current manuscript. K. L. T. receives grant support from MERCK-EMD-Serono and Gene Security Network, also unrelated to the current manuscript.; This work was supported by the William F. Milton Fund of Harvard University. NR 36 TC 26 Z9 26 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD AUG PY 2011 VL 26 IS 8 BP 2077 EP 2083 DI 10.1093/humrep/der168 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 793QD UT WOS:000292837300019 PM 21646280 ER PT J AU Huang, SS Placzek, H Livingston, J Ma, A Onufrak, F Lankiewicz, J Kleinman, K Bratzler, D Olsen, MA Lyles, R Khan, Y Wright, P Yokoe, DS Fraser, VJ Weinstein, RA Stevenson, K Hooper, D Vostok, J Datta, R Nsa, W Platt, R AF Huang, Susan S. Placzek, Hilary Livingston, James Ma, Allen Onufrak, Fallon Lankiewicz, Julie Kleinman, Ken Bratzler, Dale Olsen, Margaret A. Lyles, Rosie Khan, Yosef Wright, Paula Yokoe, Deborah S. Fraser, Victoria J. Weinstein, Robert A. Stevenson, Kurt Hooper, David Vostok, Johanna Datta, Rupak Nsa, Wato Platt, Richard TI Use of Medicare Claims to Rank Hospitals by Surgical Site Infection Risk following Coronary Artery Bypass Graft Surgery SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID NOSOCOMIAL INFECTIONS; POSTDISCHARGE SURVEILLANCE; UNITED-STATES; BENCHMARKING; ADJUSTMENT; PREVENTION; DISCHARGE AB OBJECTIVE. To evaluate whether longitudinal insurer claims data allow reliable identification of elevated hospital surgical site infection (SSI) rates. DESIGN. We conducted a retrospective cohort study of Medicare beneficiaries who underwent coronary artery bypass grafting (CABG) in US hospitals performing at least 80 procedures in 2005. Hospitals were assigned to deciles by using case mix-adjusted probabilities of having an SSI-related inpatient or outpatient claim code within 60 days of surgery. We then reviewed medical records of randomly selected patients to assess whether chart-confirmed SSI risk was higher in hospitals in the worst deciles compared with the best deciles. PARTICIPANTS. Fee-for-service Medicare beneficiaries who underwent CABG in these hospitals in 2005. RESULTS. We evaluated 114,673 patients who underwent CABG in 671 hospitals. In the best decile, 7.8% (958/12,307) of patients had an SSI-related code, compared with 24.8% (2,747/11,068) in the worst decile (P < .001). Medical record review confirmed SSI in 40% (388/980) of those with SSI-related codes. In the best decile, the chart-confirmed annual SSI rate was 3.2%, compared with 9.4% in the worst decile, with an adjusted odds ratio of SSI of 2.7 (confidence interval, 2.2-3.3; P < .001) for CABG performed in a worst-decile hospital compared with a best-decile hospital. CONCLUSIONS. Claims data can identify groups of hospitals with unusually high or low post-CABG SSI rates. Assessment of claims is more reproducible and efficient than current surveillance methods. This example of secondary use of routinely recorded electronic health information to assess quality of care can identify hospitals that may benefit from prevention programs. Infect Control Hosp Epidemiol 2011; 32(8): 775-783 C1 [Huang, Susan S.; Datta, Rupak] Univ Calif Irvine, Sch Med, Div Infect Dis, Orange, CA 92868 USA. [Huang, Susan S.; Datta, Rupak] Univ Calif Irvine, Sch Med, Hlth Policy Res Inst, Orange, CA 92868 USA. [Huang, Susan S.; Placzek, Hilary; Livingston, James; Onufrak, Fallon; Lankiewicz, Julie; Kleinman, Ken; Vostok, Johanna; Datta, Rupak; Platt, Richard] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Huang, Susan S.; Placzek, Hilary; Livingston, James; Onufrak, Fallon; Lankiewicz, Julie; Kleinman, Ken; Vostok, Johanna; Datta, Rupak; Platt, Richard] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Ma, Allen; Bratzler, Dale] Oklahoma Fdn Med Qual, Oklahoma City, OK USA. [Olsen, Margaret A.; Fraser, Victoria J.] Washington Univ, Sch Med, Div Infect Dis, St Louis, MO 63110 USA. [Lyles, Rosie; Weinstein, Robert A.] Cook Cty Hosp, Dept Med, Chicago, IL 60612 USA. [Khan, Yosef; Stevenson, Kurt] Ohio State Univ, Sch Med, Dept Infect Control, Columbus, OH 43210 USA. [Wright, Paula; Hooper, David] Massachusetts Gen Hosp, Dept Infect Control, Boston, MA 02114 USA. [Yokoe, Deborah S.; Platt, Richard] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Yokoe, Deborah S.; Platt, Richard] Brigham & Womens Hosp, Dept Infect Control, Boston, MA USA. RP Huang, SS (reprint author), Univ Calif Irvine, Sch Med, Div Infect Dis, 101 City Dr S,City Tower,Suite 400,ZC 4081, Orange, CA 92868 USA. EM sshuang@uci.edu FU CDC Prevention Epicenter [CCU115079]; Utilization and Quality Control Peer Review Organization for the State Oklahoma, Centers for Medicare and Medicaid Services, Department of Health and Human Services [HHSM-500-2006-OK0030]; Sanofi-Pasteur; GlaxoSmithKline; Pifzer Pharmaceuticals; Sage Products FX Financial support. This study was funded by the CDC Prevention Epicenters Program CCU115079 (Platt) and under contract HHSM-500-2006-OK0030, entitled "Utilization and Quality Control Peer Review Organization for the State Oklahoma, Sponsored by the Centers for Medicare and Medicaid Services, Department of Health and Human Services." The funders did not participate in study design, study conduct, analysis, data interpretation, or manuscript preparation.; Potential conflicts of interest. R.P. has had active research grants in the past 3 years from Sanofi-Pasteur, GlaxoSmithKline, and Pifzer Pharmaceuticals. D.S.Y. has received research support from Sage Products. V.J.F. has been a consultant for Steris and Verimetrix and a member of the Speakers Bureau for Pfizer, Merck, and Cubist Pharmaceuticals in the past 3 years. NR 29 TC 21 Z9 21 U1 0 U2 4 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 AUG PY 2011 VL 32 IS 8 BP 775 EP 783 DI 10.1086/660874 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 795LY UT WOS:000292976900007 PM 21768761 ER PT J AU Gupta, K Strymish, J Abi-Haidar, Y Williams, SA Itani, KMF AF Gupta, Kalpana Strymish, Judith Abi-Haidar, Youmna Williams, Sandra A. Itani, Kamal M. F. TI Preoperative Nasal Methicillin-Resistant Staphylococcus aureus Status, Surgical Prophylaxis, and Risk-Adjusted Postoperative Outcomes in Veterans SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID SITE INFECTIONS; ORTHOPEDIC-SURGERY; SURVEILLANCE CULTURES; INTRANASAL MUPIROCIN; HOSPITAL ADMISSION; COLONIZATION; EPIDEMIOLOGY; ERADICATION; PREVALENCE; CARRIAGE AB OBJECTIVES. To determine whether preoperative nasal methicillin-resistant Staphylococcus aureus (MRSA) carriage is a significant predictor of postoperative infections, after accounting for surgical infection risk and surgical prophylaxis. DESIGN. Retrospective cohort study. PATIENTS. Veterans Affairs (VA) Boston patients who had nasal MRSA polymerase chain reaction screening performed in the 31 days before clean or clean contaminated surgery in 2008-2009. METHODS. Postoperative MRSA clinical cultures and infections, total surgical site infections (SSIs), and surgical prophylaxis data were abstracted from administrative databases. MRSA infections were confirmed via chart review. Multivariate analysis of risk factors for each outcome was conducted using Poisson regression. SSI risk index was calculated for a subset of 1,551 patients assessed by the VA National Surgical Quality Improvement Program. RESULTS. Among 4,238 eligible patients, 279 (6.6%) were positive for preoperative nasal MRSA. Postoperative MRSA clinical cultures and infections, including MRSA SSIs, were each significantly increased in patients with preoperative nasal MRSA. After adjustment for surgery type, vancomycin prophylaxis, chlorhexidine/alcohol surgical skin preparation, and SSI risk index, preoperative nasal MRSA remained significantly associated with postoperative MRSA cultures (relative risk [RR], 8.81; 95% confidence interval [CI], 3.01-25.82) and infections (RR, 8.46; 95% CI, 1.70-42.04). Vancomycin prophylaxis was associated with an increased risk of total SSI in those negative for nasal MRSA (RR, 4.34; 95% CI, 2.19-8.57) but not in patients positive for nasal MRSA. CONCLUSIONS. In our population, preoperative nasal MRSA colonization was independently associated with MRSA clinical cultures and infections in the postoperative period. Vancomycin prophylaxis increased the risk of total SSI in nasal MRSA-negative patients. Infect Control Hosp Epidemiol 2011; 32(8): 791-796 C1 [Gupta, Kalpana; Strymish, Judith] Vet Affairs Boston Healthcare Syst, Dept Med, Boston, MA USA. [Abi-Haidar, Youmna; Itani, Kamal M. F.] Vet Affairs Boston Healthcare Syst, Dept Surg, Boston, MA USA. [Williams, Sandra A.] Vet Affairs Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. [Gupta, Kalpana; Abi-Haidar, Youmna; Itani, Kamal M. F.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Strymish, Judith] Harvard Univ, Sch Med, Boston, MA USA. RP Gupta, K (reprint author), VA Boston HCS, 1400 VFW Pkwy,111 Med, W Roxbury, MA 02132 USA. EM kalpana.gupta@va.gov FU Merck Pharmaceuticals; Sanofi-Aventis Pharmaceuticals FX Potential conflicts of interest. Dr. Itani receives research support for other studies from Merck Pharmaceuticals and Sanofi-Aventis Pharmaceuticals. All other authors report no conflicts of interest relevant to this article. NR 30 TC 31 Z9 31 U1 1 U2 5 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 AUG PY 2011 VL 32 IS 8 BP 791 EP 796 DI 10.1086/660362 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 795LY UT WOS:000292976900009 PM 21768763 ER PT J AU Ranieri, VM Thompson, BT Finfer, S Barie, PS Dhainaut, JF Douglas, IS Gardlund, B Marshall, JC Rhodes, A AF Ranieri, V. Marco Thompson, B. Taylor Finfer, Simon Barie, Philip S. Dhainaut, Jean-Francois Douglas, Ivor S. Gardlund, Bengt Marshall, John C. Rhodes, Andrew CA PROWESS-SHOCK Acad Steering Comm TI Unblinding plan of PROWESS-SHOCK trial SO INTENSIVE CARE MEDICINE LA English DT Letter C1 [Ranieri, V. Marco] Univ Turin, Osped S Giovanni Battista Molinette, Turin, Italy. [Thompson, B. Taylor] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Finfer, Simon] Univ Sydney, George Inst Int Hlth, Sydney, NSW 2006, Australia. [Barie, Philip S.] Weill Cornell Med Coll, Dept Surg, New York, NY 10065 USA. [Dhainaut, Jean-Francois] Paris Descartes Univ, Cochin Port Royal Hosp, Paris, France. [Douglas, Ivor S.] Denver Hlth, Denver, CO USA. [Douglas, Ivor S.] Univ Colorado, Denver, CO 80202 USA. [Gardlund, Bengt] Karolinska Univ Hosp, Dept Infect Dis, S-14186 Stockholm, Sweden. [Marshall, John C.] St Michaels Hosp, Dept Surg, Toronto, ON M5B 1W8, Canada. [Marshall, John C.] St Michaels Hosp, Dept Crit Care Med, Toronto, ON M5B 1W8, Canada. [Rhodes, Andrew] St George Hosp, London SW17 0QT, England. RP Ranieri, VM (reprint author), Univ Turin, Osped S Giovanni Battista Molinette, Turin, Italy. EM marco.ranieri@unito.it OI Douglas, Ivor/0000-0002-4541-1431 NR 2 TC 8 Z9 8 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD AUG PY 2011 VL 37 IS 8 BP 1384 EP 1385 DI 10.1007/s00134-011-2272-7 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 793IW UT WOS:000292815000022 PM 21691888 ER PT J AU Skeer, MR McCormick, MC Normand, SLT Mimiaga, MJ Buka, SL Gilman, SE AF Skeer, Margie R. McCormick, Marie C. Normand, Sharon-Lise T. Mimiaga, Matthew J. Buka, Stephen L. Gilman, Stephen E. TI Gender Differences in the Association Between Family Conflict and Adolescent Substance Use Disorders SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE SUDs; Adolescents; Family conflict; Gender differences; Conduct problems; Prospective study ID DEPRESSIVE SYMPTOMS; ALCOHOL-USE; INTERPARENTAL CONFLICT; SEX-DIFFERENCES; MENTAL-HEALTH; UNITED-STATES; DEPENDENCE; BEHAVIOR; ISSUES; ABUSE AB Purpose: The objectives of this study were (1) to examine whether the association between childhood family conflict and the risk of substance use disorders (SUDs) in adolescence differs by gender, and (2) to determine whether anxious/depressive symptoms and conduct problems explain this association among adolescent males and females. Methods: Data were obtained from 1,421 children aged 10-16 years at the time of enrollment in the Project on Human Development in Chicago Neighborhoods. We assessed gender differences in the association between childhood family conflict and adolescent SUDs by fitting a logistic regression model that included the interaction of gender and family conflict. We also investigated whether conduct problems and anxious/depressive symptoms explained the association between family conflict and SUDs differently for males and females through gender-specific mediation analyses. Results: The association between childhood family conflict and SUDs in adolescence differed by gender (p = .04). Family conflict was significantly associated with SUDs among females (OR: 1.61; CI: 1.20-2.15), but not among males (OR: 1.00; CI:.76-1.32). The elevated risk of SUDs among females exposed to family conflict was partly explained by girls' conduct problems, but not by anxious/depressive symptoms. Conclusions: Females living in families with elevated levels of conflict were more likely to engage in acting out behaviors, which was associated with the development of SUDs. Future epidemiologic research is needed to help determine when this exposure is most problematic with respect to subsequent mental health outcomes and the most crucial time to intervene. (C) 2011 Society for Adolescent Health and Medicine. All rights reserved. C1 [Skeer, Margie R.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Skeer, Margie R.; McCormick, Marie C.; Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Behav Med, Boston, MA USA. [Mimiaga, Matthew J.; Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Buka, Stephen L.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. RP Skeer, MR (reprint author), Brown Univ, Ctr Alcohol & Addict Studies, Box G-S121-4, Providence, RI 02912 USA. EM Margie_Skeer@Brown.edu RI Buka, Stephen/H-7335-2014; Gilman, Stephen/E-7632-2010; OI Buka, Stephen/0000-0002-8578-9308; Gilman, Stephen/0000-0002-8331-6419; McCormmick, Marie/0000-0002-3938-1707 FU National Institute on Alcohol Abuse and Alcoholism [1F31AA017338-01, 5T32AA07459-24]; MCHB [T76MC00001]; MCHB-EPI [T03-MC00008, T03MC07648] FX Funding for Dr Skeer was provided by the National Institute on Alcohol Abuse and Alcoholism grant numbers 1F31AA017338-01 and 5T32AA07459-24. This research was also supported by the MCHB grant number T76MC00001 and the MCHB-EPI grant numbers T03-MC00008 and T03MC07648. NR 40 TC 24 Z9 24 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD AUG PY 2011 VL 49 IS 2 BP 187 EP 192 DI 10.1016/j.jadohealth.2010.12.003 PG 6 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 795TB UT WOS:000292997600013 PM 21783052 ER PT J AU Nelson, K Taylor, L Lurie, N Escarce, J McFarland, L Fihn, SD AF Nelson, Karin Taylor, Leslie Lurie, Nicole Escarce, Jose McFarland, Lynne Fihn, Stephan D. TI Neighborhood Environment and Health Status and Mortality Among Veterans SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE neighborhood; veterans; health status ID SOCIOECONOMIC-STATUS; OLDER-ADULTS; WALKABILITY; DATABASES; WALKING; PRIMER; DEATH AB BACKGROUND: The VHA is the largest integrated US health system and is increasingly moving care into the communities where veterans reside. Veterans who utilize the VA for their care have worse health status than the general population. However, there is limited evidence about the association of neighborhood environment and health outcomes among veterans. OBJECTIVES: The primary aim of this study is to assess the relative contribution of neighborhood environment, health system, and individual characteristics to health status and mortality of veterans. METHODS: Information on personal socio-economic indicators, existing medical conditions and health status were obtained from baseline data from a multi-site, randomized trial of primary care patients (n = 15,889). The physical component scale (PCS) and mental component scale (MCS) summarized health status. Census tracts were used as proxies for neighborhoods. A summary score based on census tract data characterized the neighborhood socio-economic environment and walkability. Data were analyzed with multilevel hierarchical models. Analyses of health status were cross-sectional. Mortality analyses were longitudinal as participants were followed for an average of 722.5 days to ascertain vital status. RESULTS: Neighborhood SES was associated with PCS and MCS scores, controlling for individual socio-economic status, self-reported co-morbid disease, smoking status, and health care access. In the lowest versus highest quartiles of neighborhood SES, adjusted PCS scores were 34.4 vs. 35.4 (p < 0.05) and adjusted MCS scores were 46.2 versus 47.0 (p < 0.05). PCS score was also significantly associated with neighborhood walkability (p < 0.05). Mortality was lower for veterans living in neighborhoods with the highest decile neighborhood SES (HR 0.78, highest vs. lowest decile 95% CI 0.63, 0.97). CONCLUSIONS: Veterans living in lower SES neighborhoods have poorer health status and a higher risk of mortality, independent of individual characteristics and health care access. Neighborhood walkability was associated with higher PCS scores. C1 [Nelson, Karin; Taylor, Leslie; Fihn, Stephan D.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA 98108 USA. [Nelson, Karin; Fihn, Stephan D.] VA Puget Sound Hlth Care Syst, Gen Med Serv, Seattle, WA 98108 USA. [Nelson, Karin; McFarland, Lynne; Fihn, Stephan D.] Univ Washington, Dept Med, Seattle, WA USA. [Nelson, Karin] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA 98108 USA. [Lurie, Nicole] US Dept Hlth & Human Serv, Washington, DC USA. [Escarce, Jose] RAND Hlth, Santa Monica, CA USA. RP Nelson, K (reprint author), VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, 1100 Olive Way,Suite 1400, Seattle, WA 98108 USA. EM Karin.Nelson@va.gov FU U.S. Department of Veterans Affairs, Office of Research and Development [IIR 04-436-3]; Seattle Epidemiologic Research and Information Center FX This material is based upon work supported by the U.S. Department of Veterans Affairs, Office of Research and Development VA Health Services Research and Development Program (IIR 04-436-3) and the Seattle Epidemiologic Research and Information Center. This work was presented at the Society for General Internal Medicine National Meeting (May, 2009) and at the VA HSR&D National Meeting (February, 2009). The views expressed in this article are those of the author and do not necessarily represent the views of the Department of Veterans Affairs. NR 40 TC 5 Z9 5 U1 2 U2 6 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 AUG PY 2011 VL 26 IS 8 BP 862 EP 867 DI 10.1007/s11606-011-1710-0 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 794IO UT WOS:000292889000013 PM 21499826 ER PT J AU Rhodes, KV Kothari, CL Dichter, M Cerulli, C Wiley, J Marcus, S AF Rhodes, Karin V. Kothari, Catherine L. Dichter, Melissa Cerulli, Catherine Wiley, James Marcus, Steve TI Intimate Partner Violence Identification and Response: Time for a Change in Strategy SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE intimate partner violence; police incidents; health care screening; risk identification; interventions; emergency departments ID DOMESTIC VIOLENCE; PRIMARY-CARE; ALCOHOL INTERVENTIONS; WOMEN; EMERGENCY; EXPERIENCES; VICTIMS; INJURY; ABUSE; TRIAL AB BACKGROUND: While victims of intimate partner violence (IPV) present to health care settings for a variety of complaints; rates and predictors of case identification and intervention are unknown. OBJECTIVE: Examine emergency department (ED) case finding and response within a known population of abused women. DESIGN: Retrospective longitudinal cohort study. SUBJECTS: Police-involved female victims of IPV in a semi-rural Midwestern county. MAIN MEASURES: We linked police, prosecutor, and medical record data to examine characteristics of ED identification and response from 1999-2002; bivariate analyses and logistic regression analyses accounted for the nesting of subjects' with multiple visits. RESULTS: IPV victims (N = 993) generated 3,426 IPV-related police incidents (mean 3.61, median 3, range 1-17) over the 4-year study period; 785 (79%) generated 4,306 ED visits (mean 7.17, median 5, range 1-87), which occurred after the date of a documented IPV assault. Only 384 (9%) ED visits occurred within a week of a police-reported IPV incident. IPV identification in the ED was associated with higher violence severity, being childless and underinsured, more police incidents (mean: 4.2 vs 3.3), and more ED visits (mean: 10.6 vs 5.5) over the 4 years. The majority of ED visits occurring after a documented IPV incident were for medical complaints (3,378, 78.4%), and 72% of this cohort were never identified as victims of abuse. IPV identification was associated with the day of a police incident, transportation by police, self-disclosure of "domestic assault," and chart documentation of mental health and substance abuse issues. When IPV was identified, ED staff provided legally useful documentation (86%), police contact (50%), and social worker involvement (45%), but only assessed safety in 33% of the women and referred them to victim services 25% of the time. CONCLUSION: The majority of police-identified IPV victims frequently use the ED for health care, but are unlikely to be identified or receive any intervention in that setting. C1 [Rhodes, Karin V.] Univ Penn, Schools Med & Social Policy & Practice, Dept Emergency Med, Div Emergency Care Policy Res, Philadelphia, PA 19104 USA. [Kothari, Catherine L.] Michigan State Univ, Kalamazoo Ctr Med Studies, Kalamazoo, MI USA. [Dichter, Melissa] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Cerulli, Catherine] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Wiley, James] San Francisco State Univ, Publ Res Inst, San Francisco, CA 94132 USA. [Marcus, Steve] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. RP Rhodes, KV (reprint author), Univ Penn, Schools Med & Social Policy & Practice, Dept Emergency Med, Div Emergency Care Policy Res, Philadelphia, PA 19104 USA. EM kvr@sp2.upenn.edu OI Kothari, Catherine/0000-0001-8072-8920 FU CDC [U17/CCU551067]; National Institute of Justice [NIJ 2006-WG-BX-0007]; NIMH [K23 MH64572, K01MH75965-01]; Center for Health Equity Research and Promotion, Philadelphia VA Medical Center FX The authors wish to thank Patricia Smith, Director, Violence Against Women Prevention Program, Michigan Department of Community Health; the Kalamazoo County Prosecutor's Office, all members of the Community Advisory Board, the YWCA Domestic Violence Program, and the many research assistants who worked on this project. This project builds on data collected for the MEDCIIN Projects under the CDC cooperative agreement U17/CCU551067.; None disclosed. Research support was primarily provided by a grant from the National Institute of Justice: NIJ 2006-WG-BX-0007; additional support for investigator time was provided by NIMH K23 MH64572 (Rhodes) and K01MH75965-01 (Cerulli) and the Center for Health Equity Research and Promotion, Philadelphia VA Medical Center (Dichter). Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice the Department of Veterans Affairs or the United States Government. NR 35 TC 18 Z9 18 U1 5 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2011 VL 26 IS 8 BP 894 EP 899 DI 10.1007/s11606-011-1662-4 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 794IO UT WOS:000292889000018 PM 21404130 ER PT J AU Goenka, R Barnett, LG Silver, JS O'Neill, PJ Hunter, CA Cancro, MP Laufer, TM AF Goenka, Radhika Barnett, Lisa G. Silver, Jonathan S. O'Neill, Patrick J. Hunter, Christopher A. Cancro, Michael P. Laufer, Terri M. TI Cutting Edge: Dendritic Cell-Restricted Antigen Presentation Initiates the Follicular Helper T Cell Program but Cannot Complete Ultimate Effector Differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CXC CHEMOKINE RECEPTOR-5; PLASMA-CELLS; B-CELLS; EXPRESSION; RESPONSES; IL-21; BCL6; ACTIVATION; FOLLICLES; BLIMP-1 AB Follicular helper T (TFH) cells are critical for germinal center ( GC) formation. The processes that drive their generation and effector potential remain unclear. In this study, we define requirements for MHC class II APCs in murine TFH cell formation by either transiently ablating or restricting Ag presentation to dendritic cells (DCs). We find that cognate interactions with DCs are necessary and sufficient to prime CD4(+) T cells toward a CXCR5(+)ICOS(+)Bcl6(+) T-FH cell intermediate. However, in the absence of additional APCs, these TFH cells fail to produce IL-21. Furthermore, in vitro priming of naive T cells by B cells engenders optimal production of IL-21, which induces a GC B cell transcriptional profile. These results support a multistep model for effector TFH cell priming and GC initiation, in which DCs are necessary and sufficient to induce a TFH cell intermediate that requires additional interactions with distinct APCs for full effector function. The Journal of Immunology, 2011, 187: 1091-1095. C1 [Laufer, Terri M.] Univ Penn Sch Med, BRB 2 3 753, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Barnett, Lisa G.] Univ Penn Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Silver, Jonathan S.; Hunter, Christopher A.; Laufer, Terri M.] Univ Penn Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Laufer, Terri M.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Laufer, TM (reprint author), Univ Penn Sch Med, BRB 2 3 753, Dept Pathol & Lab Med, 421 Curie Blvd, Philadelphia, PA 19104 USA. EM cancro@mail.med.upenn.edu; tlaufer@mail.med.upenn.edu FU Veterans Administration Merit Award [BX000435]; National Institutes of Health [R01 AI 42334, R01 AI 073939, T32 AI 055428, T32 AI 007532] FX This work was supported by Veterans Administration Merit Award BX000435 (to T. M. L.), National Institutes of Health Grants R01 AI 42334 (to C. A. H.), and R01 AI 073939 (to M.P.C.). R.G. was supported by National Institutes of Health Training Grant T32 AI 055428. J.S.S. is supported by National Institutes of Health Training Grant T32 AI 007532. NR 26 TC 100 Z9 103 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2011 VL 187 IS 3 BP 1091 EP 1095 DI 10.4049/jimmunol.1100853 PG 5 WC Immunology SC Immunology GA 794CY UT WOS:000292874200006 PM 21715693 ER PT J AU Paterson, AM Brown, KE Keir, ME Vanguri, VK Riella, LV Chandraker, A Sayegh, MH Blazar, BR Freeman, GJ Sharpe, AH AF Paterson, Alison M. Brown, Keturah E. Keir, Mary E. Vanguri, Vijay K. Riella, Leonardo V. Chandraker, Anil Sayegh, Mohamed H. Blazar, Bruce R. Freeman, Gordon J. Sharpe, Arlene H. TI The Programmed Death-1 Ligand 1:B7-1 Pathway Restrains Diabetogenic Effector T Cells In Vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PD-1 PATHWAY; B7 FAMILY; EXPRESSION; TOLERANCE; MICE; AUTOIMMUNITY; ACTIVATION; RESPONSES; RECEPTOR; ANTIGEN AB Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1: B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1: B7-1 and PD-L1: programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1: B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis. The Journal of Immunology, 2011, 187: 1097-1105. C1 [Sharpe, Arlene H.] Harvard Univ, Dept Pathol, Sch Med, NRB 837, Boston, MA 02115 USA. [Vanguri, Vijay K.] Univ Massachusetts Med Sch, Dept Pathol, Worcester, MA 01655 USA. [Riella, Leonardo V.; Chandraker, Anil; Sayegh, Mohamed H.] Harvard Univ, Div Renal, Transplantat Res Ctr, Brigham & Womens Hosp,Sch Med, Boston, MA 02115 USA. [Riella, Leonardo V.; Chandraker, Anil; Sayegh, Mohamed H.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. [Blazar, Bruce R.] Univ Minnesota, Div Blood & Marrow Transplantat, Dept Pediat, Minneapolis, MN 55455 USA. [Blazar, Bruce R.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN 55455 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Freeman, Gordon J.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Harvard Univ, Dept Pathol, Sch Med, NRB 837, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM arlene_sharpe@hms.harvard.edu FU National Multiple Sclerosis Society [FG 1805-A-1]; National Institutes of Health [PO1 AI56299, R01 AI051559, PO1 AI39671, R37 A1038310] FX This work was supported by National Multiple Sclerosis Society Grant FG 1805-A-1 (to A.M.P.) and National Institutes of Health Grants PO1 AI56299 (to A. H. S., M. H. S., B.R.B., and G.J.F.), R01 AI051559 (to M.H.S. and G.J.F.), PO1 AI39671 (to A. H. S.), and R37 A1038310 (to A.H.S.). NR 32 TC 45 Z9 46 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2011 VL 187 IS 3 BP 1097 EP U75 DI 10.4049/jimmunol.1003496 PG 15 WC Immunology SC Immunology GA 794CY UT WOS:000292874200007 PM 21697456 ER PT J AU Yang, J Riella, LV Chock, S Liu, T Zhao, XZ Yuan, XL Paterson, AM Watanabe, T Vanguri, V Yagita, H Azuma, M Blazar, BR Freeman, GJ Rodig, SJ Sharpe, AH Chandraker, A Sayegh, MH AF Yang, Jun Riella, Leonardo V. Chock, Susanne Liu, Tao Zhao, Xiaozhi Yuan, Xueli Paterson, Alison M. Watanabe, Toshihiko Vanguri, Vijay Yagita, Hideo Azuma, Miyuki Blazar, Bruce R. Freeman, Gordon J. Rodig, Scott J. Sharpe, Arlene H. Chandraker, Anil Sayegh, Mohamed H. TI The Novel Costimulatory Programmed Death Ligand 1/B7.1 Pathway Is Functional in Inhibiting Alloimmune Responses In Vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL TOLERANCE; CARDIAC ALLOGRAFT-REJECTION; TISSUE EXPRESSION; PD-1; ACTIVATION; MICE; VASCULOPATHY; MOLECULE; IMMUNITY; RECEPTOR AB The programmed death ligand 1 (PDL1)/programmed death 1 (PD1) costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has been demonstrated recently that PDL1 also can bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection, suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks the PDL1-B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-gamma-, IL-4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-gamma production from alloreactive CD4(+) T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction. The Journal of Immunology, 2011, 187: 1113-1119. C1 [Yang, Jun; Riella, Leonardo V.; Chock, Susanne; Liu, Tao; Zhao, Xiaozhi; Yuan, Xueli; Watanabe, Toshihiko; Chandraker, Anil; Sayegh, Mohamed H.] Harvard Univ, Brigham & Womens Hosp, Transplantat Res Ctr, Div Renal,Sch Med, Boston, MA 02115 USA. [Yang, Jun; Riella, Leonardo V.; Chock, Susanne; Liu, Tao; Zhao, Xiaozhi; Yuan, Xueli; Watanabe, Toshihiko; Chandraker, Anil; Sayegh, Mohamed H.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Paterson, Alison M.; Rodig, Scott J.; Sharpe, Arlene H.] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. [Vanguri, Vijay] Univ Massachusetts Med Sch, Dept Pathol, Worcester, MA 01605 USA. [Yagita, Hideo] Juntendo Univ Sch Med, Dept Immunol, Tokyo 1138431, Japan. [Azuma, Miyuki] Tokyo Med & Dent Univ, Dept Mol Immunol, Tokyo 1138510, Japan. [Blazar, Bruce R.] Univ Minnesota, Dept Med Oncol, Minneapolis, MN 55455 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Freeman, Gordon J.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. RP Chandraker, A (reprint author), Harvard Univ, Brigham & Womens Hosp, Transplantat Res Ctr, Div Renal,Sch Med, 221 Longwood Ave, Boston, MA 02115 USA. EM achandraker@rics.bwh.harvard.edu FU AST/Roche; American Society of Transplantation; National Institutes of Health [AI-51559, P01 AI-41521, P01 AI-56299]; National Kidney Foundation; American Society of Nephrology FX This work was supported by an AST/Roche Basic Science Faculty development grant (to J.Y.), a research grant from the American Society of Transplantation (to L. V. R.), National Institutes of Health Grants AI-51559 and P01 AI-41521 (to M. H. S.) and P01 AI-56299 (to B.R.B., G.J.F., A.H.S., and M.H.S.), a National Kidney Foundation Clinical Scientist award (to A.C.), and an American Society of Nephrology Student Scholar grant (to S.C.). NR 30 TC 37 Z9 39 U1 2 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2011 VL 187 IS 3 BP 1113 EP 1119 DI 10.4049/jimmunol.1100056 PG 7 WC Immunology SC Immunology GA 794CY UT WOS:000292874200009 PM 21697455 ER PT J AU Kis-Toth, K Szanto, A Thai, TH Tsokos, GC AF Kis-Toth, Katalin Szanto, Attila Thai, To-Ha Tsokos, George C. TI Cytosolic DNA-Activated Human Dendritic Cells Are Potent Activators of the Adaptive Immune Response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; DOUBLE-STRANDED DNA; MAMMALIAN DNA; MURINE MACROPHAGES; AIM2 INFLAMMASOME; INTRACELLULAR DNA; CYTOPLASMIC DNA; INNATE IMMUNITY; I INTERFERONS; BACTERIAL-DNA AB Recent studies in cell lines and genetically engineered mice have demonstrated that cytosolic dsDNA could activate dendritic cells (DCs) to become effector APCs. Recognition of DNA might be a major factor in antimicrobial immune responses against cytosolic pathogens and also in human autoimmune diseases such as systemic lupus erythematosus. However, the role of cytosolic dsDNA in human DC activation and its effects on effector T and B cells are still elusive. In this study, we demonstrate that intracellular dsDNA is a potent activator of human monocyte-derived DCs as well as primary DCs. Activation by dsDNA depends on NF-kappa B activation, partially on the adaptor molecule IFN-promoter stimulator-1 and the novel cytosolic dsDNA receptor IFI16, but not on the previously recognized dsDNA sentinels absent in melanoma 2, DNA-dependent activator of IFN regulatory factor 3, RNA polymerase III, or high-mobility group boxes. More importantly, we report for the first time, to our knowledge, that human dsDNA-activated DCs, rather than LPS-or inflammatory cytokine mixture-activated DCs, represent the most potent inducers of naive CD4(+) T cells to promote Th1-type cytokine production and generate CD4(+) and CD8(+) cytotoxic T cells. dsDNA-DCs, but not LPS- or mixture-activated DCs, induce B cells to produce complement-fixing IgG1 and IgG3 Abs. We propose that cytosolic dsDNA represents a novel, more effective approach to generate DCs to enhance vaccine effectiveness in reprogramming the adaptive immune system to eradicate infectious agents, autoimmunity, allergy, and cancer. The Journal of Immunology, 2011, 187: 1222-1234. C1 [Kis-Toth, Katalin; Thai, To-Ha; Tsokos, George C.] Harvard Univ Med Sch Boston, Beth Israel Deaconess Med Ctr, Dept Rheumatol, Boston, MA 02115 USA. [Szanto, Attila] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Szanto, Attila] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Tsokos, GC (reprint author), Harvard Univ, Beth Israel Med Ctr, Sch Med, CLS 937, 330 Brookline Ave, Boston, MA 02115 USA. EM gtsokos@bidmc.harvard.edu RI Szanto, Attila/B-2198-2012 FU Rheuminations and National Institutes of Health [RO1 AI 49954, RO1 AI 68787] FX This work was supported by the Mary Kirkland Center for Lupus at the Hospital for Special Surgery funded by Rheuminations and National Institutes of Health Grants RO1 AI 49954 and RO1 AI 68787 (to G.C.T.). NR 56 TC 30 Z9 33 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2011 VL 187 IS 3 BP 1222 EP 1234 DI 10.4049/jimmunol.1100469 PG 13 WC Immunology SC Immunology GA 794CY UT WOS:000292874200022 PM 21709148 ER PT J AU Freed, KA Blangero, J Howard, T Johnson, MP Curran, JE Garcia, YR Lan, HC Abboud, HE Moses, EK AF Freed, Katy A. Blangero, John Howard, Tom Johnson, Matthew P. Curran, Joanne E. Garcia, Yvonne R. Lan, Hao-Chang Abboud, Hanna E. Moses, Eric K. TI The 57 kb deletion in cystinosis patients extends into TRPV1 causing dysregulation of transcription in peripheral blood mononuclear cells SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID NEPHROPATHIC CYSTINOSIS; CTNS MUTATIONS; GENE; MICE; CAPSAICIN; RECEPTOR AB Background Cystinosis is an autosomal recessive disease characterised by the abnormal accumulation of lysosomal cystine. Mutations in the cystinosin gene (CTNS) represent known causes for the disease. The major cystinosis mutation is a 57 kb deletion on human chromosome 17p13 that removes the majority of CTNS and the entire adjacent gene, CARKL/SHPK. Objectives In order to identify other genes that may influence the cystinosis pathobiological pathway, peripheral blood mononuclear cells (PBMC) were collected from cystinosis family members, and DNA and RNA extracted. Results Using whole genome transcriptional profiling, transient receptor potential vanilloid 1 (TRPV1) was found to be differentially expressed in association with cystinosis. This was verified using TaqMan qRT-PCR. There was a 72% reduction in PBMC TRPV1 mRNA levels in cystinosis individuals homozygous for the 57 kb deletion (n = 6) compared to unaffected individuals without the deletion (n = 6) (p = 0.002). TRPV1 is a sensory receptor located on chromosome 17p13, adjacent to CARKL/SHPK. It was ascertained that the 57 kb deletion extends from exon 10 of CTNS, upstream through CARKL/SHPK, to intron 2 of TRPV1, thus deleting the first two non-coding exons. Conclusion This is the first study to report that the 57 kb deletion extends into the TRPV1 gene causing dysregulation of transcription in PBMC isolated from cystinosis patients. C1 [Freed, Katy A.; Blangero, John; Johnson, Matthew P.; Curran, Joanne E.; Garcia, Yvonne R.; Lan, Hao-Chang; Moses, Eric K.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78245 USA. [Howard, Tom] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol & Lab Med, Los Angeles, CA USA. [Abboud, Hanna E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. RP Freed, KA (reprint author), Texas Biomed Res Inst, Dept Genet, POB 760549, San Antonio, TX 78245 USA. EM kfreed@txbiomedgenetics.org FU Cystinosis Research Foundation; National Center for Research Resources, National Institutes of Health [C06 RR017515]; Azar familiy of San Antonio; Shepperd family of San Antonio FX Financial support for this project has been generously provided by the Cystinosis Research Foundation and the Azar and Shepperd families of San Antonio. This investigation was conducted in facilities constructed with support from Research Facilities Improvement Program grants C06 RR017515 from the National Center for Research Resources, National Institutes of Health. There was no involvement in the study design, analysis or interpretation of the data by these funding sources. Cystinosis Research Foundation 18802 Bardeen AvenueIrvine, CA 92612. NR 20 TC 8 Z9 8 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD AUG PY 2011 VL 48 IS 8 BP 563 EP 566 DI 10.1136/jmg.2010.083303 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 795FK UT WOS:000292958800011 PM 21546516 ER PT J AU Yukl, SA Li, PL Fujimoto, K Lampiris, H Lu, CYM Hare, CB Deeks, SG Liegler, T Pandori, M Havlir, DV Wong, JK AF Yukl, Steven A. Li, Peilin Fujimoto, Katsuya Lampiris, Harry Lu, Chuanyi M. Hare, C. Bradley Deeks, Steven G. Liegler, Teri Pandori, Mark Havlir, Diane V. Wong, Joseph K. TI Modification of the Abbott RealTime assay for detection of HIV-1 plasma RNA viral loads less than one copy per milliliter SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV; Plasma RNA; Viral load; Single copy; Abbott ID HUMAN-IMMUNODEFICIENCY-VIRUS; POLYMERASE-CHAIN-REACTION; SUPPRESSIVE ANTIRETROVIRAL THERAPY; LOW-LEVEL VIREMIA; TYPE-1 RNA; INFECTED INDIVIDUALS; RESIDUAL VIREMIA; CLINICAL SPECIMENS; IMMUNE ACTIVATION; DNA-SEQUENCES AB Although commercial tests are approved for detection of HIV-1 plasma viral loads >= 20 copies per milliliter (ml), only one specialized research assay has been reported to detect plasma viral loads as low as 1 copy/ml. This manuscript describes a method of concentrating HIV-1 virions from up to 30 ml of plasma, which can be combined with a commercial viral load test to create a widely available, reproducible assay for quantifying plasma HIV RNA levels less than 1 copy/ml. Using this pre-analytically modified assay, samples with a known level of 0.5 copy/ml were detected in 8 of 12 replicates (mean 0.47 copy/ml; 95% confidence interval (CI) 0.14-0.81 copy/ml) and samples with a known level of 1.0 copy/ml were detected in 13 of 13 replicates (mean 1.96 copy/ml; 95% CI 1.42-2.50 copy/ml). By concentrating virus from 30 ml of plasma, HIV RNA could be measured in 16 of 19 samples (84%) from 12 of 12 subjects (mean 2.77 copy/ml; 95% CI 0.86-4.68 copy/ml). The measured viral load correlated inversely (r = -0.78; p = 0.028) with the total duration of viral suppression (viral load < 40 copies/ml). (C) 2011 Elsevier B.V. All rights reserved. C1 [Yukl, Steven A.; Li, Peilin; Fujimoto, Katsuya; Lampiris, Harry; Lu, Chuanyi M.; Wong, Joseph K.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Yukl, Steven A.; Lampiris, Harry; Lu, Chuanyi M.; Hare, C. Bradley; Deeks, Steven G.; Liegler, Teri; Havlir, Diane V.; Wong, Joseph K.] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA. [Hare, C. Bradley; Deeks, Steven G.; Liegler, Teri; Havlir, Diane V.] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Pandori, Mark] Dept Publ Hlth, San Francisco, CA 94102 USA. RP Yukl, SA (reprint author), 4150 Clement St,111W3, San Francisco, CA 94121 USA. EM steven.yukl@ucsf.edu; peilin.li@va.gov; kfujimo@abelia.ocn.ne.jp; harry.lampiris@va.gov; Mark.lu@va.gov; Chare@php.ucsf.edu; Sdeeks@php.ucsf.edu; TLiegler@sfgh.ucsf.edu; Mark.Pandori@sfdph.org; havlir@php.ucsf.edu; joseph.wong@ucsf.edu RI Fujimoto, Katsuya/G-2835-2012 FU U.S. Department of Veterans Affairs; National Institute of Health [1K23AI089397, P30-AI027763, NS051145, T32 AI60530] FX The authors thank the following people and institutions: (1) the study participants; (2) the study nurses at the San Francisco VA ID Clinic (Sandra Charles and Linda Adams); (3) the PLUS study staff; and (4) the staff at the San Francisco Department of Public Health. This work was supported in part by the U.S. Department of Veterans Affairs (VA Merit Award [JW/SY]) and the National Institute of Health (NIH grants 1K23AI089397 (SY), P30-AI027763 (SY, JW, TL), NS051145 [JW/SY], and T32 AI60530 [DH/SY]). NR 49 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD AUG PY 2011 VL 175 IS 2 BP 261 EP 265 DI 10.1016/j.jviromet.2011.04.015 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 793BF UT WOS:000292794700017 PM 21536073 ER PT J AU Kim, J Tipper, C Sodroski, J AF Kim, Jonghwa Tipper, Christopher Sodroski, Joseph TI Role of TRIM5 alpha RING Domain E3 Ubiquitin Ligase Activity in Capsid Disassembly, Reverse Transcription Blockade, and Restriction of Simian Immunodeficiency Virus SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; OLD-WORLD MONKEY; CYCLOPHILIN-A; RETROVIRAL RESTRICTION; ANTIVIRAL ACTIVITY; HUMAN-CELLS; POSTENTRY RESTRICTION; B30.2(SPRY) DOMAIN; MACACA-NEMESTRINA; HIV-1 REPLICATION AB The mammalian tripartite motif protein, TRIM5 alpha, recognizes retroviral capsids entering the cytoplasm and blocks virus infection. Depending on the particular TRIM5 alpha protein and retrovirus, complete disruption of the TRIM5 alpha RING domain decreases virus-restricting activity to various degrees. TRIM5 alpha exhibits RING domain-dependent E3 ubiquitin ligase activity, but the specific role of this activity in viral restriction is unknown. We created a panel of African green monkey TRIM5 alpha (TRIM5 alpha(AGM)) mutants, many of which are specifically altered in RING domain E3 ubiquitin ligase function, and characterized the phenotypes of these mutants with respect to restriction of simian and human immunodeficiency viruses (SIVmac and HIV-1, respectively). TRIM5 alpha(AGM) ubiquitin ligase activity was essential for both the accelerated disassembly of SIV(mac) capsids and the disruption of reverse transcription. The levels of SIV(mac) particulate capsids in the cytosol of target cells expressing the TRIM5 alpha variants strongly correlated with the levels of viral late reverse transcripts. RING-mediated ubiquitylation and B30.2(SPRY) domain-determined capsid binding independently contributed to the potency of SIV(mac) restriction by TRIM5 alpha(AGM). In contrast, TRIM5 alpha proteins attenuated in RING ubiquitin ligase function still accelerated HIV-1 capsid disassembly, inhibited reverse transcription, and blocked infection. Replacement of the helix-4/5 loop in the SIV(mac) capsid with the corresponding region of the HIV-1 capsid diminished the dependence of restriction on TRIM5 alpha RING function. Thus, ubiquitylation mediated by the RING domain of TRIM5 alpha(AGM) is essential for blocking SIVmac infection at the stage of capsid uncoating. C1 [Kim, Jonghwa; Tipper, Christopher; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,CLS 1010, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU National Institutes of Health [AI063987, AI076094]; National Institutes of Health (Center for AIDS Research) [AI06354]; International AIDS Vaccine Initiative FX We acknowledge the support of the National Institutes of Health (AI063987, AI076094, and a Center for AIDS Research Award, AI06354), the International AIDS Vaccine Initiative, and the late William F. McCarty-Cooper. NR 95 TC 20 Z9 20 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2011 VL 85 IS 16 BP 8116 EP 8132 DI 10.1128/JVI.00341-11 PG 17 WC Virology SC Virology GA 794TB UT WOS:000292923100015 PM 21680520 ER PT J AU Piton, A Gauthier, J Hamdan, FF Lafreniere, RG Yang, Y Henrion, E Laurent, S Noreau, A Thibodeau, P Karemera, L Spiegelman, D Kuku, F Duguay, J Destroismaisons, L Jolivet, P Cote, M Lachapelle, K Diallo, O Raymond, A Marineau, C Champagne, N Xiong, L Gaspar, C Riviere, JB Tarabeux, J Cossette, P Krebs, MO Rapoport, JL Addington, A DeLisi, LE Mottron, L Joober, R Fombonne, E Drapeau, P Rouleau, GA AF Piton, A. Gauthier, J. Hamdan, F. F. Lafreniere, R. G. Yang, Y. Henrion, E. Laurent, S. Noreau, A. Thibodeau, P. Karemera, L. Spiegelman, D. Kuku, F. Duguay, J. Destroismaisons, L. Jolivet, P. Cote, M. Lachapelle, K. Diallo, O. Raymond, A. Marineau, C. Champagne, N. Xiong, L. Gaspar, C. Riviere, J-B Tarabeux, J. Cossette, P. Krebs, M-O Rapoport, J. L. Addington, A. DeLisi, L. E. Mottron, L. Joober, R. Fombonne, E. Drapeau, P. Rouleau, G. A. TI Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE autism spectrum disorder; schizophrenia; X chromosome; synaptic genes; rare variants ID LINKED MENTAL-RETARDATION; MONOAMINE-OXIDASE-B; GENOMEWIDE SCREEN; SUSCEPTIBILITY LOCI; LINKAGE DISEQUILIBRIUM; POSTSYNAPTIC DENSITY; ANGELMAN SYNDROME; PROTEIN FAMILY; MUTATIONS; ASSOCIATION AB Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified > 200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1). Molecular Psychiatry (2011) 16, 867-880; doi:10.1038/mp.2010.54; published online 18 May 2010 C1 [Piton, A.; Gauthier, J.; Lafreniere, R. G.; Yang, Y.; Henrion, E.; Laurent, S.; Noreau, A.; Thibodeau, P.; Karemera, L.; Spiegelman, D.; Kuku, F.; Duguay, J.; Destroismaisons, L.; Jolivet, P.; Cote, M.; Lachapelle, K.; Diallo, O.; Raymond, A.; Marineau, C.; Xiong, L.; Gaspar, C.; Riviere, J-B; Tarabeux, J.; Cossette, P.; Rouleau, G. A.] Univ Montreal, Dept Med, Ctr Excellence Neur, CHUM Res Ctr, Montreal, PQ H2L 4M1, Canada. [Hamdan, F. F.; Rouleau, G. A.] CHU St Justine Res Ctr, Montreal, PQ, Canada. [Champagne, N.; Drapeau, P.] Univ Montreal, Dept Pathol & Cell Biol, Montreal, PQ H2L 4M1, Canada. [Champagne, N.; Drapeau, P.] Univ Montreal, Grp Rech Syst Nerveux Cent, Montreal, PQ H2L 4M1, Canada. [Krebs, M-O] Univ Paris 05, INSERM, U796, F-75252 Paris, France. [Krebs, M-O] Ctr Hosp St Anne, Paris, France. [Rapoport, J. L.; Addington, A.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [DeLisi, L. E.] VA Boston Healthcare Syst, Brockton, MA USA. [DeLisi, L. E.] Harvard Univ, Sch Med, Brockton, MA 02401 USA. [DeLisi, L. E.] NYU, Dept Psychiat, Langone Med Ctr, New York, NY 10016 USA. [Mottron, L.] CETEDUM, Montreal, PQ, Canada. [Joober, R.] McGill Univ, Douglas Mental Hlth Univ Inst, Dept Psychiat, Montreal, PQ, Canada. [Fombonne, E.] Montreal Childrens Hosp, Dept Psychiat, Montreal, PQ H3H 1P3, Canada. RP Rouleau, GA (reprint author), Univ Montreal, Dept Med, Ctr Excellence Neur, CHUM Res Ctr, 1560 Sherbrooke E,Room Y-3633, Montreal, PQ H2L 4M1, Canada. EM guy.rouleau@umontreal.ca RI piton, amelie/F-1201-2013 OI piton, amelie/0000-0003-0408-7468 FU Genome Canada; Genome Quebec; Universite de Montreal FX We thank the families involved in our study and the recruitment coordinators (Anne Desjarlais, Caroline Poulin, and Sabrina Diab). We thank Annie Levert, Judith St-Onge, and Isabelle Bachand for performing DNA extraction and paternity and identity testing. We are thankful for the efforts of the members of the McGill University and Genome Quebec Innovation Centre Sequencing (Pierre Lepage, Sebastien Brunet, and Hao Fan Yam) and Bioinformatic (Louis Letourneau and Louis Dumond Joseph) groups. This work was supported by a grant from Genome Canada and Genome Quebec and was cofunded by Universite de Montreal, for the 'Synapse-to-disease' (S2D) project. NR 86 TC 31 Z9 31 U1 4 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD AUG PY 2011 VL 16 IS 8 BP 867 EP 880 DI 10.1038/mp.2010.54 PG 14 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 795UQ UT WOS:000293001800012 ER PT J AU Taylor, BS Barretina, J Maki, RG Antonescu, CR Singer, S Ladanyi, M AF Taylor, Barry S. Barretina, Jordi Maki, Robert G. Antonescu, Cristina R. Singer, Samuel Ladanyi, Marc TI Advances in sarcoma genomics and new therapeutic targets SO NATURE REVIEWS CANCER LA English DT Review ID GASTROINTESTINAL STROMAL TUMORS; SOFT-TISSUE SARCOMAS; RECEPTOR TYROSINE KINASE; TELOMERE MAINTENANCE MECHANISMS; MESENCHYMAL PROGENITOR CELLS; ROTHMUND-THOMSON-SYNDROME; ADVANCED SOLID TUMORS; DOUBLE-STRAND BREAKS; CHOP FUSION PROTEIN; EWINGS-SARCOMA AB Increasingly, human mesenchymal malignancies are being classified by the abnormalities that drive their pathogenesis. Although many of these aberrations are highly prevalent within particular sarcoma subtypes, few are currently targeted therapeutically. Indeed, most subtypes of sarcoma are still treated with traditional therapeutic modalities, and in many cases sarcomas are resistant to adjuvant therapies. In this Review, we discuss the core molecular determinants of sarcomagenesis and emphasize the emerging genomic and functional genetic approaches that, coupled with novel therapeutic strategies, have the potential to transform the care of patients with sarcoma. C1 [Taylor, Barry S.; Antonescu, Cristina R.; Singer, Samuel; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Taylor, Barry S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Barretina, Jordi] Dana Farber Canc Inst, Boston, MA 02115 USA. [Barretina, Jordi] Broad Inst, Cambridge, MA 02142 USA. [Maki, Robert G.] Mt Sinai Sch Med, New York, NY 10029 USA. RP Ladanyi, M (reprint author), Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. EM ladanyim@mskcc.org FU Soft Tissue Sarcoma Program Project [P01 CA047179]; SPORE in Soft Tissue Sarcoma [P50 CA140146-01] FX The authors apologize to the many authors whose relevant work they were unable to cite here owing to space limitations. They thank N. Schultz for providing pathway expertise, C. D. M. Fletcher for critical reading, and M. Meyerson and C. Sander for advice and support. This work was supported in part by The Soft Tissue Sarcoma Program Project (P01 CA047179 to S. S., M. L. and C. R. A.) and the SPORE in Soft Tissue Sarcoma (P50 CA140146-01 to S. S., M. L., C. R. A. and B.S.T.). NR 209 TC 112 Z9 114 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD AUG PY 2011 VL 11 IS 8 BP 541 EP 557 DI 10.1038/nrc3087 PG 17 WC Oncology SC Oncology GA 795TH UT WOS:000292998200009 PM 21753790 ER PT J AU Grinspoon, S Fitch, K AF Grinspoon, Steven Fitch, Kathleen TI THERAPY HIV-associated dyslipidemia: the Heart Positive study SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Editorial Material ID CARDIOVASCULAR RISK; DISEASE; TRIALS; ADULTS C1 [Grinspoon, Steven; Fitch, Kathleen] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. EM sgrinspoon@partners.org NR 10 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 1759-5029 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD AUG PY 2011 VL 7 IS 8 BP 443 EP 444 DI 10.1038/nrendo.2011.109 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 796RV UT WOS:000293070500005 PM 21691307 ER PT J AU Moore, RG Miller, MC Disilvestro, P Landrum, LM Gajewski, W Ball, JJ Skates, SJ AF Moore, Richard G. Miller, M. Craig Disilvestro, Paul Landrum, Lisa M. Gajewski, Walter Ball, John J. Skates, Steven J. TI Evaluation of the Diagnostic Accuracy of the Risk of Ovarian Malignancy Algorithm in Women With a Pelvic Mass SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID GYNECOLOGIC ONCOLOGISTS; CANCER TREATMENT; HE-4; EXPRESSION; CARCINOMA; BIOMARKER; MULTIPLE; OUTCOMES; CARE; SPECIALTY AB OBJECTIVE: It is often difficult to distinguish a benign pelvic mass from a malignancy and tools to help referring physician are needed. The purpose of this study was to validate the Risk of Ovarian Malignancy Algorithm in women presenting with a pelvic mass. METHODS: This was a prospective, multicenter, blinded clinical trial that included women who presented to a gynecologist, a family practitioner, an internist, or a general surgeon with an adnexal mass. Serum HE4 and CA 125 were determined preoperatively. A Risk of Ovarian Malignancy Algorithm score was calculated and classified patients into high-risk and low-risk groups for having a malignancy. The sensitivity, specificity, negative predictive value, and positive predictive value of the Risk of Ovarian Malignancy Algorithm were estimated. RESULTS: A total of 472 patients were evaluated with 383 women diagnosed with benign disease and 89 women with a malignancy. The incidence of all cancers was 15% and 10% for ovarian cancer. In the postmenopausal group, a sensitivity of 92.3% and a specificity of 76.0% and for the premenopausal group the Risk of Ovarian Malignancy Algorithm had a sensitivity of 100% and specificity of 74.2% for detecting ovarian cancer. When considering all women together, the Risk of Ovarian Malignancy Algorithm had a sensitivity of 93.8%, a specificity of 74.9%, and a negative predictive value of 99.0%. CONCLUSION: The use of the serum biomarkers HE4 and CA 125 with the Risk of Ovarian Malignancy Algorithm has a high sensitivity for the prediction of ovarian cancer in women with a pelvic mass. These findings support the use of the Risk of Ovarian Malignancy Algorithm as a tool for the triage of women with an adnexal mass to gynecologic oncologists. (Obstet Gynecol 2011;118:280-8) DOI: 10.1097/AOG.0b013e318224fce2 C1 [Moore, Richard G.] Brown Univ, Program Womens Oncol, Women & Infants Hosp, Dept Obstet & Gynecol, Providence, RI 02925 USA. Brown Univ, Program Womens Oncol, Women & Infants Hosp, Ctr Biomarkers & Emerging Technol, Providence, RI 02925 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Gynecol Oncol Sect, Oklahoma City, OK 73190 USA. New Hanover Reg Med Ctr, Zimmer Canc Ctr, Wilmington, NC USA. Jackson Clin, Jackson, TN USA. Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Moore, RG (reprint author), Brown Univ, Program Womens Oncol, Women & Infants Hosp, Dept Obstet & Gynecol, Providence, RI 02925 USA. EM rmoore@wihri.org FU Fujirebio Diagnostics Inc.; National Cancer Institute (NCI) [CA136491-01, CA152990]; Abbott Diagnostics Inc. FX Funded by Fujirebio Diagnostics Inc. Richard G. Moore is partially supported by National Cancer Institute (NCI) grant CA136491-01 and Steven J. Skates is partially supported by NCI grant CA152990.; Dr. Moore receives research funding from Fujirebio Diagnostics Inc and Abbott Diagnostics Inc. M. Craig Miller receives consulting fees from Fujirebio Diagnostics Inc. Dr. Ball received research funding from Fujirebio Diagnostics Inc. The other authors did not report any potential conflicts of interest. NR 27 TC 84 Z9 87 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2011 VL 118 IS 2 BP 280 EP 288 DI 10.1097/AOG.0b013e318224fce2 PN 1 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 795FB UT WOS:000292956900012 PM 21775843 ER PT J AU Amari, W Zeringue, AL McDonald, JR Caplan, L Eisen, SA Ranganathan, P AF Amari, Wassila Zeringue, Angelique L. McDonald, Jay R. Caplan, Liron Eisen, Seth A. Ranganathan, Prabha TI Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis SO RHEUMATOLOGY LA English DT Article DE Non-melanoma skin cancer; Non-biologic; TNF antagonist; DMARDs; Rheumatoid arthritis ID TUMOR-NECROSIS-FACTOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; ADMINISTRATIVE DATA; FACTOR-ALPHA; MALIGNANCY; THERAPY; LYMPHOMA; MELANOMA; TRANSPLANTATION; METHOTREXATE AB Methods. We examined skin cancer risk in a cohort of 20 648 patients with RA derived from the Department of Veterans' Affairs (VA) national administrative databases. The cohort was divided into two medication groups: patients treated with non-biologic and TNF-alpha antagonist DMARDs. We defined skin cancer as the first occurrence of an International Classification of Disease, Version 9, Clinical Modification (ICD-9-CM) code for NMSC after initiation of a DMARD. Outcome risk was described using hazard ratios (HRs) with Cox proportional hazards regression for time-to-event analysis and logistic regression. We performed medical record review to validate the diagnosis of NMSC. Results. Incidence of NMSC was 18.9 and 12.7 per 1000 patient-years in patients on TNF-alpha antagonists and non-biologic DMARDs, respectively. Patients on TNF-alpha antagonists had a higher risk of developing NMSC (HR 1.42; 95% CI 1.24, 1.63). Risk factors for NMSC included older age, male gender, NSAID and glucocorticoid use and a history of prior malignancies. There was substantial agreement between ICD-9-CM diagnosis of NMSC and medical record validation (kappa = 0.61). Conclusion. TNF-alpha antagonist therapy in veterans with RA may be associated with an increased risk of NMSC, compared with therapy with non-biologic DMARDs. Rheumatologists should carefully screen patients receiving TNF-alpha antagonists for pre-cancerous skin lesions and skin cancer. C1 [Ranganathan, Prabha] Washington Univ, Sch Med, Dept Med, Div Rheumatol, St Louis, MO 63110 USA. [Zeringue, Angelique L.; McDonald, Jay R.; Eisen, Seth A.] St Louis Vet Affairs Med Ctr, Dept Med, St Louis, MO USA. [Caplan, Liron] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO USA. [Caplan, Liron] Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. RP Ranganathan, P (reprint author), Washington Univ, Sch Med, Dept Med, Div Rheumatol, 660 S Euclid Ave,Campus Box 8045, St Louis, MO 63110 USA. EM prangana@dom.wustl.edu RI Zeringue, Angelique/I-1755-2012 FU US Department of Veterans Affairs, Veterans Health Administration Health Services Research and Development Service [IAF 06-026] FX US Department of Veterans Affairs, Veterans Health Administration Health Services Research and Development Service project IAF 06-026. The views expressed in this article do not necessarily represent the views of the Department of Veterans Affairs. NR 45 TC 39 Z9 39 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD AUG PY 2011 VL 50 IS 8 BP 1431 EP 1439 DI 10.1093/rheumatology/ker113 PG 9 WC Rheumatology SC Rheumatology GA 793OD UT WOS:000292832100014 PM 21415022 ER PT J AU Rooney, T Scherzer, R Shigenaga, JK Graf, J Imboden, JB Grunfeld, C AF Rooney, Terence Scherzer, Rebecca Shigenaga, Judy K. Graf, Jonathan Imboden, John B. Grunfeld, Carl TI Levels of plasma fibrinogen are elevated in well-controlled rheumatoid arthritis SO RHEUMATOLOGY LA English DT Article DE Rheumatoid arthritis; Fibrinogen; Cardiovascular risk; 28-joint DAS; Clinical disease activity index; Simplified disease activity index; ESR; CRP; Serum amyloid A; IL-6 ID C-REACTIVE PROTEIN; ERYTHROCYTE SEDIMENTATION-RATE; CARDIOVASCULAR RISK-FACTORS; CORONARY-HEART-DISEASE; ACTIVITY SCORE; INFLAMMATION; RECOMMENDATIONS; ASSOCIATION; MORTALITY; MARKERS AB Methods. Patients with RA and controls were recruited at the University of California, San Francisco (UCSF). Disease activity was evaluated using standard composite indices. Fibrinogen, ESR, serum CRP, acute-phase serum amyloid A and levels of selected cytokines were quantified. Results. A total of 105 RA patients and 62 controls were studied. Among patients with RA, disease activity ranged from quiescent to highly active disease. Circulating fibrinogen levels were significantly higher in RA than in controls [median (interquartile range) 466 (391-575) vs 367 (309-419) mg/dl, respectively, P < 0.0001]. This difference remained highly statistically significant after adjustment for demographic variables and BMI. Although fibrinogen correlated significantly with clinical measures of disease activity, significantly elevated levels were observed at low levels of activity, even in RA patients with no detectable swollen or tender joints. In multivariable models, similar to 80% of the increased fibrinogen in RA was accounted for by increases in CRP and ESR. Conclusion. Circulating levels of fibrinogen are elevated in RA and correlated with markers of inflammation, but only modestly correlate with clinical assessments of disease activity. Even RA patients with excellent clinical disease control exhibit elevated levels compared with controls. C1 [Rooney, Terence] Univ Calif San Francisco, VA Med Ctr, Div Rheumatol, San Francisco, CA 94121 USA. [Scherzer, Rebecca; Shigenaga, Judy K.; Grunfeld, Carl] Univ Calif San Francisco, VA Med Ctr, Div Endocrinol & Metab, Dept Med, San Francisco, CA 94121 USA. [Graf, Jonathan; Imboden, John B.] Univ Calif San Francisco, San Francisco Gen Hosp, Div Rheumatol, Dept Med, San Francisco, CA 94121 USA. RP Grunfeld, C (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Metab Sect, 111F,4150 Clement St, San Francisco, CA 94121 USA. EM carl.grunfeld@ucsf.edu FU ACR; Rosalind Russell Arthritis Research Center; Albert L. and Janet A. Schultz Supporting Foundation; Hellman Family Award for Early-Career Faculty at the UCSF FX This work was supported by an ACR Within our Reach Grant for RA, the Rosalind Russell Arthritis Research Center, the Albert L. and Janet A. Schultz Supporting Foundation, and a Hellman Family Award for Early-Career Faculty at the UCSF; and with resources and the use of facilities of the Veterans Affairs Medical Centers in San Francisco. NR 39 TC 6 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD AUG PY 2011 VL 50 IS 8 BP 1458 EP 1465 DI 10.1093/rheumatology/ker011 PG 8 WC Rheumatology SC Rheumatology GA 793OD UT WOS:000292832100018 PM 21441551 ER PT J AU Verellen, RM Cavazos, JE AF Verellen, Rebecca M. Cavazos, Jose E. TI Pathophysiological Considerations of Seizures, Epilepsy, and Status Epilepticus in the Elderly SO AGING AND DISEASE LA English DT Review DE Elderly; Seizures; Epilepsy; Status; Aging; Pathophysiology AB Acute seizures, epilepsy and status epilepticus have the highest incidences in those over the age of 60 as compared to all other age groups. The most common etiological factors for epilepsy in the elderly are related to cerebrovascular disease. Diagnosing epilepsy in the elderly is challenging because of the subtle manifestations of partial seizures and the presence of age related cognitive difficulties, co-morbid conditions, and medications. Epilepsy treatment in this population is also difficult due to age related changes in pharmacokinetics and pharmacodynamics as well as individual variability. There are considerable gaps of knowledge about the basic pathophysiological mechanisms of recurrent partial onset seizures in the aged brain. This article critically reviews pathophysiological considerations that might impact the scientific approach of experimental research modeling of unprovoked seizures and epilepsy in elderly individuals, and the limited experimental epilepsy research on aged models. C1 [Verellen, Rebecca M.; Cavazos, Jose E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA. [Cavazos, Jose E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Cavazos, Jose E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Cavazos, Jose E.] Audie L Murphy Mem Vet Adm Med Ctr, San Antonio VA Epilepsy Ctr Excellence, San Antonio, TX 78229 USA. RP Cavazos, JE (reprint author), 8300 Floyd Curl Dr,MC 7883, San Antonio, TX 78229 USA. EM cavazosj@uthscsa.edu RI Cavazos, Jose/J-4122-2016; OI Cavazos, Jose/0000-0001-5777-2608 NR 58 TC 10 Z9 12 U1 0 U2 2 PU INT SOC AGING & DISEASE PI FORT WORTH PA EDITORIAL OFF, 3400 CAMP BOWIE BLVD, FORT WORTH, TX 76106 USA SN 2152-5250 J9 AGING DIS JI Aging Dis. PD AUG PY 2011 VL 2 IS 4 BP 278 EP 285 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA V32KP UT WOS:000208950400002 PM 22396879 ER PT J AU Bazick, HS Chang, D Mahadevappa, K Gibbons, FK Christopher, KB AF Bazick, Heidi S. Chang, Domingo Mahadevappa, Karthik Gibbons, Fiona K. Christopher, Kenneth B. TI Red cell distribution width and all-cause mortality in critically ill patients SO CRITICAL CARE MEDICINE LA English DT Article DE red cell distribution width; intensive care; mortality; bloodstream infection ID OBSTRUCTIVE PULMONARY-DISEASE; RENIN-ANGIOTENSIN SYSTEM; INTENSIVE-CARE PATIENTS; HEART-FAILURE; APACHE-II; T-CELLS; ADMINISTRATIVE DATABASES; MYOCARDIAL-INFARCTION; HOSPITAL MORTALITY; COMORBIDITY INDEX AB Objective: Red cell distribution width is a predictor of mortality in the general population. The prevalence of increased red cell distribution width and its significance in the intensive care unit are unknown. The objective of this study was to investigate the association between red cell distribution width at the initiation of critical care and all cause mortality. Design: Multicenter observational study. Setting: Two tertiary academic hospitals in Boston, MA. Patients: A total of 51,413 patients, aged >= 18 yrs, who received critical care between 1997 and 2007. Interventions: None. Measurements and Main Results: The exposure of interest was red cell distribution width as a predictor of mortality in the general population. The prevalence of increased red cell distribution width and its significance in the intensive care unit are unknown and categorized a priori in quintiles as <= 13.3%, 13.3% to 14.0%, 14.0% to 14.7%, 14.7% to 15.8%, and >15.8%. Logistic regression examined death by days 30, 90, and 365 postcritical care initiation, inhospital mortality, and bloodstream infection. Adjusted odds ratios were estimated by multivariable logistic regression models. Adjustment included age, sex, race, Deyo-Charlson index, coronary artery bypass grafting, myocardial infarction, congestive heart failure, hematocrit, white blood cell count, mean corpuscular volume, blood urea nitrogen, red blood cell transfusion, sepsis, and creatinine. Red cell distribution width was a particularly strong predictor of all-cause mortality 30 days after critical care initiation with a significant risk gradient across red cell distribution width quintiles after multivariable adjustment: red cell distribution width 13.3% to 14.0% (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.08-1.30; p <.001); red cell distribution width 14.0% to 14.7% (OR, 1.28; 95% CI, 1.16-1.42; p <.001); red cell distribution width 14.7% to 15.8% (OR, 1.69; 95% CI, 1.52-1.86; p <.001); red cell distribution width >15.8% (OR, 2.61; 95% CI, 2.37-2.86; p <.001), all relative to patients with red cell distribution width <= 13.3%. Similar significant robust associations postmultivariable adjustments are seen with death by days 90 and 365 postcritical care initiation as well as inhospital mortality. In a subanalysis of patients with blood cultures drawn (n = 18,525), red cell distribution width at critical care initiation was associated with the risk of bloodstream infection and remained significant after multivariable adjustment. The adjusted risk of bloodstream infection was 1.40- and 1.44-fold higher in patients with red cell distribution width values in the 14.7% to 15.8% and >15.8% quintiles, respectively, compared with those with red cell distribution width <= 13.3%. Estimating the receiver operating characteristic area under the curve shows that red cell distribution width has moderate discriminative power for 30-day mortality (area under the curve = 0.67). Conclusion: Red cell distribution width is a robust predictor of the risk of all-cause patient mortality and bloodstream infection in the critically ill. Red cell distribution width is commonly measured, inexpensive, and widely available and may reflect overall inflammation, oxidative stress, or arterial underfilling in the critically ill. (Crit Care Med 2011; 39:1913-1921) C1 [Chang, Domingo; Mahadevappa, Karthik; Christopher, Kenneth B.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Bazick, Heidi S.] Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02114 USA. [Gibbons, Fiona K.] Massachusetts Gen Hosp, Div Pulm, Boston, MA 02114 USA. RP Christopher, KB (reprint author), Brigham & Womens Hosp, Div Renal, 75 Francis St, Boston, MA 02115 USA. EM kbchristopher@partners.org FU National Institutes of Health [K08AI060881] FX Dr. Christopher is supported by National Institutes of Health grant K08AI060881. NR 70 TC 63 Z9 69 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2011 VL 39 IS 8 BP 1913 EP 1921 DI 10.1097/CCM.0b013e31821b85c6 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA 794BG UT WOS:000292868800008 PM 21532476 ER PT J AU Vantler, M Leppaenen, O Jesus, J Scherner, M Mustafov, L Berghausen, EM Caglayan, E Zhao, JJ Rosenkranz, S AF Vantler, M. Leppaenen, O. Jesus, J. Scherner, M. Mustafov, L. Berghausen, E. M. Caglayan, E. Zhao, J. J. Rosenkranz, S. TI PI3Kalpha deficiency critically reduces proliferation of smooth muscle cells in vitro and in vivo during neointima formation following balloon injury SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Vantler, M.; Jesus, J.; Scherner, M.; Mustafov, L.; Berghausen, E. M.; Caglayan, E.] Univ Cologne, D-50931 Cologne, Germany. [Leppaenen, O.] Univ Uppsala Hosp, Uppsala, Sweden. [Zhao, J. J.; Rosenkranz, S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 34 EP 34 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702701119 ER PT J AU Zeymer, U Parhofer, K Limbourg, T Roether, J Bhatt, D Steg, G AF Zeymer, U. Parhofer, K. Limbourg, T. Roether, J. Bhatt, D. Steg, G. TI Diabetes as coronary artery disease equivalent revisited. Results of the prospective REACH-registry SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Zeymer, U.; Limbourg, T.; Roether, J.] Inst Herzinfarktforsch, Ludwigshafen, Germany. [Parhofer, K.] Univ Munich, Munich, Germany. [Bhatt, D.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Steg, G.] Hosp Bichat Claude Bernard, AP HP, Dept Cardiol, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 65 EP 65 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702701237 ER PT J AU Blendea, D Altman, RK Heist, EK Barrett, C Das, S Mcculloch, M Britt, C Orencole, M Ruskin, JN Singh, JP AF Blendea, D. Altman, R. K. Heist, E. K. Barrett, C. Das, S. Mcculloch, M. Britt, C. Orencole, M. Ruskin, J. N. Singh, J. P. TI QRS voltage predicts response to CRT in patients with left bundle branch block SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Blendea, D.; Altman, R. K.; Heist, E. K.; Barrett, C.; Das, S.; Mcculloch, M.; Britt, C.; Orencole, M.; Ruskin, J. N.; Singh, J. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 140 EP 140 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702701521 ER PT J AU Fayad, ZA Mani, V Woodward, M Kallend, D Burgess, T Abt, M Fuster, V Rudd, JHF Tawakol, A Farkouh, ME AF Fayad, Z. A. Mani, V. Woodward, M. Kallend, D. Burgess, T. Abt, M. Fuster, V. Rudd, J. H. F. Tawakol, A. Farkouh, M. E. TI Primary results of the dal-PLAQUE study assessing the effect of dalcetrapib on structural and inflammatory atherosclerotic disease using non-invasive simultaneous multimodality imaging SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Fayad, Z. A.; Mani, V.; Fuster, V.; Farkouh, M. E.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Woodward, M.] Univ Sydney, George Inst, Sydney, NSW 2006, Australia. [Kallend, D.; Abt, M.] F Hoffmann La Roche Ltd, Basel, Switzerland. [Burgess, T.] Hoffmann La Roche Inc, Nutley, NJ 07110 USA. [Rudd, J. H. F.] Univ Cambridge, Cambridge, England. [Tawakol, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Woodward, Mark/D-8492-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 220 EP 220 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702702255 ER PT J AU Pavri, B Holcomb, R Gleva, M Chung, M Mela, T Gottipaty, V Shinn, T Borge, R Mitchell, K Poole, J AF Pavri, B. Holcomb, R. Gleva, M. Chung, M. Mela, T. Gottipaty, V. Shinn, T. Borge, R. Mitchell, K. Poole, J. TI Is upgrade to CRT device more likely in pacemaker or defibrillator patients? Insights from the REPLACE Registry SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Pavri, B.] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Gleva, M.] Washington Univ, Sch Med, St Louis, MO USA. [Chung, M.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Mela, T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Gottipaty, V.] S Carolina Childrens Heart Ctr, Columbia, SC USA. [Shinn, T.] Michigan Heart PC, Ypsilanti, MI USA. [Borge, R.] Abington Med Specialists, Abington, PA USA. [Mitchell, K.] Biotronik, Lake Oswego, OR USA. [Poole, J.] Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 306 EP 306 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702702583 ER PT J AU Van Soest, G Goderie, TPM Regar, E Bouma, BE Tearney, GJ Serruys, PW Oosterhuis, JW Van der Steen, AFW AF Van Soest, G. Goderie, T. P. M. Regar, E. Bouma, B. E. Tearney, G. J. Serruys, P. W. Oosterhuis, J. W. Van der Steen, A. F. W. TI Atherosclerotic tissue characterization in vivo by optical coherence tomography attenuation imaging SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Van Soest, G.; Goderie, T. P. M.; Regar, E.; Serruys, P. W.; Van der Steen, A. F. W.] Erasmus Univ, Thoraxctr, Erasmus Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Bouma, B. E.; Tearney, G. J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Oosterhuis, J. W.] Erasmus MC, Dept Pathol, Rotterdam, Netherlands. RI van Soest, Gijs/B-4881-2008 NR 0 TC 0 Z9 0 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 401 EP 401 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702703328 ER PT J AU Goldstein, S Bates, E Bhatt, D Holmes, D Kupfer, S Martinez, F Weitz, J Zannad, F Cao, C Spaeder, J AF Goldstein, S. Bates, E. Bhatt, D. Holmes, D. Kupfer, S. Martinez, F. Weitz, J. Zannad, F. Cao, C. Spaeder, J. TI Safety evaluation of the factor Xa inhibitor TAK-442 in subjects with acute coronary syndromes: phase 2 AXIOM-ACS trial results SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Goldstein, S.] Henry Ford Hosp, Detroit, MI 48202 USA. [Bates, E.] Univ Michigan, Ann Arbor, MI 48109 USA. [Bhatt, D.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, D.] Harvard Univ, Sch Med, Boston, MA USA. [Holmes, D.] Mayo Clin, Rochester, MN USA. [Kupfer, S.; Cao, C.] Takeda Global Res & Dev Ctr Inc, Deerfield, IL USA. [Martinez, F.] Natl Univ Cordoba, Cordoba, Argentina. [Weitz, J.] Hamilton Hosp, Hamilton, New Zealand. [Zannad, F.] Henri Poincare Univ Nancy, Nancy, France. [Spaeder, J.] Takeda Pharmaceut Int, Deerfield, IL USA. NR 0 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 414 EP 414 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702703376 ER PT J AU Varenhorst, C Alstrom, U Scirica, BM Hogue, CW Asenblad, N Horrow, J Brandrup-Wognsen, G Wallentin, L Held, C AF Varenhorst, C. Alstrom, U. Scirica, B. M. Hogue, C. W. Asenblad, N. Horrow, J. Brandrup-Wognsen, G. Wallentin, L. Held, C. TI Cardiac events, infections and bleeds contribute to higher vascular and non-vascular mortality with clopidogrel compared to ticagrelor treatment in patients undergoing coronary artery bypass grafting SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Varenhorst, C.; Asenblad, N.; Wallentin, L.; Held, C.] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Varenhorst, C.; Wallentin, L.; Held, C.] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Alstrom, U.] Uppsala Univ, Dept Cardiac & Thorac Anaesthesia & Surg, Uppsala, Sweden. [Scirica, B. M.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Hogue, C. W.] Johns Hopkins Univ, Sch Med, Johns Hopkins Hosp, Baltimore, MD USA. [Horrow, J.] AstraZeneca LP, Wilmington, DE USA. [Brandrup-Wognsen, G.] AstraZeneca, Molndal, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 414 EP 414 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702703374 ER PT J AU Anand, IS Rector, TS Cleland, JG Kckelvie, RS Persson, H Mcmurray, JJ Zile, M Komajda, M Massie, B Carson, P AF Anand, I. S. Rector, T. S. Cleland, J. G. Kckelvie, R. S. Persson, H. Mcmurray, J. J. Zile, M. Komajda, M. Massie, B. Carson, P. TI Prognostic value of baseline NT-proBNP and its interactions with irbesartan treatment in patients with heart failure and preserved ejection fraction: Findings from the I-PRESERVE trial SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Anand, I. S.; Rector, T. S.] Univ Minnesota, Minneapolis, MN USA. [Cleland, J. G.] Univ Hull, Castle Hill Hosp, Kingston Upon Hull, Yorks, England. [Kckelvie, R. S.] Populat Hlth Res Inst, Hamilton, ON, Canada. [Persson, H.] Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden. [Mcmurray, J. J.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Zile, M.] Med Univ S Carolina, Charleston, SC USA. [Zile, M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Komajda, M.] Hosp Pitie Salpetriere, AP HP, Paris, France. [Massie, B.] Univ Calif San Francisco, Vet Adm Med Ctr, Cardiol Sect, San Francisco, CA USA. [Carson, P.] Vet Affairs Med Ctr, Washington, DC 20422 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 495 EP 495 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702704079 ER PT J AU Berghausen, EM Janssen, W Vantler, M Zimmermann, T Ten Freyhaus, H Zhao, JJ Schermuly, RT Rosenkranz, S AF Berghausen, E. M. Janssen, W. Vantler, M. Zimmermann, T. Ten Freyhaus, H. Zhao, J. J. Schermuly, R. T. Rosenkranz, S. TI The PI 3-kinase isoform p110 alpha is essential for growth factor induced vascular remodelling in pulmonary hypertension SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Berghausen, E. M.; Vantler, M.; Zimmermann, T.; Ten Freyhaus, H.; Rosenkranz, S.] Univ Cologne, Dept Internal Med 3, D-50931 Cologne, Germany. [Janssen, W.] Max Planck Inst Heart & Lung Res, Bad Nauheim, Germany. [Zhao, J. J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Schermuly, R. T.] Univ Giessen, Lung Ctr, Univ Hosp, D-35390 Giessen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 504 EP 504 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702704110 ER PT J AU Reynolds, K Fang, MC Singer, DE Liu, ILA Black, MH Udaltsova, N Go, AS AF Reynolds, K. Fang, M. C. Singer, D. E. Liu, I. -L. A. Black, M. H. Udaltsova, N. Go, A. S. TI Health literacy and awareness of atrial fibrillation: the ATRIA2-CVRN study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Reynolds, K.; Liu, I. -L. A.; Black, M. H.] Kaiser Permanente Southern Calif, Pasadena, CA USA. [Fang, M. C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Singer, D. E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Udaltsova, N.; Go, A. S.] Kaiser Permanente Northern Calif, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 622 EP 622 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702704572 ER PT J AU De Ferrari, GM Van de Werf, F Armstrong, P Bode, C Lewis, BS Tricoci, P Guo, J Contant, C Newby, K Giugliano, RP AF De Ferrari, G. M. Van de Werf, F. Armstrong, P. Bode, C. Lewis, B. S. Tricoci, P. Guo, J. Contant, C. Newby, K. Giugliano, R. P. TI Contrast induced nephropathy predicts later mortality among patients with non-ST-segment elevation acute coronary syndrome undergoing PCI: a sub-analysis from the EARLY ACS study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [De Ferrari, G. M.] Fdn IRCCS Policlin San Mat, Dept Cardiol, Pavia, Italy. [Van de Werf, F.] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Armstrong, P.] Univ Alberta, Edmonton, AB, Canada. [Bode, C.] Univ Freiburg Klinikum, Freiburg, Germany. [Lewis, B. S.] Lady Davis Carmel Med Ctr, Haifa, Israel. [Tricoci, P.] Duke Clin Res Durham, Durham, NC USA. [Giugliano, R. P.] TIMI Study Grp, Boston, MA USA. RI De Ferrari, Gaetano/K-5188-2016 OI De Ferrari, Gaetano/0000-0003-4940-0876 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 657 EP 657 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702705083 ER PT J AU Horvat, PM Kriegel, MF Schlett, CL Alkadhi, H Vorpahl, M Stolzmann, P Scheffel, H Tearney, GJ Virmani, R Hoffmann, U AF Horvat, P. Maurovich Kriegel, M. F. Schlett, C. L. Alkadhi, H. Vorpahl, M. Stolzmann, P. Scheffel, H. Tearney, G. J. Virmani, R. Hoffmann, U. TI Computed tomography, intravascular ultrasound and optical frequency domain imaging for the detection of advanced coronary plaques: a systematic comparison with histology in ex vivo human hearts SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Horvat, P. Maurovich] Semmelweis Univ, Heart Ctr, H-1085 Budapest, Hungary. [Kriegel, M. F.; Schlett, C. L.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Cardiac MRI PET CT Prog, Boston, MA 02115 USA. [Alkadhi, H.; Stolzmann, P.; Scheffel, H.] Univ Zurich Hosp, Inst Diagnost Radiol, CH-8091 Zurich, Switzerland. [Vorpahl, M.; Virmani, R.] CV Path Inst Inc, Gaithersburg, MD USA. [Tearney, G. J.; Hoffmann, U.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 980 EP 981 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702707162 ER PT J AU Blendea, D Heist, EK Barrett, C Orencole, M Ruskin, JN Singh, JP AF Blendea, D. Heist, E. K. Barrett, C. Orencole, M. Ruskin, J. N. Singh, J. P. TI Right ventricular venous system in patients undergoing cardiac resynchronization therapy. A rotational coronary venous angiography study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Blendea, D.; Heist, E. K.; Barrett, C.; Orencole, M.; Ruskin, J. N.; Singh, J. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 1020 EP 1020 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702707308 ER PT J AU Le Tourneau, T Lardeux, A Kyndt, F Merot, J Hagege, A Levine, R Trochu, JN Schott, JJ Le Marec, H Probst, V AF Le Tourneau, T. Lardeux, A. Kyndt, F. Merot, J. Hagege, A. Levine, R. Trochu, J. N. Schott, J. J. Le Marec, H. Probst, V. TI Mitral valve phenotype in patients with filamin-A-related valvular dystrophy SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Le Tourneau, T.; Lardeux, A.; Kyndt, F.; Merot, J.; Trochu, J. N.; Schott, J. J.; Le Marec, H.; Probst, V.] Univ Hosp, Inst Thorax, Inserm UMR915, Nantes, France. [Hagege, A.] Hop Europeen Georges Pompidou, AP HP, Dept Cardiol, Paris, France. [Levine, R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RI Le Marec, Herve/D-2718-2015; KYNDT, Florence/D-6370-2015; Trochu, Jean-Noel/D-6378-2015; MEROT, Jean/D-5741-2015; probst, vincent/D-4996-2015 OI Le Marec, Herve/0000-0002-8288-8693; NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 SU 1 BP 1078 EP 1078 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TI UT WOS:000208702707531 ER PT J AU Patti, JA AF Patti, John A. TI Radiology and Congress: A Midyear Report SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Patti, JA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 202, Boston, MA 02114 USA. EM jpatti@partners.org NR 1 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2011 VL 8 IS 8 BP 525 EP 526 DI 10.1016/j.jacr.2011.06.021 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KA UT WOS:000306201600001 PM 21807341 ER PT J AU Larson, PA Pyatt, RS Grimes, CK Abudujeh, HH Chin, KW Roth, CJ AF Larson, Paul A. Pyatt, Robert S., Jr. Grimes, Charles K. Abudujeh, Hani H. Chin, Kenneth W. Roth, Christopher J. TI Getting the Most Out of RADPEER (TM) SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Peer review; performance improvement; quality assessment; quality improvement; RADPEER (TM) ID DIAGNOSTIC-PROCEDURES; ACCURACY AB RADPEER (TM) is a quality assessment and improvement product developed and marketed by the ACR. Although the program has been available since 2002 and the scoring system was revised in 2009, the ACR allows considerable flexibility in its implementation. Although that flexibility supports the local needs of radiology groups using the program, it also may lead to suboptimal implementation of the program and may limit the usefulness of the data obtained. The authors, who are members of the ACR RADPEER Committee, provide 11 specific suggestions to optimize the performance of RADPEER and suggest opportunities for future improvement of the program. C1 [Larson, Paul A.] Radiol Associates Fox Valley, Neenah, WI 54956 USA. [Pyatt, Robert S., Jr.] Chambersburg Imaging Associates, Chambersburg, PA USA. [Grimes, Charles K.] Maine Med Ctr, Portland, ME 04102 USA. [Abudujeh, Hani H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chin, Kenneth W.] San Fernando Valley Intervent Radiol & Imaging Ct, Encino, CA USA. [Roth, Christopher J.] Duke Univ, Med Ctr, Durham, NC USA. RP Larson, PA (reprint author), Radiol Associates Fox Valley, 333 S Commercial St,Suite 100, Neenah, WI 54956 USA. EM palbeans@aol.com RI Roth, Christopher/L-3395-2016 OI Roth, Christopher/0000-0002-9634-7126 NR 8 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2011 VL 8 IS 8 BP 543 EP 548 DI 10.1016/j.jacr.2010.12.018 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KA UT WOS:000306201600007 PM 21807347 ER PT J AU Singh, S Kalra, MK Thrall, JH Mahesh, M AF Singh, Sarabjeet Kalra, Mannudeep K. Thrall, James H. Mahesh, Mahadevappa TI Pointers for Optimizing Radiation Dose in Head CT Protocols SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material ID IMAGE QUALITY C1 [Kalra, Mannudeep K.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Singh, Sarabjeet; Kalra, Mannudeep K.; Thrall, James H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Mahesh, M (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21287 USA. EM mmahesh@jhmi.edu NR 7 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2011 VL 8 IS 8 BP 591 EP 593 DI 10.1016/j.jacr.2011.05.001 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KA UT WOS:000306201600016 PM 21807356 ER PT J AU Calfon, MA Rosenthal, A Mallas, G Mauskapf, A Nudelman, RN Ntziachristos, V Jaffer, FA AF Calfon, Marcella A. Rosenthal, Amir Mallas, Georgios Mauskapf, Adam Nudelman, R. Nika Ntziachristos, Vasilis Jaffer, Farouc A. TI In vivo Near Infrared Fluorescence (NIRF) Intravascular Molecular Imaging of Inflammatory Plaque, a Multimodal Approach to Imaging of Atherosclerosis SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 54; Atherosclerosis; inflammation; imaging; near infrared fluorescence; plaque; intravascular; catheter AB The vascular response to injury is a well-orchestrated inflammatory response triggered by the accumulation of macrophages within the vessel wall leading to an accumulation of lipid-laden intra-luminal plaque, smooth muscle cell proliferation and progressive narrowing of the vessel lumen. The formation of such vulnerable plaques prone to rupture underlies the majority of cases of acute myocardial infarction. The complex molecular and cellular inflammatory cascade is orchestrated by the recruitment of T lymphocytes and macrophages and their paracrine effects on endothelial and smooth muscle cells. (1) Molecular imaging in atherosclerosis has evolved into an important clinical and research tool that allows in vivo visualization of inflammation and other biological processes. Several recent examples demonstrate the ability to detect high-risk plaques in patients, and assess the effects of pharmacotherapeutics in atherosclerosis. (4) While a number of molecular imaging approaches (in particular MRI and PET) can image biological aspects of large vessels such as the carotid arteries, scant options exist for imaging of coronary arteries. (2) The advent of high-resolution optical imaging strategies, in particular near-infrared fluorescence (NIRF), coupled with activatable fluorescent probes, have enhanced sensitivity and led to the development of new intravascular strategies to improve biological imaging of human coronary atherosclerosis. Near infrared fluorescence (NIRF) molecular imaging utilizes excitation light with a defined band width (650-900 nm) as a source of photons that, when delivered to an optical contrast agent or fluorescent probe, emits fluorescence in the NIR window that can be detected using an appropriate emission filter and a high sensitivity charge-coupled camera. As opposed to visible light, NIR light penetrates deeply into tissue, is markedly less attenuated by endogenous photon absorbers such as hemoglobin, lipid and water, and enables high target-to-background ratios due to reduced autofluorescence in the NIR window. Imaging within the NIR 'window' can substantially improve the potential for in vivo imaging. (2,5) Inflammatory cysteine proteases have been well studied using activatable NIRF probes(10), and play important roles in atherogenesis. Via degradation of the extracellular matrix, cysteine proteases contribute importantly to the progression and complications of atherosclerosis(8). In particular, the cysteine protease, cathepsin B, is highly expressed and colocalizes with macrophages in experimental murine, rabbit, and human atheromata. (3,6,7) In addition, cathepsin B activity in plaques can be sensed in vivo utilizing a previously described 1-D intravascular near-infrared fluorescence technology(6), in conjunction with an injectable nanosensor agent that consists of a poly-lysine polymer backbone derivatized with multiple NIR fluorochromes (VM110/Prosense750, ex/em 750/780nm, VisEn Medical, Woburn, MA) that results in strong intramolecular quenching at baseline. (10) Following targeted enzymatic cleavage by cysteine proteases such as cathepsin B (known to colocalize with plaque macrophages), the fluorochromes separate, resulting in substantial amplification of the NIRF signal. Intravascular detection of NIR fluorescence signal by the utilized novel 2D intravascular NIRF catheter now enables high-resolution, geometrically accurate in vivo detection of cathepsin B activity in inflamed plaque. In vivo molecular imaging of atherosclerosis using catheter-based 2D NIRF imaging, as opposed to a prior 1-D spectroscopic approach, (6) is a novel and promising tool that utilizes augmented protease activity in macrophage-rich plaque to detect vascular inflammation. (11,12) The following research protocol describes the use of an intravascular 2-dimensional NIRF catheter to image and characterize plaque structure utilizing key aspects of plaque biology. It is a translatable platform that when integrated with existing clinical imaging technologies including angiography and intravascular ultrasound (IVUS), offers a unique and novel integrated multimodal molecular imaging technique that distinguishes inflammatory atheromata, and allows detection of intravascular NIRF signals in human-sized coronary arteries. C1 [Calfon, Marcella A.; Rosenthal, Amir; Mallas, Georgios; Mauskapf, Adam; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Cambridge, MA 02138 USA. [Calfon, Marcella A.; Rosenthal, Amir; Mallas, Georgios; Mauskapf, Adam; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Cambridge, MA 02138 USA. [Rosenthal, Amir; Nudelman, R. Nika; Ntziachristos, Vasilis] Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Munich, Germany. [Rosenthal, Amir; Nudelman, R. Nika; Ntziachristos, Vasilis] Tech Univ Munich, D-80290 Munich, Germany. [Mallas, Georgios] Northeastern Univ, Dept Elect & Comp Engn, Boston, MA USA. RP Calfon, MA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Cambridge, MA 02138 USA. OI Jaffer, Farouc/0000-0001-7980-384X FU National Institutes of Health [R01 HL 108229]; American Heart Association Scientist Development [0830352N]; Howard Hughes Medical Institute Career Development Award; Broadview Ventures; European Community [235689]; MGH William Schreyer Fellowship FX Support for this work was provided by National Institutes of Health grant # R01 HL 108229, American Heart Association Scientist Development Grant # 0830352N, Howard Hughes Medical Institute Career Development Award, Broadview Ventures, European Community's Seventh Framework Programme (FP7/2007-2013 under grant agreement # 235689), and the MGH William Schreyer Fellowship. NR 12 TC 4 Z9 4 U1 0 U2 8 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD AUG PY 2011 IS 54 AR UNSP e2257 DI 10.3791/2257 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36MD UT WOS:000209215100001 ER PT J AU Ataya, B Tzeng, E Zuckerbraun, BS AF Ataya, Bilal Tzeng, Edith Zuckerbraun, Brian S. TI Nitrite-Generated Nitric Oxide to Protect Against Intimal Hyperplasia Formation SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID BLOOD-PRESSURE; L-ARGININE; MOLECULAR-MECHANISMS; DIETARY NITRATE; BIOLOGY; ENDOTHELIUM; PATHWAY; DISEASE; NO; PATHOPHYSIOLOGY AB Vascular disease is a leading cause of morbidity and mortality worldwide. Current vascular therapeutic interventions directed at diseased vessels are restricted in long-term efficacy by the development of intimal hyperplasia and the reformation of flow-limiting disease. The vascular injury and inflammation that ensues from the intervention, especially in the setting of an existing atherosclerotic vascular disease, results in further endothelial dysfunction and subsequent smooth muscle cell proliferation and migration. Although the etiology of intimal hyperplasia is multifactorial, impaired nitric oxide (NO) signaling has been implicated. The vasoprotective properties of NO have been intensely studied, and many investigations have focused on harnessing this biological system for therapeutic benefit. Continued studies investigate the role of impaired NO signaling via the classical arginine/NO synthase (NOS)/NO pathway in the setting of intimal hyperplasia. Furthermore, the possible protective effects of nitrate and nitrite-generated NO via non-NOS-mediated pathways to limit vascular injury have been recently appreciated and will likely prove to be an important vasoregulatory and vasoprotective signaling pathway. (Trends Cardiovasc Med 2011;21:157-162) (C) 2011 Published by Elsevier Inc. C1 [Ataya, Bilal; Tzeng, Edith; Zuckerbraun, Brian S.] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Tzeng, Edith; Zuckerbraun, Brian S.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Zuckerbraun, BS (reprint author), Univ Pittsburgh, 200 Lothrop St,F1200 PUH, Pittsburgh, PA 15213 USA. EM zuckerbraunbs@upmc.edu NR 40 TC 11 Z9 12 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD AUG PY 2011 VL 21 IS 6 BP 157 EP 162 AR PII S1050-1738(12)00113-2 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 981CI UT WOS:000306942700001 PM 22814422 ER PT J AU Bhattacharya, A Leonard, S Tardif, S Buffenstein, R Fischer, KE Richardson, A Austad, SN Chaudhuri, AR AF Bhattacharya, Arunabh Leonard, Shanique Tardif, Suzette Buffenstein, Rochelle Fischer, Kathleen E. Richardson, Arlan Austad, Steven N. Chaudhuri, Asish R. TI Attenuation of liver insoluble protein carbonyls: indicator of a longevity determinant? SO AGING CELL LA English DT Editorial Material DE naked mole-rat; marmoset; bats; protein carbonylation; dietary restriction; oxidative stress ID DIETARY RESTRICTION; OXIDATIVE DAMAGE; ANTIOXIDANT ENZYMES; LIFE-SPAN; DISEASE; RAT; METABOLISM; PROTEASOME; SENESCENCE; ANIMALS AB Oxidative damage affects protein structure and function. Progressive accumulation of oxidized proteins is considered a putative mechanism of aging; however, empirical evidence supporting their role in aging is inconsistent. This inconsistency may reflect a failure to distinguish damage to particular cellular compartments. We found a significant reduction of protein carbonyls in the insoluble, but not in the soluble, fraction of liver tissues of long-lived compared with their short-lived counterpart. Of cellular components analyzed, only nuclear protein carbonyl level was uniformly reduced in long-lived compared with short-lived animals. This observation suggests that attenuated accumulation of protein carbonyls in the nucleus, where they can affect multiple aspects of gene expression and DNA repair, might contribute to the longevity in mammalian species. C1 [Bhattacharya, Arunabh; Leonard, Shanique; Tardif, Suzette; Buffenstein, Rochelle; Fischer, Kathleen E.; Richardson, Arlan; Austad, Steven N.; Chaudhuri, Asish R.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Bhattacharya, Arunabh; Tardif, Suzette; Richardson, Arlan; Austad, Steven N.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Buffenstein, Rochelle; Fischer, Kathleen E.; Richardson, Arlan] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Fischer, Kathleen E.; Chaudhuri, Asish R.] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Austad, Steven N.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Chaudhuri, Asish R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Chaudhuri, AR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, Texas Res Pk Campus,15355 Lambda Dr, San Antonio, TX 78245 USA. EM austad@uthscsa.edu; chaudhuria@uthscsa.edu FU NIA NIH HHS [K07 AG025063-04, R01 AG022891, K07 AG025063, K07 AG02506304, AG-022891, AG022873, R01 AG022873] NR 33 TC 10 Z9 10 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD AUG PY 2011 VL 10 IS 4 BP 720 EP 723 DI 10.1111/j.1474-9726.2011.00712.x PG 4 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 791FB UT WOS:000292648800015 PM 21463461 ER PT J AU Lockhart, SR Zimbeck, AJ Baddley, JW Marr, KA Andes, DR Walsh, TJ Kauffman, CA Kontoyiannis, DP Ito, JI Pappas, PG Chiller, T AF Lockhart, Shawn R. Zimbeck, Alicia J. Baddley, John W. Marr, Kieren A. Andes, David R. Walsh, Thomas J. Kauffman, Carol A. Kontoyiannis, Dimitrios P. Ito, James I. Pappas, Peter G. Chiller, Tom TI In Vitro Echinocandin Susceptibility of Aspergillus Isolates from Patients Enrolled in the Transplant-Associated Infection Surveillance Network SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; ANTIFUNGAL AGENTS; RECIPIENTS; ANIDULAFUNGIN; CASPOFUNGIN; TRANSNET AB We determined the echinocandin minimum effective concentration (MEC) values for caspofungin, micafungin, and anidulafungin against 288 Aspergillus isolates prospectively collected from transplant patients with proven or probable invasive aspergillosis between 2001 and 2006 as part of the Transplant-Associated Infection Surveillance Network (TRANSNET). We demonstrated that the vast majority of Aspergillus isolates had MEC values at or below the epidemiological cutoff values for caspofungin, micafungin, and anidulafungin, including those from patients who had received caspofungin. C1 [Lockhart, Shawn R.; Zimbeck, Alicia J.; Chiller, Tom] Ctr Dis Control & Prevent, Mycot Dis Branch, Atlanta, GA 30333 USA. [Baddley, John W.] Univ Alabama, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Baddley, John W.] Birmingham Vet Affairs Med Ctr, Dept Med, Infect Dis Sect, Birmingham, AL USA. [Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Andes, David R.] Univ Wisconsin, Dept Med, Div Infect Dis, Madison, WI USA. [Walsh, Thomas J.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, New York, NY USA. [Walsh, Thomas J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Kauffman, Carol A.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Kauffman, Carol A.] Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Dept Med, Houston, TX 77030 USA. [Ito, James I.] City Hope Natl Med Ctr, Dept Med, Div Infect Dis, Duarte, CA 91010 USA. [Pappas, Peter G.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. RP Lockhart, SR (reprint author), Ctr Dis Control & Prevent, Mycot Dis Branch, 1600 Clifton Rd,Mailstop G-11, Atlanta, GA 30333 USA. EM gyi2@cdc.gov FU Association of Public Health Laboratories (APHL); Astellas; Pfizer; Merck; Schering-Plough; Enzon FX A.J.Z. was supported by the Association of Public Health Laboratories (APHL). TRANSNET was sponsored by Astellas, Pfizer, Merck, and Schering-Plough. This work was funded by a grant from Merck. Potential conflicts of interest are as follows: P.G.P. receives research support and is an ad hoc advisor for Merck, Pfizer, and Astellas; J.W.B. received research grants from Merck, Astellas, and Pfizer and is a consultant/advisor for Merck and Pfizer; J.I.I. received honoraria for speakers' activities from Astellas, Cubist, Merck, and Pfizer and is a consultant for Sigma Tau; D.R.A. has received grants from and is a consultant for Merck, Astellas, and Pfizer; C.A.K. receives research support from Merck and chairs a data adjudication committee for Pfizer; K.A.M. received research grants from Merck, Astellas, and Pfizer and is on the advisory board or is consulting for Astellas, Basilea, Merck, and Pfizer; D.P.K. received research support and honoraria from Schering-Plough, Pfizer, Astellas, Enzon, and Merck; T.J.W. is in consultation with iCo, Vestagen, Trius, and Sigma Tau. All other authors have no potential conflicts. NR 17 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2011 VL 55 IS 8 BP 3944 EP 3946 DI 10.1128/AAC.00428-11 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 792HV UT WOS:000292733800040 PM 21670187 ER PT J AU Kinzel, O Alfieri, A Altamura, S Brunetti, M Bufali, S Colaceci, F Ferrigno, F Filocamo, G Fonsi, M Gallinari, P Malancona, S Hernando, JIM Monteagudo, E Orsale, MV Palumbi, MC Pucci, V Rowley, M Sasso, R Scarpelli, R Steinkuhler, C Jones, P AF Kinzel, Olaf Alfieri, Anna Altamura, Sergio Brunetti, Mirko Bufali, Simone Colaceci, Fabrizio Ferrigno, Federica Filocamo, Gessica Fonsi, Massimiliano Gallinari, Paola Malancona, Savina Hernando, Jose Ignacio Martin Monteagudo, Edith Orsale, Maria Vittoria Palumbi, Maria Cecilia Pucci, Vincenzo Rowley, Michael Sasso, Romina Scarpelli, Rita Steinkuehler, Christian Jones, Philip TI Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1 H-pyrazol-5-yl)hexahydro-imidazo[1,5-a] pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 2 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Hedgehog pathway; Smoothened antagonist; Hedgehog inhibitor ID TISSUE DISTRIBUTION; SIGNALING PATHWAY; CANCER; CYCLOPAMINE; SULFONAMIDE; INHIBITION; KINETICS; RATS; MICE AB The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kinzel, Olaf; Alfieri, Anna; Altamura, Sergio; Brunetti, Mirko; Bufali, Simone; Colaceci, Fabrizio; Ferrigno, Federica; Filocamo, Gessica; Fonsi, Massimiliano; Gallinari, Paola; Malancona, Savina; Hernando, Jose Ignacio Martin; Monteagudo, Edith; Orsale, Maria Vittoria; Palumbi, Maria Cecilia; Pucci, Vincenzo; Rowley, Michael; Sasso, Romina; Scarpelli, Rita; Steinkuehler, Christian; Jones, Philip] IRBM, Merck Res Labs Rome, I-00040 Pomezia, Rome, Italy. RP Jones, P (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, 450 Brookline Ave, Boston, MA 02115 USA. EM philip_jones@dfci.harvard.edu RI Scarpelli, Rita/A-2985-2012; Scarpelli, Rita/O-9422-2015 NR 20 TC 23 Z9 23 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 1 PY 2011 VL 21 IS 15 BP 4429 EP 4435 DI 10.1016/j.bmcl.2011.06.023 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 792GR UT WOS:000292729900010 PM 21737263 ER PT J AU Desmedt, C Michiels, S Haibe-Kains, B Loi, S Sotiriou, C AF Desmedt, Christine Michiels, Stefan Haibe-Kains, Benjamin Loi, Sherene Sotiriou, Christos TI Time to move forward from "first-generation" prognostic gene signatures in early breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Editorial Material ID PREDICTIVE ACCURACY; EXPRESSION; VALIDATION; RECURRENCE; TAMOXIFEN; ASSAY C1 [Desmedt, Christine; Michiels, Stefan; Loi, Sherene; Sotiriou, Christos] Univ Libre Bruxelles, Breast Canc Translat Res Lab, Inst Jules Bordet, B-1000 Brussels, Belgium. [Haibe-Kains, Benjamin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Haibe-Kains, Benjamin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Sotiriou, C (reprint author), Univ Libre Bruxelles, Breast Canc Translat Res Lab, Inst Jules Bordet, 121 Blvd Waterloo, B-1000 Brussels, Belgium. EM christos.sotiriou@bordet.be RI Haibe-Kains, Benjamin/D-3702-2011; Michiels, Stefan/L-1516-2013; Loi, Sherene/H-1979-2016; OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Michiels, Stefan/0000-0002-6963-2968; Loi, Sherene/0000-0001-6137-9171; Desmedt, Christine/0000-0002-5223-5579 NR 19 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2011 VL 128 IS 3 BP 643 EP 645 DI 10.1007/s10549-010-1213-4 PG 3 WC Oncology SC Oncology GA 789ZB UT WOS:000292557100006 PM 20953831 ER PT J AU Michaelson, JS Chen, LL Bush, D Fong, A Smith, B Younger, J AF Michaelson, James S. Chen, L. Leon Bush, Devon Fong, Allan Smith, Barbara Younger, Jerry TI Improved web-based calculators for predicting breast carcinoma outcomes SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Survival; Outcome; Calculator; Epidemiology; Conditional survival; Hazard function ID LYMPH-NODES CONTRIBUTES; PROGNOSTIC MODEL; CANCER DEATH; PRIMARY SITE; ADJUVANT; CHEMOTHERAPY; TAMOXIFEN; WOMEN; IRRADIATION; SURVIVAL AB We describe a set of web-based calculators, available at http://www.CancerMath.net, which estimate the risk of breast carcinoma death, the reduction in life expectancy, and the impact of various adjuvant treatment choices. The published SNAP method of the binary biological model of cancer metastasis uses information on tumor size, nodal status, and other prognostic factors to accurately estimate of breast cancer lethality at 15 years after diagnosis. By combining these 15-year lethality estimates with data on the breast cancer hazard function, breast cancer lethality can be estimated at each of the 15 years after diagnosis. A web-based calculator was then created to visualize the estimated lethality with and without a range of adjuvant therapy options at any of the 15 years after diagnosis, and enable conditional survival calculations. NIH population data was used to estimate non-breast-cancer chance of death. The accuracy of the calculators was tested against two large breast carcinoma datasets: 7,907 patients seen at two academic hospitals and 362,491 patients from the SEER national dataset. The calculators were found to be highly accurate and specific, as seen by their capacity for stratifying patients into groups differing by as little as a 2% risk of death, and accurately accounting for nodal status, histology, grade, age, and hormone receptor status. Our breast carcinoma calculators provide accurate and useful estimates of the risk of death, which can aid in analysis of the various adjuvant therapy options available to each patient. C1 [Michaelson, James S.] Massachusetts Gen Hosp, Lab Quantitat Med, Div Surg Oncol, Cambridge, MA 02139 USA. [Michaelson, James S.; Chen, L. Leon; Bush, Devon; Fong, Allan; Smith, Barbara] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Michaelson, James S.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Younger, Jerry] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Smith, Barbara] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Younger, Jerry] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Michaelson, James S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Michaelson, JS (reprint author), Massachusetts Gen Hosp, Lab Quantitat Med, Div Surg Oncol, Partners Res Bldg,65 Landsdowne St,Suite 205 A, Cambridge, MA 02139 USA. EM michaelj@helix.mgh.harvard.edu FU Department of Surgical Oncology at Massachusetts General Hospital FX Work in this article was supported through funds from the Department of Surgical Oncology at Massachusetts General Hospital. NR 23 TC 11 Z9 11 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2011 VL 128 IS 3 BP 827 EP 835 DI 10.1007/s10549-011-1366-9 PG 9 WC Oncology SC Oncology GA 789ZB UT WOS:000292557100025 PM 21327471 ER PT J AU Treon, SP Hanzis, C Manning, RJ Ioakimidis, L Patterson, CJ Hunter, ZR Sheehy, P Turnbull, B AF Treon, Steven P. Hanzis, Christina Manning, Robert J. Ioakimidis, Leukothea Patterson, Christopher J. Hunter, Zachary R. Sheehy, Patricia Turnbull, Barry TI Maintenance Rituximab is associated with improved clinical outcome in rituximab naive patients with Waldenstrom Macroglobulinaemia who respond to a rituximab-containing regimen SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE rituximab; Waldenstrom Macroglobulinaemia; lymphoma; maintenance; CD20 ID NON-HODGKINS-LYMPHOMA; 3RD INTERNATIONAL WORKSHOP; COOPERATIVE-ONCOLOGY-GROUP; CANCER-RESEARCH NETWORK; PHASE-II TRIAL; TREATMENT RECOMMENDATIONS; LYMPHOCYTIC LYMPHOMA; THERAPY; UPDATE; FLUDARABINE AB This study examined the outcome of 248 Waldenstrom macroglobulinaemia (WM) rituximab-naive patients who responded to a rituximab-containing regimen. Eighty-six patients (35%) subsequently received maintenance rituximab (M-Rituximab). No differences in baseline characteristics, and post-induction categorical responses between cohorts were observed. The median rituximab infusions during induction was 6 for both cohorts; and 8 over a 2-year period for patients receiving M-Rituximab. Categorical responses improved in 16/162 (10%) of observed, and 36/86 (41.8%) of M-Rituximab patients respectively, following induction therapy (P < 0 0001). Both progression-free (56.3 vs. 28.6 months; P = 0.0001) and overall survival (Not reached versus 116 months; P = 0.0095) were longer in patients who received M-Rituximab. Improved progression-free survival was evident despite previous treatment status, induction with rituximab alone or in combination therapy (P <= 0.0001). Best serum IgM response was lower (P < 0.0001), and haematocrit higher (P = 0.001) for patients receiving M-Rituximab. Among patients receiving M-Rituximab, an increased number of infectious events were observed, but were mainly <= grade 2 (P = 0.008). The findings of this observational study suggest improved clinical outcomes following M-Rituximab in WM patients who respond to induction with a rituximab-containing regimen. Prospective studies aimed at clarifying the role of M-Rituximab therapy in WM patients are needed to confirm these findings. C1 [Treon, Steven P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Turnbull, Barry] BioBridges, Boston, MA USA. RP Treon, SP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,44 Binney St, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu RI Hunter, Zachary/H-3018-2013 OI Hunter, Zachary/0000-0002-1689-1691 NR 25 TC 31 Z9 33 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2011 VL 154 IS 3 BP 357 EP 362 DI 10.1111/j.1365-2141.2011.08750.x PG 6 WC Hematology SC Hematology GA 791ET UT WOS:000292648000009 PM 21615385 ER PT J AU Trecartin, K Carroll, DL AF Trecartin, Kelly Carroll, Diane L. TI Nursing Interventions for Family Members Waiting During Cardiac Procedures SO CLINICAL NURSING RESEARCH LA English DT Article DE anxiety; family visitation; nursing intervention ID INTENSIVE-CARE-UNIT; EDUCATION-PROGRAM; NEEDS; EXPERIENCES AB Anxiety is shared by patients and family members (FMs) and can increase throughout the FMs waiting during invasive cardiac procedures (ICP). The purpose of this study was to measure the effects of an informational report (IR) and a postprocedure visit (PPV), on the anxiety of waiting FMs. There were 151 FMs assigned to 3 groups; Group 1 (50 FMs: standard of care [SOC]), Group 2 (50 FMs: SOC + IR), and Group 3 (51 FMs: SOC + IR + PPV). Pre/postvariables measured were: blood pressure (BP), heart rate (HR), skin temperature (ST), and anxiety. When comparing the BP, HR, ST, and anxiety there were no differences between groups with either SOC or IR. There was a significant reduction in anxiety, from baseline to the PPV in Group 3 (F = 10.1; p < .000). A PPV had an impact on FMs and a PPV should be incorporated as a nursing intervention during ICP. C1 [Carroll, Diane L.] Massachusetts Gen Hosp, Yvonne L Munn Ctr Nursing Res, Inst Patient Care, Boston, MA 02114 USA. [Trecartin, Kelly] Massachusetts Gen Hosp, Dept Cardiol, Knight Ctr Intervent Cardiovasc Therapy, Boston, MA 02114 USA. RP Carroll, DL (reprint author), Massachusetts Gen Hosp, Munn Ctr Nursing Res, POB 426, Boston, MA 02114 USA. EM dcarroll3@partners.org FU Patient Care Services, Massachusetts General Hospital, Boston, MA FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Yvonne L. Munn Nursing Research Award, Patient Care Services, Massachusetts General Hospital, Boston, MA. NR 21 TC 2 Z9 3 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1054-7738 J9 CLIN NURS RES JI Clin. Nurs. Res. PD AUG PY 2011 VL 20 IS 3 BP 263 EP 275 DI 10.1177/1054773811405520 PG 13 WC Nursing SC Nursing GA 790PC UT WOS:000292600700005 PM 21498782 ER PT J AU Williams, ME AF Williams, Mark E. TI The Goal of Blood Pressure Control for Prevention of Early Diabetic Microvascular Complications SO CURRENT DIABETES REPORTS LA English DT Article DE Diabetes mellitus; Microvascular complications; Hypertension; Primary prevention; Blood pressure control ID RENAL-FUNCTION; RISK-FACTORS; MICROALBUMINURIA; HYPERTENSION; NEPHROPATHY; MELLITUS; DISEASE; RETINOPATHY; PREVALENCE; INDIVIDUALS AB Lowering blood pressure may confer a benefit to diabetic microvascular complications comparable with glycemic control. Hypertension is causally related to kidney outcomes and is a risk factor for the development of diabetic retinopathy. The prevalence of hypertension increases as kidney disease progresses, so that it coexists with diabetes in up to 80% of those with overt nephropathy. A significant number of patients have hypertension or rising blood pressures in earlier stages, or even before microvascular complications appear. Because microalbuminuria markedly increases the risk of overt nephropathy as well as of cardiovascular complications, primary prevention (i.e., preventing or delaying the onset of microalbuminuria) continues to be explored, predominantly through use of renin-angiotensin blockade. Available data reviewed suggest that primary prevention through blood pressure reduction is more likely to benefit select groups (those with hypertension, cardiovascular risks, or old age). This review discusses the relationship between hypertension, diabetes, and kidney disease, the rationale for primary prevention, and the data that led to that conclusion. C1 Joslin Diabet Ctr, Renal Unit, Boston, MA 02215 USA. RP Williams, ME (reprint author), Joslin Diabet Ctr, Renal Unit, 1 Joslin Pl, Boston, MA 02215 USA. EM mark.williams@joslin.harvard.edu NR 53 TC 3 Z9 4 U1 0 U2 2 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD AUG PY 2011 VL 11 IS 4 BP 323 EP 329 DI 10.1007/s11892-011-0193-z PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 788RQ UT WOS:000292462500010 PM 21526351 ER PT J AU Stanton, RC AF Stanton, Robert C. TI Oxidative Stress and Diabetic Kidney Disease SO CURRENT DIABETES REPORTS LA English DT Article DE Oxidative stress; Reactive oxygen species; Antioxidants; Diabetic nephropathy; Mitochondrial superoxide, NAPDH oxidase; Superoxide dismutase; Catalase; Glutathione; Glucose 6-phosphate dehydrogenase; NADPH; Benfotiamine; alpha-lipoic acid; Vitamin E; Diabetic kidney disease ID ANGIOTENSIN-CONVERTING ENZYME; NADPH OXIDASES; SUPEROXIDE-DISMUTASE; INTENSIVE TREATMENT; ALDOSE REDUCTASE; BLOOD-PRESSURE; RENAL-DISEASE; RAT-KIDNEY; VITAMIN-E; NEPHROPATHY AB The number of people with diabetic kidney disease continues to increase worldwide despite current treatments. Of the pathophysiologic mechanisms that have been identified in the development and progression of diabetic nephropathy, oxidative stress (more accurately described as increased levels of reactive oxygen species; ROS) is of major importance. The increase in ROS is due to both increased production and to decreased and/or inadequate antioxidant function. To date, human clinical trials with antioxidants have not been shown to be effective. This is likely due, at least in part, to the lack of specificity of current agents. Recent research has determined both major sources of high glucose-induced cellular ROS production as well as high glucose-induced changes in antioxidant function. Treatments targeted at one or more of the specific diabetes-induced alterations in the regulation of ROS levels will likely lead to effective treatments that prevent the development and progression of diabetic kidney disease. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Stanton, RC (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM robert.stanton@joslin.harvard.edu NR 59 TC 48 Z9 63 U1 4 U2 22 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD AUG PY 2011 VL 11 IS 4 BP 330 EP 336 DI 10.1007/s11892-011-0196-9 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 788RQ UT WOS:000292462500011 PM 21557044 ER PT J AU Tanrikut, C McQuaid, JW Goldstein, M AF Tanrikut, Cigdem McQuaid, Joseph W. Goldstein, Marc TI The impact of varicocele and varicocele repair on serum testosterone SO CURRENT OPINION IN OBSTETRICS & GYNECOLOGY LA English DT Article DE androgen deficiency; hypogonadism; testosterone; varicocele; varicocelectomy ID PLASMA TESTOSTERONE; INFERTILE MEN; PARAMETERS; FERTILITY; IMPROVEMENT AB Purpose of review The increased risk of infertility in men with varicocele is well established. Varicocelectomy has been shown to improve semen parameters and increase pregnancy rates. Yet varicocele pathophysiology is poorly understood and potential implications for testosterone production are less clear. Evidence suggests that varicocele may result in lower serum testosterone levels and that varicocelectomy may, in turn, correct this deficit. Recent findings Several studies published in the past 18 months have assessed the effect of varicocele and varicocelectomy on serum testosterone levels. These include data gathered from two rat models of varicocele induction and outcomes after repair. Of additional interest is a study of serum testosterone levels in men after varicocelectomy, the first of its kind to stratify data by patient age and to address whether varicocele repair is effective in improving testosterone levels in older men. Summary Definitive statements regarding varicocele, varicocelectomy, and testosterone are difficult to make given the frequent absence of control groups and lack of sample group consistency. Despite this, recent well done animal and human studies suggest an adverse effect of varicocele on testosterone and a potential benefit of varicocele repair. Further controlled studies examining testosterone as a primary data point are required. C1 [Tanrikut, Cigdem; McQuaid, Joseph W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. [Tanrikut, Cigdem; Goldstein, Marc] Cornell Univ, Dept Urol, New York, NY 10021 USA. [Tanrikut, Cigdem; Goldstein, Marc] Cornell Univ, Inst Reprod Med, Weill Cornell Med Coll, New York, NY 10021 USA. [Goldstein, Marc] Rockefeller Univ, Populat Council, Ctr Biomed Res, New York, NY 10021 USA. RP Tanrikut, C (reprint author), MGH Fertil Ctr, 55 Fruit St,YAW 10A, Boston, MA 02114 USA. EM ctanrikut@partners.org NR 23 TC 9 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-872X J9 CURR OPIN OBSTET GYN JI Curr. Opin. Obstet. Gynecol. PD AUG PY 2011 VL 23 IS 4 BP 227 EP 231 DI 10.1097/GCO.0b013e328348a3e2 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 789EY UT WOS:000292498100003 PM 21681090 ER PT J AU Dutta, P Burlingham, WJ AF Dutta, Partha Burlingham, William J. TI Microchimerism: tolerance vs. sensitization SO CURRENT OPINION IN ORGAN TRANSPLANTATION LA English DT Review DE microchimerism; noninherited maternal antigens; T regulatory cells; tolerance ID NONINHERITED MATERNAL ANTIGENS; BONE-MARROW-TRANSPLANTATION; DOSE ORAL TOLERANCE; T-CELL; FETAL MICROCHIMERISM; ALLOGRAFT TOLERANCE; SYSTEMIC-SCLEROSIS; PERIPHERAL-BLOOD; HEALTHY WOMEN; NK CELLS AB Purpose of review The bidirectional exchange of cells, both mature and progenitor types, at the maternal-fetal interface is a common feature of mammalian reproduction. The presence of semiallogeneic cells in a host can have significant immunological effects on transplantation tolerance and rejection. Here, we review recent advances in this area. Recent findings Maternal microchimerism (MMc) in blood and various organs was found to be directly correlated with noninherited maternal antigen (NIMA)-specific CD4(+) regulatory T cells (Tregs), in F(1) backcross mice. In humans, MMc induced NIMA-specific FoxP3(+) CD4 Tregs in lymph nodes and spleen of fetuses. Tolerance to NIMA(+) allografts could be predicted in mice by measuring levels of the NIMA-specific Tregs in offspring before transplantation. On the contrary, fetal microchimerism (FMc) in multiparous female mice was largely confined to CD34(+) hematopoietic stem cells (HSCs) and was associated with sensitization rather than Treg induction. The recent discovery of a 'layered' T-cell development in humans whereby fetal HSCs are more likely to produce Tregs than adult HSCs, which may explain why MMc often induces tolerance, whereas FMc tends to induce sensitization. Summary Microchimerism may cause tolerance resulting in acceptance of an allograft bearing antigens shared by the microchimeric cells. However, microchimerism may also cause sensitization resulting in rejection. Distinguishing these effects prior to the transplant may revolutionize the field of living-related renal transplantation wherein MMc and FMc can exert a powerful influence on graft outcome. C1 [Dutta, Partha; Burlingham, William J.] Univ Wisconsin, Dept Surg, Madison, WI 53792 USA. [Dutta, Partha] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. RP Burlingham, WJ (reprint author), Univ Wisconsin, Dept Surg, H4-749 Clin Sci Ctr,600 Highland Ave, Madison, WI 53792 USA. EM burlingham@surgery.wisc.edu FU National Institutes of Health [5R01AI066219-04] FX The authors have no conflicts of interest to declare. This work was supported by grant no. 5R01AI066219-04 from National Institutes of Health (to W.J.B.). NR 55 TC 17 Z9 18 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1087-2418 J9 CURR OPIN ORGAN TRAN JI Curr. Opin. Organ Transpl. PD AUG PY 2011 VL 16 IS 4 BP 359 EP 365 DI 10.1097/MOT.0b013e3283484b57 PG 7 WC Transplantation SC Transplantation GA 792GX UT WOS:000292730700004 PM 21666480 ER PT J AU Kawai, T Cosimi, AB Sachs, DH AF Kawai, Tatsuo Cosimi, A. Benedict Sachs, David H. TI Preclinical and clinical studies on the induction of renal allograft tolerance through transient mixed chimerism SO CURRENT OPINION IN ORGAN TRANSPLANTATION LA English DT Review DE kidney transplantation; mixed chimerism; tolerance ID TOTAL LYMPHOID IRRADIATION; MEMORY T-CELLS; DONOR-SPECIFIC TOLERANCE; TRANSPLANTATION TOLERANCE; CYNOMOLGUS MONKEYS; BONE-MARROW; STEM-CELL; LYMPHOHEMATOPOIETIC CHIMERISM; KIDNEY-TRANSPLANTATION; NONHUMAN-PRIMATES AB Purpose of review The present review updates the current status of research for induction of tolerance through a mixed chimerism approach in nonhuman primates and humans. Recent findings Allograft tolerance has been successfully achieved with a nonmyeloablative conditioning regimen and donor bone marrow transplantation in human leukocyte antigen (HLA)-matched and mismatched kidney transplantation. In HLA-matched kidney transplantation, persistent mixed chimerism and renal allograft tolerance has been achieved in some patients. In HLA-mismatched combinations, induction of persistent mixed chimerism has not been achieved using a nonmyeloablative preparative regimen. Nevertheless, the transient mixed chimerism that has been achieved has resulted in long-term renal allograft tolerance in the majority of patients. Recent preclinical studies have demonstrated that the presence of heterologous memory T-cell responses observed in primates, but not in rodents, may be a major barrier for induction of durable chimerism and tolerance in primates. Strategies to overcome such memory T-cell responses may, therefore, be of great value in the development of reliable protocols for clinical tolerance induction. Summary Induction of tolerance in clinical kidney transplantation has been achieved via mixed chimerism approaches. Improvements in the consistency and safety of tolerance induction and extension of successful protocols to other organs and to organs from deceased donors will all be among the next steps in bringing tolerance to a wider range of clinical applications. C1 [Sachs, David H.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Dept Surg, Boston, MA 02129 USA. [Kawai, Tatsuo; Cosimi, A. Benedict] Massachusetts Gen Hosp, Transplant Ctr, Boston, MA 02129 USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Dept Surg, Bldg 149-9019,13th St, Boston, MA 02129 USA. EM david.sachs@tbrc.mgh.harvard.edu FU Immune Tolerance Network (NIH/NIAID) [NO1 AI1541]; NIH [5U01DK080653-04]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1U19DK080652-01] FX The present work was supported by grants from the Immune Tolerance Network (NIH/NIAID NO1 AI1541), NIH 5U01DK080653-04, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 1U19DK080652-01. NR 47 TC 20 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1087-2418 J9 CURR OPIN ORGAN TRAN JI Curr. Opin. Organ Transpl. PD AUG PY 2011 VL 16 IS 4 BP 366 EP 371 DI 10.1097/MOT.0b013e3283484b2c PG 6 WC Transplantation SC Transplantation GA 792GX UT WOS:000292730700005 PM 21666482 ER PT J AU Kim, TH Kim, BM Mao, JH Rowan, S Shivdasani, RA AF Kim, Tae-Hee Kim, Byeong-Moo Mao, Junhao Rowan, Sheldon Shivdasani, Ramesh A. TI Endodermal Hedgehog signals modulate Notch pathway activity in the developing digestive tract mesenchyme SO DEVELOPMENT LA English DT Article DE Hedgehog; Intestine; Stomach; Endoderm; Mesoderm; Notch; Hes1; Mouse ID GASTROINTESTINAL DEVELOPMENT; SONIC HEDGEHOG; INHIBITION; FATE; DIFFERENTIATION; INTESTINE; GROWTH; MORPHOGENESIS; CELLS AB The digestive tract epithelium and its adjoining mesenchyme undergo coordinated patterning and growth during development. The signals they exchange in the process are not fully characterized but include ligands of the Hedgehog (Hh) family, which originate in the epithelium and are necessary for mesenchymal cells to expand in number and drive elongation of the developing gut tube. The Notch signaling pathway has known requirements in fetal and adult intestinal epithelial progenitors. We detected Notch pathway activity in the embryonic gut mesenchyme and used conditional knockout mice to study its function. Selective disruption of the Notch effector gene RBP-J kappa (Rbpj) in the mesenchyme caused progressive loss of subepithelial fibroblasts and abbreviated gut length, revealing an unexpected requirement in this compartment. Surprisingly, constitutive Notch activity also induced rapid mesenchymal cell loss and impaired organogenesis, probably resulting from increased cell death and suggesting the need for a delicate balance in Notch signaling. Because digestive tract anomalies in mouse embryos with excess Notch activity phenocopy the absence of Hh signaling, we postulated that endodermal Hh restrains mesenchymal Notch pathway activity. Indeed, Hh-deficient embryos showed Notch overactivity in their defective gut mesenchyme and exposure to recombinant sonic hedgehog could override Notch-induced death of cultured fetal gut mesenchymal cells. These results reveal unexpected interactions between prominent signals in gastrointestinal development and provide a coherent explanation for Hh requirements in mesenchymal cell survival and organ growth. C1 [Kim, Tae-Hee; Kim, Byeong-Moo; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kim, Tae-Hee; Kim, Byeong-Moo; Rowan, Sheldon; Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Kim, Tae-Hee; Kim, Byeong-Moo; Rowan, Sheldon; Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mao, Junhao] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01655 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM ramesh_shivdasani@dfci.harvard.edu FU National Institutes of Health [R01DK081113]; Dana-Farber/Harvard Cancer Center [P50CA127003] FX We thank W. Zimmer, S. Artavanis-Tsakonas and T. Honjo for sharing mouse lines; A. McMahon for in situ hybridization probes and recombinant Shh; and N. Brown for the generous gift of Hes1 antibody. Supported by National Institutes of Health grant R01DK081113 (R. A. S.), a gift from the Caring for Carcinoid Foundation, and the Dana-Farber/Harvard Cancer Center SPORE Program in GI Cancers (P50CA127003). Deposited in PMC for release after 12 months. NR 32 TC 15 Z9 15 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 AUG 1 PY 2011 VL 138 IS 15 BP 3225 EP 3233 DI 10.1242/dev.066233 PG 9 WC Developmental Biology SC Developmental Biology GA 791AO UT WOS:000292632400013 PM 21750033 ER PT J AU Xia, Y Chen, Y Lu, H Brown, D Lin, H AF Xia, Yin Chen, Ying Lu, Hua Brown, Dennis Lin, Herbert TI The BMP co-receptor Dragon is required for normal renal branching morphogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 70th Annual Meeting of the Society-for-Developmental-Biology CY JUL 21-25, 2011 CL Chicago, IL SP Soc Dev Biol C1 [Xia, Yin] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Chen, Ying; Lu, Hua; Brown, Dennis; Lin, Herbert] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 2011 VL 356 IS 1 MA 117 BP 142 EP 142 DI 10.1016/j.ydbio.2011.05.141 PG 1 WC Developmental Biology SC Developmental Biology GA 792XT UT WOS:000292784400116 ER PT J AU Komatsu, Y Yu, P Kamiya, N Mishina, Y AF Komatsu, Yoshihiro Yu, Paul Kamiya, Nobuhiro Mishina, Yuji TI Augmentation of Smad-dependent BMP signaling in cranial neural crests causes craniosynostosis in mice SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 70th Annual Meeting of the Society-for-Developmental-Biology CY JUL 21-25, 2011 CL Chicago, IL SP Soc Dev Biol C1 [Komatsu, Yoshihiro; Kamiya, Nobuhiro; Mishina, Yuji] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. [Yu, Paul] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 2011 VL 356 IS 1 MA 186 BP 162 EP 162 DI 10.1016/j.ydbio.2011.05.600 PG 1 WC Developmental Biology SC Developmental Biology GA 792XT UT WOS:000292784400183 ER PT J AU Lancman, JJ Suzuki, T Hasso, SM Li, YN Chiang, C Fallon, JF AF Lancman, Joseph J. Suzuki, Takayuki Hasso, Sean M. Li, Yina Chiang, Chin Fallon, John F. TI Molecular regulation of the formation of the Phalanx Forming Region (PFR) at autopod stages of limb development SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 70th Annual Meeting of the Society-for-Developmental-Biology CY JUL 21-25, 2011 CL Chicago, IL SP Soc Dev Biol C1 [Lancman, Joseph J.] Sanford Burnham Med Res Inst, La Jolla, CA USA. [Suzuki, Takayuki] Nagoya Univ, Nagoya, Aichi 4648601, Japan. [Hasso, Sean M.] Childrens Hosp, Boston, MA 02115 USA. [Li, Yina] Massachusetts Gen Hosp, Charlestown, MA USA. [Chiang, Chin] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Fallon, John F.] Univ Wisconsin, Dept Anat, Madison, WI 53706 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 2011 VL 356 IS 1 MA 219 BP 170 EP 171 DI 10.1016/j.ydbio.2011.05.633 PG 2 WC Developmental Biology SC Developmental Biology GA 792XT UT WOS:000292784400213 ER PT J AU White, YAR Woods, DC Wood, AW AF White, Yvonne A. R. Woods, Dori C. Wood, Antony W. TI A Transgenic Zebrafish Model of Targeted Oocyte Ablation and de novo Oogenesis SO DEVELOPMENTAL DYNAMICS LA English DT Article DE zebrafish; oogenesis; transgenics; ovary; oocyte; stem cell; ablation ID GERMINAL EPITHELIUM; HEART REGENERATION; ADULT ZEBRAFISH; RAINBOW-TROUT; ONCORHYNCHUS-MYKISS; FIN REGENERATION; GENE-EXPRESSION; CELL ABLATION; SEX REVERSAL; DANIO-RERIO AB We describe here a novel transgenic zebrafish, Tg(zpc:G4VP16/UAS:nfsB-mCherry) that effectively demonstrates the targeted oocyte ablation in the adult zebrafish ovary. This transgenic line expresses bacterial nitroreductase enzyme (nfsB) under the control of the oocyte-specific zona pellucida C (zpc) gene promoter. Adult transgenic females exposed to the prodrug metronidazole demonstrated near-complete ablation of growing oocytes, resulting in ovarian degeneration and complete cessation of reproductive function. Within 4 weeks of prodrug removal, treated fish demonstrated complete anatomical regeneration of the ovary and, within 7 weeks, ovarian function (fertility) was fully restored. Together, these results demonstrate functional renewal of the oocyte pool in the adult zebrafish ovary. Accordingly, this transgenic zebrafish model system provides a novel means to investigate ovarian growth dynamics in a genetically tractable vertebrate, and may be useful for evaluating signaling interactions that regulate gonadal development processes such as de novo oogenesis. Developmental Dynamics 240:1929-1937, 2011. (C) 2011 Wiley-Liss, Inc. C1 [White, Yvonne A. R.; Woods, Dori C.; Wood, Antony W.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. [White, Yvonne A. R.; Woods, Dori C.; Wood, Antony W.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP White, YAR (reprint author), Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. EM yabrown@partners.org FU Vincent Memorial Research Funds; Ruth L. Kirschstein National Research Service [F32-AG034809] FX Grant sponsor: Vincent Memorial Research Funds; Ruth L. Kirschstein National Research Service Award; Grant number: F32-AG034809. NR 38 TC 12 Z9 13 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD AUG PY 2011 VL 240 IS 8 BP 1929 EP 1937 DI 10.1002/dvdy.22695 PG 9 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 792TH UT WOS:000292772400006 PM 21761478 ER PT J AU Wingert, RA Davidson, AJ AF Wingert, Rebecca A. Davidson, Alan J. TI Zebrafish Nephrogenesis Involves Dynamic Spatiotemporal Expression Changes in Renal Progenitors and Essential Signals From Retinoic Acid and irx3b SO DEVELOPMENTAL DYNAMICS LA English DT Article DE kidney organogenesis; nephron; segmentation; zebrafish ID KIDNEY DEVELOPMENT; IROQUOIS GENES; NO-TAIL; NEPHRON; TRANSCRIPTION; SEGMENTATION; PRONEPHROS; REVEALS; REQUIREMENT; MUTATIONS AB Kidney nephrons are composed of proximal and distal tubule segments that perform unique roles in excretion. The developmental pathways that establish nephron segment identities from renal progenitors are poorly understood. Here, we used the zebrafish pronephros to study nephron segmentation. We found that zebrafish nephron progenitors undergo elaborate spatiotemporal expression changes of many genes before adopting a segment fate. Initially, two domains of nephron progenitors are established, then are subdivided and demarcate individual nephron segments. Using genetic and chemical genetic models of retinoic acid (RA) deficiency, we discovered that RA modulates rostral progenitor formation. To delineate downstream pathways, we knocked down the irx3b transcription factor and found it regulates proximal tubule segment size and distal segment differentiation. Our results suggest a model whereby RA patterns the early field of nephron progenitors, with subsequent factors like irx3b acting to refine later progenitor subdomains and ensure activation of segment-specific gene programs. Developmental Dynamics 240:2011-2027, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Wingert, Rebecca A.; Davidson, Alan J.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Wingert, Rebecca A.; Davidson, Alan J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wingert, Rebecca A.; Davidson, Alan J.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Davidson, AJ (reprint author), Univ Auckland, Dept Mol Med & Pathol, Sch Med Sci, Private Bag 92019, Auckland 1142, New Zealand. EM a.davidson@auckland.ac.nz FU Polycystic Kidney Foundation [160a2f]; NIH-NIDDK [K01DK083512, R01DK077186]; Harvard Stem Cell Institute FX Grant sponsor: Polycystic Kidney Foundation; Grant number: 160a2f; Grant sponsor: NIH-NIDDK; Grant numbers: K01DK083512, R01DK077186.; R.A.W. thanks the staff of the Center for Zebrafish Research at the University of Notre Dame for providing ongoing husbandry of the lib zebrafish strain. R. A. W. was supported by the Polycystic Kidney Foundation, a Harvard Stem Cell Institute Seed Grant, and an NIH-NIDDK award. A.J.D. was supported by a NIH-NIDDK award and grants from the Harvard Stem Cell Institute. NR 38 TC 40 Z9 40 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD AUG PY 2011 VL 240 IS 8 BP 2011 EP 2027 DI 10.1002/dvdy.22691 PG 17 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 792TH UT WOS:000292772400014 PM 21761484 ER PT J AU Liu, Z Stanojevic, V Avadhani, S Yano, T Habener, JF AF Liu, Z. Stanojevic, V. Avadhani, S. Yano, T. Habener, J. F. TI Stromal cell-derived factor-1 (SDF-1)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis activation induces intra-islet glucagon-like peptide-1 (GLP-1) production and enhances beta cell survival SO DIABETOLOGIA LA English DT Article DE Alpha cells; Chemokine (C-X-C motif) receptor 4; Diabetes; GLP-1; Islets; Prohormone convertase; SDF-1; Stromal cell-derived factor-1 ID PANCREATIC ALPHA-CELLS; PROGENITOR CELLS; CONVERTASE 1/3; NEONATAL-RAT; STEM-CELLS; MICE; STREPTOZOTOCIN; APOPTOSIS; REGENERATION; EXPRESSION AB The endogenous production of stromal cell-derived factor-1 (SDF-1) in beta cells in transgenic mice attenuates the development of diabetes in response to streptozotocin. Here we propose that beta cell injury induces SDF-1 production, and the SDF-1/chemokine (C-X-C motif) receptor 4 (CXCR4) interaction auto-activates Sdf1 expression, resulting in the autocrine production of SDF-1 by beta cells and the paracrine activation of glucagon-like peptide-1 (GLP-1) production by alpha cells. SDF-1 production in adult mouse and human islets and rat INS-1 cells was measured in models of beta cell injury. The paracrine actions of SDF-1 on GLP-1 production in alpha cells were explored. The potential synergism between the growth-promoting actions of GLP-1 and the pro-survival actions of SDF-1 on the preservation of cell mass was evaluated by cell viability assays. In adult islets and INS-1 cells, Sdf1 expression was re-induced in response to injury. The interaction of SDF-1 with its receptor on alphaTC1 cells activated protein kinase Akt, stimulated cell proliferation and induced the expression of prohormone convertase 1/3 and the consequent production of GLP-1 in alpha cells. The combination of GLP-1 and SDF-1 additively enhanced both the growth and longevity of INS-1 beta cells. The results of these studies suggest that in response to beta cell injury and the ensuing induction of SDF-1, the biological function of alpha cells switches from the production of glucagon to the provision of the local growth factor GLP-1 which, in combination with SDF-1, promotes the growth, survival and viability of the beta cells. C1 [Liu, Z.; Stanojevic, V.; Avadhani, S.; Yano, T.; Habener, J. F.] Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. RP Habener, JF (reprint author), Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. EM jhabener@partners.org FU Juvenile Diabetes Research Foundation; Charles H. Hood Foundation of the Medical Research Foundation FX We thank K. McManus and L. Brindamour for expert experimental assistance. We thank M. Hara and D. F. Steiner for the generous gift of the PC1/3 antiserum. The studies were supported in part by research grants (J. F. Habener) and a postdoctoral fellowship (Z. Liu) from the Juvenile Diabetes Research Foundation and a grant from the Charles H. Hood Foundation of the Medical Research Foundation to Z. Liu. NR 40 TC 38 Z9 40 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2011 VL 54 IS 8 BP 2067 EP 2076 DI 10.1007/s00125-011-2181-x PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 790BC UT WOS:000292562500016 PM 21567300 ER PT J AU Shetty, GK Matarese, G Magkos, F Moon, HS Liu, XW Brennan, AM Mylvaganam, G Sykoutri, D DePaoli, AM Mantzoros, CS AF Shetty, Greeshma K. Matarese, Giuseppe Magkos, Faidon Moon, Hyun-Seuk Liu, Xiaowen Brennan, Aoife M. Mylvaganam, Geetha Sykoutri, Despina DePaoli, Alex M. Mantzoros, Christos S. TI Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID RECOMBINANT HUMAN LEPTIN; NEUROENDOCRINE ADAPTATIONS; GENERALIZED LIPODYSTROPHY; REPLACEMENT THERAPY; FOLLOW-UP; PEG-OB; EFFICACY; DEFICIENCY; STARVATION; HUMANS AB Objective: Short-term energy deprivation reduces leptin concentrations and alters the levels of circulating hormones of the hypothalamic-pituitary-peripheral axis in lean subjects. Whether the reduction in leptin concentration during long-term weight loss in obese individuals is linked to the same neuroendocrine changes seen in lean, leptin-sensitive subjects remains to be fully clarified. Methods: In this study, 24 overweight and obese adults (16 women and eight men; body mass index (BMI): 27.5-38.0 kg/m(2)) were prescribed a hypocaloric diet (-500 kcal/day) and were randomized to receive recombinant methionyl leptin (n = 18, metreleptin, 10 mg/day self-injected s.c.) or placebo (n = 6, same volume and time as metreleptin) for 6 months. Results: Metreleptin administration did not affect weight loss beyond that induced by hypocaloric diet alone (P for interaction = 0.341) but increased the serum concentrations of total leptin by six-to eight-fold (P<0.001) and led to the generation of anti-leptin antibodies. Despite free leptin concentration (P for interaction = 0.041) increasing from 9 +/- 1 ng/ml at baseline to 43 +/- 15 and 36 +/- 12 ng/ml at 3 and 6 months, respectively, changes in circulating hormones of the thyroid and IGF axes at 3 and 6 months were not significantly different in the placebo-and metreleptin-treated groups. Conclusions: Leptin does not likely mediate changes in neuroendocrine function in response to weight loss induced by a mild hypocaloric diet in overweight and obese subjects. C1 [Shetty, Greeshma K.; Magkos, Faidon; Moon, Hyun-Seuk; Liu, Xiaowen; Brennan, Aoife M.; Mylvaganam, Geetha; Sykoutri, Despina; Mantzoros, Christos S.] Harvard Univ, Sch Med, Div Endocrinol Diabet & Metab, Cambridge, MA 02138 USA. [Shetty, Greeshma K.; Magkos, Faidon; Moon, Hyun-Seuk; Liu, Xiaowen; Brennan, Aoife M.; Mylvaganam, Geetha; Sykoutri, Despina; Mantzoros, Christos S.] Harvard Univ, Sch Publ Hlth, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Matarese, Giuseppe] Consiglio Nazl Ric IEOS CNR, Ist Endocrinol & Oncol Sperimentale, Immunol Lab, Naples, Italy. [DePaoli, Alex M.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Mantzoros, Christos S.] Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA USA. RP Mantzoros, CS (reprint author), Harvard Univ, Sch Med, Div Endocrinol Diabet & Metab, Cambridge, MA 02138 USA. EM cmantzor@bidmc.harvard.edu RI Moon, Hyun-Seuk/G-8576-2015; OI Moon, Hyun-Seuk/0000-0002-5216-2090; Matarese, Giuseppe/0000-0001-9429-0616 FU National Institutes of Health [F32 DK6455001A1, DK081913, DK79929, DK58785, AG032030]; European Union [202579]; Telethon-JDRF [GJT08004]; Beth Israel Deaconess Medical Center. Amgen, Inc. FX This study was an investigator-initiated research protocol and was supported by National Institutes of Health grants F32 DK6455001A1 (to G K Shetty), DK081913, DK79929, DK58785, and AG032030 (to C S Mantzoros); the European Union Ideas Program, ERC-Starting Independent Grant `LeptinMS' n. 202579 and Telethon-JDRF Grant n. GJT08004 (to G Matarese); and a discretionary grant from Beth Israel Deaconess Medical Center. Amgen, Inc. (Thousand Oaks, CA, USA) supplied A-100 r-metHuLeptin (currently `metreleptin' by Amylin Pharmaceuticals, Inc.) for this study and approved the design of the study but had no role in the study design; conduct of the study; collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. NR 28 TC 22 Z9 22 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD AUG PY 2011 VL 165 IS 2 BP 249 EP 254 DI 10.1530/EJE-11-0252 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 792FY UT WOS:000292727400009 PM 21602313 ER PT J AU Sonnenberg, A AF Sonnenberg, Amnon TI Gambles of gastroenterology SO EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Article DE medical decision analysis; modeling; outcome research; probability theory; side-effects of medical interventions; threshold analysis AB Background Diagnostic and therapeutic procedures of gastroenterology can frequently tax a patient's health. In addition to the risk of side-effects such procedures may also reduce the patient's well-being. The probability of achieving cure depends on the interplay between the patient's initial health status and the expected efficacy of the gastroenterological interventions. Methods The mathematical concept of the 'gambler's ruin' from probability theory is used to model the interplay among the various factors affecting clinical outcome. Results The model illustrates in a quantitative manner how the physician's ultimate success in achieving cure depends on a given patient's initial health status, and the characteristics of the interventional procedures used. The analysis also illustrates that in some dire clinical situations, risking the patient's life in one single and bold step can yield a better overall outcome than trying to advance the patient's health by multiple small and cautious steps. Conclusion Using the gambler's ruin as a model for medical risk taking could contribute to medical teaching and promote the understanding of the some general principles that shape many clinical decisions in gastroenterology. Eur J Gastroenterol Hepatol 23: 651-655 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Sonnenberg, Amnon] Portland VA Med Ctr, Portland, OR USA. [Sonnenberg, Amnon] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr P3 GI, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-691X J9 EUR J GASTROEN HEPAT JI Eur. J. Gastroenterol. Hepatol. PD AUG PY 2011 VL 23 IS 8 BP 651 EP 655 DI 10.1097/MEG.0b013e328347afac PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 789GK UT WOS:000292503100003 PM 21623189 ER PT J AU Branco-de-Almeida, LS Kajiya, M Cardoso, CR Silva, MJB Ohta, K Rosalen, PL Franco, GCN Han, XZ Taubman, MA Kawai, T AF Branco-de-Almeida, Luciana S. Kajiya, Mikihito Cardoso, Cristina R. Silva, Marcelo J. B. Ohta, Kouji Rosalen, Pedro L. Franco, Gilson C. N. Han, Xiaozhe Taubman, Martin A. Kawai, Toshihisa TI Selective serotonin reuptake inhibitors attenuate the antigen presentation from dendritic cells to effector T lymphocytes SO FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY LA English DT Article DE Fluoxetine; serotonin (5-HT); dendritic cells; antigen presentation; ICOS-L; CD86 ID KAPPA-B LIGAND; PERIODONTAL-DISEASE; INTERFERON-GAMMA; BONE-RESORPTION; RECEPTOR ACTIVATOR; IMMUNE-RESPONSE; ANTIDEPRESSANTS; FLUOXETINE; EXPRESSION; ICOS AB Fluoxetine, one of the selective serotonin reuptake inhibitors (SSRIs), has been found to possess immune modulation effects, in addition to its antidepressant effects. However, it remains unclear whether SSRIs can suppress the antigen-presenting function of dendritic cells (DCs). Therefore, Fluoxetine was applied to a co-culture of Aggregatibacter actinomycetemcomitans (Aa)-reactive T cells (x Aa-T) isolated from Aa-immunized mice and DCs. This resulted in the suppressed proliferation of x Aa-T stimulated with Aa-antigen presentation by DCs. Specifically, Fluoxetine increased the extracellular 5-hydroxytryptamine (5-HT) in the x Aa-T/DC co-culture, whereas exogenously applied 5-HT promoted T-cell proliferation in the x Aa-T/DC co-culture, indicating that Fluoxetine-mediated suppression of x Aa-T/DC responses cannot be attributed to extracellular 5-HT. Instead, Fluoxetine remarkably suppressed the expression of costimulatory molecule ICOS-L on DCs. Fluoxetine also promoted a greater proportion of CD86(Low) immature DCs than CD86(High) mature DCs, while maintaining the expression levels of CD80, MHC-class-II and PD-L1. These results suggested that Fluoxetine suppressed the ability of DCs to present bacterial antigens to T cells, and the resulting T-cell proliferation, in a SERT/5-HT-independent manner and that diminished expression of ICOS-L on DCs and increase of CD86(Low) immature DCs caused by Fluoxetine might be partially associated with Fluoxetine-mediated suppression of DC/T-cell responses. C1 [Branco-de-Almeida, Luciana S.; Kajiya, Mikihito; Cardoso, Cristina R.; Silva, Marcelo J. B.; Ohta, Kouji; Han, Xiaozhe; Taubman, Martin A.; Kawai, Toshihisa] Forsyth Inst, Dept Immunol, Boston, MA USA. [Branco-de-Almeida, Luciana S.; Rosalen, Pedro L.] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Physiol Sci, Campinas, SP, Brazil. [Kajiya, Mikihito; Ohta, Kouji; Kawai, Toshihisa] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Cardoso, Cristina R.] Univ Fed Triangulo Mineiro, Dept Biol Sci, Uberaba, MG, Brazil. [Franco, Gilson C. N.] Univ Taubate, Dept Oral Biol, Taubate, SP, Brazil. RP Kawai, T (reprint author), Forsyth Inst, Dept Immunol, 245 1st St Cambridge, Cambridge, MA 02142 USA. EM tkawai@forsyth.org RI Rosalen, Pedro/I-3718-2012; Franco, Gilson/F-9312-2012; Branco-de-Almeida, Luciana /J-8946-2012; Silva, Marcelo/J-4298-2012 OI Silva, Marcelo/0000-0002-5807-4286 FU NIH, National Institute of Dental and Craniofacial Research [DE-03420, DE-18499, DE-19917]; Brazilian Government Agencies [FAPESP 2008/00566, 6PDEE/CAPES-BEX 4073/08-8] FX This study was supported in part by NIH grants DE-03420, DE-18499 and DE-19917 from the National Institute of Dental and Craniofacial Research. The authors thank the Brazilian Government Agencies for fellowships to L. S. B.-A. (FAPESP 2008/00566 and 6PDEE/CAPES-BEX 4073/08-8). NR 51 TC 9 Z9 10 U1 1 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0928-8244 J9 FEMS IMMUNOL MED MIC JI FEMS Immunol. Med. Microbiol. PD AUG PY 2011 VL 62 IS 3 BP 283 EP 294 DI 10.1111/j.1574-695X.2011.00816.x PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 792UM UT WOS:000292775900004 PM 21569123 ER PT J AU Payer, B Lee, JT Namekawa, SH AF Payer, Bernhard Lee, Jeannie T. Namekawa, Satoshi H. TI X-inactivation and X-reactivation: epigenetic hallmarks of mammalian reproduction and pluripotent stem cells SO HUMAN GENETICS LA English DT Review ID SEX-CHROMOSOME INACTIVATION; PRIMORDIAL GERM-CELLS; EARLY MOUSE DEVELOPMENT; XIST RNA; DOSAGE COMPENSATION; FACULTATIVE HETEROCHROMATIN; MEIOTIC CHROMOSOMES; NONCODING RNA; CENTER REGION; ES CELLS AB X-chromosome inactivation is an epigenetic hallmark of mammalian development. Chromosome-wide regulation of the X-chromosome is essential in embryonic and germ cell development. In the male germline, the X-chromosome goes through meiotic sex chromosome inactivation, and the chromosome-wide silencing is maintained from meiosis into spermatids before the transmission to female embryos. In early female mouse embryos, X-inactivation is imprinted to occur on the paternal X-chromosome, representing the epigenetic programs acquired in both parental germlines. Recent advances revealed that the inactive X-chromosome in both females and males can be dissected into two elements: repeat elements versus unique coding genes. The inactive paternal X in female preimplantation embryos is reactivated in the inner cell mass of blastocysts in order to subsequently allow the random form of X-inactivation in the female embryo, by which both Xs have an equal chance of being inactivated. X-chromosome reactivation is regulated by pluripotency factors and also occurs in early female germ cells and in pluripotent stem cells, where X-reactivation is a stringent marker of naive ground state pluripotency. Here we summarize recent progress in the study of X-inactivation and X-reactivation during mammalian reproduction and development as well as in pluripotent stem cells. C1 [Payer, Bernhard; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Payer, Bernhard; Lee, Jeannie T.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Payer, Bernhard; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Namekawa, Satoshi H.] Univ Cincinnati, Coll Med, Div Reprod Sci,Dept Pediat, Perinatal Inst,Cincinnati Childrens Hosp,Med Ctr, Cincinnati, OH USA. RP Payer, B (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM payer@molbio.mgh.harvard.edu; satoshi.namekawa@cchmc.org RI Payer, Bernhard/F-7353-2010 OI Payer, Bernhard/0000-0002-4694-2082 FU International Human Frontier Science Program Organization (HFSP); NIH [RO1-GM58839]; Cincinnati Children's Hospital Medical Center FX We thank Yuya Ogawa, Yesu Jeon and Ho-Su Sin for critical reading and Erin L. Adams for editing of the manuscript. This work was supported by a fellowship of the International Human Frontier Science Program Organization (HFSP) to B. P., an NIH grant (RO1-GM58839) to J.T.L, and the Developmental Fund and Trustee Grant at Cincinnati Children's Hospital Medical Center to S.H.N. J.T.L. is an investigator of the Howard Hughes Medical Institute. NR 140 TC 35 Z9 36 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD AUG PY 2011 VL 130 IS 2 BP 265 EP 280 DI 10.1007/s00439-011-1024-7 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 790BE UT WOS:000292562700011 PM 21667284 ER PT J AU Yildiz, A Vieta, E Tohen, M Baldessarini, RJ AF Yildiz, Aysegul Vieta, Eduard Tohen, Mauricio Baldessarini, Ross J. TI Factors modifying drug and placebo responses in randomized trials for bipolar mania SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Bipolar I disorder; mania; meta-analysis; placebo response; randomized controlled trials ID RELEASE CARBAMAZEPINE CAPSULES; SODIUM EXTENDED-RELEASE; DOUBLE-BLIND; CLINICAL-TRIALS; MIXED EPISODES; ARIPIPRAZOLE MONOTHERAPY; RISPERIDONE MONOTHERAPY; MOOD DISORDERS; I DISORDER; MULTICENTER AB Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for bipolar mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects' age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo-treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95% CI 5.77-7.76) and ineffective (7.61, 95% CI 5.47-8.75) drugs. Lesser placebo responses (MD) and greater drug-placebo differences (Hedges' g) were associated with fewer study sites, younger patients' age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drug-associated improvement (MD) and drug-placebo contrast (Hedges' g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for mania, fewer sites may limit placebo response and enhance drug-placebo contrasts. C1 [Yildiz, Aysegul] Dokuz Eylul Univ, Dept Psychiat, Izmir, Turkey. [Yildiz, Aysegul; Vieta, Eduard; Tohen, Mauricio; Baldessarini, Ross J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Yildiz, Aysegul; Vieta, Eduard; Tohen, Mauricio; Baldessarini, Ross J.] Massachusetts Gen Hosp, Int Consortium Bipolar Disorder Res, McLean Div, Boston, MA 02114 USA. [Vieta, Eduard] Univ Barcelona, Bipolar Disorders Program, Inst Clin Neurosci, Hosp Clin,IDIBAPS,CIBERSAM, Barcelona, Spain. [Tohen, Mauricio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Yildiz, A (reprint author), Dokuz Eylul Univ Inciralti, Dept Psychiat, Izmir, Turkey. EM agul_yildiz@hotmail.com RI Vieta, Eduard/I-6330-2013 OI Vieta, Eduard/0000-0002-0548-0053 FU Spanish Ministry of Science and Innovation [PR 2007-0358]; Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM); Bruce J. Anderson Foundation; McLean Private Donors' Research Fund FX This work was supported, in part, by the Spanish Ministry of Science and Innovation (PR 2007-0358), Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM) (to E.V.); by a grant from the Bruce J. Anderson Foundation and the McLean Private Donors' Research Fund (to R.J.B.). The sponsors had no influence on conduct, analysis, or report. Dr Aysegul Yildiz made meta-analytical calculations. Seren Ozer, B.Sc. made valuable contributions to study identification and selection, and data extraction. For providing unpublished information, we thank Drs Charles Bowden, Paul Keck Jr., Roger McIntyre, Harrison G. Pope Jr., Steven Potkin, Richard Weisler, and their colleagues, as well as clinical investigators or other representatives of Abbott, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Johnson & Johnson, Novartis, and Pfizer Pharmaceutical Corporations.; Dr Yildiz has received research grants from and/or served as a consultant or speaker for Actavis, Ali-Raif, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Pfizer, Sanofi-Aventis, and Servier Corporations. Dr Vieta has received grant support, speakers' honoraria, or has been an advisor to Almirall, AstraZeneca, Bristol-Meyer Squibb, Ei Lilly, Forest, GlaxoSmithKline, Janssen-Cilag, Jazz, Johnson & Johnson, Merck, Novartis, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Takeda, United BioSource, and Wyeth Corporations, but neither he nor family members hold equity positions in pharmaceutical or biomedical corporations. Dr Tohen is a former employee of Eli Lilly (2008). He has acted as consultant or speaker for the following companies: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Otzuka, Sepracor and Wyeth; his spouse is a current Eli Lilly employee and minor stockholder. NR 62 TC 24 Z9 24 U1 1 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD AUG PY 2011 VL 14 IS 7 BP 863 EP 875 DI 10.1017/S1461145710001641 PG 13 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 790UJ UT WOS:000292614400001 PM 21299919 ER PT J AU Levkovitz, Y Rabany, L Harel, EV Zangen, A AF Levkovitz, Yechiel Rabany, Liron Harel, Eiran Vadim Zangen, Abraham TI Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: a feasibility study SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Cognition; negative symptoms; schizophrenia; transcranial magnetic stimulation ID BRAIN-REGIONS; RTMS; COIL AB Treatment for negative symptoms and cognitive deficits, core elements of schizophrenia, remains inadequate. Stimulation of the prefrontal cortex via transcranial magnetic stimulation (TMS) yields only moderate results, possibly due to limited stimulation depth. Deep-TMS enables deeper and wider stimulation than before. This preliminary study is the first to examine deep-TMS as a possible add-on treatment for negative symptoms and cognitive deficits of schizophrenia. The effect of 20 daily deep-TMS sessions (20 Hz, 120% motor threshold) over the prefrontal cortex of 15 patients indicated improvement in cognition and negative symptoms that was maintained at 2-wk post-treatment follow-up. C1 [Levkovitz, Yechiel; Rabany, Liron; Harel, Eiran Vadim] Shalvata Mental Hlth Care Ctr, Emot Cognit Res Ctr, Hod Hasharon, Israel. [Levkovitz, Yechiel; Rabany, Liron; Harel, Eiran Vadim] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Levkovitz, Yechiel] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rabany, Liron] Tel Aviv Univ, Gordon Fac Social Sci, IL-69978 Tel Aviv, Israel. [Zangen, Abraham] Weitzman Inst Sci, Dept Neurobiol, Rehovot, Israel. RP Levkovitz, Y (reprint author), Shalvata Mental Hlth Care Ctr, Emot Cognit Res Ctr, Hod Hasharon, Israel. EM levkovit@netvision.net.il NR 25 TC 31 Z9 35 U1 0 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD AUG PY 2011 VL 14 IS 7 BP 991 EP 996 DI 10.1017/S1461145711000642 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 790UJ UT WOS:000292614400011 PM 21524336 ER PT J AU Koh, AE Njoroge, SW Feliu, M Cook, A Selig, MK Latchman, YE Sharpe, AH Colvin, RB Paul, E AF Koh, Anna E. Njoroge, Sarah W. Feliu, Marianela Cook, Alexis Selig, Martin K. Latchman, Yvette E. Sharpe, Arlene H. Colvin, Robert B. Paul, Elahna TI The SLAM family member CD48 (Slamf2) protects lupus-prone mice from autoimmune nephritis SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE CD48 (Slamf2); Lupus nephritis; Anti-DNA autoantibodies; Systemic lupus erythematosus; Murine lupus; Sle1b ID NATURAL-KILLER-CELLS; T-CELL; MURINE LUPUS; LYMPHOPROLIFERATIVE DISEASE; 2B4/CD48 INTERACTIONS; SUSCEPTIBILITY LOCUS; IMMUNE-RESPONSES; NK-CELLS; ERYTHEMATOSUS; RECEPTOR AB Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains (i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 (Slam) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48(-/-)). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD484(-/-)) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in subendothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low-grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48(-/-) animals, neither BALB.129CD48(-/-) mice nor B6 x BALB/c F1.129CD48(-/-) progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Koh, Anna E.; Njoroge, Sarah W.; Feliu, Marianela; Cook, Alexis; Paul, Elahna] Harvard Univ, Sch Med, Div Pediat Nephrol, Boston, MA 02114 USA. [Koh, Anna E.; Njoroge, Sarah W.; Feliu, Marianela; Cook, Alexis; Selig, Martin K.; Colvin, Robert B.; Paul, Elahna] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Selig, Martin K.; Colvin, Robert B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Latchman, Yvette E.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Latchman, Yvette E.; Sharpe, Arlene H.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Paul, E (reprint author), Harvard Univ, Sch Med, Div Pediat Nephrol, YAW 6C,55 Fruit St, Boston, MA 02114 USA. EM aekoh417@gmail.com; sarah.w.njoroge@vanderbilt.edu; feliu20m@mtholyoke.edu; acook3@partners.org; mselig@partners.org; yvettel@psbcresearch.org; arlene_sharpe@hms.harvard.edu; colvin@helix.mgh.harvard.edu; epaul@partners.org FU Lupus Research Institute; NIH [R01DK079989, P01AI-065687] FX We thank Tricia Della Pelle for technical support and Harald Jueppner and Adam Lacy-Hulbert for critical reading of the manuscript. This work was supported by awards from the Lupus Research Institute and NIH R01DK079989 to EP and NIH P01AI-065687 to AHS and YEL. NR 34 TC 16 Z9 16 U1 0 U2 2 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 AUG PY 2011 VL 37 IS 1 BP 48 EP 57 DI 10.1016/j.jaut.2011.03.004 PG 10 WC Immunology SC Immunology GA 792CC UT WOS:000292717100007 PM 21561736 ER PT J AU Goergen, CJ Sosnovik, DE AF Goergen, Craig J. Sosnovik, David E. TI From Molecules to Myofibers: Multiscale Imaging of the Myocardium SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH LA English DT Article DE MRI; Myocardium; Molecular imaging; Microstructure; Fluorescence; Diffusion MRI ID DIFFUSION TENSOR MRI; MAGNETIC-RESONANCE; IN-VIVO; INFARCTED MYOCARDIUM; PROTEASE ACTIVITY; CONTRAST AGENTS; TRACTOGRAPHY; NANOPARTICLE; HEART; MYELOPEROXIDASE AB Pathology in the heart can be examined at several scales, ranging from the molecular to the macroscopic. Traditionally, fluorescence-based techniques such as flow cytometry have been used to study the myocardium at the molecular, cellular, and microscopic levels. Recent advances in magnetic resonance imaging (MRI), however, have made it possible to image certain cellular and molecular events in the myocardium noninvasively in vivo. In addition, diffusion MRI has been used to image myocardial fiber architecture and microstructure in the intact heart. Diffusion MRI tractography, in particular, is providing novel insights into myocardial microsctructure in both health and disease. Recent developments have also been made in fluorescence imaging, making it possible to image fluorescent probes in the heart of small animals noninvasively in vivo. Moreover, techniques have been developed to perform in vivo fluorescence tomography of the mouse heart. These advances in MRI and fluorescence imaging allow events in the myocardium to be imaged at several scales linking molecular changes to alterations in microstructure and microstructural changes to gross function. A complete and integrated picture of pathophysiology in the myocardium is thus obtained. This multiscale approach has the potential to be of significant value not only in preclinical research but, ultimately, in the clinical arena as well. C1 [Sosnovik, David E.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Goergen, Craig J.; Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. [Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP Sosnovik, DE (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,Room 2301,13th St, Boston, MA 02129 USA. EM sosnovik@nmr.mgh.harvard.edu OI Goergen, Craig/0000-0001-8883-7953 FU National Institutes of Health [R01 HL093038] FX Dr. Sosnovik has been funded in part by the following National Institutes of Health grant: R01 HL093038. NR 50 TC 7 Z9 7 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1937-5387 J9 J CARDIOVASC TRANSL JI J. Cardiovasc. Transl. Res. PD AUG PY 2011 VL 4 IS 4 SI SI BP 493 EP 503 DI 10.1007/s12265-011-9284-0 PG 11 WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental SC Cardiovascular System & Cardiology; Research & Experimental Medicine GA 791QT UT WOS:000292680400011 PM 21643889 ER PT J AU Greenstein, RJ Cameron, W Brown, ST AF Greenstein, Robert J. Cameron, William Brown, Sheldon T. TI Considered "negative" for MAP, these results would be very "positive" for tuberculoid leprosy SO JOURNAL OF CROHNS & COLITIS LA English DT Letter ID MYCOBACTERIUM C1 [Greenstein, Robert J.; Brown, Sheldon T.] James J Peters VAMC, Dept Surg, Bronx, NY USA. [Cameron, William] Ottawa Hosp Res Inst, Div Infect Dis, Ottawa, ON, Canada. RP Greenstein, RJ (reprint author), James J Peters VAMC, Dept Surg, Bronx, NY USA. EM BGAxis@aol.com OI Cameron, Bill/0000-0002-0090-3539 NR 6 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-9946 J9 J CROHNS COLITIS JI J. Crohns Colitis PD AUG PY 2011 VL 5 IS 4 BP 373 EP 373 DI 10.1016/j.crohns.2011.03.013 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 792YJ UT WOS:000292786000015 PM 21683311 ER PT J AU Mannstadt, M Holick, E Zhao, WP Juppner, H AF Mannstadt, Michael Holick, Emily Zhao, Wenping Jueppner, Harald TI Mutational analysis of GCMB, a parathyroid-specific transcription factor, in parathyroid adenoma of primary hyperparathyroidism SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID FAMILIAL ISOLATED HYPOPARATHYROIDISM; CELLS-MISSING-HOMOLOG; AUTOSOMAL-DOMINANT HYPOPARATHYROIDISM; TUMOR-SUPPRESSOR GENE; DNA-BINDING; SECONDARY/TERTIARY HYPERPARATHYROIDISM; GLAND DEVELOPMENT; RECEPTOR GENE; HORMONE; IDENTIFICATION AB Sporadic primary hyperparathyroidism (PHPT), one of the most common endocrine disorders, is characterized by hypercalcemia and elevated PTH levels. The majority of cases are caused by a benign parathyroid adenoma, but somatic or de novo germ-line mutations that lead to adenoma formation have only been identified in few glands. GCMB is a parathyroid-specific transcription factor, which causes hypoparathyroidism when inactivated on both parental alleles or when a dominant-negative, heterozygous mutation is present. It is overexpressed in some parathyroid adenomas, and we therefore tested the hypothesis that GCMB mutations can be a cause of parathyroid adenomas. Nucleotide sequence analysis was performed on all coding exons and exon-intron borders of GCMB in 30 sporadic parathyroid adenomas and we identified several known polymorphisms that were either heterozygous or homozygous. In addition, one of the 30 investigated glands revealed a novel heterozygous missense mutation, c. 1144G>A, which introduced methionine at position 382 for valine (V382M), a conserved amino acid residue. Western blot analysis using mutant GCMB (GCMB-V382M) from lysates of transiently transfected DF-1 fibroblasts, luciferase assays using extracts from these cells, and electrophoretic mobility assays failed to reveal differences between wild-type and mutant GCMB in expression level, transactivational capacity, and DNA-binding ability. Furthermore, pulse-chase experiments demonstrated no difference in half-life of wild-type and mutant protein. We conclude that mutations in the transcription factor GCMB do not seem to play a major role in the pathogenesis of PHPT. Journal of Endocrinology (2011) 210, 165-171 C1 [Mannstadt, Michael; Holick, Emily; Zhao, Wenping; Jueppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Jueppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Mannstadt, M (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Thier 1051,55 Fruit St, Boston, MA 02114 USA. EM mmannstadt@partners.org FU National Institute of Diabetes and Digestive and Kidney Disease [K08-DK081669-01, R37-46718] FX This research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Disease (K08-DK081669-01 to M M and R37-46718 to H J). NR 34 TC 5 Z9 6 U1 0 U2 0 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD AUG PY 2011 VL 210 IS 2 BP 165 EP 171 DI 10.1530/JOE-10-0247 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 792QR UT WOS:000292764400005 PM 21642377 ER PT J AU Vance, D Larsen, KI Eagerton, G Wright, MA AF Vance, David Larsen, Kirsten I. Eagerton, Gregory Wright, Mary A. TI Comorbidities and Cognitive Functioning: Implications for Nursing Research and Practice SO JOURNAL OF NEUROSCIENCE NURSING LA English DT Article ID OLDER-ADULTS; DEPRESSIVE SYMPTOMS; ALZHEIMERS-DISEASE; BRAIN STRUCTURE; BLOOD-PRESSURE; PERFORMANCE; IMPAIRMENT; ASSOCIATION; MEMORY; HIV AB Optimal cognitive functioning is necessary to successfully negotiate one's environment, yet medical conditions can interfere with brain health, thus negatively impacting cognitive functioning. Such comorbidities include hypertension, heart disease, diabetes, depression, and HIV, as well as others. The physiological properties of these comorbidities can reduce one's cognitive reserve and limit one's cognitive efficiency. This article provides an overview of a few common comorbidities known to affect cognitive functioning and addresses ways in which cognitive functioning may be ameliorated and protected or mitigated in lieu of cognitive declines in such clinical populations. Implications for nursing practice and research are posited. C1 [Vance, David; Wright, Mary A.] Univ Alabama Birmingham, Sch Nursing, Birmingham, AL USA. [Larsen, Kirsten I.] Univ Alabama Birmingham, UAB Hosp, Birmingham, AL USA. [Eagerton, Gregory] Birmingham VA Med Ctr, Patient Nursing Serv, Birmingham, AL USA. RP Vance, D (reprint author), Univ Alabama Birmingham, Sch Nursing, Birmingham, AL USA. EM devance@uab.edu OI Vance, David/0000-0002-0498-6263 NR 51 TC 19 Z9 19 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0888-0395 J9 J NEUROSCI NURS JI J. Neurosci. Nurs. PD AUG PY 2011 VL 43 IS 4 BP 215 EP 224 DI 10.1097/JNN.0b013e3182212a04 PG 10 WC Clinical Neurology; Nursing SC Neurosciences & Neurology; Nursing GA 792QK UT WOS:000292763300008 PM 21796044 ER PT J AU Wulkersdorfer, B Kao, KK Agopian, VG Dunn, JC Wu, BM Stelzner, M AF Wulkersdorfer, Beatrix Kao, Kenneth K. Agopian, Vatche G. Dunn, James C. Wu, Ben M. Stelzner, Matthias TI Growth Factors Adsorbed on Polyglycolic Acid Mesh Augment Growth of Bioengineered Intestinal Neomucosa SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE tissue engineering; growth factors; scaffolds; Matrigel; small intestine; neomucosa ID GLUCAGON-LIKE PEPTIDE-2; SMALL-BOWEL RESECTION; STEM-CELL TRANSPLANTATION; ENGINEERED SMALL-INTESTINE; IN-VITRO; BASEMENT-MEMBRANE; EPITHELIAL-CELLS; TRANSFERRIN RECEPTOR; SGLT1 EXPRESSION; FACTOR RELEASE AB Production of tissue engineered small intestine (TESI) has been limited by the relatively large amount of native tissue required to generate neomucosa. The influence of growth factors and three-dimensional (3D) extracellular matrices on TESI has been studied both in vitro and in vivo, and positive growth effects on tissue mass and differentiation were noted. The present study investigates the impact of single doses of glucagon-like peptide-2 (GLP-2), hepatocyte growth factor (HGF), or holo-transferrin adsorbed onto a polyglycolic (PGA) mesh scaffold using a rat small-intestinal organoid transplant model. In Experiment I, intestinal organoids were seeded onto PGA mesh discs, suspended in either Matrigel (n = 8) or a vehicle control (n = 8), and implanted into syngenic recipients. In Experiment II, GLP-2 (n = 8), HGF (n = 8), or transferrin (n = 8) were adsorbed onto PGA mesh discs. Intestinal organoids were then suspended in Matrigel and seeded onto each growth factor-loaded PGA disc or onto control discs without growth factors (n = 12). In addition, organoids were suspended in vehicle and seeded onto control discs (n = 12). All discs were implanted into syngenic recipients. After 4 wk, histologic analysis of the samples revealed significantly greater neomucosal surface area (3.62 +/- 0.33 mm(2) versus 0.92 +/- 0.11 mm(2), P < 0.0001) and cyst diameter (2.83 +/- 0.14 mm versus 2.06 +/- 0.07 mm, P < 0.0001) in groups treated with Matrigel compared with vehicle controls. The addition of holo-transferrin to the scaffolds further augmented neomucosal surface area (9.11 +/- 0.66 mm(2) versus 3.01 +/- 0.22 mm(2), P < 0.01), whereas that of GLP-2 stimulated the formation of increased numbers of cysts (8.88 +/- 0.46 versus 4.18 +/- 0.25, P < 0.01). These data suggest that Matrigel and growth factors adsorbed to polymer scaffolds can be used to manipulate the morphology of TESI. Published by Elsevier Inc. C1 [Stelzner, Matthias] Univ Calif Los Angeles, Dept Surg, VA Greater Los Angeles, Hlth Care Syst, Los Angeles, CA 90073 USA. [Dunn, James C.; Wu, Ben M.] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA 90073 USA. RP Stelzner, M (reprint author), Univ Calif Los Angeles, Dept Surg, VA Greater Los Angeles, Hlth Care Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Matthias.Stelzner@va.gov NR 69 TC 8 Z9 8 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD AUG PY 2011 VL 169 IS 2 BP 169 EP 178 DI 10.1016/j.jss.2009.11.719 PG 10 WC Surgery SC Surgery GA 791BF UT WOS:000292634100009 PM 20444471 ER PT J AU Lima, XT Kimball, AB AF Lima, X. T. Kimball, A. B. TI Skin carotenoid levels in adult patients with psoriasis SO JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY LA English DT Article DE carotenoids; nutrition; psoriasis; retinoids; vitamin A ID NUTRITION EXAMINATION SURVEY; SERUM CONCENTRATIONS; ALPHA-TOCOPHEROL; NATIONAL-HEALTH; VITAMIN-A; OBESITY; ASSOCIATIONS; POPULATION; ARTHRITIS; AMERICANS AB Background Psoriasis is an inflammatory disease that not only affects the skin but can also have systemic implications such as obesity and nutritional deficiencies. Carotenoids are vitamin A provitamins with anti-oxidant properties that are present in human tissues including skin. Objectives To determine whether psoriasis is associated with lower levels of skin carotenoid levels. Methods In this cross-sectional study, skin carotenoid levels were measured on the palms of 44 patients with psoriasis and 72 patients without psoriasis. A linear regression model was used to evaluate the relationship between psoriasis and carotenoid levels (primary aim) and to determine if severity of disease was associated with carotenoid levels (secondary aim). Potential confounders included demographic factors, smoking status, body mass index and multivitamin intake. Results The mean carotenoid levels in the psoriasis and no psoriasis groups were respectively 22 099 and 29 180 and presence of psoriasis was found to be significantly related to lower levels of carotenoids in both univariable and multivariable analysis (P < 0.05). In the psoriasis group, the Psoriasis Area and Severity Index score was not significantly related to carotenoid levels (P = 0.07). Conclusions Patients with psoriasis appear to have lower skin carotenoid counts than patients without psoriasis. C1 [Lima, X. T.; Kimball, A. B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Unit Res Trials & Outcomes Skin CURTIS, Boston, MA 02115 USA. RP Kimball, AB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Unit Res Trials & Outcomes Skin CURTIS, Boston, MA 02115 USA. EM harvardskinstudies@partners.org FU Nu Skin FX The Raman spectrometer was provided by Nu Skin. NR 26 TC 6 Z9 6 U1 4 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0926-9959 J9 J EUR ACAD DERMATOL JI J. Eur. Acad. Dermatol. Venereol. PD AUG PY 2011 VL 25 IS 8 BP 945 EP 949 DI 10.1111/j.1468-3083.2010.03888.x PG 5 WC Dermatology SC Dermatology GA 790SA UT WOS:000292608300011 PM 21054574 ER PT J AU Spurgeon, SE Pindyck, T Okada, C Chen, YY Chen, ZQ Mater, E Abbi, K Epner, EM AF Spurgeon, Stephen E. Pindyck, Talia Okada, Craig Chen, Yiyi Chen, Zunqiu Mater, Elana Abbi, Kamal Epner, Elliot M. TI Cladribine plus rituximab is an effective therapy for newly diagnosed mantle cell lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Article DE Mantle cell lymphoma; cladribine; rituximab; response ID INTERNATIONAL PROGNOSTIC INDEX; PROGRESSION-FREE SURVIVAL; CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; STUDY-GROUP GLSG; TERM-FOLLOW-UP; HAIRY-CELL; PHASE-II; 2-CHLORODEOXYADENOSINE; FLUDARABINE AB Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that is incurable with standard chemotherapy. There is no consensus on the best initial therapy, especially for elderly patients, who are not candidates for aggressive treatment approaches. Current National Comprehensive Cancer Network (NCCN) treatment guidelines include rituximab (R) plus cladribine for the initial treatment of MCL. However, few data are available to substantiate this recommendation. Therefore, to further define the role of R-cladribine for the initial treatment of MCL, we performed a retrospective chart review of 31 patients with MCL (median age, 67) treated with R-cladribine. The majority of responding patients also received R maintenance. The overall response rate was 87%, with 61% of patients achieving a complete remission (CR/CRu). The estimated median follow-up was 32.5 months, median PFS was 37.5 months, and median OS was 85.2 months. One of 19 (5.3%) subjects in CR/CRu relapsed (median follow-up of 23 months). CR/CRu was associated with improved survival (p < 0.0001), while a high mantle cell international prognostic index (MIPI) was associated with worse survival (p = 0.05). There was one toxic death (neutropenic pseudomonal sepsis) related to treatment. R-cladribine is an effective therapy for previously untreated MCL, and these results validate the use of R-cladribine for the initial treatment of MCL. C1 [Spurgeon, Stephen E.] Oregon Hlth & Sci Univ, Knight Canc Ctr, Ctr Hematol Malignancies, Knight Canc Inst, Portland, OR 97239 USA. [Pindyck, Talia; Chen, Yiyi; Chen, Zunqiu] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA. [Okada, Craig] Portland VA Med Ctr, Portland, OR USA. [Abbi, Kamal; Epner, Elliot M.] Penn State Hershey Canc Inst, Hershey, PA USA. RP Spurgeon, SE (reprint author), Oregon Hlth & Sci Univ, Knight Canc Ctr, Ctr Hematol Malignancies, Knight Canc Inst, Mailcode UHN 73C,3181 Sam Jackson Pk Rd, Portland, OR 97239 USA. EM spurgeos@ohsu.edu RI abbi, Kamal Kant Singh/M-4189-2014 OI abbi, Kamal Kant Singh/0000-0003-1186-7817 NR 40 TC 17 Z9 19 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 2011 VL 52 IS 8 BP 1488 EP 1494 DI 10.3109/10428194.2011.575489 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 792LU UT WOS:000292747300013 PM 21623691 ER PT J AU Aldana-Masangkay, GI Rodriguez-Gonzalez, A Lin, T Ikeda, AK Hsieh, YT Kim, YM Lomenick, B Okemoto, K Landaw, EM Wang, DP Mazitschek, R Bradner, JE Sakamoto, KM AF Aldana-Masangkay, Grace I. Rodriguez-Gonzalez, Agustin Lin, Tara Ikeda, Alan K. Hsieh, Yao-Te Kim, Yong-Mi Lomenick, Brett Okemoto, Kazuo Landaw, Elliot M. Wang, Dongpeng Mazitschek, Ralph Bradner, James E. Sakamoto, Kathleen M. TI Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells SO LEUKEMIA & LYMPHOMA LA English DT Article DE Tubacin; HDAC6; ALL; aggresome pathway ID HISTONE DEACETYLASE-6; PROTEIN-DEGRADATION; ACETYLATED TUBULIN; SIGNALING PATHWAYS; SODIUM-PUMP; NA+,K+-ATPASE; INHIBITION; CYTOSKELETON; PROTEASOME; ATPASE AB Over the past decade, histone deacetylase inhibitors have increasingly been used to treat various malignancies. Tubacin (tubulin acetylation inducer) is a small molecule that inhibits histone deacetylase 6 (HDAC6) and induces acetylation of alpha-tubulin. We observed a higher antiproliferative effect of tubacin in acute lymphoblastic leukemia (ALL) cells than in normal hematopoietic cells. Treatment with tubacin led to the induction of apoptotic pathways in both pre-B and T cell ALL cells at a 50% inhibitory concentration (IC(50)) of low micromolar concentrations. Acetylation of alpha-tubulin increases within the first 30 min following treatment of ALL cells with tubacin. We also observed an accumulation of polyubiquitinated proteins and poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the signaling pathways activated by tubacin appear to be distinct from those observed in multiple myeloma. In this article, we demonstrate that tubacin enhances the effects of chemotherapy to treat primary ALL cells in vitro and in vivo. These results suggest that targeting HDAC6 alone or in combination with chemotherapy could provide a novel approach to treat ALL. C1 [Aldana-Masangkay, Grace I.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Aldana-Masangkay, Grace I.; Ikeda, Alan K.; Sakamoto, Kathleen M.] Univ Calif Los Angeles, David Geffen Sch Med,Dept Pathol & Lab Med,Calif, Inst Mol Biol,Mattel Childrens Hosp UCLA,Jonsson, Div Hematol Oncol,Dept Pediat,Gwynne Hazen Cherry, Los Angeles, CA 90095 USA. [Rodriguez-Gonzalez, Agustin] Univ Heidelberg, D-6900 Heidelberg, Germany. [Lin, Tara] Louisiana State Univ, Dept Med, Div Hematol Oncol, New Orleans, LA USA. [Hsieh, Yao-Te; Kim, Yong-Mi] Childrens Hosp Los Angeles, USC Norris Comprehens Canc Ctr, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Lomenick, Brett] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Okemoto, Kazuo] Ohio State Univ, Dept Neurol Surg, Columbus, OH 43210 USA. [Landaw, Elliot M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Wang, Dongpeng; Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Bradner, James E.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sakamoto, KM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM KSakamoto@mednet.ucla.edu RI Mazitschek, Ralph/E-3741-2013 OI Mazitschek, Ralph/0000-0002-1105-689X FU Jonsson Comprehensive Cancer Center; William Lawrence and Blanche Hughes Foundation; National Institutes of Health (NIH) [HL75826, HL83077, P50-CA86355]; St. Baldrick's Foundation; Eugene Cota-Robles Fellowship (ECR) FX This work was supported by the Jonsson Comprehensive Cancer Center Seed Grant (A.R.-G. and K.M.S.), and the William Lawrence and Blanche Hughes Foundation. K.M.S. is a recipient of National Institutes of Health (NIH) R01 grants HL75826 and HL83077 and the St. Baldrick's Foundation Research Award. K.M.S. and M.M. are Scholars of the Leukemia and Lymphoma Society. D. W. and R. M. are funded by NIH grant P50-CA86355. G. I. A.-M. is supported by the Eugene Cota-Robles Fellowship (ECR) grant and a Minority Supplement from NIH R01HL075826. We also would like to thank Markus Muschen for providing the expression profile data and reading the manuscript; and James Ch'ng for his technical assistance. NR 35 TC 20 Z9 23 U1 1 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 2011 VL 52 IS 8 BP 1544 EP 1555 DI 10.3109/10428194.2011.570821 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 792LU UT WOS:000292747300021 PM 21699378 ER PT J AU Li, YF Wong, ES Sales, AE Sharp, ND Needleman, J Maciejewski, ML Lowy, E Alt-White, AC Liu, CF AF Li, Yu-Fang Wong, Edwin S. Sales, Anne E. Sharp, Nancy D. Needleman, Jack Maciejewski, Matthew L. Lowy, Elliott Alt-White, Anna C. Liu, Chuan-Fen TI Nurse Staffing and Patient Care Costs in Acute Inpatient Nursing Units SO MEDICAL CARE LA English DT Article DE nurse staffing; patient outcomes; mortality; length of stay; health care costs ID VETERANS AFFAIRS HOSPITALS; ADVERSE EVENTS; ADMINISTRATIVE DATA; QUALITY; MORTALITY; OUTCOMES; CLINICS; SAMPLE AB Objective: Studies suggest that a business case for improving nurse staffing can be made to increase registered nurse (RN) skill mix without changing total licensed nursing hours. It is unclear whether a business case for increasing RN skill mix can be justified equally among patients of varying health needs. This study evaluated whether nursing hours per patient day (HPPD) and skill mix are associated with higher inpatient care costs within acute medical/surgical inpatient units using data from the Veterans Health Administration. Methods: Retrospective cross-sectional study, including 139,360 inpatient admissions to 292 acute medical/surgical units at 125 Veterans Health Administration medical centers between February and June 2003, was conducted. Dependent variables were inpatient costs per admission and costs per patient day. Results: The average costs per surgical and medical admission were $18,624 and $6,636, respectively. Costs per admission were positively associated with total nursing HPPD among medical admissions ($164.49 per additional HPPD, P < 0.001), but not among surgical admissions. Total nursing HPPD and RN skill mix were associated with higher costs per hospital day for both medical admissions ($79.02 per additional HPPD and $5.64 per 1% point increase in nursing skill mix, both P < 0.001) and surgical admissions ($112.47 per additional HPPD and $13.31 per 1% point increase in nursing skill mix, both P < 0.001). Patients experiencing complications or transferring to an intensive care unit had higher inpatient costs than other patients. Conclusions: The association of nurse staffing level with costs per admission differed for medical versus surgical admissions. C1 [Li, Yu-Fang; Wong, Edwin S.; Sharp, Nancy D.; Lowy, Elliott; Liu, Chuan-Fen] VA Puget Sound Hlth Care Syst, NW Ctr Outcomes Res Older Adults, Seattle, WA USA. [Li, Yu-Fang] Qual & Safety Analyt Ctr, VA Off, Seattle, WA USA. [Li, Yu-Fang] Univ Washington, Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Wong, Edwin S.; Sharp, Nancy D.; Lowy, Elliott; Liu, Chuan-Fen] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Sales, Anne E.] VA Inpatient Evaluat Ctr, Ann Arbor, MI USA. [Needleman, Jack] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. [Maciejewski, Matthew L.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Maciejewski, Matthew L.] Duke Univ, Med Ctr, Dept Med, Div Gen Internal Med, Durham, NC 27710 USA. [Alt-White, Anna C.] Dept Vet Affairs, Off Nursing Serv, Washington, DC USA. RP Li, YF (reprint author), VA Puget Sound Hlth Care Syst, NW Ctr Outcomes Res Older Adults, Seattle, WA USA. EM yufang.li@va.gov RI Sales, Anne/D-9678-2012; Needleman, Jack/I-5461-2013; OI Needleman, Jack/0000-0002-2875-0589; Sales, Anne/0000-0001-9360-3334 FU Department of Veterans Affairs, Health Services Research and Development (HSRD) [ECI 04-186]; VA HSRD FX Supported by an Investigator Initiated Research Award (ECI 04-186) from the Department of Veterans Affairs, Health Services Research and Development (HSRD).; Dr Wong is currently supported by the VA HSRD post-doctoral fellowship program. NR 30 TC 5 Z9 5 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 2011 VL 49 IS 8 BP 708 EP 715 DI 10.1097/MLR.0b013e318223a9f1 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 792PH UT WOS:000292758500005 PM 21758025 ER PT J AU Hawkins, MS Sevick, MA Richardson, CR Fried, LF Arena, VC Kriska, AM AF Hawkins, Marquis S. Sevick, Mary Ann Richardson, Caroline R. Fried, Linda F. Arena, Vincent C. Kriska, Andrea M. TI Association between Physical Activity and Kidney Function: National Health and Nutrition Examination Survey SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE UNITED STATES; GLOMERULAR FILTRATION RATE; ACCELEROMETER; SURVEY ID GLOMERULAR-FILTRATION-RATE; EXAMINATION SURVEY NHANES; CARDIOVASCULAR-DISEASE; RACIAL/ETHNIC GROUPS; METABOLIC SYNDROME; DIABETES-MELLITUS; COMPUTER-SCIENCE; SERUM CREATININE; GLYCEMIC CONTROL; RENAL-FUNCTION AB HAWKINS, M. S., M. A. SEVICK, C. R. RICHARDSON, L. F. FRIED, V. C. ARENA, and A. M. KRISKA. Association between Physical Activity and Kidney Function: National Health and Nutrition Examination Survey. Med. Sci. Sports Exerc., Vol. 43, No. 8, pp. 1457-1464, 2011. Introduction: Chronic kidney disease is a condition characterized by the deterioration of the kidney's ability to remove waste products from the body. Although treatments to slow the progression of the disease are available, chronic kidney disease may eventually lead to a complete loss of kidney function. Previous studies have shown that physical activities of moderate intensity may have renal benefits. Few studies have examined the effects of total movement on kidney function. The purpose of this study was to determine the association between time spent at all levels of physical activity intensity and sedentary behavior and kidney function. Methods: Data were obtained from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey, a cross-sectional study of a complex, multistage probability sample of the US population. Physical activity was assessed using an accelerometer and questionnaire. Glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease study formula. To assess linear associations between levels of physical activity and sedentary behavior with log-transformed estimated GFR (eGFR), linear regression was used. Results: In general, physical activity (light and total) was related to log eGFR in females and males. For females, the association between light and total physical activity with log eGFR was consistent regardless of diabetes status. For males, the association between light and total physical activity and log eGFR was only significant in males without diabetes. Conclusions: When examining the association between physical activity, measured objectively with an accelerometer, and kidney function, total and light physical activities were found to be positively associated with kidney function. C1 [Hawkins, Marquis S.; Kriska, Andrea M.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Sevick, Mary Ann; Fried, Linda F.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Richardson, Caroline R.] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Richardson, Caroline R.] Ann Arbor Vet Affairs Med Ctr, HSR&D VA Ctr Clin Management Res, Ann Arbor, MI USA. [Arena, Vincent C.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. RP Hawkins, MS (reprint author), 3512 5th Ave,Room 308, Pittsburgh, PA 15261 USA. EM hawkinsm@edc.pitt.edu OI Arena, Vincent/0000-0002-1634-7207; Kriska, Andrea/0000-0002-3522-0869 NR 38 TC 30 Z9 31 U1 2 U2 9 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 AUG PY 2011 VL 43 IS 8 BP 1457 EP 1464 DI 10.1249/MSS.0b013e31820c0130 PG 8 WC Sport Sciences SC Sport Sciences GA 792TM UT WOS:000292773000010 PM 21200336 ER PT J AU Prasad, A Jia, YH Chakraborty, A Li, YT Jain, SK Zhong, J Roy, SG Loison, F Mondal, S Sakai, J Blanchard, C Snyder, SH Luo, HR AF Prasad, Amit Jia, Yonghui Chakraborty, Anutosh Li, Yitang Jain, Supriya K. Zhong, Jia Roy, Saurabh Ghosh Loison, Fabien Mondal, Subhanjan Sakai, Jiro Blanchard, Catlyn Snyder, Solomon H. Luo, Hongbo R. TI Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling SO NATURE IMMUNOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; PLECKSTRIN HOMOLOGY DOMAIN; OVARIAN-CARCINOMA CELLS; TUMOR-SUPPRESSOR PTEN; HYDROGEN-PEROXIDE; NADPH-OXIDASE; DIPHOSPHOINOSITOL POLYPHOSPHATES; PYROPHOSPHATES; CHEMOTAXIS; P47(PHOX) AB Inositol phosphates are widely produced throughout animal and plant tissues. Diphosphoinositol pentakisphosphate (InsP7) contains an energetic pyrophosphate bond. Here we demonstrate that disruption of inositol hexakisphosphate kinase 1 (InsP6K1), one of the three mammalian inositol hexakisphosphate kinases (InsP6Ks) that convert inositol hexakisphosphate (InsP6) to InsP7, conferred enhanced phosphatidylinositol-(3,4,5)-trisphosphate (PtdIns(3,4,5)P(3))-mediated membrane translocation of the pleckstrin homology domain of the kinase Akt and thus augmented downstream PtdIns(3,4,5)P(3) signaling in mouse neutrophils. Consequently, these neutrophils had greater phagocytic and bactericidal ability and amplified NADPH oxidase-mediated production of superoxide. These phenotypes were replicated in human primary neutrophils with pharmacologically inhibited InsP6Ks. In contrast, an increase in intracellular InsP7 blocked chemoattractant-elicited translocation of the pleckstrin homology domain to the membrane and substantially suppressed PtdIns(3,4,5)P(3)-mediated cellular events in neutrophils. Our findings establish a role for InsP7 in signal transduction and provide a mechanism for modulating PtdIns(3,4,5)P(3) signaling in neutrophils. C1 [Prasad, Amit; Jia, Yonghui; Li, Yitang; Jain, Supriya K.; Zhong, Jia; Roy, Saurabh Ghosh; Loison, Fabien; Mondal, Subhanjan; Sakai, Jiro; Blanchard, Catlyn; Luo, Hongbo R.] Harvard Univ, Sch Med, Dept Pathol, Dept Lab Med,Childrens Hosp Boston, Boston, MA 02115 USA. [Chakraborty, Anutosh; Snyder, Solomon H.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Chakraborty, Anutosh; Snyder, Solomon H.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Luo, Hongbo R.] Harvard Univ, Sch Med, Dana Farber Harvard Canc Ctr, Boston, MA USA. RP Luo, HR (reprint author), Harvard Univ, Sch Med, Dept Pathol, Dept Lab Med,Childrens Hosp Boston, Boston, MA 02115 USA. EM hongbo.luo@childrens.harvard.edu RI Loison, Fabien/G-3385-2014; OI Loison, Fabien/0000-0002-6678-1730; Sakai, Jiro/0000-0002-2526-2766 FU US National Institutes of Health [HL085100, AI076471, HL092020, GM076084] FX We thank L. Silberstein, J. Manis and L. Chai for discussions. Supported by the US National Institutes of Health (HL085100, AI076471, HL092020 and GM076084 to H.R.L.). NR 49 TC 35 Z9 37 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2011 VL 12 IS 8 BP 752 EP U144 DI 10.1038/ni.2052 PG 10 WC Immunology SC Immunology GA 794BT UT WOS:000292870700013 PM 21685907 ER PT J AU Thiery, J Keefe, D Boulant, S Boucrot, E Walch, M Martinvalet, D Goping, IS Bleackley, RC Kirchhausen, T Lieberman, J AF Thiery, Jerome Keefe, Dennis Boulant, Steeve Boucrot, Emmanuel Walch, Michael Martinvalet, Denis Goping, Ing Swie Bleackley, R. Chris Kirchhausen, Tomas Lieberman, Judy TI Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells SO NATURE IMMUNOLOGY LA English DT Article ID GRANULE-MEDIATED CYTOTOXICITY; TOXIC LYMPHOCYTES-T; PLASMA-MEMBRANE; IMMUNOLOGICAL SYNAPSE; SERINE PROTEASE; REPAIR; DEATH; APOPTOSIS; DELIVERY; ACIDIFICATION AB How the pore-forming protein perforin delivers apoptosis-inducing granzymes to the cytosol of target cells is uncertain. Perforin induces a transient Ca(2+) flux in the target cell, which triggers a process to repair the damaged cell membrane. As a consequence, both perforin and granzymes are endocytosed into enlarged endosomes called 'gigantosomes'. Here we show that perforin formed pores in the gigantosome membrane, allowing endosomal cargo, including granzymes, to be gradually released. After about 15 min, gigantosomes ruptured, releasing their remaining content. Thus, perforin delivers granzymes by a two-step process that involves first transient pores in the cell membrane that trigger the endocytosis of granzyme and perforin and then pore formation in endosomes to trigger cytosolic release. C1 [Thiery, Jerome; Keefe, Dennis; Boulant, Steeve; Boucrot, Emmanuel; Walch, Michael; Martinvalet, Denis; Kirchhausen, Tomas; Lieberman, Judy] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Thiery, Jerome; Keefe, Dennis; Boulant, Steeve; Boucrot, Emmanuel; Walch, Michael; Martinvalet, Denis; Kirchhausen, Tomas; Lieberman, Judy] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Thiery, Jerome; Keefe, Dennis; Walch, Michael; Martinvalet, Denis; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Boulant, Steeve; Boucrot, Emmanuel; Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Martinvalet, Denis] Univ Geneva, Dept Cell Physiol & Metab, Geneva, Switzerland. [Goping, Ing Swie; Bleackley, R. Chris] Univ Alberta, Dept Biochem, Edmonton, AB, Canada. RP Lieberman, J (reprint author), Childrens Hosp, Immune Dis Inst, 300 Longwood Ave, Boston, MA 02115 USA. EM lieberman@idi.harvard.edu RI Lieberman, Judy/A-2717-2015 FU US National Institutes of Health [AI063430, GM075252]; Canadian Institutes of Health Research; Canadian Cancer Society; Stiefel-Zangger Foundation; Human Frontier Science Program Organization; Harvard Digestive Diseases Center; Immune Disease Institute; GlaxoSmithKline Alliance FX We thank Y. Jones (University of Oxford) for the mammalian expression vector pHLseq; G.M. Griffiths (Oxford University) for 2d4 mouse antibody to human perforin; and E. Marino for assistance with microscopy and image analysis. Supported by the US National Institutes of Health (AI063430 to J.L. and GM075252 to T.K.), the Canadian Institutes of Health Research (R.C.B.), the Canadian Cancer Society (RCB), the Stiefel-Zangger Foundation (M.W.), the Human Frontier Science Program Organization (E.B.), the Harvard Digestive Diseases Center (S.B.) and the Immune Disease Institute and GlaxoSmithKline Alliance (S.B.). NR 49 TC 83 Z9 85 U1 3 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 AUG PY 2011 VL 12 IS 8 BP 770 EP U146 DI 10.1038/ni.2050 PG 9 WC Immunology SC Immunology GA 794BT UT WOS:000292870700015 PM 21685908 ER PT J AU Nakaya, HI Wrammert, J Lee, EK Racioppi, L Marie-Kunze, S Haining, WN Means, AR Kasturi, SP Khan, N Li, GM McCausland, M Kanchan, V Kokko, KE Li, SZ Elbein, R Mehta, AK Aderem, A Subbarao, K Ahmed, R Pulendran, B AF Nakaya, Helder I. Wrammert, Jens Lee, Eva K. Racioppi, Luigi Marie-Kunze, Stephanie Haining, W. Nicholas Means, Anthony R. Kasturi, Sudhir P. Khan, Nooruddin Li, Gui-Mei McCausland, Megan Kanchan, Vibhu Kokko, Kenneth E. Li, Shuzhao Elbein, Rivka Mehta, Aneesh K. Aderem, Alan Subbarao, Kanta Ahmed, Rafi Pulendran, Bali TI Systems biology of vaccination for seasonal influenza in humans SO NATURE IMMUNOLOGY LA English DT Article ID YELLOW-FEVER VACCINE; PROTEIN-KINASE-IV; PLASMA-CELL DIFFERENTIATION; IMMUNE-RESPONSES; TRANSCRIPTION FACTOR; ANTIBODY-RESPONSES; DENDRITIC CELLS; VIRUS VACCINES; CUTTING EDGE; T-CELLS AB Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). TIV induced higher antibody titers and more plasmablasts than LAIV did. In subjects vaccinated with TIV, early molecular signatures correlated with and could be used to accurately predict later antibody titers in two independent trials. Notably, expression of the kinase CaMKIV at day 3 was inversely correlated with later antibody titers. Vaccination of CaMKIV-deficient mice with TIV induced enhanced antigen-specific antibody titers, which demonstrated an unappreciated role for CaMKIV in the regulation of antibody responses. Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines. C1 [Nakaya, Helder I.; Wrammert, Jens; Marie-Kunze, Stephanie; Kasturi, Sudhir P.; Khan, Nooruddin; Li, Gui-Mei; McCausland, Megan; Kanchan, Vibhu; Li, Shuzhao; Ahmed, Rafi; Pulendran, Bali] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Nakaya, Helder I.; Marie-Kunze, Stephanie; Kasturi, Sudhir P.; Khan, Nooruddin; Li, Shuzhao; Pulendran, Bali] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Wrammert, Jens; Li, Gui-Mei; McCausland, Megan; Kanchan, Vibhu; Ahmed, Rafi] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Lee, Eva K.] Georgia Inst Technol, Sch Ind & Syst Engn, Ctr Operat Res Med & Healthcare, Atlanta, GA 30332 USA. [Racioppi, Luigi] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC USA. [Racioppi, Luigi; Means, Anthony R.] Univ Naples Federico 2, Dept Cellular & Mol Biol & Pathol, Naples, Italy. [Haining, W. Nicholas] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kokko, Kenneth E.] Emory Univ, Sch Med, Dept Med, Div Nephrol, Atlanta, GA USA. [Elbein, Rivka; Mehta, Aneesh K.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. [Aderem, Alan] Inst Syst Biol, Seattle, WA USA. [Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Pulendran, Bali] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. RP Pulendran, B (reprint author), Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM bpulend@emory.edu RI Mehta, Aneesh/B-8054-2012; Nakaya, Helder/A-1397-2010; OI Mehta, Aneesh/0000-0002-6552-9162; Nakaya, Helder/0000-0001-5297-9108; racioppi, luigi/0000-0002-9207-6752 FU US National Institutes of Health [U19AI090023, HHSN266200700006C, U54AI057157, R37AI48638, R01DK057665, U19AI057266, N01 AI50025, AI30048, AI057266, DK074701, UL1 RR025008]; Bill & Melinda Gates Foundation [38645]; National Science Foundation (E.K.L. laboratory); Centers for Disease Control (E.K.L. laboratory) FX We thank B.T. Rouse and R. Compans for discussion and comments on the manuscript, and H. Oluoch for technical assistance. Supported the US National Institutes of Health (U19AI090023, HHSN266200700006C, U54AI057157, R37AI48638, R01DK057665, U19AI057266 and N01 AI50025 for the B. P. laboratory; AI30048 and AI057266 for the R.A. laboratory; DK074701 for the A.R.M. laboratory; Intramural Research Program of the National Institute of Allergy and Infectious Diseases for the K.S. laboratory; and UL1 RR025008 from the Clinical and Translational Science Award program, National Center for Research Resources for clinical work), the Bill & Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery 38645 to the R.A. and B.P. laboratories), the National Science Foundation (E.K.L. laboratory) and the Centers for Disease Control (E.K.L. laboratory). NR 54 TC 291 Z9 294 U1 5 U2 55 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2011 VL 12 IS 8 BP 786 EP U149 DI 10.1038/ni.2067 PG 11 WC Immunology SC Immunology GA 794BT UT WOS:000292870700017 PM 21743478 ER PT J AU Halko, MA Datta, A Plow, EB Scaturro, J Bikson, M Merabet, LB AF Halko, M. A. Datta, A. Plow, E. B. Scaturro, J. Bikson, M. Merabet, L. B. TI Neuroplastic changes following rehabilitative training correlate with regional electrical field induced with tDCS SO NEUROIMAGE LA English DT Article ID DIRECT-CURRENT STIMULATION; NONINVASIVE BRAIN-STIMULATION; HUMAN MOTOR CORTEX; TRANSCRANIAL DIRECT; VISUAL-CORTEX; MAJOR DEPRESSION; CEREBRAL CORTEX; STROKE PATIENTS; CURRENT FLOW; RECOVERY AB Transcranial direct current stimulation (tDCS) has recently emerged as a promising approach to enhance neurorehabilitative outcomes. However, little is known about how the local electrical field generated by tDCS relates to underlying neuroplastic changes and behavior. To address this question, we present a case study analysis of an individual with hemianopia due to stroke and who benefited from a combined visual rehabilitation training and tDCS treatment program. Activation associated with a visual motion perception task (obtained by functional magnetic resonance imaging; fMRI) was used to characterize local changes in brain activity at baseline and after training. Individualized, high-resolution electrical field modeling reproducing precise cerebral and lesioned tissue geometry, predicted distortions of current flow in peri-lesional areas and diffuse clusters of peak electric fields. Using changes in fMRI signal as an index of cortical recovery, correlations to the electrical field map were determined. Significant correlations between the electrical field and change in fMRI signal were region specific including cortical areas under the anode electrode and peri-lesional visual areas. These patterns were consistent with effective tDCS facilitated rehabilitation. We describe the methodology used to analyze tDCS mechanisms through combined fMRI and computational modeling with the ultimate goal of developing a rationale for individualized therapy. (c) 2011 Elsevier Inc. All rights reserved. C1 [Merabet, L. B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Vis Rehabil Ctr,Med Sch, Boston, MA 02115 USA. [Halko, M. A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Dept Neurol,Med Sch, Boston, MA 02215 USA. [Plow, E. B.] Cleveland Clin Fdn, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA. [Datta, A.; Scaturro, J.; Bikson, M.] CUNY City Coll, Dept Biomed Engn, New York, NY 10031 USA. RP Merabet, LB (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Vis Rehabil Ctr,Med Sch, Boston, MA 02115 USA. EM lotfi_merabet@meei.harvard.edu RI Halko, Mark/G-8633-2016 OI Halko, Mark/0000-0002-7427-0789 FU Novavision VRT Inc.; National Institutes of Health [K23-EY016131] FX This work was supported by an investigator-initiated pilot grant from Novavision VRT Inc. and by the National Institutes of Health (K23-EY016131 to LBM). NR 49 TC 37 Z9 38 U1 0 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2011 VL 57 IS 3 SI SI BP 885 EP 891 DI 10.1016/j.neuroimage.2011.05.026 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 792CK UT WOS:000292717900023 PM 21620985 ER PT J AU Kwong, KK Wu, O Chan, ST Nelissen, K Kholodov, M Chesler, DA AF Kwong, Kenneth K. Wu, Ona Chan, Suk-Tak Nelissen, Koen Kholodov, Mykhaylo Chesler, David A. TI Early time points perfusion imaging: Relative time of arrival, maximum derivatives and fractional derivatives SO NEUROIMAGE LA English DT Article DE Cerebral blood flow; Dynamic susceptibility contrast-enhanced magnetic resonance imaging; Relative time of arrival; Maximum gradient; Maximum second derivative; Fractional derivative; Early time points (ET) perfusion imaging method ID CEREBRAL-BLOOD-FLOW; SINGULAR-VALUE DECOMPOSITION; SUSCEPTIBILITY CONTRAST MRI; HIGH-RESOLUTION MEASUREMENT; ARTERIAL INPUT FUNCTIONS; TRACER BOLUS PASSAGES; MAGNETIC-RESONANCE; COMPUTED-TOMOGRAPHY; QUANTIFICATION; DISPERSION AB Time of arrival (TOA) of a bolus of contrast agent to the tissue voxel is a reference time point critical for the Early Time Points Perfusion Imaging Method (ET) to make relative cerebral blood flow (rCBF) maps. Due to the low contrast to noise (CNR) condition at TOA, other useful reference time points known as relative time of arrival data points (rTOA) are investigated. Candidate rTOA's include the time to reach the maximum derivative, the maximum second derivative, and the maximum fractional derivative. Each rTOA retains the same relative time distance from TOA for all tissue flow levels provided that ET's basic assumption is met, namely, no contrast agent has a chance to leave the tissue before the time of rTOA. The ET's framework insures that rCBF estimates by different orders of the derivative are theoretically equivalent to each other and monkey perfusion imaging results supported the theory. In rCBF estimation, maximum values of higher order fractional derivatives may be used to replace the maximum derivative which runs a higher risk of violating ET's assumption. Using the maximum values of the derivative of orders ranging from 1 to 1.5 to 2. estimated rCBF results were found to demonstrate a gray white matter ratio of approximately 3, a number consistent with flow ratio reported in the literature. (C) 2011 Elsevier Inc. All rights reserved. C1 [Kwong, Kenneth K.; Wu, Ona; Chan, Suk-Tak; Nelissen, Koen; Chesler, David A.] Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Dept Radiol, Charlestown, MA 02129 USA. [Nelissen, Koen] Univ Leuven, Lab Neuro & Psychofysiol Katholieke, B-3000 Louvain, BE, Belgium. [Kholodov, Mykhaylo] York Univ, N York, ON M3J 1P3, Canada. RP Kwong, KK (reprint author), MGH NMR Ctr, 149 13th St,Mailcode 2301, Charlestown, MA 02129 USA. EM kwong@nmr.mgh.harvard.edu RI Chan, Suk-tak/G-5846-2015 FU National Institutes of Health [R01NS59775]; Athinoula A. Martinos Center for Biomedical Imaging FX We would like to acknowledge the support of the Athinoula A. Martinos Center for Biomedical Imaging. This study was supported in part by the National Institutes of Health (grant R01NS59775). We would like to acknowledge Dr. Tuan Cao-Huu for his computation advice and his years of generous support of our research effort. NR 37 TC 1 Z9 1 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2011 VL 57 IS 3 SI SI BP 979 EP 990 DI 10.1016/j.neuroimage.2011.05.017 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 792CK UT WOS:000292717900032 PM 21600995 ER PT J AU Cohen-Adad, J Leblond, H Delivet-Mongrain, H Martinez, M Benali, H Rossignol, S AF Cohen-Adad, J. Leblond, H. Delivet-Mongrain, H. Martinez, M. Benali, H. Rossignol, S. TI Wallerian degeneration after spinal cord lesions in cats detected with diffusion tensor imaging SO NEUROIMAGE LA English DT Article DE DTI; Q-Ball imaging; Spinal cord injury; Diffuse axonal injury; Wallerian degeneration ID WHITE-MATTER PATHOLOGY; IN-VIVO; MULTIPLE-SCLEROSIS; FIBER TRACKING; AXONAL INJURY; ANGULAR RESOLUTION; WATER DIFFUSION; MOUSE MODEL; QUANTITATIVE ASSESSMENT; CORTICOSPINAL TRACTS AB One goal of in vivo neuroimaging is the detection of neurodegenerative processes and anatomical reorganizations after spinal cord (SC) injury. Non-invasive examination of white matter fibers in the living SC can be conducted using magnetic resonance diffusion-weighted imaging. However, this technique is challenging at the spinal level due to the small cross-sectional size of the cord and the presence of physiological motion and susceptibility artifacts. In this study, we acquired in vivo high angular resolution diffusion imaging (HARDI) data at 3T in cats submitted to partial SC injury. Cats were imaged before. 3 and 21 days after injury. Spatial resolution was enhanced to 1.5 x 1.5 x 1 mm(3) using super-resolution technique and distortions were corrected using the reversed gradient method. Tractography-derived regions of interest were generated in the dorsal, ventral, right and left quadrants. to evaluate diffusion tensor imaging (DTI) and Q-Ball imaging metrics with regards to their sensitivity in detecting primary and secondary lesions. A three-way ANOVA tested the effect of session (intact, D3, D21), cross-sectional region (left, right, dorsal and ventral) and rostrocaudal location. Significant effect of session was found for FA (P<0.001), GFA (P<0.05) and radial diffusivity (P<0.001). Post-hoc paired T-test corrected for multiple comparisons showed significant changes at the lesion epicenter (P<0.005). More interestingly, significant changes were also found several centimeters from the lesion epicenter at both 3 and 21 days. This decrease was specific to the type of fibers, i.e.. rostrally to the lesion on the dorsal aspect of the cord and caudally to the lesion ipsilaterally, suggesting the detection of Wallerian degeneration. (C) 2011 Elsevier Inc. All rights reserved. C1 [Cohen-Adad, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Cohen-Adad, J.; Leblond, H.; Delivet-Mongrain, H.; Martinez, M.; Rossignol, S.] Univ Montreal, Fac Med, Dept Physiol, GRSNC, Montreal, PQ H3C 3J7, Canada. [Benali, H.] UPMC, Pitie Salpetriere Hosp, INSERM, UMR 678, Paris, France. RP Cohen-Adad, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging, 149 13 St, Charlestown, MA 02129 USA. EM jcohen@nmr.mgh.harvard.edu FU Christopher and Dana Reeve Foundation; Multidisciplinary Team for Locomotor Rehabilitation of the Canadian Institute of Health Research; Canada Research Chair; Association pour la Recherche sur la Sclerose en Plaques (ARSEP, France) FX The authors thank Dr. Janyne Provencher (GRSNC) and Carollyn Hurst (Functional Neuroimaging Unit of the Centre de Recherche de l'Institut de Geriatrie) for help with acquisition and Dr. Maxime Descoteaux for providing the code to compute the Q-Ball ODF. This study was supported by the Christopher and Dana Reeve Foundation (S.R.) and by the Multidisciplinary Team for Locomotor Rehabilitation of the Canadian Institute of Health Research (S.R.) and a Canada Research Chair (S.R.). J.C-A received support from the Association pour la Recherche sur la Sclerose en Plaques (ARSEP, France). NR 79 TC 23 Z9 23 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2011 VL 57 IS 3 SI SI BP 1068 EP 1076 DI 10.1016/j.neuroimage.2011.04.068 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 792CK UT WOS:000292717900040 PM 21596140 ER PT J AU Gilden, D Mahalingam, R Nagel, MA Pugazhenthi, S Cohrs, RJ AF Gilden, D. Mahalingam, R. Nagel, M. A. Pugazhenthi, S. Cohrs, R. J. TI Review: The neurobiology of varicella zoster virus infection SO NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY LA English DT Review DE animal model; apoptosis; latency; neurological disease; VZV ID HUMAN TRIGEMINAL GANGLIA; HERPES-SIMPLEX-VIRUS; AFRICAN-GREEN MONKEYS; POLYMERASE-CHAIN-REACTION; DORSAL-ROOT GANGLIA; BLOOD MONONUCLEAR-CELLS; LATENCY-ASSOCIATED TRANSCRIPT; OUTER RETINAL NECROSIS; HUMAN SENSORY GANGLIA; VZV IGG ANTIBODY AB Varicella zoster virus (VZV) is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. Although VZV cannot be isolated from human ganglia, nucleic acid hybridization and, later, polymerase chain reaction proved that VZV is latent in ganglia. Declining VZV-specific host immunity decades after primary infection allows virus to reactivate spontaneously, resulting in shingles (zoster) characterized by pain and rash restricted to one to three dermatomes. Multiple other serious neurological and ocular disorders also result from VZV reactivation. This review summarizes the current state of knowledge of the clinical and pathological complications of neurological and ocular disease produced by VZV reactivation, molecular aspects of VZV latency, VZV virology and VZV-specific immunity, the role of apoptosis in VZV-induced cell death and the development of an animal model provided by simian varicella virus infection of monkeys. C1 [Gilden, D.; Mahalingam, R.; Nagel, M. A.; Cohrs, R. J.] Univ Colorado, Sch Med, Dept Neurol, Aurora, CO 80045 USA. [Gilden, D.] Univ Colorado, Sch Med, Dept Microbiol, Aurora, CO 80045 USA. [Pugazhenthi, S.] Univ Colorado, Sch Med, Dept Med, Aurora, CO 80045 USA. [Pugazhenthi, S.] Denver VA Med Ctr, Denver, CO USA. RP Gilden, D (reprint author), Univ Colorado, Sch Med, Dept Neurol, 12700 E 19th Ave,Box B182, Aurora, CO 80045 USA. EM don.gilden@ucdenver.edu FU NIH [AG006127, AG032958, NS067070]; Veterans Administration [NEUD-004-07F] FX The authors' studies cited in this Review were funded by NIH grants AG006127 to DG, AG032958 to DG, SP, RJC and NS067070 to MAN; and Merit Review grant NEUD-004-07F from the Veterans Administration to SP. NR 202 TC 55 Z9 55 U1 2 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0305-1846 J9 NEUROPATH APPL NEURO JI Neuropathol. Appl. Neurobiol. PD AUG PY 2011 VL 37 IS 5 BP 441 EP 463 DI 10.1111/j.1365-2990.2011.01167.x PG 23 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 791VF UT WOS:000292694300001 PM 21342215 ER PT J AU Kaplan, GB Moore, KA AF Kaplan, Gary B. Moore, Katherine A. TI The use of cognitive enhancers in animal models of fear extinction SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Review DE Fear; Anxiety; Extinction; Gamma-aminobutyric acid; Glutamate; Brain derived neurotrophic factor; Amygdala; Prefrontal cortex; Plasticity ID CYCLOSERINE FACILITATES EXTINCTION; HIPPOCAMPAL INACTIVATION DISRUPTS; VENTROMEDIAL PREFRONTAL CORTEX; POSTTRAUMATIC-STRESS-DISORDER; ENDOGENOUS CANNABINOID SYSTEM; RANDOMIZED CONTROLLED-TRIAL; CONTEXT CONDITIONED FEAR; ACTIVATED PROTEIN-KINASE; DOPAMINE D-1 RECEPTOR; POTENTIATED STARTLE AB In anxiety disorders, such as posttraumatic stress disorders and phobias, classical conditioning pairs natural (unconditioned) fear-eliciting stimuli with contextual or discrete cues resulting in enduring fear responses to multiple stimuli. Extinction is an active learning process that results in a reduction of conditioned fear responses after conditioned stimuli are no longer paired with unconditioned stimuli. Fear extinction often produces incomplete effects and this highlights the relative permanence of bonds between conditioned stimuli and conditioned fear responses. The animal research literature is rich in its demonstration of cognitive enhancing agents that alter fear extinction. This review specifically examines the fear extinguishing effects of cognitive enhancers that act on gamma-aminobutyric acid (GABA), glutamatergic, cholinergic, adrenergic, dopaminergic, and cannabinoid signaling pathways. It also examines the effects of compounds that alter epigenetic and neurotrophic mechanisms in fear extinction. Of these cognitive enhancers, glutamatergic N-methyl D-aspartate (NMDA) receptor agonists, such as D-cycloserine, have enhanced fear extinction in a context-, dose- and time-dependent manner. Agents that function as glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonists, alpha2-adrenergic receptor antagonists (such as yohimbine), neurotrophic factors (brain derived neurotrophic factor or BDNF) and histone deacetylase inhibitors (valproate and sodium butyrate) also improve fear extinction in animals. However, some have anxiogenic effects and their contextual and temporal effects need to be more reliably demonstrated. Various cognitive enhancers produce changes in cortico-amygdala synaptic plasticity through multiple mechanisms and these neural changes enhance fear extinction. We need to better define the changes in neural plasticity produced by these agents in order to develop more effective compounds. In the clinical setting, such use of effective cognitive enhancers with cue exposure therapy, using compounds derived from animal model studies, provides great hope for the future treatment of anxiety disorders. Published by Elsevier Inc. C1 [Kaplan, Gary B.] VA Boston Healthcare Syst, Mental Hlth Serv, Boston, MA USA. [Moore, Katherine A.] VA Boston Healthcare Syst, Res Serv, Boston, MA USA. [Kaplan, Gary B.; Moore, Katherine A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Moore, Katherine A.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Kaplan, Gary B.] VA Boston Healthcare Syst, Psychiat Serv, Boston, MA USA. RP Kaplan, GB (reprint author), VA Boston, 150 S Huntington Ave, Boston, MA 02130 USA. EM gary.kaplan@va.gov FU Department of Veterans Affairs; Department of Defense FX The authors acknowledge grants from the Department of Veterans Affairs (Merit Reviews) and the Department of Defense (CDMRP Concept Award). Both authors contributed to and have approved the final draft of the manuscript. NR 146 TC 49 Z9 53 U1 5 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD AUG PY 2011 VL 99 IS 2 SI SI BP 217 EP 228 DI 10.1016/j.pbb.2011.01.009 PG 12 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 791OA UT WOS:000292673300009 PM 21256147 ER PT J AU Goff, DC Hill, M Barch, D AF Goff, Donald C. Hill, Michele Barch, Deanna TI The treatment of cognitive impairment in schizophrenia SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Schizophrenia; Cognition; Pharmacology; Drug development; Clinical trials ID PLACEBO-CONTROLLED-TRIAL; SCHIZOTYPAL PERSONALITY-DISORDER; DONEPEZIL ADJUNCTIVE TREATMENT; 5-HT6 RECEPTOR ANTAGONISTS; DOPAMINE D-1 RECEPTOR; CEREBRAL-BLOOD-FLOW; OF-CONCEPT TRIAL; DOUBLE-BLIND; WORKING-MEMORY; D-CYCLOSERINE AB Cognitive deficits are major contributors to disability in schizophrenia. Many pharmacologic targets have been identified for cognitive enhancing agents, including receptors involved in dopaminergic, glutamatergic, GABAergic, serotonergic and cholinergic neurotransmission. In addition, new approaches to drug development have been directed towards neuroprotection and the facilitation of neuroplasticity. While several pharmacologic agents and cognitive remediation have shown promise in early trials, no treatment has yet demonstrated efficacy in large replication trials. The experience with different pharmacologic targets is reviewed and methodologic issues are discussed with recommendations for future research. (C) 2010 Elsevier Inc. All rights reserved. C1 [Goff, Donald C.] Massachusetts Gen Hosp, Freedom Trail Clin, Schizophrenia Program, Boston, MA 02114 USA. [Goff, Donald C.; Hill, Michele] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Barch, Deanna] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna] Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. [Barch, Deanna] Washington Univ, Dept Radiol, St Louis, MO 63130 USA. RP Goff, DC (reprint author), Massachusetts Gen Hosp, Freedom Trail Clin, Schizophrenia Program, 25 Staniford St, Boston, MA 02114 USA. EM goff@psych.mgh.harvard.edu RI Barch, Deanna/G-8638-2013 FU [5K24MH002025 (DG)] FX Supported by 5K24MH002025 (DG). NR 152 TC 53 Z9 56 U1 2 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD AUG PY 2011 VL 99 IS 2 SI SI BP 245 EP 253 DI 10.1016/j.pbb.2010.11.009 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 791OA UT WOS:000292673300011 PM 21115035 ER PT J AU Brady, KT Gray, KM Tolliver, BK AF Brady, Kathleen T. Gray, Kevin M. Tolliver, Bryan K. TI Cognitive enhancers in the treatment of substance use disorders: Clinical evidence SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Review DE Cognition; Addiction; Pharmacotherapy; Medications; Substance use disorders; Learning and memory ID PLACEBO-CONTROLLED TRIAL; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; COCAINE-DEPENDENT INDIVIDUALS; TOBACCO WITHDRAWAL SYNDROME; DRUG-SEEKING BEHAVIOR; DOUBLE-BLIND; D-CYCLOSERINE; METHAMPHETAMINE DEPENDENCE; PREFRONTAL CORTEX AB Attenuation of drug reward has been the major focus of medication development in the addiction area to date. With the growth of research in the area of cognitive neuroscience, the importance of executive function and inhibitory cognitive control in addictive disorders is becoming increasingly apparent. An emerging strategy in the pharmacotherapy of addictions and other psychiatric disorders involves the use of medications that improve cognitive function. In particular, agents that facilitate inhibitory and attentional control, improve abstraction, planning and mental flexibility could be beneficial in the treatment of substance use disorders. Because there are multiple neurotransmitter systems involved in the regulation of cognitive function, agents from a number of drug classes have been tested. In particular, agents acting through the cholinergic, adrenergic and glutamatergic systems have shown potential for improving cognitive function in a number of psychiatric and neurologic disorders, but most of these agents have not been tested in the treatment of individuals with substance use disorders. This manuscript provides a review of clinical data supporting the use of the major classes of cognitive enhancing agents in substance use disorders. Agents that have shown promise in cognitive enhancement in other disorders, and have a theoretical or mechanistic rationale for application to substance use disorders are also highlighted. (C) 2011 Elsevier Inc. All rights reserved. C1 [Brady, Kathleen T.; Gray, Kevin M.; Tolliver, Bryan K.] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Brady, Kathleen T.] Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Brady, KT (reprint author), Med Univ S Carolina, Dept Psychiat, 67 President St, Charleston, SC 29425 USA. EM bradyk@musc.edu; graykm@musc.edu; tollive@musc.edu FU NIDA NIH HHS [R01 DA023188, R01 DA023188-03, R01 DA023188-04, R01 DA026777, R21 DA026085, R21 DA026085-02, R25 DA020537] NR 140 TC 37 Z9 39 U1 8 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD AUG PY 2011 VL 99 IS 2 SI SI BP 285 EP 294 DI 10.1016/j.pbb.2011.04.017 PG 10 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 791OA UT WOS:000292673300015 PM 21557964 ER PT J AU Barnett, JH Huang, J Perlis, RH Young, MM Rosenbaum, JF Nierenberg, AA Sachs, G Nimgaonkar, VL Miklowitz, DJ Smoller, JW AF Barnett, J. H. Huang, J. Perlis, R. H. Young, M. M. Rosenbaum, J. F. Nierenberg, A. A. Sachs, G. Nimgaonkar, V. L. Miklowitz, D. J. Smoller, J. W. TI Personality and bipolar disorder: dissecting state and trait associations between mood and personality SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Bipolar disorder; extraversion; NEO-FFI; neuroticism; personality ID NATIONALLY REPRESENTATIVE SAMPLE; POPULATION-BASED TWIN; MAJOR DEPRESSION; 5-FACTOR MODEL; UNIPOLAR DEPRESSION; ANXIETY DISORDERS; SOCIAL PHOBIA; NEUROTICISM; RISK; SYMPTOMS AB Background. Some personality characteristics have previously been associated with an increased risk for psychiatric disorder. Longitudinal studies are required in order to tease apart temporary (state) and enduring (trait) differences in personality among individuals with bipolar disorder (BD). This study aimed to determine whether there is a characteristic personality profile in BD, and whether associations between BD and personality are best explained by state or trait effects. Method. A total of 2247 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder study completed the NEO Five-Factor Inventory administered at study entry, and at 1 and 2 years. Results. Personality in BD was characterized by high neuroticism (N) and openness (O), and low agreeableness (A), conscientiousness (C) and extraversion (E). This profile was replicated in two independent samples, and openness was found to distinguish BD from major depressive disorder. Latent growth modeling demonstrated that manic symptoms were associated with increased E and decreased A, and depressed symptoms with higher N and lower E, A, C and O. During euthymic phases, high N and low E scores predicted a future depression-prone course. Conclusions. While there are clear state effects of mood on self-reported personality, personality variables during euthymia predict future course of illness. Personality disturbances in extraversion, neuroticism and openness may be enduring characteristics of patients with BD. C1 [Barnett, J. H.; Huang, J.; Perlis, R. H.; Young, M. M.; Smoller, J. W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Barnett, J. H.; Huang, J.; Perlis, R. H.; Young, M. M.; Smoller, J. W.] Massachusetts Gen Hosp, Psychiat Genet Program Mood & Anxiety Disorders, Dept Psychiat, Boston, MA 02114 USA. [Barnett, J. H.] Univ Cambridge, Dept Psychiat, Cambridge, England. [Barnett, J. H.] Cambridge Cognit Ltd, Cambridge, England. [Perlis, R. H.; Nierenberg, A. A.; Sachs, G.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Perlis, R. H.; Nierenberg, A. A.; Sachs, G.] Harvard Univ, Sch Med, Boston, MA USA. [Nimgaonkar, V. L.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Nimgaonkar, V. L.] WPIC, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Miklowitz, D. J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat, Semel Inst, Los Angeles, CA 90024 USA. RP Smoller, JW (reprint author), Simches Res Bldg,185 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM jsmoller@hms.harvard.edu FU NIH [MH079799, MH063445, MH63420]; Millennium Pharmaceuticals; University of Cambridge FX This work was also supported by NIH grants MH079799 and MH063445 (J.W.S.) and MH63420 (V.L.N.). Collection of data from the MGH sample was supported by a grant from Millennium Pharmaceuticals to J.W.S. and J.F.R.; J.H.B. was supported by the University of Cambridge Parke-Davis Exchange Fellowship. NR 64 TC 36 Z9 37 U1 4 U2 18 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD AUG PY 2011 VL 41 IS 8 BP 1593 EP 1604 DI 10.1017/S0033291710002333 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 791XZ UT WOS:000292704400003 PM 21134316 ER PT J AU Kearney, DJ McDermott, K Martinez, M Simpson, TL AF Kearney, D. J. McDermott, K. Martinez, M. Simpson, T. L. TI Association of participation in a mindfulness programme with bowel symptoms, gastrointestinal symptom-specific anxiety and quality of life SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID VISCERAL SENSITIVITY INDEX; PTSD CHECKLIST; HEALTH-STATUS; PSYCHOMETRIC PROPERTIES; PSYCHOLOGICAL TREATMENT; ALTERNATIVE MEDICINE; BEHAVIORAL TREATMENT; COGNITIVE THERAPY; CONTROLLED TRIAL; UNITED-STATES AB Background Stress perception and GI-specific anxiety play key roles in irritable bowel syndrome (IBS). Mindfulness-based stress reduction (MBSR) is a widely available stress reduction course, which has not been evaluated for IBS. Aim To determine whether participation in MBSR is associated with improvement in bowel symptoms, GI-specific anxiety, and IBS-Quality of Life. Methods This is a prospective study of 93 participants in MBSR. We applied measures of Rome III IBS status, bowel symptoms (IBS-Severity Scoring System, IBS-SSS), IBS-Quality of Life (IBS-QOL), GI-specific anxiety (Visceral Sensitivity Index, VSI), mindfulness (Five Facet Mindfulness Questionnaire-FFMQ), and functional status (SF-8) at baseline and 2 and 6 months after enrolment. Results At 2 months, participation in MBSR was associated with small nonsignificant changes in IBS-SSS, IBS-QOL and VSI: d = -0.25, d = 0.08, d = -0.16, respectively. At 6 months, there was no significant change in IBS-SSS (d = -0.36); whereas for IBS-QOL and VSI there were significant improvements (IBS-QOL: d = 0.33, P = 0.044; VSI: d = -0.40, P = 0.014). For patients meeting Rome III IBS criteria (n = 43), changes in IBS-SSS, IBS-QOL and VSI were not statistically significant, but there was a significant correlation between the change in VSI and the change in FFMQ across the three time periods (r = 0.33). Conclusions Participation in MBSR is associated with improvement IBS-related quality of life and GI-specific anxiety. Randomised controlled trials are warranted to further assess the role of MBSR for IBS symptomatology. C1 [Kearney, D. J.] Univ Washington, Sch Med, Dept Med, Div Gastroenterol, Seattle, WA 98195 USA. [McDermott, K.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Simpson, T. L.] VA Puget Sound Hlth Care Syst, CESATE, Seattle, WA USA. [Simpson, T. L.] VA Puget Sound Hlth Care Syst, MIRECC, Seattle, WA USA. [Simpson, T. L.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Kearney, DJ (reprint author), Seattle VAMC 111GI,1660 S Columbian Way, Seattle, WA 98108 USA. EM David.kearney@va.gov FU VA Puget Sound Health Care System FX Declaration of personal interests: This work was supported by resources from VA Puget Sound Health Care System. We wish to thank Kurt Hoelting, M. Div., who taught some of the MBSR courses for this study. We also wish to thank the Veterans who participated in this research. Declaration of funding interests: None. NR 64 TC 20 Z9 20 U1 3 U2 23 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD AUG PY 2011 VL 34 IS 3 BP 363 EP 373 DI 10.1111/j.1365-2036.2011.04731.x PG 11 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 787RQ UT WOS:000292394800011 PM 21651595 ER PT J AU Walker, RH AF Walker, Ruth H. TI Differential Diagnosis of Chorea SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Chorea; Huntington's disease; Basal ganglia; Neuroacanthocytosis; Huntington disease-like ID DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; CALCIFICATION FAHR-DISEASE; CREUTZFELDT-JAKOB-DISEASE; BENIGN HEREDITARY CHOREA; DEEP BRAIN-STIMULATION; ADULT-ONSET CHOREA; TERM-FOLLOW-UP; HUNTINGTONS-DISEASE; BASAL GANGLIA; MOVEMENT-DISORDERS AB Chorea is a common movement disorder that can be caused by a large variety of structural, neurochemical (including pharmacologic), or metabolic disturbances to basal ganglia function, indicating the vulnerability of this brain region. The diagnosis is rarely indicated by the simple phenotypic appearance of chorea, and can be challenging, with many patients remaining undiagnosed. Clues to diagnosis may be found in the patient's family or medical history, on neurologic examination, or upon laboratory testing and neuroimaging. Increasingly, advances in genetic medicine are identifying new disorders and expanding the phenotype of recognized conditions. Although most therapies at present are supportive, correct diagnosis is essential for appropriate genetic counseling, and ultimately, for future molecular therapies. C1 [Walker, Ruth H.] James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY 10468 USA. [Walker, Ruth H.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. RP Walker, RH (reprint author), James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY 10468 USA. EM ruth.walker@mssm.edu NR 103 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD AUG PY 2011 VL 11 IS 4 BP 385 EP 395 DI 10.1007/s11910-011-0202-2 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 788RU UT WOS:000292462900005 PM 21465146 ER PT J AU Ryan, J Bloch, K Archer, SL AF Ryan, J. Bloch, K. Archer, S. L. TI Rodent models of pulmonary hypertension: harmonisation with the world health organisation's categorisation of human PH SO INTERNATIONAL JOURNAL OF CLINICAL PRACTICE LA English DT Review ID FAWN-HOODED RAT; SMOOTH-MUSCLE-CELLS; NITRIC-OXIDE SYNTHASE; 5-HYDROXYTRYPTAMINE TRANSPORTER GENE; CHRONICALLY HYPOXIC RATS; RECEPTOR-DEFICIENT RATS; AORTA-BANDED RATS; ARTERIAL-HYPERTENSION; HEART-FAILURE; II RECEPTOR AB The WHO classification of pulmonary hypertension (PH) recognises five distinct groups, all sharing a mean, resting, pulmonary artery pressure (PAP) > 25 mmHg. The aetiology of PH varies by group (1-pulmonary vascular disease, 2-high left heart filling pressures, 3-hypoxia, 4-unresolved pulmonary embolism and 5-miscellaneous). Inclusion in a group reflects shared histological, haemodynamic and pathophysiological features and has therapeutic implications. Advantages of using rodent models to understand the pathophysiology of human PH and to test experimental therapies include the economy, safety and mechanistic certainty they provide. As rodent models are meant to reflect human PH, they should be categorised by a parallel PH classification and limitations in achieving this ideal recognised. Challenges with rodent models include: accurate phenotypic characterisation (haemodynamics, histology and imaging), species and strain variations in the natural history of PH, and poor fidelity to the relevant human PH group. Rat models of group 1 PH include: monocrotaline (+/- pneumonectomy), chronic hypoxia + SU-5416 (a VEGF receptor inhibitor) and the fawn-hooded rat (FHR). Mouse models of group 1 PH include: transgenic mice overexpressing the serotonin transporter or dominant-negative mutants of bone morphogenetic protein receptor-2. Group 1 PH is also created by infecting S100A4/Mts1 mice with gamma-herpesvirus. The histological features of group 1 PH, but not PH itself, are induced by exposure to Schistosoma mansoni or Stachybotrys chartarum. Group 3 PH is modelled by exposure of rats or mice to chronic hypoxia. Rodent models of groups 2, 4 and 5 PH are needed. Comprehensive haemodynamic, histological and molecular phenotyping, coupled with categorisation into WHO PH groups, enhances the utility of rodent models. C1 [Ryan, J.; Archer, S. L.] Univ Chicago, Dept Med, Cardiol Sect, Chicago, IL 60637 USA. [Bloch, K.] Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Archer, SL (reprint author), Univ Chicago, Dept Med, Cardiol Sect, S Maryland Ave,MC6080, Chicago, IL 60637 USA. EM sarcher@medicine.bsd.uchicago.edu RI Ryan, John/B-7632-2012; Archer, Stephen/C-3621-2013 FU American Heart Association (AHA); Roche Foundation for Anemia Research; [NIH-RO1-HL071115]; [1RC1HL099462-01] FX This work is supported by NIH-RO1-HL071115 and 1RC1HL099462-01, the American Heart Association (AHA) and the Roche Foundation for Anemia Research. The authors acknowledge Drs. Glenn Marsboom and Christian Wietholt for contributing the images in Figure 4. NR 108 TC 24 Z9 24 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1368-5031 J9 INT J CLIN PRACT JI Int. J. Clin. Pract. PD AUG PY 2011 VL 65 SU 172 SI SI BP 15 EP 34 DI 10.1111/j.1742-1241.2011.02710.x PG 20 WC Medicine, General & Internal; Pharmacology & Pharmacy SC General & Internal Medicine; Pharmacology & Pharmacy GA 789LF UT WOS:000292516300004 ER PT J AU Lin, JC Guerrieri, JG Moore, AA AF Lin, James C. Guerrieri, Joy Gioia Moore, Alison A. TI Drinking Patterns and the Development of Functional Limitations in Older Adults: Longitudinal Analyses of the Health and Retirement Survey SO JOURNAL OF AGING AND HEALTH LA English DT Article DE alcohol; drinking patterns; functional limitations ID MODERATE ALCOHOL-CONSUMPTION; CORONARY-HEART-DISEASE; ISCHEMIC-STROKE; UNITED-STATES; US ADULTS; AGE 50; MORTALITY; RISK; MEN; PEOPLE AB Objective: To examine whether consistent low-risk drinking is associated with lower risk of developing functional limitations among older adults. Method: Data were obtained from five waves of the Health and Retirement Study. Function was assessed by questions measuring four physical abilities and five instrumental activities of daily living. Five different drinking patterns were determined using data over two consecutive survey periods. Results: Over the follow-up periods, 38.6% of older adults developed functional limitations. Consistent low-risk drinkers had lower odds of developing functional limitations compared with consistent abstainers, and the effect of consistent low-risk drinking was greater among those aged 50 to 64 years compared with those aged >= 65 years. Other drinking patterns were not associated with lower odds of incident functional limitation. Discussion: Consistent low-risk drinking was associated with lower odds of developing functional limitations, and this association was greater among older middle-aged adults aged 50 to 64 years. C1 [Lin, James C.] Cheng Ching Hosp, Dept Med, Taichung 40764, Taiwan. [Lin, James C.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Guerrieri, Joy Gioia] Mayo Clin, Rochester, MN USA. [Moore, Alison A.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. RP Lin, JC (reprint author), Cheng Ching Hosp, Dept Med, 118 Sec 3,Chun Kang Rd, Taichung 40764, Taiwan. EM jlin1207@ucla.edu FU NIA NIH HHS [T35 AG026736, T35 AG026736-06, P30AG021684, P30 AG021684-07, P30 AG021684]; NIAAA NIH HHS [R01 AA013937, K24 AA015957-04, K24 AA015957, K24 AA15957] NR 37 TC 12 Z9 12 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 J9 J AGING HEALTH JI J. Aging Health PD AUG PY 2011 VL 23 IS 5 BP 806 EP 821 DI 10.1177/0898264310397541 PG 16 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA 788NE UT WOS:000292450900003 PM 21311049 ER PT J AU Banaszak-Holl, J Liang, J Quinones, A Cigolle, C Lee, IC Verbrugge, LM AF Banaszak-Holl, Jane Liang, Jersey Quinones, Ana Cigolle, Christine Lee, I-Cha Verbrugge, Lois M. TI Trajectories of Functional Change Among Long Stayers in Nursing Homes: Does Baseline Impairment Matter? SO JOURNAL OF AGING AND HEALTH LA English DT Article DE health services; nursing homes; physical function ID MINIMUM DATA SET; RESIDENT ASSESSMENT INSTRUMENT; SELF-RATED HEALTH; DISABLEMENT PROCESS; OLDER PERSONS; TERM-CARE; RELIABILITY; FRAILTY; MDS; DISABILITY AB Objectives: This study reports findings on functional change trajectories for long-stay residents by examining the effects of baseline medical conditions and functional status on changes in physical impairment across residents' length of stay (LOS). Method: A 5% sample of nursing home residents from Michigan from 1999 through 2003 was used to create longitudinal episodes of care including Minimum Data Set (MDS) assessments. Data were analyzed using hierarchical linear models. Results: On average, physical impairment increases throughout a resident's stay and is more rapid later in the stay. Greater physical and cognitive impairment at baseline leads to increasing impairment for residents whereas presence of baseline medical conditions, including heart disease and hip fracture, leads to slower rates of impairment. Discussion: Baseline functional status is critical to predicting changes in impairment while the impact of medical diagnoses is significant but weaker than the effect of baseline impairment. C1 [Banaszak-Holl, Jane] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Quinones, Ana] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Quinones, Ana] Portland VA Med Ctr, Portland, OR USA. [Cigolle, Christine] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Lee, I-Cha] Univ Calif Irvine, Irvine, CA USA. RP Banaszak-Holl, J (reprint author), Univ Michigan, Sch Publ Hlth, 1415 Washington Hts, Ann Arbor, MI 48109 USA. EM janebh@umich.edu FU NIA NIH HHS [K08 AG031837] NR 42 TC 3 Z9 3 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 J9 J AGING HEALTH JI J. Aging Health PD AUG PY 2011 VL 23 IS 5 BP 862 EP 882 DI 10.1177/0898264311399759 PG 21 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA 788NE UT WOS:000292450900006 PM 21436394 ER PT J AU Saylor, PJ Morton, RA Hancock, ML Barnette, KG Steiner, MS Smith, MR AF Saylor, Philip J. Morton, Ronald A. Hancock, Michael L. Barnette, K. Gary Steiner, Mitchell S. Smith, Matthew R. TI Factors Associated With Vertebral Fractures in Men Treated With Androgen Deprivation Therapy for Prostate Cancer SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; androgens; fractures; bone; osteoporosis ID BONE-MINERAL DENSITY; OLDER MEN; OSTEOPOROTIC FRACTURES; HORMONE AGONISTS; RANCHO BERNARDO; SEX STEROIDS; ELDERLY-MEN; RISK; ESTRADIOL; WOMEN AB Purpose: Androgen deprivation therapy for prostate cancer causes accelerated loss of bone mineral density and is associated with increased fracture risk. We evaluated risk factors associated with vertebral fractures among men enrolled in a fracture prevention trial. Materials and Methods: Analysis included men receiving androgen deprivation therapy for prostate cancer and enrolled in a phase III fracture prevention trial. All men were 70 years old or older or had a low bone mineral density (T-score less than -1.5 for the lumbar spine or total hip). We analyzed demographic and laboratory characteristics of men with and those without vertebral fractures at study entry. Results: Of the 1,244 subjects 162 (13.0%) had a vertebral fracture at baseline. The 2 factors significantly associated with vertebral fractures were white race (p = 0.028 compared with nonwhite race) and osteoporosis (p = 0.002 for osteoporosis at any site, p = 0.053 for osteoporosis at the spine, p = 0.002 for osteoporosis at the hip). Lower bone mineral density was also significantly associated with vertebral fractures when analyzed as a continuous variable. Factors not associated with vertebral fractures included age, country of residence, androgen deprivation therapy duration at baseline, androgen deprivation therapy mode, body mass index, testosterone, estradiol, C-telopeptide, bone specific alkaline phosphatase and osteocalcin. Results were similar in analyses limited to men 70 years old or older. Conclusions: White race and low bone mineral density were significantly associated with vertebral fractures in this study of men treated with androgen deprivation for prostate cancer. These observations should inform the assessment and management of fracture risk among such men. C1 [Saylor, Philip J.; Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA 02114 USA. [Morton, Ronald A.] GTx Inc, Memphis, TN USA. RP Saylor, PJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, 55 Fruit St,Yawkey 7E, Boston, MA 02114 USA. EM psaylor@partners.org FU American Society of Clinical Oncology; Prostate Cancer Foundation; National Institutes of Health [5K24CA12199002] FX Recipient of grants from the American Society of Clinical Oncology and the Prostate Cancer Foundation.; Recipient of a National Institutes of Health K24 Midcareer Investigator Award (5K24CA12199002) and awards from the Prostate Cancer Foundation. NR 29 TC 13 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2011 VL 186 IS 2 BP 482 EP 486 DI 10.1016/j.juro.2011.03.111 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 789VJ UT WOS:000292545100035 PM 21679977 ER PT J AU Kerfoot, BP Baker, H Connelly, D Joseph, DB Matson, S Ritchey, ML AF Kerfoot, B. Price Baker, Harley Connelly, Donna Joseph, David B. Matson, Sonia Ritchey, Michael L. TI Do Chief Resident Scores on the In-Service Examination Predict Their Performance on the American Board of Urology Qualifying Examination? SO JOURNAL OF UROLOGY LA English DT Article DE urology; education, medical, graduate; educational measurement; internship and residency; certification AB Purpose: The American Urological Association In-Service Examination and the American Board of Urology Qualifying Examination are written multiple choice tests that cover all domains in urology. We investigated whether In-Service Examination performance could identify chief residents who scored in the lowest quartile on the Qualifying Examination. Materials and Methods: All urology chief residents in the United States and Canada in 2008 and 2009 were eligible to participate in this study. In-Service Examination 2008 and Qualifying Examination 2009 performance data were obtained from the American Urological Association and American Board of Urology, respectively. Data were analyzed with the Pearson correlation and descriptive statistics. Results: Of the 257 American and Canadian chief residents who completed the Qualifying Examination 2009, 194 (75%) enrolled in this study and were included in analysis. Overall In-Service Examination 2008 scores correlated significantly with Qualifying Examination 2009 scores (r = 0.55, p < 0.001), accounting for 30% of score variance. Substantial variability in In-Service Examination-Qualifying Examination rankings was notable among individual residents. An In-Service Examination 2008 cutoff percentile rank of 40% identified chief residents in the lowest quartile on the Qualifying Examination 2009 with 71% sensitivity, 77% specificity, and a likelihood ratio of 3.1 and 0.4 (positive and negative likelihood ratios, respectively). Conclusions: The substantial variability of In-Service Examination-Qualifying Examination performance among individual chief residents limits In-Service Examination predictive utility. A single In-Service Examination score should not be used to make a high stakes judgment about an individual resident. In-Service Examination scores should be used as 1 part of an overall evaluation program to prospectively identify residents who could benefit from additional educational support. C1 [Kerfoot, B. Price] Vet Affairs Boston Healthcare Syst, Surg Serv, Urol Sect, Jamaica Plain, MA 02130 USA. [Kerfoot, B. Price] Harvard Univ, Sch Med, Boston, MA USA. [Baker, Harley] Calif State Univ, Channel Isl, CA USA. [Connelly, Donna; Matson, Sonia] Amer Urol Assoc, Linthicum, MD USA. [Joseph, David B.] Univ Alabama, Div Urol, Birmingham, AL USA. [Ritchey, Michael L.] Mayo Clin, Dept Urol, Phoenix, AZ USA. RP Kerfoot, BP (reprint author), Vet Affairs Boston Healthcare Syst, Surg Serv, Urol Sect, 150 S Huntington Ave,151DIA, Jamaica Plain, MA 02130 USA. EM price.kerfoot@gmail.com FU American Urological Association; American Urological Association Foundation, Linthicum, Maryland; Astellas Pharma US, Inc.; United States Agency for Healthcare Research and Quality FX Supported by the American Urological Association and American Urological Association Foundation, Linthicum, Maryland, Astellas Pharma US, Inc. and the United States Agency for Healthcare Research and Quality. NR 5 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 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2011 VL 186 IS 2 BP 634 EP 637 DI 10.1016/j.juro.2011.03.126 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 789VJ UT WOS:000292545100103 PM 21683391 ER PT J AU Zhang, M AF Zhang, Min TI Re: Expression of Estrogen Related Proteins in Hormone Refractory Prostate Cancer: Association With Tumor Progression SO JOURNAL OF UROLOGY LA English DT Letter C1 Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Zhang, M (reprint author), Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. EM mzhnag5@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2011 VL 186 IS 2 BP 756 EP 756 DI 10.1016/j.juro.2011.03.160 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 789VJ UT WOS:000292545100131 PM 21683411 ER PT J AU Matreyek, KA Engelman, A AF Matreyek, Kenneth A. Engelman, Alan TI The Requirement for Nucleoporin NUP153 during Human Immunodeficiency Virus Type 1 Infection Is Determined by the Viral Capsid SO JOURNAL OF VIROLOGY LA English DT Article ID NUCLEAR-PORE COMPLEX; REVERSE TRANSCRIPTION COMPLEXES; MURINE LEUKEMIA-VIRUS; NONDIVIDING CELLS; RETROTRANSPOSON TF1; PREINTEGRATION COMPLEXES; RETROVIRAL INFECTION; HIV-1 REPLICATION; DNA INTEGRATION; ANEMIA-VIRUS AB Lentiviruses likely infect nondividing cells by commandeering host nuclear transport factors to facilitate the passage of their preintegration complexes (PICs) through nuclear pore complexes (NPCs) within nuclear envelopes. Genome-wide small interfering RNA screens previously identified karyopherin beta transportin-3 (TNPO3) and NPC component nucleoporin 153 (NUP153) as being important for infection by human immunodeficiency virus type 1 (HIV-1). The knockdown of either protein significantly inhibited HIV-1 infectivity, while infection by the gammaretrovirus Moloney murine leukemia virus (MLV) was unaffected. Here, we establish that primate lentiviruses are particularly sensitive to NUP153 knockdown and investigate HIV-1-encoded elements that contribute to this dependency. Mutants lacking functional Vpr or the central DNA flap remained sensitive to NUP153 depletion, while MLV/HIV-1 chimera viruses carrying MLV matrix, capsid, or integrase became less sensitive when the latter two elements were substituted. Two capsid missense mutant viruses, N74D and P90A, were largely insensitive to NUP153 depletion, as was wild-type HIV-1 when cyclophilin A was depleted simultaneously or when infection was conducted in the presence of cyclosporine A. The codepletion of NUP153 and TNPO3 yielded synergistic effects that outweighed those calculated based on individual knockdowns, indicating potential interdependent roles for these factors during HIV-1 infection. Quantitative PCR revealed normal levels of late reverse transcripts, a moderate reduction of 2-long terminal repeat (2-LTR) circles, and a relatively large reduction in integrated proviruses upon NUP153 knockdown. These results suggest that capsid, likely by the qualities of its uncoating, determines whether HIV-1 requires cellular NUP153 for PIC nuclear import. C1 [Engelman, Alan] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Engelman, A (reprint author), Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, 450 Brookline Ave,CLS 1010, Boston, MA 02215 USA. EM alan_engelman@dfci.harvard.edu OI Matreyek, Kenneth/0000-0001-9149-551X FU National Institutes of Health [AI052014, P30AI060354]; Harvard University Center for AIDS Research FX This work was supported by National Institutes of Health grant AI052014 (A. E.) and the Harvard University Center for AIDS Research, an NIH-funded program (P30AI060354) that is supported by the following NIH institutes and centers: NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, and NCCAM. NR 85 TC 83 Z9 83 U1 1 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2011 VL 85 IS 15 BP 7818 EP 7827 DI 10.1128/JVI.00325-11 PG 10 WC Virology SC Virology GA 788LV UT WOS:000292447300033 PM 21593146 ER PT J AU Chow, FC Edlow, BL Frosch, MP Copen, WA Greer, DM AF Chow, Felicia C. Edlow, Brian L. Frosch, Matthew P. Copen, William A. Greer, David M. TI Outcome in Patients with H1N1 Influenza and Cerebrovascular Injury Treated with Extracorporeal Membrane Oxygenation SO NEUROCRITICAL CARE LA English DT Article DE H1N1 influenza; Extracorporeal membrane oxygenation; Stroke; Intracerebral hemorrhage; Magnetic resonance imaging; Susceptibility-weighted imaging ID ACUTE NECROTIZING ENCEPHALOPATHY; INFECTION; EMBOLISM AB Although intracranial hemorrhage and infarction have been reported in patients with H1N1 influenza infection treated with extracorporeal membrane oxygenation (ECMO), the clinical outcomes of these patients are not well described. The authors present two patients with H1N1 influenza infection and diffuse cerebrovascular injury in the setting of ECMO. Diffuse cerebrovascular injury including intraparenchymal hemorrhage was found on head CT and brain MRI in both cases and confirmed by autopsy in one patient who died. Punctate foci of susceptibility effect were seen in both patients on T2* susceptibility-weighted or susceptibility-sensitive gradient echo sequences. These foci of susceptibility effect were consistent with infarction on histopathologic evaluation in the patient who died. The other patient made an excellent clinical recovery. Frequent and early surveillance imaging should be obtained in patients with H1N1 influenza infection undergoing ECMO, although the presence of diffuse cerebral injury, including intraparenchymal hemorrhage and multifocal punctate susceptibility effect, does not necessarily portend a poor prognosis. C1 [Chow, Felicia C.; Edlow, Brian L.] Massachusetts Gen Hosp, Dept Neurol, Wang Ambulatory Care Ctr, Boston, MA 02114 USA. [Chow, Felicia C.; Edlow, Brian L.; Frosch, Matthew P.; Copen, William A.] Harvard Univ, Boston, MA 02115 USA. [Copen, William A.] Massachusetts Gen Hosp, Div Neuroradiol, Dept Radiol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Greer, David M.] Yale New Haven Med Ctr, Dept Neurol, New Haven, CT 06504 USA. [Greer, David M.] Yale Univ, Sch Med, New Haven, CT USA. [Greer, David M.] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. RP Chow, FC (reprint author), Massachusetts Gen Hosp, Dept Neurol, Wang Ambulatory Care Ctr, 15 Parkman St,Suite 835, Boston, MA 02114 USA. EM fcchow@partners.org NR 14 TC 8 Z9 8 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 J9 NEUROCRIT CARE JI Neurocrit. Care PD AUG PY 2011 VL 15 IS 1 BP 156 EP 160 DI 10.1007/s12028-011-9534-7 PG 5 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA 789XI UT WOS:000292552100025 PM 21465323 ER PT J AU Blum, JL Kinsey, GR Monian, P Sun, B Cummings, BS McHowat, J Schnellmann, RG AF Blum, Jason L. Kinsey, Gilbert R. Monian, Prashant Sun, Bin Cummings, Brian S. McHowat, Jane Schnellmann, Rick G. TI Profiling of fatty acids released during calcium-induced mitochondrial permeability transition in isolated rabbit kidney cortex mitochondria SO TOXICOLOGY IN VITRO LA English DT Article DE Fatty acid profiling; Kidney; Calcium-independent phospholipase A(2) gamma; Mitochondrial swelling ID CA2+-INDEPENDENT PHOSPHOLIPASE A(2); CELL-DEATH; LIVER-MITOCHONDRIA; OXIDATIVE STRESS; INNER MEMBRANE; APOPTOSIS; METABOLISM; CA2+; IDENTIFICATION; ACCUMULATION AB Increases in intracellular Ca(2+) during cellular stress often lead to the mitochondrial permeability transition (MPT). We examined changes in fatty acids (FAs) released from isolated renal cortical mitochondria subjected to Ca(2+)-induced MPT. Exposing mitochondria to Ca(2+) stimulated mitochondrial swelling and release of FAs such as arachidonic (20:4) and docosahexenoic acids which increased 71% and 32%, respectively, and linoleic (18:2) which decreased 23% compared to controls. Stearic (18:0), oleic (18:1), and linoleic (18:3) acids were unchanged. To elucidate a mechanism for FA release, mitochondria were pre-treated with bromoenolactone (BEL) to inhibit Ca(2+)-independent phospholipase A(2) gamma activity (iPLA(2)gamma). BEL blocked Ca(2+)-induced release of arachidonic and behenic (22:0) acids. Finally, four FAs were released in the absence of Ca(2+) in a BEL-sensitive manner, including arachidonic and docosatrienoic acids. Thus, extensive FA release occurs during Ca(2+)-induced MPT, and that mitochondrial iPLA(2)gamma maintains mitochondrial arachidonic acid homeostasis under both basal and Ca(2+)-induced stress conditions. Published by Elsevier Ltd. C1 [Blum, Jason L.; Kinsey, Gilbert R.; Schnellmann, Rick G.] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Coll Pharm, Ctr Cell Death Injury & Regenerat, Charleston, SC 29425 USA. [Schnellmann, Rick G.] Ralph H Johnson VA Med Ctr Charleston, Charleston, SC 29401 USA. [Monian, Prashant; Sun, Bin; Cummings, Brian S.] Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA. [McHowat, Jane] St Louis Univ, Sch Med, Dept Pathol, St Louis, MO 63104 USA. RP Schnellmann, RG (reprint author), Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Coll Pharm, Ctr Cell Death Injury & Regenerat, POB 250140, Charleston, SC 29425 USA. EM schnell@musc.edu RI Kinsey, Gilbert/J-8322-2012; OI Blum, Jason/0000-0003-1381-6802 FU National Institutes of Health [DK-62028, C06 RR-015455, P20 RR-016461]; Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs; National Institutes of Health National Research Service [F32 DK-081267] FX This work was supported by a National Institutes of Health Grant No. DK-62028 and by the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs. to RGS. J.L.B. was supported by an individual National Institutes of Health National Research Service Award training fellowship (F32 DK-081267). The Medical University of South Carolina animal facilities were funded by National Institutes of Health Grant No. C06 RR-015455. The South Carolina INBRE was funded by National Institutes of Health Grant No. P20 RR-016461. The authors also thank Dr. Yefim Manevich (Medical University of South Carolina) for his advice and constructive discussions during the execution of these experiments and Dr. Jennifer Schnellmann for her assistance in preparing this manuscript. NR 36 TC 7 Z9 7 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD AUG PY 2011 VL 25 IS 5 BP 1001 EP 1006 DI 10.1016/j.tiv.2011.03.014 PG 6 WC Toxicology SC Toxicology GA 787HH UT WOS:000292366700001 PM 21443943 ER PT J AU Stagakis, E Bertsias, G Verginis, P Nakou, M Hatziapostolou, M Kritikos, H Iliopoulos, D Boumpas, DT AF Stagakis, Elias Bertsias, George Verginis, Panayotis Nakou, Magdalene Hatziapostolou, Maria Kritikos, Heraklis Iliopoulos, Dimitrios Boumpas, Dimitrios T. TI Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID PROGRAMMED CELL-DEATH-4; GRANULOPOIESIS SIGNATURES; GENE-EXPRESSION; BONE-MARROW; ERYTHEMATOSUS; ACTIVATION; CANCER; TRANSCRIPTION; INFLAMMATION; AUTOIMMUNITY AB Objective MicroRNAs (miRNAs) regulate the expression of genes involved in immune activation. A study was undertaken to characterise the miRNA signature and identify novel genes involved in the regulation of immune responses in systemic lupus erythematosus (SLE). Methods The expression of 365 miRNAs in peripheral blood mononuclear cells of patients with SLE and healthy controls was analysed using TaqMan Low Density Arrays. The results were validated by quantitative real-time PCR and potential target genes were identified using prediction analysis software. The effect of miR-21 on T cell function was assessed by transfection with antago-miR-21 or pre-miR-21. Results A 27-miRNA signature was identified in patients with SLE; 19 miRNAs correlated with disease activity. Eight miRNAs were deregulated specifically in T cells and four miRNAs in B cells. miR-21 was upregulated and strongly correlated with SLE disease activity (r(2) = 0.92). Compared with controls, CD4 T lymphocytes from patients with SLE had higher basal and activation-induced miR-21 expression. Silencing of miR-21 reversed the activated phenotype of T cells from patients with SLE-namely, enhanced proliferation, interleukin 10 production, CD40L expression and their capacity to drive B cell maturation into Ig-secreting CD19+CD38(hi)IgD-(plasma cells. Overexpression of mMiR-21 in normal T cells led to acquisition of an activated phenotype. Investigation of putative gene-targets showed that PDCD4 (a selective protein translation inhibitor) was suppressed by miR-21 and its expression was decreased in active SLE. Conclusions miRNAs represent potential biomarkers in SLE as their expression reflects underlying pathogenic processes and correlates with disease activity. Upregulated miR-21 affects PDCD4 expression and regulates aberrant T cell responses in human SLE. C1 [Boumpas, Dimitrios T.] Univ Crete, Sch Med, Dept Rheumatol Clin Immunol & Allergy, Lab Autoimmun & Inflammat, Iraklion, Greece. [Stagakis, Elias; Bertsias, George; Nakou, Magdalene] Univ Crete, Sch Med, Grad Program Mol Basis Human Dis, Iraklion, Greece. [Verginis, Panayotis; Boumpas, Dimitrios T.] Fdn Res & Technol, Inst Mol Biol & Biotechnol, Iraklion, Greece. [Hatziapostolou, Maria; Iliopoulos, Dimitrios] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Hatziapostolou, Maria; Iliopoulos, Dimitrios] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Boumpas, DT (reprint author), Univ Crete, Sch Med, Dept Rheumatol Clin Immunol & Allergy, Lab Autoimmun & Inflammat, POB 2208, Iraklion, Greece. EM boumpasd@med.uoc.gr RI Hatziapostolou, Maria/N-1820-2015 OI Hatziapostolou, Maria/0000-0003-2493-7028 FU Hellenic Society of Rheumatology; Pancretan Health Association; Hellenic Ministry of Education, Hellenic Republic; European Union FX This work is supported by the Hellenic Society of Rheumatology, the Pancretan Health Association, the Hellenic Ministry of Education, Hellenic Republic and the European Union (EPEAEK Fund and Sixth Framework Programme AutoCure program). NR 39 TC 122 Z9 138 U1 1 U2 10 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD AUG PY 2011 VL 70 IS 8 BP 1496 EP 1506 DI 10.1136/ard.2010.139857 PG 11 WC Rheumatology SC Rheumatology GA 784WC UT WOS:000292188100027 PM 21602271 ER PT J AU Sonis, ST AF Sonis, Stephen T. TI Oral mucositis SO ANTI-CANCER DRUGS LA English DT Review DE chemotherapy; head and neck cancer; oral mucositis; radiation ID HERPES-SIMPLEX-VIRUS; CONTROLLED-TRIAL; CANCER-PATIENTS; HEAD; NECK; EFFICACY; THERAPY AB Oral mucositis remains one of the most common and troubling side effects of standard chemoradiation regimens used for the treatment of head and neck cancer. Virtually all patients who receive cumulative radiation doses of more than 30Gy that includes oral mucosal fields will develop the condition. Not only does mucositis cause extreme discomfort, often necessitating opioid analgesia, but it is also associated with increased use of health resources and cost of treatment. The incremental cost of mucositis in patients with head and neck cancer is more than $17 000 (US). Much has been learned about the pathobiology that underlies the condition. The departure from the historical paradigm of direct cell death as being the primary cause for mucosal injury in favor of a more comprehensive view of the impact of chemoradiation on all the cells of the mucosa, has resulted in a picture of mucositis pathogenesis, which is biologically broad based. Although there are currently few treatment options for oral mucositis at the moment, the recognition that its underlying biology is complex has provided a range of treatment options that are currently being developed. Anti-Cancer Drugs 22: 607-612 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Sonis, Stephen T.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Sonis, Stephen T.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sonis, ST (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM ssonis@partners.org NR 22 TC 56 Z9 56 U1 3 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD AUG PY 2011 VL 22 IS 7 BP 607 EP 612 DI 10.1097/CAD.0b013e3283462086 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 782SS UT WOS:000292032200005 PM 21709615 ER PT J AU De Costa, AM Young, MRI AF De Costa, Anna-Maria Young, M. Rita I. TI Immunotherapy for head and neck cancer: advances and deficiencies SO ANTI-CANCER DRUGS LA English DT Review DE head and neck cancer; head and neck squamous cell carcinomas; immunosuppression; immunotherapy; suppressor cells; tumor antigens ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR RECEPTOR; CD34(+) PROGENITOR CELLS; REGULATORY T-CELLS; PHASE-II TRIAL; REFRACTORY COLORECTAL-CANCER; PERIPHERAL-BLOOD; INTERFERON-ALPHA; CLINICAL-TRIAL; DENDRITIC CELLS AB The concept of immunotherapy as a treatment for cancer patients has been in existence for decades. However, more recent immune therapeutic approaches have involved targeting of tumor-specific antigens. Although improvements have been made in using such immune stimulatory treatment strategies for a variety of solid cancers, the use of these strategies for patients with head and neck squamous cell carcinoma (HNSCC) is lagging behind. Immunotherapeutic approaches for HNSCC are particularly complicated by the profound immune suppression that is induced by HNSCC, which potentially decreases the effectiveness of immune stimulatory efforts. Trials involving patients with various solid cancers have shown the enhanced effectiveness of combining various immunotherapeutic approaches or combining immunotherapy with chemotherapy or radiation therapy. Treatment of HNSCC with such combination approaches has not been extensively investigated and has the added challenge of the need to overcome the HNSCC-induced immune suppression. This study focuses on clinical trials that have tested immunotherapeutic approaches for HNSCC patients and the challenges associated with such approaches. In addition, it will call attention to immunotherapeutic strategies that have been shown to be successful in the treatment of other solid cancers to identify potential strategies that may apply to the treatment of HNSCC. Anti-Cancer Drugs 22: 674-681 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [De Costa, Anna-Maria; Young, M. Rita I.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. [De Costa, Anna-Maria] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Young, M. Rita I.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. [Young, M. Rita I.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Young, MRI (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Res Serv 151, Charleston, SC 29401 USA. EM rita.young@va.gov FU Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs; National Institutes of Health [R01 DE018168, R01CA128837] FX This study was supported by the Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs, and by Grants R01 DE018168 and R01CA128837 from the National Institutes of Health to MRIY. NR 85 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD AUG PY 2011 VL 22 IS 7 BP 674 EP 681 DI 10.1097/CAD.0b013e328340fd18 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 782SS UT WOS:000292032200014 PM 21037467 ER PT J AU Wang, AJ Tang, ZY Park, IH Zhu, YQ Patel, S Daley, GQ Li, S AF Wang, Aijun Tang, Zhenyu Park, In-Hyun Zhu, Yiqian Patel, Shyam Daley, George Q. Li, Song TI Induced pluripotent stem cells for neural tissue engineering SO BIOMATERIALS LA English DT Article DE Stem cells; Scaffold; Nerve guide; Nerve tissue engineering; Nanofibers; Neural crest stem cell ID PERIPHERAL-NERVE REGENERATION; HUMAN SOMATIC-CELLS; CREST STEM; DEFINED FACTORS; DIFFERENTIATION; SCAFFOLDS; GUIDANCE; LINES; BETA AB Induced pluripotent stem cells (iPSCs) hold great promise for cell therapies and tissue engineering. Neural crest stem cells (NCSCs) are multipotent and represent a valuable system to investigate iPSC differentiation and therapeutic potential. Here we derived NCSCs from human iPSCs and embryonic stem cells (ESCs), and investigated the potential of NCSCs for neural tissue engineering. The differentiation of iPSCs and the expansion of derived NCSCs varied in different cell lines, but all NCSC lines were capable of differentiating into mesodermal and ectodermal lineages, including neural cells. Tissue-engineered nerve conduits were fabricated by seeding NCSCs into nanofibrous tubular scaffolds, and used as a bridge for transected sciatic nerves in a rat model. Electrophysiological analysis showed that only NCSC-engrafted nerve conduits resulted in an accelerated regeneration of sciatic nerves at 1 month. Histological analysis demonstrated that NCSC transplantation promoted axonal myelination. Furthermore, NCSCs differentiated into Schwann cells and were integrated into the myelin sheath around axons. No teratoma formation was observed for up to 1 year after NCSC transplantation in vivo. This study demonstrates that iPSC-derived multipotent NCSCs can be directly used for tissue engineering and that the approach that combines stem cells and scaffolds has tremendous potential for regenerative medicine applications. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Wang, Aijun; Tang, Zhenyu; Zhu, Yiqian; Li, Song] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Park, In-Hyun; Daley, George Q.] Childrens Hosp Boston, Howard Hughes Med Inst, Manton Ctr Orphan Dis Res, Stem Cell Transplantat Program,Div Pediat Hematol, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Patel, Shyam] Nanonerve Inc, Fremont, CA USA. RP Li, S (reprint author), Univ Calif Berkeley, Dept Bioengn, B108A Stanley Hall, Berkeley, CA 94720 USA. EM song_li@berkeley.edu RI Wang, Aijun/C-7559-2013 OI Wang, Aijun/0000-0002-2985-3627 FU National Institute of Health [EB012240, HL083900, HL102815, HL100001]; Manton Center for Orphan Diseases; Howard Hughes Medical Institute; California Institute for Regenerative Medicine [TG2-01164] FX We thank Julia Chu for her excellent technical excellent assistance. This work was supported in part by the grants from National Institute of Health (EB012240 and HL083900 to SI., HL102815 and HL100001 to G.Q.D.), Manton Center for Orphan Diseases (to G.Q.D.), the Howard Hughes Medical Institute (to G.Q.D.), and a postdoctoral training grant TG2-01164 from California Institute for Regenerative Medicine (to A.W.). NR 24 TC 68 Z9 78 U1 9 U2 67 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2011 VL 32 IS 22 BP 5023 EP 5032 DI 10.1016/j.biomaterials.2011.03.070 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 780ZP UT WOS:000291900700005 PM 21514663 ER PT J AU Kwong, B Liu, HP Irvine, DJ AF Kwong, Brandon Liu, Haipeng Irvine, Darrell J. TI Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy SO BIOMATERIALS LA English DT Article DE Tumor immunotherapy; Agonistic anti-CD40; CpG oligonucleotides; Localized biodistribution; Liposome delivery; Reduced toxicity ID ANTI-CD40 MONOCLONAL-ANTIBODY; T-CELL IMMUNITY; RECOMBINANT HUMAN INTERLEUKIN-12; IN-SITU VACCINATION; PHASE-I; CANCER-IMMUNOTHERAPY; CD40 ANTIBODY; SOLID TUMORS; INFLAMMATORY RESPONSE; CPG OLIGONUCLEOTIDES AB Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical use even as monotherapies is hampered by dose-limiting inflammatory toxicity provoked upon systemic exposure. We hypothesized that by anchoring immuno-agonist compounds to lipid nanoparticles we could retain the bioactivity of therapeutics in the local tumor tissue and tumor-draining lymph node, but limit systemic exposure to these potent molecules. We prepared PEGylated liposomes bearing surface-conjugated anti-CD40 and CpG and assessed their therapeutic efficacy and systemic toxicity compared to soluble versions of the same immuno-agonists, injected intratumorally in the B16F10 murine model of melanoma. Anti-CD40/CpG-liposomes significantly inhibited tumor growth and induced a survival benefit similar to locally injected soluble anti-CD40 + CpG. Biodistribution analyses following local delivery showed that the liposomal carriers successfully sequestered anti-CD40 and CpG in vivo, reducing leakage into systemic circulation while allowing draining to the tumor-proximal lymph node. Contrary to locally-administered soluble immunotherapy, anti-CD40/CpG-liposomes did not elicit significant increases in serum levels of ALT enzyme, systemic inflammatory cytokines, or overall weight loss, confirming that off-target inflammatory effects had been minimized. The development of a delivery strategy capable of inducing robust anti-tumor responses concurrent with minimal systemic side effects is crucial for the continued progress of potent immunotherapies toward widespread clinical translation. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kwong, Brandon; Liu, Haipeng; Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Irvine, Darrell J.] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02114 USA. [Irvine, Darrell J.] Harvard Univ, Boston, MA 02115 USA. [Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Irvine, DJ (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM djirvine@mit.edu RI Liu, Haipeng/A-1879-2012 FU Dana-Farber/Harvard Cancer Center - MIT FX This work was supported in part by the Dana-Farber/Harvard Cancer Center - MIT Bridge Project Fund. DJI is an investigator of the Howard Hughes Medical Institute. The authors would like to acknowledge the Swanson Biotechnology Center (SBC) of the Koch Institute at MIT for the use of flow cytometry and histology facilities. W. Zhang at the SBC performed the cryosectioning for histological analysis. NR 81 TC 45 Z9 45 U1 9 U2 48 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2011 VL 32 IS 22 BP 5134 EP 5147 DI 10.1016/j.biomaterials.2011.03.067 PG 14 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 780ZP UT WOS:000291900700016 PM 21514665 ER PT J AU Kenar, H Kose, GT Toner, M Kaplan, DL Hasirci, V AF Kenar, Halime Kose, Gamze T. Toner, Mehmet Kaplan, David L. Hasirci, Vasif TI A 3D aligned microfibrous myocardial tissue construct cultured under transient perfusion SO BIOMATERIALS LA English DT Article DE Cardiac tissue engineering; Stem cell; Cell morphology; Polyhydroxybutyric acid; Polylactic acid; DMA (dynamic mechanical analysis) ID HUMAN UMBILICAL-CORD; MESENCHYMAL STEM-CELLS; CARDIAC TISSUE; IN-VITRO; SCAFFOLDS; MATRIX; HEART; TRANSPLANTATION; CARDIOMYOCYTES; LINEAGE AB The goal of this study was to design and develop a myocardial patch to use in the repair of myocardial infarctions or to slow down tissue damage and improve long-term heart function. The basic 3D construct design involved two biodegradable macroporous tubes, to allow transport of growth media to the cells within the construct, and cell seeded, aligned fiber mats wrapped around them. The microfibrous mat housed mesenchymal stem cells (MSCs) from human umbilical cord matrix (Wharton's Jelly) aligned in parallel to each other in a similar way to cell organization in native myocardium. Aligned micron-sized fiber mats were obtained by electrospinning a polyester blend (PHBV (5% HV), P(L-D,L)LA (70:30) and poly(glycerol sebacate) (PGS)). The micron-sized electrospun parallel fibers were effective in Wharton's Jelly (WJ) MSCs alignment and the cells were able to retract the mat. The 3D construct was cultured in a microbioreactor by perfusing the growth media transiently through the macroporous tubing for two weeks and examined by fluorescence microscopy for cell distribution and preservation of alignment. The fluorescence images of thin sections of 3D constructs from static and perfused cultures confirmed enhanced cell viability, uniform cell distribution and alignment due to nutrient provision from inside the 3D structure. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kenar, Halime; Hasirci, Vasif] Middle E Tech Univ, Dept Biol Sci, Biotechnol Res Unit, BIOMAT, TR-06531 Ankara, Turkey. [Kenar, Halime; Kose, Gamze T.; Hasirci, Vasif] Middle E Tech Univ, Biotechnol Res Unit, BIOMATEN Ctr Excellence Biomat & Tissue Engn, TR-06531 Ankara, Turkey. [Kose, Gamze T.] Yeditepe Univ, Dept Genet & Bioengn, TR-34755 Istanbul, Turkey. [Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Surg Serv, Boston, MA 02114 USA. [Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Toner, Mehmet] Shriners Hosp Children, Boston, MA 02114 USA. [Kaplan, David L.] Tufts Univ, Dept Biomed Engn, Bioengn & Biotechnol Ctr, Medford, MA 02155 USA. RP Hasirci, V (reprint author), Middle E Tech Univ, Dept Biol Sci, Biotechnol Res Unit, BIOMAT, TR-06531 Ankara, Turkey. EM vhasirci@metu.edu.tr FU EU; TUBITAK FX The authors gratefully acknowledge Prof. Dr. Y. Gungen and Mr. O. Erisoz (Genel Patoloji Merkezi Ltd., Ankara) for the cryosections of the construct, and METU Central Laboratory for the DMA of the mats. This study was supported by EU FP6 Network of Excellence project EXPERTISSUES, and TUBITAK BIDEB Integrated PhD Program (BDP). NR 37 TC 38 Z9 40 U1 6 U2 77 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2011 VL 32 IS 23 BP 5320 EP 5329 DI 10.1016/j.biomaterials.2011.04.025 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 780ZR UT WOS:000291900900002 PM 21570112 ER PT J AU Bracco, P Oral, E AF Bracco, Pierangiola Oral, Ebru TI Vitamin E-stabilized UHMWPE for Total Joint Implants: A Review SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID MOLECULAR-WEIGHT POLYETHYLENE; ELECTRON-SPIN RESONANCE; CRACK PROPAGATION RESISTANCE; BEAM IRRADIATION OXIDATION; CROSS-LINKED POLYETHYLENE; TOTAL HIP-ARTHROPLASTY; HAP-PAUL-AWARD; ALPHA-TOCOPHEROL; MECHANICAL-PROPERTIES; FATIGUE RESISTANCE AB Osteolysis due to wear of UHMWPE limits the longevity of joint arthroplasty. Oxidative degradation of UHMWPE gamma-sterilized in air increases its wear while decreasing mechanical strength. Vitamin E stabilization of UHMWPE was proposed to improve oxidation resistance while maintaining wear resistance and fatigue strength. We reviewed the preclinical research on the development and testing of vitamin E-stabilized UHMWPE with the following questions in mind: (1) What is the rationale behind protecting irradiated UHMWPE against oxidation by vitamin E? (2) What are the effects of vitamin E on the microstructure, tribologic, and mechanical properties of irradiated UHMWPE? (3) Is vitamin E expected to affect the periprosthetic tissue negatively? We performed searches in PubMed, Scopus, and Science Citation Index to review the development of vitamin E-stabilized UHMWPEs and their feasibility as clinical implants. The rationale for using vitamin E in UHMWPE was twofold: improving oxidation resistance of irradiated UHMWPEs and fatigue strength of irradiated UHMWPEs with an alternative to postirradiation melting. Vitamin E-stabilized UHMWPE showed oxidation resistance superior to that of irradiated UHMWPEs with detectable residual free radicals. It showed equivalent wear and improved mechanical strength compared to irradiated and melted UHMWPE. The biocompatibility was confirmed by simulating elution, if any, of the antioxidant from implants. Vitamin E-stabilized UHMWPE offers a joint arthroplasty technology with good mechanical, wear, and oxidation properties. Vitamin E-stabilized, irradiated UHMWPEs were recently introduced clinically. The rationale behind using vitamin E and in vitro tests comparing its performance to older materials are of great interest for improving longevity of joint arthroplasties. C1 [Bracco, Pierangiola] Univ Turin, Dipartimento Chim, IFM & NIS Ctr Excellence, I-10125 Turin, Italy. [Oral, Ebru] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. RP Bracco, P (reprint author), Univ Turin, Dipartimento Chim, IFM & NIS Ctr Excellence, Via Pietro Guria 7, I-10125 Turin, Italy. EM pierangiola.bracco@unito.it RI Bracco, Pierangiola/G-8522-2011 OI Bracco, Pierangiola/0000-0003-0477-2086 FU NIH [AR051142]; Biomet, Inc, Warsaw, IN; Bioster SpA, Seriate, Italy; Lima Lto, San Daniele del Friuli, Italy; Zimmer, Inc, Warsaw, IN; Harris Orthopaedic Laboratory funds FX One or more of the authors or of the authors' institutions have received funding from NIH Grant AR051142 (EO); Biomet, Inc, Warsaw, IN (EO); Bioster SpA, Seriate, Italy (PB); Lima Lto, San Daniele del Friuli, Italy (PB); Zimmer, Inc, Warsaw, IN (EO, PB); and Harris Orthopaedic Laboratory funds (EO). This work was performed at Universita di Torino and Massachusetts General Hospital. NR 84 TC 71 Z9 75 U1 2 U2 43 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD AUG PY 2011 VL 469 IS 8 BP 2286 EP 2293 DI 10.1007/s11999-010-1717-6 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 785ZL UT WOS:000292271700020 PM 21132413 ER PT J AU Stein, DJ Craske, MG Friedman, MJ Phillips, KA AF Stein, Dan J. Craske, Michelle G. Friedman, Matthew J. Phillips, Katharine A. TI Meta-structure Issues for the DSM-5: How Do Anxiety Disorders, Obsessive-Compulsive and Related Disorders, Post-Traumatic Disorders, and Dissociative Disorders Fit Together? SO CURRENT PSYCHIATRY REPORTS LA English DT Editorial Material DE DSM-5; ICD-11; Anxiety disorders; Obsessive-compulsive disorder; Post-traumatic disorders; Dissociative disorders; Classification; Stereotypic disorders; Pathophysiology; Etiology; Category; Nosology AB The question of how to optimally organize into chapters and label the different categories of mental disorders is an important one for DSM-5 and ICD-11. The grouping of mental disorders, or meta-structure, should arguably reflect knowledge on the validity of different conditions and their relationships, and should ideally contribute to improving the clinical utility of the nosology by guiding clinical assessment and management. The DSM-5 Anxiety, Obsessive-Compulsive Spectrum, Posttraumatic, and Dissociative Disorders Workgroup has reviewed the nature of anxiety disorders, the possibility of including a new category of obsessive-compulsive spectrum disorders in the DSM-5, and the concept of traumatic stress disorders. It is difficult to devise a perfect nosology that dissects nature at her joints; instead, any particular approach to the meta-structure would seem to have pros and cons that must be carefully weighed. Despite the imperfections of any meta-structure, we are hopeful that each revision of the nosology will bring with it greater diagnostic validity and clinical utility. C1 [Stein, Dan J.] Univ Cape Town, Dept Psychiat, Groote Schuur Hosp J2, ZA-7925 Cape Town, South Africa. [Craske, Michelle G.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Craske, Michelle G.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Friedman, Matthew J.] US Dept Vet Affairs, Natl Ctr PTSD, Hanover, NH USA. [Friedman, Matthew J.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Psychiat, Hanover, NH 03756 USA. [Friedman, Matthew J.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Pharmacol & Toxicol, Hanover, NH 03756 USA. [Phillips, Katharine A.] Brown Univ, Alpert Med Sch, Rhode Isl Hosp, Providence, RI 02912 USA. [Phillips, Katharine A.] Brown Univ, Alpert Med Sch, Dept Psychiat & Human Behav, Providence, RI 02912 USA. RP Stein, DJ (reprint author), Univ Cape Town, Dept Psychiat, Groote Schuur Hosp J2, Anzio Rd, ZA-7925 Cape Town, South Africa. EM dan.stein@uct.ac.za RI Stein, Dan/A-1752-2008 OI Stein, Dan/0000-0001-7218-7810 NR 8 TC 24 Z9 25 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD AUG PY 2011 VL 13 IS 4 BP 248 EP 250 DI 10.1007/s11920-011-0207-1 PG 3 WC Psychiatry SC Psychiatry GA 786KY UT WOS:000292308400003 PM 21603904 ER PT J AU Stolzmann, P Donati, OF Desbiolles, L Kozerke, S Hoffmann, U Alkadhi, H Scheffel, H AF Stolzmann, Paul Donati, Olivio F. Desbiolles, Lotus Kozerke, Sebastian Hoffmann, Udo Alkadhi, Hatem Scheffel, Hans TI Coronary artery plaques and myocardial ischaemia SO EUROPEAN RADIOLOGY LA English DT Article DE Coronary artery plaque; Myocardial ischaemia; Cardiac magnetic resonance; Computed tomography coronary angiography; Coronary artery disease ID CARDIAC COMPUTED-TOMOGRAPHY; NONINVASIVE DETECTION; MAGNETIC-RESONANCE; NUCLEAR-CARDIOLOGY; CT ANGIOGRAPHY; DISEASE; ACCURACY; ULTRASOUND; RADIOLOGY; COMMITTEE AB To prospectively examine coronary artery plaques as predictors of myocardial ischaemia using cardiac magnetic resonance (CMR). Fifty-two patients (46 men; age 64 +/- 10) with suspected coronary artery disease (CAD) referred for catheter coronary angiography (CA) underwent CMR and computed tomography coronary angiography (CTCA). All coronary segments were evaluated for morphological stenosis based on CA. Any plaque according to its composition was assessed based on CTCA. Numbers of total and calcified coronary artery plaques represented the best predictors of myocardial ischaemia (AUC = 0.87; [95%CI: 0.77-0.97] and AUC = 0.87; [95%CI: 0.77-0.96], respectively, p = 0.56) with the total plaque number significantly higher in patients with corresponding ischaemia than those without (p < 0.01, p < 0.05 adjusted for pre-test probability and stenosis). Compared with the AUC of coronary stenosis assessment by CA (AUC = 0.90; [95%CI: 0.80-1.00]), AUCs were equivalent using either the total number or the number of calcified plaques alone (p = 0.73 and p = 0.69). Multivariate logistic regression analyses demonstrated the total plaque number as an independent predictor of ischaemia (odds +20%; [95%CI: 1.096-1.368]), improving a model including clinical probability estimates of CAD (c-statistics, 0.66 to 0.89). Coronary artery plaque number according to CTCA is a significant, independent predictor of myocardial ischaemia with similar accuracy to stenosis assessment. C1 [Stolzmann, Paul; Hoffmann, Udo; Alkadhi, Hatem; Scheffel, Hans] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Stolzmann, Paul; Hoffmann, Udo; Alkadhi, Hatem; Scheffel, Hans] Harvard Univ, Sch Med, Boston, MA USA. [Stolzmann, Paul; Donati, Olivio F.; Alkadhi, Hatem; Scheffel, Hans] Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland. [Desbiolles, Lotus] KSSG, Dept Radiol, St Gallen, Switzerland. [Kozerke, Sebastian] Univ Zurich, Inst Biomed Engn, Zurich, Switzerland. [Kozerke, Sebastian] ETH, Zurich, Switzerland. RP Stolzmann, P (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. EM pstolzmann@partners.org RI Kozerke, Sebastian/J-3209-2015 OI Kozerke, Sebastian/0000-0003-3725-8884 NR 17 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD AUG PY 2011 VL 21 IS 8 BP 1628 EP 1634 DI 10.1007/s00330-011-2097-3 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 786LX UT WOS:000292311000007 PM 21373773 ER PT J AU Sonpavde, G Agarwal, N Choueiri, TK Kantoff, PW AF Sonpavde, Guru Agarwal, Neeraj Choueiri, Toni K. Kantoff, Philip W. TI Recent advances in immunotherapy for the treatment of prostate cancer SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE CTLA-4; immunotherapy; PD-1; prostate cancer; PROSTVAC-VF TRICOM; sipuleucel-T ID PHASE-I TRIAL; MONOCLONAL-ANTIBODY J591; CYTOTOXIC T-LYMPHOCYTES; MEMBRANE ANTIGEN; TUMOR-CELLS; SOLID TUMORS; CLINICAL-TRIALS; IMMUNE-SYSTEM; CELLULAR IMMUNOTHERAPY; COMBINATION THERAPY AB Introduction: Prostate cancer vaccines attempt to induce cancer-specific systemic immune responses and represent a new class of targeted therapies, many of which are non-toxic. Several vaccine technologies are in development. Areas covered: An autologous antigen presenting cell vaccine loaded with prostate acid phosphatase conjugated with GM-CSF, sipuleucel-T confers a survival advantage in men with metastatic castration-resistant prostate cancer (CRPC) and is now FDA approved based on the IMPACT trial. A poxvirus-based vaccine, PROSTVAC-VF TRICOM targeting prostate-specific antigen (PSA), has demonstrated improved survival in a randomized Phase II trial of patients with metastatic CRPC. Novel T lymphocyte checkpoint inhibitors of cytotoxic T lymphocyte antigen 4 and programmed death-1 are also emerging. Recognition of improved survival without an earlier clinical signal of activity by conventional criteria has led to new guidelines to evaluate immunotherapeutic agents. The clinical benefit of combining vaccines with chemotherapy, radiotherapy and other immunotherapeutic and biologic agents is being evaluated in the context of disappointing results of combination GVAX vaccine and docetaxel chemotherapy. Expert opinion: To build on the success of early phase trials, efforts must be made to optimize vaccine approaches and patient selection. C1 [Choueiri, Toni K.; Kantoff, Philip W.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Sonpavde, Guru] Texas Oncol, Houston, TX USA. [Sonpavde, Guru] Vet Affairs Med Ctr, Houston, TX 77030 USA. [Sonpavde, Guru] Baylor Coll Med, Houston, TX 77030 USA. [Agarwal, Neeraj] Univ Utah, Salt Lake City, UT USA. [Choueiri, Toni K.; Kantoff, Philip W.] Harvard Univ, Sch Med, Boston, MA USA. RP Kantoff, PW (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 44 Binney St Ste D1230, Boston, MA 02115 USA. EM philip_kantoff@dfci.harvard.edu FU Bellicum Pharmaceuticals FX N Agarwal and TK Choueiri state no conflict of interest and have received no payment in preparation of this manuscript. G Sonpavde is on the advisory board and is a speaker for Dendreon and receives funding from Bellicum Pharmaceuticals. PW Kantoff is a consultant for Dendreon, Bellicum Pharmaceuticals and BN-IT. NR 99 TC 8 Z9 9 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD AUG PY 2011 VL 11 IS 8 BP 997 EP 1009 DI 10.1517/14712598.2011.575357 PG 13 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 785CG UT WOS:000292204400003 PM 21675925 ER PT J AU Mabbott, NA Baillie, JK Kobayashi, A Donaldson, DS Ohmori, H Yoon, SO Freedman, AS Freeman, TC Summers, KM AF Mabbott, Neil A. Baillie, J. Kenneth Kobayashi, Atsushi Donaldson, David S. Ohmori, Hitoshi Yoon, Sun-Ok Freedman, Arnold S. Freeman, Tom C. Summers, Kim M. TI Expression of mesenchyme-specific gene signatures by follicular dendritic cells: insights from the meta-analysis of microarray data from multiple mouse cell populations SO IMMUNOLOGY LA English DT Article DE clustering; follicular dendritic cell; mesenchyme; meta-analysis; microarray; transcriptomics ID LYMPHOTOXIN-BETA-RECEPTOR; B-CELLS; GERMINAL CENTER; LYMPH-NODE; SOMATIC HYPERMUTATION; EXTRACELLULAR-MATRIX; AUTOIMMUNE-DISEASE; STROMAL CELLS; IGG RESPONSES; LYMPHOCYTES AB Follicular dendritic cells (FDC) are an important subset of stromal cells within the germinal centres of lymphoid tissues. They are specialized to trap and retain antigen-containing immune complexes on their surfaces to promote B-cell maturation and immunoglobulin isotype class-switching. However, little is known of the cell types from which FDC originate. To address fundamental questions associated with the relationships between FDC and other cell populations, we took advantage of the growing body of publicly available data for transcriptome analysis. We obtained a large number of gene expression data files from a range of different primary mouse cells and cell lines and subjected these data to network-based cluster analysis using BIOLAYOUT EXPRESS(3D). Genes with related function clustered together in distinct regions of the graph and enabled the identification of transcriptional networks that underpin the functional activity of distinct cell populations. Several gene clusters were identified that were selectively expressed by cells of mesenchymal lineage and contained classic mesenchymal cell markers and extracellular matrix genes including various collagens, Acta2, Bgn, Fbn1 and Twist1. Our analysis showed that FDC also express highly many of these mesenchyme-associated genes. Promoter analysis of the genes comprising the mesenchymal clusters identified several regulatory motifs that are binding sites for candidate transcription factors previously known to be candidate regulators of mesenchyme-specific genes. Together, these data suggest FDC are a specialized mesenchymal cell population within the germinal centres of lymphoid tissues. C1 [Mabbott, Neil A.; Baillie, J. Kenneth; Kobayashi, Atsushi; Donaldson, David S.; Freeman, Tom C.; Summers, Kim M.] Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland. [Mabbott, Neil A.; Baillie, J. Kenneth; Kobayashi, Atsushi; Donaldson, David S.; Freeman, Tom C.; Summers, Kim M.] Univ Edinburgh, Royal Dick Sch Vet Sci, Easter Bush EH25 9RG, Midlothian, Scotland. [Kobayashi, Atsushi] Tohoku Univ, Grad Sch Med, Sendai, Miyagi 980, Japan. [Ohmori, Hitoshi] Okayama Univ, Dept Biotechnol, Okayama 7008530, Japan. [Yoon, Sun-Ok] Ochsner Clin Fdn, Cellular Immunol Lab, New Orleans, LA USA. [Freedman, Arnold S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Mabbott, NA (reprint author), Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland. EM neil.mabbott@roslin.ed.ac.uk; kim.summers@roslin.ed.ac.uk RI Baillie, John Kenneth/F-3124-2011; Summers, Kim/M-4086-2015; OI Baillie, John Kenneth/0000-0001-5258-793X; Summers, Kim/0000-0002-7084-4386; Donaldson, David/0000-0002-8523-7853; Mabbott, Neil/0000-0001-7395-1796 FU Biotechnology and Biological Sciences Research Council (BBSRC); BBSRC Japan; Wellcome Trust; National Institutes of Health [P01CA92625] FX We thank Masaki Hikida (Kyoto University, Japan) and Prof. Yong-Sung Choi (Ochsner Clinic Foundation, New Orleans) for helpful discussions and for providing access to raw data files. This research was supported by Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Grant funding, a BBSRC Japan Partnering Award (NAM), a Wellcome Trust Clinical Fellowship (JKB) and National Institutes of Health grant P01CA92625 (ASF). NR 75 TC 31 Z9 31 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD AUG PY 2011 VL 133 IS 4 BP 482 EP 498 DI 10.1111/j.1365-2567.2011.03461.x PG 17 WC Immunology SC Immunology GA 786TZ UT WOS:000292332100009 PM 21635249 ER PT J AU Parker, MA Jiang, K Kempfle, JS Mizutari, K Simmons, CL Bieber, R Adams, J Edge, ASB AF Parker, Mark A. Jiang, Kevin Kempfle, Judith S. Mizutari, Kunio Simmons, Caitlin L. Bieber, Rebecca Adams, Joe Edge, Albert S. B. TI TAK1 Expression in the Cochlea: A Specific Marker for Adult Supporting Cells SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE cochlea; Deiters' cell; phalangeal cell; pillar cell; development; gene expression ID MOUSE INNER-EAR; MAMMALIAN COCHLEA; HAIR-CELLS; TGF-BETA; IN-VIVO; SIGNALING PATHWAYS; DAMAGED COCHLEA; KINASE TAK1; ORGAN; SOX2 AB Transforming growth factor-beta-activated kinase-1 (TAK1) is a mitogen activated protein kinase kinase kinase that is involved in diverse biological roles across species. Functioning downstream of TGF-beta and BMP signaling, TAK1 mediates the activation of the c-Jun N-terminal kinase signaling pathway, serves as the target of pro-inflammatory cytokines, such as TNF-alpha, mediates NF-kappa I(2) activation, and plays a role in Wnt/Fz signaling in mesenchymal stem cells. Expression of TAK1 in the cochlea has not been defined. Data mining of previously published murine cochlear gene expression databases indicated that TAK1, along with TAK1 interacting proteins 1 (TAB1), and 2 (TAB2), is expressed in the developing and adult cochlea. The expression of TAK1 in the developing cochlea was confirmed using RT-PCR and immunohistochemistry. Immunolabeling of TAK1 in embryonic, neonatal, and mature cochleas via DAB chromogenic and fluorescent immunohistochemistry indicated that TAK1 is broadly expressed in both the developing otocyst and periotic mesenchyme at E12.5 but becomes more restricted to specific types of supporting cells as the organ of Corti matures. By P1, TAK1 immunolabeling is found in cells of the stria vascularis, hair cells, supporting cells, and Kolliker's organ. By P16, TAK1 labeling is limited to cochlear supporting cells. In the adult cochlea, TAK1 immunostaining is only present in the cytoplasm of Deiters' cells, pillar cells, inner phalangeal cells, and inner border cells, with no expression in any other cochlear cell types. While the role of TAK1 in the inner ear is unclear, TAK1 expression may be used as a novel marker for specific sub-populations of supporting cells. C1 [Parker, Mark A.; Jiang, Kevin; Kempfle, Judith S.; Mizutari, Kunio; Adams, Joe; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Parker, Mark A.; Kempfle, Judith S.; Mizutari, Kunio; Adams, Joe; Edge, Albert S. B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Parker, Mark A.; Simmons, Caitlin L.; Bieber, Rebecca] Emerson Coll, Dept Commun Sci & Disorders, Boston, MA 02116 USA. [Edge, Albert S. B.] Harvard Univ, Sch Med, Hlth Sci & Technol Program, Boston, MA 02115 USA. [Mizutari, Kunio] Keio Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Shinjuku Ku, Tokyo 1608582, Japan. RP Parker, MA (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St,4th Floor, Boston, MA 02114 USA. EM Mark_Parker@meei.harvard.edu FU National Institute of Deafness and other Communicative Disorders [R03DC010065, RO1DC007174, P30DC05209] FX The authors would like to thank Amy Osborne for her artwork and the National Institute of Deafness and other Communicative Disorders (R03DC010065-Parker; RO1DC007174-Edge; P30DC05209-MEEI Core Support for Hearing Research) for supporting this work. NR 67 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD AUG PY 2011 VL 12 IS 4 BP 471 EP 483 DI 10.1007/s10162-011-0265-4 PG 13 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 782YE UT WOS:000292047900005 PM 21472480 ER PT J AU Brunet, A Poundja, J Tremblay, J Bui, E Thomas, E Orr, SP Azzoug, A Birmes, P Pitman, RK AF Brunet, Alain Poundja, Joaquin Tremblay, Jacques Bui, Eric Thomas, Emilie Orr, Scott P. Azzoug, Abdelmadjid Birmes, Philippe Pitman, Roger K. TI Trauma Reactivation Under the Influence of Propranolol Decreases Posttraumatic Stress Symptoms and Disorder 3 Open-Label Trials SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Letter ID PTSD; MEMORY C1 [Brunet, Alain; Poundja, Joaquin; Tremblay, Jacques; Thomas, Emilie; Azzoug, Abdelmadjid] Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. [Brunet, Alain; Tremblay, Jacques] McGill Univ, Montreal, PQ, Canada. [Bui, Eric; Birmes, Philippe] Univ Toulouse 3, Lab Stress Traumat JE 2511, F-31062 Toulouse, France. [Bui, Eric; Birmes, Philippe] CHU Toulouse, Toulouse, France. [Poundja, Joaquin; Thomas, Emilie; Azzoug, Abdelmadjid] Univ Montreal, Montreal, PQ, Canada. [Orr, Scott P.; Pitman, Roger K.] Massachusetts Gen Hosp, Charlestown, MA USA. [Orr, Scott P.; Pitman, Roger K.] Harvard Univ, Sch Med, Charlestown, MA USA. RP Brunet, A (reprint author), Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. EM alain.brunet@douglas.mcgill.ca RI Bui, Eric/J-8347-2015 OI Bui, Eric/0000-0002-1413-6473 NR 16 TC 71 Z9 72 U1 3 U2 31 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD AUG PY 2011 VL 31 IS 4 BP 547 EP 550 DI 10.1097/JCP.0b013e318222f360 PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 786DX UT WOS:000292284600032 PM 21720237 ER PT J AU Thurber, GM Weissleder, R AF Thurber, Greg M. Weissleder, Ralph TI Quantitating Antibody Uptake In Vivo: Conditional Dependence on Antigen Expression Levels SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Antibody localization; Antigen expression; Tumor targeting; Binding site barrier; Saturation ID TUMOR RESPONSE; VASCULAR-PERMEABILITY; MONOCLONAL-ANTIBODY; EGFR EXPRESSION; SOLID TUMORS; CANCER; PET; XENOGRAFTS; GROWTH; MICE AB Antibodies form an important class of cancer therapeutics, and there is intense interest in using them for imaging applications in diagnosis and monitoring of cancer treatment. Despite the expanding body of knowledge describing pharmacokinetic and pharmacodynamic interactions of antibodies in vivo, discrepancies remain over the effect of antigen expression level on tumoral uptake with some reports indicating a relationship between uptake and expression and others showing no correlation. Using a cell line with high epithelial cell adhesion molecule expression and moderate epidermal growth factor receptor expression, fluorescent antibodies with similar plasma clearance were imaged in vivo. A mathematical model and mouse xenograft experiments were used to describe the effect of antigen expression on uptake of these high-affinity antibodies. As predicted by the theoretical model, under subsaturating conditions, uptake of the antibodies in such tumors is similar because localization of both probes is limited by delivery from the vasculature. In a separate experiment, when the tumor is saturated, the uptake becomes dependent on the number of available binding sites. In addition, targeting of small micrometastases is shown to be higher than larger vascularized tumors. These results are consistent with the prediction that high affinity antibody uptake is dependent on antigen expression levels for saturating doses and delivery for subsaturating doses. It is imperative for any probe to understand whether quantitative uptake is a measure of biomarker expression or transport to the region of interest. The data provide support for a predictive theoretical model of antibody uptake, enabling it to be used as a starting point for the design of more efficacious therapies and timely quantitative imaging probes. C1 [Thurber, Greg M.; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Weissleder, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu OI Thurber, Greg/0000-0001-7570-2080 FU [P50 CA86355]; [U24 CA092782]; [T32 CA079443] FX This work was supported by grants P50 CA86355, U24 CA092782, and T32 CA079443. NR 44 TC 18 Z9 18 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD AUG PY 2011 VL 13 IS 4 BP 623 EP 632 DI 10.1007/s11307-010-0397-7 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 786LN UT WOS:000292310000003 PM 20809210 ER PT J AU Wolfe, J AF Wolfe, Joanne TI Recognizing a Global Need for High Quality Pediatric Palliative Care SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material ID CHILDREN; CANCER; LIFE; SYMPTOMS; END; ONCOLOGY; INTEGRATION; PARENTS C1 [Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Wolfe, Joanne] Childrens Hosp Boston, Dept Med, Boston, MA USA. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave,SM-206, Boston, MA 02115 USA. EM joanne_wolfe@dfci.harvard.edu NR 19 TC 6 Z9 6 U1 1 U2 3 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2011 VL 57 IS 2 BP 187 EP 188 DI 10.1002/pbc.23151 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 786JE UT WOS:000292301400001 PM 21495165 ER PT J AU Huang, SP Bao, BY Wu, MT Choueiri, TK Goggins, WB Huang, CY Pu, YS Yu, CC Huang, CH AF Huang, Shu-Pin Bao, Bo-Ying Wu, Ming-Tsang Choueiri, Toni K. Goggins, William B. Huang, Chao-Yuan Pu, Yeong-Shiau Yu, Chia-Cheng Huang, Chun-Hsiung TI Impact of Prostate-Specific Antigen (PSA) Nadir and Time to PSA Nadir on Disease Progression in Prostate Cancer Treated With Androgen-Deprivation Therapy SO PROSTATE LA English DT Article DE prostate cancer; androgen-deprivation therapy; metastatic prostate cancer; prostate-specific antigen kinetics; time to prostate-specific antigen nadir; prostate-specific antigen nadir ID BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; PROGNOSTIC-SIGNIFICANCE; POSTRADICAL PROSTATECTOMY; ANTIANDROGEN WITHDRAWAL; BILATERAL ORCHIECTOMY; HORMONAL-THERAPY; SURVIVAL; RECEPTOR; FLUTAMIDE AB BACKGROUND. The influence of PSA kinetics on the outcome of metastatic prostate cancer after androgen deprivation therapy (ADT) is not well understood. We evaluated the prognostic significance of PSA nadir and time to PSA nadir as well as their potential interactive effect on the progression of disease after ADT. METHODS. A total of 650 men with advanced or metastatic prostate cancer treated with ADT were studied. The prognostic significance of PSA nadir and time to PSA nadir on disease progression were analyzed using Kaplan-Meier analysis and the Cox regression model. RESULTS. We found that both PSA nadir and time to PSA nadir were independent and significant predictors of disease progression. Patients with higher PSA nadir (>= 0.2 ng/ml) and shorter time to PSA nadir (< 10 months) had significant shorter time to disease progression after adjusting for other covariates. The combined analyses showed a potential synergistic effect of these two variables on disease progression. Patient with higher PSA nadir and shorter time to PSA nadir had significantly higher risk for disease progression compared to those with lower PSA nadir and longer time to PSA nadir (Hazard Ratios (HR) = 3.11, P<0.001). CONCLUSIONS. We concluded that both PSA nadir and time to PSA nadir are significant predictors of disease progression for prostate cancer patients receiving ADT. Prostate 71: 1189-1197, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Huang, Shu-Pin; Huang, Chun-Hsiung] Kaohsiung Med Univ Hosp, Dept Urol, Kaohsiung, Taiwan. [Huang, Shu-Pin; Huang, Chun-Hsiung] Kaohsiung Med Univ, Dept Urol, Coll Med, Fac Med, Kaohsiung 807, Taiwan. [Huang, Shu-Pin] Kaohsiung Med Univ, Kaohsiung Municipal Hsiao Kang Hosp, Dept Urol, Kaohsiung 807, Taiwan. [Bao, Bo-Ying] China Med Univ, Dept Pharm, Taichung, Taiwan. [Wu, Ming-Tsang] Kaohsiung Med Univ Hosp, Dept Family Med, Kaohsiung, Taiwan. [Wu, Ming-Tsang] Kaohsiung Med Univ, Grad Inst Occupat Safety & Hlth, Kaohsiung 807, Taiwan. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goggins, William B.] Chinese Univ Hong Kong, Sch Publ Hlth, Div Biostat, Hong Kong, Hong Kong, Peoples R China. [Huang, Chao-Yuan; Pu, Yeong-Shiau] Natl Taiwan Univ, Dept Urol, Taipei 10764, Taiwan. [Yu, Chia-Cheng] Kaohsiung Vet Gen Hosp, Div Urol, Dept Surg, Kaohsiung, Taiwan. RP Huang, SP (reprint author), Kaohsiung Med Univ, Dept Urol, Coll Med, Fac Med, 100 Shih Chuan 1st Rd, Kaohsiung 807, Taiwan. EM shpihu@yahoo.com.tw RI Wu, Ming-Tsang/G-5637-2012; Bao, Bo-Ying/D-1789-2012; OI Bao, Bo-Ying/0000-0001-5510-6513; HUANG, CHAO-YUAN/0000-0002-9322-6062; PU, YEONG-SHIAU/0000-0002-2859-3966 FU Taiwan National Science Council [NSC 95-2314-B-037-053-MY2, NSC 96-2314-B-037-012-MY3]; Kaohsiung Medical University Hospital [KMUH96-6G27, KMUH96-6G28]; Kaohsiung Municipal Hsiao-Kang Hospital [kmhk-96-009, kmhk-97-008] FX This study was supported by grants from the Taiwan National Science Council (NSC 95-2314-B-037-053-MY2 and NSC 96-2314-B-037-012-MY3), Kaohsiung Medical University Hospital (KMUH96-6G27 and KMUH96-6G28) and Kaohsiung Municipal Hsiao-Kang Hospital (kmhk-96-009 and kmhk-97-008). We thank Ms. Chao-Shih Chen and Professor Hung-Yi Chuang for help on data analyses. NR 41 TC 20 Z9 23 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-4137 J9 PROSTATE JI Prostate PD AUG 1 PY 2011 VL 71 IS 11 BP 1189 EP 1197 DI 10.1002/pros.21334 PG 9 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 786UB UT WOS:000292332300006 PM 21656829 ER PT J AU Bellot, G Pascal, R Mendre, C Urbach, S Mouillac, B Demene, H AF Bellot, Gaetan Pascal, Robert Mendre, Christiane Urbach, Serge Mouillac, Bernard Demene, Helene TI Expression, purification and NMR characterization of the cyclic recombinant form of the third intracellular loop of the vasopressin type 2 receptor SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE G-protein coupled receptor; Vasopressin receptor subtype 2; Intracellular loop; Affinity purification; Nuclear magnetic resonance ID PROTEIN-COUPLED RECEPTOR; DOUBLE-TRANSMEMBRANE DOMAIN; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; CB2 RECEPTOR; PEPTIDE; BIOSYNTHESIS; DESIGN; ANTAGONISTS; STABILITY AB The vasopressin type 2 (V2R) receptor belongs to the class of G-protein coupled receptors. It is mainly expressed in the membrane of kidney tubules, where it is activated by the extracellular arginine vasopressin. In men, inactivating and activating mutations cause nephrogenic diabetes insipidus and the nephrogenic syndrome of inappropriate antidiuresis respectively. Like most GPCRs, V2R's third intracellular loop (V2R-i3) is involved in the binding and activation of its major effector, the G alpha S protein. We overexpressed the V2R(224-274) fragment corresponding to V2R-i3 as a fusion protein with thioredoxin A at the N-terminus and a hexahistidine tag between the two proteins. Recombinant V2R-i3 was designed to harbor N- and C-terminal cysteines, in order to introduce a disulfide bond between N- and C-terminal extremities and hence reproduce the hairpin fold presumably present in the full-length receptor. The fusion protein was produced as inclusion bodies in Escherichia coli and purified by nickel affinity chromatography under denaturing conditions. After a refolding step, thioredoxin and hexahistidine tags were specifically cleaved with the tobacco etch virus protease. The hydrolysis yield, initially very low, increased up to 80% thanks to optimization of buffers and refolding methods. The cleaved fragment, V2(224-274), devoid of any tag, was then eluted with low imidazole concentrations in a second nickel affinity chromatography in denaturing conditions. The final yield was sufficient to prepare a (15)N-(13)C labeled NMR sample suitable for triple resonance experiments. We assigned all NMR resonances and confirmed the correct peptide sequence. As expected, the peptide forms a hairpin stabilized by a disulfide bond between its N- and C-terminal parts, thus mimicking its native structure in the full-length receptor. This study may provide a strategy for producing and studying the structure/function relationship of GPCR fragments. (C) 2011 Elsevier Inc. All rights reserved. C1 [Bellot, Gaetan; Demene, Helene] INSERM, Ctr Biochim Struct, U1054, F-34090 Montpellier, France. [Bellot, Gaetan; Demene, Helene] Univ Montpellier 1, CNRS, UMR 5048, Ctr Biochim Struct, F-34090 Montpellier, France. [Bellot, Gaetan; Demene, Helene] Univ Montpellier 2, CNRS, UMR 5048, Ctr Biochim Struct, F-34090 Montpellier, France. [Bellot, Gaetan] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bellot, Gaetan] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Pascal, Robert] Univ Montpellier 1, CNRS, Inst Biomol Max Mousseron, UMR 5247, F-34095 Montpellier, France. [Mendre, Christiane; Urbach, Serge; Mouillac, Bernard] Inst Genom Fonct, INSERM, U661, F-34094 Montpellier, France. [Mendre, Christiane; Urbach, Serge; Mouillac, Bernard] Univ Montpellier 1, CNRS, UMR 5203, Inst Genom Fonct, F-34094 Montpellier, France. [Mendre, Christiane; Urbach, Serge; Mouillac, Bernard] Univ Montpellier 2, CNRS, UMR 5203, Inst Genom Fonct, F-34094 Montpellier, France. [Pascal, Robert] Univ Montpellier 2, CNRS, Inst Biomol Max Mousseron, UMR 5247, F-34095 Montpellier, France. RP Demene, H (reprint author), INSERM, Ctr Biochim Struct, U1054, 29 Rue Navacelles, F-34090 Montpellier, France. EM helene.demene@cbs.cnrs.fr RI MOUILLAC, Bernard/M-3896-2014; Pascal, Robert/O-1559-2013 OI Pascal, Robert/0000-0001-9579-2503 FU French Minister of Research FX G.B. was a recipient of fellowship from the French Minister of Research. All MALDI and ESI mass spectrometry experiments were done at the facility "Plateform of functional proteomics" (Institut de Genomique Fonctionnelle). NMR experiments were recorded and analyzed using the facilities of the Structural Biology RIO/IbiZA platform (Centre de Biochimie Structurale). We thank Y. Bessin for his help with V2R-i3 production and M. Cohen-Gonsaud for helpful discussions. NR 36 TC 3 Z9 3 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD AUG PY 2011 VL 78 IS 2 BP 131 EP 138 DI 10.1016/j.pep.2011.04.020 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 782PA UT WOS:000292020400003 PM 21575724 ER PT J AU Phan, CM Macklin, EA Bredella, MA Dadrich, M Flechsig, P Yoo, AJ Hirsch, JA Gupta, R AF Phan, Catherine M. Macklin, Eric A. Bredella, Miriam A. Dadrich, Monica Flechsig, Paul Yoo, Albert J. Hirsch, Joshua A. Gupta, Rajiv TI Trabecular structure analysis using C-arm CT: comparison with MDCT and flat-panel volume CT SO SKELETAL RADIOLOGY LA English DT Article DE C-arm CT; Flat-panel volume CT (fpVCT); Multi-detector CT (MDCT); Trabecular structure; Reproducibility ID COMPUTED-TOMOGRAPHY; POSTMENOPAUSAL WOMEN; FINITE-ELEMENT; BONE-STRUCTURE; DISTAL RADIUS; FRACTURE RISK; FUNDAMENTAL PRINCIPLES; MECHANICAL-PROPERTIES; HYPOGONADAL MEN; REPRODUCIBILITY AB Purpose This paper assesses interscan, interreader, and intrareader variability of C-arm CT and compares it to that of flat-panel volume-CT (fpVCT) and high-definition multi-detector-CT (HD-MDCT). Methods Five cadaver knee specimens were imaged using C-arm-CT, fpVCT, and HD-MDCT. Apparent (app.) trabecular bone volume fraction (BV/TV), app. trabecular number (TbN), app. trabecular spacing (TbSp), and app. trabecular thickness (TbTh) of the proximal tibia were measured by three readers. Interreader, intrareader, and interscan variability for C-arm CT was expressed as coefficient of variation (CV), standard deviation (SD), and intraclass correlation coefficient (ICC). Results With the exception of app.TbSp (CV: 7.05-9.35%, SD: 0.06-0.09, ICC: 0.89-0.94), the variability of C-arm CT was low (CV: 2.41-6.43%, SD: 0.01-0.048, ICC: 0.65-0.98). Its interreader reliability (CV: 2.66-4.55%, SD: 0.01-0.03, ICC: 0.81-0.95) was comparable to that of HD-MDCT (CV: 2.41-4.08%, SD: 0.014-0.016, ICC: 0.95-0.96), and fpVCT (CV: 3.13-5.63%, SD: 0.009-0.036, ICC: 0.64-0.98) for all parameters except app.TbSp. Conclusions C-arm CT is a reliable method for assessing trabecular bone architectural parameters with the exception of app.TbSp due to spatial resolution limitation. C1 [Phan, Catherine M.; Bredella, Miriam A.; Yoo, Albert J.; Hirsch, Joshua A.; Gupta, Rajiv] Massachusetts Gen Hosp Neuroradiol, Dept Radiol, Boston, MA 02114 USA. [Phan, Catherine M.; Macklin, Eric A.; Bredella, Miriam A.; Yoo, Albert J.; Hirsch, Joshua A.; Gupta, Rajiv] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Dept Med, Boston, MA 02114 USA. [Dadrich, Monica; Flechsig, Paul] German Canc Res Ctr, D-69120 Heidelberg, Germany. RP Phan, CM (reprint author), Massachusetts Gen Hosp Neuroradiol, Dept Radiol, GRB 273A,55 Fruit St, Boston, MA 02114 USA. EM cmphan@partners.org; emacklin@partners.org; mbredella@partners.org; monika_dadrich@hotmail.com; paul.flechsig@googlemail.com; ajyoo@partners.org; jahirsch@partners.org; rgupta1@partners.org RI Macklin, Eric/E-2955-2013 OI Macklin, Eric/0000-0003-1618-3502 NR 39 TC 8 Z9 8 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD AUG PY 2011 VL 40 IS 8 BP 1065 EP 1072 DI 10.1007/s00256-010-1002-5 PG 8 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 785EE UT WOS:000292209400013 PM 20658286 ER PT J AU Das, F Dey, N Venkatesan, B Kasinath, BS Ghosh-Choudhury, N Choudhury, GG AF Das, Falguni Dey, Nirmalya Venkatesan, Balachandar Kasinath, Balakuntalam S. Ghosh-Choudhury, Nandini Choudhury, Goutam Ghosh TI High glucose upregulation of early-onset Parkinson's disease protein DJ-1 integrates the PRAS40/TORC1 axis to mesangial cell hypertrophy SO CELLULAR SIGNALLING LA English DT Article DE Akt kinase; Kidney; Diabetes; mTOR ID TUMOR-SUPPRESSOR PTEN; MESSENGER-RNA TRANSLATION; DIABETIC-NEPHROPATHY; OXIDATIVE STRESS; RENAL HYPERTROPHY; PI3K PATHWAY; AKT KINASE; GENE DJ-1; BINDING; RAPAMYCIN AB The Akt kinase signaling pathway is frequently deregulated in many human diseases including cancer, autoimmune disease and diabetes. In nephropathy, associated with diabetes, increased Akt signal transduction results in glomerular especially mesangial cell hypertrophy. The mechanism of Akt activation by elevated glucose is poorly understood. The oncogene DJ-1 prevents oxidative damage and apoptosis of dopaminergic neurons in animal models of Parkinson's disease and in culture. We identified DJ-1 to increase in response to high glucose in renal glomerular mesangial cells concomitant with an increase in phosphorylation of Akt in a time-dependent manner. Plasmid-derived overexpression as well as down-regulation of DJ-1 by siRNA showed the requirement of this protein in high glucose-stimulated Akt phosphorylation. The tumor suppressor protein PTEN acts as a negative regulator of Akt activation. Interestingly, DJ-1 was associated with PTEN and this interaction was significantly increased in response to high glucose. High glucose-induced increase in DJ-1 promoted phosphorylation of the PRAS40, a negative regulator of TORC1 kinase activity, resulting in activating and inactivating phosphorylation of S6 kinase and 4EBP-1, respectively. Furthermore, DJ-1 increased protein synthesis and hypertrophy of mesangial cells. Our results provide evidence for a unique mechanism whereby DJ-1 induces Akt/PRAS40/TORC1-mediated hypertrophy in response to high glucose. (C) 2011 Elsevier Inc. All rights reserved. C1 [Das, Falguni; Dey, Nirmalya; Venkatesan, Balachandar; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Kasinath, Balakuntalam S.; Ghosh-Choudhury, Nandini; Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, VA Res, San Antonio, TX USA. [Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Res, San Antonio, TX USA. [Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP Choudhury, GG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Mail Code 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU Juvenile Diabetes Research Foundation [1-2008-185]; NIH [RO1 DK50190, RO1 AR52425, DK 077295, RC2A 036613]; VA Research Service; Cancer Therapy and Research Center, San Antonio FX The authors thank Drs. Brent Wagner and Anthony J. Valente, Department of Medicine, University of Texas Health Science Center at San Antonio for critically reading the manuscript. This work was supported by The Juvenile Diabetes Research Foundation 1-2008-185 and NIH RO1 DK50190 grants to GGC. GGC is a recipient of VA Senior Research Career Scientist Award and is supported by VA Research Service Merit Review grant. NGC is supported by VA Merit Review, Ronald P Williams Orthopedic Oncology Developmental Research Award from Cancer Therapy and Research Center, San Antonio and NIH RO1 AR52425 grants. BSK is supported by grants from NIH (DK 077295 and RC2A 036613) and VA Research Service. NR 49 TC 24 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD AUG PY 2011 VL 23 IS 8 BP 1311 EP 1319 DI 10.1016/j.cellsig.2011.03.012 PG 9 WC Cell Biology SC Cell Biology GA 776BO UT WOS:000291509700010 PM 21426932 ER PT J AU Mellinghoff, IK Lassman, AB Wen, PY AF Mellinghoff, Ingo K. Lassman, Andrew B. Wen, Patrick Y. TI Signal Transduction Inhibitors and Antiangiogenic Therapies for Malignant Glioma SO GLIA LA English DT Article DE glioma; kinase inhibitors; angiogenesis ID GROWTH-FACTOR RECEPTOR; RECURRENT GLIOBLASTOMA-MULTIFORME; CHRONIC MYELOID-LEUKEMIA; ANTI-ANGIOGENIC THERAPY; BRAIN-TUMOR CONSORTIUM; ASPARTIC ACID PEPTIDE; HIGH-GRADE GLIOMAS; CELL LUNG-CANCER; PHASE-II TRIAL; KINASE INHIBITORS AB Detailed characterization of the cancer genome in a large number of primary human glioblastomas has identified recurrent alterations that result in deregulation of signal transduction pathways and are "druggable" with a growing number of small molecule pharmaceuticals. While many of these compounds have shown clinical activity in other human cancers harboring similar genetic alterations, the clinical experience in glioblastoma has been disappointing thus far with only rare and transient radiographic responses. Our understanding of drug resistance is confounded by the uncertainty of drug delivery across the blood brain barrier and the limited knowledge to what extent the growth of these tumors depends on any particular signaling pathway. This uncertainty is, at least in part, due to shortcomings in the current approach to evaluate signal transduction inhibitors in glioma patients, including drug testing in molecularly unselected patient populations, limited documentation of drug penetration and target inhibition in tumor tissue, and use of radiographic response criteria that may not be optimal for the evaluation of these compounds. (C) 2011 Wiley-Liss, Inc. C1 [Mellinghoff, Ingo K.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Mellinghoff, Ingo K.; Lassman, Andrew B.] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Mellinghoff, Ingo K.; Lassman, Andrew B.] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10021 USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02115 USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Mellinghoff, IK (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. EM mellingi@mskcc.org; Patrick_Wen@dfci.harvard.edu FU National Cancer Institute [U54CA143798-01, U01 CA141502]; American Society of Clinical Oncology; Doris Duke Charitable Foundation; Leon Levy Foundation FX Grant sponsor: National Cancer Institute; Grant number: U54CA143798-01, U01 CA141502; Grant sponsors: American Society of Clinical Oncology, Doris Duke Charitable Foundation, Leon Levy Foundation. NR 91 TC 15 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD AUG PY 2011 VL 59 IS 8 SI SI BP 1205 EP 1212 DI 10.1002/glia.21137 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 777CN UT WOS:000291591800009 PM 21351155 ER PT J AU Yang, Z Huang, CYC Candiotti, KA Zeng, XL Yuan, TY Li, JL Yu, H Abdi, S AF Yang, Zhe Huang, Chun-Yuh Charles Candiotti, Keith A. Zeng, Xiaoling Yuan, Taiyi Li, Jinliang Yu, Hong Abdi, Salahadin TI Sox-9 Facilitates Differentiation of Adipose Tissue-Derived Stem Cells into a Chondrocyte-Like Phenotype In Vitro SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE disc degeneration; gene therapy; nucleus pulposus cell; Sox-9; stem cells; type II collagen ID PSEUDOTYPED RETROVIRAL VECTOR; DEGENERATIVE DISC DISEASE; STROMAL CELLS; INTERVERTEBRAL DISC; COLLAGEN GENE; THERAPY; CHONDROGENESIS; EXPRESSION; ALGINATE; GROWTH AB The purpose of this study is to test whether ectopic expression of Sox-9 can induce adipose tissue-derived stem cells (ASCs) to function as real nucleus pulposus (NP) cells in vitro. Adenoviral vectors expressing Sox-9 were reported to infect the chondroblastic and human disc cells, which resulted in increased Sox-9 and type II collagen production. ASCs were isolated from rat inguinal adipose pad, characterized, and transduced in vitro with a retroviral vector encoding the Sox-9 gene. Sox-9-engineered ASCs (ASCs/Sox-9) were induced for the chondrocyte-like cell differentiation by 3D cultured in alginate beads and TGF-beta 3 for 2 weeks. Expression of exogenous Sox-9 protein was detected. Type II collagen and Aggrecan gene expressions of induced ASCs/Sox-9 were measured using real-time PCR; proteoglycans expressions were measured by checking the glycosaminoglycan content and type II collagen production by enzyme-linked immunosorbent assay. Isolated ASCs were CD 29(+)/CD44(+)/C-Kit(-)/Lin(-)/CD34(-)/CD45(-). ASCs/Sox-9 expressed marked increase in exogenous Sox-9 protein. After induction, type II collagen gene expression was sevenfold higher in mRNA levels, with an approximately twofold increase in protein levels of ASCs/Sox-9 compared to ASCs. Type II collagen and proteoglycan productions were significantly increased in the ASCs/Sox-9 compared to the ASCs. In addition, co-culture of induced ASCs/Sox-9 with matured NP cells resulted in enhanced increase in proteoglycan and type II collagen production. Constitutive retroviral expression of Sox-9 could efficiently induce ASCs differentiation into chondrocyte-like cells. This novel approach may provide a practicable system for a simple and rapid differentiation of ASCs into chondrocyte-like cells which may be potentially used as a stem cell-based therapeutic tool for the treatment of degenerative disc diseases. (C) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29: 1291-1297, 2011 C1 [Abdi, Salahadin] Harvard Univ, Sch Med, Dept Anesthesiol, BIDMC, Boston, MA 02115 USA. [Yu, Hong] Miami Vet Affairs Hlth Care Syst, Miami, FL 33125 USA. [Li, Jinliang] Univ Miami, Dept Pediat, Miller Sch Med, Miami, FL 33136 USA. [Huang, Chun-Yuh Charles; Yuan, Taiyi] Univ Miami, Dept Biomed Engn, Tissue Biomech Lab, Coral Gables, FL 33124 USA. [Yang, Zhe; Candiotti, Keith A.; Zeng, Xiaoling] Univ Miami, Miller Sch Med, Dept Anesthesiol, Miami, FL 33136 USA. RP Abdi, S (reprint author), Harvard Univ, Sch Med, Dept Anesthesiol, BIDMC, Boston, MA 02115 USA. EM sabdi@bidmc.harvard.edu FU University of Miami FX The authors thank Dr. Zhao-jun Liu for critical review of the manuscript. We are grateful to Dr. Frank M. Philips (Professor, University of Chicago Medical Center, Chicago, IL) for his generous provision of Sox-9 cDNA. We also thank Dr. Xiaoqing Lu and Dr. Yanping Zhang for expert technical assistance. This work was supported by a University of Miami SAC grant. NR 32 TC 18 Z9 25 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD AUG PY 2011 VL 29 IS 8 BP 1291 EP 1297 DI 10.1002/jor.21336 PG 7 WC Orthopedics SC Orthopedics GA 777KQ UT WOS:000291614800021 PM 21400575 ER PT J AU Linnman, C Rougemont-Bucking, A Beucke, JC Zeffiro, TA Milad, MR AF Linnman, Clas Rougemont-Buecking, Ansgar Beucke, Jan Carl Zeffiro, Thomas A. Milad, Mohammed R. TI Unconditioned responses and functional fear networks in human classical conditioning SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE fMRI; Conditioning; Psychophysiological interaction; Connectivity; Insula; PPI ID TEMPORAL DIFFERENCE MODELS; HUMAN RED NUCLEUS; HUMAN BRAIN; POTENTIATED STARTLE; PERIAQUEDUCTAL GRAY; NEURAL ORGANIZATION; PREFRONTAL CORTEX; PAIN PERCEPTION; EXTINCTION; PREDICTION AB Human imaging studies examining fear conditioning have mainly focused on the neural responses to conditioned cues. In contrast, the neural basis of the unconditioned response and the mechanisms by which fear modulates inter-regional functional coupling have received limited attention. We examined the neural responses to an unconditioned stimulus using a partial-reinforcement fear conditioning paradigm and functional MRI. The analysis focused on: (1) the effects of an unconditioned stimulus (an electric shock) that was either expected and actually delivered, or expected but not delivered, and (2) on how related brain activity changed across conditioning trials, and (3) how shock expectation influenced interregional coupling within the fear network. We found that: (1) the delivery of the shock engaged the red nucleus, amygdale, dorsal striatum, insula, somatosensory and cingulate cortices, (2) when the shock was expected but not delivered, only the red nucleus, the anterior insular and dorsal anterior cingulate cortices showed activity increases that were sustained across trials, and (3) psycho-physiological interaction analysis demonstrated that fear led to increased red nucleus coupling to insula but decreased hippocampus coupling to the red nucleus, thalamus and cerebellum. The hippocampus and the anterior insula may serve as hubs facilitating the switch between engagement of a defensive immediate fear network and a resting network. (C) 2011 Elsevier B.V. All rights reserved. C1 [Linnman, Clas; Beucke, Jan Carl; Milad, Mohammed R.] Harvard Univ, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. [Linnman, Clas; Beucke, Jan Carl; Zeffiro, Thomas A.; Milad, Mohammed R.] Massachusetts Gen Hosp, Neural Syst Grp, Charlestown, MA 02129 USA. [Rougemont-Buecking, Ansgar] CHUV, Serv Psychiat Commun, Lausanne, Switzerland. RP Linnman, C (reprint author), Harvard Univ, Sch Med, Dept Psychiat, 149 13th St CNY 2518, Charlestown, MA 02129 USA. EM linnman@nmr.mgh.harvard.edu; Ansgar.Rougemont-Buecking@chuv.ch; jan@nmr.mgh.harvard.edu; zeffiro@nmr.mgh.harvard.edu; milad@nmr.mgh.harvard.edu OI Linnman, Clas/0000-0001-8449-894X FU National Institutes of Health [1R01MH081975]; Centre Hospital-ier Universitaite Vaudois and University of Lausanne, Switzerland; Societe Acadernique Vaudoise, Lausanne, Switzerland; Ev. Studienwerk Villigst (Schwerte, Germany); MircoTransponders FX We would like to thank Sarah Igoe and Mohamed Zeidan for helpful comments on the manuscript. This work was supported by the National Institutes of Health grant to MRM (Grant # 1R01MH081975). ARB received funding from the Centre Hospital-ier Universitaite Vaudois and University of Lausanne, Switzerland, as well as from the Societe Acadernique Vaudoise, Lausanne, Switzerland. JCB received funding from Ev. Studienwerk Villigst (Schwerte, Germany) and is an ERP scholar of the German National Academic Foundation.; MRM has received consultation funds from MircoTransponders in a project that is not related to this manuscript. The other authors of this article have no financial or other relationships that might lead to a conflict of interest. NR 34 TC 38 Z9 38 U1 2 U2 30 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD AUG 1 PY 2011 VL 221 IS 1 BP 237 EP 245 DI 10.1016/j.bbr.2011.02.045 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 767VJ UT WOS:000290886200029 PM 21377494 ER PT J AU Rigosi, E Frasnelli, E Vinegoni, C Antolini, R Anfora, G Vallortigara, G Haase, A AF Rigosi, Elisa Frasnelli, Elisa Vinegoni, Claudio Antolini, Renzo Anfora, Gianfranco Vallortigara, Giorgio Haase, Albrecht TI Searching for anatomical correlates of olfactory lateralization in the honeybee antennal lobes: A morphological and behavioural study SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Apis mellifera; Brain asymmetry; Olfactory learning; Antennal lobes; Two-photon microscopy ID APIS-MELLIFERA; STRUCTURAL PLASTICITY; INSECT BRAIN; BEE; GLOMERULI; REPRESENTATION; MICROSCOPY; NEURONS; ATLAS; CODE AB The honeybee, Apis mellifera L (Hymenoptera: Apidae), has recently become a model for studying brain asymmetry among invertebrates. A strong lateralization favouring the right antenna was discovered in odour learning and short-term memory recall experiments, and a lateral shift favouring the left antenna for long-term memory recall. Corresponding morphological asymmetries have been found in the distribution of olfactory sensilla between the antennae and confirmed by electrophysiological odour response measurements in isolated right and left antennae. The aim of this study was to investigate whether a morphological asymmetry can be observed in the volume of the primary olfactory centres of the central nervous system, the antennal lobes (ALs). Precise volume measurements of a subset of their functional units, the glomeruli, were performed in both sides of the brain, exploiting the advantages of two-photon microscopy. This novel method allowed minimal invasive acquisition of volume images of the ALs, avoiding artefacts from brain extraction and dehydration. The study was completed by a series of behavioural experiments in which response asymmetry in odour recall following proboscis extension reflex conditioning was assessed for odours, chosen to stimulate strong activity in the same glomeruli as in the morphological study. The volumetric measurements found no evidence of lateralization in the investigated glomeruli within the experimental limits. Instead, in the behavioural experiments, a striking odour dependence of the lateralization was observed. The results are discussed on the basis of recent neurophysiological and ethological experiments in A. mellifera. (C) 2011 Elsevier BM. All rights reserved. C1 [Rigosi, Elisa; Vallortigara, Giorgio] Univ Trent, Ctr Mind Brain Sci, CIMeC, I-38068 Rovereto, TN, Italy. [Rigosi, Elisa; Anfora, Gianfranco] Fdn E Mach, IASMA Res & Innovat Ctr, I-38010 San Michele All Adige, TN, Italy. [Frasnelli, Elisa] Konrad Lorenz Inst Evolut & Cognit Res, A-3422 Altenberg, Austria. [Vinegoni, Claudio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Vinegoni, Claudio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA 02114 USA. [Antolini, Renzo; Haase, Albrecht] Univ Trent, Dept Phys, I-38050 Povo, TN, Italy. [Antolini, Renzo; Haase, Albrecht] Univ Trent, BIOtech Res Ctr, I-38050 Povo, TN, Italy. RP Rigosi, E (reprint author), Univ Trent, Ctr Mind Brain Sci, CIMeC, Corso Bettini 31, I-38068 Rovereto, TN, Italy. EM elisa.rigosi@unitn.it RI Haase, Albrecht/H-4248-2012; OI Haase, Albrecht/0000-0002-8324-0047; ANFORA, Gianfranco/0000-0003-2545-1409 FU Provincia Autonoma di Trento; Fondazione Cassa di Risparmio di Trento e Rovereto; NIH [RO1EB006432] FX This work has been realised with the support from the Provincia Autonoma di Trento and the Fondazione Cassa di Risparmio di Trento e Rovereto. C.V. acknowledges Provincia Autonoma di Trento (project COMNFI) and NIH grant RO1EB006432. NR 29 TC 9 Z9 9 U1 1 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD AUG 1 PY 2011 VL 221 IS 1 BP 290 EP 294 DI 10.1016/j.bbr.2011.03.015 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 767VJ UT WOS:000290886200036 PM 21402106 ER PT J AU Abdul-Aziz, D Tierney, HT Deschler, DG AF Abdul-Aziz, Dunia Tierney, Hien T. Deschler, Daniel G. TI Surgical management of cervical chyloma following parathyroidectomy SO AURIS NASUS LARYNX LA English DT Article DE Chyloma; Lymphocele; Neck mass; Thoracic duct; Parathyroidectomy ID NECK DISSECTION; THORACIC-DUCT; LYMPHOCELE; SCLEROTHERAPY; LEAKAGE AB Although rare, chylomas can present as a neck mass, especially in the post-operative setting. Here, we present a case of a persistent cervical chyloma following parathyroidectomy and propose a management algorithm for this clinical entity. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Abdul-Aziz, Dunia; Tierney, Hien T.; Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Div Head & Neck Surg, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Deschler, DG (reprint author), Massachusetts Eye & Ear Infirm, Div Head & Neck Surg, Dept Otol & Laryngol, Boston, MA 02114 USA. EM daniel_deschler@meei.harvard.edu NR 17 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0385-8146 EI 1879-1476 J9 AURIS NASUS LARYNX JI Auris Nasus Larynx PD AUG PY 2011 VL 38 IS 4 BP 528 EP 531 DI 10.1016/j.anl.2010.09.012 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA 751HS UT WOS:000289608700018 PM 21257276 ER PT J AU Shao, FW Yuan, HS Josephson, L Weissleder, R Hilderbrand, SA AF Shao, Fangwei Yuan, Hushan Josephson, Lee Weissleder, Ralph Hilderbrand, Scott A. TI Facile synthesis of monofunctional pentamethine carbocyanine fluorophores SO DYES AND PIGMENTS LA English DT Article DE Pentamethine; Carbocyanine; Fluorophore; Near infrared; Monofunctional; Symmetric ID IN-VIVO; SUCCINIMIDYL ESTERS; LABELING REAGENTS; FLUOROCHROMES; PROBES; TUMORS; DYE AB A high-yield route to symmetric, conjugatable pentamethine carbocyanine dyes with far-red/near infrared (NIR) emission between 650 and 700 nm is reported. The dyes are prepared via condensation of indolium or benz[e]indolium inner salts with an alkyl carboxylic acid derivatized malonaldehyde dianil or alternatively in a one-pot reaction without isolation of the malonaldehyde intermediate. The fluorophores are water-soluble, have bright fluorescence emission, are easily prepared in good yield, and are promising candidates for use in a variety of biochemical and in vivo imaging applications. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Shao, Fangwei; Weissleder, Ralph; Hilderbrand, Scott A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Charlestown, MA 02129 USA. [Yuan, Hushan; Josephson, Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Nucl Med & Mol Imaging, Charlestown, MA 02129 USA. RP Hilderbrand, SA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, 149,13th St, Charlestown, MA 02129 USA. EM Scott_Hilderbrand@hms.harvard.edu RI Shao, Fangwei/B-7026-2011 FU NIH [U01-HL080731, P50-CA086355] FX The authors would like to thank Dr. Mark Karver for his assistance in characterization of the fluorophores. This work is supported by NIH grants U01-HL080731 and P50-CA086355. NR 19 TC 21 Z9 21 U1 1 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0143-7208 J9 DYES PIGMENTS JI Dyes Pigment. PD AUG PY 2011 VL 90 IS 2 BP 119 EP 122 DI 10.1016/j.dyepig.2010.12.008 PG 4 WC Chemistry, Applied; Engineering, Chemical; Materials Science, Textiles SC Chemistry; Engineering; Materials Science GA 739SH UT WOS:000288737800005 PM 21475610 ER PT J AU Maughan-Brown, B Venkataramani, AS AF Maughan-Brown, Brendan Venkataramani, Atheendar S. TI Measuring concurrent partnerships: potential for underestimation in UNAIDS recommended method SO AIDS LA English DT Article AB Research on concurrent sexual partnerships has been constrained by inconsistent and inaccurate measurements of these partnerships. Recently, a UNAIDS working group recommended a method based on sexual partner histories to improve the measurement of concurrency. Using recent survey data for young adults living in Cape Town, South Africa, we found that this method could result in underestimates of concurrency due to respondents' failure to report additional sexual partners. C1 [Maughan-Brown, Brendan] Univ Cape Town, SALDRU, ZA-7701 Cape Town, South Africa. [Venkataramani, Atheendar S.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Maughan-Brown, B (reprint author), Univ Cape Town, SALDRU, ZA-7701 Cape Town, South Africa. EM brendan.maughanbrown@gmail.com FU Washington University School of Medicine Forum for International Health and Tropical Medicine; US National Institute for Child Health and Human Development; Andrew W. Mellon Foundation; Health Economics & HIV/AIDS Research Division (HEARD) at the University of KwaZulu-Natal FX We would like to thank Murray Leibbrandt, Timothy Mah and two anonymous referees for their helpful comments and suggestions. Dr A.S. Venkataramani acknowledges the Washington University School of Medicine Forum for International Health and Tropical Medicine for funding travel to South Africa. The Cape Area Panel Study is a joint project of the universities of Cape Town and Michigan. Waves 3 and 5 were funded primarily by the US National Institute for Child Health and Human Development, the Andrew W. Mellon Foundation and the Health Economics & HIV/AIDS Research Division (HEARD) at the University of KwaZulu-Natal. Further information is available at http://www.caps.uct.ac.za. NR 10 TC 15 Z9 15 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2011 VL 25 IS 12 BP 1549 EP 1551 DI 10.1097/QAD.0b013e32834905c4 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 791BW UT WOS:000292636300014 PM 21617519 ER PT J AU Zhuo, M Wu, GX Wu, LJ AF Zhuo, Min Wu, Gongxiong Wu, Long-Jun TI Neuronal and microglial mechanisms of neuropathic pain SO MOLECULAR BRAIN LA English DT Review ID ANTERIOR CINGULATE CORTEX; LONG-TERM-POTENTIATION; PERIPHERAL-NERVE INJURY; DORSAL-HORN NEURONS; STIMULATED ADENYLYL CYCLASES; SPINAL GLIAL ACTIVATION; PROINFLAMMATORY CYTOKINE EXPRESSION; SENSING ION CHANNELS; INFLAMMATORY PAIN; CATHEPSIN-S AB Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury. Effective treatment for neuropathic pain is still lacking, due in part to poor understanding of pathological mechanisms at the molecular level. Neuronal mechanisms of neuropathic pain, especially synaptic plasticity, are the major focus of many investigators. N-methyl-D-aspartate (NMDA) receptor dependent synaptic plasticity at the spinal and cortical levels is believed to contribute to enhanced sensory responses after injury. Glial cells, including astrocytes and microglia, have recently been implicated in neuropathic pain. These glial cells form close interactions with neurons and thus may modulate nociceptive transmission under pathological conditions. In this review, we present recent progress in the study of neuronal and microglial mechanisms underlying neuropathic pain. We propose that activity-dependent neuronal plasticity is a key target for treatment in neuropathic pain. C1 [Zhuo, Min; Wu, Long-Jun] Xi An Jiao Tong Univ, Ctr Neuron & Dis, Frontier Inst Sci & Technol, Xian 710049, Peoples R China. [Zhuo, Min] Univ Toronto, Ctr Study Pain, Fac Med, Dept Physiol, Toronto, ON M5S 1A8, Canada. [Wu, Gongxiong] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Wu, Long-Jun] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Wu, Long-Jun] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. RP Zhuo, M (reprint author), Xi An Jiao Tong Univ, Ctr Neuron & Dis, Frontier Inst Sci & Technol, Xian 710049, Peoples R China. EM min.zhuo@utoronto.ca RI Zhuo, Min/A-2072-2008; OI Zhuo, Min/0000-0001-9062-3241; Wu, Long-Jun/0000-0001-8019-3380 FU Canadian Institutes of Health Research [CIHR66975, CIHR84256]; EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health; Canada Research Chair FX Supported by grants from the Canadian Institutes of Health Research (CIHR66975, CIHR84256), the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, and the Canada Research Chair to M. Z. L.-J.W. was supported by postdoctoral fellowship from the Canadian Institutes of Health Research, and is Lefler fellow in Harvard Medical School. We thank J. Stefan Kaczmarek for helpful comments and critical reading of the manuscript. NR 116 TC 78 Z9 89 U1 5 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-6606 J9 MOL BRAIN JI Mol. Brain PD JUL 30 PY 2011 VL 4 AR 31 DI 10.1186/1756-6606-4-31 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 007XV UT WOS:000308922600001 PM 21801430 ER PT J AU Egan, GJ Hasenkamp, W Wilcox, L Green, A Hsu, N Boshoven, W Lewison, B Keyes, MD Duncan, E AF Egan, Glenn J. Hasenkamp, Wendy Wilcox, Lisette Green, Amanda Hsu, Nancy Boshoven, William Lewison, Barbara Keyes, Megan D. Duncan, Erica TI Declarative memory and WCST-64 performance in subjects with schizophrenia and healthy controls SO PSYCHIATRY RESEARCH LA English DT Article DE Wisconsin Card Sorting Test; Benton Visual Retention Test; California Verbal Learning Test; Executive functioning ID CARD-SORTING TEST; ASSOCIATE RECOGNITION TEST; NEUROCOGNITIVE DEFICITS; NEUROPSYCHOLOGICAL DEFICITS; DYSFUNCTION; RELIABILITY; VALIDITY; STIMULI; SCALE AB The Wisconsin Card Sorting Test (WCST) is a set-switching task used extensively to study impaired executive functioning in schizophrenia. Declarative memory deficits have also been associated with schizophrenia and may affect WCST performance because continued correct responding depends on remembering the outcome of previous responses. This study examined whether performance in visual and verbal declarative memory tasks were associated with WCST performance. Subjects comprised 30 patients with schizophrenia or schizoaffective disorder (SCZ) and 30 demographically matched healthy controls (CON) who were tested on the WCST, the Benton Visual Retention Test (BVRT), the California Verbal Learning Test (CVLT), and the Continuous Performance Test (CPT). SCZ subjects showed significant correlations between visual and verbal declarative memory and performance on the WCST-64 that were in the hypothesized direction such that worse memory performance was associated with worse performance on the WCST. CON subjects did not show a significant relationship between visual or verbal memory and WCST-64 performance. Fisher's r to z transformations indicated that the associations between declarative memory and WCST-64 performance in the SCZ subjects differed significantly from those of CON subjects. The findings suggest that interpretations of WCST-64 scores for subjects with schizophrenia should be considered in light of their declarative memory functioning. (C) 2011 Published by Elsevier Ireland Ltd. C1 [Egan, Glenn J.; Boshoven, William; Lewison, Barbara; Duncan, Erica] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30303 USA. [Egan, Glenn J.; Hasenkamp, Wendy; Wilcox, Lisette; Lewison, Barbara; Duncan, Erica] Atlanta VA Med Ctr, Decatur, GA USA. [Green, Amanda] Grady Mem Hosp, Atlanta, GA USA. [Hsu, Nancy] Virginia Commonwealth Univ, Med Ctr, Richmond, VA USA. [Keyes, Megan D.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Egan, GJ (reprint author), Emory Univ, Sch Med, Dept Psychiat, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303 USA. EM glenn.egan@emory.edu RI Duncan, Erica/B-1671-2016 FU Veterans Affairs Merit Review Grant Program; National Institute on Drug Addiction [MH1R01DA018294-01A2]; Mental Health Service and Research and Development Service at the Atlanta Veterans Affairs Medical Center; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine FX This study was primarily supported by the Veterans Affairs Merit Review Grant Program (E. Duncan). Additional support was received from the National Institute on Drug Addiction (MH1R01DA018294-01A2, E. Duncan), the Mental Health Service and Research and Development Service at the Atlanta Veterans Affairs Medical Center, and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine. The authors are grateful for the editorial assistance of Griffin Fry. NR 44 TC 5 Z9 5 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUL 30 PY 2011 VL 188 IS 2 BP 191 EP 196 DI 10.1016/j.psychres.2011.02.026 PG 6 WC Psychiatry SC Psychiatry GA 791OM UT WOS:000292674500003 PM 21481945 ER PT J AU AhnAllen, CG Tidey, JW AF AhnAllen, Christopher G. Tidey, Jennifer W. TI Personalized smoking environment cue reactivity in smokers with schizophrenia and controls: A pilot study SO PSYCHIATRY RESEARCH LA English DT Article DE Cigarette smoking; Schizophrenia; Nicotine ID ABSTINENCE AB Exposure to to smoking cues increases craving to smoke and negatively changes mood in smokers with schizophrenia (SWS). This pilot study compared reactivity to real-world smoking environments versus neutral environments in SWS (n=10) and non-psychiatric control smokers (CON; n=10). Results indicate that both SWS and CON experienced increases in smoking urges when viewing images of their smoking environments and that SWS tended to report greater increases in withdrawal-related negative mood than CON when viewing images of their smoking environments. These findings signify that personalized smoking environments trigger smoking urges in SWS and suggest that extinguishing this reactivity may aid cessation efforts in this population. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [AhnAllen, Christopher G.; Tidey, Jennifer W.] Brown Univ, Alpert Med Sch, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. RP AhnAllen, CG (reprint author), VA Boston Healthcare Syst, Inpatient Mental Hlth Serv, Ward 23B, Brockton, MA 02301 USA. EM christopher.ahnallen@va.gov FU Brown University Center for Alcohol and Addictions Studies; [R01-DA14002] FX This study was supported by R01-DA14002 to JWT and a Research Excellence Award from the Brown University Center for Alcohol and Addictions Studies to CGA We thank Laura Dionne for data management assistance, Netesha Reid and Amy Adolfo for technical support and the study participants for their contributions. NR 14 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUL 30 PY 2011 VL 188 IS 2 BP 286 EP 288 DI 10.1016/j.psychres.2011.04.005 PG 3 WC Psychiatry SC Psychiatry GA 791OM UT WOS:000292674500018 PM 21550670 ER PT J AU Brown, AB Biederman, J Valera, E Makris, N Doyle, A Whitfield-Gabrieli, S Mick, E Spencer, T Faraone, S Seidman, L AF Brown, Ariel Beth Biederman, Joseph Valera, Eve Makris, Nikos Doyle, Alysa Whitfield-Gabrieli, Susan Mick, Eric Spencer, Thomas Faraone, Stephen Seidman, Larry TI Relationship of DAT1 and adult ADHD to task-positive and task-negative working memory networks SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE fMRI; Default-mode network; Attention; Dopamine ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DOPAMINE TRANSPORTER GENE; DEFICIT HYPERACTIVITY DISORDER; DEFAULT-MODE NETWORK; FUNCTIONAL NEUROANATOMY; PREFRONTAL CORTEX; BRAIN ACTIVATION; REGULATING GENES; GENOTYPE; SLC6A3 AB Alterations in working memory, default-mode network (DMN), and dopamine transporter have all been proposed as endophenotypes for attention-deficit/hyperactivity disorder (ADHD). Despite evidence that these systems are interrelated, their relationship to each other has never been studied in the context of ADHD. In order to understand the potential mediating effects of task-positive and task-negative networks between DAT1 and diagnosis, we tested effects of genotype and diagnosis on regions of positive and negative BOLD signal change (as measured with fMRI) in 53 adults with ADHD and 38 control subjects during a working memory task. We also examined the relationship of these responses to ADHD symptoms. Our results yielded four principal findings: 1) association of the DAT1 9R allele with adult ADHD, 2) marginal DAT1 association with task-related suppression in left medial PFC, 3) marginal genotype x diagnosis interaction in the dorsal anterior cingulate cortex, and 4) correlation of DMN suppression to ADHD symptoms. These findings replicate the association of the 9R allele with adult ADHD. Further, we show that DMN suppression is likely linked to DAT1 and to severity of inattention in ADHD. DMN may therefore be a target of DAT1 effects, and lie on the path between the gene and inattention in ADHD. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Brown, Ariel Beth; Biederman, Joseph; Valera, Eve; Doyle, Alysa; Mick, Eric; Spencer, Thomas; Seidman, Larry] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Programs Pediat Psychopharmacol & Adul, Boston, MA 02114 USA. [Brown, Ariel Beth; Biederman, Joseph; Valera, Eve; Doyle, Alysa; Mick, Eric; Spencer, Thomas; Seidman, Larry] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Brown, Ariel Beth; Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Valera, Eve] MIT, Psychiat Neuroimaging Res Program, Dept Psychiat, Cambridge, MA 02139 USA. [Makris, Nikos] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Makris, Nikos] Boston Univ, Sch Med, Dept Radiol Serv, Boston, MA 02118 USA. [Makris, Nikos] Massachusetts Gen Hosp East, Ctr Morphometr Anal, Boston, MA 02129 USA. [Faraone, Stephen] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA. [Seidman, Larry] Harvard Univ, Massachusetts Mental Hlth Ctr, Beth Israel Deaconess Med Ctr, Publ Psychiat Div,Dept Psychiat,Med Sch, Boston, MA 02215 USA. RP Brown, AB (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Programs Pediat Psychopharmacol & Adul, 55 Fruit St,WRN 627C, Boston, MA 02114 USA. EM ariel@nmr.mgh.harvard.edu OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NIMH [MH 62152, MH 57934, MH 071535, HD37694, MH64019, HD36317]; Boston University School of Medicine, Division of Graduate Medical Sciences; National Alliance for Research on Schizophrenia; Janssen Pharmaceuticals; March of Dimes Foundation; Mental Illness and Neuroscience Discovery (MIND) Institute; Kimmerly-Neil Fund for the Study of Cognition and Psychiatric Disorders in Children; Pediatric Psychopharmacology Council; National Center for Research Resources [P41RR14075]; Elminda; Janssen; McNeil; Shire; Fundacion Areces; Medice Pharmaceuticals; Spanish Child Psychiatry Association; Abbott; Alza; Astra Zeneca; Bristol Myers Squibb; Celltech; Cephalon; Eli Lilly and Co.; Esai; Forest; Glaxo; Gliatech; Merck; NARSAD; NIDA; New River; NICHD; Novartis; Noven; Neurosearch; Organon; Otsuka; Pfizer; Pharmacia; Prechter Foundation; Stanley Foundation; UCB Pharma, Inc.; Wyeth; Ortho-McNeil Janssen Scientific Affairs; Shire Pharmaceuticals; Shire Laboratories, Inc; Eli Lilly Company; Glaxo-Smith Kline; Janssen Pharmaceutical; McNeil Pharmaceutical; Novartis Pharmaceuticals; National Institute of Mental Health; Ortho-McNeil; Shire Development; National Institutes of Health FX This research was supported by grants from: NIMH MH 62152 (LJS), MH 57934 (SF), MH 071535 (EV), HD37694 (SF), MH64019 (TS), HD36317 (JB); Boston University School of Medicine, Division of Graduate Medical Sciences Graduate Student Research Fellowship (AB); the National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award (JB); Janssen Pharmaceuticals (JB); the March of Dimes Foundation (LJS), the Mental Illness and Neuroscience Discovery (MIND) Institute (LJS); the Kimmerly-Neil Fund for the Study of Cognition and Psychiatric Disorders in Children; the Pediatric Psychopharmacology Council Fund; and the National Center for Research Resources (P41RR14075).; Dr. Joseph Biederman is currently receiving research support from the following sources: Elminda, Janssen, McNeil, and Shire. In 2010, Dr. Joseph Biederman did not receive any outside income. In 2009, Dr. Joseph Biederman received a speaker's fee from the following sources: Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. In previous years, Dr. Joseph Biederman received research support, consultation fees, or speaker's fees for/from the following additional sources: Abbott, Alza, Astra Zeneca, Bristol Myers Squibb, Celltech, Cephalon, Eli Lilly and Co.,Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, Merck, NARSAD, NIDA, New River, NICHD, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc. and Wyeth.; Dr. Eric Mick receives research support from the following sources: Ortho-McNeil Janssen Scientific Affairs, Pfizer, Shire Pharmaceuticals, and has been an advisory board member for Shire Pharmaceuticals.; Dr. Thomas Spencer has received research support from, has been a speaker for or on a speaker bureau or has been an Advisor or on an Advisory Board of the following sources: Shire Laboratories, Inc, Eli Lilly & Company, Glaxo-Smith Kline, Janssen Pharmaceutical, McNeil Pharmaceutical, Novartis Pharmaceuticals, Cephalon, Pfizer and the National Institute of Mental Health.; Dr. Stephen Faraone has, in the past year received consulting fees and has been on Advisory Boards for Eli Lilly, Ortho-McNeil and Shire Development and has received research support from Shire and the National Institutes of Health. In previous years, Dr. Faraone has received consulting fees or has been on Advisory Boards or has been a speaker for the following sources: Shire, McNeil, Janssen, Novartis, Pfizer, Ortho-McNeil and Eli Lilly. In previous years he has received research support from Eli Lilly, Shire, Pfizer and the National Institutes of Health. NR 66 TC 23 Z9 24 U1 1 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUL 30 PY 2011 VL 193 IS 1 BP 7 EP 16 DI 10.1016/j.pscychresns.2011.01.006 PG 10 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 788US UT WOS:000292470500002 PM 21596533 ER PT J AU Cronican, JJ Beier, KT Davis, TN Tseng, JC Li, WD Thompson, DB Shih, AF May, EM Cepko, CL Kung, AL Zhou, Q Liu, DR AF Cronican, James J. Beier, Kevin T. Davis, Tina N. Tseng, Jen-Chieh Li, Weida Thompson, David B. Shih, Allen F. May, Erin M. Cepko, Constance L. Kung, Andrew L. Zhou, Qiao Liu, David R. TI A Class of Human Proteins that Deliver Functional Proteins into Mammalian Cells In Vitro and In Vivo SO CHEMISTRY & BIOLOGY LA English DT Article ID HUMAN IMMUNODEFICIENCY VIRUS; MEMBRANE-PERMEABLE PEPTIDES; PENETRATING PEPTIDES; FUSION PROTEIN; DEK; DNA AB We discovered a class of naturally occurring human proteins with unusually high net positive charge that can potently deliver proteins in functional form into mammalian cells both in vitro and also in murine retina, pancreas, and white adipose tissues in vivo. These findings represent diverse macromolecule delivery agents for in vivo applications, and also raise the possibility that some of these human proteins may penetrate cells as part of their native biological functions. C1 [Cronican, James J.; Thompson, David B.; Shih, Allen F.; May, Erin M.; Liu, David R.] Harvard Univ, Dept Chem & Chem Biol, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Beier, Kevin T.; Cepko, Constance L.] Harvard Univ, Sch Med, Dept Genet, Howard Hughes Med Inst, Boston, MA 02115 USA. [Beier, Kevin T.; Cepko, Constance L.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. [Davis, Tina N.; Tseng, Jen-Chieh; Kung, Andrew L.] Harvard Univ, Sch Med, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Davis, Tina N.; Tseng, Jen-Chieh; Kung, Andrew L.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Davis, Tina N.; Tseng, Jen-Chieh; Kung, Andrew L.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. [Li, Weida; Zhou, Qiao] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Liu, DR (reprint author), Harvard Univ, Dept Chem & Chem Biol, Howard Hughes Med Inst, 12 Oxford St, Cambridge, MA 02138 USA. EM drliu@fas.harvard.edu RI Li, Weida/M-4700-2013; OI Shih, Allen/0000-0002-7459-4986; Kung, Andrew/0000-0002-9091-488X FU National Institutes of Health/NIGMS [R01GM065400, R01 GM095501]; Howard Hughes Medical Institute; NIDDK [U01 DK089536]; Harvard Stem Cell Institute (HSCI) FX We thank Paul Cohen and Bruce Spiegelman for assistance with white adipose tissue delivery experiments. We are grateful to Juliana Brown and Laurie Jackson-Grusby for assistance with pancreas injections. This work was supported by the National Institutes of Health/NIGMS (R01GM065400 and R01 GM095501) and by the Howard Hughes Medical Institute. Q.Z. is supported by NIDDK U01 DK089536 and the Harvard Stem Cell Institute (HSCI). D.R.L. is a consultant for Permeon Biologics, a company that has licensed Harvard's intellectual property on macromolecule delivery. NR 31 TC 49 Z9 49 U1 2 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUL 29 PY 2011 VL 18 IS 7 BP 833 EP 838 DI 10.1016/j.chembiol.2011.07.003 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809VQ UT WOS:000294085200006 PM 21802004 ER PT J AU Miduturu, CV Deng, XM Kwiatkowski, N Yang, WNA Brault, L Filippakopoulos, P Chung, E Yang, QK Schwaller, J Knapp, S King, RW Lee, JD Herrgard, S Zarrinkar, P Gray, NS AF Miduturu, Chandrasekhar V. Deng, Xianming Kwiatkowski, Nicholas Yang, Wannian Brault, Laurent Filippakopoulos, Panagis Chung, Eunah Yang, Qingkai Schwaller, Juerg Knapp, Stefan King, Randall W. Lee, Jiing-Dwan Herrgard, Sanna Zarrinkar, Patrick Gray, Nathanael S. TI High-Throughput Kinase Profiling: A More Efficient Approach toward the Discovery of New Kinase Inhibitors SO CHEMISTRY & BIOLOGY LA English DT Article ID PIM SERINE/THREONINE KINASES; SPINDLE-ASSEMBLY CHECKPOINT; IN-VITRO; PROTEIN-KINASES; STRUCTURAL INSIGHTS; INTERACTION MAP; DNA-DAMAGE; CANCER; IDENTIFICATION; POTENT AB Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that "high-throughput kinase profiling" is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors. C1 [Miduturu, Chandrasekhar V.; Deng, Xianming; Kwiatkowski, Nicholas; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Miduturu, Chandrasekhar V.; Deng, Xianming; Kwiatkowski, Nicholas; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Yang, Wannian] Weis Ctr Res, Danville, PA 17822 USA. [Brault, Laurent; Schwaller, Juerg] Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland. [Filippakopoulos, Panagis; Knapp, Stefan] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7DQ, England. [Filippakopoulos, Panagis; Knapp, Stefan] Univ Oxford, Dept Clin Pharmacol, Oxford OX3 7DQ, England. [Chung, Eunah; King, Randall W.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Yang, Qingkai; Lee, Jiing-Dwan] Scripps Res Inst, Dept Immunol & Microbiol Sci, La Jolla, CA 92037 USA. [Herrgard, Sanna; Zarrinkar, Patrick] Ambit Biosci, San Diego, CA 92121 USA. RP Gray, NS (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM Nathanael_Gray@dfci.harvard.edu RI schwaller, juerg/A-3044-2016; OI Yang, Qingkai/0000-0001-6628-5393; King, Randall/0000-0001-7882-8180; Filippakopoulos, Panagis/0000-0002-1515-1317; Knapp, Stefan/0000-0001-5995-6494 FU NIH [CA130876-03, HG005693-02, U54 HG006097-01, HD 23696-21, GM66492]; Canadian Institutes for Health Research; Canadian Foundation for Innovation; Genome Canada through the Ontario Genomics Institute; GlaxoSmithKline; Karolinska Institutet; Knut and Alice Wallenberg Foundation; Ontario Innovation Trust; Ontario Ministry for Research and Innovation; Merck Co.; Novartis Research Foundation; Swedish Agency for Innovation Systems; Swedish Foundation for Strategic Research; Wellcome Trust FX We thank Ambit Biosciences KINOMEscan high-throughput kinase selectivity profiling services for screening all the compounds against members of the human kinase. We thank Life Technologies Corporation, Select Screen Kinase Profiling Service for performing enzymatic biochemical kinase profiling. Funding was provided by NIH grants: CA130876-03, HG005693-02, U54 HG006097-01 (N.S.G.), HD 23696-21 (E.C.), and GM66492 (R.W.K.). The Structural Genomics Consortium is a registered charity (1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. P.Z. and S.H. are former and current employees, respectively, at Ambit Biosciences. The kinase inhibitor profiling service KINOMEscan previously owned by Ambit Biosicences is now part of DiscoveRx Corporation. NR 57 TC 39 Z9 40 U1 1 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD JUL 29 PY 2011 VL 18 IS 7 BP 868 EP 879 DI 10.1016/j.chembiol.2011.05.010 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809VQ UT WOS:000294085200010 PM 21802008 ER PT J AU Kuai, LT Ong, SE Madison, JM Wang, X Duvall, JR Lewis, TA Luce, CJ Conner, SD Pearlman, DA Wood, JL Schreiber, SL Carr, SA Scolnick, EM Haggarty, SJ AF Kuai, Letian Ong, Shao-En Madison, Jon M. Wang, Xiang Duvall, Jeremy R. Lewis, Timothy A. Luce, Catherine J. Conner, Sean D. Pearlman, David A. Wood, John L. Schreiber, Stuart L. Carr, Steven A. Scolnick, Edward M. Haggarty, Stephen J. TI AAK1 Identified as an Inhibitor of Neuregulin-1/ErbB4-Dependent Neurotrophic Factor Signaling Using Integrative Chemical Genomics and Proteomics SO CHEMISTRY & BIOLOGY LA English DT Article ID NERVE GROWTH-FACTOR; CHOLINE-ACETYLTRANSFERASE ACTIVITY; TRK PROTOONCOGENE PRODUCT; PROTEIN-KINASE INHIBITOR; PC12 CELLS; TYROSINE PHOSPHORYLATION; FACTOR RECEPTOR; BIOLOGICAL-ACTIVITY; NEURITE OUTGROWTH; ERBB RECEPTORS AB Target identification remains challenging for the field of chemical biology. We describe an integrative chemical genomic and proteomic approach combining the use of differentially active analogs of small molecule probes with stable isotope labeling by amino acids in cell culture-mediated affinity enrichment, followed by subsequent testing of candidate targets using RNA interference-mediated gene silencing. We applied this approach to characterizing the natural product K252a and its ability to potentiate neuregulin-1 (Nrg1)/ErbB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4)-dependent neurotrophic factor signaling and neuritogenesis. We show that AAK1 (adaptor-associated kinase 1) is a relevant target of K252a, and that the loss of AAK1 alters ErbB4 trafficking and expression levels, providing evidence for a previously unrecognized role for AAK1 in Nrg1 -mediated neurotrophic factor signaling. Similar strategies should lead to the discovery of novel targets for therapeutic development. C1 [Kuai, Letian; Madison, Jon M.; Luce, Catherine J.; Pearlman, David A.; Scolnick, Edward M.; Haggarty, Stephen J.] Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Ong, Shao-En; Wang, Xiang; Duvall, Jeremy R.; Lewis, Timothy A.; Schreiber, Stuart L.; Carr, Steven A.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Conner, Sean D.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Wood, John L.] Colorado State Univ, Dept Chem, Ft Collins, CO 80523 USA. [Haggarty, Stephen J.] Harvard Univ, Ctr Human Genet Res, Massachusetts Gen Hosp, Dept Neurol,Med Sch, Boston, MA 02114 USA. RP Haggarty, SJ (reprint author), Stanley Ctr Psychiat Res, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM haggarty@chgr.mgh.harvard.edu OI Haggarty, Stephen J./0000-0002-7872-168X FU Stanley Medical Research Institute; Broad Institute SPARC; US National Institutes of Health (NIH) [1R21MH087896-01]; US National Cancer Institute's Initiative for Chemical Genetics [N01-CO-12400]; NIH [RL1HG004671, RL1CA133834, RL1GM084437, UL1RR024924] FX We thank members of the Broad Chemical Biology and Proteomics Platforms, as well as the Stanley Center for Psychiatric Research for support, and access to key instrumentation and reagents. This work was supported by grants from the Stanley Medical Research Institute, the Broad Institute SPARC, and the US National Institutes of Health (NIH) (1R21MH087896-01). The project has also been funded in part with funds from the US National Cancer Institute's Initiative for Chemical Genetics (contract number N01-CO-12400) and an NIH grant for Genomics Based Drug Discovery-Target ID project (RL1HG004671), administratively linked to RL1CA133834, RL1GM084437, and UL1RR024924. L.K, S.-E.O., C.J.L., and J.M.M. developed biochemical methods, designed, experiments, and analyzed data. J.L.W. provided advice on chemical inhibitors and synthesized analogs of K252a. J.R.D., T.A.L., and X.W. designed, synthesized, and characterized the K252a-based affinity probes. S.-E.O., L.K., and S.A.C. designed, performed, and interpreted the SILAC-target identification studies. S.D.C. provided key reagents and advice for the AAK1 kinase assay, biochemical studies, and data interpretation. D.A.P. designed and performed the K252a-AAK1 computational studies. S.L.S., S.A.C., EMS., and S.J.H. provided funding, mentoring, and advised in experimental design and data interpretation. L.K., J.M.M., and S.J.H. prepared the manuscript, which was edited by all authors. The corresponding author (S.J.H.) certifies that all authors have agreed to all the content in the manuscript, including the data as presented. There were no competing financial interests. NR 68 TC 12 Z9 12 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUL 29 PY 2011 VL 18 IS 7 BP 891 EP 906 DI 10.1016/j.chembiol.2011.03.017 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809VQ UT WOS:000294085200012 PM 21802010 ER PT J AU Chung, YSA Kocks, C AF Chung, Yoon-Suk Alexander Kocks, Christine TI Recognition of Pathogenic Microbes by the Drosophila Phagocytic Pattern Recognition Receptor Eater SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CATIONIC ANTIMICROBIAL PEPTIDES; MACROPHAGE SCAVENGER RECEPTORS; INNATE IMMUNE-SYSTEM; PSEUDOMONAS-AERUGINOSA; OUTER-MEMBRANE; TEICHOIC-ACIDS; PEPTIDOGLYCAN; PROTEIN; RESISTANCE; BACTERIA AB Non-opsonic phagocytosis is a primordial form of pathogen recognition that is mediated by the direct interaction of phagocytic receptors with microbial surfaces. In the fruit fly Drosophila melanogaster, the EGF-like repeat containing scavenger receptor Eater is expressed by phagocytes and is required to survive infections with Gram-positive and Gram-negative bacteria. However, the mechanisms by which this receptor recognizes different types of bacteria are poorly understood. To address this problem, we generated a soluble, Fc-tagged receptor variant of Eater comprising the N-terminal 199 amino acids including four EGF-like repeats. We first established that Eater-Fc displayed specific binding to broad yet distinct classes of heat- or ethanol-inactivated microbes and behaved similarly to the membrane-bound, full-length Eater receptor. We then used Eater-Fc as a tool to probe Eater binding to the surface of live bacteria. Eater-Fc bound equally well to naive or inactivated Staphylococcus aureus or Enterococcus faecalis, suggesting that in vivo, Eater directly targets live Gram-positive bacteria, enabling their phagocytic clearance and destruction. By contrast, Eater-Fc was unable to interact with live, naive Gram-negative bacteria (Escherichia coli, Serratia marcescens, and Pseudomonas aeruginosa). For these bacteria, Eater-Fc binding required membrane-disrupting treatments. Furthermore, we found that cecropin A, a cationic, membrane-disrupting antimicrobial peptide, could promote Eater-Fc binding to live E. coli, even at sublethal concentrations. These results suggest a previously unrecognized mechanism by which antimicrobial peptides cooperate with phagocytic receptors to extend the range of microbes that can be targeted by a single, germline-encoded receptor. C1 [Kocks, Christine] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Kocks, C (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, 185 Cambridge St,CPZN 7-250, Boston, MA 02114 USA. EM kocks@molbio.mgh.harvard.edu FU National Institutes of Health [P01 AI44220]; National Institutes of Health Center for the Study of Inflammatory Bowel Disease [DK43351]; Boston Area Diabetes and Endocrinology Research Center [DK57521] FX This work was supported, in whole or in part, by National Institutes of Health Grant P01 AI44220.; We thank Bol-Luel Lee for the gift of a baculovirus expression plasmid, Janice Lee for synthesizing dsRNAs, Joseph Garlick, Ji-Joon Song, and Robert E. Kingston for help with baculovirus expression, Dominique Ferrandon, Frederick M. Ausubel, and Iain Fraser for microbial strains, David McLaughlin, Lizabeth A. Perkins, and the members of the Ausubel laboratory for support, advice, suggestions, or comments on the manuscript, in particular Brent Cezairliyan, Mark Rosenzweig, and Fred Ausubel. EM was performed by Mary McKee in the Microscopy Core of the Center for Systems Biology/Program in Membrane Biology, which is partially supported by a National Institutes of Health Center for the Study of Inflammatory Bowel Disease Grant DK43351 and a Boston Area Diabetes and Endocrinology Research Center Award DK57521. NR 67 TC 20 Z9 20 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 29 PY 2011 VL 286 IS 30 BP 26524 EP 26532 DI 10.1074/jbc.M110.214007 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 796UK UT WOS:000293078200031 PM 21613218 ER PT J AU Ahn, JY Yang, LY Paster, BJ Ganly, I Morris, L Pei, ZH Hayes, RB AF Ahn, Jiyoung Yang, Liying Paster, Bruce J. Ganly, Ian Morris, Luc Pei, Zhiheng Hayes, Richard B. TI Oral Microbiome Profiles: 16S rRNA Pyrosequencing and Microarray Assay Comparison SO PLOS ONE LA English DT Article ID PERIODONTITIS; MICROFLORA; SEQUENCES; PROJECT AB Objectives: The human oral microbiome is potentially related to diverse health conditions and high-throughput technology provides the possibility of surveying microbial community structure at high resolution. We compared two oral microbiome survey methods: broad-based microbiome identification by 16S rRNA gene sequencing and targeted characterization of microbes by custom DNA microarray. Methods: Oral wash samples were collected from 20 individuals at Memorial Sloan-Kettering Cancer Center. 16S rRNA gene survey was performed by 454 pyrosequencing of the V3-V5 region (450 bp). Targeted identification by DNA microarray was carried out with the Human Oral Microbe Identification Microarray (HOMIM). Correlations and relative abundance were compared at phylum and genus level, between 16S rRNA sequence read ratio and HOMIM hybridization intensity. Results: The major phyla, Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria were identified with high correlation by the two methods (r = 0.70 similar to 0.86). 16S rRNA gene pyrosequencing identified 77 genera and HOMIM identified 49, with 37 genera detected by both methods; more than 98% of classified bacteria were assigned in these 37 genera. Concordance by the two assays (presence/absence) and correlations were high for common genera (Streptococcus, Veillonella, Leptotrichia, Prevotella, and Haemophilus; Correlation = 0.70-0.84). Conclusion: Microbiome community profiles assessed by 16S rRNA pyrosequencing and HOMIM were highly correlated at the phylum level and, when comparing the more commonly detected taxa, also at the genus level. Both methods are currently suitable for high-throughput epidemiologic investigations relating identified and more common oral microbial taxa to disease risk; yet, pyrosequencing may provide a broader spectrum of taxa identification, a distinct sequence-read record, and greater detection sensitivity. C1 [Ahn, Jiyoung; Hayes, Richard B.] NYU, Dept Environm Med, Sch Med, Div Epidemiol, New York, NY 10016 USA. [Yang, Liying; Pei, Zhiheng] NYU, Dept Pathol, Sch Med, New York, NY 10016 USA. [Paster, Bruce J.] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Ganly, Ian; Morris, Luc] Mem Sloan Kettering Canc Ctr, Dept Head & Neck Surg, New York, NY 10021 USA. RP Ahn, JY (reprint author), NYU, Dept Environm Med, Sch Med, Div Epidemiol, 550 1St Ave, New York, NY 10016 USA. EM jiyoung.ahn@nyumc.org OI Ganly, Ian/0000-0001-7636-5426; Yang, Liying/0000-0003-1442-4915; Hayes, Richard/0000-0002-0918-661X; Pei, Zhiheng/0000-0001-8570-6747 FU National Institutes of Health Roadmap Initiative and National Cancer Institute [UH3CA140233]; National Cancer Institute [R01 CA159036]; National Institute of Allergy and Infectious Diseases [R01AI063477] FX This work was supported by grants UH3CA140233 from Human Microbiome Project of the National Institutes of Health Roadmap Initiative and National Cancer Institute, R01 CA159036 from National Cancer Institute, and R01AI063477 from the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 69 Z9 73 U1 0 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 JUL 29 PY 2011 VL 6 IS 7 AR e22788 DI 10.1371/journal.pone.0022788 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799KV UT WOS:000293286500029 PM 21829515 ER PT J AU Korb, MA Thakkar, U AF Korb, Michele A. Thakkar, Umesh TI Facilitating Scientific Investigations and Training Data Scientists SO SCIENCE LA English DT Editorial Material C1 [Korb, Michele A.] Calif State Univ Hayward, Dept Teacher Educ, Coll Educ & Allied Studies, Hayward, CA 94542 USA. [Thakkar, Umesh] Univ Illinois, Coordinated Sci Lab, Urbana, IL 61801 USA. [Thakkar, Umesh] Vet Hlth Adm, Off Publ Hlth, US Dept Vet Affairs, Washington, DC 20420 USA. RP Korb, MA (reprint author), Calif State Univ Hayward, Dept Teacher Educ, Coll Educ & Allied Studies, Hayward, CA 94542 USA. EM michele.korb@csueastbay.edu; uthakkar@illinois.edu NR 8 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 29 PY 2011 VL 333 IS 6042 BP 534 EP 535 DI 10.1126/science.1196981 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 798PI UT WOS:000293222400032 PM 21798922 ER PT J AU Mukhtar, MS Carvunis, AR Dreze, M Epple, P Steinbrenner, J Moore, J Tasan, M Galli, M Hao, T Nishimura, MT Pevzner, SJ Donovan, SE Ghamsari, L Santhanam, B Romero, V Poulin, MM Gebreab, F Gutierrez, BJ Tam, S Monachello, D Boxem, M Harbort, CJ McDonald, N Gai, LT Chen, HM He, YJ Vandenhaute, J Roth, FP Hill, DE Ecker, JR Vidal, M Beynon, J Braun, P Dangl, JL AF Mukhtar, M. Shahid Carvunis, Anne-Ruxandra Dreze, Matija Epple, Petra Steinbrenner, Jens Moore, Jonathan Tasan, Murat Galli, Mary Hao, Tong Nishimura, Marc T. Pevzner, Samuel J. Donovan, Susan E. Ghamsari, Lila Santhanam, Balaji Romero, Viviana Poulin, Matthew M. Gebreab, Fana Gutierrez, Bryan J. Tam, Stanley Monachello, Dario Boxem, Mike Harbort, Christopher J. McDonald, Nathan Gai, Lantian Chen, Huaming He, Yijian Vandenhaute, Jean Roth, Frederick P. Hill, David E. Ecker, Joseph R. Vidal, Marc Beynon, Jim Braun, Pascal Dangl, Jeffery L. CA European Union Effectoromics Conso TI Independently Evolved Virulence Effectors Converge onto Hubs in a Plant Immune System Network SO SCIENCE LA English DT Article ID ARABIDOPSIS-THALIANA; DISEASE RESISTANCE; DEFENSE RESPONSES; ARMS-RACE; INFECTION; PATHOGENS; GENOME; VIRUS AB Plants generate effective responses to infection by recognizing both conserved and variable pathogen-encoded molecules. Pathogens deploy virulence effector proteins into host cells, where they interact physically with host proteins to modulate defense. We generated an interaction network of plant-pathogen effectors from two pathogens spanning the eukaryote-eubacteria divergence, three classes of Arabidopsis immune system proteins, and similar to 8000 other Arabidopsis proteins. We noted convergence of effectors onto highly interconnected host proteins and indirect, rather than direct, connections between effectors and plant immune receptors. We demonstrated plant immune system functions for 15 of 17 tested host proteins that interact with effectors from both pathogens. Thus, pathogens from different kingdoms deploy independently evolved virulence proteins that interact with a limited set of highly connected cellular hubs to facilitate their diverse life-cycle strategies. C1 [Carvunis, Anne-Ruxandra; Dreze, Matija; Hao, Tong; Pevzner, Samuel J.; Ghamsari, Lila; Santhanam, Balaji; Romero, Viviana; Poulin, Matthew M.; Gebreab, Fana; Gutierrez, Bryan J.; Tam, Stanley; Monachello, Dario; Roth, Frederick P.; Hill, David E.; Vidal, Marc; Braun, Pascal] Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. [Carvunis, Anne-Ruxandra; Dreze, Matija; Hao, Tong; Pevzner, Samuel J.; Ghamsari, Lila; Santhanam, Balaji; Romero, Viviana; Poulin, Matthew M.; Gebreab, Fana; Gutierrez, Bryan J.; Tam, Stanley; Monachello, Dario; Roth, Frederick P.; Hill, David E.; Vidal, Marc; Braun, Pascal] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Mukhtar, M. Shahid; Epple, Petra; Nishimura, Marc T.; Harbort, Christopher J.; McDonald, Nathan; He, Yijian; Dangl, Jeffery L.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Carvunis, Anne-Ruxandra; Dreze, Matija; Hao, Tong; Pevzner, Samuel J.; Ghamsari, Lila; Santhanam, Balaji; Romero, Viviana; Poulin, Matthew M.; Gebreab, Fana; Gutierrez, Bryan J.; Tam, Stanley; Hill, David E.; Vidal, Marc; Braun, Pascal] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Carvunis, Anne-Ruxandra] CNRS, Computat & Math Biol Grp, TIMC IMAG, UMR5525, F-38706 La Tronche, France. [Carvunis, Anne-Ruxandra] Univ Grenoble, Fac Med, F-38706 La Tronche, France. [Dreze, Matija; Vandenhaute, Jean] Fac Univ Notre Dame Paix, Unite Rech Biol Mol, B-5000 Namur, Wallonia Brusse, Belgium. [Steinbrenner, Jens; Donovan, Susan E.] Univ Warwick, Sch Life Sci, Wellesbourne CV35, Warwick, England. [Moore, Jonathan] Univ Warwick, Warwick Syst Biol Ctr, Coventry CV4 7AL, W Midlands, England. [Tasan, Murat] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Galli, Mary; Gai, Lantian; Chen, Huaming; Ecker, Joseph R.] Salk Inst Biol Studies, Genom Anal Lab, La Jolla, CA 92037 USA. [Pevzner, Samuel J.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. [Monachello, Dario] Univ Evry Val Essonne European Res Lab UEVE ERL, CNRS, Inst Natl Rech Agron INRA, Unite Mixte Rech Genom Vegetale URGV,UM, F-91057 Evry, France. [Boxem, Mike] Univ Utrecht, NL-3584 CH Utrecht, Netherlands. [Roth, Frederick P.] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Sch Med, Boston, MA 02115 USA. [Ecker, Joseph R.] Salk Inst Biol Studies, Biol Lab, La Jolla, CA 92037 USA. [Dangl, Jeffery L.] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. [Dangl, Jeffery L.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Dangl, Jeffery L.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. RP Vidal, M (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. EM marc_vidal@dfci.harvard.edu; jim.beynon@warwick.ac.uk; pascal_braun@dfci.harvard.edu; dangl@email.unc.edu RI Van den Ackerveken, Guido/B-8568-2011; Hill, David/B-6617-2011; Moore, Jonathan/D-1796-2013; Ecker, Joseph/B-9144-2008; Roth, Frederick/H-6308-2011; Braun, Pascal/B-9669-2013; Boxem, Mike/B-8857-2011; OI Roth, Frederick/0000-0002-6628-649X; Van den Ackerveken, Guido/0000-0002-0183-8978; Moore, Jonathan/0000-0002-5486-0407; Ecker, Joseph/0000-0001-5799-5895; Braun, Pascal/0000-0003-2012-6746; Boxem, Mike/0000-0003-3966-4173; , /0000-0001-7002-8488; Nishimura, Marc/0000-0003-4666-6900 FU NIH [GM-066025, P50-HG004233]; NSF [2010 0929410, 0703905, 0520253, 0313578, 0726408]; U.S. Department of Energy (DOE) [FG02-95ER20187]; U.K. Biotechnology and Biological Sciences Research Council [E024815, F005806, G015066]; European Commission [LSHG-CT-2006-037704]; European Research Area in Plant Genomics FX This work was funded by NIH GM-066025, NSF 2010 0929410, and U.S. Department of Energy (DOE) FG02-95ER20187 to J.L.D.; U.K. Biotechnology and Biological Sciences Research Council E024815, F005806 and G015066 to J.B.; NSF 0703905 to M. V., J.R.E., D. E. H.; NIH P50-HG004233 to M. V.; and NSF 0520253, 0313578 and 0726408 to J.R.E. D. M. was supported by AGRONOMICS LSHG-CT-2006-037704 from Sixth Framework Programme of the European Commission to C. Lurin. We acknowledge that the NSF funded the Arabidopsis Biological Research Center and the Salk Institute Genomic Analysis Laboratory (SIGnAL) projects for seeds and clones, respectively. We thank L. Baxter (Warwick Systems Biology, UK) for Arabidopsis/Papaya ortholog identification; B. Charloteaux (Center of Cancer Systems Biology, Boston, USA) for assisting in some bioinformatics analyses; B. Kemmerling (University of Tuebingen, Germany) for several RLK clones not contained in SIGnAL; and C. Somerville and Y. Gu (University of California, Berkeley, USA), T. Mengiste (Purdue University, USA), and X.-W. Deng (Yale University, USA) for seeds. The EU Effectoromics Consortium was funded by the European Research Area in Plant Genomics and includes A. Cabral and G. van den Ackerveken (Utrecht University, The Netherlands); J. Bator, R. Yatusevich, S. Katou and J. Parker (Max Planck Institute for Plant Breeding Research, Cologne, Germany); G. Fabro and J. Jones (The Sainsbury Laboratory, Norwich, UK); and M. Coates and T. Payne (University of Warwick, Warwick, UK). M. V. is a Chercheur Qualifie Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium). Binary interaction data are supplied in table S2 in SOM. Homozygous mutant seed stocks noted in Figure 4 are available from the Arabidopsis Biological Resource Center (ABRC). Author contributions are listed in the SOM. NR 33 TC 294 Z9 302 U1 11 U2 138 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 29 PY 2011 VL 333 IS 6042 BP 596 EP 601 DI 10.1126/science.1203659 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 798PI UT WOS:000293222400053 PM 21798943 ER PT J AU Braun, P Carvunis, AR Charloteaux, B Dreze, M Ecker, JR Hill, DE Roth, FP Vidal, M Galli, M Balumuri, P Bautista, V Chesnut, JD Kim, RC de los Reyes, C Gilles, P Kim, CJ Matrubutham, U Mirchandani, J Olivares, E Patnaik, S Quan, R Ramaswamy, G Shinn, P Swamilingiah, GM Wu, S Ecker, JR Dreze, M Byrdsong, D Dricot, A Duarte, M Gebreab, F Gutierrez, BJ MacWilliams, A Monachello, D Mukhtar, MS Poulin, MM Reichert, P Romero, V Tam, S Waaijers, S Weiner, EM Vidal, M Hill, DE Braun, P Galli, M Carvunis, AR Cusick, ME Dreze, M Romero, V Roth, FP Tasan, M Yazaki, J Braun, P Ecker, JR Carvunis, AR Ahn, YY Barabasi, AL Charloteaux, B Chen, HM Cusick, ME Dangl, JL Dreze, M Ecker, JR Fan, CY Gai, LT Galli, M Ghoshal, G Hao, T Hill, DE Lurin, C Milenkovic, T Moore, J Mukhtar, MS Pevzner, SJ Przulj, N Rabello, S Rietman, EA Rolland, T Roth, FP Santhanam, B Schmitz, RJ Spooner, W Stein, J Tasan, M Vandenhaute, J Ware, D Braun, P Vidal, M Braun, P Carvunis, AR Charloteaux, B Dreze, M Galli, M Vidal, M AF Braun, Pascal Carvunis, Anne-Ruxandra Charloteaux, Benoit Dreze, Matija Ecker, Joseph R. Hill, David E. Roth, Frederick P. Vidal, Marc Galli, Mary Balumuri, Padmavathi Bautista, Vanessa Chesnut, Jonathan D. Kim, Rosa Cheuk de los Reyes, Chris Gilles, Patrick, II Kim, Christopher J. Matrubutham, Uday Mirchandani, Jyotika Olivares, Eric Patnaik, Suswapna Quan, Rosa Ramaswamy, Gopalakrishna Shinn, Paul Swamilingiah, Geetha M. Wu, Stacy Ecker, Joseph R. Dreze, Matija Byrdsong, Danielle Dricot, Amelie Duarte, Melissa Gebreab, Fana Gutierrez, Bryan J. MacWilliams, Andrew Monachello, Dario Mukhtar, M. Shahid Poulin, Matthew M. Reichert, Patrick Romero, Viviana Tam, Stanley Waaijers, Selma Weiner, Evan M. Vidal, Marc Hill, David E. Braun, Pascal Galli, Mary Carvunis, Anne-Ruxandra Cusick, Michael E. Dreze, Matija Romero, Viviana Roth, Frederick P. Tasan, Murat Yazaki, Junshi Braun, Pascal Ecker, Joseph R. Carvunis, Anne-Ruxandra Ahn, Yong-Yeol Barabasi, Albert-Laszlo Charloteaux, Benoit Chen, Huaming Cusick, Michael E. Dangl, Jeffery L. Dreze, Matija Ecker, Joseph R. Fan, Changyu Gai, Lantian Galli, Mary Ghoshal, Gourab Hao, Tong Hill, David E. Lurin, Claire Milenkovic, Tijana Moore, Jonathan Mukhtar, M. Shahid Pevzner, Samuel J. Przulj, Natasa Rabello, Sabrina Rietman, Edward A. Rolland, Thomas Roth, Frederick P. Santhanam, Balaji Schmitz, Robert J. Spooner, William Stein, Joshua Tasan, Murat Vandenhaute, Jean Ware, Doreen Braun, Pascal Vidal, Marc Braun, Pascal Carvunis, Anne-Ruxandra Charloteaux, Benoit Dreze, Matija Galli, Mary Vidal, Marc CA Arabidopsis Interactome Mapping Co TI Evidence for Network Evolution in an Arabidopsis Interactome Map SO SCIENCE LA English DT Article ID PROTEIN-INTERACTION NETWORKS; DUPLICATED GENES; GENOME; DIVERGENCE; EXPRESSION; PLASTICITY; BINDING; EVOLVES; PLANTS; FATE AB Plants have unique features that evolved in response to their environments and ecosystems. A full account of the complex cellular networks that underlie plant-specific functions is still missing. We describe a proteome-wide binary protein-protein interaction map for the interactome network of the plant Arabidopsis thaliana containing about 6200 highly reliable interactions between about 2700 proteins. A global organization of plant biological processes emerges from community analyses of the resulting network, together with large numbers of novel hypothetical functional links between proteins and pathways. We observe a dynamic rewiring of interactions following gene duplication events, providing evidence for a model of evolution acting upon interactome networks. This and future plant interactome maps should facilitate systems approaches to better understand plant biology and improve crops. C1 [Carvunis, Anne-Ruxandra; Charloteaux, Benoit; Dricot, Amelie; Gutierrez, Bryan J.; MacWilliams, Andrew; Carvunis, Anne-Ruxandra; Barabasi, Albert-Laszlo; Fan, Changyu; Santhanam, Balaji] Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. [Carvunis, Anne-Ruxandra; Dricot, Amelie; MacWilliams, Andrew; Carvunis, Anne-Ruxandra; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Carvunis, Anne-Ruxandra; Dricot, Amelie; MacWilliams, Andrew; Carvunis, Anne-Ruxandra] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Carvunis, Anne-Ruxandra] CNRS, Computat & Math Biol Grp, UMR5525, F-38706 La Tronche, France. [Carvunis, Anne-Ruxandra] Univ Grenoble, Fac Med, F-38706 La Tronche, France. [Charloteaux, Benoit] Univ Liege, GIGA R, Unit Anim Genom, B-4000 Liege, Wallonia Brusse, Belgium. [Charloteaux, Benoit] Univ Liege, Fac Vet Med, B-4000 Liege, Wallonia Brusse, Belgium. [Dreze, Matija; Vandenhaute, Jean] Fac Univ Notre Dame Paix, Unite Rech Biol Mol, B-5000 Namur, Wallonia Brusse, Belgium. [Ecker, Joseph R.; de los Reyes, Chris; Kim, Christopher J.; Chen, Huaming] Salk Inst Biol Studies, Genom Anal Lab, La Jolla, CA 92037 USA. [Ecker, Joseph R.] Salk Inst Biol Studies, Plant Biol Lab, La Jolla, CA 92037 USA. [Balumuri, Padmavathi; Chesnut, Jonathan D.; Gilles, Patrick, II; Matrubutham, Uday; Mirchandani, Jyotika; Olivares, Eric; Patnaik, Suswapna; Ramaswamy, Gopalakrishna; Swamilingiah, Geetha M.] Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02115 USA. [Balumuri, Padmavathi; Chesnut, Jonathan D.; Gilles, Patrick, II; Matrubutham, Uday; Mirchandani, Jyotika; Olivares, Eric; Patnaik, Suswapna; Ramaswamy, Gopalakrishna; Swamilingiah, Geetha M.] Harvard Univ, Sch Med, Dept Mol Pharmacol, Boston, MA 02115 USA. [Ahn, Yong-Yeol; Barabasi, Albert-Laszlo; Ghoshal, Gourab; Rabello, Sabrina] Northeastern Univ, Dept Phys, Ctr Complex Network Res CCNR, Boston, MA 02115 USA. [Mukhtar, M. Shahid; Dangl, Jeffery L.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Monachello, Dario; Lurin, Claire] Univ Evry Val Essonne, Unite Rech Genom Vegetale, Inst Natl Rech Agron, Unite Mixtes Rech,ERL Ctr Natl Rech Sci, F-91057 Evry, France. [Milenkovic, Tijana] Univ Notre Dame, Dept Comp Sci & Engn, Notre Dame, IN 46556 USA. [Moore, Jonathan] Univ Warwick, Warwick Syst Biol Ctr, Coventry CV4 7AL, W Midlands, England. [Pevzner, Samuel J.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Pevzner, Samuel J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Przulj, Natasa] Univ London Imperial Coll Sci Technol & Med, Dept Comp, London SW7 2AZ, England. [Spooner, William; Stein, Joshua; Ware, Doreen] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Spooner, William] Eagle Genom Ltd, Cambridge CB4 1JD, England. [Ware, Doreen] Cornell Univ, USDA, ARS, Robert W Holley Ctr Agr & Hlth, Ithaca, NY 14853 USA. RP Vidal, M (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. EM ecker@salk.edu; david_hill@dfci.harvard.edu; marc_vidal@dfci.harvard.edu; pascal_braun@dfci.harvard.edu RI Yazaki, Junshi/B-1557-2012; Hill, David/B-6617-2011; Moore, Jonathan/D-1796-2013; Ecker, Joseph/B-9144-2008; Roth, Frederick/H-6308-2011; Braun, Pascal/B-9669-2013; OI Moore, Jonathan/0000-0002-5486-0407; Ecker, Joseph/0000-0001-5799-5895; Braun, Pascal/0000-0003-2012-6746; , /0000-0001-7002-8488 FU NSF [0703905, 0520253, 0313578, 0703908]; National Human Genome Research Institute [R01HG001715]; Canada Excellence Research Chairs Program; Canadian Institute for Advanced Research Fellowship; James S. McDonnell Foundation [220020084]; Sixth Framework Programme [LSHG-CT-2006-037704]; National Institute of General Medical Sciences [R01GM066025]; U.S. Department of Agriculture, Agricultural Research Service [1907-21000-030]; NIH [F32HG004098, F32HG004830]; Biotechnology and Biological Sciences Research Council [F005806] FX We thank P. Benfey, H. Yu, M. Nordborg, P. Ronald, M Snyder, and R. Wing as well as members of the Dana-Farber Cancer Institute Center for Cancer Systems Biology, for helpful discussions. This work was supported by the following grants: NSF 0703905 to M. V., J.R.E., and D. E. H.; National Human Genome Research Institute R01HG001715 to M. V., D. E. H., and F. P. R.; NSF 0520253 and NSF 0313578 to J.R.E.; Canada Excellence Research Chairs Program and Canadian Institute for Advanced Research Fellowship to F. P. R.; James S. McDonnell Foundation 220020084 to A.-L. B; Sixth Framework Programme LSHG-CT-2006-037704 (AGRON-OMICS) to C. L.; National Institute of General Medical Sciences R01GM066025 to J.L.D.; U.S. Department of Agriculture, Agricultural Research Service 1907-21000-030 to D. W.; NIH National Research Service Award fellowships F32HG004098 to M. T. and F32HG004830 to R.J.S.; Biotechnology and Biological Sciences Research Council grant F005806 to Jim Beynon in support of J.M.; and NSF 0703908 to D. W. in support of J.S. and W. S. M. V. is a Chercheur Qualifie Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia- Brussels Federation, Belgium). Data reported here are available at the Web site http://interactome.dfci.harvard.edu/A_thaliana NR 42 TC 286 Z9 664 U1 10 U2 156 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 29 PY 2011 VL 333 IS 6042 BP 601 EP 607 DI 10.1126/science.1203877 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 798PI UT WOS:000293222400054 ER PT J AU Chang, EW Kobler, JB Yun, SH AF Chang, Ernest W. Kobler, James B. Yun, Seok H. TI Triggered optical coherence tomography for capturing rapid periodic motion SO SCIENTIFIC REPORTS LA English DT Article ID CANINE VOCAL FOLD; IN-VIVO; SWEPT SOURCE; MEDIAL SURFACE; SCANS; PHONATION; 2ND AB Quantitative cross-sectional imaging of vocal folds during phonation is potentially useful for diagnosis and treatments of laryngeal disorders. Optical coherence tomography (OCT) is a powerful technique, but its relatively low frame rates makes it challenging to visualize rapidly vibrating tissues. Here, we demonstrate a novel method based on triggered laser scanning to capture 4-dimensional (4D) images of samples in motu at audio frequencies over 100 Hz. As proof-of-concept experiments, we applied this technique to imaging the oscillations of biopolymer gels on acoustic vibrators and aerodynamically driven vibrations of the vocal fold in an ex vivo calf larynx model. Our results suggest that triggered 4D OCT may be useful in understanding and assessing the function of vocal folds and developing novel treatments in research and clinical settings. C1 [Chang, Ernest W.; Yun, Seok H.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Chang, Ernest W.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Kobler, James B.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Yun, Seok H.] Korea Adv Inst Sci & Technol, WCU Grad Sch Nanosci & Technol, Taejon 305701, South Korea. [Yun, Seok H.] Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. RP Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM syun@hms.harvard.edu FU Wellman graduate student fellowship; Center for Integration of Medicine and Innovative Technology; Eugene B. Casey Foundations; Institute of Laryngology and Voice Restoration; Korea National Research Foundation [R31-2008-000-10071-0]; National Institutes of Health [P41 RR032042] FX Authors would like to thank Eunnie YK Lee and Christine Hsieh for their help with experiments and Dr. Steven Zeitels for discussions. This work was supported by the Wellman graduate student fellowship (E. W. C.), Center for Integration of Medicine and Innovative Technology, the Eugene B. Casey Foundations and the Institute of Laryngology and Voice Restoration, the Korea National Research Foundation (R31-2008-000-10071-0), and National Institutes of Health (P41 RR032042). NR 22 TC 7 Z9 7 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 28 PY 2011 VL 1 AR 48 DI 10.1038/srep00048 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 835QD UT WOS:000296050000003 PM 22355567 ER PT J AU Li, QY Eklund, AC Birkbak, NJ Desmedt, C Haibe-Kains, B Sotiriou, C Symmans, WF Pusztai, L Brunak, S Richardson, AL Szallasi, Z AF Li, Qiyuan Eklund, Aron C. Birkbak, Nicolai J. Desmedt, Christine Haibe-Kains, Benjamin Sotiriou, Christos Symmans, W. Fraser Pusztai, Lajos Brunak, Soren Richardson, Andrea L. Szallasi, Zoltan TI Consistent metagenes from cancer expression profiles yield agent specific predictors of chemotherapy response SO BMC BIOINFORMATICS LA English DT Article ID NEGATIVE BREAST-CANCER; GENE-EXPRESSION; PROSTATE-CANCER; MOLECULAR SUBTYPES; HISTOLOGIC GRADE; OVARIAN-CANCER; CARCINOMAS; SURVIVAL; ADENOCARCINOMA; RESISTANCE AB Background: Genome scale expression profiling of human tumor samples is likely to yield improved cancer treatment decisions. However, identification of clinically predictive or prognostic classifiers can be challenging when a large number of genes are measured in a small number of tumors. Results: We describe an unsupervised method to extract robust, consistent metagenes from multiple analogous data sets. We applied this method to expression profiles from five "double negative breast cancer" (DNBC) (not expressing ESR1 or HER2) cohorts and derived four metagenes. We assessed these metagenes in four similar but independent cohorts and found strong associations between three of the metagenes and agent-specific response to neoadjuvant therapy. Furthermore, we applied the method to ovarian and early stage lung cancer, two tumor types that lack reliable predictors of outcome, and found that the metagenes yield predictors of survival for both. Conclusions: These results suggest that the use of multiple data sets to derive potential biomarkers can filter out data set-specific noise and can increase the efficiency in identifying clinically accurate biomarkers. C1 [Richardson, Andrea L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Li, Qiyuan; Eklund, Aron C.; Birkbak, Nicolai J.; Brunak, Soren; Szallasi, Zoltan] Tech Univ Denmark, Dept Syst Biolol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Li, Qiyuan] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Desmedt, Christine; Sotiriou, Christos] Inst Jules Bordet, Dept Med Oncol, B-1000 Brussels, Belgium. [Haibe-Kains, Benjamin] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Pusztai, Lajos] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Szallasi, Zoltan] Harvard Univ, Childrens Hosp, Sch Med, Informat Program,Harvard MIT Div Hlth Sci & Techn, Boston, MA 02115 USA. RP Richardson, AL (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM arichardson@partners.org; zszallasi@chip.org RI Haibe-Kains, Benjamin/D-3702-2011; OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Szallasi, Zoltan/0000-0001-5395-7509; Eklund, Aron Charles/0000-0003-0861-1001; Desmedt, Christine/0000-0002-5223-5579 FU National Institutes of Health [1PO1CA-092644-01]; Breast Cancer Research Foundation (ZS, ALR); Danish Council for Independent Research, Medical Sciences (FSS) (ZS, ACE); BioSim (NoE) [LSHB-CT-2004-005137]; Harvard SPORE in breast cancer (ZS, ALR) [CA089393] FX This work was supported in part by the National Institutes of Health through grant 1PO1CA-092644-01 and by the Breast Cancer Research Foundation (ZS, ALR), by the Danish Council for Independent Research, Medical Sciences (FSS) (ZS, ACE), and by BioSim (NoE), FP6, LSHB-CT-2004-005137 (QL) and by the Harvard SPORE in breast cancer CA089393 (ZS, ALR). NR 54 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 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUL 28 PY 2011 VL 12 AR 310 DI 10.1186/1471-2105-12-310 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 806SE UT WOS:000293830500001 PM 21798043 ER PT J AU Tugwell, P Singh, JA Wells, GA AF Tugwell, Peter Singh, Jasvinder A. Wells, George A. TI THERAPEUTICS Biologicals for rheumatoid arthritis SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID MODIFYING ANTIRHEUMATIC DRUGS; EULAR RECOMMENDATIONS; DISEASE; SAFETY; MANAGEMENT; INFLIXIMAB; AGENTS AB This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Philip Routledge, professor of clinical pharmacology, Cardiff University. To suggest a topic for this series, please email us at practice@bmj.com. C1 [Tugwell, Peter] Univ Ottawa, Dept Med, Inst Populat Hlth, Ottawa, ON K1N 6N5, Canada. [Tugwell, Peter] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON K1N 6N5, Canada. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama, Birmingham, AL 35294 USA. [Wells, George A.] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Wells, George A.] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. RP Tugwell, P (reprint author), Univ Ottawa, Dept Med, Inst Populat Hlth, Ottawa, ON K1N 6N5, Canada. EM tugwell.bb@uottawa.ca OI singh, jasvinder/0000-0003-3485-0006; Tugwell, Peter/0000-0001-5062-0556 FU Canadian Institutes of Health Research (CIHR); Takeda; Savient; Wyeth; Amgen; URL Pharma; Novartis; Bristol-Myers Squibb FX All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work. PT received honorariums for quality of life consultancy with Bristol-Myers Squibb; chairs data safety monitoring boards for Chelsea Therapeutics and UCB, mandated for the Food and Drug Administration; is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives "arms length" funding from 36 companies; co-chaired an industry board of six companies (Abbott, Bristol-Myers Squibb, Merck, Roche, Schering Plough, UCB) for a biologicals registry of the Ontario Rheumatology Association, the Ontario Biologics Research Initiative (an arms-length registry that independently collects information, supported by a grant from the Canadian Institutes of Health Research (CIHR) matched by funding from these drug companies); and receives an honorarium from the CIHR grant. JAS has received speaker honorariums from Abbott, research and travel grants from Takeda, Savient, Wyeth, and Amgen, and consultant fees from URL Pharma, Takeda, Savient, and Novartis; he is a member of the executive of OMERACT. GAW received honorariums for consultancy with Novartis, Bristol-Myers Squibb, and Abbott; a grant from Bristol-Myers Squibb; and speaker honorariums from Abbott; he is a member of the executive of OMERACT and of the Scientific Committee for the Ontario Biologics Research Initiative. NR 23 TC 7 Z9 7 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUL 28 PY 2011 VL 343 AR d4027 DI 10.1136/bmj.d4027 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 801LT UT WOS:000293441100001 PM 21798970 ER PT J AU Whitlock, JA Silverman, LB AF Whitlock, James A. Silverman, Lewis B. TI Childhood T-ALL: it's time to move on SO BLOOD LA English DT Editorial Material ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDREN; TRIAL C1 [Whitlock, James A.] Hosp Sick Children, Toronto, ON, Canada. Dana Farber Canc Inst, Boston, MA USA. RP Whitlock, JA (reprint author), Hosp Sick Children, Toronto, ON, Canada. NR 10 TC 4 Z9 5 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 JUL 28 PY 2011 VL 118 IS 4 BP 828 EP 829 DI 10.1182/blood-2011-05-348375 PG 4 WC Hematology SC Hematology GA 798PC UT WOS:000293221700003 PM 21799094 ER PT J AU Payne, EM Bolli, N Rhodes, J Abdel-Wahab, OI Levine, R Hedvat, CV Stone, R Khanna-Gupta, A Sun, H Kanki, JP Gazda, HT Beggs, AH Cotter, FE Look, AT AF Payne, Elspeth M. Bolli, Niccolo Rhodes, Jennifer Abdel-Wahab, Omar I. Levine, Ross Hedvat, Cyrus V. Stone, Richard Khanna-Gupta, Arati Sun, Hong Kanki, John P. Gazda, Hanna T. Beggs, Alan H. Cotter, Finbarr E. Look, A. Thomas TI Ddx18 is essential for cell-cycle progression in zebrafish hematopoietic cells and is mutated in human AML SO BLOOD LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; ACUTE MYELOID-LEUKEMIA; RIBOSOMAL-SUBUNIT BIOGENESIS; SACCHAROMYCES-CEREVISIAE; POSITIONAL CLONING; HELICASE HAS1P; PROTEIN S19; GENE; RNA; MUTATIONS AB In a zebrafish mutagenesis screen to identify genes essential for myelopoiesis, we identified an insertional allele hi1727, which disrupts the gene encoding RNA helicase dead-box 18 (Ddx18). Homozygous Ddx18 mutant embryos exhibit a profound loss of myeloid and erythroid cells along with cardiovascular abnormalities and reduced size. These mutants also display prominent apoptosis and a G1 cell-cycle arrest. Loss of p53, but not Bcl-xl overexpression, rescues myeloid cells to normal levels, suggesting that the hematopoietic defect is because of p53dependent G1 cell-cycle arrest. We then sequenced primary samples from 262 patients with myeloid malignancies because genes essential for myelopoiesis are often mutated in human leukemias. We identified 4 nonsynonymous sequence variants (NSVs) of DDX18 in acute myeloid leukemia (AML) patient samples. RNA encoding wild-type DDX18 and 3 NSVs rescued the hematopoietic defect, indicating normal DDX18 activity. RNA encoding one mutation, DDX18-E76del, was unable to rescue hematopoiesis, and resulted in reduced myeloid cell numbers in ddx18(hi1727/+) embryos, indicating this NSV likely functions as a dominant- negative allele. These studies demonstrate the use of the zebrafish as a robust in vivo system for assessing the function of genes mutated in AML, which will become increasingly important as more sequence variants are identified by next-generation resequencing technologies. (Blood. 2011;118(4):903-915) C1 [Payne, Elspeth M.; Cotter, Finbarr E.] UCL, Inst Canc, Barts & London Sch Med, London WC1E 6BT, England. [Payne, Elspeth M.; Bolli, Niccolo; Rhodes, Jennifer; Kanki, John P.; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Abdel-Wahab, Omar I.; Levine, Ross] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Abdel-Wahab, Omar I.; Levine, Ross] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. [Hedvat, Cyrus V.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Khanna-Gupta, Arati; Sun, Hong] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Hematol, Boston, MA 02115 USA. [Gazda, Hanna T.; Beggs, Alan H.] Harvard Univ, Childrens Hosp Boston, Sch Med, Div Genet & Program Genom,Manton Ctr Orphan Dis R, Boston, MA 02115 USA. [Look, A. Thomas] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol,Dept Pediat, Boston, MA 02115 USA. RP Payne, EM (reprint author), UCL, Inst Canc, Barts & London Sch Med, Paul OGorman Bldg,72 Huntley St, London WC1E 6BT, England. EM e.payne@ucl.ac.uk; Thomas_look@dfci.harvard.edu RI Bolli, Niccolo/D-4057-2011; OI Bolli, Niccolo/0000-0002-1018-5139; HEDVAT, CYRUS/0000-0003-0045-3491; Beggs, Alan/0000-0001-8818-0568; Abdel-Wahab, Omar/0000-0002-3907-6171 FU American-Italian Cancer Foundation; Leukemia and Lymphoma Society; Leukemia and Lymphoma Research UK; National Institutes of Health (NIH) [NIH-5T32 CA009382-26, CA93152]; Diamond-Blackfan Anemia Foundation FX N.B. has been supported by a "Princess Borghese and Anna Bulgari Fellowship" from The American-Italian Cancer Foundation, and is currently a Leukemia and Lymphoma Society Special Fellow. E.M.P. is the recipient of the GSK Greg Harper Clinical Research Training Fellowship from Leukemia and Lymphoma Research UK, and was formerly supported by the National Institutes of Health (NIH-5T32 CA009382-26). This work was supported by NIH grant CA93152 (A.T.L. and J.P.K.). H.T.G. is supported by the Diamond-Blackfan Anemia Foundation Research grant. NR 49 TC 16 Z9 16 U1 2 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 28 PY 2011 VL 118 IS 4 BP 903 EP 915 DI 10.1182/blood-2010-11-318022 PG 13 WC Hematology SC Hematology GA 798PC UT WOS:000293221700017 PM 21653321 ER PT J AU Porichis, F Kwon, DS Zupkosky, J Tighe, DP McMullen, A Brockman, MA Pavlik, DF Rodriguez-Garcia, M Pereyra, F Freeman, GJ Kavanagh, DG Kaufmann, DE AF Porichis, Filippos Kwon, Douglas S. Zupkosky, Jennifer Tighe, Daniel P. McMullen, Ashley Brockman, Mark A. Pavlik, David F. Rodriguez-Garcia, Marta Pereyra, Florencia Freeman, Gordon J. Kavanagh, Daniel G. Kaufmann, Daniel E. TI Responsiveness of HIV-specific CD4 T cells to PD-1 blockade SO BLOOD LA English DT Article ID CHRONIC VIRAL-INFECTION; DISEASE PROGRESSION; THERAPEUTIC VACCINATION; UP-REGULATION; IN-VITRO; ACTIVATION; RESPONSES; IL-21; EXHAUSTION; EXPRESSION AB Defining the T helper functions impaired by programmed death-1 (PD-1) is crucial for understanding its role in defective HIV control and determining the therapeutic potential of targeting this inhibitory pathway. We describe here the relationships among disease stage, levels of PD-1 expression, and reversibility of CD4 T-cell impairment. PD-L1 blockade in vitro enhanced HIV-specific production of Th0 (IL-2), Th1 (IFN-gamma), Th2 (IL-13), and TFH (IL-21) cytokines by CD4 T cells. PD-L1 blockade caused an early increase in cytokine transcription and translation that preceded cell proliferation. Although the impact of PD-L1 blockade on cytokine expression and, to a lesser extent, cell proliferation was associated with markers of disease progression, restoration of cytokine secretion was also observed in most subjects with undetectable viremia. PD-L1 blockade restored cytokine secretion in both PD-1intermediate and PD1high sorted CD4 T-cell subsets. Com-pared with PD-1high HIV-specific CD8 T cells, PD-1high HIV-specific CD4 T cells showed lower expression of the inhibitory molecules CD160 and 2B4, demonstrating marked differences in expression of inhibitory receptors between T-cell subsets. These data show that PD-1 impairs HIV-specific T helper responses both by limiting expansion of these cells and by inhibiting effector functions of multiple differentiated CD4 T-cell subsets. (Blood. 2011; 118(4): 965-974) C1 [Porichis, Filippos; Kwon, Douglas S.; Zupkosky, Jennifer; Tighe, Daniel P.; McMullen, Ashley; Pavlik, David F.; Rodriguez-Garcia, Marta; Pereyra, Florencia; Kavanagh, Daniel G.; Kaufmann, Daniel E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst,MIT & Harvard, Boston, MA USA. [Kwon, Douglas S.; Pereyra, Florencia] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Kwon, Douglas S.; Kaufmann, Daniel E.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Brockman, Mark A.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Brockman, Mark A.] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Dept Med, Boston, MA 02115 USA. RP Kaufmann, DE (reprint author), MIT & Harvard, Massachusetts Gen Hosp E, Ragon Inst, MGH, Rm 5239,149 13th St, Charlestown, MA 02129 USA. EM dkaufmann@partners.org OI Brockman, Mark/0000-0001-6432-1426 FU National Heart, Lung, and Blood Institute of the National Institutes of Health [RO1 HL-092565]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [P0 AI-080192, P0 AI056299]; Concerned Parents for AIDS Research Foundation; Mark and Lisa Schwartz Foundation FX This study was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (RO1 HL-092565; D.E.K.), the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (P0 AI-080192, D.E.K., D.G.K., and G.J.F.; and P0 AI056299, G.J.F.), the Concerned Parents for AIDS Research Foundation (D.E.K.), and the Mark and Lisa Schwartz Foundation (gift). NR 51 TC 68 Z9 71 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 28 PY 2011 VL 118 IS 4 BP 965 EP 974 DI 10.1182/blood-2010-12-328070 PG 10 WC Hematology SC Hematology GA 798PC UT WOS:000293221700023 PM 21652684 ER PT J AU Marko, NF Quackenbush, J Weil, RJ AF Marko, Nicholas F. Quackenbush, John Weil, Robert J. TI Why Is There a Lack of Consensus on Molecular Subgroups of Glioblastoma? Understanding the Nature of Biological and Statistical Variability in Glioblastoma Expression Data SO PLOS ONE LA English DT Article ID MICROARRAY EXPERIMENTAL-DESIGN; FALSE DISCOVERY RATE; CONTROL MAQC PROJECT; PROBE LEVEL DATA; GENE-EXPRESSION; SAMPLE-SIZE; QUALITY-CONTROL; NCBI GEO; PREDICTS SURVIVAL; NOISE AB Introduction: Gene expression patterns characterizing clinically-relevant molecular subgroups of glioblastoma are difficult to reproduce. We suspect a combination of biological and analytic factors confounds interpretation of glioblastoma expression data. We seek to clarify the nature and relative contributions of these factors, to focus additional investigations, and to improve the accuracy and consistency of translational glioblastoma analyses. Methods: We analyzed gene expression and clinical data for 340 glioblastomas in The Cancer Genome Atlas (TCGA). We developed a logic model to analyze potential sources of biological, technical, and analytic variability and used standard linear classifiers and linear dimensional reduction algorithms to investigate the nature and relative contributions of each factor. Results: Commonly-described sources of classification error, including individual sample characteristics, batch effects, and analytic and technical noise make measurable but proportionally minor contributions to inconsistent molecular classification. Our analysis suggests that three, previously underappreciated factors may account for a larger fraction of classification errors: inherent non-linear/non-orthogonal relationships among the genes used in conjunction with classification algorithms that assume linearity; skewed data distributions assumed to be Gaussian; and biologic variability (noise) among tumors, of which we propose three types. Conclusions: Our analysis of the TCGA data demonstrates a contributory role for technical factors in molecular classification inconsistencies in glioblastoma but also suggests that biological variability, abnormal data distribution, and non-linear relationships among genes may be responsible for a proportionally larger component of classification error. These findings may have important implications for both glioblastoma research and for translational application of other large-volume biological databases. C1 [Marko, Nicholas F.; Weil, Robert J.] Cleveland Clin, Dept Neurosurg, Cleveland, OH 44106 USA. [Marko, Nicholas F.; Weil, Robert J.] Cleveland Clin, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44106 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Marko, NF (reprint author), Cleveland Clin, Dept Neurosurg, Cleveland, OH 44106 USA. EM markon@ccf.org; weilr@ccf.org FU Neuro-oncology Center at the Cleveland Clinic Foundation FX The authors wish to thank the Melvin Burkhardt chair in neurosurgical oncology and the Karen Colina Wilson research endowment within the Brain Tumor and Neuro-oncology Center at the Cleveland Clinic Foundation for partial support and funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There are no current external funding sources for this study. NR 76 TC 9 Z9 9 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2011 VL 6 IS 7 AR e20826 DI 10.1371/journal.pone.0020826 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799KC UT WOS:000293284600001 PM 21829433 ER PT J AU Vaid, M Prasad, R Sun, Q Katiyar, SK AF Vaid, Mudit Prasad, Ram Sun, Qian Katiyar, Santosh K. TI Silymarin Targets beta-Catenin Signaling in Blocking Migration/Invasion of Human Melanoma Cells SO PLOS ONE LA English DT Article ID CUTANEOUS MELANOMA; COLORECTAL-CANCER; PATHWAY; EXPRESSION; CYCLOOXYGENASE-2; LOCALIZATION; INHIBITION; ACTIVATION; MUTATIONS; GROWTH AB Metastatic melanoma is a leading cause of death from skin diseases, and is often associated with activation of Wnt/beta-catenin signaling pathway. We have examined the inhibitory effect of silymarin, a plant flavanoid from Silybum marianum, on cell migration of metastasis-specific human melanoma cell lines (A375 and Hs294t) and assessed whether Wnt/beta-catenin signaling is the target of silymarin. Using an in vitro invasion assay, we found that treatment of human melanoma cell lines with silymarin resulted in concentration-dependent inhibition of cell migration, which was associated with accumulation of cytosolic beta-catenin, while reducing the nuclear accumulation of beta-catenin (i.e., b-catenin inactivation) and reducing the levels of matrix metalloproteinase (MMP)-2 and MMP-9 which are the down-stream targets of beta-catenin. Silymarin enhanced: (i) the levels of casein kinase 1 alpha, glycogen synthase kinase-3 beta and phosphorylated-beta-catenin on critical residues Ser(45), Ser(33/37) and Thr(41), and (ii) the binding of beta-transducin repeat-containing proteins (beta-TrCP) with phospho forms of beta-catenin in melanoma cells. These events play important roles in degradation or inactivation of beta-catenin. To verify whether beta-catenin is a potent molecular target of silymarin, the effect of silymarin was determined on beta-catenin-activated (Mel 1241) and beta-catenin-inactivated (Mel 1011) melanoma cells. Treatment of Mel 1241 cells with silymarin or FH535, an inhibitor of Wnt/beta-catenin pathway, significantly inhibited cell migration of Mel 1241 cells, which was associated with the elevated levels of casein kinase 1 alpha and glycogen synthase kinase-3 beta, and decreased accumulation of nuclear beta-catenin and inhibition of MMP-2 and MMP-9 levels. However, this effect of silymarin and FH535 was not found in Mel 1011 melanoma cells. These results indicate for the first time that silymarin inhibits melanoma cell migration by targeting beta-catenin signaling pathway. C1 [Vaid, Mudit; Prasad, Ram; Sun, Qian; Katiyar, Santosh K.] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Vaid, M (reprint author), Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU Veterans Administration Merit Review Award FX This work was supported by funds from the Veterans Administration Merit Review Award (SKK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 53 Z9 55 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2011 VL 6 IS 7 AR e23000 DI 10.1371/journal.pone.0023000 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799KC UT WOS:000293284600070 PM 21829575 ER PT J AU Barth, WH Kwolek, CJ Abrams, JL Ecker, JL Roberts, DJ AF Barth, William H., Jr. Kwolek, Christopher J. Abrams, Joshua L. Ecker, Jeffrey L. Roberts, Drucilla J. TI Case 23-2011: A 40-Year-Old Pregnant Woman with Placenta Accreta Who Declined Blood Products SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 [Barth, William H., Jr.; Ecker, Jeffrey L.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Kwolek, Christopher J.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Abrams, Joshua L.] Massachusetts Gen Hosp, Off Gen Counsel, Boston, MA 02114 USA. [Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Barth, William H., Jr.; Ecker, Jeffrey L.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Kwolek, Christopher J.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Roberts, Drucilla J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Barth, WH (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 8 TC 3 Z9 3 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 28 PY 2011 VL 365 IS 4 BP 359 EP 366 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 798AJ UT WOS:000293172200016 PM 21793748 ER PT J AU Simard, JM Kahle, KT Walcott, BP AF Simard, J. Marc Kahle, Kristopher T. Walcott, Brian P. TI Craniectomy in Diffuse Traumatic Brain Injury SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Simard, J. Marc] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Kahle, Kristopher T.; Walcott, Brian P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Simard, JM (reprint author), Univ Maryland, Sch Med, Baltimore, MD 21201 USA. EM msimard@smail.umaryland.edu NR 2 TC 5 Z9 5 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 28 PY 2011 VL 365 IS 4 BP 374 EP 374 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 798AJ UT WOS:000293172200021 PM 21793753 ER PT J AU Ranganathan, S Noyes, NC Migliorini, M Winkles, JA Battey, FD Hyman, BT Smith, E Yepes, M Mikhailenko, I Strickland, DK AF Ranganathan, Sripriya Noyes, Nathaniel C. Migliorini, Mary Winkles, Jeffrey A. Battey, Frances D. Hyman, Bradley T. Smith, Elizabeth Yepes, Manuel Mikhailenko, Irina Strickland, Dudley K. TI LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DI-LEUCINE MOTIF; DEPENDENT LIGAND DISSOCIATION; LDL-RECEPTOR; PLASMINOGEN-ACTIVATOR; ALZHEIMERS-DISEASE; WW DOMAIN; SIGNAL-TRANSDUCTION; INSULIN-RECEPTOR; APOLIPOPROTEIN-E; ENDOCYTOSIS AB We have identified a novel low-density lipoprotein (LDL) receptor family member, termed LDL receptor class A domain containing 3 (LRAD3), which is expressed in neurons. The LRAD3 gene encodes an similar to 50 kDa type I transmembrane receptor with an ectodomain containing three LDLa repeats, a transmembrane domain, and a cytoplasmic domain containing a conserved dileucine internalization motif and two polyproline motifs with potential to interact with WW-domain-containing proteins. Immunohistochemical analysis of mouse brain reveals LRAD3 expression in the cortex and hippocampus. In the mouse hippocampal-derived cell line HT22, LRAD3 partially colocalizes with amyloid precursor protein (APP) and interacts with APP as revealed by coimmunoprecipitation experiments. To identify the portion of APP that interacts with LRAD3, we used solid-phase binding assays that demonstrated that LRAD3 failed to bind to a soluble APP fragment (sAPP alpha) released after alpha-secretase cleavage. In contrast, C99, the beta-secretase product that remains cell associated, coprecipitated with LRAD3, confirming that regions within this portion of APP are important for associating with LRAD3. The association of LRAD3 with APP increases the amyloidogenic pathway of APP processing, resulting in a decrease in sAPP alpha production and increased A beta peptide production. Pulse-chase experiments confirm that LRAD3 expression significantly decreases the cellular half-life of mature APP. These results reveal that LRAD3 influences APP processing and raises the possibility that LRAD3 alters APP function in neurons, including its downstream signaling. C1 [Ranganathan, Sripriya; Noyes, Nathaniel C.; Migliorini, Mary; Winkles, Jeffrey A.; Battey, Frances D.; Smith, Elizabeth; Mikhailenko, Irina; Strickland, Dudley K.] Univ Maryland, Ctr Vasc & Inflammatory Dis, Sch Med, Baltimore, MD 21201 USA. [Ranganathan, Sripriya; Noyes, Nathaniel C.; Migliorini, Mary; Winkles, Jeffrey A.; Battey, Frances D.; Smith, Elizabeth; Mikhailenko, Irina; Strickland, Dudley K.] Univ Maryland, Dept Surg, Sch Med, Baltimore, MD 21201 USA. [Ranganathan, Sripriya; Noyes, Nathaniel C.; Migliorini, Mary; Winkles, Jeffrey A.; Battey, Frances D.; Smith, Elizabeth; Mikhailenko, Irina; Strickland, Dudley K.] Univ Maryland, Dept Physiol, Sch Med, Baltimore, MD 21201 USA. [Hyman, Bradley T.] Harvard Univ, Massachusetts Gen Hosp, Massachusetts Gen Inst Neurodegenerat Dis, Alzheimers Dis Res Lab,Dept Neurol,Sch Med, Charlestown, MA 02129 USA. [Yepes, Manuel] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Yepes, Manuel] Emory Univ, Sch Med, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. RP Strickland, DK (reprint author), Univ Maryland, Ctr Vasc & Inflammatory Dis, Sch Med, 800 W Baltimore St,Room 219, Baltimore, MD 21201 USA. EM dstrickland@som.umaryland.edu RI Yepes, Manuel/C-3576-2011 FU NIH [PO1 HL54710, HL50784, NS55126, NS49478]; American Heart Association FX This work is supported by NIH Grants PO1 HL54710 (D.K.S.), HL50784 (D.K.S.), NS55126 (J.A.W.), and NS49478 (M.Y.) and a Scientist Development Award from the American Heart Association (S.R.). NR 58 TC 16 Z9 18 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 27 PY 2011 VL 31 IS 30 BP 10836 EP 10846 DI 10.1523/JNEUROSCI.5065-10.2011 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 798AG UT WOS:000293171900011 PM 21795536 ER PT J AU Cea, M Soncini, D Fruscione, F Raffaghello, L Garuti, A Emionite, L Moran, E Magnone, M Zoppoli, G Reverberi, D Caffa, I Salis, A Cagnetta, A Bergamaschi, M Casciaro, S Pierri, I Damonte, G Ansaldi, F Gobbi, M Pistoia, V Ballestrero, A Patrone, F Bruzzone, S Nencioni, A AF Cea, Michele Soncini, Debora Fruscione, Floriana Raffaghello, Lizzia Garuti, Anna Emionite, Laura Moran, Eva Magnone, Mirko Zoppoli, Gabriele Reverberi, Daniele Caffa, Irene Salis, Annalisa Cagnetta, Antonia Bergamaschi, Micaela Casciaro, Salvatore Pierri, Ivana Damonte, Gianluca Ansaldi, Filippo Gobbi, Marco Pistoia, Vito Ballestrero, Alberto Patrone, Franco Bruzzone, Santina Nencioni, Alessio TI Synergistic Interactions between HDAC and Sirtuin Inhibitors in Human Leukemia Cells SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; ACUTE MYELOID-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; MYELODYSPLASTIC SYNDROMES; HEMATOLOGIC MALIGNANCIES; BIOSYNTHESIS INHIBITOR; ANTITUMOR-ACTIVITY; MELANOMA-CELLS; APOPTOSIS; P53 AB Aberrant histone deacetylase (HDAC) activity is frequent in human leukemias. However, while classical, NAD(+)-independent HDACs are an established therapeutic target, the relevance of NAD(+)-dependent HDACs (sirtuins) in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD(+)-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527) and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction wasmonitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD(+) levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA-interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD(+)-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited. C1 [Cea, Michele; Soncini, Debora; Garuti, Anna; Moran, Eva; Zoppoli, Gabriele; Caffa, Irene; Casciaro, Salvatore; Ballestrero, Alberto; Patrone, Franco; Nencioni, Alessio] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Cea, Michele; Cagnetta, Antonia] Harvard Univ, Sch Med, Jerome Lipper Multiple Myeloma Ctr, Dana Farber Canc Inst,Boston Novartis Inst BioMed, Cambridge, MA 02138 USA. [Fruscione, Floriana] ABC, Genoa, Italy. [Raffaghello, Lizzia; Pistoia, Vito] IRCCS G Gaslini, Lab Oncol, Genoa, Italy. [Emionite, Laura] Natl Canc Inst, Anim Facil, Genoa, Italy. [Magnone, Mirko; Salis, Annalisa; Damonte, Gianluca; Bruzzone, Santina] Univ Genoa, Biochem Sect, Dept Expt Med, Genoa, Italy. [Reverberi, Daniele] Natl Canc Inst, Med Oncol Div C, Genoa, Italy. [Cagnetta, Antonia; Bergamaschi, Micaela; Pierri, Ivana; Gobbi, Marco] San Martino Hosp, Dept Hematol & Oncol, Genoa, Italy. [Ansaldi, Filippo] Univ Genoa, Dept Hlth Sci, Genoa, Italy. RP Cea, M (reprint author), Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. EM A.Nencioni@gmx.net RI Bruzzone, Santina/A-4264-2015; Zoppoli, Gabriele/B-6935-2016; Caffa, Irene/J-9835-2016; OI Bruzzone, Santina/0000-0003-2034-3716; Zoppoli, Gabriele/0000-0003-3890-5588; Caffa, Irene/0000-0003-1111-9915; Raffaghello, Lizzia/0000-0003-2357-0607 FU Associazione Italiana per la Ricerca sul Cancro (AIRC); Associazione Italiana contro le Leucemie-Linfomi e Mieloma; University of Genoa FX This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, AN and LR), the Associazione Italiana contro le Leucemie-Linfomi e Mieloma, and by the University of Genoa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 30 Z9 32 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2011 VL 6 IS 7 AR e22739 DI 10.1371/journal.pone.0022739 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799JJ UT WOS:000293282700069 PM 21818379 ER PT J AU Hermos, JA Lawler, EV AF Hermos, John A. Lawler, Elizabeth V. TI Opioid Overdose-Related Deaths SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID PREVALENCE C1 [Hermos, John A.; Lawler, Elizabeth V.] Vet Affairs Boston Healthcare Syst, VA Cooperat Studies Program, Boston, MA USA. RP Hermos, JA (reprint author), Vet Affairs Boston Healthcare Syst, VA Cooperat Studies Program, Boston, MA USA. EM john.hermos@va.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 27 PY 2011 VL 306 IS 4 BP 380 EP 380 DI 10.1001/jama.2011.1038 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 797KL UT WOS:000293125800014 PM 21791682 ER PT J AU Merkow, RP Ko, CY AF Merkow, Ryan P. Ko, Clifford Y. TI Evidence-Based Medicine in Surgery The Importance of Both Experimental and Observational Study Designs SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID RANDOMIZED CLINICAL-TRIAL; INVASIVE BREAST-CANCER; ANTIREFLUX SURGERY; FOLLOW-UP; TOTAL MASTECTOMY; IRRADIATION C1 [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90095 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Merkow, Ryan P.] Univ Colorado, Sch Med, Dept Surg, Aurora, CO USA. [Merkow, Ryan P.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. [Merkow, Ryan P.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. RP Ko, CY (reprint author), Univ Calif Los Angeles, Dept Surg, 10833 LeConte Ave 72-215 CHS, Los Angeles, CA 90095 USA. EM cko@mednet.ucla.edu NR 12 TC 23 Z9 23 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 27 PY 2011 VL 306 IS 4 BP 436 EP 437 DI 10.1001/jama.2011.1059 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 797KL UT WOS:000293125800033 PM 21791695 ER PT J AU Geng, EH Glidden, DV Bwana, MB Musinguzi, N Emenyonu, N Muyindike, W Christopoulos, KA Neilands, TB Yiannoutsos, CT Deeks, SG Bangsberg, DR Martin, JN AF Geng, Elvin H. Glidden, David V. Bwana, Mwebesa Bosco Musinguzi, Nicolas Emenyonu, Nneka Muyindike, Winnie Christopoulos, Katerina A. Neilands, Torsten B. Yiannoutsos, Constantin T. Deeks, Steven G. Bangsberg, David R. Martin, Jeffrey N. TI Retention in Care and Connection to Care among HIV-Infected Patients on Antiretroviral Therapy in Africa: Estimation via a Sampling-Based Approach SO PLOS ONE LA English DT Article ID COMPETING RISKS; PATIENTS LOST; RURAL UGANDA; FOLLOW-UP; PROGRAMS; MORTALITY; OUTCOMES AB Introduction: Current estimates of retention among HIV-infected patients on antiretroviral therapy (ART) in Africa consider patients who are lost to follow-up (LTF) as well as those who die shortly after their last clinic visit to be no longer in care and to represent limitations in access to care. Yet many lost patients may have "silently" transferred and deaths shortly after the last clinic visit more likely represent limitations in clinical care rather than access to care after initial linkage. Methods: We evaluated HIV-infected adults initiating ART from 1/1/2004 to 9/30/2007 at a clinic in rural Uganda. A representative sample of lost patients was tracked in the community to obtain updated information about care at other ART sites. Updated outcomes were incorporated with probability weights to obtain "corrected" estimates of retention for the entire clinic population. We used the competing risks approach to estimate "connection to care"-the percentage of patients accessing care over time (including those who died while in care). Results: Among 3,628 patients, 829 became lost, 128 were tracked and in 111, updated information was obtained. Of 111, 79 (71%) were alive and 35/48 (73%) of patients interviewed in person were in care and on ART. Patient retention for the clinic population assuming lost patients were not in care was 82.3%, 68.9%, and 60.1% at 1, 2 and 3 years. Incorporating updated care information from the sample of lost patients increased estimates of patient retention to 85.8% to 90.9%, 78.9% to 86.2% and 75.8% to 84.7% at the same time points. Conclusions: Accounting for "silent transfers" and early deaths increased estimates of patient retention and connection to care substantially. Deaths soon after the last clinic visit (potentially reflecting limitations in clinical effectiveness) and disconnection from care among patient who were alive each accounted for approximately half of failures of retention. C1 [Geng, Elvin H.; Christopoulos, Katerina A.; Deeks, Steven G.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div HIV AIDS, San Francisco, CA 94143 USA. [Glidden, David V.; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Bwana, Mwebesa Bosco; Musinguzi, Nicolas; Emenyonu, Nneka; Muyindike, Winnie] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. [Neilands, Torsten B.] Univ Calif San Francisco, Ctr AIDS Prevent Studies, Dept Med, San Francisco, CA USA. [Yiannoutsos, Constantin T.] Indiana Univ, Dept Med, Div Biostat, Indianapolis, IN USA. [Emenyonu, Nneka; Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Geng, Elvin H.; Glidden, David V.; Bwana, Mwebesa Bosco; Musinguzi, Nicolas; Emenyonu, Nneka; Muyindike, Winnie; Yiannoutsos, Constantin T.; Bangsberg, David R.; Martin, Jeffrey N.] E Africa Int Epidemiol Databases Evaluate AIDS Ie, Eldoret, Kenya. RP Geng, EH (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div HIV AIDS, San Francisco, CA 94143 USA. EM genge@php.ucsf.edu FU National Institutes of Health [K23 AI084544, U01 AI069911, R01 MH054907, P30 AI027763]; United States President's Emergency Plan for AIDS Relief (PEPFAR) FX Funding was provided by the National Institutes of Health (K23 AI084544, U01 AI069911, R01 MH054907, P30 AI027763) and the United States President's Emergency Plan for AIDS Relief (PEPFAR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 33 Z9 33 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 JUL 26 PY 2011 VL 6 IS 7 AR e21797 DI 10.1371/journal.pone.0021797 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 798BE UT WOS:000293175100008 PM 21818265 ER PT J AU McCaffery, JM Jablonski, KA Franks, PW Dagogo-Jack, S Wing, RR Knowler, WC Delahanty, L Dabelea, D Hamman, R Shuldiner, AR Florez, JC AF McCaffery, Jeanne M. Jablonski, Kathleen A. Franks, Paul W. Dagogo-Jack, Sam Wing, Rena R. Knowler, William C. Delahanty, Linda Dabelea, Dana Hamman, Richard Shuldiner, Alan R. Florez, Jose C. CA Diabet Prevention Program Res Grp TI TCF7L2 Polymorphism, Weight Loss and Proinsulin: Insulin Ratio in the Diabetes Prevention Program SO PLOS ONE LA English DT Article ID VARIANTS; GENE; POPULATION; SECRETION; ASSOCIATION; CONVERSION; EVOLUTION; GLUCOSE; RISK AB Aims: TCF7L2 variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses. Methods: We examined the potential role of the TCF7L2 rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N = 2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults. Results: We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (P, 0.001), higher baseline proinsulin: insulin ratio (p<0.0001) and increased proinsulin: insulin ratio over a median of 2.5 years of follow-up (P = 0.003). Effects were comparable across treatment arms. Conclusions: The combination of a lack of impact of the TCF7L2 genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin: insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production. C1 [McCaffery, Jeanne M.; Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [McCaffery, Jeanne M.; Wing, Rena R.] Miriam Hosp, Weight Control & Diabet Res Ctr, Providence, RI 02906 USA. [McCaffery, Jeanne M.; Wing, Rena R.] Brown Med Sch, Providence, RI USA. [Franks, Paul W.] Lund Univ, Dept Genet & Mol Epidemiol, Malmo, Sweden. [Dagogo-Jack, Sam] Univ Tennessee, Coll Med, Div Endocrinol Diabet & Metab, Memphis, TN USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Delahanty, Linda; Dabelea, Dana] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Hamman, Richard] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Metab, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP McCaffery, JM (reprint author), George Washington Univ, Ctr Biostat, Rockville, MD USA. EM dppmail@bsc.gwu.edu RI de Bakker, Paul/B-8730-2009; Uwaifo, Gabriel/M-2361-2016; OI de Bakker, Paul/0000-0001-7735-7858; Uwaifo, Gabriel/0000-0002-6962-9304; Franks, Paul/0000-0002-0520-7604 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health, the National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; American Diabetes Association; McKesson BioServices Corp.; Matthews Media Group, Inc.; Henry M. Jackson Foundation FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, and the American Diabetes Association. This research was also supported, in part, by the intramural research program of the NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Bristol-Myers Squibb and Parke-Davis provided medication; LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co. and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 22 TC 13 Z9 13 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 26 PY 2011 VL 6 IS 7 AR e21518 DI 10.1371/journal.pone.0021518 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 798BE UT WOS:000293175100004 PM 21814547 ER PT J AU Selesniemi, K Lee, HJ Muhlhauser, A Tilly, JL AF Selesniemi, Kaisa Lee, Ho-Joon Muhlhauser, Ailene Tilly, Jonathan L. TI Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bioenergetics; fertility; germ cell; oogenesis; ovary ID ADVANCED REPRODUCTIVE AGE; CALORIC RESTRICTION; MITOCHONDRIAL BIOGENESIS; OXIDATIVE STRESS; ANTIAGING DRUGS; FEMALE MEIOSIS; RHESUS-MONKEYS; MOUSE EGGS; PGC-1-ALPHA; WOMEN AB Increased meiotic spindle abnormalities and aneuploidy in oocytes of women of advanced maternal ages lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Despite the significance of the problem, strategies to sustain oocyte quality with age have remained elusive. Here we report that adult female mice maintained under 40% caloric restriction (CR) did not exhibit aging-related increases in oocyte aneuploidy, chromosomal misalignment on the metaphase plate, meiotic spindle abnormalities, or mitochondrial dysfunction (aggregation, impaired ATP production), all of which occurred in oocytes of age-matched ad libitum-fed controls. The effects of CR on oocyte quality in aging females were reproduced by deletion of the metabolic regulator, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Thus, CR during adulthood or loss of PGC-1 alpha function maintains female germline chromosomal stability and its proper segregation during meiosis, such that ovulated oocytes of aged female mice previously maintained on CR or lacking PGC-1 alpha are comparable to those of young females during prime reproductive life. C1 [Selesniemi, Kaisa; Lee, Ho-Joon; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Dept Obstet & Gyn, Boston, MA 02114 USA. [Muhlhauser, Ailene] Washington State Univ, Ctr Reprod Biol, Pullman, WA 99164 USA. [Muhlhauser, Ailene] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. RP Tilly, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Dept Obstet & Gyn, Boston, MA 02114 USA. EM jtilly@partners.org FU National Institutes of Health [R37-AG012279]; Henry and Vivian Rosenberg Philanthropic Fund; Sea Breeze Foundation; Vincent Memorial Research Funds; Massachusetts General Hospital's Executive Committee on Research (ECOR) FX We are grateful to P. A. Hunt for technical support in assessing oocyte aneuploidy, D. A. Sinclair for critical reading of the manuscript before submission, B. M. Spiegelman for providing Pgc-1 alpha mutant mice, and D. C. Woods and R. Tyszkowski for technical assistance. This study was supported by National Institutes of Health's Method to Extend Research in Time (MERIT) Award R37-AG012279, the Henry and Vivian Rosenberg Philanthropic Fund, the Sea Breeze Foundation, and Vincent Memorial Research Funds. K. S. is a recipient of a Massachusetts General Hospital's Executive Committee on Research (ECOR) Fund for Medical Discovery Award. NR 60 TC 72 Z9 74 U1 0 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2011 VL 108 IS 30 BP 12319 EP 12324 DI 10.1073/pnas.1018793108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797LS UT WOS:000293129900030 PM 21730149 ER PT J AU Cheung, HW Cowley, GS Weir, BA Boehm, JS Rusin, S Scott, JA East, A Ali, LD Lizotte, PH Wong, TC Jiang, GZ Hsiao, J Mermel, CH Getz, G Barretina, J Gopal, S Tamayo, P Gould, J Tsherniak, A Stransky, N Luo, BA Ren, Y Drapkin, R Bhatia, SN Mesirov, JP Garraway, LA Meyerson, M Lander, ES Root, DE Hahn, WC AF Cheung, Hiu Wing Cowley, Glenn S. Weir, Barbara A. Boehm, Jesse S. Rusin, Scott Scott, Justine A. East, Alexandra Ali, Levi D. Lizotte, Patrick H. Wong, Terence C. Jiang, Guozhi Hsiao, Jessica Mermel, Craig H. Getz, Gad Barretina, Jordi Gopal, Shuba Tamayo, Pablo Gould, Joshua Tsherniak, Aviad Stransky, Nicolas Luo, Biao Ren, Yin Drapkin, Ronny Bhatia, Sangeeta N. Mesirov, Jill P. Garraway, Levi A. Meyerson, Matthew Lander, Eric S. Root, David E. Hahn, William C. TI Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE high throughput; RNAi; oncogene; lineage ID SURVIVAL ONCOGENE; GENOMIC ANALYSES; CARCINOMA; LUNG; MELANOMA; KINASE; MODEL; PAX8 AB A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially over-expressed in ovarian cancer cell lines. One such gene, PAX8, is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of PAX8 selectively induces apoptotic cell death of ovarian cancer cells. These results identify PAX8 as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways. C1 [Cheung, Hiu Wing; Cowley, Glenn S.; Weir, Barbara A.; Boehm, Jesse S.; Rusin, Scott; Scott, Justine A.; East, Alexandra; Ali, Levi D.; Lizotte, Patrick H.; Wong, Terence C.; Jiang, Guozhi; Hsiao, Jessica; Mermel, Craig H.; Getz, Gad; Barretina, Jordi; Gopal, Shuba; Tamayo, Pablo; Gould, Joshua; Tsherniak, Aviad; Stransky, Nicolas; Luo, Biao; Bhatia, Sangeeta N.; Mesirov, Jill P.; Garraway, Levi A.; Meyerson, Matthew; Lander, Eric S.; Root, David E.; Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Cheung, Hiu Wing; Mermel, Craig H.; Barretina, Jordi; Garraway, Levi A.; Meyerson, Matthew; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mermel, Craig H.; Garraway, Levi A.; Meyerson, Matthew; Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Drapkin, Ronny] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ren, Yin; Bhatia, Sangeeta N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Drapkin, Ronny; Meyerson, Matthew] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bhatia, Sangeeta N.; Garraway, Levi A.; Hahn, William C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Bhatia, Sangeeta N.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Lander, ES (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM lander@broadinstitute.org; droot@broadinstitute.org; william_hahn@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; Drapkin, Ronny/E-9944-2016; OI Drapkin, Ronny/0000-0002-6912-6977; Boehm, Jesse/0000-0002-6795-6336; Lizotte, Patrick/0000-0001-9510-0036 FU National Institutes of Health [R33 CA128625, U54 CA112962, RC2 CA148268]; Novartis Pharmaceuticals; Richard Hunt; H. L. Snyder Foundation FX We thank M. Reich, A. Derr, and T. Liefield for assistance with analysis and data portal creation. This work was supported in part by National Institutes of Health Grants R33 CA128625, U54 CA112962, and RC2 CA148268, Novartis Pharmaceuticals, Richard Hunt, and the H. L. Snyder Foundation. NR 29 TC 171 Z9 174 U1 0 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 JUL 26 PY 2011 VL 108 IS 30 BP 12372 EP 12377 DI 10.1073/pnas.1109363108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797LS UT WOS:000293129900039 PM 21746896 ER PT J AU Middleton, LE Manini, TM Simonsick, EM Harris, TB Barnes, DE Tylavsky, F Brach, JS Everhart, JE Yaffe, K AF Middleton, Laura E. Manini, Todd M. Simonsick, Eleanor M. Harris, Tamara B. Barnes, Deborah E. Tylavsky, Frances Brach, Jennifer S. Everhart, James E. Yaffe, Kristine TI Activity Energy Expenditure and Incident Cognitive Impairment in Older Adults SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY QUESTIONNAIRES; ALZHEIMERS-DISEASE; EXERCISE; DEMENTIA; DECLINE; HEALTH; RISK; WOMEN; VARIABILITY; POPULATION AB Background: Studies suggest that physically active people have reduced risk of incident cognitive impairment in late life. However, these studies are limited by reliance on self-reports of physical activity, which only moderately correlate with objective measures and often exclude activity not readily quantifiable by frequency and duration. The objective of this study was to investigate the relationship between activity energy expenditure (AEE), an objective measure of total activity, and incidence of cognitive impairment. Methods: We calculated AEE as 90% of total energy expenditure (assessed during 2 weeks using doubly labeled water) minus resting metabolic rate (measured using indirect calorimetry) in 197 men and women (mean age, 74.8 years) who were free of mobility and cognitive impairments at study baseline (1998-1999). Cognitive function was assessed at baseline and 2 or 5 years later using the Modified Mini-Mental State Examination. Cognitive impairment was defined as a decline of at least 1.0 SD (9 points) between baseline and follow-up evaluations. Results: After adjustment for baseline Modified Mini-Mental State Examination scores, demographics, fatfree mass, sleep duration, self-reported health, and diabetes mellitus, older adults in the highest sex-specific tertile of AEE had lower odds of incident cognitive impairment than those in the lowest tertile (odds ratio, 0.09; 95% confidence interval, 0.01-0.79). There was also a significant dose response between AEE and incidence of cognitive impairment (P=.05 for trend over tertiles). Conclusions: These findings indicate that greater AEE may be protective against cognitive impairment in a dose-response manner. The significance of overall activity in contrast to vigorous or light activity should be determined. C1 [Middleton, Laura E.] Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Heart & Stroke Fdn Ctr Stroke Recovery, Toronto, ON M4N 3M5, Canada. [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Bethesda, MD 20892 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Barnes, Deborah E.; Yaffe, Kristine] San Francisco VA Med Ctr, Dept Psychiat, San Francisco, CA USA. [Barnes, Deborah E.; Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Tylavsky, Frances] Univ Tennessee, Dept Biostat & Epidemiol, Memphis, TN USA. [Brach, Jennifer S.] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA USA. [Everhart, James E.] NIDDK, Epidemiol & Data Syst Program, Bethesda, MD USA. RP Middleton, LE (reprint author), Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Heart & Stroke Fdn Ctr Stroke Recovery, 2075 Bayview Ave,A421, Toronto, ON M4N 3M5, Canada. EM Middleton_l@hotmail.com RI Middleton, Laura/C-6024-2009 OI Middleton, Laura/0000-0001-8624-3123 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, K01-AG-024069, AG 031155]; National Institutes of Health, National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases; Canadian Institute of Health Research fellowship; National Institute on Aging Claude D. Pepper Center [P30AG028740]; Alzheimer's Association [IIRG-06-27306]; American Federation of Aging Research Paul Beeson Career Development Award [K23 AG026766-01] FX This work was supported by National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr Middleton is supported by a Canadian Institute of Health Research fellowship; Dr Manini is supported by grant P30AG028740 from the National Institute on Aging Claude D. Pepper Center; Dr Barnes was supported in part by grant K01-AG-024069 from the National Institute on Aging and grant IIRG-06-27306 from the Alzheimer's Association; Dr Brach is supported in part by a National Institutes on Aging and American Federation of Aging Research Paul Beeson Career Development Award (K23 AG026766-01); and Dr Yaffe is supported in part by NIA grant AG 031155 and an Independent Investigator Award from the Alzheimer's Association. NR 44 TC 58 Z9 61 U1 2 U2 21 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 25 PY 2011 VL 171 IS 14 BP 1251 EP 1257 DI 10.1001/archinternmed.2011.277 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 796WN UT WOS:000293084300007 PM 21771893 ER PT J AU Groeneveld, PW Polsky, D Yang, F Yang, L Epstein, AJ AF Groeneveld, Peter W. Polsky, Daniel Yang, Feifei Yang, Lin Epstein, Andrew J. TI The Impact of New Cardiovascular Device Technology on Health Care Costs SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID THERAPY; DISEASE C1 [Groeneveld, Peter W.; Polsky, Daniel; Yang, Feifei; Yang, Lin; Epstein, Andrew J.] Univ Penn, Sch Med, Dept Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Groeneveld, Peter W.; Epstein, Andrew J.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Dept Vet Affairs, Philadelphia, PA USA. [Groeneveld, Peter W.; Epstein, Andrew J.] Pittsburgh Vet Affairs Hlth Care Syst, Pittsburgh, PA USA. [Groeneveld, Peter W.; Polsky, Daniel; Epstein, Andrew J.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Groeneveld, PW (reprint author), Univ Penn, Sch Med, Dept Med, Div Gen Internal Med, 1229 Blockley Hall,423 Serv Dr, Philadelphia, PA 19104 USA. EM petergro@mail.med.upenn.edu FU AHRQ HHS [1R01HS018403, R01 HS018403]; NHLBI NIH HHS [R01 HL086919-03, 1R01HL086919, R01 HL086919] NR 8 TC 10 Z9 10 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 25 PY 2011 VL 171 IS 14 BP 1289 EP 1291 DI 10.1001/archinternmed.2011.141 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 796WN UT WOS:000293084300016 PM 21518936 ER PT J AU Wang, K Otu, HH Chen, Y Lee, Y Latham, K Cibelli, JB AF Wang, Kai Otu, Hasan H. Chen, Ying Lee, Young Latham, Keith Cibelli, Jose B. TI Reprogrammed Transcriptome in Rhesus-Bovine Interspecies Somatic Cell Nuclear Transfer Embryos SO PLOS ONE LA English DT Article ID MATERNAL MESSENGER-RNAS; ZYGOTIC GENE ACTIVATION; STEM-CELLS; PREIMPLANTATION DEVELOPMENT; MOUSE; OOCYTES; OLIGONUCLEOTIDE; DEGRADATION; MICROARRAYS; ZEBRAFISH AB Background: Global activation of the embryonic genome (EGA), one of the most critical steps in early mammalian embryo development, is recognized as the time when interspecies somatic cell nuclear transfer (iSCNT) embryos fail to thrive. Methodology/Principal Findings: In this study, we analyzed the EGA-related transcriptome of rhesus-bovine iSCNT 8-to 16-cell embryos and dissected the reprogramming process in terms of embryonic gene activation, somatic gene silencing, and maternal RNA degradation. Compared with fibroblast donor cells, two thousand and seven genes were activated in iSCNT embryos, one quarter of them reaching expression levels comparable to those found in in vitro fertilized (IVF) rhesus embryos. This suggested that EGA in iSCNT embryos had partially recapitulated rhesus embryonic development. Eight hundred and sixty somatic genes were not silenced properly and continued to be expressed in iSCNT embryos, which indicated incomplete nuclear reprogramming. We compared maternal RNA degradation in bovine oocytes between bovine-bovine SCNT and iSCNT embryos. While maternal RNA degradation occurred in both SCNT and iSCNT embryos, we saw more limited overall degradation of maternal RNA in iSCNT embryos than in SCNT embryos. Several important maternal RNAs, like GPF9, were not properly processed in SCNT embryos. Conclusions/Significance: Our data suggested that iSCNT embryos are capable of triggering EGA, while a portion of somatic cell-associated genes maintain their expression. Maternal RNA degradation seems to be impaired in iSCNT embryos. Further understanding of the biological roles of these genes, networks, and pathways revealed by iSCNT may expand our knowledge about cell reprogramming, pluripotency, and differentiation. C1 [Wang, Kai; Chen, Ying; Cibelli, Jose B.] Michigan State Univ, E Lansing, MI 48824 USA. [Otu, Hasan H.] Harvard Univ, Sch Med, BIDMC Genom Ctr, Boston, MA USA. [Otu, Hasan H.] Istanbul Bilgi Univ, Dept Bioengn, Istanbul, Turkey. [Lee, Young; Latham, Keith] Temple Univ, Philadelphia, PA 19122 USA. [Cibelli, Jose B.] Programa Andaluz Terapia Celular, Andalucia, Spain. RP Wang, K (reprint author), Michigan State Univ, E Lansing, MI 48824 USA. EM Cibelli@anr.msu.edu RI chen, ying/G-4926-2011; wang, kai/G-4932-2011; OI Otu, Hasan/0000-0002-9253-8152 FU Michigan State University (MSU) Foundation; Michigan Agricultural Experiment Station (MAES); Naylor Family Foundation; Dubai Harvard Foundation for Medical Research FX This work was supported by the Michigan State University (MSU) Foundation, MSU's Vice President of Research, and the Michigan Agricultural Experiment Station (MAES), as well as the Naylor Family Foundation. HHO is partially supported by a grant from the Dubai Harvard Foundation for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 10 Z9 13 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 25 PY 2011 VL 6 IS 7 AR e22197 DI 10.1371/journal.pone.0022197 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 798AP UT WOS:000293172900016 PM 21799794 ER PT J AU Wherrett, DK Bundy, B Becker, DJ DiMeglio, LA Gitelman, SE Goland, R Gottlieb, PA Greenbaum, CJ Herold, KC Marks, JB Monzavi, R Moran, A Orban, T Palmer, JP Raskin, P Rodriguez, H Schatz, D Wilson, DM Krischer, JP Skyler, JS AF Wherrett, Diane K. Bundy, Brian Becker, Dorothy J. DiMeglio, Linda A. Gitelman, Stephen E. Goland, Robin Gottlieb, Peter A. Greenbaum, Carla J. Herold, Kevan C. Marks, Jennifer B. Monzavi, Roshanak Moran, Antoinette Orban, Tihamer Palmer, Jerry P. Raskin, Philip Rodriguez, Henry Schatz, Desmond Wilson, Darrell M. Krischer, Jeffrey P. Skyler, Jay S. CA Type 1 Diabet TrialNet GAD Study G TI Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial SO LANCET LA English DT Article ID BETA-CELL FUNCTION; INSULIN-SECRETION; ORAL TOLERANCE; IMMUNOTHERAPY; COMPLICATIONS; PATHOGENESIS; PROGRESSION; MELLITUS; PREVENT; MICE AB Background Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes. Methods Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 mu g GAD-alum, two injections of 20 mu g GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399. Findings 145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0.412 nmol/L (95% CI 0.349-0.478) in the GAD-alum group, 0.382 nmol/L (0.322-0.446) in the GAD-alum plus alum group, and 0.413 nmol/L (0.351-0.477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0.998 (95% CI 0.779-1.22; p=0.98) for GAD-alum versus alum, and 0.926 (0.720-1.13; p=0.50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups. Interpretation Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. C1 [Marks, Jennifer B.; Skyler, Jay S.] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Wherrett, Diane K.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Bundy, Brian; Krischer, Jeffrey P.] Univ S Florida, Tampa, FL USA. [Becker, Dorothy J.] Univ Pittsburgh, Pittsburgh, PA USA. [DiMeglio, Linda A.; Rodriguez, Henry] Indiana Univ Sch Med, Indianapolis, IN USA. [Gitelman, Stephen E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Goland, Robin] Columbia Univ, New York, NY USA. [Gottlieb, Peter A.] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Greenbaum, Carla J.] Benaroya Res Inst, Seattle, WA USA. [Herold, Kevan C.] Yale Univ, Sch Med, New Haven, CT USA. [Monzavi, Roshanak] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Moran, Antoinette] Univ Minnesota, Minneapolis, MN USA. [Orban, Tihamer] Joslin Diabet Ctr, Boston, MA 02215 USA. [Palmer, Jerry P.] Univ Washington, Sch Med, Seattle, WA USA. [Raskin, Philip] Univ Texas SW Med Sch, Dallas, TX USA. [Schatz, Desmond] Univ Florida, Gainesville, FL USA. [Wilson, Darrell M.] Stanford Univ, Stanford, CA 94305 USA. RP Skyler, JS (reprint author), Univ Miami, Miller Sch Med, Diabet Res Inst, POB 016960,D-110, Miami, FL 33136 USA. EM jskyler@miami.edu RI Skyler, Jay/F-4211-2016; OI DiMeglio, Linda/0000-0002-8033-6078 FU US National Institutes of Health; Eli Lilly; Medtronic; Diamyd; Tolerx; Bayhill Therapeutics; Macrogenics; Omni BioTherapeutics; Merck; Osiris Therapeutics; Aegera; Andromeda Biotech; Biodel; Boehringer Ingelheim; Calibra; CPEX; Generex; Hoffman-LaRoche; MannKind; Novo-Nordisk; Reata; Pfizer; Genentech; Halozyme; Intuity; Becton-Dickinson; MannKind Corporation; GlaxoSmithKline; Salutria Pharmaceuticals; Veroscience; Roche; Exsulin; NIH through the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infections Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, U01 DK085509, HHSN267200800019C]; National Center for Research Resources [UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, M01 RR00400]; Juvenile Diabetes Research Foundation International (JDRF); American Diabetes Association (ADA) FX US National Institutes of Health.; DKW reports receiving lecture fees from Eli Lilly and Medtronic. DJB reports receiving a grant from Diamyd. SEG reports serving on an advisory board for Genentech. RG reports receiving grants from Diamyd and Tolerx. PAG reports serving on advisory boards for Genentech, Eli Lilly, Sanofi-Aventis, and Tolerx; and reports receiving grants from Bayhill Therapeutics, Diamyd, Macrogenics, Omni BioTherapeutics, and Tolerx. CJG reports receiving grants from Bayhill Therapeutics, Diamyd, and Tolerx. JBM reports serving on an advisory board for Amgen. AM reports serving on an advisory board for Pfizer, and receiving grants from Tolerx, Merck, and Osiris Therapeutics. TO reports serving on the data safety monitoring board for Osiris Therapeutics, and being a founder of Orban Biotech. JPP reports being a consultant and receiving research grants and leading studies for Diamyd. PR reports serving on advisory boards for Amgen, AstraZeneca, MannKind, and Novo-Nordisk; serving on speakers bureaus for Merck and Novo-Nordisk; and receiving grants from Aegera, Andromeda Biotech, Bayhill Therapeutics, Biodel, Boehringer Ingelheim, Calibra, CPEX, Generex, Hoffman-LaRoche, MannKind, Novo-Nordisk, Osiris Therapeutics, and Reata. HR reports serving on an advisory board For Marcadia Biotech; serving as a consultant to Eli Lilly, Genentech, Bayer, EMD Serono, and Merck; being on the speakers bureau of Eli Lilly and Novo-Nordisk; and receiving grant support from Macrogenics and Eli Lilly. DS reports serving on advisory boards for Andromeda, Eli Lilly, GlaxoSmithKline, and Roche; giving a lecture supported by Pfizer; and receiving a grant from Diamyd. DMW reports serving on an advisory boards for DexCom and Genentech; and receiving grants support from Genentech, Diamyd, and Osiris Therapeutics. JSS reports serving on boards for Amylin Pharmaceuticals, DexCom, and Sanofi-Aventis; receiving grants from Bayhill Therapeutics, Halozyme, Intuity, and Osiris Therapeutics; receiving consultancy fees from Becton-Dickinson, Merck, MannKind Corporation, GlaxoSmithKline, Salutria Pharmaceuticals, Veroscience, Roche, and Exsulin; and receiving speakers' fees and payment for development of an educational presentation from Novo-Nordisk; and holds stock in Amylin Pharmaceuticals and Dexcom. BB, LAD, KCH, RM, and JPK declare that they have no conflicts of interest.; The sponsor of the trial was the Type 1 Diabetes TrialNet Study Group. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by NIH through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infections Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, via cooperative agreements (U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, and U01 DK085509) and a contract (HHSN267200800019C); and through the National Center for Research Resources, via clinical translational science awards (UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, and UL1 RR031986) and a general clinical research center award (M01 RR00400). Trial Net also receives non-financial support from the Juvenile Diabetes Research Foundation International (JDRF) and the American Diabetes Association (ADA). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of NIH, JDRF, or ADA. Diamyd Medical (Stockholm, Sweden) provided CAD-alum and placebo (alum), but had no involvement with the final study design, study conduct or management, data collection, data analysis, data interpretation, or writing of the report. There are no agreements concerning confidentiality of the data between Diamyd and the authors or the institutions named, in the credit lines. The authors did provide Diamyd Medical a copy of the original report before submission. Roche Diagnostics (Indianapolis, IN, USA) provided blood glucose monitoring metres and strips to research patients. No funds were paid for preparation of this report. NR 37 TC 139 Z9 144 U1 3 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUL 23 PY 2011 VL 378 IS 9788 BP 319 EP 327 DI 10.1016/S0140-6736(11)60895-7 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 803XL UT WOS:000293615800029 PM 21714999 ER PT J AU Helfrich, CD Blevins, D Smith, JL Kelly, PA Hogan, TP Hagedorn, H Dubbert, PM Sales, AE AF Helfrich, Christian D. Blevins, Dean Smith, Jeffrey L. Kelly, P. Adam Hogan, Timothy P. Hagedorn, Hildi Dubbert, Patricia M. Sales, Anne E. TI Predicting implementation from organizational readiness for change: a study protocol SO IMPLEMENTATION SCIENCE LA English DT Article ID HEPATITIS PREVENTION SERVICES; CHRONIC LIVER-DISEASE; PRIMARY-CARE; ATYPICAL ANTIPSYCHOTICS; SCHIZOPHRENIA; MODEL; DEPRESSION; CLINICS; RISK; INSTRUMENTS AB Background: There is widespread interest in measuring organizational readiness to implement evidence-based practices in clinical care. However, there are a number of challenges to validating organizational measures, including inferential bias arising from the halo effect and method bias - two threats to validity that, while well-documented by organizational scholars, are often ignored in health services research. We describe a protocol to comprehensively assess the psychometric properties of a previously developed survey, the Organizational Readiness to Change Assessment. Objectives: Our objective is to conduct a comprehensive assessment of the psychometric properties of the Organizational Readiness to Change Assessment incorporating methods specifically to address threats from halo effect and method bias. Methods and Design: We will conduct three sets of analyses using longitudinal, secondary data from four partner projects, each testing interventions to improve the implementation of an evidence-based clinical practice. Partner projects field the Organizational Readiness to Change Assessment at baseline (n = 208 respondents; 53 facilities), and prospectively assesses the degree to which the evidence-based practice is implemented. We will conduct predictive and concurrent validities using hierarchical linear modeling and multivariate regression, respectively. For predictive validity, the outcome is the change from baseline to follow-up in the use of the evidence-based practice. We will use intra-class correlations derived from hierarchical linear models to assess inter-rater reliability. Two partner projects will also field measures of job satisfaction for convergent and discriminant validity analyses, and will field Organizational Readiness to Change Assessment measures at follow-up for concurrent validity (n = 158 respondents; 33 facilities). Convergent and discriminant validities will test associations between organizational readiness and different aspects of job satisfaction: satisfaction with leadership, which should be highly correlated with readiness, versus satisfaction with salary, which should be less correlated with readiness. Content validity will be assessed using an expert panel and modified Delphi technique. Discussion: We propose a comprehensive protocol for validating a survey instrument for assessing organizational readiness to change that specifically addresses key threats of bias related to halo effect, method bias and questions of construct validity that often go unexplored in research using measures of organizational constructs. C1 [Helfrich, Christian D.] VA Puget Sound Healthcare Syst, NW Hlth Serv Res & Dev Ctr Excellence, Seattle, WA USA. [Helfrich, Christian D.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Blevins, Dean] Ctr Dis Control & Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Div HIV AIDS Prevent, Atlanta, GA USA. [Kelly, P. Adam] SE Louisiana Vet Hlth Care Network, Res Serv, New Orleans, LA USA. [Smith, Jeffrey L.] VA Mental Hlth Qual Enhancement Res Initiat, N Little Rock, AR USA. [Hogan, Timothy P.] Edward Hines Jr Vet Affairs Hosp, Ctr Management Complex Chron Care, eHlth Qual Enhancement Res Initiat, Hines, IL USA. [Hogan, Timothy P.] Edward Hines Jr Vet Affairs Hosp, Spinal Cord Injury Qual Enhancement Res Initiat, Hines, IL USA. [Hogan, Timothy P.] Loyola Univ, Stritch Sch Med, Program Hlth Serv Res, Chicago, IL 60611 USA. [Hagedorn, Hildi] Minneapolis VA Healthcare Syst, VA Subst Use Disorders Qual Enhancement Res Initi, Minneapolis, MN USA. [Dubbert, Patricia M.] S Cent VA Mental Illness Res Educ & Clin Ctr MIRE, N Little Rock, AR USA. [Dubbert, Patricia M.] S Cent VA Geriatr Res Educ & Clin Ctr GRECC, N Little Rock, AR USA. [Sales, Anne E.] VA Inpatient Evaluat Ctr, Cincinnati, OH USA. [Sales, Anne E.] VA Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. RP Helfrich, CD (reprint author), VA Puget Sound Healthcare Syst, NW Hlth Serv Res & Dev Ctr Excellence, Seattle, WA USA. EM christian.helfrich@va.gov RI Sales, Anne/D-9678-2012; Helfrich, Christian/D-2382-2016; OI Helfrich, Christian/0000-0002-9827-4768; Sales, Anne/0000-0001-9360-3334 FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [IIR 09-067] FX This study has been funded by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service, project grant number IIR 09-067. We wish to thank Rachel Orlando and Penny White for project support for this research study. The views expressed in this article are the authors' and do not necessarily reflect the position or policy of the US Department of Veterans Affairs. NR 80 TC 10 Z9 10 U1 6 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUL 22 PY 2011 VL 6 AR 76 DI 10.1186/1748-5908-6-76 PG 12 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 808MU UT WOS:000293982600001 PM 21777479 ER PT J AU Dey, N Das, F Mariappan, MM Mandal, CC Ghosh-Choudhury, N Kasinath, BS Choudhury, GG AF Dey, Nirmalya Das, Falguni Mariappan, Meenalakshmi M. Mandal, Chandi Charan Ghosh-Choudhury, Nandini Kasinath, Balakuntalam S. Choudhury, Goutam Ghosh TI MicroRNA-21 Orchestrates High Glucose-induced Signals to TOR Complex 1, Resulting in Renal Cell Pathology in Diabetes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA TRANSLATION; INDUCED COLLAGEN EXPRESSION; GROWTH-FACTOR-BETA; MESANGIAL CELLS; FIBRONECTIN EXPRESSION; SUPEROXIDE-DISMUTASE; EPITHELIAL-CELLS; PROTEIN-SYNTHESIS; MAMMALIAN TARGET; TRANSGENIC MICE AB Hyperglycemia induces a wide array of signaling pathways in the kidney that lead to hypertrophy and matrix expansion, eventually culminating in progressive kidney failure. High glucose-induced reduction of the tumor suppressor protein phosphatase and tensin homolog deleted in chromosome 10 (PTEN) contributes to renal cell hypertrophy and matrix expansion. We identified microRNA-21 (miR-21) as the molecular link between high glucose and PTEN suppression. Renal cortices from OVE26 type 1 diabetic mice showed significantly elevated levels of miR-21 associated with reduced PTEN and increased fibronectin content. In renal mesangial cells, high glucose increased the expression of miR-21, which targeted the 3'-UTR of PTEN mRNA to inhibit PTEN protein expression. Overexpression of miR-21 mimicked the action of high glucose, which included a reduction in PTEN expression and a concomitant increase in Akt phosphorylation. In contrast, expression of miR-21 Sponge, to inhibit endogenous miR-21, prevented down-regulation of PTEN and phosphorylation of Akt induced by high glucose. Interestingly, high glucose-stimulated miR-21 inactivated PRAS40, a negative regulator of TORC1. Finally, miR-21 enhanced high glucose-induced TORC1 activity, resulting in renal cell hypertrophy and fibronectin expression. Thus, our results identify a previously unrecognized function of miR-21 that is the reciprocal regulation of PTEN levels and Akt/TORC1 activity that mediate critical pathologic features of diabetic kidney disease. C1 [Dey, Nirmalya; Das, Falguni; Mariappan, Meenalakshmi M.; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Mandal, Chandi Charan; Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, Vet Affairs Res, San Antonio, TX USA. [Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. RP Choudhury, GG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU National Institutes of Health [RO1 DK50190, RO1 AR52425, DK077295, RC2A 036613]; Juvenile Diabetes Research Foundation [1-2008-185]; Veterans Affairs; Cancer Therapy and Research Center, San Antonio, TX; Veterans Affairs Research Service FX This work was supported, in whole or in part, by National Institutes of Health Grants RO1 DK50190 (to G. G. C.), RO1 AR52425 (to N. G. C.), and DK077295 and RC2A 036613 (to B. S. K.). This work was also supported by Juvenile Diabetes Research Foundation Grant 1-2008-185 (to G. G. C.).; Supported by a Veterans Affairs merit review grant and a Ronald P. Williams Orthopedic Oncology Developmental Research Award from the Cancer Therapy and Research Center, San Antonio, TX.; Supported by a grant from the Veterans Affairs Research Service. NR 81 TC 91 Z9 100 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 22 PY 2011 VL 286 IS 29 BP 25586 EP 25603 DI 10.1074/jbc.M110.208066 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 796SS UT WOS:000293073000021 PM 21613227 ER PT J AU Tokhtaeva, E Sachs, G Souda, P Bassilian, S Whitelegge, JP Shoshani, L Vagin, O AF Tokhtaeva, Elmira Sachs, George Souda, Puneet Bassilian, Sara Whitelegge, Julian P. Shoshani, Liora Vagin, Olga TI Epithelial Junctions Depend on Intercellular Trans-interactions between the Na,K-ATPase beta(1) Subunits SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CANINE KIDNEY-CELLS; E-CADHERIN; TIGHT JUNCTIONS; ADHESION; GLYCOSYLATION; ANKYRIN; ATPASE; IDENTIFICATION; NA+,K+-ATPASE; ORGANIZATION AB N-Glycans of the Na,K-ATPase beta(1) subunit are important for intercellular adhesion in epithelia, suggesting that epithelial junctions depend on N-glycan-mediated interactions between the beta(1) subunits of neighboring cells. The level of co-immunoprecipitation of the endogenous beta(1) subunit with various YFP-linked beta(1) subunits expressed in Madin-Darby canine kidney cells was used to assess beta(1)-beta(1) interactions. The amount of co-precipitated endogenous dog beta(1) was greater with dog YFP-beta(1) than with rat YFP-beta(1), showing that amino acid-mediated interactions are important for beta(1)-beta(1) binding. Co-precipitation of beta(1) was also less with the unglycosylated YFP-beta(1) than with glycosylated YFP-beta(1), indicating a role for N-glycans. Mixing cells expressing dog YFP-beta(1) with non-transfected cells increased the amount of co-precipitated beta(1), confirming the presence of intercellular (YFP-beta(1))-beta(1) complexes. Accordingly, disruption of intercellular junctions decreased the amount of co-precipitated beta(1) subunits. The decrease in beta(1) co-precipitation both with rat YFP-beta(1) and unglycosylated YFP-beta(1) was associated with decreased detergent stability of junctional proteins and increased paracellular permeability. Reducing N-glycan branching by specific inhibitors increased (YFP-beta(1))-beta(1) co-precipitation and strengthened intercellular junctions. Therefore, interactions between the beta(1) subunits of neighboring cells maintain integrity of intercellular junctions, and alterations in the beta(1) subunit N-glycan structure can regulate stability and tightness of intercellular junctions. C1 [Tokhtaeva, Elmira; Sachs, George; Bassilian, Sara; Vagin, Olga] Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90073 USA. [Tokhtaeva, Elmira; Sachs, George; Bassilian, Sara; Vagin, Olga] Vet Adm Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. [Souda, Puneet; Whitelegge, Julian P.] Univ Calif Los Angeles, NPI Semel Inst, Pasarow Mass Spectrometry Lab, Los Angeles, CA 90024 USA. [Shoshani, Liora] IPN, CINVESTAV, Dept Physiol Biophys & Neurosci, Mexico City 07360, DF, Mexico. RP Vagin, O (reprint author), VAGLAHS W Los Angeles, 11301 Wilshire Blvd,Bldg 113,Rm 324, Los Angeles, CA 90073 USA. EM olgav@ucla.edu FU National Institutes of Health [DK077149, DK058333]; National Institutes of Health-NCRR [S10 RR023045] FX This work was supported, in whole or in part, by National Institutes of Health Grants DK077149 and DK058333.; We thank Dr. Glenn Nagami (UCLA) and Dr. Ralf Jacob (Marburg University) for careful reading of the manuscript and helpful suggestions. The LTQ-FT was purchased with National Institutes of Health-NCRR support from Grant S10 RR023045. NR 31 TC 16 Z9 16 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 22 PY 2011 VL 286 IS 29 BP 25801 EP 25812 DI 10.1074/jbc.M111.252247 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 796SS UT WOS:000293073000042 PM 21642423 ER PT J AU Burger, DE Wang, LM Ban, LQ Okubo, Y Kuhtreiber, WM Leichliter, AK Faustman, DL AF Burger, Douglas E. Wang, Limei Ban, Liqin Okubo, Yoshiaki Kuehtreiber, Willem M. Leichliter, Ashley K. Faustman, Denise L. TI Novel Automated Blood Separations Validate Whole Cell Biomarkers SO PLOS ONE LA English DT Article ID PERIPHERAL-BLOOD; T-CELLS; LYMPHOCYTES; INHIBITORS AB Background: Progress in clinical trials in infectious disease, autoimmunity, and cancer is stymied by a dearth of successful whole cell biomarkers for peripheral blood lymphocytes (PBLs). Successful biomarkers could help to track drug effects at early time points in clinical trials to prevent costly trial failures late in development. One major obstacle is the inaccuracy of Ficoll density centrifugation, the decades-old method of separating PBLs from the abundant red blood cells (RBCs) of fresh blood samples. Methods and Findings: To replace the Ficoll method, we developed and studied a novel blood-based magnetic separation method. The magnetic method strikingly surpassed Ficoll in viability, purity and yield of PBLs. To reduce labor, we developed an automated platform and compared two magnet configurations for cell separations. These more accurate and labor-saving magnet configurations allowed the lymphocytes to be tested in bioassays for rare antigen-specific T cells. The automated method succeeded at identifying 79% of patients with the rare PBLs of interest as compared with Ficoll's uniform failure. We validated improved upfront blood processing and show accurate detection of rare antigen-specific lymphocytes. Conclusions: Improving, automating and standardizing lymphocyte detections from whole blood may facilitate development of new cell-based biomarkers for human diseases. Improved upfront blood processes may lead to broad improvements in monitoring early trial outcome measurements in human clinical trials. C1 [Burger, Douglas E.] Massachusetts Gen Hosp, Dept Med, Immunobiol Labs, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Burger, DE (reprint author), Massachusetts Gen Hosp, Dept Med, Immunobiol Labs, Charlestown, MA USA. EM faustman@helix.mgh.harvard.edu FU Iacocca Foundation; James Pendleton Charitable Trust; Friends United; Partnerships for Cure; National Institutes of Health (NIH) FX This work was supported by The Iacocca Foundation, James Pendleton Charitable Trust, Friends United, Partnerships for Cure, and 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 16 TC 3 Z9 3 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 JUL 22 PY 2011 VL 6 IS 7 AR e22430 DI 10.1371/journal.pone.0022430 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797BJ UT WOS:000293097300046 PM 21799852 ER PT J AU Woo, J Miletich, I Kim, BM Sharpe, PT Shivdasani, RA AF Woo, Janghee Miletich, Isabelle Kim, Byeong-Moo Sharpe, Paul T. Shivdasani, Ramesh A. TI Barx1-Mediated Inhibition of Wnt Signaling in the Mouse Thoracic Foregut Controls Tracheo-Esophageal Septation and Epithelial Differentiation SO PLOS ONE LA English DT Article ID ESOPHAGEAL ATRESIA; MULTIPLE ROLES; LUNG; MORPHOGENESIS; TRACHEA; STOMACH; BARX1; MECHANISMS; IDENTITY; PLAYERS AB Mesenchymal cells underlying the definitive endoderm in vertebrate animals play a vital role in digestive and respiratory organogenesis. Although several signaling pathways are implicated in foregut patterning and morphogenesis, and despite the clinical importance of congenital tracheal and esophageal malformations in humans, understanding of molecular mechanisms that allow a single tube to separate correctly into the trachea and esophagus is incomplete. The homoebox gene Barx1 is highly expressed in prospective stomach mesenchyme and required to specify this organ. We observed lower Barx1 expression extending contiguously from the proximal stomach domain, along the dorsal anterior foregut mesenchyme and in mesenchymal cells between the nascent esophagus and trachea. This expression pattern exactly mirrors the decline in Wnt signaling activity in late development of the adjacent dorsal foregut endoderm and medial mainstem bronchi. The hypopharynx in Barx1(-/-) mouse embryos is abnormally elongated and the point of esophagotracheal separation shows marked caudal displacement, resulting in a common foregut tube that is similar to human congenital tracheo-esophageal fistula and explains neonatal lethality. Moreover, the Barx1(-/-) esophagus displays molecular and cytologic features of respiratory endoderm, phenocopying abnormalities observed in mouse embryos with activated beta-catenin. The zone of canonical Wnt signaling is abnormally prolonged and expanded in the proximal Barx1(-/-) foregut. Thus, as in the developing stomach, but distinct from the spleen, Barx1 control of thoracic foregut specification and tracheo-esophageal septation is tightly associated with down-regulation of adjacent Wnt pathway activity. C1 [Woo, Janghee; Kim, Byeong-Moo; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Woo, Janghee] Harvard Univ, Grad Program Biol & Biomed Sci, Cambridge, MA 02138 USA. [Miletich, Isabelle; Sharpe, Paul T.] Kings Coll London, Dept Craniofacial Dev, Inst Dent, London WC2R 2LS, England. [Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA USA. RP Woo, J (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM ramesh_shivdasani@dfci.harvard.edu FU National Institutes of Health [R01DK081113]; Harvard Stem Cell Institute FX This work was supported by National Institutes of Health grant R01DK081113 (RAS) and a graduate fellowship from the Harvard Stem Cell Institute (JW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 16 Z9 16 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 22 PY 2011 VL 6 IS 7 AR e22493 DI 10.1371/journal.pone.0022493 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797BJ UT WOS:000293097300054 PM 21799872 ER PT J AU Liu, SZ Shiotani, B Lahiri, M Marechal, A Tse, A Leung, CCY Glover, JNM Yang, XHH Zou, L AF Liu, Shizhou Shiotani, Bunsyo Lahiri, Mayurika Marechal, Alexandre Tse, Alice Leung, Charles Chung Yun Glover, J. N. Mark Yang, Xiaohong H. Zou, Lee TI ATR Autophosphorylation as a Molecular Switch for Checkpoint Activation SO MOLECULAR CELL LA English DT Article ID DEPENDENT PROTEIN-KINASE; DOUBLE-STRAND BREAKS; DNA-DAMAGE CHECKPOINT; CHK1 ACTIVATION; BUDDING YEAST; CATALYTIC SUBUNIT; HUMAN RAD9; IN-VIVO; REPLICATION; PHOSPHORYLATION AB The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master checkpoint regulator safeguarding the genome. Upon DNA damage, the ATR-ATRIP complex is recruited to sites of DNA damage by RPA-coated single-stranded DNA and activated by an elusive process. Here, we show that ATR is transformed into a hyperphosphorylated state after DNA damage, and that a single autophosphorylation event at Thr 1989 is crucial for ATR activation. Phosphorylation of Thr 1989 relies on RPA, ATRIP, and ATR kinase activity, but unexpectedly not on the ATR stimulator TopBP1. Recruitment of ATR-ATRIP to RPA-ssDNA leads to congregation of ATR-ATRIP complexes and promotes Thr 1989 phosphorylation in trans. Phosphorylated Thr 1989 is directly recognized by TopBP1 via the BRCT domains 7 and 8, enabling TopBP1 to engage ATR-ATRIP, to stimulate the ATR kinase, and to facilitate ATR substrate recognition. Thus, ATR autophosphorylation on RPA-ssDNA is a molecular switch to launch robust checkpoint response. C1 [Liu, Shizhou; Shiotani, Bunsyo; Lahiri, Mayurika; Marechal, Alexandre; Tse, Alice; Yang, Xiaohong H.; Zou, Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Zou, Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Liu, Shizhou] China Med Univ, Affiliated Hosp 1, Dept Med Oncol, Shenyang 110001, Peoples R China. [Leung, Charles Chung Yun; Glover, J. N. Mark] Univ Alberta, Sch Mol & Syst Med, Dept Biochem, Edmonton, AB T6G 2H7, Canada. RP Zou, L (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM zou.lee@mgh.harvard.edu FU NIH [GM076388]; ACS [RSG-08-297]; Federal Share of MGH Proton Program FX We thank S. Elledge, A. Ciccia, J. Bartek, J. Lukas, D. Cortez, D. Chen, B. Chen, Q. Ge, and R. Polakiewicz for reagents; and members of the Zou lab for discussion. This work was supported by grants from NIH (GM076388), ACS (RSG-08-297), and the Federal Share of MGH Proton Program to L.Z. NR 61 TC 93 Z9 96 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 22 PY 2011 VL 43 IS 2 BP 192 EP 202 DI 10.1016/j.molcel.2011.06.019 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 797TG UT WOS:000293152400007 PM 21777809 ER PT J AU Soldner, F Laganiere, J Cheng, AW Hockemeyer, D Gao, Q Alagappan, R Khurana, V Golbe, LI Myers, RH Lindquist, S Zhang, L Guschin, D Fong, LK Vu, BJ Meng, XD Urnov, FD Rebar, EJ Gregory, PD Zhang, HS Jaenisch, R AF Soldner, Frank Laganiere, Josee Cheng, Albert W. Hockemeyer, Dirk Gao, Qing Alagappan, Raaji Khurana, Vikram Golbe, Lawrence I. Myers, Richard H. Lindquist, Susan Zhang, Lei Guschin, Dmitry Fong, Lauren K. Vu, B. Joseph Meng, Xiangdong Urnov, Fyodor D. Rebar, Edward J. Gregory, Philip D. Zhang, H. Steve Jaenisch, Rudolf TI Generation of Isogenic Pluripotent Stem Cells Differing Exclusively at Two Early Onset Parkinson Point Mutations SO CELL LA English DT Article ID ZINC-FINGER NUCLEASES; DOUBLE-STRAND BREAK; HUMAN SOMATIC-CELLS; COPY NUMBER; MAMMALIAN-CELLS; HUMAN ESCS; DISEASE; GENOME; PATIENT; REPAIR AB Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations. By combining zinc finger nuclease (ZFN)-mediated genome editing and iPSC technology, we provide a generally applicable solution to this problem, generating sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the a-synuclein gene. The robust capability to genetically correct disease-causing point mutations in patient-derived hiPSCs represents significant progress for basic biomedical research and an advance toward hiPSC-based cell replacement therapies. C1 [Soldner, Frank; Cheng, Albert W.; Hockemeyer, Dirk; Gao, Qing; Alagappan, Raaji; Khurana, Vikram; Lindquist, Susan; Jaenisch, Rudolf] Whitehead Inst, Cambridge, MA 02142 USA. [Lindquist, Susan; Jaenisch, Rudolf] MIT, Dept Biol, Cambridge, MA 02139 USA. [Cheng, Albert W.] MIT, Computat & Syst Biol Program, Cambridge, MA 02139 USA. [Laganiere, Josee; Zhang, Lei; Guschin, Dmitry; Fong, Lauren K.; Vu, B. Joseph; Meng, Xiangdong; Urnov, Fyodor D.; Rebar, Edward J.; Gregory, Philip D.; Zhang, H. Steve] Sangamo BioSci Inc, Pt Richmond Tech Ctr, Richmond, CA 94804 USA. [Khurana, Vikram] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Khurana, Vikram] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Myers, Richard H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Golbe, Lawrence I.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, New Brunswick, NJ 08903 USA. RP Jaenisch, R (reprint author), Whitehead Inst, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM jaenisch@wi.mit.edu OI Myers, Richard/0000-0002-8365-2674; Laganiere, Josee/0000-0003-0775-3331 FU NIH [R01-CA084198, R37-HD045022]; Howard Hughes Medical Institute FX We thank Ping Xu and Tenzin Lungjangwa for technical support and Jessica Dausman, Kibibi Ganz, Ruth Flannery, and Dongdong Fu for their help with animal husbandry and processing of teratomas. We would like to thank Tom Volkert and Jeong-Ah Kwon of the Whitehead Genome Technology Core for their help with the CNV analysis; Nicki Watson of the W.M. Keck Microscopy Facility for help with confocal microscopy; and Patti Wisniewski and Chad Araneo of the Whitehead Institute FACS facility for their help with cell sorting. We thank Gladys Dulay for construction of ZFN vectors and Elo Leung for computational analysis for the off-target study. We thank all of the members of the Jaenisch lab for helpful discussions and comments on the manuscript. R.J. was supported by NIH grants R01-CA084198 and R37-HD045022. This research was supported, in part, by a Collaborative Innovation Award from the Howard Hughes Medical Institute. R.J. is an adviser to Stemgent and a cofounder of Fate Therapeutics. D.H. is a Merck Fellow of the Life Sciences Research Foundation. J.L., L.K.F., L.Z., F.D.U., P.D.G., H.S.Z., D.J., B.J.V., X.M., and E.J.R. are full-time employees of Sangamo BioSciences, Inc. NR 48 TC 336 Z9 358 U1 7 U2 64 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 22 PY 2011 VL 146 IS 2 BP 318 EP 331 DI 10.1016/j.cell.2011.06.019 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 795XS UT WOS:000293013000013 PM 21757228 ER PT J AU Kroshinsky, D Stone, JH Nazarian, RM AF Kroshinsky, Daniela Stone, John H. Nazarian, Rosalynn M. TI Case 22-2011: A 79-Year-Old Man with a Rash, Arthritis, and Ocular Erythema SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPOCOMPLEMENTEMIC URTICARIAL VASCULITIS; CUTANEOUS LEUKOCYTOCLASTIC VASCULITIS; VALVULAR HEART-DISEASE; JACCOUDS ARTHROPATHY; SCLERITIS; LESIONS; ANCA C1 [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Stone, John H.] Massachusetts Gen Hosp, Dept Rheumatol, Boston, MA 02114 USA. [Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kroshinsky, Daniela] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Stone, John H.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Nazarian, Rosalynn M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Kroshinsky, D (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. OI Nazarian, Rosalynn/0000-0003-4003-7193 NR 21 TC 1 Z9 1 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 21 PY 2011 VL 365 IS 3 BP 252 EP 263 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 794QI UT WOS:000292915500011 PM 21774714 ER PT J AU Steensma, DP Stone, RM AF Steensma, David P. Stone, Richard M. TI Lenalidomide in AML: Del(5q) or who? SO BLOOD LA English DT Editorial Material ID ACUTE MYELOID-LEUKEMIA; OLDER; PATIENT C1 [Steensma, David P.; Stone, Richard M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. OI Steensma, David/0000-0001-5130-9284 NR 11 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 21 PY 2011 VL 118 IS 3 BP 481 EP 482 DI 10.1182/blood-2011-05-354324 PG 2 WC Hematology SC Hematology GA 795IG UT WOS:000292967300001 PM 21778344 ER PT J AU Jakubowiak, AJ Griffith, KA Reece, DE Hofmeister, CC Lonial, S Zimmerman, TM Campagnaro, EL Schlossman, RL Laubach, JP Raje, NS Anderson, T Mietzel, MA Harvey, CK Wear, SM Barrickman, JC Tendler, CL Esseltine, DL Kelley, SL Kaminski, MS Anderson, KC Richardson, PG AF Jakubowiak, Andrzej J. Griffith, Kent A. Reece, Donna E. Hofmeister, Craig C. Lonial, Sagar Zimmerman, Todd M. Campagnaro, Erica L. Schlossman, Robert L. Laubach, Jacob P. Raje, Noopur S. Anderson, Tara Mietzel, Melissa A. Harvey, Colleen K. Wear, Sandra M. Barrickman, Jennifer C. Tendler, Craig L. Esseltine, Dixie-Lee Kelley, Susan L. Kaminski, Mark S. Anderson, Kenneth C. Richardson, Paul G. TI Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial SO BLOOD LA English DT Article ID LATE-ONSET TOXICITIES; FRONT-LINE TREATMENT; MELPHALAN-PREDNISONE; THALIDOMIDE; CYCLOPHOSPHAMIDE; THERAPY; COMBINATION; INDUCTION AB This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (>= VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m(2), pegylated liposomal doxorubicin 30 mg/m(2), and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% >= VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568. (Blood. 2011;118(3):535-543) C1 [Jakubowiak, Andrzej J.; Griffith, Kent A.; Anderson, Tara; Mietzel, Melissa A.; Harvey, Colleen K.; Kaminski, Mark S.] Univ Michigan, Ann Arbor, MI 48109 USA. [Reece, Donna E.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Hofmeister, Craig C.] Ohio State Univ, Columbus, OH 43210 USA. [Lonial, Sagar; Zimmerman, Todd M.] Univ Chicago, Chicago, IL 60637 USA. [Campagnaro, Erica L.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Schlossman, Robert L.; Laubach, Jacob P.; Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Raje, Noopur S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wear, Sandra M.; Kelley, Susan L.] Multiple Myeloma Res Consortium, Norwalk, CT USA. [Barrickman, Jennifer C.] Celgene Corp, Summit, NJ USA. [Tendler, Craig L.] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ USA. [Esseltine, Dixie-Lee] Takeda Oncol Co, Millennium Pharmaceut, Cambridge, MA USA. RP Jakubowiak, AJ (reprint author), Univ Michigan, 1500 E Med Ctr Dr,Room 4216 Canc Ctr,SPC 5936, Ann Arbor, MI 48109 USA. EM ajakubow@umich.edu RI Hofmeister, Craig/E-3256-2011 OI Hofmeister, Craig/0000-0003-4816-1607 FU Celgene; Centocor Ortho Biotech Services; Millennium Pharmaceuticals; Multiple Myeloma Research Consortium; National Cancer Institute [K12CA133250]; Ortho Biotech; Celgene Corporation; BMS; Exelixis; Johnson Johnson; AstraZeneca; Acetylon FX This study was supported by Celgene, Centocor Ortho Biotech Services, Millennium Pharmaceuticals, and the Multiple Myeloma Research Consortium. C.C.H. is a Paul Calabresi scholar on grant K12CA133250 from the National Cancer Institute. The content is solely the responsibility of the authors and does not represent the official views of the National Cancer Institute or the National Institutes of Health. The authors received editorial support from Adriana Stan, PhD, of Excerpta Medica in the preparation of this manuscript, which was funded by Celgene. The authors are fully responsible for the content and editorial decisions for this manuscript.; A.J.J. is a consultant with Ortho Biotech, Celgene Corporation, Millennium Pharmaceuticals, Onyx Pharmaceuticals, BMS, and Exelixis; has received honoraria from Ortho Biotech, Celgene Corporation, Millennium Pharmaceuticals, BMS, and Exelixis (all of which were discontinued as of August 2010); is on the speakers' bureaus of Celgene, Ortho Biotech, and Millennium Pharmaceuticals (all of which were discontinued as of August 2010); and is on the advisory committee for Millennium Pharmaceuticals, BMS, and Onyx. D. E. R. has received research funding from Celgene Corporation, Johnson & Johnson, and Ortho Biotech; is on the advisory board of Celgene Corporation and Ortho Biotech; and has given unrestricted educational talks for Celgene Corporation and Ortho Biotech. S. L. is a consultant with Celgene Corporation, Millennium Pharmaceuticals, Novartis, BMS, and Onyx and is on the advisory board for Merck. T.M.Z. is a member of the board of directors, speakers' bureaus, or advisory committees for Celgene Corporation and Millennium Pharmaceuticals. N.S.R. is a consultant with Amgen, Celgene Corporation, and Novartis and has received research funding from AstraZeneca and Acetylon. T. A. is on the speakers' bureaus for Celgene Corporation and Millennium Pharmaceuticals. J.C.B. has ownership interest in and is an employee of Celgene Corporation. C. L. T. has ownership interest in Johnson & Johnson. D.-L.E. is employed by Millennium Pharmaceuticals and has ownership interest in Johnson & Johnson. S. L. K. is employed by the Multiple Myeloma Research Consortium. K. C. A. has ownership interest in Acetylon and is on the advisory boards of Celgene Corporation, Novartis, Millennium Pharmaceuticals, Onyx, BMS, and Merck. P. G. R. is on the advisory board of Millennium Pharmaceuticals, Celgene Corporation, Novartis, Johnson & Johnson, and BMS. K. A. G., C. C. H., E. L. C., R. L. S., J.P.L., M. A. M., C. K. H., S. M. W., and M. S. K. declare no competing financial interests. NR 38 TC 43 Z9 45 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 21 PY 2011 VL 118 IS 3 BP 535 EP 543 DI 10.1182/blood-2011-02-334755 PG 9 WC Hematology SC Hematology GA 795IG UT WOS:000292967300014 PM 21596852 ER PT J AU Meynard, D Vaja, V Sun, CC Corradini, E Chen, SZ Lopez-Otin, C Grgurevic, L Hong, CC Stirnberg, M Gutschow, M Vukicevic, S Babitt, JL Lin, HY AF Meynard, Delphine Vaja, Valentina Sun, Chia Chi Corradini, Elena Chen, Shanzhuo Lopez-Otin, Carlos Grgurevic, Lovorka Hong, Charles C. Stirnberg, Marit Guetschow, Michael Vukicevic, Slobodan Babitt, Jodie L. Lin, Herbert Y. TI Regulation of TMPRSS6 by BMP6 and iron in human cells and mice SO BLOOD LA English DT Article ID ANTIMICROBIAL PEPTIDE HEPCIDIN; PROTEASE MATRIPTASE-2 TMPRSS6; GENOME-WIDE ASSOCIATION; JUVENILE HEMOCHROMATOSIS; SIGNAL-TRANSDUCTION; ID PROTEINS; MOUSE-LIVER; EXPRESSION; BONE; GENE AB Mutations in transmembrane protease, serine 6 (TMPRSS6), encoding matriptase-2, are responsible for the familial anemia disorder iron-refractory iron deficiency anemia (IRIDA). Patients with IRIDA have inappropriately elevated levels of the iron regulatory hormone hepcidin, suggesting that TMPRSS6 is involved in negatively regulating hepcidin expression. Hepcidin is positively regulated by iron via the bone morphogenetic protein (BMP)-SMAD signaling pathway. In this study, we investigated whether BMP6 and iron also regulate TMPRSS6 expression. Here we demonstrate that, in vitro, treatment with BMP6 stimulates TMPRSS6 expression at the mRNA and protein levels and leads to an increase in matriptase-2 activity. Moreover, we identify that inhibitor of DNA binding 1 is the key element of the BMP-SMAD pathway to regulate TMPRSS6 expression in response to BMP6 treatment. Finally, we show that, in mice, Tmprss6 mRNA expression is stimulated by chronic iron treatment or BMP6 injection and is blocked by injection of neutralizing antibody against BMP6. Our results indicate that BMP6 and iron not only induce hepcidin expression but also induce TMPRSS6, a negative regulator of hepcidin expression. Modulation of TMPRSS6 expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels. (Blood. 2011;118(3):747-756) C1 [Meynard, Delphine; Vaja, Valentina; Sun, Chia Chi; Corradini, Elena; Chen, Shanzhuo; Babitt, Jodie L.; Lin, Herbert Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol,Div Nephrol,Ctr Syst Biol, Boston, MA 02114 USA. [Vaja, Valentina] Univ Milan, Fdn Ist Ricovero & Cura Carattere Sci Ca Granda, Milan, Italy. [Corradini, Elena] Univ Hosp Modena & Reggio Emilia, Ctr Hemochromatosis, Modena, Italy. [Lopez-Otin, Carlos] Univ Oviedo, Inst Univ Oncol, Dept Bioquim & Biol Mol, Oviedo, Spain. [Grgurevic, Lovorka; Vukicevic, Slobodan] Univ Zagreb, Sch Med, Lab Mineralized Tissues, Zagreb 41001, Croatia. [Hong, Charles C.] Vanderbilt Univ, Sch Med, Div Cardiovasc Med, Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. [Stirnberg, Marit; Guetschow, Michael] Univ Bonn, Inst Pharmazeut, D-5300 Bonn, Germany. RP Lin, HY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol,Div Nephrol,Ctr Syst Biol, 185 Cambridge St,CPZN 8216, Boston, MA 02114 USA. EM lin.herbert@mgh.harvard.edu RI meynard, delphine/B-4236-2014; Lopez-Otin, Carlos/C-6657-2013; Corradini, Elena/O-4167-2016 OI Lopez-Otin, Carlos/0000-0001-6964-1904; Corradini, Elena/0000-0001-9477-2164 FU Massachusetts General Hospital (MGH); Massachusetts Biomedical Research Corporation at Massachusetts General Hospital; National Institutes of Health [K08 DK075846, RO1 DK087727, RO1 DK-069533, RO1 DK-071837] FX D.M. was supported by the MGH Fund for Medical Discovery (Postdoctoral Fellowship Award). E. C. was supported in part by the Massachusetts Biomedical Research Corporation at Massachusetts General Hospital (Tosteson Postdoctoral Fellowship Awards). J.L.B. was supported in part by the National Institutes of Health (grants K08 DK075846 and RO1 DK087727) and the Massachusetts General Hospital (Claflin Distinguished Scholar Award). H.Y.L. was supported in part by the National Institutes of Health (grants RO1 DK-069533 and RO1 DK-071837). NR 52 TC 50 Z9 50 U1 1 U2 14 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 21 PY 2011 VL 118 IS 3 BP 747 EP 756 DI 10.1182/blood-2011-04-348698 PG 10 WC Hematology SC Hematology GA 795IG UT WOS:000292967300038 PM 21622652 ER PT J AU Chen, ACH Arany, PR Huang, YY Tomkinson, EM Sharma, SK Kharkwal, GB Saleem, T Mooney, D Yull, FE Blackwell, TS Hamblin, MR AF Chen, Aaron C-H Arany, Praveen R. Huang, Ying-Ying Tomkinson, Elizabeth M. Sharma, Sulbha K. Kharkwal, Gitika B. Saleem, Taimur Mooney, David Yull, Fiona E. Blackwell, Timothy S. Hamblin, Michael R. TI Low-Level Laser Therapy Activates NF-kB via Generation of Reactive Oxygen Species in Mouse Embryonic Fibroblasts SO PLOS ONE LA English DT Article ID CYTOCHROME-C-OXIDASE; KAPPA-B ACTIVATION; PROTEIN-KINASE-D; SIGNALING PATHWAY; TRANSCRIPTION FACTOR; INFRARED RADIATION; GENE-EXPRESSION; IR RADIATION; RED-LIGHT; CELLS AB Background: Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear. Methodology/Principal Findings: In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm(2) and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration. Conclusion: We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT. C1 [Chen, Aaron C-H; Arany, Praveen R.; Huang, Ying-Ying; Tomkinson, Elizabeth M.; Sharma, Sulbha K.; Kharkwal, Gitika B.; Saleem, Taimur; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Arany, Praveen R.] Harvard Univ, Program Leder Human Biol & Translat Med, Cambridge, MA 02138 USA. [Arany, Praveen R.] Harvard Univ, Program Biol Sci Dent Med, Cambridge, MA 02138 USA. [Arany, Praveen R.] Harvard Univ, Sch Dent Med, Program Oral & Maxillofacial Pathol, Boston, MA 02115 USA. [Arany, Praveen R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Arany, Praveen R.; Mooney, David; Hamblin, Michael R.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Huang, Ying-Ying; Kharkwal, Gitika B.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Huang, Ying-Ying] Guangxi Med Univ, Aesthet & Plast Ctr, Nanning, Peoples R China. [Tomkinson, Elizabeth M.] Smith Coll, Northampton, MA 01063 USA. [Saleem, Taimur] Aga Khan Med Coll, Karachi, Pakistan. [Yull, Fiona E.; Blackwell, Timothy S.] Vanderbilt Univ, Sch Med, Dept Med & Canc Biol, Nashville, TN 37212 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Chen, ACH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI Huang, Ying-ying/G-3153-2011; OI Huang, Ying-ying/0000-0003-3066-6981; Yull, Fiona/0000-0003-1636-7942; Hamblin, Michael/0000-0001-6431-4605 FU National Institutes of Health (NIH) [R01AI050875]; Center for Integration of Medicine and Innovative Technology [DAMD17-02-2-0006]; CDMRP Program in TBI [W81XWH-09-1-0514]; Air Force Office of Scientific Research [FA9950-04-1-0079] FX This work was supported by National Institutes of Health (NIH) grant R01AI050875, Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006), CDMRP Program in TBI (W81XWH-09-1-0514) and Air Force Office of Scientific Research (FA9950-04-1-0079). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 116 Z9 121 U1 3 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2011 VL 6 IS 7 AR e22453 DI 10.1371/journal.pone.0022453 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 795FA UT WOS:000292956800058 PM 21814580 ER PT J AU Roberts, DA Hansen, VN Thompson, MG Poludniowski, G Niven, A Seco, J Evans, PM AF Roberts, D. A. Hansen, V. N. Thompson, M. G. Poludniowski, G. Niven, A. Seco, J. Evans, P. M. TI Comparative study of a low-Z cone-beam computed tomography system SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MEGAVOLTAGE CT SCANNER; RADIATION-THERAPY; CARBON TARGET; IMAGE QUALITY; RADIOTHERAPY; VERIFICATION; LOCALIZATION; LINE AB Computed tomography images have been acquired using an experimental (low atomic number (Z) insert) megavoltage cone-beam imaging system. These images have been compared with standard megavoltage and kilovoltage imaging systems. The experimental system requires a simple modification to the 4 MeV electron beam from an Elekta Precise linac. Low-energy photons are produced in the standard medium-Z electron window and a low-Z carbon electron absorber located after the window. The carbon electron absorber produces photons as well as ensuring that all remaining electrons from the source are removed. A detector sensitive to diagnostic x-ray energies is also employed. Quantitative assessment of cone-beam computed tomography (CBCT) contrast shows that the low-Z imaging system is an order of magnitude or more superior to a standard 6 MV imaging system. CBCT data with the same contrast-to-noise ratio as a kilovoltage imaging system (0.15 cGy) can be obtained in doses of 11 and 244 cGy for the experimental and standard 6 MV systems, respectively. Whilst these doses are high for everyday imaging, qualitative images indicate that kilovoltage like images suitable for patient positioning can be acquired in radiation doses of 1-8 cGy with the experimental low-Z system. C1 [Roberts, D. A.; Hansen, V. N.; Poludniowski, G.; Evans, P. M.] Royal Marsden NHS Fdn Trust, Joint Dept Phys, Surrey, England. [Roberts, D. A.; Hansen, V. N.; Poludniowski, G.; Evans, P. M.] Royal Marsden NHS Fdn Trust, Inst Canc Res, Surrey, England. [Roberts, D. A.; Thompson, M. G.; Niven, A.] Elekta Ltd, Crawley, W Sussex, England. [Seco, J.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Roberts, DA (reprint author), Royal Marsden NHS Fdn Trust, Joint Dept Phys, Surrey, England. EM david.roberts@elekta.com RI Evans, Philip/A-6257-2009; Seco, Joao/J-4451-2012 FU Elekta Ltd; The Institute of Cancer Research; Cancer Research UK [C46/A3970] FX This work is supported by Elekta Ltd and The Institute of Cancer Research. Work of the ICR radiotherapy physics group is partially supported by Cancer Research UK under programme grant C46/A3970. We are grateful for information provided by Elekta Ltd and Perkin Elmer for the purposes of modelling the linac and detectors. We are extremely grateful to Kevin Brown, Craig Cummings, Alan Hitchings, Chris Knox, Andrew Lake, Clive Long, Abdul Sayeed and Nick Smith for component manufacture, the gating interface and for advice on various aspects of this project and paper. NR 26 TC 6 Z9 6 U1 0 U2 2 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 JUL 21 PY 2011 VL 56 IS 14 BP 4453 EP 4464 DI 10.1088/0031-9155/56/14/014 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 786JM UT WOS:000292303100015 PM 21719950 ER PT J AU Lakhashe, SK Wang, W Siddappa, NB Hemashettar, G Polacino, P Hu, SL Villinger, F Else, JG Novembre, FJ Yoon, JK Lee, SJ Montefiori, DC Ruprecht, RM Rasmussen, RA AF Lakhashe, Samir K. Wang, Wendy Siddappa, Nagadenahalli B. Hemashettar, Girish Polacino, Patricia Hu, Shiu-Lok Villinger, Francois Else, James G. Novembre, Francis J. Yoon, John K. Lee, Sandra J. Montefiori, David C. Ruprecht, Ruth M. Rasmussen, Robert A. TI Vaccination against Heterologous R5 Clade C SHIV: Prevention of Infection and Correlates of Protection SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELLS; RHESUS-MONKEYS; HIV-1 INFECTION; ANTIBODY ACTIVITIES; IMMUNE-RESPONSE; SOUTHERN AFRICA; SUBTYPE-C; NEUTRALIZATION; MACAQUES AB A safe, efficacious vaccine is required to stop the AIDS pandemic. Disappointing results from the STEP trial implied a need to include humoral anti-HIV-1 responses, a notion supported by RV144 trial data even though correlates of protection are unknown. We vaccinated rhesus macaques with recombinant simian immunodeficiency virus (SIV) Gag-Pol particles, HIV-1 Tat and trimeric clade C (HIV-C) gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a simian-human immunodeficiency virus (SHIV) that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all controls became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time. C1 [Lakhashe, Samir K.; Wang, Wendy; Siddappa, Nagadenahalli B.; Hemashettar, Girish; Yoon, John K.; Lee, Sandra J.; Ruprecht, Ruth M.; Rasmussen, Robert A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lakhashe, Samir K.; Siddappa, Nagadenahalli B.; Lee, Sandra J.; Ruprecht, Ruth M.; Rasmussen, Robert A.] Harvard Univ, Sch Med, Boston, MA USA. [Polacino, Patricia; Hu, Shiu-Lok] Univ Washington, Seattle, WA 98195 USA. [Villinger, Francois; Else, James G.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Novembre, Francis J.] Emory Univ, Sch Med, Dept Microbiol, Atlanta, GA USA. [Villinger, Francois; Else, James G.; Novembre, Francis J.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Montefiori, David C.] Duke Univ, Durham, NC USA. RP Lakhashe, SK (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM ruth_ruprecht@dfci.harvard.edu RI Lakhashe, Samir/F-1150-2014; Hu, Shiu-Lok/A-3196-2008; OI Hu, Shiu-Lok/0000-0003-4336-7964; Byrareddy, Siddappa /0000-0002-7423-1763 FU National Institutes of Health [PO1 AI048240]; [RR-00165] FX This work was supported by National Institutes of Health grant PO1 AI048240 to RMR, SLH, RAR and JLE. Base grant RR-00165 provided support to the Yerkes National Primate Research Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 18 Z9 18 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 JUL 20 PY 2011 VL 6 IS 7 AR e22010 DI 10.1371/journal.pone.0022010 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794WE UT WOS:000292931200020 PM 21799765 ER PT J AU Hayakawa, K Pham, LDD Som, AT Lee, BJ Guo, SZ Lo, EH Arai, K AF Hayakawa, Kazuhide Pham, Loc-Duyen D. Som, Angel T. Lee, Brian J. Guo, Shuzhen Lo, Eng H. Arai, Ken TI Vascular Endothelial Growth Factor Regulates the Migration of Oligodendrocyte Precursor Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BLOOD-BRAIN-BARRIER; IN-VITRO; NERVOUS-SYSTEM; VEGF; ANGIOGENESIS; NEURONS; NEURODEGENERATION; NEUROPROTECTION; PROLIFERATION; NEUROGENESIS AB Originally identified as an angiogenic factor, vascular endothelial growth factor (VEGF-A) is now known to play multiple roles in the CNS, including the direct regulation of neuronal and astrocytic functions. Here, we ask whether VEGF-A can also have a novel role in white matter by modulating oligodendrocyte precursor cells (OPCs). OPCs were cultured from rat neonatal cortex. Expression of VEGF-receptor2/KDR/Flk-1 was confirmed with Western blot and immunostaining. VEGF-A did not affect proliferation or differentiation in OPC cultures, but VEGF-A promoted OPC migration in a concentration-dependent manner. Consistent with this migration phenotype, VEGF-A-treated OPCs showed reorganization of actin cytoskeleton in leading-edge processes. VEGF-A-induced migration and actin reorganization were inhibited by an anti-Flk-1 receptor-blocking antibody. Mechanistically, VEGF-A induced binding of focal adhesion kinase (FAK) with paxillin. The FAK inhibitor PF573228 reduced VEGF-A-induced OPC migration. VEGF-A signaling also evoked a transient rise in reactive oxygen species (ROS), and OPC migration was increased when antioxidants were removed from the culture media. Our findings demonstrate that VEGF-A can induce OPC migration via an ROS- and FAK-dependent mechanism, and suggest a novel role for VEGF-A in white-matter maintenance and homeostasis. C1 [Arai, Ken] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Arai, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, MGH E 149-2401, Charlestown, MA 02129 USA. EM Lo@helix.mgh.harvard.edu; Karai@partners.org FU Deane Foundation; American Heart Association; NIH FX This work was supported by the Deane Foundation, American Heart Association, and NIH. NR 32 TC 42 Z9 42 U1 0 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 20 PY 2011 VL 31 IS 29 BP 10666 EP 10670 DI 10.1523/JNEUROSCI.1944-11.2011 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 794SH UT WOS:000292921100024 PM 21775609 ER PT J AU Guo, J Si, L Kong, Y Flaherty, KT Xu, XW Zhu, YY Corless, CL Li, L Li, HF Sheng, XN Cui, CL Chi, ZH Li, SM Han, M Mao, LL Lin, XD Du, N Zhang, XS Li, JL Wang, BC Qin, SK AF Guo, Jun Si, Lu Kong, Yan Flaherty, Keith T. Xu, Xiaowei Zhu, Yanyan Corless, Christopher L. Li, Li Li, Haifu Sheng, Xinan Cui, Chuanliang Chi, Zhihong Li, Siming Han, Mei Mao, Lili Lin, Xuede Du, Nan Zhang, Xiaoshi Li, Junling Wang, Baocheng Qin, Shukui TI Phase II, Open-Label, Single-Arm Trial of Imatinib Mesylate in Patients With Metastatic Melanoma Harboring c-Kit Mutation or Amplification SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; PROGNOSTIC-FACTORS; CLINICAL-EFFICACY; TYROSINE KINASE; HONG-KONG; THERAPY; SAFETY; ACTIVATION AB Purpose Melanomas harbor aberrations in the c-Kit gene. We tested the efficiency of the tyrosine kinase inhibitor imatinib in selected patients with metastatic melanoma harboring c-Kit mutations or amplifications. Patients and Methods Forty-three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial. Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or disease progression occurred. Fifteen patients who experienced progression of disease were allowed to escalate the dose to 800 mg/d. Results Forty-three patients were eligible for evaluation, and the median follow-up time was 12.0 months. The median progression-free survival (PFS) was 3.5 months, and the 6-month PFS rate was 36.6%. Rate of total disease control was 53.5%: 10 patients (23.3%; 95% CI, 10.2% to 36.4%) and 13 patients (30.2%; 95% CI, 16.0% to 44.4%) achieved partial response (PR) and stable disease (SD), respectively. Eighteen patients (41.9%) demonstrated regression of tumor mass. Notably, nine of the 10 PRs were observed in patients with mutations in exons 11 or 13. The 1-year overall survival (OS) rate was 51.0%. The median PFS and OS times for patients who had PR or SD versus disease progression were 9.0 months versus 1.5 months (P < .001) and 15.0 months versus 9.0 months (P = .036), respectively. Imatinib 400 mg/d was well tolerated, and only one of the 15 patients who received dose escalation to 800 mg/d achieved SD. Conclusion Imatinib demonstrated significant activity in patients with metastatic melanoma harboring genetic c-Kit aberrations, with an overall response rate of 23.3%. Escalation to 800 mg/d could not restore disease control. J Clin Oncol 29:2904-2909. (C) 2011 by American Society of Clinical Oncology C1 [Guo, Jun] Peking Univ, Dept Renal Canc & Melanoma, Key Lab Carcinogenesis & Translat Res, Minist Educ,Canc Hosp & Inst, Beijing 100142, Peoples R China. [Du, Nan] Chinese Peoples Liberat Army Postgrad Med Sch, Affiliated Hosp 1, Beijing, Peoples R China. [Li, Junling] Chinese Acad Med Sci, Canc Inst & Hosp, Beijing 100730, Peoples R China. [Lin, Xuede] Fujian Med Univ, Affiliated Hosp 1, Fuzhou, Fujian, Peoples R China. [Zhang, Xiaoshi] Sun Yat Sen Univ, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China. [Wang, Baocheng] Gen Hosp Jinan Mil Reg, Jinan, Peoples R China. [Qin, Shukui] 81 Hosp Peoples Liberat Army, Peoples Liberat Army Canc Ctr, Nanjing, Peoples R China. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Xu, Xiaowei] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Corless, Christopher L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Guo, J (reprint author), Peking Univ, Dept Renal Canc & Melanoma, Key Lab Carcinogenesis & Translat Res, Minist Educ,Canc Hosp & Inst, 52 Fucheng Rd, Beijing 100142, Peoples R China. EM guoj307@126.com FU Novartis; Program for New Century Excellent Talents in University [985-2-085-113]; National Natural Science Foundation of China [30973483]; Novartis Oncology in China [CSTI571BCN18T] FX Research Funding: Christopher L. Corless, Novartis; Supported by grants No. 985-2-085-113 from the Program for New Century Excellent Talents in University, No. 30973483 from the National Natural Science Foundation of China, and No. CSTI571BCN18T from Novartis Oncology in China. NR 34 TC 242 Z9 262 U1 3 U2 20 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2011 VL 29 IS 21 BP 2904 EP 2909 DI 10.1200/JCO.2010.33.9275 PG 6 WC Oncology SC Oncology GA 793KF UT WOS:000292819700020 PM 21690468 ER PT J AU Zhao, W Varghese, M Yemul, S Pan, Y Cheng, A Marano, P Hassan, S Vempati, P Chen, F Qian, XJ Pasinetti, GM AF Zhao, Wei Varghese, Merina Yemul, Shrishailam Pan, Yong Cheng, Alice Marano, Paul Hassan, Sadiq Vempati, Prashant Chen, Fei Qian, Xianjuan Pasinetti, Giulio M. TI Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1 alpha) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis SO MOLECULAR NEURODEGENERATION LA English DT Article ID NEURON DEGENERATION; TRANSGENIC MICE; MITOCHONDRIAL DYSFUNCTION; 3-NITROPROPIONIC ACID; HUNTINGTONS-DISEASE; AXONAL-TRANSPORT; PROTEIN-KINASE; ALS; NEURODEGENERATION; INHIBITION AB Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) is a principal regulator of mitochondrial biogenesis and oxidative metabolism. Results: In this study, we examined whether PGC-1 alpha plays a protective role in ALS by using a double transgenic mouse model where PGC-1 alpha is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1 alpha). Our results indicate that PGC-1 alpha significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord. Conclusion: Our results demonstrate that PGC-1 alpha plays a beneficial role in a mouse model of ALS, suggesting that PGC-1 alpha may be a potential therapeutic target for ALS therapy. C1 [Zhao, Wei; Varghese, Merina; Yemul, Shrishailam; Pan, Yong; Cheng, Alice; Marano, Paul; Hassan, Sadiq; Vempati, Prashant; Chen, Fei; Qian, Xianjuan; Pasinetti, Giulio M.] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Zhao, Wei; Varghese, Merina; Yemul, Shrishailam; Pan, Yong; Cheng, Alice; Vempati, Prashant; Chen, Fei; Qian, Xianjuan; Pasinetti, Giulio M.] James J Peters Vet Affairs Med Ctr, GRECC, Bronx, NY 10468 USA. RP Pasinetti, GM (reprint author), Mt Sinai Sch Med, Dept Neurol, New York, NY USA. EM giulio.pasinetti@mssm.edu NR 34 TC 47 Z9 47 U1 2 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD JUL 19 PY 2011 VL 6 AR 51 DI 10.1186/1750-1326-6-51 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 808AB UT WOS:000293943800001 PM 21771318 ER PT J AU Kwon, S Dong, ZM Wu, PC AF Kwon, Steve Dong, Zhao Ming Wu, Peter C. TI Sentinel lymph node biopsy for high-risk cutaneous squamous cell carcinoma: clinical experience and review of literature SO WORLD JOURNAL OF SURGICAL ONCOLOGY LA English DT Review DE sentinel lymph node; squamous cell carcinoma; cutaneous; staging ID EARLY-STAGE MELANOMA; EPIDERMOLYSIS-BULLOSA; PROGNOSTIC-FACTORS; MULTICENTER TRIAL; BREAST-CANCER; SKIN; LYMPHADENECTOMY; VALIDATION; NECK; DISSECTION AB High-risk cutaneous squamous cell carcinoma (SCC) is associated with an increased risk of metastases. The role of sentinel lymph node (SLN) biopsy in these patients remains unclear. To address this uncertainty, we collected clinical data on six patients with clinical N0 high-risk SCC that underwent SLN biopsy between 1999 and 2006 and performed a literature review of SLN procedures for SCC to study the utility of SLN biopsy. There were no positive SLN identified among six cases and there was one local and one distant recurrence on follow-up. Literature review identified 130 reported cases of SLN biopsy for SCC. The SLN positivity rate was 14.1%, 10.1%, and 18.6%; false negative rate was 15.4%, 0%, and 22.2%; and the negative predictive value was 97.8%, 100%, and 95.2% for all sites, head/neck, and truncal/extremity sites, respectively. SLN biopsy remains an investigational staging tool in clinically node-negative high-risk SCC patients. The higher false negative rate and lower negative predictive value among SCC of the trunk/extremity compared to SCC of the head/neck sites suggests a more cautious approach when treating patients with the former. Given the paucity of long-term follow up, an emphasis is placed upon the need for close surveillance regardless of SLN status. C1 [Kwon, Steve; Wu, Peter C.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Dong, Zhao Ming] VA Puget Sound Hlth Care Syst, Dept Pathol, Seattle, WA USA. [Wu, Peter C.] VA Puget Sound Hlth Care Syst, Dept Surg, Seattle, WA USA. RP Wu, PC (reprint author), Univ Washington, Dept Surg, Seattle, WA 98195 USA. EM pcwu@uw.edu NR 40 TC 25 Z9 27 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7819 J9 WORLD J SURG ONCOL JI World J. Surg. Oncol. PD JUL 19 PY 2011 VL 9 AR 80 DI 10.1186/1477-7819-9-80 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA 808HB UT WOS:000293967200002 PM 21771334 ER PT J AU Lee, J Hirsh, AS Wittner, BS Maeder, ML Singavarapu, R Lang, M Janarthanan, S McDermott, U Yajnik, V Ramaswamy, S Joung, JK Sgroi, DC AF Lee, Jeongeun Hirsh, Andrew S. Wittner, Ben S. Maeder, Morgan L. Singavarapu, Rajasekhar Lang, Magdalena Janarthanan, Sailajah McDermott, Ultan Yajnik, Vijay Ramaswamy, Sridhar Joung, J. Keith Sgroi, Dennis C. TI Induction of Stable Drug Resistance in Human Breast Cancer Cells Using a Combinatorial Zinc Finger Transcription Factor Library SO PLOS ONE LA English DT Article ID ESTROGEN-RECEPTOR EXPRESSION; GENE-EXPRESSION; PHENOTYPIC ALTERATION; INCREASE PRODUCTION; DNA RECOGNITION; HUMAN GENOME; TAMOXIFEN; IDENTIFICATION; PROFILES; PROTEINS AB Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs) provide a robust tool for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to fulvestrant, a clinically important anti-endocrine therapeutic agent. From a diverse collection of nearly 400,000 different ZF-TFs, we isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor-positive breast cancer cell lines. Comparative gene expression profile analysis of the six different ZF-TF-transduced breast cancer cell lines revealed five distinct clusters of differentially expressed genes. One cluster was shared among all 6 ZF-TF-transduced cell lines and therefore constituted a common fulvestrant-resistant gene expression signature. Pathway enrichment-analysis of this common fulvestrant resistant signature also revealed significant overlap with gene sets associated with an estrogen receptor-negative-like state and with gene sets associated with drug resistance to different classes of breast cancer anti-endocrine therapeutic agents. Enrichment-analysis of the four remaining unique gene clusters revealed overlap with myb-regulated genes. Finally, we also demonstrated that the common fulvestrant-resistant signature is associated with poor prognosis by interrogating five independent, publicly available human breast cancer gene expression datasets. Our results demonstrate that artificial ZF-TF libraries can be used successfully to induce stable drug-resistance in human cancer cell lines and to identify a gene expression signature that is associated with a clinically relevant drug-resistance phenotype. C1 [Lee, Jeongeun; Hirsh, Andrew S.; Maeder, Morgan L.; Singavarapu, Rajasekhar; Lang, Magdalena; Joung, J. Keith; Sgroi, Dennis C.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Lee, Jeongeun; Hirsh, Andrew S.; Wittner, Ben S.; Maeder, Morgan L.; Singavarapu, Rajasekhar; Lang, Magdalena; Ramaswamy, Sridhar; Joung, J. Keith; Sgroi, Dennis C.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Hirsh, Andrew S.; Maeder, Morgan L.; Lang, Magdalena; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Lee, Jeongeun; Hirsh, Andrew S.; Singavarapu, Rajasekhar; Lang, Magdalena; Joung, J. Keith; Sgroi, Dennis C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Wittner, Ben S.; Ramaswamy, Sridhar] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Janarthanan, Sailajah; Yajnik, Vijay] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [McDermott, Ultan] Genome Res Ltd, Wellcome Trust Sanger Inst, Hinxton, England. RP Lee, J (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. EM jjoung@partners.org; dsgroi@partners.org OI McDermott, Ultan/0000-0001-9032-4700 FU National Institutes of Health (NIH) [R01-CA112021, R01 GM069906, T32 CA009216]; Department of Defense [W81XWH-062-033]; AstraZeneca Inc.; Avon Foundation FX This study was supported by National Institutes of Health (NIH) R01-CA112021 (D. C. S.), the Department of Defense Breast Cancer Research Program grant W81XWH-062-033 (D. C. S.), NIH R01 GM069906 (J.K.J.), AstraZeneca Inc. (D. C. S. and J.K.J.), and the Avon Foundation (D. C. S.). A. S. H. was supported by NIH T32 CA009216. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 7 Z9 7 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 JUL 19 PY 2011 VL 6 IS 7 AR e21112 DI 10.1371/journal.pone.0021112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794VN UT WOS:000292929500003 PM 21818254 ER PT J AU Abrams, TE Vaughan-Sarrazin, M Fan, VS Kaboli, PJ AF Abrams, Thad E. Vaughan-Sarrazin, Mary Fan, Vincent S. Kaboli, Peter J. TI Geographic Isolation and the Risk for Chronic Obstructive Pulmonary Disease-Related Mortality SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; QUALITY-OF-LIFE; HOSPITAL MORTALITY; 30-DAY MORTALITY; FUEL COMBUSTION; HEART-FAILURE; BIOMASS SMOKE; HEALTH; VETERANS; CARE AB Background: Little is known about the possible differences in outcomes between patients with chronic obstructive pulmonary disease (COPD) who live in rural areas and those who live in urban areas of the United States. Objective: To determine whether COPD-related mortality is higher in persons living in rural areas, and to assess whether hospital characteristics influence any observed associations. Design: Retrospective cohort study. Setting: 129 acute care Veterans Affairs hospitals. Patients: Hospitalized patients with a COPD exacerbation. Measurements: Patient rurality (primary exposure); 30-day mortality (primary outcome); and hospital volume and hospital rurality, defined as the mean proportion of hospital admissions coming from rural areas (secondary exposures). Results: 18 809 patients (71% of the study population) lived in urban areas, 5671 (21%) in rural areas, and 1919 (7%) in isolated rural areas. Mortality was increased in patients living in isolated rural areas compared with urban areas (5.0% vs. 3.8%; P = 0.002). The increase in mortality associated with living in an isolated rural area persisted after adjustment for patient characteristics and hospital rurality and volume (odds ratio [OR], 1.42 [95% CI, 1.07 to 1.89]; P = 0.016). Adjusted mortality did not seem to be higher in patients living in nonisolated rural areas (OR, 1.09 [CI, 0.90 to 1.32]; P = 0.47). Results were unchanged in analyses assessing the influence of an omitted confounder on estimates. Limitations: The study population was limited to mostly male inpatients who were veterans. Results were based on administrative data. Conclusion: Patients with COPD living in isolated rural areas of the United States seem to be at greater risk for COPD exacerbation-related mortality than those living in urban areas, independent of hospital rurality and volume. Mortality was not increased for patients living in nonisolated rural areas. C1 [Abrams, Thad E.] Iowa City Vet Affairs Healthcare Syst, Vet Rural Hlth Resource Center Cent Reg, Ctr Comprehens Access & Delivery Res & Evaluat, Iowa City Vet Affairs Med Ctr,Vet Hlth Adm Off Ru, Iowa City, IA 52246 USA. Univ Iowa, Iowa City, IA USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. Univ Washington, Seattle, WA 98195 USA. RP Abrams, TE (reprint author), Iowa City Vet Affairs Healthcare Syst, Vet Rural Hlth Resource Center Cent Reg, Ctr Comprehens Access & Delivery Res & Evaluat, Iowa City Vet Affairs Med Ctr,Vet Hlth Adm Off Ru, 601 Highway 6 W,Mailstop 152, Iowa City, IA 52246 USA. EM Thad-Abrams@va.gov FU Veterans Health Administration Office of Rural Health; Veterans Rural Health Resource Center-Central Region; Health Services Research and Development Service through the Center for Comprehensive Access and Delivery Research and Evaluation at the Iowa City Veterans Affairs Healthcare System, U. S. Department of Veterans Affairs [HFP 04-149] FX By the Veterans Health Administration Office of Rural Health, Veterans Rural Health Resource Center-Central Region, and the Health Services Research and Development Service, through the Center for Comprehensive Access and Delivery Research and Evaluation at the Iowa City Veterans Affairs Healthcare System, U. S. Department of Veterans Affairs (grant HFP 04-149). NR 0 TC 14 Z9 14 U1 0 U2 6 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 JUL 19 PY 2011 VL 155 IS 2 BP 80 EP + DI 10.7326/0003-4819-155-2-201107190-00003 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 793KW UT WOS:000292822000014 PM 21768581 ER PT J AU Williams, BA Sudore, RL Greifinger, R Morrison, RS AF Williams, Brie A. Sudore, Rebecca L. Greifinger, Robert Morrison, R. Sean TI Balancing Punishment and Compassion for Seriously III Prisoners SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID PALLIATIVE CARE; LIFE; DISABILITY; END AB Compassionate release is a program that allows some eligible, seriously ill prisoners to die outside of prison before sentence completion. It became a matter of federal statute in 1984 and has been adopted by most U. S. prison jurisdictions. Incarceration is justified on 4 principles: retribution, rehabilitation, deterrence, and incapacitation. Compassionate release derives from the theory that changes in health status may affect these principles and thus alter justification for incarceration and sentence completion. The medical profession is intricately involved in this process because eligibility for consideration for compassionate release is generally based on medical evidence. Many policy experts are calling for broader use of compassionate release because of many factors, such as an aging prison population, overcrowding, the increasing deaths in custody, and the soaring medical costs of the criminal justice system. Even so, the medical eligibility criteria of many compassionate-release guidelines-which often assume a definitive prognosis-are clinically flawed, and procedural barriers may further limit their rational application. We propose changes to address these flaws. C1 [Williams, Brie A.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA USA. CUNY, Mt Sinai Sch Med, John Jay Coll Criminal Justice, New York, NY 10021 USA. Natl Palliat Care Res Ctr, New York, NY USA. James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Williams, BA (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St,Box 181-G, San Francisco, CA 94121 USA. EM brie.williams@ucsf.edu FU Brookdale Leadership in Aging Fellowship; National Institute on Aging [K23AG033102, K24 AG022345]; National Palliative Care Research Center; Pfizer FX By a grant from the Brookdale Leadership in Aging Fellowship and the National Institute on Aging (K23AG033102) (Dr. Williams), from Mid-Career-Investigator Award in Patient-Oriented Research from the National Institute on Aging (K24 AG022345) and the National Palliative Care Research Center (Dr. Morrison), and a Pfizer Fellowship in Clear Health Communication (Dr. Sudore). NR 0 TC 12 Z9 12 U1 4 U2 18 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 JUL 19 PY 2011 VL 155 IS 2 BP 122 EP 126 DI 10.7326/0003-4819-155-2-201107190-00348 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 793KW UT WOS:000292822000019 PM 21628351 ER PT J AU Fang, MC Go, AS Chang, YC Borowsky, LH Pomernacki, NK Udaltsova, N Singer, DE AF Fang, Margaret C. Go, Alan S. Chang, Yuchiao Borowsky, Leila H. Pomernacki, Niela K. Udaltsova, Natalia Singer, Daniel E. CA ATRIA Anticoagulation Risk Factors TI A New Risk Scheme to Predict Warfarin-Associated Hemorrhage The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE anticoagulants; atrial fibrillation; hemorrhage; risk prediction; warfarin ID VENOUS THROMBOEMBOLISM; STROKE PREVENTION; THERAPY; REGISTRY AB Objectives The purpose of this study was to develop a risk stratification score to predict warfarin-associated hemorrhage. Background Optimal decision making regarding warfarin use for atrial fibrillation requires estimation of hemorrhage risk. Methods We followed up 9,186 patients with atrial fibrillation contributing 32,888 person-years of follow-up on warfarin, obtaining data from clinical databases and validating hemorrhage events using medical record review. We used Cox regression models to develop a hemorrhage risk stratification score, selecting candidate variables using bootstrapping approaches. The final model was internally validated by split-sample testing and compared with 6 published hemorrhage risk schemes. Results We observed 461 first major hemorrhages during follow-up (1.4% annually). Five independent variables were included in the final model and weighted by regression coefficients: anemia (3 points), severe renal disease (e. g., glomerular filtration rate <30 ml/min or dialysis-dependent, 3 points), age >= 75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Major hemorrhage rates ranged from 0.4% (0 points) to 17.3% per year (10 points). Collapsed into a 3-category risk score, major hemorrhage rates were 0.8% for low risk (0 to 3 points), 2.6% for intermediate risk (4 points), and 5.8% for high risk (5 to 10 points). The c-index for the continuous risk score was 0.74 and 0.69 for the 3-category score, higher than in the other risk schemes. There was net reclassification improvement versus all 6 comparators (from 27% to 56%). Conclusions A simple 5-variable risk score was effective in quantifying the risk of warfarin-associated hemorrhage in a large community-based cohort of patients with atrial fibrillation. (J Am Coll Cardiol 2011;58:395-401) (C) 2011 by the American College of Cardiology Foundation C1 [Fang, Margaret C.] Univ Calif San Francisco, Div Hosp Med, Dept Med, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Go, Alan S.; Pomernacki, Niela K.; Udaltsova, Natalia] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Chang, Yuchiao; Borowsky, Leila H.; Singer, Daniel E.] Massachusetts Gen Hosp, Clin Epidemiol Unit, Boston, MA 02114 USA. RP Fang, MC (reprint author), Univ Calif San Francisco, Div Hosp Med, Dept Med, 505 Parnassus Ave,Box 0131, San Francisco, CA 94143 USA. EM mfang@medicine.ucsf.edu RI 刘, 李陆/H-8469-2015 FU National Institute on Aging [R01 AG15478, K23 AG028978]; National Heart, Lung, and Blood Institute [U19 HL91179, RC2HL101589]; Massachusetts General Hospital (Boston, Massachusetts); Daiichi Sankyo, Inc.; Johnson Johnson, Inc. FX This study was supported by the National Institute on Aging (R01 AG15478 and K23 AG028978), the National Heart, Lung, and Blood Institute (U19 HL91179 and RC2HL101589), the Eliot B. and Edith C. Shoolman Fund of the Massachusetts General Hospital (Boston, Massachusetts), and a research grant from Daiichi Sankyo, Inc. The funding sources had no role in study design, data collection, data analysis, data interpretation, or preparation of this paper. Dr. Go has received research support from Johnson & Johnson, Inc. Dr. Singer has consulted for Boehringer Ingelheim, Daiichi Sankyo, Inc., Johnson & Johnson, Inc., Merck and Co., Bayer Schering Pharma, and Sanofi-Aventis, Inc., and has received research support from Daiichi Sankyo, Inc. All other authors have reported that they have no relationships to disclose. NR 18 TC 283 Z9 286 U1 1 U2 9 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 JUL 19 PY 2011 VL 58 IS 4 BP 395 EP 401 DI 10.1016/j.jacc.2011.03.031 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 791RF UT WOS:000292681600009 PM 21757117 ER PT J AU Ardissino, D Berzuini, C Merlini, PA Mannucci, PM Surti, A Burtt, N Voight, B Tubaro, M Peyvandi, F Spreafico, M Celli, P Lina, D Notarangelo, MF Ferrario, M Fetiveau, R Casari, G Galli, M Ribichini, F Rossi, ML Bernardi, F Marziliano, N Zonzin, P Mauri, F Piazza, A Foco, L Bernardinelli, L Altshuler, D Kathiresan, S AF Ardissino, Diego Berzuini, Carlo Merlini, Piera Angelica Mannucci, Pier Mannuccio Surti, Aarti Burtt, Noel Voight, Benjamin Tubaro, Marco Peyvandi, Flora Spreafico, Marta Celli, Patrizia Lina, Daniela Notarangelo, Maria Francesca Ferrario, Maurizio Fetiveau, Raffaela Casari, Giorgio Galli, Michele Ribichini, Flavio Rossi, Marco L. Bernardi, Francesco Marziliano, Nicola Zonzin, Pietro Mauri, Francesco Piazza, Alberto Foco, Luisa Bernardinelli, Luisa Altshuler, David Kathiresan, Sekar CA Italian Atherosclerosis Thrombosis TI Influence of 9p21.3 Genetic Variants on Clinical and Angiographic Outcomes in Early-Onset Myocardial Infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE early-onset myocardial infarction; outcomes; rs1333040; 9p21.3 genetic variants ID CORONARY-ARTERY-DISEASE; CHROMOSOME 9P21; HEART-DISEASE; 4 SNPS; ASSOCIATION; LOCUS; SUSCEPTIBILITY; POPULATION; METAANALYSIS; REPLICATION AB Objectives The purpose of this study was to test whether the 9p21.3 variant rs1333040 influences the occurrence of new cardiovascular events and coronary atherosclerosis progression after early-onset myocardial infarction. Background 9p21.3 genetic variants are associated with ischemic heart disease, but it is not known whether they influence prognosis after an acute coronary event. Methods Within the Italian Genetic Study of Early-onset Myocardial Infarction, we genotyped rs1333040 in 1,508 patients hospitalized for a first myocardial infarction before the age of 45 years who underwent coronary angiography without index event coronary revascularization. They were followed up for major cardiovascular events and angiographic coronary atherosclerosis progression. Results Over 16,599 person-years, there were 683 cardiovascular events and 492 primary endpoints: 77 cardiovascular deaths, 223 reoccurrences of myocardial infarction, and 383 coronary artery revascularizations. The rs1333040 genotype had a significant influence (p = 0.01) on the primary endpoint, with an adjusted hazard ratio of 1.19 (95% confidence interval [CI]: 1.08 to 1.37) for heterozygous carriers and 1.41 (95% CI: 1.06 to 1.87) for homozygous carriers. Analysis of the individual components of the primary endpoints provided no significant evidence that the rs1333040 genotype influenced the hazard of cardiovascular death (p = 0.24) or the reoccurrence of myocardial infarction (p = 0.57), but did provide significant evidence that it influenced on the hazard of coronary revascularization, with adjusted heterozygous and homozygous ratios of 1.38 (95% CI: 1.17 to 1.63) and 1.90 (95% CI: 1.36 to 2.65) (p = 0.00015), respectively. It also significantly influenced the angiographic endpoint of coronary atherosclerosis progression (p = 0.002). Conclusions In early-onset myocardial infarction, the 9p21.3 variant rs1333040 affects the progression of coronary atherosclerosis and the probability of coronary artery revascularization during long-term follow-up. (J Am Coll Cardiol 2011;58:426-34) (C) 2011 by the American College of Cardiology Foundation C1 [Ardissino, Diego] Univ Parma, Azienda Osped, Unita Operat Cardiol, Div Cardiol, I-43100 Parma, Italy. [Berzuini, Carlo] Ctr Math Sci, Stat Lab, Cambridge, England. [Merlini, Piera Angelica; Mauri, Francesco] Azienda Osped Niguarda Ca Granda, Div Cardiol, Milan, Italy. [Mannucci, Pier Mannuccio; Peyvandi, Flora; Spreafico, Marta; Altshuler, David] Univ Milan, Osped Maggiore Mangiagalli & Regina Elena, Fdn Ist Ricovero & Cura Carattere Sci, Dept Internal Med & Med Specialties, Milan, Italy. [Surti, Aarti; Burtt, Noel; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Voight, Benjamin; Altshuler, David; Kathiresan, Sekar] Broad Inst Massachusetts Inst Technol & Harvard U, Program Med & Populat Genet, Cambridge, MA USA. [Voight, Benjamin; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Voight, Benjamin; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Tubaro, Marco] Osped San Filippo Neri, Div Cardiol, Rome, Italy. [Celli, Patrizia] Osped San Camillo, Div Cardiol, Rome, Italy. [Ferrario, Maurizio; Fetiveau, Raffaela; Marziliano, Nicola] Policlin San Matteo, Fdn Ist Ricovero Cura & Carattere Sci, I-27100 Pavia, Italy. [Casari, Giorgio] Univ Vita Salute San Raffaele, Milan, Italy. [Casari, Giorgio] Ist Sci San Raffaele, I-20132 Milan, Italy. [Galli, Michele] Osped Livorno, Div Cardiol, Livorno, Italy. [Ribichini, Flavio] Univ Verona, Osped Borgo Trento, Div Cardiol, I-37100 Verona, Italy. [Rossi, Marco L.] Ist Clin Humanitas, Ist Ricovero Cura & Carattere Sci, Div Cardiol, Milan, Italy. [Bernardi, Francesco] Univ Ferrara, Dept Biochem & Mol Biol, I-44100 Ferrara, Italy. [Zonzin, Pietro] Osped Rovigo, Div Cardiol, Rovigo, Italy. [Piazza, Alberto] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Foco, Luisa; Bernardinelli, Luisa] Univ Pavia, Dept Appl Hlth Sci, I-27100 Pavia, Italy. [Bernardinelli, Luisa] MRC, Biostat Unit, Cambridge CB2 2BW, England. [Altshuler, David; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Ardissino, D (reprint author), Univ Parma, Azienda Osped, Unita Operat Cardiol, Div Cardiol, Via Gramsci 14, I-43100 Parma, Italy. EM cardiologia.parma@ao.pr.it RI Altshuler, David/A-4476-2009; Mannucci, Pier/C-3102-2014; OI Altshuler, David/0000-0002-7250-4107; Piazza, Alberto/0000-0002-2355-4183; CASARI, Giorgio/0000-0002-0115-8980; Peyvandi, Flora/0000-0001-7423-9864 FU Italian charitable foundation "Associazione per lo Studio della Trombosi in Cardiologia"; Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group; Pfizer; Merck; Almylam FX This study was supported by the Italian charitable foundation "Associazione per lo Studio della Trombosi in Cardiologia" and the Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group. The Italian foundation "Associazione per lo Studio della Trombosi in Cardiologia" and the Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group were not involved in designing or conducting the study; in data collection, management, analysis, or interpretation; or in preparing, reviewing, or approving the manuscript. Dr. Galli is employed by Mundipharma Italy. Dr. Kathiresan has received research grants from Pfizer, Merck, and Almylam. All other authors have reported that they have no relationships to disclose. NR 22 TC 33 Z9 38 U1 3 U2 5 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 JUL 19 PY 2011 VL 58 IS 4 BP 426 EP 434 DI 10.1016/j.jacc.2010.11.075 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 791RF UT WOS:000292681600014 PM 21757122 ER PT J AU Chen, AA Thomas, DK Ong, LL Schwartz, RE Golub, TR Bhatia, SN AF Chen, Alice A. Thomas, David K. Ong, Luvena L. Schwartz, Robert E. Golub, Todd R. Bhatia, Sangeeta N. TI Humanized mice with ectopic artificial liver tissues SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID C VIRUS-INFECTION; TRANSPLANTED HEPATOCYTES; INDUCED HEPATOTOXICITY; CYTOCHROME-P450 2D6; HEPATIC TISSUES; CHIMERIC MICE; MOUSE MODEL; HYDROGELS; TOXICITY; CELLS AB "Humanized" mice offer a window into aspects of human physiology that are otherwise inaccessible. The best available methods for liver humanization rely on cell transplantation into immunodeficient mice with liver injury but these methods have not gained widespread use due to the duration and variability of hepatocyte repopulation. In light of the significant progress that has been achieved in clinical cell transplantation through tissue engineering, we sought to develop a humanized mouse model based on the facile and ectopic implantation of a tissue-engineered human liver. These human ectopic artificial livers (HEALs) stabilize the function of cryopreserved primary human hepatocytes through juxtacrine and paracrine signals in polymeric scaffolds. In contrast to current methods, HEALs can be efficiently established in immunocompetent mice with normal liver function. Mice transplanted with HEALs exhibit humanized liver functions persistent for weeks, including synthesis of human proteins, human drug metabolism, drug-drug interaction, and drug-induced liver injury. Here, mice with HEALs are used to predict the disproportionate metabolism and toxicity of "major" human metabolites using multiple routes of administration and monitoring. These advances may enable manufacturing of reproducible in vivo models for diverse drug development and research applications. C1 [Chen, Alice A.; Ong, Luvena L.; Bhatia, Sangeeta N.] MIT, Div Hlth Sci & Technol, Harvard Massachusetts Inst Technol, Cambridge, MA 02139 USA. [Chen, Alice A.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Chen, Alice A.; Schwartz, Robert E.; Bhatia, Sangeeta N.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Thomas, David K.; Golub, Todd R.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02142 USA. [Thomas, David K.] Dana Farber Canc Inst, Div Adult Palliat Care, Boston, MA 02115 USA. [Schwartz, Robert E.; Bhatia, Sangeeta N.] Brigham & Womens Hosp, Div Med, Boston, MA 02115 USA. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Thomas, David K.; Golub, Todd R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Golub, Todd R.; Bhatia, Sangeeta N.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. RP Bhatia, SN (reprint author), MIT, Div Hlth Sci & Technol, Harvard Massachusetts Inst Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM sbhatia@mit.edu OI /0000-0001-5317-3018 FU National Institutes of Health [EB008396, DK56966]; National Cancer Institute [RL1CA133834]; Howard Hughes Medical Institute; National Defense Science and Engineering and National Science Foundation FX We gratefully acknowledge support from the National Institutes of Health (EB008396, DK56966), National Cancer Institute (RL1CA133834 to D. K. T.), Howard Hughes Medical Institute (S.N.B.), and National Defense Science and Engineering and National Science Foundation Graduate Research Programs (A. A. C.). We thank Steven Katz, Semmie Kim, and Sarah Han for technical assistance, Dr. Howard Green (Harvard University) for the 3T3-J2 line, Dr. Naoya Kobayashi (Okayama University) for the TMNK-1 (LEC) line, Dr. John Schoggins and Dr. Charles Rice (Rockefeller University) for the albumin-luciferase lentivirus construct, and Dr. Scott Malstrom (Massachusetts Institute of Technology) for animal imaging assistance. We also thank Dr. Salman Khetani (Hepregen), Dr. Robert Gould (Broad Institute), Dr. Thomas Baillie (University of Washington), Dr. Catherine Murray, Dr. Kelly Stevens, Dr. Sandra March, and Shengyong Ng for insightful discussions. NR 42 TC 74 Z9 76 U1 2 U2 27 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 19 PY 2011 VL 108 IS 29 BP 11842 EP 11847 DI 10.1073/pnas.1101791108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794DY UT WOS:000292876900032 PM 21746904 ER PT J AU Vizcarra, CL Kreutz, B Rodal, AA Toms, AV Lu, J Zheng, W Quinlan, ME Eck, MJ AF Vizcarra, Christina L. Kreutz, Barry Rodal, Avital A. Toms, Angela V. Lu, Jun Zheng, Wei Quinlan, Margot E. Eck, Michael J. TI Structure and function of the interacting domains of Spire and Fmn-family formins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACTIN NUCLEATION; CAPPING PROTEIN; AUTOREGULATORY DOMAIN; HOMOLOGY-2 DOMAIN; FISSION YEAST; MOUSE OOCYTES; ATP-ACTIN; VERY-KIND; ADP-ACTIN; CAPPUCCINO AB Evidence for cooperation between actin nucleators is growing. The WH2-containing nucleator Spire and the formin Cappuccino interact directly, and both are essential for assembly of an actin mesh during Drosophila oogenesis. Their interaction requires the kinase noncatalytic C-lobe domain (KIND) domain of Spire and the C-terminal tail of the formin. Here we describe the crystal structure of the KIND domain of human Spir1 alone and in complex with the tail of Fmn2, a mammalian ortholog of Cappuccino. The KIND domain is structurally similar to the C-lobe of protein kinases. The Fmn2 tail is coordinated in an acidic cleft at the base of the domain that appears to have evolved via deletion of a helix from the canonical kinase fold. Our functional analysis of Cappuccino reveals an unexpected requirement for its tail in actin assembly. In addition, we find that the KIND/tail interaction blocks nucleation by Cappuccino and promotes its displacement from filament barbed ends providing insight into possible modes of cooperation between Spire and Cappuccino. C1 [Vizcarra, Christina L.; Quinlan, Margot E.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Kreutz, Barry; Toms, Angela V.; Lu, Jun; Zheng, Wei; Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Kreutz, Barry; Toms, Angela V.; Lu, Jun; Zheng, Wei; Eck, Michael J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Rodal, Avital A.] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. [Rodal, Avital A.] Brandeis Univ, Rosenstiel Basic Med Sci Ctr, Waltham, MA 02454 USA. [Quinlan, Margot E.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. RP Quinlan, ME (reprint author), Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. EM margot@chem.ucla.edu; eck@red.dfci.harvard.edu FU National Research Foundation of Korea [R33-10108]; NCRR [RR-15301]; NIH [GM071834]; Burroughs-Wellcome Fund; March of Dimes Foundation [5-FY10-81]; NIH NRSA [F32GM087857] FX We thank H. K. Song for helpful discussions and for support through the World Class University Program of the National Research Foundation of Korea (Award R33-10108). We thank the NE-CAT beamline staff at the Advanced Photon source for assitance with data collection; the NE-CAT is supported by NCRR award RR-15301. This work was supported in part by NIH Grant GM071834 (M.J.E.), grants from the Burroughs-Wellcome Fund (Career Award in the Biomedical Sciences), and March of Dimes Foundation Grant #5-FY10-81 (M. E. Q.), and NIH NRSA postdoctoral fellowship F32GM087857 (C.L.V.). NR 40 TC 44 Z9 48 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 19 PY 2011 VL 108 IS 29 BP 11884 EP 11889 DI 10.1073/pnas.1105703108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794DY UT WOS:000292876900039 PM 21730168 ER PT J AU Casaletto, JB Saotome, I Curto, M McClatchey, AI AF Casaletto, Jessica B. Saotome, Ichiko Curto, Marcello McClatchey, Andrea I. TI Ezrin-mediated apical integrity is required for intestinal homeostasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE actomyosin contractility; planar cell polarity; colon; Merlin ID PLANAR CELL POLARITY; SPINDLE ORIENTATION; ADAPTER PROTEINS; ERM PROTEINS; KINASE SLIK; MORPHOGENESIS; MOESIN; ORGANIZATION; TISSUE; MEMBRANE AB Individual cell types are defined by architecturally and functionally specialized cortical domains. The Ezrin, Radixin, and Moesin (ERM) proteins play a major role in organizing cortical domains by assembling membrane protein complexes and linking them to the cortical actin cytoskeleton. Many studies have focused on the individual roles of the ERM proteins in stabilizing the membrane-cytoskeleton interface, controlling the distribution and function of apical membrane complexes, regulating the small GTPase Rho, or establishing cell-cell junctions. We previously found that deletion of the mouse Ezrin gene yields severe defects in apical integrity throughout the developing intestinal epithelium, resulting in incomplete villus morphogenesis and neonatal death. However, the molecular function of Ezrin in building the apical surface of the intestinal epithelium was not clear. By deleting Ezrin in the adult mouse intestinal epithelium, we provide evidence that Ezrin performs multiple molecular functions that collaborate to build the functional apical surface of the intestinal epithelium in vivo. The loss of Ezrin-mediated apical integrity in the adult intestine yields severe morphological consequences during intestinal homeostasis, including defects in cell geometry, extrusion, junctional remodeling, and spindle orientation. Surprisingly, deletion of Ezrin either before or after villus morphogenesis yields villus fusion, revealing a previously unrecognized step in intestinal homeostasis. Our studies indicate that the function of Ezrin in building and maintaining the apical domain is essential not only for intestinal morphogenesis but also for homeostasis in the mature intestine. C1 [McClatchey, Andrea I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Pathol, Charlestown, MA 02129 USA. RP McClatchey, AI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Charlestown, MA 02129 USA. EM mcclatch@helix.mgh.harvard.edu FU National Institutes of Health [R01GM087558]; Children's Tumor Foundation FX We thank Sylvie Robine for Vil-Cre-ERT2 mice; Ben Margolis for anti-Crumbs3 antibodies; Bill Fowle and Thomas Diefenbach for assistance with electron and confocal microscopy; and Kevin Haigis, Silvia Fre, and Matt Tyska for advice and discussion. This work was supported by National Institutes of Health Grant R01GM087558 (to A. I. M.) and a Children's Tumor Foundation Young Investigator Award (to J.B.C.). NR 44 TC 28 Z9 29 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 19 PY 2011 VL 108 IS 29 BP 11924 EP 11929 DI 10.1073/pnas.1103418108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794DY UT WOS:000292876900046 PM 21730140 ER PT J AU Galarce, EM Minsky, S Viswanath, K AF Galarce, Ezequiel M. Minsky, Sara Viswanath, K. TI Socioeconomic status, demographics, beliefs and A(H1N1) vaccine uptake in the United States SO VACCINE LA English DT Article DE H1N1; Vaccine uptake; Social determinants; Inequalities; Psychosocial factors ID A H1N1 2009; INFLUENZA VACCINATION; MONOVALENT AB Early vaccination against influenza viruses is a cost-effective solution to prevent contagion and reduce influenza-related morbidity and mortality. In the face of pandemic viruses, such as the A(H1N1), adequate rates of vaccine uptake play a critical role in containing the spread and effects of the disease. In order to understand the reasons underlying the relatively low 2009-2010 A(H1N1) vaccination rates, we conducted an online survey of 1569 respondents drawn from a nationally representative sample of United States (U.S.) adults age 18, and older. Because prior research suggests that vaccination rates are especially low among some U.S. population subgroups, we oversampled participants from minority ethnic/racial groups and those living under the Federal Poverty Level. Our results show that A(H1N1) vaccine uptake is associated with sociodemographic factors, A(H1N1)-related beliefs and seasonal vaccination. That is, A(H1N1) vaccination is strongly associated with age, urbanicity, perceiving the A(H1N1) vaccine as safe and seasonal flu vaccine uptake. Perceptions of safety and season flu vaccination show the strongest associations with A(H1N1) uptake. The reasons people gave to decline vaccination varied by respondents' sociodemographic group. For example, Black participants were the most likely ethnic/racial group to reported having tried to get the vaccine but found it unavailable. Together, these findings suggest some clear pointers towards strategic public health communication efforts calling for communication campaigns towards audiences segmented by social class, race/ethnicity and beliefs, often what advertisers call "psychodemographics". (C) 2011 Elsevier Ltd. All rights reserved. C1 [Galarce, Ezequiel M.; Viswanath, K.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Galarce, Ezequiel M.; Minsky, Sara; Viswanath, K.] Dana Farber Canc Inst, Boston, MA USA. RP Galarce, EM (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave,Kresge Bldg,7th Floor, Boston, MA 02115 USA. EM ezequiel_galarce@dfci.harvard.edu FU CDC [1P01TP000307] FX This research was supported by CDC grant 1P01TP000307 (Viswanath, PI). NR 18 TC 46 Z9 46 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 18 PY 2011 VL 29 IS 32 BP 5284 EP 5289 DI 10.1016/j.vaccine.2011.05.014 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 808OB UT WOS:000293987200026 PM 21621577 ER PT J AU Carter, EA Bonab, AA Hamrahi, V Pitman, J Winter, D Macintosh, LJ Cyr, EM Paul, K Yerxa, J Jung, W Tompkins, RG Fischman, AJ AF Carter, Edward A. Bonab, Ali A. Hamrahi, Victoria Pitman, Justin Winter, Daniel Macintosh, Lacey J. Cyr, Erika M. Paul, Kasie Yerxa, John Jung, Walter Tompkins, Ronald G. Fischman, Alan J. TI Effects of burn injury, cold stress and cutaneous wound injury on the morphology and energy metabolism of murine brown adipose tissue (BAT) in vivo SO LIFE SCIENCES LA English DT Article DE Brown fat; PET; Metabolism ID GLUCOSE-UTILIZATION; INSULIN-RESISTANCE; PEDIATRIC-PATIENTS; SKELETAL-MUSCLE; ADULT HUMANS; RAT; SENSITIVITY; ADAPTATION; MECHANISM; EXPOSURE AB Aims: Cold stress has been shown to produce dramatic increases in 2-fluoro-2-deoxy-D-Glucose ((18)FDG) accumulation by brown adipose tissue (BAT) in rodents. However, neither the effects of other types of stress on (18)FDG accumulation nor the effects of stressors on the accumulation of tracers of other aspects of energy metabolism have been evaluated. In this report we studied the effects of cold stress, burn injury and cutaneous wounds on murine BAT at the macroscopic, microscopic and metabolic level. Main methods: Glucose metabolism was studied with (18)FDG, fatty acid accumulation was evaluated with trans-9(RS)-(18)F-fluoro-3,4(RS,RS)-methyleneheptadecanoic acid (FCPHA) and tricarboxcylic acid cycle (TCA) activity was evaluated with (3)H acetate. Key findings: All three stressors produced dramatic changes in BAT at the macroscopic and microscopic level. Macroscopically, BAT from the stressed animals appeared to be a much darker brown in color. Microscopically BAT of stressed animals demonstrated significantly fewer lipid droplets and an overall decrease in lipid content. Accumulation of (18)FDG by BAT was significantly (p<0.01) increased by all 3 treatments (Cold: similar to 16 fold, burn similar to 7 Fold and cutaneous wound similar to 14 fold) whereas uptake of FDG by white fat was unchanged. This effect was also demonstrated non invasively by mu PET imaging. Although less prominent than with (18)FDG, BAT uptake of FCPHA and acetate were also significantly increased by all three treatments. These findings suggest that in addition to cold stress, burn injury and cutaneous wounds produce BAT activation in mice. Significance: This study demonstrates brown fat activated by several stressors leads to increased uptake of various substrates. (C) 2011 Elsevier Inc. All rights reserved. C1 [Carter, Edward A.] Shriners Hosp Children, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Carter, Edward A.; Bonab, Ali A.; Tompkins, Ronald G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Carter, Edward A.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Bonab, Ali A.; Pitman, Justin; Winter, Daniel; Macintosh, Lacey J.; Cyr, Erika M.; Paul, Kasie; Yerxa, John] Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. RP Carter, EA (reprint author), Shriners Hosp Children, Massachusetts Gen Hosp, Room 237,51 Blossom St, Boston, MA 02114 USA. EM carter.ea@gmail.com RI Yerxa, John/E-7252-2017 OI Yerxa, John/0000-0002-5283-3069 FU National Institutes of Health [2P50 GM21700-27A]; Shriners Hospitals for Children FX This work was supported in part by grants from the National Institutes of Health (2P50 GM21700-27A) and Shriners Hospitals for Children. NR 37 TC 14 Z9 16 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JUL 18 PY 2011 VL 89 IS 3-4 BP 78 EP 85 DI 10.1016/j.lfs.2011.04.014 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 790XO UT WOS:000292624300003 PM 21565200 ER PT J AU Geschka, S Kretschmer, A Sharkovska, Y Evgenov, OV Lawrenz, B Hucke, A Hocher, B Stasch, JP AF Geschka, Sandra Kretschmer, Axel Sharkovska, Yuliya Evgenov, Oleg V. Lawrenz, Bettina Hucke, Andreas Hocher, Berthold Stasch, Johannes-Peter TI Soluble Guanylate Cyclase Stimulation Prevents Fibrotic Tissue Remodeling and Improves Survival in Salt-Sensitive Dahl Rats SO PLOS ONE LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; PULMONARY ARTERIAL-HYPERTENSION; CHRONIC HEART-FAILURE; NITRIC-OXIDE; CARDIOVASCULAR-DISEASE; OXIDATIVE STRESS; OSTEOPONTIN; FIBROSIS; RIOCIGUAT; PRESSURE AB Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. Methods and Results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions. C1 [Geschka, Sandra; Hucke, Andreas; Stasch, Johannes-Peter] Bayer HealthCare, Cardiol Res, Wuppertal, Germany. [Kretschmer, Axel] Bayer HealthCare, Global Biomarker, Wuppertal, Germany. [Sharkovska, Yuliya; Hocher, Berthold] Univ Potsdam, Inst Nutr Sci, Potsdam, Germany. [Sharkovska, Yuliya; Hocher, Berthold] Charite, Cardiovasc Res Ctr, Inst Pharmacol & Toxicol, Berlin, Germany. [Evgenov, Oleg V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Lawrenz, Bettina] Bayer HealthCare, Pathol, Wuppertal, Germany. [Stasch, Johannes-Peter] Univ Halle Wittenberg, Inst Pharm, Halle, Germany. RP Geschka, S (reprint author), Bayer HealthCare, Cardiol Res, Wuppertal, Germany. EM johannes-peter.stasch@bayer.com NR 39 TC 37 Z9 38 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2011 VL 6 IS 7 AR e21853 DI 10.1371/journal.pone.0021853 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HY UT WOS:000292812400018 PM 21789188 ER PT J AU Bansal, N Hsu, CY Zhao, SJ Whooley, MA Ix, JH AF Bansal, Nisha Hsu, Chi-yuan Zhao, Shoujun Whooley, Mary A. Ix, Joachim H. TI Relation of Body Mass Index to Urinary Creatinine Excretion Rate in Patients With Coronary Heart Disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; LEFT-VENTRICULAR HYPERTROPHY; ARTERY-DISEASE; HEMODIALYSIS-PATIENTS; NUTRITIONAL-STATUS; PROGNOSTIC VALUE; CYSTATIN-C; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; ALL-CAUSE AB In patients with prevalent coronary heart disease (CHD), studies have found a paradoxical relation in that patients with higher body mass indexes (BMIs) have lower mortality. One possibility is that patients with higher BMIs have greater muscle mass, and higher BMI may be a marker of better overall health status. The aim of this study was to evaluate whether the paradoxical association of BMI with mortality in patients with CHD is attenuated when accounting for urinary creatinine excretion, a marker of muscle mass. The Heart and Soul Study is an observational study of outpatients with stable CHD. Outpatient 24-hour timed urine collections were obtained. Participants were followed up for death for 5.9 +/- 1.9 years. Cox proportional-hazards models were used to evaluate the association between gender-specific BMI quintiles and mortality. There were 886 participants in the study population. Participants in higher quintiles of BMI were younger, were more likely to have diabetes mellitus and hypertension, and had higher urinary creatinine excretion rate. Compared to the lowest BMI quintile, subjects in higher BMI quintiles were less likely to die during follow-up. Adjustment for major demographic variables, traditional cardiovascular risk factors, and kidney function did not attenuate the relation. Additional adjustment for urinary creatinine excretion rate did not materially change the association between BMI and all-cause mortality. In conclusion, low muscle mass and low BMI are each associated with greater all-cause mortality, but low muscle mass does not appear to explain why CHD patients with low BMIs have worse prognosis. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:179-184) C1 [Bansal, Nisha; Hsu, Chi-yuan; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94112 USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Zhao, Shoujun; Whooley, Mary A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Family & Preventat Med, Div Prevent Med, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Dept Med, Nephrol Sect, San Diego, CA USA. RP Bansal, N (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94112 USA. EM nisha.bansal@ucsf.edu FU American Kidney Fund, Rockville, Maryland; National Heart, Lung, and Blood Institute, Bethesda, Maryland [1R01HL096851]; American Heart Association, Dallas, Texas; National Institute of Diabetes and Digestive and Kidney Diseases [1 K23DK088865]; United States Department of Veterans Affairs, Washington, District of Columbia; American Federation for Aging Research, New York, New York; Robert Wood Johnson Foundation, Princeton, New Jersey; Nancy Kirwan Heart Research Fund, San Francisco, California; Ischemia Research and Education Foundation, San Bruno, California; National Heart, Lung, and Blood Institute [R01 HL079235] FX This study was supported by a grant from the American Kidney Fund, Rockville, Maryland, to Dr. Bansal; Grant 1R01HL096851 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, to Dr. Ix; and a Fellow-to-Faculty Transition Award from the American Heart Association, Dallas, Texas, to Dr. Ix. The study was also supported by Grant 1 K23DK088865 from the National Institute of Diabetes and Digestive and Kidney Diseases to Dr. Bansal. The Heart and Soul Study was funded by the United States Department of Veterans Affairs, Washington, District of Columbia; the American Federation for Aging Research, New York, New York; the Robert Wood Johnson Foundation, Princeton, New Jersey; the Nancy Kirwan Heart Research Fund, San Francisco, California; the Ischemia Research and Education Foundation, San Bruno, California; and Grant R01 HL079235 from the National Heart, Lung, and Blood Institute. NR 29 TC 4 Z9 5 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2011 VL 108 IS 2 BP 179 EP 184 DI 10.1016/j.amjcard.2011.03.020 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 809DH UT WOS:000294031500002 PM 21529727 ER PT J AU Sun, HY Singh, N AF Sun, Hsin-Yun Singh, Nina TI Opportunistic Infection-Associated Immune Reconstitution Syndrome in Transplant Recipients SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID REGULATORY T-CELLS; INFLAMMATORY SYNDROME IRIS; VERSUS-HOST-DISEASE; CRYPTOCOCCAL MENINGITIS; CEREBROSPINAL-FLUID; CORTICOSTEROID-THERAPY; LIVER-TRANSPLANTATION; CALCINEURIN INHIBITOR; INTERLEUKIN-12 FAMILY; PARADOXICAL RESPONSE AB Reversal of pathogen-induced immunosuppression upon employment of effective antimicrobial therapy and withdrawal of iatrogenic immunosuppression has the potential to shift the host immune repertoire towards pathologic inflammatory responses conducive to immune reconstitution syndrome (IRS). Posttransplant IRS has been observed with fungi, M. tuberculosis, cytomegalovirus, and polyoma virus nephropathy. This review discusses the existing state of knowledge regarding IRS and the immune mechanisms that underlie its pathogenesis, with significant implications for developing reliable diagnostic biomarkers and optimal management strategies for post-transplant opportunistic infection-associated IRS. C1 [Sun, Hsin-Yun; Singh, Nina] VA Pittsburgh Healthcare Syst, Infect Dis Sect, Pittsburgh, PA USA. [Singh, Nina] Univ Pittsburgh, Pittsburgh, PA USA. [Sun, Hsin-Yun] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Sun, Hsin-Yun] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. RP Singh, N (reprint author), VA Med Ctr, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. EM nis5@pitt.edu OI SUN, HSIN-YUN/0000-0003-0074-7721 FU Pfizer FX N. S. has received investigator-initiated research support from Pfizer. H.-Y. S.: No reported conflicts. NR 101 TC 30 Z9 30 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 JUL 15 PY 2011 VL 53 IS 2 BP 168 EP 176 DI 10.1093/cid/cir276 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 796BA UT WOS:000293024000011 PM 21690625 ER PT J AU Cheng, J Zhu, YH He, SD Lu, YP Chen, J Han, B Petrillo, M Wrzeszczynski, KO Yang, SM Dai, P Zhai, SQ Han, DY Zhang, MQ Li, W Liu, XZ Li, HW Chen, ZY Yuan, HJ AF Cheng, Jing Zhu, Yuhua He, Sudan Lu, Yanping Chen, Jing Han, Bing Petrillo, Marco Wrzeszczynski, Kazimierz O. Yang, Shiming Dai, Pu Zhai, Suoqiang Han, Dongyi Zhang, Michael Q. Li, Wei Liu, Xuezhong Li, Huawei Chen, Zheng-Yi Yuan, Huijun TI Functional Mutation of SMAC/DIABLO, Encoding a Mitochondrial Proapoptotic Protein, Causes Human Progressive Hearing Loss DFNA64 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID INDUCED APOPTOSIS; OXIDATIVE STRESS; CELL-DEATH; DEAFNESS; ACTIVATION; EXPRESSION; DISCOVERY; COCHLEA; GENES; LOCUS AB SMAC/DIABLO is a mitochondrial proapoptotic protein that is released from mitochondria during apoptosis and counters the inhibitory activities of inhibitor of apoptosis proteins, IAPs. By linkage analysis and candidate screening, we identified a heterozygous SMAC/DIABLO mutation, c.377C>T (p.Ser126Leu, refers to p.Ser71Leu in the mature protein) in a six-generation Chinese kindred characterized by dominant progressive nonsyndromic hearing loss, designated as DFNA64. SMAC/DIABLO is highly expressed in human embryonic ears and is enriched in the developing mouse inner-ear hair cells, suggesting it has a role in the development and homeostasis of hair cells. We used a functional study to demonstrate that the SMAC/DIABLO(S71L) mutant, while retaining the proapoptotic function, triggers significant degradation of both wild-type and mutant SMAC/DIABLO and renders host mitochondria susceptible to calcium-induced loss of the membrane potential. Our work identifies DFNA64 as the human genetic disorder associated with SMAC/DIABLO malfunction and suggests that mutant SMAC/DIABLO(S71L) might cause mitochondrial dysfunction. C1 [Cheng, Jing; Zhu, Yuhua; Chen, Jing; Han, Bing; Yang, Shiming; Dai, Pu; Zhai, Suoqiang; Han, Dongyi; Yuan, Huijun] Chinese Peoples Liberat Army Gen Hosp, Inst Otolaryngol, Beijing 100853, Peoples R China. [He, Sudan] Natl Inst Biol Sci, Beijing 102206, Peoples R China. [He, Sudan] Soochow Univ, Affiliated Hosp 1, Jiangsu Inst Hematol, Cyrus Tang Hematol Ctr, Suzhou 215325, Peoples R China. [Lu, Yanping] Chinese Peoples Liberat Army Gen Hosp, Dept Obstet & Gynecol, Beijing 100853, Peoples R China. [Petrillo, Marco; Chen, Zheng-Yi] Harvard Univ, Eaton Peabody Lab, Massachusetts Eye & Ear Infirm, Dept Otolaryngol,Med Sch, Boston, MA 02114 USA. [Wrzeszczynski, Kazimierz O.; Zhang, Michael Q.] Cold Spring Harbor Lab, Michael Zhang Lab, Cold Spring Harbor, NY 11724 USA. [Li, Wei] Chinese Acad Sci, Inst Genet & Dev Biol, Beijing 100101, Peoples R China. [Liu, Xuezhong] Univ Miami, Dept Otolaryngol, Miami, FL 33136 USA. [Li, Huawei] Fudan Univ, Affiliated Eye & Otolaryngol Hosp, Dept Otol & Skull Base Surg, Shanghai 200031, Peoples R China. RP Yuan, HJ (reprint author), Chinese Peoples Liberat Army Gen Hosp, Inst Otolaryngol, Beijing 100853, Peoples R China. EM yuanhj301@yahoo.com.cn FU National High Technology Research and Development Program of China (863 Program) [2007AA02E466]; National Natural Science Foundation of China [81030017, 30728030]; National Institutes of Health [R01 DC006908, R01 DC05575]; Fredrick and Ines Yeatts Inner Ear Hair Cell Regeneration Fellowship; Chinese National Programs for Fundamental Research and Development (973 Program) [2011CB504506] FX We sincerely thank Xiaodong Wang for extensive help in invaluable scientific input and manuscript revision, Xue Zhang and Hui Jiang for helpful discussions, and Yueshuai Song and Chunhua Xu for technical assistance with the figure preparation and graphical artwork. These investigations were supported by grants from the National High Technology Research and Development Program of China (863 Program, 2007AA02E466) and the Key Project of National Natural Science Foundation of China (81030017) to H.J.Y., grants from the National Natural Science Foundation of China (30728030) and National Institutes of Health (R01 DC006908) to Z.Y.C., a grant from the Fredrick and Ines Yeatts Inner Ear Hair Cell Regeneration Fellowship to M.P., a grant from the National Institutes of Health (R01 DC05575) to X.Z.L., and a grant from the Chinese National Programs for Fundamental Research and Development (973 Program, 2011CB504506) to H.W.L. We thank all the family members for their participation and support in this study. NR 26 TC 16 Z9 23 U1 1 U2 14 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 JUL 15 PY 2011 VL 89 IS 1 BP 56 EP 66 DI 10.1016/j.ajhg.2011.05.027 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 796HF UT WOS:000293041700005 PM 21722859 ER PT J AU Mann, SL Hazlett, EA Byne, W Hof, PR Buchsbaum, MS Cohen, BH Goldstein, KE Haznedar, MM Mitsis, EM Siever, LJ Chu, KW AF Mann, Sarah L. Hazlett, Erin A. Byne, William Hof, Patrick R. Buchsbaum, Monte S. Cohen, Barry H. Goldstein, Kim E. Haznedar, M. Mehmet Mitsis, Effie M. Siever, Larry J. Chu, King-Wai TI Anterior and posterior cingulate cortex volume in healthy adults: Effects of aging and gender differences SO BRAIN RESEARCH LA English DT Article DE Cingulate cortex; Aging; Gender differences; MRI; Gray matter; Morphometry ID COMORBIDITY SURVEY REPLICATION; AGE-RELATED DIFFERENCES; GRAY-MATTER VOLUME; SEX-DIFFERENCES; CEREBRAL-CORTEX; BRAIN STRUCTURE; MEMORY PERFORMANCE; ALZHEIMER-DISEASE; SIGNAL INTENSITY; BIPOLAR DISORDER AB The cingulate cortex frequently shows gray matter loss with age as well as gender differences in structure and function, but little is known about whether individual cingulate Brodmann areas show gender-specific patterns of age-related volume decline. This study examined age-related changes, gender differences, and the interaction of age and gender in the relative volume of cingulate gray matter in areas 25, 24, 31, 23, and 29, over seven decades of adulthood. Participants included healthy, age-matched men and women, aged 20-87 (n=70). Main findings were as follows: (1) The whole cingulate showed significant age-related volume declines (averaging 5.54% decline between decades, 20s-80s). Each of the five cingulate areas also showed a significant decline with age, and individual areas showed different patterns of decline across the decades: Smaller volume with age was most evident in area 31, followed by 25 and 24. (2) Women had relatively larger cingulate gray matter volume than men overall and in area 24. (3) Men and women showed different patterns of age-related volume decline in area 31, at midlife and late in life. By delineating normal gender differences and age-related morphometric changes in the cingulate cortex over seven decades of adulthood, this study improves the baseline for comparison with structural irregularities in the cingulate cortex associated with psychopathology. The Brodmann area-based approach also facilitates comparisons across studies that aim to draw inferences between age- and gender-related structural differences in the cingulate gyrus and corresponding differences in cingulate function. Published by Elsevier B.V. C1 [Hazlett, Erin A.; Byne, William; Haznedar, M. Mehmet; Siever, Larry J.; Chu, King-Wai] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY 10468 USA. [Mann, Sarah L.; Hazlett, Erin A.; Byne, William; Goldstein, Kim E.; Haznedar, M. Mehmet; Mitsis, Effie M.; Siever, Larry J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Hof, Patrick R.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Psychiat & Radiol, La Jolla, CA 92093 USA. [Cohen, Barry H.] NYU, Dept Psychol, New York, NY 10003 USA. RP Hazlett, EA (reprint author), James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, 130 W Kingsbridge Rd,Room 6A-45, Bronx, NY 10468 USA. EM erin.hazlett@mssm.edu FU Charles A. Dana Foundation; NIMH [MH073911]; VISN 3 Mental Illness Research, Education, and Clinical Center, Department of Veterans Affairs FX The collection of the MRI data was supported by a grant from the Charles A. Dana Foundation to Drs. Mohs and Buchsbaum. This research was supported in part by a NIMH grant to Dr. Hazlett (MH073911) and the VISN 3 Mental Illness Research, Education, and Clinical Center, Department of Veterans Affairs. NR 90 TC 19 Z9 22 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 15 PY 2011 VL 1401 BP 18 EP 29 DI 10.1016/j.brainres.2011.05.050 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 794ZN UT WOS:000292941400003 PM 21669408 ER PT J AU Salama, AKS Hodi, FS AF Salama, April K. S. Hodi, F. Stephen TI Cytotoxic T-Lymphocyte-Associated Antigen-4 SO CLINICAL CANCER RESEARCH LA English DT Article ID CTLA-4 FUNCTION; REGULATORY T; COMBINATION IMMUNOTHERAPY; ANTI-CTLA-4 ANTIBODIES; CANCER-IMMUNOTHERAPY; PROSTATE-CANCER; PHASE-II; MELANOMA; BLOCKADE; IPILIMUMAB AB Cancer immunotherapy relies on the ability of the immune system to target tumor-specific antigens to generate an immune response. This initial response requires both binding of the MHC/antigen peptide to T-cell receptor complex, along with a second costimulatory signal created by the binding of CD28 on the T cell, with B7 located on the antigen-presenting cell. Regulatory checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), serve to attenuate this signal, thereby preventing autoimmunity. Its key role in regulating the immune system has made CTLA-4 an attractive therapeutic target for cancer, with the development of fully human monoclonal antibodies that have successfully targeted CTLA-4 in clinical trials. Augmentation of the immune response via blockade of CTLA-4 represents a significant advance in the field of oncology and has shown an improvement in survival for patients with metastatic melanoma. An increased understanding of the components of this pathway and the identification of other methods to modulate the immune system hold great promise for future therapy. Clin Cancer Res; 17(14); 4622-8. (C)2011 AACR. C1 [Salama, April K. S.] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Mol Oncol, Boston, MA 02115 USA. [Hodi, F. Stephen] Harvard Univ, Sch Med, Boston, MA USA. RP Hodi, FS (reprint author), 44 Binney St, Boston, MA 02115 USA. EM stephen_hodi@dfci.harvard.edu FU Bristol-Myers Squibb; Pfizer FX F.S. Hodi: commercial research support and consultant, Bristol-Myers Squibb and Pfizer. A. K. S. Salama disclosed no potential conflicts of interest. NR 56 TC 42 Z9 43 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2011 VL 17 IS 14 BP 4622 EP 4628 DI 10.1158/1078-0432.CCR-10-2232 PG 7 WC Oncology SC Oncology GA 793JI UT WOS:000292816900002 PM 21467163 ER PT J AU Ryan, CJ Shah, S Efstathiou, E Smith, MR Taplin, ME Bubley, GJ Logothetis, CJ Kheoh, T Kilian, C Haqq, CM Molina, A Small, EJ AF Ryan, Charles J. Shah, Shreya Efstathiou, Eleni Smith, Matthew R. Taplin, Mary-Ellen Bubley, Glenn J. Logothetis, Christopher J. Thian Kheoh Kilian, Christine Haqq, Christopher M. Molina, Arturo Small, Eric J. TI Phase II Study of Abiraterone Acetate in Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer Displaying Bone Flare Discordant with Serologic Response SO CLINICAL CANCER RESEARCH LA English DT Article ID ANTIGEN WORKING GROUP; ANTIANDROGEN WITHDRAWAL; CLINICAL-TRIALS; THERAPY; INHIBITOR; CYP17; KETOCONAZOLE; GUIDELINES; CARCINOMA; RECOMMENDATIONS AB Purpose: Abiraterone is an oral inhibitor of CYP17, which is essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with castration-resistant prostate cancer (CRPC), without prior chemotherapy or CYP17-targeted therapy, and frequency of bone scans discordant with prostate-specific antigen (PSA) and clinical response. Experimental Design: Thirty-three patients received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating "disease progression" in context of a 50% or more decline in PSA level, with scan improvement or stability 3 months later. Results: A 50% or more decline in PSA level at week 12 was confirmed in 22 of 33 (67%) patients. Declines in PSA level of 50% or more were seen in 26 of 33 (79%) patients. Undetectable PSA levels (<= 0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression were 63 weeks and 16.3 months, respectively. Twenty-three patients were evaluable for bone scan flare. Progression was indicated in radiologist's report in 12 of 23 (52%), and 11 of 12 subsequently showed improvement or stability. As prospectively defined, bone scan flare was observed in 11 of 23 (48%) evaluable patients or 11 of 33 (33%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports. Conclusion: Clinical responses to abiraterone plus prednisone were frequent and durable in men with metastatic CRPC. Further investigation is needed to clarify the confounding effect of bone scan flare on patient management and interpretation of results. Clin Cancer Res; 17(14); 4854-61. (C)2011 AACR. C1 [Ryan, Charles J.; Shah, Shreya; Kilian, Christine; Small, Eric J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Genitourinary Med Oncol Program, San Francisco, CA 94115 USA. [Efstathiou, Eleni; Logothetis, Christopher J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Taplin, Mary-Ellen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bubley, Glenn J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Thian Kheoh; Haqq, Christopher M.; Molina, Arturo] Ortho Biotech Oncol Res & Dev, Los Angeles, CA USA. RP Ryan, CJ (reprint author), Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Genitourinary Med Oncol Program, 1600 Divisadero St, San Francisco, CA 94115 USA. EM ryanc@medicine.ucsf.edu OI Gunn, Christine/0000-0003-3340-2834 FU Cougar Biotechnology; Department of Defense Prostate Cancer Clinical Trials Consortium FX This study was supported by Cougar Biotechnology and the Department of Defense Prostate Cancer Clinical Trials Consortium. NR 22 TC 108 Z9 114 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2011 VL 17 IS 14 BP 4854 EP 4861 DI 10.1158/1078-0432.CCR-11-0815 PG 8 WC Oncology SC Oncology GA 793JI UT WOS:000292816900025 PM 21632851 ER PT J AU de Groot, JF Piao, Y Tran, H Gilbert, M Wu, HK Liu, J Bekele, BN Cloughesy, T Mehta, M Robins, HI Lassman, A DeAngelis, L Camphausen, K Chen, A Yung, WKA Prados, M Wen, PY Heymach, JV AF de Groot, John F. Piao, Yuji Hai Tran Gilbert, Mark Wu, Hua-Kang Liu, Jun Bekele, B. Nebiyou Cloughesy, Tim Mehta, Minesh Robins, H. Ian Lassman, Andrew DeAngelis, Lisa Camphausen, Kevin Chen, Alice Yung, W. K. A. Prados, Michael Wen, Patrick Y. Heymach, John V. TI Myeloid Biomarkers Associated with Glioblastoma Response to Anti-VEGF Therapy with Aflibercept SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CARBONIC-ANHYDRASE-IX; PHASE-II; IN-VIVO; TUMOR ANGIOGENESIS; MALIGNANT GLIOMA; CANCER-PATIENTS; RECTAL-CANCER; BEVACIZUMAB; CELLS AB Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma. Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients. Results: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1(+) monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9. Conclusions: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis. Clin Cancer Res; 17(14); 4872-81. (C) 2011 AACR. C1 [de Groot, John F.; Piao, Yuji; Gilbert, Mark; Yung, W. K. A.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Hai Tran; Wu, Hua-Kang; Heymach, John V.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Liu, Jun; Bekele, B. Nebiyou] Univ Texas MD Anderson Canc Ctr, Dept Appl Math & Biostat, Houston, TX 77030 USA. [Cloughesy, Tim] Univ Calif Los Angeles, Los Angeles, CA USA. [Mehta, Minesh; Robins, H. Ian] Univ Wisconsin, Madison, WI USA. [Lassman, Andrew; DeAngelis, Lisa] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Chen, Alice] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Prados, Michael] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP de Groot, JF (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, 1515 Holcombe Blvd,Unit 431, Houston, TX 77030 USA. EM jdegroot@mdanderson.org OI mehta, minesh/0000-0002-4812-5713 FU AstraZeneca; Adnexus; Exelixis; Genentech; Bayer; Merck; Schering Plough; Tomotherapy; Keryx; Bristol Myers-Squibb; Campus Bio LP; Cephalon; Eisai; Imclone; Novartis; Merck/EMD; NIH: NABTC [U01-CA62399]; ASCO; [1R21A126127] FX J.F. de Groot: commercial research grants, AstraZeneca, Adnexus, Exelixis; consultant/advisory board, Genentech. M. Gilbert: consultant/advisory board, Genentech. M. Mehta: stock options, Tomotherapy, Pharmacyclics; consultant/advisory board, Genentech, Adnexus, Bayer, Merck, Schering Plough, Tomotherapy, Stemina. A. Lassman: commercial research grants, Genentech, Keryx; consultant/advisory board, Bristol Myers-Squibb, Campus Bio LP, Cephalon, Eisai, Genentech, Imclone, Merck, Schering Plough. WKA Yung: commercial research grant, Novartis; consultant/advisory board, Genentech, Merck/EMD, Schering Plough. The other authors disclosed no potential conflicts of interest.; The clinical trial was funded by the NIH: NABTC # U01-CA62399. Correlative studies supported in part by 1R21A126127 and an ASCO Career Development Award, both to J.F. de Groot. NR 38 TC 28 Z9 29 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2011 VL 17 IS 14 BP 4872 EP 4881 DI 10.1158/1078-0432.CCR-11-0271 PG 10 WC Oncology SC Oncology GA 793JI UT WOS:000292816900027 PM 21632852 ER PT J AU Lee, LJ Alexander, B Schnitt, SJ Comander, A Gallagher, B Garber, JE Tung, N AF Lee, Larissa J. Alexander, Brian Schnitt, Stuart J. Comander, Amy Gallagher, Bridget Garber, Judy E. Tung, Nadine TI Clinical Outcome of Triple Negative Breast Cancer in BRCA1 Mutation Carriers and Noncarriers SO CANCER LA English DT Article DE breast cancer; BRCA1; chemotherapy; triple negative; prognosis ID IMMUNOHISTOCHEMICAL MARKERS; BASAL CYTOKERATIN; ESTROGEN-RECEPTOR; YOUNG-WOMEN; RECURRENCE; EXPRESSION; SURVIVAL; SUBTYPES; METASTASES; PHENOTYPE AB Women with BRCA1 mutations develop breast cancer with similar pathologic features to sporadic triple negative (TN) breast cancer, a subtype associated with early disease relapse and poor outcome. The clinical outcome of women with and without BRCA1 mutations who had TN breast cancer treated with conventional chemotherapy were compared. METHODS: Women with stage I to III TN breast cancer who had BRCA1 testing within 36 months of diagnosis and received alkylating chemotherapy were identified from clinical databases and a Specialized Program of Research Excellence (SPORE) specimen bank. EIRCA2 mutation carriers were excluded, resulting in a study cohort of 46 BRCA1 carriers and 71 noncarriers. Sites of metastasis, relapse rates, and survival were compared among carriers and noncarriers. The median follow-up was 75 months. RESULTS: BRCA1 carriers were younger at diagnosis (P < .001) and had smaller tumors (P = .03) than noncarriers. Freedom from distant metastasis at 5 years was 76% for carriers and 70% for noncarriers (hazard ratio [HP] 0.79, P = .5). Sites of distant recurrence did not differ significantly (P = .15), although BRCA1 carriers had a propensity for brain relapse (58% vs 24%, P = .06). Overall survival at 5 years was 82% for carriers and 74% for noncarriers (HR 0.64, P = .25). Adjusting for age and stage, BRCA1 mutation status was not an independent predictor of survival (HR 0.73, P = .48). CONCLUSIONS: BRCA1 mutation carriers with TN disease had similar survival rates to noncarriers when treated with alkylating chemotherapy. Women with BRCA1-related breast cancer may benefit from novel therapies that target DNA repair, and further study is needed to identify sporadic TN breast cancers with a BRCA-deficient phenotype. Cancer 2011;117:3093-100. (C) 2011 American Cancer Society C1 [Comander, Amy; Gallagher, Bridget; Tung, Nadine] Beth Israel Deaconess Med Ctr, Div Med Oncol, Boston, MA 02215 USA. [Lee, Larissa J.; Alexander, Brian] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Lee, Larissa J.; Alexander, Brian; Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, Larissa J.; Alexander, Brian; Schnitt, Stuart J.; Comander, Amy; Garber, Judy E.; Tung, Nadine] Harvard Univ, Sch Med, Boston, MA USA. [Schnitt, Stuart J.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. RP Tung, N (reprint author), Beth Israel Deaconess Med Ctr, Div Med Oncol, 330 Brookline Ave, Boston, MA 02215 USA. EM ntung@bidmc.harvard.edu FU Breast Cancer Research Foundation; Dana Farber/Harvard Cancer Center [CA 006516]; Dana Farber/Harvard Cancer Center Breast SPORE [CA 089393] FX This research was supported by grants from the Breast Cancer Research Foundation, the Dana Farber/Harvard Cancer Center (CA 006516), and the Dana Farber/Harvard Cancer Center Breast SPORE (CA 089393). NR 37 TC 30 Z9 31 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2011 VL 117 IS 14 BP 3093 EP 3100 DI 10.1002/cncr.25911 PG 8 WC Oncology SC Oncology GA 789SQ UT WOS:000292537000006 PM 21264845 ER PT J AU Corcoran, RB Contino, G Deshpande, V Tzatsos, A Conrad, C Benes, CH Levy, DE Settleman, J Engelman, JA Bardeesy, N AF Corcoran, Ryan B. Contino, Gianmarco Deshpande, Vikram Tzatsos, Alexandros Conrad, Claudius Benes, Cyril H. Levy, David E. Settleman, Jeffrey Engelman, Jeffrey A. Bardeesy, Nabeel TI STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis SO CANCER RESEARCH LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; DUCTAL ADENOCARCINOMA; SIGNAL TRANSDUCER; CELL-LINE; SERINE PHOSPHORYLATION; MITOCHONDRIAL STAT3; JAK2 INHIBITOR; CANCER; ACTIVATION; TRANSFORMATION AB The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development, whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis. Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a more than 30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine-phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component. Correspondingly, upregulation of the IL6/LIF-gp130 pathway accounted for the strong STAT3 activation in PDAC subsets. To define functions of STAT3 in vivo, we developed mouse models that test the impact of conditional inactivation of STAT3 in KRAS-driven PDAC. We showed that STAT3 is required for the development of the earliest premalignant pancreatic lesions, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Moreover, acute STAT3 inactivation blocked PDAC initiation in a second in vivo model. Our results show that STAT3 has critical roles throughout the course of PDAC pathogenesis, supporting the development of therapeutic approaches targeting this pathway. Moreover, our work suggests that gp130 and phospho-STAT3 expression may be effective biomarkers for predicting response to JAK2 inhibitors. Cancer Res; 71(14); 5020-9. (C)2011 AACR. C1 [Corcoran, Ryan B.; Contino, Gianmarco; Tzatsos, Alexandros; Conrad, Claudius; Benes, Cyril H.; Settleman, Jeffrey; Engelman, Jeffrey A.; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Corcoran, Ryan B.; Contino, Gianmarco; Tzatsos, Alexandros; Benes, Cyril H.; Settleman, Jeffrey; Engelman, Jeffrey A.; Bardeesy, Nabeel] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Contino, Gianmarco] European Inst Oncol, Div Gen & Laparoscop Surg, Milan, Italy. [Contino, Gianmarco] Univ Milan, Milan, Italy. [Levy, David E.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Levy, David E.] NYU, Sch Med, Inst Canc, New York, NY USA. RP Bardeesy, N (reprint author), Massachusetts Gen Hosp, Ctr Canc, 185 Cambridge St, Boston, MA 02114 USA. EM Bardeesy.Nabeel@mgh.harvard.edu OI Contino, Gianmarco/0000-0001-5874-0405; Levy, David/0000-0002-7320-7788 FU AstraZeneca; NIH [T32 CA071345, R0AI28900]; Fondazione Umberto Veronesi; Associazione Italiana per la ricerca sul Cancro; AACR-Pancreatic Cancer Action Network; Waxman Foundation for Cancer Research; NIH (NCI) [2P01CA117969-06]; Lynda Verville Cancer Research Foundation; Dana-Farber/Harvard Cancer Center [P50 CA127003] FX J.A. Engelman has received research funding from AstraZeneca. The other authors disclosed no potential conflicts of interest.; R.B. Corcoran was supported by NIH training grant T32 CA071345. G. Contino was supported by Fondazione Umberto Veronesi and Associazione Italiana per la ricerca sul Cancro. D. E. Levy was supported by NIH R0AI28900. This work was supported by grants to N. Bardeesy from the AACR-Pancreatic Cancer Action Network, Waxman Foundation for Cancer Research, NIH (NCI 2P01CA117969-06), Lynda Verville Cancer Research Foundation, and Dana-Farber/Harvard Cancer Center Gastrointestinal Cancer SPORE grant P50 CA127003 (to N. Bardeesy and J.A. Engelman). NR 49 TC 130 Z9 132 U1 3 U2 19 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2011 VL 71 IS 14 BP 5020 EP 5029 DI 10.1158/0008-5472.CAN-11-0908 PG 10 WC Oncology SC Oncology GA 792QN UT WOS:000292763700028 PM 21586612 ER PT J AU Habib, SL AF Habib, Samy L. TI Tuberin and mTOR A key apoptotic pathway in diabetes SO CELL CYCLE LA English DT Editorial Material ID TUBULAR EPITHELIAL-CELLS; MOLECULE BAD; EXPRESSION; GLUCOSE C1 Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, S Texas Vet Healthcare Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. RP Habib, SL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, S Texas Vet Healthcare Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. EM habib@uthscsa.edu NR 10 TC 3 Z9 3 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUL 15 PY 2011 VL 10 IS 14 BP 2237 EP 2238 DI 10.4161/cc.10.14.15849 PG 2 WC Cell Biology SC Cell Biology GA 792ST UT WOS:000292770400001 PM 21673498 ER PT J AU Dooley, AL Winslow, MM Chiang, DY Banerji, S Stransky, N Dayton, TL Snyder, EL Senna, S Whittaker, CA Bronson, RT Crowley, D Barretina, J Garraway, L Meyerson, M Jacks, T AF Dooley, Alison L. Winslow, Monte M. Chiang, Derek Y. Banerji, Shantanu Stransky, Nicolas Dayton, Talya L. Snyder, Eric L. Senna, Stephanie Whittaker, Charles A. Bronson, Roderick T. Crowley, Denise Barretina, Jordi Garraway, Levi Meyerson, Matthew Jacks, Tyler TI Nuclear factor I/B is an oncogene in small cell lung cancer SO GENES & DEVELOPMENT LA English DT Article DE small cell lung cancer; mouse model; Nuclear factor I/B ID CONDITIONAL MOUSE MODEL; MYELOID-LEUKEMIA GENOME; COPY-NUMBER ALTERATIONS; RETINOBLASTOMA GENE; SOMATIC INACTIVATION; TOBACCO EXPOSURE; BREAST-CANCER; LIVER-CANCER; EXPRESSION; CARCINOMA AB Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed after it has metastasized. Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels. Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear factor I/B (Nfib), in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation. C1 [Dooley, Alison L.; Winslow, Monte M.; Dayton, Talya L.; Snyder, Eric L.; Senna, Stephanie; Whittaker, Charles A.; Crowley, Denise; Jacks, Tyler] MIT, Dept Biol, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Chiang, Derek Y.; Banerji, Shantanu; Stransky, Nicolas; Barretina, Jordi; Garraway, Levi; Meyerson, Matthew] Canc Program, Broad Inst, Cambridge, MA 02142 USA. [Chiang, Derek Y.; Banerji, Shantanu; Barretina, Jordi; Garraway, Levi; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Dept Med Oncol, Boston, MA 02115 USA. [Bronson, Roderick T.] Tufts Univ, Sch Med & Vet Med, Dept Pathol, North Grafton, MA 01536 USA. [Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Jacks, T (reprint author), MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM tjacks@mit.edu RI Meyerson, Matthew/E-7123-2012 FU Ludwig Center for Molecular Oncology at MIT; Howard Hughes Medical Institute; National Cancer Institute [P30-CA14051]; Alfred P. Sloan Foundation; International Association for the Study of Lung Cancer FX We acknowledge D. Feldser, E. Meylan, N. Dimitrova, and T. Papagiannakopoulos for advice, and C. Kim-Kiselak for critical reading of the manuscript. We thank Jacks laboratory members and T. Parisi for reagents. We are indebted to the Koch Institute Core Facilities: D. Cook and A. Leshinsky (Biopolymers), E. Vasile (Microscopy), and G. Paradis (Flow Cytometry). We thank M. Luo (BioMicro Center) for microarray support and M. Leversha at Sloan Kettering Cancer Center Cytogenetics core facility for FISH. This work was supported by the Ludwig Center for Molecular Oncology at MIT, the Howard Hughes Medical Institute, and in part by the Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute. T.J. is a Howard Hughes Investigator, the David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar. M. M. W was a Merck Fellow of the Damon Runyon Cancer Research Foundation and a Genentech Post-doctoral Fellow. D.Y.C. is supported by an Alfred P. Sloan Foundation Research Fellowship, and S. B. is supported by an International Association for the Study of Lung Cancer Fellowship. A. L. D., M. M. W., and T.J. designed the experiments. A. L. D., M. M. W., T. D., and S. S. performed the experiments. D.Y.C. analyzed the mouse copy number analysis, and C. W. provided bioinformatics support. S. B., N. S., J.B., L. G., and M. M. performed the human copy number analysis. E. S. and R. B. provided histopathological analysis, and D. C. provided histological support. NR 36 TC 57 Z9 61 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 JUL 15 PY 2011 VL 25 IS 14 BP 1470 EP 1475 DI 10.1101/gad.2046711 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 792PE UT WOS:000292758200004 PM 21764851 ER PT J AU Jacobsen, JC Gregory, GC Woda, JM Thompson, MN Coser, KR Murthy, V Kohane, IS Gusella, JF Seong, IS MacDonald, ME Shioda, T Lee, JM AF Jacobsen, Jessie C. Gregory, Gillian C. Woda, Juliana M. Thompson, Morgan N. Coser, Kathryn R. Murthy, Vidya Kohane, Isaac S. Gusella, James F. Seong, Ihn Sik MacDonald, Marcy E. Shioda, Toshi Lee, Jong-Min TI HD CAG-correlated gene expression changes support a simple dominant gain of function SO HUMAN MOLECULAR GENETICS LA English DT Article ID HUNTINGTONS-DISEASE GENE; KNOCK-IN MICE; TRINUCLEOTIDE REPEAT; EMBRYONIC LETHALITY; REDUCED PENETRANCE; MUTANT HUNTINGTIN; TRANSCRIPTION; MOUSE; MUTATION; EXPANSION AB Huntington's disease is initiated by the expression of a CAG repeat-encoded polyglutamine region in full-length huntingtin, with dominant effects that vary continuously with CAG size. The mechanism could involve a simple gain of function or a more complex gain of function coupled to a loss of function (e. g. dominant negative-graded loss of function). To distinguish these alternatives, we compared genome-wide gene expression changes correlated with CAG size across an allelic series of heterozygous CAG knock-in mouse embryonic stem (ES) cell lines (Hdh(Q20/7), Hdh(Q50/7), Hdh(Q91/7), Hdh(Q111/7)), to genes differentially expressed between Hdh(ex4/5/ex4/5) huntingtin null and wild-type (Hdh(Q7/7)) parental ES cells. The set of 73 genes whose expression varied continuously with CAG length had minimal overlap with the 754-member huntingtin-null gene set but the two were not completely unconnected. Rather, the 172 CAG length-correlated pathways and 238 huntingtin-null significant pathways clustered into 13 shared categories at the network level. A closer examination of the energy metabolism and the lipid/sterol/lipoprotein metabolism categories revealed that CAG length-correlated genes and huntingtin-null-altered genes either were different members of the same pathways or were in unique, but interconnected pathways. Thus, varying the polyglutamine size in full-length huntingtin produced gene expression changes that were distinct from, but related to, the effects of lack of huntingtin. These findings support a simple gain-of-function mechanism acting through a property of the full-length huntingtin protein and point to CAG-correlative approaches to discover its effects. Moreover, for therapeutic strategies based on huntingtin suppression, our data highlight processes that may be more sensitive to the disease trigger than to decreased huntingtin levels. C1 [Jacobsen, Jessie C.; Gregory, Gillian C.; Woda, Juliana M.; Thompson, Morgan N.; Murthy, Vidya; Gusella, James F.; Seong, Ihn Sik; MacDonald, Marcy E.; Lee, Jong-Min] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Coser, Kathryn R.; Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA 02129 USA. [Kohane, Isaac S.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Kohane, Isaac S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02114 USA. [Kohane, Isaac S.] I2b2 Natl Ctr Biomed Comp, Boston, MA 02115 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Simches Res Bldg,Room 5818,185 Cambridge St, Boston, MA 02114 USA. EM jlee51@partners.org RI Kohane, Isaac Kohane/K-3716-2012 OI Kohane, Isaac Kohane/0000-0003-2192-5160 FU National Institute of Neurological Disorders and Stroke [NS32765]; Massachusetts HD Center Without Walls [NS16367]; i2b2 [LM008748-01]; Huntington's Disease Society of America Coalition for the Cure Normal Function Team; Anonymous Donor; Hereditary Disease Foundation; American Australian Association; Neurological Foundation of New Zealand FX This work was supported by National Institute of Neurological Disorders and Stroke (grant number NS32765 to M.E.M.), The Massachusetts HD Center Without Walls (grant number NS16367 to J.F.G. and M.E.M.), i2b2 (grant number LM008748-01 to I.S.K.), the Huntington's Disease Society of America Coalition for the Cure Normal Function Team (to M.E.M. and J.F.G.), and an Anonymous Donor. J.M.W. was the recipient of the Milton Wexler Postdoctoral Fellowship from the Hereditary Disease Foundation. G.G. was the recipient of the Sir Keith Murdoch Fellowship from the American Australian Association. J.J. is the recipient of the Philip Wrightson Fellowship from the Neurological Foundation of New Zealand. NR 54 TC 36 Z9 36 U1 1 U2 4 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 JUL 15 PY 2011 VL 20 IS 14 BP 2846 EP 2860 DI 10.1093/hmg/ddr195 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 790AG UT WOS:000292560300013 PM 21536587 ER PT J AU Mak, RH Mccarthy, EP Das, P Hong, TS Mamon, HJ Hoffman, KE AF Mak, Raymond H. Mccarthy, Ellen P. Das, Prajnan Hong, Theodore S. Mamon, Harvey J. Hoffman, Karen E. TI ADOPTION OF PREOPERATIVE RADIATION THERAPY FOR RECTAL CANCER FROM 2000 TO 2006: A SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS PATTERNS-OF-CARE STUDY SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Rectal; Adenocarcinoma; SEER; Preoperative; Radiation therapy ID POSTOPERATIVE ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; RADIOTHERAPY; CARCINOMA; SURVIVAL; STAGE; CHEMORADIOTHERAPY; BREAST AB Purpose: The German rectal study determined that preoperative radiation therapy (RT) as a component of combined-modality therapy decreased local tumor recurrence, increased sphincter preservation, and decreased treatment toxicity compared with postoperative RT for rectal cancer. We evaluated the use of preoperative RT after the presentation of the landmark German rectal study results and examined the impact of tumor and sociodemographic factors on receiving preoperative RT. Methods and Materials: In total, 20,982 patients who underwent surgical resection for T3-T4 and/or node-positive rectal adenocarcinoma diagnosed from 2000 through 2006 were identified from the Surveillance, Epidemiology, and End Results tumor registries. We analyzed trends in preoperative RT use before and after publication of the findings from the German rectal study. We also performed multivariate logistic regression to identify factors associated with receiving preoperative RT. Results: Among those treated with RT, the proportion of patients treated with preoperative RT increased from 33.3% in 2000 to 63.8% in 2006. After adjustment for age; gender; race/ethnicity; marital status; Surveillance, Epidemiology, and End Results registry; county-level education; T stage; N stage; tumor size; and tumor grade, there was a significant association between later year of diagnosis and an increase in preoperative RT use (adjusted odds ratio, 1.26/y increase; 95% confidence interval, 1.23-1.29). When we compared the years before and after publication of the German rectal study (2000-2003 vs. 2004-2006), patients were more likely to receive preoperative RT than postoperative RT in 2004-2006 (adjusted odds ratio, 2.35; 95% confidence interval, 2.13-2.59). On multivariate analysis, patients who were older, who were female, and who resided in counties with lower educational levels had significantly decreased odds of receiving preoperative RT. Conclusions: After the publication of the landmark German rectal study, there was widespread, rapid adoption of preoperative RT for locally advanced rectal cancer. However, preoperative RT may be underused in certain sociodemographic groups. (C) 2011 Elsevier Inc. C1 [Das, Prajnan; Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Mak, Raymond H.] Harvard Radiat Oncol Program, Boston, MA USA. [Mccarthy, Ellen P.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Mamon, Harvey J.] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. RP Hoffman, KE (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, 1515 Holcombe Blvd,Unit 1202, Houston, TX 77030 USA. EM khoffman1@mdanderson.org NR 24 TC 11 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2011 VL 80 IS 4 BP 978 EP 984 DI 10.1016/j.ijrobp.2010.03.056 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 789AR UT WOS:000292486200003 PM 20961695 ER PT J AU Baldys, A Raymond, JR AF Baldys, Aleksander Raymond, John R. TI Role of c-Cbl Carboxyl Terminus in Serotonin 5-HT2A Receptor Recycling and Resensitization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; INDEPENDENT INTERNALIZATION; DOWN-REGULATION; TRAFFICKING; ENDOCYTOSIS; UBIQUITINATION; HRS; DEGRADATION; ENDOSOMES; MECHANISM AB The 5-hydroxytryptamine 2A receptor (5-HT2AR) undergoes constitutive and agonist-dependent internalization. Despite many advances in our understanding of G protein-coupled receptor trafficking, the exact mechanism of endocytic sorting of G protein-coupled receptors remains obscure. Recently, we have reported a novel finding documenting a global role for the ubiquitin ligase c-Cbl in regulating vesicular sorting of epidermal growth factor receptor (Baldys, A., Gooz, M., Morinelli, T. A., Lee, M. H., Raymond, J. R., Jr., Luttrell, L. M., and Raymond, J. R., Sr. (2009) Biochemistry 48, 1462-1473). Thus, we tested the hypothesis that c-Cbl might play a role in 5-HT2AR recycling. In this study, we demonstrated an association of 5-HT2AR with c-Cbl. Furthermore, down-regulation of c-Cbl by RNA interference blocked efficient recycling of 5-HT2AR to the plasma membrane. Immunofluorescence microscopy revealed that 5-HT2A receptors were trapped in early endosome antigen 1- and Rab11-positive sorting endosomes in cells overexpressing c-Cbl mutants lacking carboxyl termini. This inhibitory effect was associated with a relative decrease in association of c-Cbl truncation proteins with the 5-HT2AR, compared with that observed for the full-length c-Cbl fusion protein. Consistent with the delayed recycling, 5-HT2AR resensitization was greatly attenuated in the presence of c-Cbl mutants lacking carboxyl termini, as detected by changes in the cytosolic calcium. Taken together, these studies have led to the discovery that the C-terminal region of c-Cbl plays a crucial role in the temporal and spatial control of 5-HT2AR recycling. C1 Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Med Serv, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29425 USA. RP Raymond, JR (reprint author), Med Coll Wisconsin, Off President, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM jraymondj@mcw.edu FU National Institutes of Health [DK052448, GM063909]; Department of Veterans Affairs; American Heart Association; Medical University of South Carolina Division of Nephrology and Dialysis Clinics, Inc. FX This work was supported, in whole or in part, by National Institutes of Health Grants DK052448 and GM063909 (to J. R. R.), Department of Veterans Affairs Merit and Research Enhancement Award Program grants (to J. R. R.), a American Heart Association (Mid-Atlantic) fellowship (to A. B.), and laboratory endowments jointly supported by the Medical University of South Carolina Division of Nephrology and Dialysis Clinics, Inc. (to J. R. R.). NR 28 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 15 PY 2011 VL 286 IS 28 BP 24656 EP 24665 DI 10.1074/jbc.M110.119891 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 789WD UT WOS:000292547900016 PM 21464131 ER PT J AU Rahmaniyan, M Curley, RW Obeid, LM Hannun, YA Kraveka, JM AF Rahmaniyan, Mehrdad Curley, Robert W. Obeid, Lina M. Hannun, Yusuf A. Kraveka, Jacqueline M. TI Identification of Dihydroceramide Desaturase as a Direct in Vitro Target for Fenretinide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METABOLITE 4-OXO-FENRETINIDE; IRREVERSIBLE INHIBITION; ORAL FENRETINIDE; BREAST-CANCER; CELL-DEATH; CERAMIDE; SPHINGOLIPIDS; APOPTOSIS; CHEMOPREVENTION; BIOSYNTHESIS AB The dihydroceramide desaturase (DES) enzyme is responsible for inserting the 4,5-trans-double bond to the sphingolipid backbone of dihydroceramide. We previously demonstrated that fenretinide (4-HPR) inhibited DES activity in SMS-KCNR neuroblastoma cells. In this study, we investigated whether 4-HPR acted directly on the enzyme in vitro. N-C8:0-D-erythro-dihydroceramide (C-8-dhCer) was used as a substrate to study the conversion of dihydroceramide into ceramide in vitro using rat liver microsomes, and the formation of tritiated water after the addition of the tritiated substrate was detected and used to measure DES activity. NADH served as a cofactor. The apparent K-m for C-8-dhCer and NADH were 1.92 +/- 0.36 mu M and 43.4 +/- 6.47 mu M, respectively; and the V-max was 3.16 +/- 0.24 and 4.11 +/- 0.18 nmol/min/g protein. Next, the effects of 4-HPR and its metabolites on DES activity were investigated. 4-HPR was found to inhibit DES in a dose-dependent manner. At 20 min, the inhibition was competitive; however, longer incubation times demonstrated the inhibition to be irreversible. Among the major metabolites of 4-HPR, 4-oxo-N-(4-hydroxyphenyl) retinamide (4-oxo-4-HPR) showed the highest inhibitory effect with substrate concentration of 0.5 mu M, with an IC50 of 1.68 mu M as compared with an IC50 of 2.32 mu M for 4-HPR. N-(4-Methoxyphenyl) retinamide (4-MPR) and 4-Oxo-N-(4-methoxyphenyl) retinamide (4-oxo-4-MPR) had minimal effects on DES activity. A known competitive inhibitor of DES, C-8-cyclopropenylceramide was used as a positive control. These studies define for the first time a direct in vitro target for 4-HPR and suggest that inhibitors of DES may be used as therapeutic interventions to regulate ceramide desaturation and consequent function. C1 [Rahmaniyan, Mehrdad; Kraveka, Jacqueline M.] Med Univ S Carolina, Dept Pediat, Div Hematol Oncol, Charleston, SC USA. [Curley, Robert W.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Obeid, Lina M.; Hannun, Yusuf A.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Obeid, Lina M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Obeid, Lina M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Kraveka, JM (reprint author), Med Univ S Carolina, Dept Pediat Hematol Oncol, 135 Rutledge Ave,MSC 558, Charleston, SC 29425 USA. EM kravekjm@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [K01-CA100767, P01-CA97132, R01-AG016583, R01-CA49837, C06-RR018823]; Office of Research and Development; Department of Veterans Affairs; Ralph H. Johnson VA Medical Center (Charleston, SC) from the National Center for Research Resources [P20-RR17677]; Rally Foundation for Childhood Cancer Research; Monica Kreber Golf Tournament; Chase After a Cure Foundation; Hyundai Hope on Wheels FX This work was supported, in whole or in part, by National Institutes of Health Grants K01-CA100767 (to J. M. K.), P01-CA97132 (to Y. A. H. and L. M. O.), R01-AG016583 (to L. M. O.), R01-CA49837 (to R. W. C.), C06-RR018823 (Lipidomics Core), and by a MERIT award by the Office of Research and Development (to L. M. O.). This work was also supported by the Department of Veterans Affairs, Ralph H. Johnson VA Medical Center (Charleston, SC) by Grant P20-RR17677 from the National Center for Research Resources and by grants from the Rally Foundation for Childhood Cancer Research, the Monica Kreber Golf Tournament, the Chase After a Cure Foundation, and Hyundai Hope on Wheels (to J. M. K.). NR 41 TC 36 Z9 37 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 15 PY 2011 VL 286 IS 28 BP 24754 EP 24764 DI 10.1074/jbc.M111.250779 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 789WD UT WOS:000292547900026 PM 21543327 ER PT J AU Yuan, KY Jing, G Chen, JF Liu, H Zhang, K Li, YB Wu, H McDonald, JM Chen, YB AF Yuan, Kaiyu Jing, Gu Chen, Jianfeng Liu, Hui Zhang, Kui Li, Yuebin Wu, Hui McDonald, Jay M. Chen, Yabing TI Calmodulin Mediates Fas-induced FADD-independent Survival Signaling in Pancreatic Cancer Cells via Activation of Src-Extracellular Signal-regulated Kinase (ERK) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; GASTROINTESTINAL TUMOR-CELLS; DEATH DOMAIN PROTEIN; INDUCED APOPTOSIS; CHOLANGIOCARCINOMA CELLS; INHIBITORY PROTEIN; GROWTH-FACTORS; IMMUNE-SYSTEM; CD95 LIGAND; PROLIFERATION AB Pancreatic cancer remains a devastating malignancy with a poor prognosis and is largely resistant to current therapies. To understand the resistance of pancreatic tumors to Fas death receptor-induced apoptosis, we investigated the molecular mechanisms of Fas-activated survival signaling in pancreatic cancer cells. We found that knockdown of the Fas-associated protein with death domain (FADD), the adaptor that mediates downstream signaling upon Fas activation, rendered Fas-sensitive MiaPaCa-2 and BxPC-3 pancreatic cells resistant to Fas-induced apoptosis. By contrast, Fas activation promoted the survival of the FADD knockdown MiaPaCa-2 and BxPC-3 cells in a concentration-dependent manner. The pharmacological inhibitor of ERK, PD98059, abrogated Fas-promoted cell survival in FADD knockdown MiaPaCa-2 and BxPC-3 cells. Furthermore, increased phosphorylation of Src was demonstrated to mediate Fas-induced ERK activation and cell survival. Immunoprecipitation of Fas in the FADD knockdown cells identified the presence of increased calmodulin, Src, and phosphorylated Src in the Fas-associated protein complex upon Fas activation. Trifluoperazine, a calmodulin antagonist, inhibited Fas-induced recruitment of calmodulin, Src, and phosphorylated Src. Consistently, trifluoperazine blocked Fas-promoted cell survival. A direct interaction of calmodulin and Src and their binding site were identified with recombinant proteins. These results support an essential role of calmodulin in mediating Fas-induced FADD-independent activation of Src-ERK signaling pathways, which promote survival signaling in pancreatic cancer cells. Understanding the molecular mechanisms responsible for the resistance of pancreatic cells to apoptosis induced by Fas-death receptor signaling may provide molecular insights into designing novel therapies to treat pancreatic tumors. C1 [Yuan, Kaiyu; Jing, Gu; Chen, Jianfeng; McDonald, Jay M.; Chen, Yabing] Univ Alabama, Sch Dent, Dept Pathol, Birmingham, AL 35294 USA. [Liu, Hui] Univ Alabama, Sch Dent, Dept Physiol, Birmingham, AL 35294 USA. [Zhang, Kui] Univ Alabama, Sch Dent, Dept Biostat, Birmingham, AL 35294 USA. [Li, Yuebin; Wu, Hui] Univ Alabama, Sch Dent, Dept Pediat Dent, Birmingham, AL 35294 USA. [Li, Yuebin; Wu, Hui] Univ Alabama, Sch Med, Dept Pediat Dent, Birmingham, AL 35294 USA. [Yuan, Kaiyu; Jing, Gu; Chen, Jianfeng; McDonald, Jay M.; Chen, Yabing] Univ Alabama, Sch Med, Dept Pathol, Birmingham, AL 35294 USA. [Liu, Hui] Univ Alabama, Sch Med, Dept Physiol, Birmingham, AL 35294 USA. [Zhang, Kui] Univ Alabama, Sch Med, Dept Biostat, Birmingham, AL 35294 USA. [McDonald, Jay M.; Chen, Yabing] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. RP Chen, YB (reprint author), Univ Alabama, Sch Dent, Dept Pathol, 710 Shelby Res Bldg,1825 Univ Blvd, Birmingham, AL 35294 USA. EM ybchen@uab.edu FU Department of Pathology, University of Alabama at Birmingham; Veterans Affairs merit review award FX This work was supported in part by start-up funds from the Department of Pathology, University of Alabama at Birmingham (to Y. C.), and a Veterans Affairs merit review award (to J. M. M.). NR 59 TC 20 Z9 21 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 15 PY 2011 VL 286 IS 28 BP 24776 EP 24784 DI 10.1074/jbc.M110.202804 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 789WD UT WOS:000292547900028 PM 21613217 ER PT J AU Zhou, L Opalinska, J Sohal, D Yu, YT Mo, YK Bhagat, T Abdel-Wahab, O Fazzari, M Figueroa, M Alencar, C Zhang, JH Kambhampati, S Parmar, S Nischal, S Hueck, C Suzuki, M Freidman, E Pellagatti, A Boultwood, J Steidl, U Sauthararajah, Y Yajnik, V Mcmahon, C Gore, SD Platanias, LC Levine, R Melnick, A Wickrema, A Greally, JM Vermaa, A AF Zhou, Li Opalinska, Joanna Sohal, Davendra Yu, Yiting Mo, Yongkai Bhagat, Tushar Abdel-Wahab, Omar Fazzari, Melissa Figueroa, Maria Alencar, Cristina Zhang, Jinghang Kambhampati, Suman Parmar, Simrit Nischal, Sangeeta Hueck, Christoph Suzuki, Masako Freidman, Ellen Pellagatti, Andrea Boultwood, Jacqueline Steidl, Ulrich Sauthararajah, Yogen Yajnik, Vijay Mcmahon, Christine Gore, Steven D. Platanias, Leonidas C. Levine, Ross Melnick, Ari Wickrema, Amittha Greally, John M. Vermaa, Amit TI Aberrant Epigenetic and Genetic Marks Are Seen in Myelodysplastic Leukocytes and Reveal Dock4 as a Candidate Pathogenic Gene on Chromosome 7q SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA METHYLATION; CYTOSINE METHYLATION; EXPRESSION PROFILES; POOR-PROGNOSIS; CD34(+) CELLS; LEUKEMIA; KINASE; HYPERMETHYLATION; PREDICTS; CANCER AB Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways. Additionally, array comparative genomic hybridization revealed that novel as well as previously characterized deletions and amplifications could also be visualized in peripheral blood leukocytes, thus potentially reducing the need for bone marrow samples for future studies. Using integrative analysis, potentially pathogenic genes silenced by genetic deletions and aberrant hypermethylation in different patients were identified. DOCK4, a GTPase regulator located in the commonly deleted 7q31 region, was identified by this unbiased approach. Significant hypermethylation and reduced expression of DOCK4 in MDS bone marrow stem cells was observed in two large independent datasets, providing further validation of our findings. Finally, DOCK4 knockdown in primary marrow CD34(+) stem cells led to decreased erythroid colony formation and increased apoptosis, thus recapitulating the bone marrow failure seen in MDS. These findings reveal widespread novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region. C1 [Zhou, Li; Opalinska, Joanna; Sohal, Davendra; Yu, Yiting; Mo, Yongkai; Bhagat, Tushar; Fazzari, Melissa; Alencar, Cristina; Zhang, Jinghang; Nischal, Sangeeta; Hueck, Christoph; Suzuki, Masako; Freidman, Ellen; Steidl, Ulrich; Mcmahon, Christine; Greally, John M.; Vermaa, Amit] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Abdel-Wahab, Omar; Levine, Ross] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Figueroa, Maria; Melnick, Ari] Weill Cornell Med Sch, New York, NY 10065 USA. [Kambhampati, Suman] Kansas City Vet Affairs Med Ctr, Kansas City, MO 64128 USA. [Parmar, Simrit] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Pellagatti, Andrea; Boultwood, Jacqueline] John Radcliffe Hosp, Oxford OX3 9DU, England. [Wickrema, Amittha] Univ Chicago, Sch Med, Chicago, IL 60637 USA. [Sauthararajah, Yogen] Cleveland Clin, Cleveland, OH 44195 USA. [Yajnik, Vijay] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gore, Steven D.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Platanias, Leonidas C.] Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Platanias, Leonidas C.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL 60611 USA. RP Greally, JM (reprint author), Albert Einstein Coll Med, Bronx, NY 10461 USA. EM john.greally@einstein.yu.edu; amit.verma@einstein.yu.edu OI Pellagatti, Andrea/0000-0002-6122-0221; Abdel-Wahab, Omar/0000-0002-3907-6171; Boultwood, Jacqueline/0000-0002-4330-2928 FU National Institutes of Health [RO1HL082846, RO1AG02913801, CA009173]; American Cancer Society; Gabrielle Angel Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants RO1HL082846, RO1AG02913801, and CA009173. This work was also supported by American Cancer Society, Partnership for Cures grant and the Gabrielle Angel Foundation. NR 44 TC 20 Z9 22 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 JUL 15 PY 2011 VL 286 IS 28 BP 25211 EP 25223 DI 10.1074/jbc.M111.235028 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 789WD UT WOS:000292547900067 PM 21532034 ER PT J AU Vetting, MW Hegde, SS Wang, MH Jacoby, GA Hooper, DC Blanchard, JS AF Vetting, Matthew W. Hegde, Subray S. Wang, Minghua Jacoby, George A. Hooper, David C. Blanchard, John S. TI Structure of QnrB1, a Plasmid-mediated Fluoroquinolone Resistance Factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PENTAPEPTIDE REPEAT PROTEINS; QUINOLONE-RESISTANCE; DNA GYRASE; IIA TOPOISOMERASES; CRYSTAL-STRUCTURE; INTRINSIC RESISTANCE; TRANSFERABLE PLASMID; MICROCIN B17; GENE; CRYSTALLIZATION AB QnrB1 is a plasmid-encoded pentapeptide repeat protein (PRP) that confers a moderate degree of resistance to fluoroquinolones. Its gene was cloned into an expression vector with an N-terminal polyhistidine tag, and the protein was purified by nickel affinity chromatography. The structure of QnrB1 was determined by a combination of trypsinolysis, surface mutagenesis, and single anomalous dispersion phasing. QnrB1 folds as a right-handed quadrilateral beta-helix with a highly asymmetric dimeric structure typical of PRP-topoisomerase poison resistance factors. The threading of pentapeptides into the beta-helical fold is interrupted by two noncanonical PRP sequences that produce outward projecting loops that interrupt the regularity of the PRP surface. Deletion of the larger upper loop eliminated the protective effect of QnrB1 on DNA gyrase toward inhibition by quinolones, whereas deletion of the smaller lower loop drastically reduced the protective effect. These loops are conserved among all plasmid-based Qnr variants (QnrA, QnrC, QnrD, and QnrS) and some chromosomally encoded Qnr varieties. A mechanism in which PRP-topoisomerase poison resistance factors bind to and disrupt the quinolone-DNA-gyrase interaction is proposed. C1 [Vetting, Matthew W.; Hegde, Subray S.; Blanchard, John S.] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA. [Wang, Minghua; Hooper, David C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Jacoby, George A.] Lahey Clin Fdn, Burlington, MA 01805 USA. RP Blanchard, JS (reprint author), Albert Einstein Coll Med, Dept Biochem, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM blanchar@aecom.yu.edu FU National Institutes of Health [R01AI033696, R01AI057576] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01AI033696 (to J. S. B.) and R01AI057576 (to D. C. H. and G. A. J.). NR 55 TC 25 Z9 27 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 JUL 15 PY 2011 VL 286 IS 28 BP 25265 EP 25273 DI 10.1074/jbc.M111.226936 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 789WD UT WOS:000292547900072 PM 21597116 ER PT J AU Novgorodov, SA Wu, BX Gudz, TI Bielawski, J Ovchinnikova, TV Hannun, YA Obeid, LM AF Novgorodov, Sergei A. Wu, Bill X. Gudz, Tatyana I. Bielawski, Jacek Ovchinnikova, Tatiana V. Hannun, Yusuf A. Obeid, Lina M. TI Novel Pathway of Ceramide Production in Mitochondria THIOESTERASE AND NEUTRAL CERAMIDASE PRODUCE CERAMIDE FROM SPHINGOSINE AND ACYL-CoA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAT-LIVER MITOCHONDRIA; PERMEABILITY TRANSITION PORE; RADIATION-INDUCED APOPTOSIS; LONG-CHAIN; SPHINGOLIPID METABOLISM; COA THIOESTERASES; MOLECULAR-CLONING; ENDOPLASMIC-RETICULUM; ENZYMATIC HYDROLYSIS; RESPIRATORY-CHAIN AB Reports suggest that excessive ceramide accumulation in mitochondria is required to initiate the intrinsic apoptotic pathway and subsequent cell death, but how ceramide accumulates is unclear. Here we report that liver mitochondria exhibit ceramide formation from sphingosine and palmitoyl-CoA and from sphingosine and palmitate. Importantly, this activity was markedly decreased in liver from neutral ceramidase (NCDase)-deficient mice. Moreover, the levels of ceramide were dissimilar in liver mitochondria of WT and NCDase KO mice. These results suggest that NCDase is a key participant of ceramide formation in liver mitochondria. We also report that highly purified liver mitochondria have ceramidase, reverse ceramidase, and thioesterase activities. Increased accessibility of palmitoyl-CoA to the mitochondrial matrix with the pore-forming peptide zervamicin IIB resulted in 2-fold increases in palmitoyl-CoA hydrolysis by thioesterase. This increased hydrolysis was accompanied by an increase in ceramide formation, demonstrating that both outer membrane and matrix localized thioesterases can regulate ceramide formation. Also, ceramide formation might occur both in the outer mitochondrial membrane and in the mitochondrial matrix, suggesting the existence of distinct ceramide pools. Taken together, these results suggest that the reverse activity of NCDase contributes to sphingolipid homeostasis in this organelle in vivo. C1 [Novgorodov, Sergei A.; Obeid, Lina M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Gudz, Tatyana I.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Novgorodov, Sergei A.; Wu, Bill X.; Bielawski, Jacek; Hannun, Yusuf A.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Gudz, Tatyana I.; Obeid, Lina M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Ovchinnikova, Tatiana V.] Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. RP Obeid, LM (reprint author), Med Univ S Carolina, Dept Med, 114 Doughty St,MSC779, Charleston, SC 29425 USA. EM obeidl@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [AG16583, CA87584, P20RR17677-04]; Russian Federal Target Program [NK-602P/19, P1159]; Office of Research and Development, Department of Veterans Affairs, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; National Center for Research Resources [C06 RR018823] FX This work was supported, in whole or in part, by National Institutes of Health Grants AG16583 (to L.M.O.), CA87584 (to Y.A.H.), and P20RR17677-04 (to T.I.G.). This work was also supported by the Russian Federal Target Program "Scientific and Science-Educational Personnel of Innovative Russia" (project NK-602P/19, state contract P1159) (to T.V.O.). This manuscript is based upon work supported in part by a MERIT Awards by the Office of Research and Development, Department of Veterans Affairs, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (to L.M.O. and T.I.G.).; We thank Kathy Wiita-Fisk for administrative assistance, Stefka Spassieva for critical reading of the manuscript, and Christian Frezza for valuable advice related to isolation of mouse mitochondria. We thank Dr. Richard Proia for generously providing anti-NCDase antibody. We thank Dr. Jennifer G. Schnellmann for help with preparation of the manuscript. Measurement of sphingolipids was conducted by the Lipidomics Core of MUSC in a facility constructed with support from the National Institutes of Health Grant C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. NR 96 TC 39 Z9 41 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 15 PY 2011 VL 286 IS 28 BP 25352 EP 25362 DI 10.1074/jbc.M110.214866 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 789WD UT WOS:000292547900081 PM 21613224 ER PT J AU Counter, SA Buchanan, LH Ortega, F van der Velde, J Borg, E AF Counter, S. A. Buchanan, Leo H. Ortega, Fernando van der Velde, Jeannette Borg, Erik TI Assessment of auditory brainstem function in lead-exposed children using stapedius muscle reflexes SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Middle ear muscle; Stapedius; Acoustic reflex; Auditory nerve; Facial nerve; Impedance; Immittance; Lead poisoning; Brainstem; Auditory nervous system ID BLOOD LEAD; EVOKED-POTENTIALS; ACOUSTIC REFLEX; DISORDERS; DYSFUNCTION; DIAGNOSIS; RESPONSES; DEFICITS; WORKERS; SYSTEM AB The purpose of this study was to investigate the neurological integrity and physiological status of the auditory brainstem tracts and nuclei in children with chronic lead (Pb) exposure using non-invasive acoustic stapedius reflex (ASR) measurements of afferent and efferent-neuromuscular auditory function. Following audiological examinations, uncrossed (ipsilateral) and crossed (contralateral) brainstem ASR responses were evoked by pure tone (500, 1000, and 2000 Hz), and broadband noise (bandwidth: 125-4000 Hz) stimulus activators. The ASR threshold (ASRT), amplitude growth, and decay/fatigue were measured by conventional clinical middle ear immittance methods in a group of Andean children (age range: 2-18 years) with a history of chronic environmental Pb exposure from occupational Pb glazing. Blood lead (PbB) levels of the study group (n = 117) ranged from 4.0 to 83.7 mu g/dL with a mean PbB level of 33.5 mu g/dL (SD: 23.6; median: 33.0: CDC III Classification). The PbB distribution data indicated that 77.8% (n = 91) of the children had PbB levels greater than the CDC action line of 10 mu g/dL Repeatable, normal ASRTs were elicited for ipsilateral (mean: <= 90 dB HL) and contralateral (mean: <= 97dB HL) stimulation for each acoustic activator. Spearman Rho correlation analysis indicated no significant association between PbB level and ipsilateral or contralateral ASRT for any of the stimulus activators. The ASR amplitude growth results showed typical growth functions with no Pb-associated aberrations. No statistical association was found between ASR decay/adaptation (ASRD) and PbB level for any of the stimulus activators. The results of stapedius muscle reflex testing using several stimulus activators showed no significant relationship between PbB level and the physiological integrity of the auditory brainstem mediated ASR responses in children with chronic Pb exposure and elevated PbB levels. (C) 2011 Published by Elsevier B.V. C1 [Counter, S. A.] Harvard Univ, Sch Med, Dept Neurol, Biol Labs, Cambridge, MA 02138 USA. [Counter, S. A.] Massachusetts Gen Hosp, Dept Neurophysiol, Boston, MA 02114 USA. [Buchanan, Leo H.] Univ Massachusetts, Dept Pediat, Sch Med, Eunice Kennedy Shriver Ctr, Waltham, MA USA. [Buchanan, Leo H.] Harvard Univ, Hlth Serv, Dept Otolaryngol, Cambridge, MA 02138 USA. [Ortega, Fernando] Univ San Francisco Quito, Coll Hlth Sci, Integrated Community Dev Dept, Quito, Ecuador. [van der Velde, Jeannette] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Borg, Erik] Univ Hosp Orebro, Audiol Res Ctr Ahlsens, Orebro, Sweden. RP Counter, SA (reprint author), Harvard Univ, Sch Med, Dept Neurol, Biol Labs, 16 Divin Ave, Cambridge, MA 02138 USA. EM allen_counter@harvard.edu FU Universidad San Francisco de Quito FX We appreciate the support of Ing. Luis Parodi V., Dr. Miguel Falconi Puig, Dr. Gonzalo Mantilla, and the Universidad San Francisco de Quito. We are grateful to Dr. Jeremy Bloxham, Harvard University Biological Laboratories, and University of Massachusetts Medical School/Shriver Center for support. We thank Anthony B. Jacobs for excellent technical assistance; Dr. Nader Rafai, and the Boston Children's Hospital Department of Laboratory Medicine for laboratory support. NR 51 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD JUL 15 PY 2011 VL 306 IS 1-2 BP 29 EP 37 DI 10.1016/j.jns.2011.04.003 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 791KN UT WOS:000292664200006 PM 21546039 ER PT J AU Doyle, T Chen, ZM Obeid, LM Salvemini, D AF Doyle, Tim Chen, Zhoumou Obeid, Lina M. Salvemini, Daniela TI Sphingosine-1-phosphate acting via the S1P(1) receptor is a downstream signaling pathway in ceramide-induced hyperalgesia SO NEUROSCIENCE LETTERS LA English DT Article DE Ceramide; Sphingosine-1-phosphate; Sphingosine kinase; Hyperalgesia; Sphingosine-1-phosphate receptor subtype 1 (S1PR(1)) ID RAT SENSORY NEURONS; NERVE GROWTH-FACTOR; MORPHINE ANTINOCICEPTIVE TOLERANCE; SPHINGOSINE KINASE; THERAPEUTIC TARGETS; INFLAMMATORY PAIN; SPINAL CERAMIDE; IN-VIVO; SPHINGOLIPIDS; EXCITABILITY AB Ceramide is a potent pro-inflammatory sphingolipid recently shown to exert potent hyperalgesic responses in rats. Once generated, ceramide is converted by sphingosine kinase (SphK) 1 and/or 2 to one of its active metabolite sphingosine-1-phosphate (SIP), which in turn signals through G-protein coupled S1P receptors. The objectives of this paper were to define whether ceramide-induced hyperalgesia is driven by S1P. Our results show that intraplantar injection of ceramide in rats led to a time-dependent development of thermal hyperalgesia that was associated with an increase in tumor necrosis factor-a (TNF-alpha) in paw tissues. The development of hyperalgesia was significantly attenuated by a soluble TNF receptor I. TNF-alpha is known to activate SphK1, thus SIP production, and our results demonstrate that, the development of hyperalgesia was attenuated in a dose-dependent fashion by a well characterized inhibitor of SphK1 and SphK2 (SK-I) and by a murine monoclonal anti-SI P antibody (LT1002). LT1017, the isotype-matched control monoclonal antibody for LT1002, had no effect. Our results further demonstrate that SIP contributes to the development of hyperalgesia via the SIP receptor 1 subtype (S1PR(1)), since responses were blocked by a well characterized S1PR(1) antagonist, W146, but not by its inactive enantiomer, W140. Collectively, these results provide mechanistic evidence implicating the S1P-to-S1PR(1) pathway as a downstream signaling pathway in ceramide-induced hyperalgesia. Targeting SIP may be a novel therapeutic approach in pain management. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Doyle, Tim; Chen, Zhoumou; Salvemini, Daniela] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. [Obeid, Lina M.] Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. [Obeid, Lina M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Salvemini, D (reprint author), St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, 1402 S Grand Blvd, St Louis, MO 63104 USA. EM salvemd@slu.edu OI obeid, lina/0000-0002-0734-0847 FU VA Merit Award [R01 GM062887]; [R01 DA024074]; [R21 DA023056] FX Supported by R01 DA024074 and R21 DA023056 (DS), and VA Merit Award and R01 GM062887 (LO). We would like to thank Amgen (Thousand Oaks, CA) for their kind gift of the soluble TNF receptor I (sTNFR1) and Lpath (San Diego, CA) for their kind gift of the murine monoclonal anti-S1P antibody. LT1002 and LT1017 (isotype-matched control mAb). NR 33 TC 12 Z9 13 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 15 PY 2011 VL 499 IS 1 BP 4 EP 8 DI 10.1016/j.neulet.2011.05.018 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 793EW UT WOS:000292804200002 PM 21605625 ER PT J AU Mazzanti, ML Walvick, RP Zhou, X Sun, YP Shah, N Mansour, J Gereige, J Albert, MS AF Mazzanti, Mary L. Walvick, Ronn P. Zhou, Xin Sun, Yanping Shah, Niral Mansour, Joey Gereige, Jessica Albert, Mitchell S. TI Distribution of Hyperpolarized Xenon in the Brain Following Sensory Stimulation: Preliminary MRI Findings SO PLOS ONE LA English DT Article ID CEREBRAL-BLOOD-FLOW; LASER-POLARIZED XE-129; POSITRON-EMISSION-TOMOGRAPHY; FUNCTIONAL MRI; SOMATOSENSORY STIMULATION; FOREPAW STIMULATION; RELAXATION-TIMES; CARRIER AGENTS; RAT; NMR AB In hyperpolarized xenon magnetic resonance imaging (HP Xe-129 MRI), the inhaled spin-1/2 isotope of xenon gas is used to generate the MR signal. Because hyperpolarized xenon is an MR signal source with properties very different from those generated from water-protons, HP Xe-129 MRI may yield structural and functional information not detectable by conventional proton-based MRI methods. Here we demonstrate the differential distribution of HP Xe-129 in the cerebral cortex of the rat following a pain stimulus evoked in the animal's forepaw. Areas of higher HP Xe-129 signal corresponded to those areas previously demonstrated by conventional functional MRI (fMRI) methods as being activated by a forepaw pain stimulus. The percent increase in HP Xe-129 signal over baseline was 13-28%, and was detectable with a single set of pre and post stimulus images. Recent innovations in the production of highly polarized Xe-129 should make feasible the emergence of HP Xe-129 MRI as a viable adjunct method to conventional MRI for the study of brain function and disease. C1 [Mazzanti, Mary L.; Walvick, Ronn P.; Zhou, Xin; Sun, Yanping; Shah, Niral; Mansour, Joey; Gereige, Jessica; Albert, Mitchell S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Zhou, Xin] Chinese Acad Sci, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance & Atom & Mol Phys, Wuhan Ctr Magnet Resonance, Wuhan, Peoples R China. [Sun, Yanping] Dana Farber Canc Inst, Ctr Biomed Imaging Oncol, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Albert, Mitchell S.] Thunder Bay Reg Res Inst, Thunder Bay, ON, Canada. RP Mazzanti, ML (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. EM xinzhou@wipm.ac.cn; albertmi@tbh.net RI Zhou, Xin/D-9987-2016 OI Zhou, Xin/0000-0002-5580-7907 FU Amersham Health Inc. FX Amersham Health Inc., provided funding for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 21 Z9 21 U1 3 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 15 PY 2011 VL 6 IS 7 AR e21607 DI 10.1371/journal.pone.0021607 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HT UT WOS:000292811700001 PM 21789173 ER PT J AU Min, JL Taylor, JM Richards, JB Watts, T Pettersson, FH Broxholme, J Ahmadi, KR Surdulescu, GL Lowy, E Gieger, C Newton-Cheh, C Perola, M Soranzo, N Surakka, I Lindgren, CM Ragoussis, J Morris, AP Cardon, LR Spector, TD Zondervan, KT AF Min, Josine L. Taylor, Jennifer M. Richards, J. Brent Watts, Tim Pettersson, Fredrik H. Broxholme, John Ahmadi, Kourosh R. Surdulescu, Gabriela L. Lowy, Ernesto Gieger, Christian Newton-Cheh, Chris Perola, Markus Soranzo, Nicole Surakka, Ida Lindgren, Cecilia M. Ragoussis, Jiannis Morris, Andrew P. Cardon, Lon R. Spector, Tim D. Zondervan, Krina T. TI The Use of Genome-Wide eQTL Associations in Lymphoblastoid Cell Lines to Identify Novel Genetic Pathways Involved in Complex Traits SO PLOS ONE LA English DT Article ID COMMON VARIANTS; MICROARRAY PLATFORMS; EXPRESSION ANALYSES; LOCI; DISEASE; RISK; METAANALYSIS; POPULATIONS; NUCLEOTIDE; PHENOTYPES AB The integrated analysis of genotypic and expression data for association with complex traits could identify novel genetic pathways involved in complex traits. We profiled 19,573 expression probes in Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) from 299 twins and correlated these with 44 quantitative traits (QTs). For 939 expressed probes correlating with more than one QT, we investigated the presence of eQTL associations in three datasets of 57 CEU HapMap founders and 86 unrelated twins. Genome-wide association analysis of these probes with 2.2 m SNPs revealed 131 potential eQTLs (1,989 eQTL SNPs) overlapping between the HapMap datasets, five of which were in cis (58 eQTL SNPs). We then tested 535 SNPs tagging the eQTL SNPs, for association with the relevant QT in 2,905 twins. We identified nine potential SNP-QT associations (P<0.01) but none significantly replicated in five large consortia of 1,097-16,129 subjects. We also failed to replicate previous reported eQTL associations with body mass index, plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides levels derived from lymphocytes, adipose and liver tissue. Our results and additional power calculations suggest that proponents may have been overoptimistic in the power of LCLs in eQTL approaches to elucidate regulatory genetic effects on complex traits using the small datasets generated to date. Nevertheless, larger tissue-specific expression data sets relevant to specific traits are becoming available, and should enable the adoption of similar integrated analyses in the near future. C1 [Min, Josine L.; Pettersson, Fredrik H.; Lindgren, Cecilia M.; Morris, Andrew P.; Cardon, Lon R.; Zondervan, Krina T.] Univ Oxford, Wellcome Trust Ctr Human Genet, Genet & Genom Epidemiol Unit, Oxford, England. [Richards, J. Brent] McGill Univ, Dept Med, Montreal, PQ, Canada. [Richards, J. Brent] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Richards, J. Brent; Ahmadi, Kourosh R.; Surdulescu, Gabriela L.; Soranzo, Nicole; Spector, Tim D.] Kings Coll London, Twin Res & Genet Epidemiol Unit, London WC2R 2LS, England. [Watts, Tim; Ragoussis, Jiannis] Univ Oxford, Wellcome Trust Ctr Human Genet, Genom Lab, Oxford, England. [Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Munich, Germany. [Newton-Cheh, Chris] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Broad Inst Harvard & MIT, Boston, MA USA. [Perola, Markus; Surakka, Ida] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Perola, Markus; Surakka, Ida] Natl Inst Hlth Welf, Helsinki, Finland. [Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge, England. [Cardon, Lon R.] GlaxoSmithKline Inc, King Of Prussia, PA USA. RP Min, JL (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Genet & Genom Epidemiol Unit, Oxford, England. EM josine.min@well.ox.ac.uk; krinaz@well.ox.ac.uk RI Taylor, Jennifer/A-1686-2010; Zondervan, Krina/M-1143-2013; OI Taylor, Jennifer/0000-0003-4231-0181; Zondervan, Krina/0000-0002-0275-9905; Lowy Gallego, Ernesto/0000-0001-9312-1159; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554 FU European Community [LSHG-CT-2004-512066]; Wellcome Trust; Department of Health NIHR Biomedical Centre; Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany; German Federal Ministry of Education and Research (BMBF); German National Genome Research Network (NGFN) FX This work was supported The European Community's Sixth Framework Programme, MolPAGE Consortium [LSHG-CT-2004-512066] and by the Wellcome Trust [Wellcome Trust Senior Fellowship to A.P.M. and Wellcome Trust Career Development Fellowships to C.M.L. and K.T.Z.]. TwinsUK is supported by a Department of Health NIHR Biomedical Centre Grant to Guy and St Thomas' Hospitals and King's College London. The MONICA/KORA Augsburg studies were supported by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF) and the German National Genome Research Network (NGFN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 20 Z9 21 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 15 PY 2011 VL 6 IS 7 AR e22070 DI 10.1371/journal.pone.0022070 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HT UT WOS:000292811700020 PM 21789213 ER PT J AU Kida, K Yamada, M Tokuda, K Marutani, E Kakinohana, M Kaneki, M Ichinose, F AF Kida, Kotaro Yamada, Marina Tokuda, Kentaro Marutani, Eizo Kakinohana, Manabu Kaneki, Masao Ichinose, Fumito TI Inhaled Hydrogen Sulfide Prevents Neurodegeneration and Movement Disorder in a Mouse Model of Parkinson's Disease SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID OXIDATIVE STRESS; VERTEBRATE BLOOD; MPTP; MICE; NEUROPROTECTION; INFLAMMATION; NEURONS AB Parkinson's disease is one of the major neurodegenerative disorders. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cause Parkinson's disease like symptoms and biochemical changes in humans and animals. Hydrogen sulfide (H(2)S) has been shown to protect neurons. The goal of this study was to examine the effects of inhaled H(2)S in a mouse model of Parkinson's disease induced by MPTP. Male C57BL/6J mice received MPTP at 80 mg/kg and breathed air with or without 40 ppm H(2)S for 8 h/day for 7 days. Administration of MPTP induced movement disorder and decreased tyrosine hydroxylase (TH)-containing neurons in the substantia nigra and striatum in mice that breathed air. Inhalation of H(2)S prevented the MPTP-induced movement disorder and the degeneration of TH-containing neurons. Inhaled H(2)S also prevented apoptosis of the TH-containing neurons and gliosis in nigrostriatal region after administration of MPTP. The neuroprotective effect of inhaled H(2)S after MPTP administration was associated with upregulation of genes encoding antioxidant proteins, including heme oxygenase-1 and glutamate-cysteine ligase. These observations suggest that inhaled H(2)S prevents neurodegeneration in a mouse model of Parkinson's disease induced by MPTP, potentially via upregulation of antioxidant defense mechanisms and inhibition of inflammation and apoptosis in the brain. Antioxid. Redox Signal. 15, 343-352. C1 [Kida, Kotaro; Yamada, Marina; Tokuda, Kentaro; Marutani, Eizo; Kakinohana, Manabu; Kaneki, Masao; Ichinose, Fumito] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Yamada, Marina; Kaneki, Masao] Shriners Hosp Children, Boston, MA USA. RP Ichinose, F (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 149 13th St,4315, Charlestown, MA 02129 USA. EM fichinose@partners.org FU NIH [DK05827, HL101930] FX This work was supported by grants from NIH DK05827 to Dr. Kaneki and HL101930 to Dr. Ichinose. NR 33 TC 51 Z9 58 U1 0 U2 16 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL 15 PY 2011 VL 15 IS 2 BP 343 EP 352 DI 10.1089/ars.2010.3671 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 787FC UT WOS:000292361000004 PM 21050138 ER PT J AU Terada, R Warren, S Lu, JT Chien, KR Wessels, A Kasahara, H AF Terada, Ryota Warren, Sonisha Lu, Jonathan T. Chien, Kenneth R. Wessels, Andy Kasahara, Hideko TI Ablation of Nkx2-5 at mid-embryonic stage results in premature lethality and cardiac malformation SO CARDIOVASCULAR RESEARCH LA English DT Article DE Genetics; Heart defects; Congenital; Conduction; Contractility ID CONGENITAL HEART-DISEASE; LIGHT-CHAIN KINASE; HOMEOBOX GENE; CONDUCTION SYSTEM; RAT-HEART; ATRIOVENTRICULAR-CONDUCTION; CONNEXIN40-DEFICIENT MICE; HOMEODOMAIN PROTEIN; CONTRACTION DEFECTS; VERTEBRATE HEART AB Aims Human congenital heart disease linked to mutations in the homeobox transcription factor, NKX2-5, is characterized by cardiac anomalies, including atrial and ventricular septal defects as well as conduction and occasional defects in contractility. In the mouse, homozygous germline deletion of Nkx2-5 gene results in death around E10.5. It is, however, not established whether Nkx2-5 is necessary for cardiac development beyond this embryonic stage. Because human NKX2-5 mutations are related to septum secundum type atrial septal defects (ASD), we hypothesized that Nkx2-5 deficiency during the processes of septum secundum formation may cause cardiac anomalies; thus, we analysed mice with tamoxifen-inducible Nkx2-5 ablation beginning at E12.5 when the septum secundum starts to develop. Methods and results Using tamoxifen-inducible Nkx2-5 gene-targeted mice, this study demonstrates that Nkx2-5 ablation beginning at E12.5 results in embryonic death by E17.5. Analysis of mutant embryos at E16.5 shows arrhythmias, contraction defects, and cardiac malformations, including ASD. Quantitative measurements using serial section histology and three-dimensional reconstruction demonstrate growth retardation of the septum secundum and enlarged foramen ovale in Nkx2-5-ablated embryos. Functional cardiac defects may be attributed to abnormal expression of transcripts critical for conduction and contraction, including cardiac voltage-gated Na(+) channel pore-forming alpha-subunit (Na(v)1.5-alpha), gap junction protein connexin40, cardiac myosin light chain kinase, and sarcolipin within 4 days after tamoxifen injection. Conclusion Nkx2-5 is necessary for survival after the mid-embryonic stage for cardiac function and formation by regulating the expression of its downstream target genes. C1 [Terada, Ryota; Warren, Sonisha; Kasahara, Hideko] Univ Florida, Coll Med, Dept Physiol & Funct Genom, Gainesville, FL 32610 USA. [Lu, Jonathan T.] Columbia Univ, Dept Med, Div Cardiol, New York, NY USA. [Chien, Kenneth R.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Wessels, Andy] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. RP Kasahara, H (reprint author), Univ Florida, Coll Med, Dept Physiol & Funct Genom, 1600 SW Archer Rd M540, Gainesville, FL 32610 USA. EM hkasahar@phys.med.ufl.edu FU National Institutes of Health [HL081577] FX This work was funded by the National Institutes of Health (HL081577 to H.K.). NR 64 TC 31 Z9 37 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JUL 15 PY 2011 VL 91 IS 2 BP 289 EP 299 DI 10.1093/cvr/cvr037 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 786WM UT WOS:000292338600013 PM 21285290 ER PT J AU Naunheim, MR Walcott, BP Nahed, BV Simpson, AK Agarwalla, PK Coumans, JV AF Naunheim, Matthew R. Walcott, Brian P. Nahed, Brian V. Simpson, Andrew K. Agarwalla, Pankaj K. Coumans, Jean-Valery TI The Quality of Randomized Controlled Trial Reporting in Spine Literature SO SPINE LA English DT Article DE CONSORT; randomized controlled trial; spine; study methodology ID CONSORT STATEMENT; CLINICAL-TRIALS; SURGICAL TRIALS; SURGERY; STANDARDS AB Study Design. Retrospective literature review. Objective. To assess the quality of randomized controlled trial reporting in spine surgery. Summary of Background Data. The use of the Consolidated Standards of Reporting Trials (CONSORT) criteria in clinical trials aims to improve adherence to a set of generally accepted practices in the reporting of randomized controlled trials. Randomized controlled trials in spine surgery are important sources of evidence-based practice, but the quality of their execution and reporting have not been reported adequately. Methods. All randomized controlled trials published in three selected dedicated spine journals from 2008 were reviewed with respect to the 40 criteria derived from CONSORT descriptors; 10 criteria applying to the abstract, and 30 to the body of the article. Each article was scored by three reviewers in group format for each criterion and was assigned a score. Reviewers always came to a consensus before assigning a score. Results. A total of 32 RCTs met the inclusion criteria for this review. The average modified CONSORT score was 65%. Disclosing certain criteria was associated with a higher overall score, including method of generation of random sequence (P < 0.000071), allocation concealment (P < 0.00014), inclusion of a flow chart or description of patient numbers at different stages (P < 0.00034), and identification of outcome measures (P < 0.00064). Conclusion. Conclusions drawn from current randomized controlled trials in the spine literature may thus be difficult to interpret. Greater effort must be put into compliance with these guidelines to improve data quality. C1 [Naunheim, Matthew R.; Walcott, Brian P.; Nahed, Brian V.; Agarwalla, Pankaj K.; Coumans, Jean-Valery] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Naunheim, Matthew R.; Walcott, Brian P.; Nahed, Brian V.; Agarwalla, Pankaj K.; Coumans, Jean-Valery] Harvard Univ, Sch Med, Boston, MA USA. [Simpson, Andrew K.] Harvard Combined Orthopaed Residency Program, Boston, MA USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,White Bldg,Room 502, Boston, MA 02114 USA. EM walcott.brian@mgh.harvard.edu NR 18 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JUL 15 PY 2011 VL 36 IS 16 BP 1326 EP 1330 DI 10.1097/BRS.0b013e3181f2aef0 PG 5 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 788MY UT WOS:000292450300020 PM 21224750 ER PT J AU Enestvedt, BK Sonnenberg, A AF Enestvedt, B. K. Sonnenberg, A. TI Practice patterns for achalasia - room for improvement? authors' reply SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter ID FATTY LIVER-DISEASE; TRANSIENT ELASTOGRAPHY; STIFFNESS MEASUREMENT; FIBROSIS; DIAGNOSIS; CHINESE C1 [Enestvedt, B. K.] Oregon Hlth & Sci Univ, Div Gastroenterol, Portland, OR 97201 USA. Portland VA Med Ctr P3 GI, Portland VA Med Ctr, Portland, OR USA. RP Enestvedt, BK (reprint author), Oregon Hlth & Sci Univ, Div Gastroenterol, Portland, OR 97201 USA. EM sonnenbe@ohsu.edu NR 10 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUL 15 PY 2011 VL 34 IS 2 BP 253 EP 254 DI 10.1111/j.1365-2036.2011.04696.x PG 4 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 784JD UT WOS:000292152300016 ER PT J AU Dombrovski, AY Szanto, K Siegle, GJ Wallace, ML Forman, SD Sahakian, B Reynolds, CF Clark, L AF Dombrovski, Alexandre Y. Szanto, Katalin Siegle, Greg J. Wallace, Meredith L. Forman, Steven D. Sahakian, Barbara Reynolds, Charles F., III Clark, Luke TI Lethal Forethought: Delayed Reward Discounting Differentiates High- and Low-Lethality Suicide Attempts in Old Age SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Aged; choice behavior; cognition; decision making; depressive disorder; executive function; reward; suicide; time perception ID AGGRESSIVE BEHAVIORS; INTERTEMPORAL CHOICE; COMPLETED SUICIDE; DECISION-MAKING; WORKING-MEMORY; RATING-SCALE; IMPULSIVITY; DEPRESSION; THINKING; ADDICTS AB Background: The decision to commit suicide may be impulsive, but lethal suicidal acts often involve planning and forethought. People who attempt suicide make disadvantageous decisions in other contexts, but nothing is known about the way they decide about the future. Can the willingness to postpone future gratification differentiate between individuals prone to serious, premeditated and less serious, unplanned suicidal acts? Methods: Four groups of depressed participants aged 60 and older made choices between smaller immediate and larger delayed monetary rewards: 15 who had made high-lethality suicide attempts, 14 who had made low-lethality suicide attempts, 12 who seriously contemplated suicide, and 42 people with depression, but no history of suicidal thoughts. The reference group was 31 psychiatrically healthy elders. Results: Individuals who had made low-lethality attempts displayed an exaggerated preference for immediate rewards compared with nonsuicidal depressed and healthy control subjects. Those who had carried out high-lethality suicide attempts were more willing to delay future rewards, compared with low-lethality attempters. Better planned suicide attempts were also associated with willingness to wait for larger rewards. These effects were unchanged after accounting for education, global cognitive function, substance use disorders, psychotropic medications, and possible brain injury from attempts. Discount rates were correlated with having debt, but were not significantly associated with income, hopelessness, depressive severity, premorbid IQ, age at first attempt, or choice of violent means. Conclusions: Although clinicians often focus on impulsivity in patients at risk for suicide, these data suggest that identifying biological characteristics and treatments for nonimpulsive suicidal older people may be even more important. C1 [Dombrovski, Alexandre Y.; Szanto, Katalin; Siegle, Greg J.; Wallace, Meredith L.; Forman, Steven D.; Reynolds, Charles F., III] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. [Forman, Steven D.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Sahakian, Barbara; Clark, Luke] Univ Cambridge, Dept Expt Psychol, Behav & Clin Neurosci Inst, Cambridge CB2 1TN, England. RP Dombrovski, AY (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. EM dombrovskia@upmc.edu RI Szanto, Katalin/B-8389-2014; OI Dombrovski, Alexandre/0000-0002-2054-4772 FU National Institute of Mental Health [K23 MH086620, K23 MH070471, P30MH52247, T32 MH016804]; Center for Injury Research and Control/Centers for Disease Control; American Foundation for Suicide Prevention; John A. Hartford Foundation; University of Pittsburgh Medical Center Endowment in Geriatric Psychiatry; Forest Laboratories; Pfizer; Bristol-Myers Squibb; Wyeth; Eli Lilly FX This work was supported by National Institute of Mental Health Grant Nos. K23 MH086620, K23 MH070471, P30MH52247, and T32 MH016804; Center for Injury Research and Control/Centers for Disease Control; the American Foundation for Suicide Prevention; the John A. Hartford Foundation, and the University of Pittsburgh Medical Center Endowment in Geriatric Psychiatry.; Dr. Sahakian has served as a consultant to Boehringer-Ingelheim, Cambridge Cognition, GlaxoSmithKline, Eli Lilly, Novartis, and Shire. Dr. Reynolds has received pharmaceutical supplies for his National Institutes of Health-sponsored work from Forest Laboratories, Pfizer, Bristol-Myers Squibb, Wyeth, and Eli Lilly. Dr. Clark has served as a consultant to Cambridge Cognition. Dr. Forman was employed as a Staff Physician, Behavioral Health Service, department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, during the conduct of this study. The study contents do not represent the views of the Department of Veteran Affairs or the U. S. government. All other authors have no biomedical financial interests or potential conflicts of interest. NR 50 TC 53 Z9 53 U1 3 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2011 VL 70 IS 2 BP 138 EP 144 DI 10.1016/j.biopsych.2010.12.025 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 782UC UT WOS:000292036600008 PM 21329911 ER PT J AU Ongur, D Haddad, S Prescot, AP Jensen, JE Siburian, R Cohen, BM Renshaw, PF Smoller, JW AF Oenguer, Dost Haddad, Stephen Prescot, Andrew P. Jensen, J. Eric Siburian, Richie Cohen, Bruce M. Renshaw, Perry F. Smoller, Jordan W. TI Relationship Between Genetic Variation in the Glutaminase Gene GLS1 and Brain Glutamine/Glutamate Ratio Measured In Vivo SO BIOLOGICAL PSYCHIATRY LA English DT Article DE J-resolved; megapress; magnetic resonance spectroscopy (MRS); neurotransmission ID DORSOLATERAL PREFRONTAL CORTEX; GAMMA-AMINOBUTYRIC-ACID; ANTERIOR CINGULATE; MAJOR DEPRESSION; BIPOLAR DISORDER; MOOD DISORDERS; PSYCHIATRIC-DISORDERS; GLUTAMATE METABOLISM; MESSENGER-RNA; PROTON MRS AB Background: Abnormalities in glutamatergic neurotransmission are implicated in several psychiatric disorders, but in vivo neurochemical studies of the glutamate (Glu) system have been hampered by a lack of adequate probes. By contrast, glutamine (Gln) and Glu can be quantified separately in proton magnetic resonance spectroscopy studies in vivo. Accumulating evidence suggests that the Gln/Glu ratio is a putative index of glutamatergic neurotransmission but interpretation of changes in the Gln/Glu ratio depends on the conditions of the system, including ammonia levels. Methods: Here, we explored whether variation in GLS1 (the gene encoding the brain isoform of glutaminase, which catalyzes Gln-to-Glu conversion) is associated with Gln/Glu measured in vivo in two brain regions (anterior cingulate cortex, parieto-occipital cortex). Results: A specific haplotype of four single nucleotide polymorphisms within GLS1 was significantly associated with Gln/Glu in the parieto-occipital cortex in an magnetic resonance spectroscopy-genetics dataset optimized for Gln/Glu detection (n = 42). This finding was replicated in a second magnetic resonance spectroscopy dataset that was optimized for gamma-aminobutyric acid detection where Gln and Glu measurements could still be extracted (n = 40). Conclusions: These findings suggest that genetic variation in a key component of glutamatergic machinery is associated with a putative in vivo index of glutamatergic neurotransmission. Thus, GLS1 genotype might provide insight into normal brain function and into the pathophysiology of many psychiatric conditions where glutamatergic neurotransmission has been implicated. It might also serve as a biomarker for predicting response to existing and novel therapeutic interventions in psychiatry that target glutamatergic neurotransmission. C1 [Oenguer, Dost; Jensen, J. Eric; Cohen, Bruce M.] McLean Hosp, Belmont, MA 02478 USA. [Oenguer, Dost; Jensen, J. Eric; Cohen, Bruce M.; Smoller, Jordan W.] Harvard Univ, Sch Med, Boston, MA USA. [Haddad, Stephen; Siburian, Richie; Smoller, Jordan W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Prescot, Andrew P.] Univ Utah, Sch Med, Salt Lake City, UT USA. RP Ongur, D (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. EM dongur@partners.org FU National Institute of Mental Health [K23MH079982, K24DA015116, R01MH079799]; Shervert Frazier Research Institute at McLean Hospital; Counter-Drug Technology Assessment Center, an office within the Office of National Drug Control Policy [DABT63-99-C]; Army Contracting Agency; Eli Lilly; GlaxoSmithKline; Roche FX This study was funded by K23MH079982 (DO) from the National Institute of Mental Health, K24DA015116 (PFR), R01MH079799 (JWS), and the Shervert Frazier Research Institute at McLean Hospital (BMC). It was also sponsored in part by the Counter-Drug Technology Assessment Center, an office within the Office of National Drug Control Policy, via Contract Number DABT63-99-C, awarded by the Army Contracting Agency. Dr. Renshaw is a consultant to Novartis, GlaxoSmithKline, and Kyowa Hakko and has received research support from Eli Lilly, GlaxoSmithKline, and Roche. Dr. Ongur has received free study drug from Sanofi. None of the other authors reported any biomedical financial interests or potential conflicts of interest. NR 51 TC 12 Z9 13 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 JUL 15 PY 2011 VL 70 IS 2 BP 169 EP 174 DI 10.1016/j.biopsych.2011.01.033 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 782UC UT WOS:000292036600012 PM 21457947 ER PT J AU Kemp, MM Wang, Q Fuller, JH West, N Martinez, NM Morse, EM Weiwer, M Schreiber, SL Bradner, JE Koehler, AN AF Kemp, Melissa M. Wang, Qiu Fuller, Jason H. West, Nathan Martinez, Nicole M. Morse, Elizabeth M. Weiwer, Michel Schreiber, Stuart L. Bradner, James E. Koehler, Angela N. TI A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Histone deacetylase; Non-selective inhibitor; Hydroxy-pyrimidine; SAR studies ID HISTONE DEACETYLASE INHIBITORS; BIOLOGICAL EVALUATION; DESIGN; CANCER; DISCOVERY; POTENT AB Histone deacetylases (HDACs) are enzymes involved in many important biological functions. They have been linked to a variety of cancers, psychiatric disorders, and other diseases. Since small molecules can serve as probes to study the relevant biological roles of HDACs, novel scaffolds are necessary to develop more efficient, selective drug candidates. Screening libraries of molecules may yield structurally diverse probes that bind these enzymes and modulate their functions in cells. Here we report a small molecule with a novel hydroxy-pyrimidine scaffold that inhibits multiple HDAC enzymes and modulates acetylation levels in cells. Analogs were synthesized in an effort to evaluate structure-activity relationships. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kemp, Melissa M.; Wang, Qiu; Fuller, Jason H.; West, Nathan; Martinez, Nicole M.; Morse, Elizabeth M.; Weiwer, Michel; Schreiber, Stuart L.; Bradner, James E.; Koehler, Angela N.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Wang, Qiu; Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [West, Nathan; Morse, Elizabeth M.; Bradner, James E.] Dana Farber Canc Inst, Div Hematol Neoplasia, Boston, MA 02115 USA. [Schreiber, Stuart L.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Koehler, AN (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM koehler@broadinstitute.org FU National Institute of General Medical Sciences (NIGMS) [38627]; National Cancer Institute's Initiative for Chemical Genetics (ICG) [N01-CO-12400] FX This research was supported in part by a grant from the National Institute of General Medical Sciences (NIGMS 38627 to S. L. S.) and in part with Federal funds from the National Cancer Institute's Initiative for Chemical Genetics (ICG), under Contract No. 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 the mention of trade names, commercial products or organizations imply endorsement by the US Government. S. L. S is an investigator with the Howard Hughes Medical Institute. NR 33 TC 10 Z9 10 U1 0 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUL 15 PY 2011 VL 21 IS 14 BP 4164 EP 4169 DI 10.1016/j.bmcl.2011.05.098 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 784VM UT WOS:000292186400009 PM 21696956 ER PT J AU Lange, S Gogel, S Leung, KY Vernay, B Nicholas, AP Causey, CP Thompson, PR Greene, NDE Ferretti, P AF Lange, Sigrun Goegel, Stefanie Leung, Kit-Yi Vernay, Bertrand Nicholas, Anthony P. Causey, Corey P. Thompson, Paul R. Greene, Nicholas D. E. Ferretti, Patrizia TI Protein deiminases: New players in the developmentally regulated loss of neural regenerative ability SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Apoptosis; Deimination/citrullination; Development; Peptidyl arginine deiminase; Regeneration; Spinal cord ID SPINAL-CORD-INJURY; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PEPTIDYLARGININE DEIMINASE; CITRULLINATED PROTEINS; ARGININE METHYLATION; MULTIPLE-SCLEROSIS; GENETIC INFLUENCES; FUNCTIONAL REPAIR; MOUSE-BRAIN; CELL-DEATH AB Spinal cord regenerative ability is lost with development, but the mechanisms underlying this loss are still poorly understood. In chick embryos, effective regeneration does not occur after E13, when spinal cord injury induces extensive apoptotic response and tissue damage. As initial experiments showed that treatment with a calcium chelator after spinal cord injury reduced apoptosis and cavitation, we hypothesized that developmentally regulated mediators of calcium-dependent processes in secondary injury response may contribute to loss of regenerative ability. To this purpose we screened for such changes in chick spinal cords at stages of development permissive (E11) and non-permissive (E15) for regeneration. Among the developmentally regulated calcium-dependent proteins identified was PAD3, a member of the peptidylarginine deiminase (PAD) enzyme family that converts protein arginine residues to citrulline, a process known as deimination or citrullination. This post-translational modification has not been previously associated with response to injury. Following injury, PAD3 up-regulation was greater in spinal cords injured at E15 than at E11. Consistent with these differences in gene expression, deimination was more extensive at the non-regenerating stage, E15, both in the gray and white matter. As deimination paralleled the extent of apoptosis, we investigated the effect of blocking PAD activity on cell death and deiminated-histone 3, one of the PAD targets we identified by mass-spectrometry analysis of spinal cord deiminated proteins. Treatment with the PAD inhibitor, Cl-amidine, reduced the abundance of deiminated-histone 3, consistent with inhibition of PAD activity, and significantly reduced apoptosis and tissue loss following injury at E15. Altogether, our findings identify PADs and deimination as developmentally regulated modulators of secondary injury response, and suggest that PADs might be valuable therapeutic targets for spinal cord injury. (C) 2011 Elsevier Inc. All rights reserved. C1 [Lange, Sigrun; Goegel, Stefanie; Vernay, Bertrand; Ferretti, Patrizia] UCL Inst Child Hlth, Dev Biol Unit, London WC1N 1EH, England. [Leung, Kit-Yi; Greene, Nicholas D. E.] UCL Inst Child Hlth, Neural Dev Unit, London WC1N 1EH, England. [Nicholas, Anthony P.] Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. [Nicholas, Anthony P.] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. [Causey, Corey P.] Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. [Thompson, Paul R.] Scripps Res Inst, Dept Chem, Scripps Florida, FL 33458 USA. RP Ferretti, P (reprint author), UCL Inst Child Hlth, Dev Biol Unit, 30 Guilford St, London WC1N 1EH, England. EM ferretti@ich.ucl.ac.uk OI Ferretti, Patrizia/0000-0002-3590-6772; Greene, Nicholas/0000-0002-4170-5248; Vernay, Bertrand/0000-0002-7843-3872 FU BBSRC FX This work was supported by the BBSRC. NR 55 TC 30 Z9 31 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2011 VL 355 IS 2 BP 205 EP 214 DI 10.1016/j.ydbio.2011.04.015 PG 10 WC Developmental Biology SC Developmental Biology GA 787EN UT WOS:000292359500004 PM 21539830 ER PT J AU Hu, Y Liu, J Wang, JF Liu, QS AF Hu, Yi Liu, Jing Wang, Junfeng Liu, Qingsong TI The controversial links among calorie restriction, SIRT1, and resveratrol SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE Calorie restriction; SIRT1; Resveratrol; Deacetylase; Life span ID ACTIVATED PROTEIN-KINASE; SMALL-MOLECULE ACTIVATORS; LIFE-SPAN EXTENSION; OXIDATIVE STRESS; ENDOTHELIAL-CELLS; SACCHAROMYCES-CEREVISIAE; HISTONE DEACETYLASE; DIETARY RESTRICTION; METABOLIC SYNDROME; INDUCED APOPTOSIS AB It has been widely known that slow metabolism induced by calorie restriction (CR) can extend the life span of model organisms though the underlying mechanism remains poorly understood. Accumulated evidence suggests that SIRT1 may be actively involved in CR-induced signaling pathways. As a putative activator of SIRT1, resveratrol, known for the French paradox, can partially mimic the physiological effects of CR. While the deacetylase activity of SIRT1 is important for the beneficial effects of resveratrol, resveratrol-induced SIRT1 activation has recently been challenged by the observations that resveratrol could not induce SIRT1-mediated deacetylation of native substrates in vitro. To resolve the discrepancy of resveratrol-induced activation of SIRT1 deacetylase activity between the in vitro and in vivo assays, a model of indirect SIRT1 activation by resveratrol is proposed. In this review, we will discuss the emerging roles of SIRT1 and resveratrol in CR and focus on debate over the links between SIRT1 and resveratrol. (C) 2011 Elsevier Inc. All rights reserved. C1 [Liu, Qingsong] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Hu, Yi] Harvard Univ, Sch Med, Ctr Neurol Dis, Cambridge, MA 02139 USA. [Hu, Yi] Brigham & Womens Hosp, Cambridge, MA 02139 USA. [Liu, Jing; Wang, Junfeng; Liu, Qingsong] Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China. [Liu, Jing] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Liu, Qingsong] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Liu, QS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM nkliuqs97@gmail.com OI liu, qing song/0000-0002-7829-2547 NR 107 TC 39 Z9 40 U1 1 U2 40 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 JUL 15 PY 2011 VL 51 IS 2 BP 250 EP 256 DI 10.1016/j.freeradbiomed.2011.04.034 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 787BV UT WOS:000292352500003 PM 21569839 ER PT J AU Jelcick, AS Yuan, Y Leehy, BD Cox, LC Silveira, AC Qiu, F Schenk, S Sachs, AJ Morrison, MA Nystuen, AM DeAngelis, MM Haider, NB AF Jelcick, Austin S. Yuan, Yang Leehy, Barrett D. Cox, Lakeisha C. Silveira, Alexandra C. Qiu, Fang Schenk, Sarah Sachs, Andrew J. Morrison, Margaux A. Nystuen, Arne M. DeAngelis, Margaret M. Haider, Neena B. TI Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina SO PLOS ONE LA English DT Article ID COMPLEMENT FACTOR-H; MACULAR DEGENERATION; SYSTEMS BIOLOGY; DISEASE; STRAINS; PHOTORECEPTOR; MUTATIONS; DYSTROPHY; MICE; ABCR AB Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects. Microarray analyses were performed on retinas from the following mouse strains: C57BL6/J, AKR/J, CAST/EiJ, and NOD. NON-H2(-nb1) at embryonic day 18.5 (E18.5) and postnatal day 30.5 (P30.5). Over 3000 differentially expressed genes were identified between strains and developmental stages. Differential gene expression was confirmed by qRT-PCR, Western blot, and immunohistochemistry. Three major gene networks were identified that function to regulate retinal or photoreceptor development, visual perception, cellular transport, and signal transduction. Many of the genes in these networks are implicated in retinal diseases such as bradyopsia, night-blindness, and cone-rod dystrophy. Our analysis revealed strain specific variations in cone photoreceptor cell patterning and retinal function. This study highlights the substantial impact of genetic background on both development and function of the retina and the level of gene expression differences tolerated for normal retinal function. These strain specific genetic variations may also be present in other tissues. In addition, this study will provide valuable insight for the development of more accurate models for human retinal diseases. C1 [Jelcick, Austin S.; Yuan, Yang; Leehy, Barrett D.; Cox, Lakeisha C.; Schenk, Sarah; Sachs, Andrew J.; Nystuen, Arne M.] Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA. [Silveira, Alexandra C.; Morrison, Margaux A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Ocular Mol Genet Inst, Boston, MA USA. [Qiu, Fang] Univ Nebraska Med Ctr, Div Biostat, Omaha, NE USA. [DeAngelis, Margaret M.] Univ Utah, Moran Eye Ctr, Salt Lake City, UT USA. [Haider, Neena B.] Harvard Univ, Sch Med, Schepens Eye Res Inst, Dept Ophthalmol, Boston, MA USA. RP Jelcick, AS (reprint author), Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA. EM nhaider@unmc.edu RI DeAngelis, e/J-7863-2015 FU National Center for Research Resources, NIH [NIH 5 P20 RRO18788-02]; Hope for Vision FX This study was supported by the Center for Biomedical Excellence Award through the National Center for Research Resources, NIH (NIH 5 P20 RRO18788-02 (NBH)), and Hope for Vision (NBH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 19 Z9 19 U1 0 U2 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 JUL 14 PY 2011 VL 6 IS 7 AR e21858 DI 10.1371/journal.pone.0021858 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HP UT WOS:000292811300019 PM 21779340 ER PT J AU Treon, SP Soumerai, JD Hunter, ZR Patterson, CJ Ioakimidis, L Kahl, B Boxer, M AF Treon, Steven P. Soumerai, Jacob D. Hunter, Zachary R. Patterson, Christopher J. Ioakimidis, Leukothea Kahl, Brad Boxer, Michael TI Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CONSENSUS PANEL RECOMMENDATIONS; 2ND INTERNATIONAL WORKSHOP; COOPERATIVE-ONCOLOGY-GROUP; WALDENSTROMS MACROGLOBULINEMIA; RITUXIMAB THERAPY; CD52 EXPRESSION; MAST-CELLS; PHASE-II; CAMPATH-1H AB CD52 is expressed on malignant cells in lymphoplasmacytic lymphoma (LPL), including IgM-secreting Waldenstrom macroglobulinemia (WM). We examined the activity of alemtuzumab in 28 symptomatic LPL (27 IgM and 1 IgA) patients. The median prior number of therapies for these patients was 2 (range, 0-5) and 43% had refractory disease. Patients received alemtuzumab at 30 mg IV 3 times weekly for up to 12 weeks after test dosing, and also received hydrocortisone, acyclovir, and Bactrim or equivalent prophylaxis. Patients had a complete response (n = 1), a partial response (n = 9), or a MR (n = 11) for an overall and major response rate of 75% and 36%, respectively. Median serum Ig decreased from 3510 to 1460 mg/dL (P < .001 at best response). With a median follow-up of 64 months, the median time to progression was 14.5 months. Hematologic and infectious complications, including CMV reactivation, were more common in previously treated patients and were indirectly associated with 3 deaths. Long-term follow-up revealed late-onset autoimmune thrombocytopenia (AITP) in 4 patients at a median of 13.6 months after therapy, which contributed to 1 death. Alemtuzumab is an active therapy in patients with LPL, but short-and long-term toxicities need to be carefully weighed against other available treatment options. Late AITP is a newly recognized complication of alemtuzumab in this patient population. This study is registered at www.clinicaltrials.gov as NCT00142181. (Blood.2011;118(2):276-281) C1 [Treon, Steven P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Kahl, Brad] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Boxer, Michael] Univ Arizona, Tucson, AZ USA. RP Treon, SP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,44 Binney St, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu RI Hunter, Zachary/H-3018-2013 OI Hunter, Zachary/0000-0002-1689-1691 FU Dana-Farber Cancer Institute; Berlex Pharmaceuticals Inc; National Institutes of Health [K23CA087977-03]; Berlex Pharmaceuticals FX This work was supported by grants from the Research Fund for Waldenstrom's at the Dana-Farber Cancer Institute; by Berlex Pharmaceuticals Inc; by the Peter and Helen Bing Fund at the Dana-Farber Cancer Institute; and by a National Institutes of Health Career Development Award (K23CA087977-03 to S. P. T.).; Berlex Pharmaceuticals provided research funding and drug replacement in support of these studies. The authors declare no competing financial interests. NR 34 TC 19 Z9 19 U1 0 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 14 PY 2011 VL 118 IS 2 BP 276 EP 281 DI 10.1182/blood-2011-02-338558 PG 6 WC Hematology SC Hematology GA 792IB UT WOS:000292735100012 PM 21566092 ER PT J AU Brunstein, CG Fuchs, EJ Carter, SL Karanes, C Costa, LJ Wu, J Devine, SM Wingard, JR Aljitawi, OS Cutler, CS Jagasia, MH Ballen, KK Eapen, M O'Donnell, PV AF Brunstein, Claudio G. Fuchs, Ephraim J. Carter, Shelly L. Karanes, Chatchada Costa, Luciano J. Wu, Juan Devine, Steven M. Wingard, John R. Aljitawi, Omar S. Cutler, Corey S. Jagasia, Madan H. Ballen, Karen K. Eapen, Mary O'Donnell, Paul V. CA Blood & Marrow Transplant Clinical TI Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; POSTTRANSPLANTATION CYCLOPHOSPHAMIDE; HEMATOLOGIC MALIGNANCIES; FLUDARABINE; ENGRAFTMENT; OUTCOMES; ADULTS AB The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of non-relapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603). (Blood.2011;118(2):282-288) C1 [Brunstein, Claudio G.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Fuchs, Ephraim J.] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. [Carter, Shelly L.; Wu, Juan] Emmes Corp, Rockville, MD USA. [Karanes, Chatchada] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Costa, Luciano J.] Med Univ S Carolina, Charleston, SC 29425 USA. [Devine, Steven M.] Ohio State Univ, Columbus, OH 43210 USA. [Wingard, John R.] Univ Florida, Coll Med, Gainesville, FL USA. [Aljitawi, Omar S.] Univ Kansas, Kansas City, KS USA. [Cutler, Corey S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Jagasia, Madan H.] Vanderbilt Univ, Nashville, TN USA. [Ballen, Karen K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Eapen, Mary] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [O'Donnell, Paul V.] Univ Washington, Fred Hutchinson Canc Ctr, Seattle, WA 98195 USA. RP Brunstein, CG (reprint author), Mayo Mail Code 480,420 Delaware St SE, Minneapolis, MN 55403 USA. EM bruns072@umn.edu; fuchsep@jhmi.edu FU National Heart, Lung, and Blood Institute (National Institutes of Health, Bethesda, MD) [UO1-HL069294]; National Cancer Institute (NIH) FX This work was supported in part by grant UO1-HL069294 from the National Heart, Lung, and Blood Institute (National Institutes of Health, Bethesda, MD) and the National Cancer Institute (NIH). NR 21 TC 228 Z9 231 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 14 PY 2011 VL 118 IS 2 BP 282 EP 288 DI 10.1182/blood-2011-03-344853 PG 7 WC Hematology SC Hematology GA 792IB UT WOS:000292735100013 PM 21527516 ER PT J AU Franz, B May, KF Dranoff, G Wucherpfennig, K AF Franz, Bettina May, Kenneth F., Jr. Dranoff, Glenn Wucherpfennig, Kai TI Ex vivo characterization and isolation of rare memory B cells with antigen tetramers SO BLOOD LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; PLASMA-CELLS; SECRETING CELLS; PERIPHERAL-BLOOD; CPG DNA; INDIVIDUALS; PROLIFERATE; GENERATION; DIVERSITY; RESPONSES AB Studying human antigen-specific memory B cells has been challenging because of low frequencies in peripheral blood, slow proliferation, and lack of antibody secretion. Therefore, most studies have relied on conversion of memory B cells into antibody-secreting cells by in vitro culture. To facilitate direct ex vivo isolation, we generated fluorescent antigen tetramers for characterization of memory B cells by using tetanus toxoid as a model antigen. Brightly labeled memory B cells were identified even 4 years after last immunization, despite low frequencies ranging from 0.01% to 0.11% of class-switched memory B cells. A direct comparison of monomeric to tetrameric antigen labeling demonstrated that a substantial fraction of the B-cell repertoire can be missed when monomeric antigens are used. The specificity of the method was confirmed by antibody reconstruction from single-cell sorted tetramer(+) B cells with single-cell RT-PCR of the B-cell receptor. All antibodies bound to tetanus antigen with high affinity, ranging from 0.23 to 2.2 nM. Furthermore, sequence analysis identified related memory B cell and plasmablast clones isolated more than a year apart. Therefore, antigen tetramers enable specific and sensitive ex vivo characterization of rare memory B cells as well as the production of fully human antibodies. (Blood.2011;118(2):348-357) C1 [Franz, Bettina; Wucherpfennig, Kai] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [May, Kenneth F., Jr.; Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [May, Kenneth F., Jr.; Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [May, Kenneth F., Jr.; Dranoff, Glenn] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wucherpfennig, Kai] Harvard Univ, Sch Med, Program Immunol, Boston, MA USA. RP Wucherpfennig, K (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Dana 1410,450 Brookline Ave, Boston, MA 02115 USA. EM kai_wucherpfennig@dfci.harvard.edu FU Melanoma Research Alliance; Research Foundation for the Treatment of Ovarian Cancer; National Institutes of Health [PO1 AI045757] FX This study was supported by a grant from the Melanoma Research Alliance (to G. D. and K. W.), a grant from the Research Foundation for the Treatment of Ovarian Cancer (to G. D.), and the National Institutes of Health (PO1 AI045757 to K. W.). B. F. is a PhD candidate at Heidelberg University, Germany and this work is submitted in partial fulfillment of the requirement for the PhD. NR 32 TC 35 Z9 35 U1 1 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 14 PY 2011 VL 118 IS 2 BP 348 EP 357 DI 10.1182/blood-2011-03-341917 PG 10 WC Hematology SC Hematology GA 792IB UT WOS:000292735100020 PM 21551230 ER PT J AU Chen, YY Sullivan, C Peng, C Shan, Y Hu, YG Li, DG Li, SG AF Chen, Yaoyu Sullivan, Con Peng, Cong Shan, Yi Hu, Yiguo Li, Dongguang Li, Shaoguang TI A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia SO BLOOD LA English DT Article ID MACROPHAGE SCAVENGER RECEPTOR; INITIATING CELLS; SELF-RENEWAL; MICE; INHIBITION; BCR/ABL; CANCER; CML; MAINTENANCE; PATHWAYS AB We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5(-/-) LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5(-/-) LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and beta-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML. (Blood.2011;118(2):390-400) C1 [Chen, Yaoyu; Peng, Cong; Shan, Yi; Li, Shaoguang] Univ Massachusetts, Sch Med, Dept Med, Div Hematol Oncol, Worcester, MA 01605 USA. [Sullivan, Con] Maine Inst Human Genet & Hlth, Bangor, ME USA. [Hu, Yiguo] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Li, Dongguang] Edith Cowan Univ, Sch Comp & Secur Sci, Mt Lawley, Australia. RP Li, SG (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Hematol Oncol, 364 Plantat St, Worcester, MA 01605 USA. EM shaoguang.li@umassmed.edu RI Peng, Cong/H-2286-2011; Shan, Yi/E-3862-2016 FU Leukemia & Lymphoma Society; National Institutes of Health [R01-CA122142, R01-CA114199] FX This work was supported by the grants from the Leukemia & Lymphoma Society and the National Institutes of Health (R01-CA122142, R01-CA114199 to S. L.). S. L. is a Scholar of the Leukemia & Lymphoma Society. NR 28 TC 17 Z9 17 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 14 PY 2011 VL 118 IS 2 BP 390 EP 400 DI 10.1182/blood-2010-11-316760 PG 11 WC Hematology SC Hematology GA 792IB UT WOS:000292735100024 PM 21596859 ER PT J AU Takeda, Y Li, QL Kazarov, AR Epardaud, M Elpek, K Turley, SJ Hemler, ME AF Takeda, Yoshito Li, Qinglin Kazarov, Alexander R. Epardaud, Mathieu Elpek, Kutlu Turley, Shannon J. Hemler, Martin E. TI Diminished metastasis in tetraspanin CD151-knockout mice SO BLOOD LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; LAMININ-BINDING INTEGRINS; IN-VIVO; POTENTIAL TARGET; CELL-MIGRATION; BREAST-CANCER; TUMOR-CELLS; T-CELLS; CD151; EXPRESSION AB Tetraspanin protein CD151 on tumor cells supports invasion and metastasis. In the present study, we show that host animal CD151 also plays a critical role. CD151-null mice showed markedly diminished experimental lung metastasis after injection of Lewis lung carcinoma or B16F10 melanoma cells. Diminished tumor cell residence in the lungs was evident 6-24 hours after injection. Consistent with an endothelial cell deficiency, isolated CD151-null mouse lung endothelial cells showed diminished support for B16F10 adhesion and transendothelial migration, diminished B16F10-induced permeability, and diminished B16F10 adhesion to extracellular matrix deposited by CD151-null mouse lung endothelial cells. However, CD151 deletion did not affect the size of metastatic foci or subcutaneous primary B16F10 tumors, tumor aggregation, tumor clearance from the blood, or tumor-induced immune cell activation and recruitment. Therefore, the effects of host CD151 on metastasis do not involve altered local tumor growth or immune surveillance. VEGF-induced endothelial cell signaling through Src and Akt was diminished in CD151-null endothelial cells. However, deficient signaling was not accompanied by reduced endothelial permeability either in vitro (monolayer permeability assay) or in vivo (VEGF-stimulated Miles assay). In summary, diminished metastasis in CD151-null host animals may be due to impaired tumor-endothelial interactions, with underlying defects in mouse lung endothelial cell extracellular matrix production. (Blood. 2011; 118(2): 464-472) C1 [Takeda, Yoshito; Li, Qinglin; Kazarov, Alexander R.; Epardaud, Mathieu; Elpek, Kutlu; Turley, Shannon J.; Hemler, Martin E.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Hemler, ME (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM martin_hemler@dfci.harvard.edu RI Li, Qinglin/K-2570-2015 OI Li, Qinglin/0000-0002-4125-1944 FU National Institutes of Health [CA42368] FX This work was supported by National Institutes of Health Grant CA42368 (to M. E. H.). NR 50 TC 26 Z9 28 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 JUL 14 PY 2011 VL 118 IS 2 BP 464 EP 472 DI 10.1182/blood-2010-08-302240 PG 9 WC Hematology SC Hematology GA 792IB UT WOS:000292735100033 PM 21536858 ER PT J AU Hu, ZT Pym, ECG Babu, K Murray, ABV Kaplan, JM AF Hu, Zhitao Pym, Edward C. G. Babu, Kavita Murray, Amy B. Vashlishan Kaplan, Joshua M. TI A Neuropeptide-Mediated Stretch Response Links Muscle Contraction to Changes in Neurotransmitter Release SO NEURON LA English DT Article ID DENSE-CORE VESICLE; CAENORHABDITIS-ELEGANS LACKING; SYNAPTIC-TRANSMISSION; MASS-SPECTROMETRY; C. ELEGANS; SYNAPTOBREVIN; DROSOPHILA; RECEPTOR; MUTANTS; PDF AB Although Caenorhabditis elegans has been utilized extensively to study synapse formation and function, relatively little is known about synaptic plasticity in C. elegans. We show that a brief treatment with the cholinesterase inhibitor aldicarb induces a form of presynaptic potentiation whereby ACh release at neuromuscular junctions (NMJs) is doubled. Aldicarb-induced potentiation was eliminated by mutations that block processing of proneuropeptides, by mutations inactivating a single proneuropeptide (NLP-12), and by those inactivating an NLP-12 receptor (CKR-2). NLP-12 expression is limited to a single stretch-activated neuron, DVA. Analysis of a YFP-tagged NLP-12 suggests that aldicarb stimulates DVA secretion of NLP-12. Mutations disrupting the DVA mechanoreceptor (TRP-4) decreased aldicarb-induced NLP-12 secretion and blocked aldicarb-induced synaptic potentiation. Mutants lacking NLP-12 or CKR-2 have decreased locomotion rates. Collectively, these results suggest that NLP-12 mediates a mechanosensory feedback loop that couples muscle contraction to changes in presynaptic release, thereby providing a mechanism for proprioceptive control of locomotion. C1 [Hu, Zhitao; Pym, Edward C. G.; Babu, Kavita; Murray, Amy B. Vashlishan; Kaplan, Joshua M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Hu, Zhitao; Pym, Edward C. G.; Babu, Kavita; Kaplan, Joshua M.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Murray, Amy B. Vashlishan] Emerson Coll, Dept Commun Sci & Disorders, Boston, MA 02116 USA. RP Kaplan, JM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kaplan@molbio.mgh.harvard.edu RI hu, zhitao/H-5626-2011 FU NIH [DK80215] FX We thank the following for strains and reagents: Liliane Schoofs, Tom Janssen, Shawn Xu, and the C. elegans Genetics Stock Center. We thank members of the Kaplan laboratory for critical comments on the manuscript. This work was supported by an NIH research grant to J.M.K. (DK80215). NR 38 TC 29 Z9 32 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 14 PY 2011 VL 71 IS 1 BP 92 EP 102 DI 10.1016/j.neuron.2011.04.021 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 793FQ UT WOS:000292806200009 PM 21745640 ER PT J AU Babu, K Hu, ZT Chien, SC Garriga, G Kaplan, JM AF Babu, Kavita Hu, Zhitao Chien, Shih-Chieh Garriga, Gian Kaplan, Joshua M. TI The Immunoglobulin Super Family Protein RIG-3 Prevents Synaptic Potentiation and Regulates Wnt Signaling SO NEURON LA English DT Article ID ELEGANS NEUROMUSCULAR-JUNCTION; DROSOPHILA EGF RECEPTOR; CAENORHABDITIS-ELEGANS; C-ELEGANS; ADHESION MOLECULES; NEURONAL POLARITY; REQUIRES RETROMER; AMPA RECEPTORS; SUPERFAMILY; SYNAPSES AB Cell surface Ig superfamily proteins (IgSF) have been implicated in several aspects of neuron development and function. Here, we describe the function of a Caenorhabditis elegans IgSF protein, RIG-3. Mutants lacking RIG-3 have an exaggerated paralytic response to a cholinesterase inhibitor, aldicarb. Although RIG-3 is expressed in motor neurons, heightened drug responsiveness was caused by an aldicarb-induced increase in muscle ACR-16 acetylcholine receptor (AChR) abundance, and a corresponding potentiation of postsynaptic responses at neuromuscular junctions. Mutants lacking RIG-3 also had defects in the anteroposterior polarity of the ALM mechanosensory neurons. The effects of RIG-3 on synaptic transmission and ALM polarity were both mediated by changes in Wnt signaling, and in particular by inhibiting CAM-1, a Ror-type receptor tyrosine kinase that binds Wnt ligands. These results identify RIG-3 as a regulator of Wnt signaling, and suggest that RIG-3 has an anti-plasticity function that prevents activity-induced changes in postsynaptic receptor fields. C1 [Babu, Kavita; Hu, Zhitao; Kaplan, Joshua M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Babu, Kavita; Hu, Zhitao; Kaplan, Joshua M.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Chien, Shih-Chieh; Garriga, Gian] Univ Calif Berkeley, Dept Mol Cell Biol, Berkeley, CA 94720 USA. [Garriga, Gian] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. RP Kaplan, JM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kaplan@molbio.mgh.harvard.edu RI hu, zhitao/H-5626-2011 FU NIH [NS32196, NS32057] FX This work was supported by grants from the NIH (NS32196 to J.M.K. and NS32057 to G.G.). We thank the following for strains, reagents, and advice: C. elegans Genetic Stock Center, Villu Maricq, Jihong Bai, Ed Pym, and Eyleen O'Rourke. We also thank members of the Kaplan laboratory for suggestions and comments on this manuscript. NR 76 TC 8 Z9 11 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 14 PY 2011 VL 71 IS 1 BP 103 EP 116 DI 10.1016/j.neuron.2011.05.034 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 793FQ UT WOS:000292806200010 PM 21745641 ER PT J AU Jones, CU Hunt, D McGowan, DG Amin, MB Chetner, MP Bruner, DW Leibenhaut, MH Husain, SM Rotman, M Souhami, L Sandler, HM Shipley, WU AF Jones, Christopher U. Hunt, Daniel McGowan, David G. Amin, Mahul B. Chetner, Michael P. Bruner, Deborah W. Leibenhaut, Mark H. Husain, Siraj M. Rotman, Marvin Souhami, Luis Sandler, Howard M. Shipley, William U. TI Radiotherapy and Short-Term Androgen Deprivation for Localized Prostate Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID THERAPY ONCOLOGY GROUP; RANDOMIZED CONTROLLED-TRIAL; EXTERNAL-BEAM RADIOTHERAPY; DOSE-ESCALATION TRIAL; RADIATION-THERAPY; RADICAL PROSTATECTOMY; HORMONAL-THERAPY; GROUP RTOG; FOLLOW-UP; SUPPRESSION AB BACKGROUND It is not known whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma. METHODS From 1994 through 2001, we randomly assigned 1979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng per milliliter or less to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years. RESULTS The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P = 0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P = 0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients. CONCLUSIONS Among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng per milliliter or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men. (Funded by the National Cancer Institute; RTOG 94-08 ClinicalTrials.gov number, NCT00002597.) C1 [Jones, Christopher U.; Leibenhaut, Mark H.] Radiol Associates Sacramento, Sacramento, CA 95816 USA. [Hunt, Daniel] Univ Penn, Radiat Therapy Oncol Grp, Ctr Stat, Philadelphia, PA 19104 USA. [Bruner, Deborah W.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [McGowan, David G.] Cross Canc Inst, Dept Radiat Oncol, Edmonton, AB T6G 1Z2, Canada. [Chetner, Michael P.] Univ Alberta, Dept Surg, Div Urol, Edmonton, AB, Canada. [Husain, Siraj M.] Tom Baker Canc Clin, Dept Radiat Oncol, Calgary, AB, Canada. [Amin, Mahul B.] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Sandler, Howard M.] Cedars Sinai Med Ctr, Dept Radiat Oncol, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Rotman, Marvin] SUNY Hlth Sci Ctr, Dept Radiat Oncol, Brooklyn, NY 11203 USA. [Souhami, Luis] McGill Univ, Dept Radiat Oncol, Montreal, PQ H3A 2T5, Canada. [Shipley, William U.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Jones, CU (reprint author), Radiol Associates Sacramento, 1500 Expo Pkwy, Sacramento, CA 95816 USA. EM jonesc@radiological.com FU National Cancer Institute [U10 CA21661, U10 CA37422, U10 CA32115]; Amgen; Ferring; GlaxoSmithKline; Eli Lilly; Calypso Medical; Varian FX Supported by grants (U10 CA21661, to the Radiation Therapy Oncology Group [RTOG]; U10 CA37422, to the Community Clinical Oncology Program; and U10 CA32115, to the RTOG Statistical Center) from the National Cancer Institute.; Dr. Chetner reports receiving lecture fees from and serving on the advisory boards of Amgen, Ferring, GlaxoSmithKline, and Eli Lilly and receiving fees for the development of educational presentations from Amgen and GlaxoSmithKline; and Dr. Sandler, consulting fees from Calypso Medical and Varian. No other potential conflict of interest relevant to this article was reported. NR 39 TC 240 Z9 245 U1 2 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 14 PY 2011 VL 365 IS 2 BP 107 EP 118 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 791SP UT WOS:000292685500007 PM 21751904 ER PT J AU Wechsler, ME Kelley, JM Boyd, IOE Dutile, S Marigowda, G Kirsch, I Israel, E Kaptchuk, TJ AF Wechsler, Michael E. Kelley, John M. Boyd, Ingrid O. E. Dutile, Stefanie Marigowda, Gautham Kirsch, Irving Israel, Elliot Kaptchuk, Ted J. TI Active Albuterol or Placebo, Sham Acupuncture, or No Intervention in Asthma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AIRWAY-OBSTRUCTION; CONTROLLED-TRIALS; FATAL ASTHMA; PERCEPTION; SUGGESTION; DYSPNEA AB BACKGROUND In prospective experimental studies in patients with asthma, it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention. We compared the effects of a bronchodilator, two placebo interventions, and no intervention on outcomes in patients with asthma. METHODS In a double-blind, crossover pilot study, we randomly assigned 46 patients with asthma to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, or no intervention. Using a block design, we administered one each of these four interventions in random order during four sequential visits (3 to 7 days apart); this procedure was repeated in two more blocks of visits (for a total of 12 visits by each patient). At each visit, spirometry was performed repeatedly over a period of 2 hours. Maximum forced expiratory volume in 1 second (FEV(1)) was measured, and patients' self-reported improvement ratings were recorded. RESULTS Among the 39 patients who completed the study, albuterol resulted in a 20% increase in FEV1, as compared with approximately 7% with each of the other three interventions (P<0.001). However, patients' reports of improvement after the intervention did not differ significantly for the albuterol inhaler (50% improvement), placebo inhaler (45%), or sham acupuncture (46%), but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control (21%) (P<0.001). CONCLUSIONS Although albuterol, but not the two placebo interventions, improved FEV1 in these patients with asthma, albuterol provided no incremental benefit with respect to the self-reported outcomes. Placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma. However, from a clinical-management and research-design perspective, patient self-reports can be unreliable. An assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes. (Funded by the National Center for Complementary and Alternative Medicine.) C1 [Wechsler, Michael E.; Boyd, Ingrid O. E.; Dutile, Stefanie; Marigowda, Gautham; Israel, Elliot] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Wechsler, Michael E.; Kelley, John M.; Boyd, Ingrid O. E.; Dutile, Stefanie; Marigowda, Gautham; Kirsch, Irving; Israel, Elliot; Kaptchuk, Ted J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kelley, John M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kirsch, Irving; Kaptchuk, Ted J.] Beth Israel Deaconess Med Ctr, Program Placebo Studies, Boston, MA 02215 USA. [Kelley, John M.] Endicott Coll, Dept Psychol, Beverly, MA USA. [Kirsch, Irving] Univ Hull, Dept Psychol, Kingston Upon Hull HU6 7RX, N Humberside, England. RP Wechsler, ME (reprint author), Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. EM mwechsler@partners.org RI Wechsler, Michael /B-3979-2013 OI Wechsler, Michael /0000-0003-3505-2946 FU National Center for Complementary and Alternative Medicine; National Center for Complementary and Alternative Medicine, National Institutes of Health [R21-AT002793-01, K24-AT004095]; GlaxoSmithKline; Merck; Schering-Plough; Asthmatx; Genentech; Sunovion; Cephalon; MedImmune; NKT Therapeutics; Boehringer Ingelheim; Novartis; AstraZeneca; Abbott; Amgen; Astellas Pharma US; BI Worldwide; Cowen; Gilead Sciences; Icagen; Johnson Johnson; newMentor; Ono Pharmaceutical; PDL BioPharma; Pulmatrix; Teva Pharmaceuticals; Ficksman and Conley; Prince, Lobel, Glovsky, and Tye; Campbell, Campbell, Edwards, and Conroy; Diedrich and Donohue; Sulloway and Hollis; Ryan Ryan Deluca; Aerovance; Biota; Ception FX Funded by the National Center for Complementary and Alternative Medicine.; Supported by grants (R21-AT002793-01 and K24-AT004095) from the National Center for Complementary and Alternative Medicine, National Institutes of Health.; Dr. Wechsler reports receiving fees for consulting and advisory-board membership from GlaxoSmithKline, Merck, Schering-Plough, Asthmatx, Genentech, Sunovion (formerly Sepracor), Cephalon, MedImmune, NKT Therapeutics, and Boehringer Ingelheim; lecture fees from Merck, Novartis, AstraZeneca, and GlaxoSmithKline; and grant support from GlaxoSmithKline and Asthmatx. Dr. Israel reports receiving fees for consulting and advisory-board membership from Abbott, Amgen, Astellas Pharma US, BI Worldwide, Cowen, Gilead Sciences, GlaxoSmithKline, Icagen, Johnson & Johnson, MedImmune, Merck, newMentor, NKT Therapeutics, Novartis, Ono Pharmaceutical, PDL BioPharma, Pulmatrix, Schering-Plough, Sunovion (formerly Sepracor), and Teva Pharmaceuticals; lecture fees from Merck; fees for expert testimony from Ficksman and Conley; Prince, Lobel, Glovsky, and Tye; Campbell, Campbell, Edwards, and Conroy; Diedrich and Donohue; Sulloway and Hollis; and Ryan Ryan Deluca; and grant support from Aerovance, Amgen, Biota, Ception, Genentech, Icagen, Johnson & Johnson, MedImmune, and Novartis. No other potential conflict of interest relevant to this article was reported. NR 28 TC 115 Z9 118 U1 5 U2 32 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 14 PY 2011 VL 365 IS 2 BP 119 EP 126 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 791SP UT WOS:000292685500008 PM 21751905 ER PT J AU Shaw, AT Forcione, DG Digumarthy, SR Iafrate, AJ AF Shaw, Alice T. Forcione, David G. Digumarthy, Subba R. Iafrate, A. John TI Case 21-2011: A 31-Year-Old Man with ALK-Positive Adenocarcinoma of the Lung Adenocarcinoma of the lung (non-small-cell lung cancer), with anaplastic lymphoma kinase (ALK) gene rearrangement. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EML4-ALK FUSION GENE; PHASE-III; MUTATIONS; GEFITINIB; EGFR; CHEMOTHERAPY; FEATURES; TUMORS; KRAS C1 [Shaw, Alice T.] Massachusetts Gen Hosp, Ctr Thorac Cancers, Boston, MA 02114 USA. [Forcione, David G.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Digumarthy, Subba R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Shaw, Alice T.; Forcione, David G.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Digumarthy, Subba R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Iafrate, A. John] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Ctr Thorac Cancers, Boston, MA 02114 USA. FU Pfizer; Ariad; Chugai; Millennium; Abbott Molecular FX Dr. Shaw reports receiving consulting fees from Pfizer, Ariad, Chugai, and Millennium; and Dr. Iafrate, consulting fees from Pfizer and Abbott Molecular. No other potential conflict of interest relevant to this article was reported. NR 25 TC 7 Z9 7 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 14 PY 2011 VL 365 IS 2 BP 158 EP 167 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 791SP UT WOS:000292685500014 PM 21751909 ER PT J AU D'Amico, AV AF D'Amico, Anthony V. TI Risk-Based Management of Prostate Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ANDROGEN SUPPRESSION; RANDOMIZED-TRIAL; RADIOTHERAPY; RADIATION; THERAPY C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. NR 10 TC 12 Z9 13 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 14 PY 2011 VL 365 IS 2 BP 169 EP 171 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 791SP UT WOS:000292685500015 PM 21751910 ER PT J AU Herbert, MR AF Herbert, Martha R. TI SHANK3, the Synapse, and Autism SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Herbert, Martha R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Herbert, Martha R.] Harvard Univ, Sch Med, Boston, MA USA. RP Herbert, MR (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 5 TC 26 Z9 27 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 14 PY 2011 VL 365 IS 2 BP 173 EP 175 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 791SP UT WOS:000292685500017 PM 21751912 ER PT J AU Tierney, L Sievers, AC AF Tierney, Lawrence Sievers, Amy C. TI Case 10-2011: Fever, Confusion, and Liver Failure REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Tierney, Lawrence] VA Med Ctr, San Francisco, CA USA. [Sievers, Amy C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Tierney, L (reprint author), VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 14 PY 2011 VL 365 IS 2 BP 187 EP 187 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 791SP UT WOS:000292685500039 ER PT J AU Carpenter, D Kesselheim, AS Joffe, S AF Carpenter, Daniel Kesselheim, Aaron S. Joffe, Steven TI Reputation and Precedent in the Bevacizumab Decision SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Carpenter, Daniel] Harvard Univ, Dept Govt, Cambridge, MA 02138 USA. [Kesselheim, Aaron S.; Joffe, Steven] Harvard Univ, Sch Med, Boston, MA USA. [Kesselheim, Aaron S.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Joffe, Steven] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Joffe, Steven] Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Carpenter, D (reprint author), Harvard Univ, Dept Govt, Cambridge, MA 02138 USA. OI Joffe, Steven/0000-0002-0667-7384 NR 4 TC 20 Z9 21 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 JUL 14 PY 2011 VL 365 IS 2 AR e3 DI 10.1056/nejmp1107201 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 791SP UT WOS:000292685500006 PM 21707383 ER PT J AU Raj, L Ide, T Gurkar, AU Foley, M Schenone, M Li, XY Tolliday, NJ Golub, TR Carr, SA Shamji, AF Stern, AM Mandinova, A Schreiber, SL Lee, SW AF Raj, Lakshmi Ide, Takao Gurkar, Aditi U. Foley, Michael Schenone, Monica Li, Xiaoyu Tolliday, Nicola J. Golub, Todd R. Carr, Steven A. Shamji, Alykhan F. Stern, Andrew M. Mandinova, Anna Schreiber, Stuart L. Lee, Sam W. TI Selective killing of cancer cells by a small molecule targeting the stress response to ROS SO NATURE LA English DT Article ID HUMAN TUMOR-CELLS; APOPTOSIS; GENE; MECHANISMS; INDUCTION; ONCOGENE; PROTEINS; ENZYMES; DEATH AB Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage)(1). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells(2). Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress(3-5). C1 [Raj, Lakshmi; Ide, Takao; Gurkar, Aditi U.; Mandinova, Anna; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Raj, Lakshmi; Ide, Takao; Gurkar, Aditi U.; Mandinova, Anna; Lee, Sam W.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Foley, Michael; Schenone, Monica; Li, Xiaoyu; Tolliday, Nicola J.; Golub, Todd R.; Carr, Steven A.; Shamji, Alykhan F.; Stern, Andrew M.; Mandinova, Anna; Schreiber, Stuart L.; Lee, Sam W.] Broad Inst Harvard & MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA. RP Lee, SW (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. EM amandinova@partners.org; stuart_schreiber@harvard.edu; swlee@partners.org RI Bell, Tiffany/F-4403-2010 FU NIH [CA142805, CA127247, CA085681, CA080058]; National Cancer Institute's Initiative for Chemical Genetics [N01-CO-12400]; Cancer Target Discovery and Development Network [5 RC2 CA148399-02]; National Institutes of Health [RL1HG004671, RL1CA133834, RL1GM084437, UL1RR024924] FX We thank K. Chu, L. Brown-Endres, E. Lerner and F. Neville for their help in preparing the manuscript, W. C. Hahn for BJ cell lines, V. Band for 76N cells, D. Beer for H1975 cells and K. Todorova, G. Wei, S. Ong, S. Norton and F. An for technical assistance. This project has been supported in part by grants CA142805, CA127247, CA085681 and CA080058 from NIH. This research was supported by the National Cancer Institute's Initiative for Chemical Genetics Contract (N01-CO-12400) and Cancer Target Discovery and Development Network grant (5 RC2 CA148399-02), as well as the National Institutes of Health Genomics Based Drug Discovery-Target ID Project Grant (RL1HG004671, which is administratively linked to National Institutes of Health Grants RL1CA133834, RL1GM084437 and UL1RR024924). S.L.S. is an Investigator with the Howard Hughes Medical Institute. NR 27 TC 458 Z9 480 U1 30 U2 233 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 14 PY 2011 VL 475 IS 7355 BP 231 EP 234 DI 10.1038/nature10167 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791UA UT WOS:000292690500051 PM 21753854 ER PT J AU Gandy, S AF Gandy, Sam TI PERSPECTIVE Prevention is better than cure SO NATURE LA English DT Editorial Material ID ALZHEIMERS-DISEASE; COMPOUND-B C1 [Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Gandy, Sam] James J Peters VA Med Ctr, New York, NY USA. RP Gandy, S (reprint author), Mt Sinai Sch Med, Alzheimers Dis Res Ctr, New York, NY 10029 USA. EM samuel.gandy@mssm.edu FU NIA NIH HHS [P50 AG005138] NR 7 TC 15 Z9 16 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 14 PY 2011 VL 475 IS 7355 BP S15 EP S15 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791UA UT WOS:000292690500007 PM 21760576 ER PT J AU Qu, J Myhr, KL AF Qu, Juan Myhr, Karen L. TI The Morphology and Intrinsic Excitability of Developing Mouse Retinal Ganglion Cells SO PLOS ONE LA English DT Article ID MUDPUPPY NECTURUS MACULOSUS; CATS RETINA; VISUAL EXPERIENCE; CLASSIFICATION; ORGANIZATION; DIVERSITY; PATHWAYS; PATTERNS; MUTANT; BRISK AB The retinal ganglion cells (RGCs) have diverse morphology and physiology. Although some studies show that correlations between morphological properties and physiological properties exist in cat RGCs, these properties are much less distinct and their correlations are unknown in mouse RGCs. In this study, using three-dimensional digital neuron reconstruction, we systematically analyzed twelve morphological parameters of mouse RGCs as they developed in the first four postnatal weeks. The development of these parameters fell into three different patterns and suggested that contact from bipolar cells and eye opening might play important roles in RGC morphological development. Although there has been a general impression that the morphological parameters are not independent, such as RGCs with larger dendritic fields usually have longer but sparser dendrites, there was not systematic study and statistical analysis proving it. We used Pearson's correlation coefficients to determine the relationship among these morphological parameters and demonstrated that many morphological parameters showed high statistical correlation. In the same cells we also measured seven physiological parameters using whole-cell patch-clamp recording, focusing on intrinsic excitability. We previously reported the increase in intrinsic excitability in mouse RGCs during early postnatal development. Here we showed that strong correlations also existed among many physiological parameters that measure the intrinsic excitability. However, Pearson's correlation coefficient revealed very limited correlation across morphological and physiological parameters. In addition, principle component analysis failed to separate RGCs into clusters using combined morphological and physiological parameters. Therefore, despite strong correlations within the morphological parameters and within the physiological parameters, postnatal mouse RGCs had only limited correlation between morphology and physiology. This may be due to developmental immaturity, or to selection of parameters. C1 [Qu, Juan; Myhr, Karen L.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Myhr, Karen L.] Wayne State Univ, Dept Anat & Cell Biol, Detroit, MI USA. RP Qu, J (reprint author), Harvard Univ, Sch Med, Howe Lab Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. EM kmyhr@wayne.edu FU Wayne State University FX This work was supported by Wayne State University Startup funds to Dr. Karen Myhr. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 2 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 13 PY 2011 VL 6 IS 7 AR e21777 DI 10.1371/journal.pone.0021777 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 792WQ UT WOS:000292781500015 PM 21765913 ER PT J AU Race, E Keane, MM Verfaellie, M AF Race, Elizabeth Keane, Margaret M. Verfaellie, Mieke TI Medial Temporal Lobe Damage Causes Deficits in Episodic Memory and Episodic Future Thinking Not Attributable to Deficits in Narrative Construction SO JOURNAL OF NEUROSCIENCE LA English DT Article ID REMOTE AUTOBIOGRAPHICAL MEMORIES; MENTAL TIME-TRAVEL; WORKING-MEMORY; RELATIONAL MEMORY; RETROGRADE-AMNESIA; HIPPOCAMPUS; IMPAIRMENT; BINDING; EVENTS; BRAIN AB The medial temporal lobe (MTL) makes critical contributions to episodic memory, but its contributions to episodic future thinking remain a matter of debate. By one view, imagining future events relies on MTL mechanisms that also support memory for past events. Alternatively, it has recently been suggested that future thinking is independent of MTL-mediated processes and can be supported by regions outside the MTL. The current study investigated the nature and necessity of MTL involvement in imagining the future and tested the novel hypothesis that the MTL contributes to future thinking by supporting online binding processes related to narrative construction. Human amnesic patients with well characterized MTL damage and healthy controls constructed narratives about (1) future events, (2) past events, and (3) visually presented pictures. While all three tasks place similar demands on narrative construction, only the past and future conditions require memory/future thinking to mentally generate relevant narrative information. Patients produced impoverished descriptions of both past and future events but were unimpaired at producing detailed picture narratives. In addition, future-thinking performance positively correlated with episodic memory performance but did not correlate with picture narrative performance. Finally, future-thinking impairments were present when MTL lesions were restricted to the hippocampus and did not depend on the presence of neural damage outside the MTL. These results indicate that the ability to generate and maintain a detailed narrative is preserved in amnesia and suggest that a common MTL mechanism supports both episodic memory and episodic future thinking. C1 [Race, Elizabeth] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA 02130 USA. [Race, Elizabeth; Keane, Margaret M.; Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02130 USA. [Keane, Margaret M.] Wellesley Coll, Dept Psychol, Wellesley, MA 02481 USA. RP Race, E (reprint author), VA Boston Healthcare Syst, Memory Disorders Res Ctr, 150 S Huntington Ave 151-A, Boston, MA 02130 USA. EM race@bu.edu OI Verfaellie, Mieke/0000-0001-5535-4584 FU Office of Research and Development, Medical Research Service, Department of Veterans Affairs FX This research was supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. NR 54 TC 123 Z9 124 U1 2 U2 40 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 13 PY 2011 VL 31 IS 28 BP 10262 EP 10269 DI 10.1523/JNEUROSCI.1145-11.2011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 791WP UT WOS:000292699600017 PM 21753003 ER PT J AU Ziogas, A Horick, NK Kinney, AY Lowery, JT Domchek, SM Isaacs, C Griffin, CA Moorman, PG Edwards, KL Hill, DA Berg, JS Tomlinson, GE Anton-Culver, H Strong, LC Kasten, CH Finkelstein, DM Plon, SE AF Ziogas, Argyrios Horick, Nora K. Kinney, Anita Y. Lowery, Jan T. Domchek, Susan M. Isaacs, Claudine Griffin, Constance A. Moorman, Patricia G. Edwards, Karen L. Hill, Deirdre A. Berg, Jonathan S. Tomlinson, Gail E. Anton-Culver, Hoda Strong, Louise C. Kasten, Carol H. Finkelstein, Dianne M. Plon, Sharon E. TI Clinically Relevant Changes in Family History of Cancer Over Time SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BREAST-CANCER; COLORECTAL-CANCER; HIGH-RISK; INHERITANCE; ONSET; WOMEN AB Context Knowledge of family cancer history is important for assessing cancer risk and guiding screening recommendations. Objective To quantify how often throughout adulthood clinically significant changes occur in cancer family history that would result in recommendations for earlier or intense screening. Design and Setting Descriptive study examining baseline and follow-up family history data from participants in the Cancer Genetics Network (CGN), a US national population-based cancer registry, between 1999 and 2009. Participants Adults with a personal history, family history, or both of cancer enrolled in the CGN through population-based cancer registries. Retrospective colorectal, breast, and prostate cancer screening-specific analyses included 9861, 2547, and 1817 participants, respectively; prospective analyses included 1533, 617, and 163 participants, respectively. Median follow-up was 8 years (range, 0-11 years). Screening-specific analyses excluded participants with the cancer of interest. Main Outcome Measures Percentage of individuals with clinically significant family histories and rate of change over 2 periods: (1) retrospectively, from birth until CGN enrollment and (2) prospectively, from enrollment to last follow-up. Results Retrospective analysis revealed that the percentages of participants who met criteria for high-risk screening based on family history at ages 30 and 50 years, respectively, were as follows: for colorectal cancer, 2.1% (95% confidence interval [CI], 1.8%-2.4%) and 7.1%(95% CI, 6.5%-7.6%); for breast cancer, 7.2%(95% CI, 6.1%-8.4%) and 11.4% (95% CI, 10.0%-12.8%); and for prostate cancer, 0.9%(95% CI, 0.5%-1.4%) and 2.0% (95% CI, 1.4%-2.7%). In prospective analysis, the numbers of participants who newly met criteria for high-risk screening based on family history per 100 persons followed up for 20 years were 2 (95% CI, 0-7) for colorectal cancer, 6 (95% CI, 2-13) for breast cancer, and 8 (95% CI, 3-16) for prostate cancer. The rate of change in cancer family history was similar for colorectal and breast cancer between the 2 analyses. Conclusion Clinically relevant family history of colorectal, breast, and prostate cancer that would result in recommendations for earlier or intense cancer screening increases between ages 30 and 50 years, although the absolute rate is low for prostate cancer. JAMA. 2011; 306(2): 172-178 C1 [Ziogas, Argyrios; Anton-Culver, Hoda] Univ Calif Irvine, Irvine, CA 92717 USA. [Horick, Nora K.; Finkelstein, Dianne M.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Finkelstein, Dianne M.] Harvard Univ, Boston, MA 02115 USA. [Kinney, Anita Y.] Huntsman Canc Inst, Salt Lake City, UT USA. [Kinney, Anita Y.] Univ Utah, Salt Lake City, UT USA. [Lowery, Jan T.] Univ Colorado, Aurora, CO USA. [Domchek, Susan M.] Univ Penn, Philadelphia, PA 19104 USA. [Isaacs, Claudine] Georgetown Univ, Washington, DC USA. [Griffin, Constance A.] Johns Hopkins Univ, Baltimore, MD USA. [Moorman, Patricia G.] Duke Univ, Med Ctr, Durham, NC USA. [Edwards, Karen L.] Univ Washington, Seattle, WA 98195 USA. [Hill, Deirdre A.] Univ New Mexico, Albuquerque, NM 87131 USA. [Berg, Jonathan S.] Univ N Carolina, Chapel Hill, NC USA. [Tomlinson, Gail E.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Tomlinson, Gail E.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Strong, Louise C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Plon, Sharon E.] Baylor Coll Med, Houston, TX 77030 USA. [Kasten, Carol H.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Finkelstein, DM (reprint author), 50 Staniford St,Ste 560, Boston, MA 02114 USA. EM dfinkel-stein@partners.org FU National Cancer Institute [U01CA078284, U24CA078134, U24CA078164, U24CA078156, U24CA078148, U24CA078146, U24CA078174, U24CA078157, U24CA078142, HHSN2612007440000C] FX The CGN is supported by grants U01CA078284, U24CA078134, U24CA078164, U24CA078156, U24CA078148, U24CA078146, U24CA078174, U24CA078157, and U24CA078142 and contract HHSN2612007440000C from the National Cancer Institute. NR 21 TC 16 Z9 17 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 13 PY 2011 VL 306 IS 2 BP 172 EP 178 DI 10.1001/jama.2011.955 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 791CO UT WOS:000292639400024 PM 21750294 ER PT J AU Daigle, SR Olhava, EJ Therkelsen, CA Majer, CR Sneeringer, CJ Song, J Johnston, LD Scott, MP Smith, JJ Xiao, YH Jin, L Kuntz, KW Chesworth, R Moyer, MP Bernt, KM Tseng, JC Kung, AL Armstrong, SA Copeland, RA Richon, VM Pollock, RM AF Daigle, Scott R. Olhava, Edward J. Therkelsen, Carly A. Majer, Christina R. Sneeringer, Christopher J. Song, Jeffrey Johnston, L. Danielle Scott, Margaret Porter Smith, Jesse J. Xiao, Yonghong Jin, Lei Kuntz, Kevin W. Chesworth, Richard Moyer, Mike P. Bernt, Kathrin M. Tseng, Jen-Chieh Kung, Andrew L. Armstrong, Scott A. Copeland, Robert A. Richon, Victoria M. Pollock, Roy M. TI Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor SO CANCER CELL LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HISTONE METHYLTRANSFERASE; MLL TRANSLOCATIONS; H3K79 METHYLATION; SET DOMAIN; GENE; MEIS1; HOXA9; CLASSIFICATION; TRANSCRIPTION AB Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL. C1 [Daigle, Scott R.; Olhava, Edward J.; Therkelsen, Carly A.; Majer, Christina R.; Sneeringer, Christopher J.; Song, Jeffrey; Johnston, L. Danielle; Scott, Margaret Porter; Smith, Jesse J.; Jin, Lei; Kuntz, Kevin W.; Chesworth, Richard; Moyer, Mike P.; Copeland, Robert A.; Richon, Victoria M.; Pollock, Roy M.] Epizyme Inc, Cambridge, MA 02139 USA. [Xiao, Yonghong] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Bernt, Kathrin M.; Kung, Andrew L.; Armstrong, Scott A.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Bernt, Kathrin M.; Kung, Andrew L.; Armstrong, Scott A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bernt, Kathrin M.; Kung, Andrew L.; Armstrong, Scott A.] Harvard Univ, Med, Boston, MA 02115 USA. [Tseng, Jen-Chieh; Kung, Andrew L.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02215 USA. [Armstrong, Scott A.] Harvard Stem Cell Inst, Boston, MA 02138 USA. RP Pollock, RM (reprint author), Epizyme Inc, 325 Vassar St, Cambridge, MA 02139 USA. EM rpollock@epizyme.com RI Bernt, Kathrin/L-1826-2016; OI Bernt, Kathrin/0000-0002-5400-0482; Kung, Andrew/0000-0002-9091-488X FU NCI NIH HHS [P01 CA066996]; NHLBI NIH HHS [K08 HL102264] NR 45 TC 387 Z9 390 U1 4 U2 36 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 JUL 12 PY 2011 VL 20 IS 1 BP 53 EP 65 DI 10.1016/j.ccr.2011.06.009 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 793CK UT WOS:000292797800008 PM 21741596 ER PT J AU Bernt, KM Zhu, N Sinha, AU Vempati, S Faber, J Krivtsov, AV Feng, ZH Punt, N Daigle, A Bullinger, L Pollock, RM Richon, VM Kung, AL Armstrong, SA AF Bernt, Kathrin M. Zhu, Nan Sinha, Amit U. Vempati, Sridhar Faber, Joerg Krivtsov, Andrei V. Feng, Zhaohui Punt, Natalie Daigle, Amanda Bullinger, Lars Pollock, Roy M. Richon, Victoria M. Kung, Andrew L. Armstrong, Scott A. TI MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L SO CANCER CELL LA English DT Article ID METHYLTRANSFERASE GENE EZH2; MIXED-LINEAGE LEUKEMIA; ACUTE MYELOID-LEUKEMIA; HISTONE METHYLTRANSFERASE; MYELODYSPLASTIC SYNDROMES; SOMATIC MUTATIONS; TRANSCRIPTION; LEUKEMOGENESIS; EXPRESSION; CHROMATIN AB The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia. C1 [Bernt, Kathrin M.; Zhu, Nan; Sinha, Amit U.; Vempati, Sridhar; Krivtsov, Andrei V.; Feng, Zhaohui; Punt, Natalie; Daigle, Amanda; Kung, Andrew L.; Armstrong, Scott A.] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. [Bernt, Kathrin M.; Zhu, Nan; Sinha, Amit U.; Vempati, Sridhar; Krivtsov, Andrei V.; Feng, Zhaohui; Punt, Natalie; Daigle, Amanda; Kung, Andrew L.; Armstrong, Scott A.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Faber, Joerg] Johannes Gutenberg Univ Mainz, D-05131 Mainz, Germany. [Bullinger, Lars] Univ Ulm, D-98091 Ulm, Germany. [Pollock, Roy M.; Richon, Victoria M.] Epizyme Inc, Cambridge, MA 02139 USA. [Kung, Andrew L.; Armstrong, Scott A.] Harvard Stem Cell Inst, Boston, MA 02138 USA. RP Armstrong, SA (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. EM andrew_kung@dfci.harvard.edu; scott.armstrong@childrens.harvard.edu RI Bernt, Kathrin/L-1826-2016; OI Bernt, Kathrin/0000-0002-5400-0482; Kedaigle, Amanda/0000-0001-6156-5046; Krivtsov, Andrei/0000-0002-5511-1686; Kung, Andrew/0000-0002-9091-488X FU American Cancer Society; Leukemia and Lymphoma Society; Gabrielle's Angel Foundation; National Cancer Institute [CA105423, 1RC2CA148222, CA140575, CA684841]; NIGMS [GM083054]; NHLBI [K08 HL102264]; William Lawrence and Blanche Hughes Foundation; Deutsche Forschungsgemeinschaft [BU 1339/3-1] FX We thank Yuko Fujiwara and Stuart Orkin for blastocyst injections and helpful suggestions, Konstanze Dohner and the German-Austrian AML Study Group for providing leukemia samples, and Ronald Mathieu for assistance with FAGS. This work was supported by grants from the American Cancer Society, the Leukemia and Lymphoma Society, Gabrielle's Angel Foundation, and the National Cancer Institute (CA105423, 1RC2CA148222, CA140575, CA684841) to S.A.A. A.L.K. was supported by NIGMS Grant GM083054. K.M.B. was supported by NHLBI Career Development Award K08 HL102264 and funding from the William Lawrence and Blanche Hughes Foundation. L.B. was supported in part by the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1). V.M.R. and R.M.P. are employees and S.A.A. is a consultant for Epizyme Inc. NR 47 TC 296 Z9 302 U1 4 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JUL 12 PY 2011 VL 20 IS 1 BP 66 EP 78 DI 10.1016/j.ccr.2011.06.010 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 793CK UT WOS:000292797800009 PM 21741597 ER PT J AU Scott, KL Nogueira, C Heffernan, TP van Doorn, R Dhakal, S Hanna, JA Min, CY Jaskelioff, M Xiao, YH Wu, CJ Cameron, LA Perry, SR Zeid, R Feinberg, T Kim, M Vande Woude, G Granter, SR Bosenberg, M Chu, GC DePinho, RA Rimm, DL Chin, L AF Scott, Kenneth L. Nogueira, Cristina Heffernan, Timothy P. van Doorn, Remco Dhakal, Sabin Hanna, Jason A. Min, Chengyin Jaskelioff, Mariela Xiao, Yonghong Wu, Chang-Jiun Cameron, Lisa A. Perry, Samuel R. Zeid, Rhamy Feinberg, Tamar Kim, Minjung Vande Woude, George Granter, Scott R. Bosenberg, Marcus Chu, Gerald C. DePinho, Ronald A. Rimm, David L. Chin, Lynda TI Proinvasion Metastasis Drivers in Early-Stage Melanoma Are Oncogenes SO CANCER CELL LA English DT Article ID RESISTANT ACID-PHOSPHATASE; HUMAN BREAST-CANCER; IN-VIVO; TISSUE MICROARRAYS; MALIGNANT-MELANOMA; BONE METASTASES; HOX GENES; EXPRESSION; ACTIVATION; SURVIVAL AB Clinical and genomic evidence suggests that the metastatic potential of a primary tumor may be dictated by prometastatic events that have additional oncogenic capability. To test this "deterministic" hypothesis, we adopted a comparative oncogenomics-guided function-based strategy involving: (1) comparison of global transcriptomes of two genetically engineered mouse models with contrasting metastatic potential, (2) genomic and transcriptomic profiles of human melanoma, (3) functional genetic screen for enhancers of cell invasion, and (4) evidence of expression selection in human melanoma tissues. This integrated effort identified six genes that are potently proinvasive and oncogenic. Furthermore, we show that one such gene, ACP5, confers spontaneous metastasis in vivo, engages a key pathway governing metastasis, and is prognostic in human primary melanomas. C1 [Scott, Kenneth L.; Nogueira, Cristina; Heffernan, Timothy P.; Dhakal, Sabin; Min, Chengyin; Jaskelioff, Mariela; Xiao, Yonghong; Wu, Chang-Jiun; Perry, Samuel R.; Zeid, Rhamy; Feinberg, Tamar; Kim, Minjung; Chu, Gerald C.; DePinho, Ronald A.; Chin, Lynda] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Scott, Kenneth L.; Nogueira, Cristina; Heffernan, Timothy P.; van Doorn, Remco; Dhakal, Sabin; Min, Chengyin; Jaskelioff, Mariela; Wu, Chang-Jiun; Feinberg, Tamar; Kim, Minjung; Chu, Gerald C.; DePinho, Ronald A.; Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nogueira, Cristina] Univ Porto, IPATIMUP Med Fac, Inst Mol Pathol & Immunol, P-4200465 Oporto, Portugal. [van Doorn, Remco] Leiden Univ, Med Ctr, Dept Dermatol, NL-2300 RC Leiden, Netherlands. [Hanna, Jason A.; Bosenberg, Marcus; Rimm, David L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Vande Woude, George] Van Andel Res Inst, Grand Rapids, MI 49503 USA. [Granter, Scott R.; Chu, Gerald C.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Chin, L (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. EM lynda_chin@dfci.harvard.edu RI Nogueira, Cristina/N-4574-2015; OI Nogueira, Cristina/0000-0002-0853-5304; Hanna, Jason/0000-0001-7253-7964 FU American Cancer Society; National Institutes of Health Training; FCT [Praxis XXI/BD/21794/99]; KWF; NIH [RO1 CA93947, U01 CA84313, P50 CA93683]; Melanoma Research Foundation; American Skin Association FX Genomic studies and analyses were performed by the Belfer Institute for Applied Cancer Science. The authors wish to thank members of the Chin laboratory for helpful discussion, particularly Shan Jiang for mouse colony work and Bob Xiong for computational assistance. The authors acknowledge the generous gifts of ORF clones provided by Drs. Marc Vidal and David Hill of the human ORFeome in Center for Cancer System Biology, and the HMEL468 primed melanocytes (PMEL/hTERT/CDK4(R24C)/p53DD/BRAFV600E) provided by Dr. David Fisher. Wide-field microscopy images for this study were acquired in the Confocal and Light Microscopy Core Facility at the Dana-Farber Cancer Institute. K.L.S. was supported by a postdoctoral fellowship from the American Cancer Society and was previously supported by a National Institutes of Health Training Grant appointment in the Department of Dermatology at Brigham and Women's Hospital, Boston. C.N. was supported by a fellowship from FCT (Praxis XXI/BD/21794/99). R.v.D. was supported by a KWF fellowship for medical specialists. This work is supported by grants from the NIH (RO1 CA93947, U01 CA84313, and P50 CA93683), and by an Established Investigator Award from the Melanoma Research Foundation to L.C. L.C. is the recipient of the Abby S. & Howard P. Milstein Innovation Award by American Skin Association. Technology/intellectual property pertaining to this manuscript has been exclusively licensed to Metamark Genetics, a development-stage molecular diagnostics company cofounded by L.C., D.L.R., and R.A.D. D.L.R. is cofounder, stockholder in, and consultant to HistoRx, the exclusive licensee of the Yale held patent on the AQUA technology that was used in this work. NR 46 TC 67 Z9 67 U1 0 U2 12 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 JUL 12 PY 2011 VL 20 IS 1 BP 92 EP 103 DI 10.1016/j.ccr.2011.05.025 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 793CK UT WOS:000292797800011 PM 21741599 ER PT J AU Ni, M Chen, YW Lim, E Wimberly, H Bailey, ST Imai, Y Rimm, DL Liu, XS Brown, M AF Ni, Min Chen, Yiwen Lim, Elgene Wimberly, Hallie Bailey, Shannon T. Imai, Yuuki Rimm, David L. Liu, X. Shirley Brown, Myles TI Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer SO CANCER CELL LA English DT Article ID INDEPENDENT PROSTATE-CANCER; MAMMARY-GLAND DEVELOPMENT; GENE-EXPRESSION PATTERNS; SIGNALING PATHWAY; BETA-CATENIN; WNT; TUMORS; ALPHA; TRANSCRIPTION; INHIBITION AB Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25%-30% of cases that are ER negative (ER-). Androgen receptor (AR) is expressed in 60%-70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER- breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER-/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER-/HER2+ breast cancers. C1 [Chen, Yiwen; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Chen, Yiwen; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Ni, Min; Lim, Elgene; Bailey, Shannon T.; Imai, Yuuki; Brown, Myles] Dana Farber Canc Inst, Div Mol & Cellular Oncol, Dept Med Oncol, Boston, MA 02215 USA. [Ni, Min; Lim, Elgene; Bailey, Shannon T.; Imai, Yuuki; Brown, Myles] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Ni, Min; Lim, Elgene; Bailey, Shannon T.; Imai, Yuuki; Brown, Myles] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Wimberly, Hallie; Rimm, David L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. RP Liu, XS (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. EM xsliu@jimmy.harvard.edu; myles_brown@dfci.harvard.edu RI Bailey, Shannon/B-8045-2014; OI Lim, Elgene/0000-0001-8065-8838; Brown, Myles/0000-0002-8213-1658 FU National Cancer Institute [P01CA080111]; National Institutes of Health [R01HG004069]; Department of Defense [W81XWH-10-1-0037] FX We are grateful to Cheng Fan, Joel Parker, Philip Bernard and Charles Perou for kindly sharing their data sets. We thank Yi Zheng and Xi Chen for technical support. We thank Michael Verzi, Thomas Wester ling, Mathieu Lupien, and Jian Xu for helpful advice and discussions. This work was partly supported by a grant from the National Cancer Institute (P01CA080111 to M.B.), the National Institutes of Health (R01HG004069 to X.S.L.), and a Department of Defense Award (W81XWH-10-1-0037 to M.N.). NR 55 TC 137 Z9 143 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JUL 12 PY 2011 VL 20 IS 1 BP 119 EP 131 DI 10.1016/j.ccr.2011.05.026 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 793CK UT WOS:000292797800013 PM 21741601 ER PT J AU Li, SQ Zhu, JG Zhang, WL Chen, YR Zhang, K Popescu, LM Ma, XL Lau, WB Rong, R Yu, XQ Wang, BB Li, YF Xiao, CS Zhang, MM Wang, SY Yu, LP Chen, AF Yang, XC Cai, J AF Li, Shuqiang Zhu, Jianguo Zhang, Weili Chen, Youren Zhang, Ke Popescu, Laurentiu M. Ma, Xinliang Lau, Wayne Bond Rong, Rong Yu, Xueqing Wang, Bingbing Li, Yafeng Xiao, Chuanshi Zhang, Mingming Wang, Shuyan Yu, Liping Chen, Alex F. Yang, Xinchun Cai, Jun TI Signature microRNA Expression Profile of Essential Hypertension and Its Novel Link to Human Cytomegalovirus Infection SO CIRCULATION LA English DT Article DE cytomegalovirus; hypertension; interferon regulatory factor-1; microRNAs ID NITRIC-OXIDE SYNTHASE; SMOOTH-MUSCLE-CELLS; II TYPE-2 RECEPTOR; KAPPA-B; CARDIOVASCULAR-DISEASE; ENDOTHELIAL-CELLS; GENE-EXPRESSION; BLOOD-PRESSURE; NUCLEAR FACTOR; RATS AB Background-Essential hypertension has been recognized as a disease resulting from a combination of environmental and genetic factors. Recent studies demonstrated that microRNAs (miRNAs) are involved in cardiac hypertrophy and heart failure. However, little is known about the roles of miRNAs in essential hypertension. Methods and Results-Using microarray-based miRNA expression profiling, we compared the miRNA expressions in plasma samples from 13 hypertensive patients and 5 healthy control subjects. Twenty-seven miRNAs were found to be differentially expressed. The expressions of selected miRNAs (miR-296-5p, let-7e, and a human cytomegalovirus [HCMV]-encoded miRNA, hcmv-miR-UL112) were validated independently in plasma samples from 24 hypertensive patients and 22 control subjects. The absolute expression levels of hcmv-miR-UL112, miR-296-5p, and let-7e were further determined in 127 patients and 67 control subjects (fold changes are 2.5, 0.5, and 1.7 respectively; all P < 0.0001). Additionally, we demonstrated that interferon regulatory factor 1 is a direct target of hcmv-miR-UL112. Increased HCMV seropositivity and quantitative titers were found in the hypertension group compared with the control group (52.7% versus 30.9%, P = 0.0005; 1870 versus 54 copies per 1 mL plasma, P < 0.0001). Seropositivity, log-transformed copies of HCMV, and hcmv-miR-UL112 were independently associated with an increased risk of hypertension (odds ratio, 2.48; 95% confidence interval, 1.48 to 4.15; P = 0.0005; odds ratio, 1.97; 95% confidence interval, 1.58 to 2.46; P < 0.0001; and odds ratio, 2.55; 95% confidence interval, 1.98 to 3.27; P < 0.0001, respectively). Conclusions-We report for the first time a circulating miRNA profile for hypertensive patients and demonstrate a novel link between HCMV infection and essential hypertension. These findings may reveal important insights into the pathogenesis of essential hypertension. C1 [Li, Shuqiang; Zhu, Jianguo; Zhang, Mingming; Wang, Shuyan; Yang, Xinchun; Cai, Jun] Capital Med Univ, Dept Cardiol, Chaoyang Hosp, Beijing 100020, Peoples R China. [Li, Shuqiang; Wang, Bingbing] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Zhang, Weili] Fuwai Hosp, Peking Union Med Coll, Beijing, Peoples R China. [Zhang, Weili] Chinese Acad Med Sci, Beijing 100730, Peoples R China. [Chen, Youren] Shantou Univ, Dept Cardiol, Coll Med, Affiliated Hosp, Shantou, Peoples R China. [Zhang, Ke] Tech Univ Munich, German Res Ctr Environm Hlth, D-8000 Munich, Germany. [Popescu, Laurentiu M.] Carol Davila Univ Med & Pharm, Dept Cellular & Mol Med, Bucharest, Romania. [Popescu, Laurentiu M.] Victor Babes Natl Inst Pathol, Bucharest, Romania. [Ma, Xinliang; Lau, Wayne Bond] Thomas Jefferson Univ, Dept Emergency Med, Philadelphia, PA 19107 USA. [Rong, Rong; Yu, Xueqing] Sun Yat Sen Univ, Dept Nephrol, Affiliated Hosp 1, Guangzhou 510275, Guangdong, Peoples R China. [Li, Yafeng; Xiao, Chuanshi] Shanxi Med Univ, Hosp 2, Dept Cardiol, Taiyuan, Peoples R China. [Chen, Alex F.] Univ Pittsburgh, Sch Med, VA Vasc Surg Res, Dept Surg, Pittsburgh, PA USA. [Cai, Jun] Capital Med Univ, Key Lab Remodeling Related Cardiovasc Dis, Minist Educ, Beijing 100020, Peoples R China. RP Yang, XC (reprint author), Capital Med Univ, Dept Cardiol, Chaoyang Hosp, 8th Gongtinanlu Rd, Beijing 100020, Peoples R China. EM yangxc2010@hotmail.com; caijun7879@yahoo.com.cn FU National Natural Science Foundation of China [81050012]; Beijing Nova Program [2009B39]; Beijing Natural Science Foundation [7102057]; Scientific Research Foundation for the Returned Overseas Chinese Scholars; Education Ministry of China FX This work is supported by grants from the National Natural Science Foundation of China (No. 81050012), Beijing Nova Program (No. 2009B39), Beijing Natural Science Foundation (No. 7102057), and Scientific Research Foundation for the Returned Overseas Chinese Scholars, Education Ministry of China. NR 45 TC 147 Z9 173 U1 6 U2 33 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 12 PY 2011 VL 124 IS 2 BP 175 EP U154 DI 10.1161/CIRCULATIONAHA.110.012237 PG 33 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 790PO UT WOS:000292601900015 PM 21690488 ER PT J AU Crooks, KR Allingham, RR Qin, XJ Liu, YT Gibson, JR Santiago-Turla, C Larocque-Abramson, KR Del Bono, E Challa, P Herndon, LW Akafo, S Wiggs, JL Schmidt, S Hauser, MA AF Crooks, Kristy R. Allingham, R. Rand Qin, Xuejun Liu, Yutao Gibson, Jason R. Santiago-Turla, Cecilia Larocque-Abramson, Karen R. Del Bono, Elizabeth Challa, Pratap Herndon, Leon W. Akafo, Stephen Wiggs, Janey L. Schmidt, Silke Hauser, Michael A. TI Genome-Wide Linkage Scan for Primary Open Angle Glaucoma: Influences of Ancestry and Age at Diagnosis SO PLOS ONE LA English DT Article ID ORDERED SUBSET ANALYSIS; GENETIC-LINKAGE; LOCUS; MAPS; REGION; IDENTIFICATION; DISEQUILIBRIUM; LOCALIZATION; MUTATIONS AB Primary open-angle glaucoma (POAG) is the most common form of glaucoma and one of the leading causes of vision loss worldwide. The genetic etiology of POAG is complex and poorly understood. The purpose of this work is to identify genomic regions of interest linked to POAG. This study is the largest genetic linkage study of POAG performed to date: genomic DNA samples from 786 subjects (538 Caucasian ancestry, 248 African ancestry) were genotyped using either the Illumina GoldenGate Linkage 4 Panel or the Illumina Infinium Human Linkage-12 Panel. A total of 5233 SNPs was analyzed in 134 multiplex POAG families (89 Caucasian ancestry, 45 African ancestry). Parametric and non-parametric linkage analyses were performed on the overall dataset and within race-specific datasets (Caucasian ancestry and African ancestry). Ordered subset analysis was used to stratify the data on the basis of age of glaucoma diagnosis. Novel linkage regions were identified on chromosomes 1 and 20, and two previously described loci-GLC1D on chromosome 8 and GLC1I on chromosome 15-were replicated. These data will prove valuable in the context of interpreting results from genome-wide association studies for POAG. C1 [Crooks, Kristy R.; Allingham, R. Rand; Qin, Xuejun; Liu, Yutao; Gibson, Jason R.; Larocque-Abramson, Karen R.; Schmidt, Silke; Hauser, Michael A.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. [Allingham, R. Rand; Santiago-Turla, Cecilia; Challa, Pratap; Herndon, Leon W.; Hauser, Michael A.] Duke Univ, Med Ctr, Dept Ophthalmol, Ctr Eye, Durham, NC 27710 USA. [Del Bono, Elizabeth; Wiggs, Janey L.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Del Bono, Elizabeth; Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Akafo, Stephen] Univ Ghana, Sch Med, Dept Surg, Unit Ophthalmol, Accra, Ghana. RP Crooks, KR (reprint author), Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. EM mike.hauser@duke.edu FU NCRR/NIH [1 UL1 RR024128-01]; NIH [R01EY013315, R01EY019126, RO1EY015543, R01EY015872, P30EY014104] FX The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was supported in part by a generous donation by Roger Milliken, Spartanburg, South Carolina and by the research infrastructure of the Duke Center for Human Genetics. This work was also supported by CTSA grant 1 UL1 RR024128-01 from NCRR/NIH, NIH grants R01EY013315 (MAH), R01EY019126 (MAH), RO1EY015543 (RRA), R01EY015872 (JLW), and P30EY014104 (Core support at the Massachusetts Eye and Ear Infirmary). NR 31 TC 8 Z9 8 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 JUL 12 PY 2011 VL 6 IS 7 AR e21967 DI 10.1371/journal.pone.0021967 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791WM UT WOS:000292699000017 PM 21765929 ER PT J AU Morina, N von Lersner, U Prigerson, HG AF Morina, Nexhmedin von Lersner, Ulrike Prigerson, Holly G. TI War and Bereavement: Consequences for Mental and Physical Distress SO PLOS ONE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NEUROPSYCHIATRIC INTERVIEW MINI; COMPLICATED GRIEF; HEALTH OUTCOMES; TRAUMATIC GRIEF; BOSNIAN REFUGEES; PARENTAL DEATH; DEPRESSION; VALIDITY; SURVIVORS AB Background: Little is known about the long-term impact of the killing of a parent in childhood or adolescence during war on distress and disability in young adulthood. This study assessed current prevalence rates of mental disorders and levels of dysfunction among young adults who had lost their father due to war-related violence in childhood or adolescence. Methods: 179 bereaved young adults and 175 non-bereaved young adults were interviewed a decade after experiencing the war in Kosovo. Prevalence rates of Major Depressive Episode (MDE), anxiety, and substance use disorders, and current suicide risk were assessed using the Mini-International Neuropsychiatric Interview. The syndrome of Prolonged Grief Disorder (PGD) was assessed with the Prolonged Grief Disorder Interview (PG-13). Somatic symptoms were measured with the Patient Health Questionnaire. General health distress was assessed with the General Health Questionnaire. Findings: Bereaved participants were significantly more likely to suffer from either MDE or any anxiety disorder than non-bereaved participants (58.7% vs. 40%). Among bereaved participants, 39.7% met criteria for Post-Traumatic Stress Disorder, 34.6% for PGD, and 22.3% for MDE. Bereaved participants with PGD were more likely to suffer from MDE, any anxiety disorder, or current suicide risk than bereaved participants without PGD. Furthermore, these participants reported significantly greater physical distress than bereaved participants without PGD. Conclusion: War-related loss during middle childhood and adolescence presents significant risk for adverse mental health and dysfunction in young adulthood in addition to exposure to other war-related traumatic events. Furthermore, the syndrome of PGD can help to identify those with the greatest degree of distress and dysfunction. C1 [Morina, Nexhmedin] Univ Amsterdam, Dept Clin Psychol, NL-1018 WB Amsterdam, Netherlands. [von Lersner, Ulrike] Humboldt Univ, Dept Psychol, Berlin, Germany. [Prigerson, Holly G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Morina, N (reprint author), Univ Amsterdam, Dept Clin Psychol, NL-1018 WB Amsterdam, Netherlands. EM n.morina@uva.nl RI Morina, Nexhmedin/D-4976-2012 OI Morina, Nexhmedin/0000-0002-2331-9140 FU Children and War Foundation; German Psychological Society (DGPs), division for Clinical Psychology and Psychotherapy FX This study was supported by the Children and War Foundation (www.childrenandwar.org). The preparation for the study was also supported by a travel scholarship to the Harvard Medical School in Boston, USA, given to the first author by the German Psychological Society (DGPs), division for Clinical Psychology and Psychotherapy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 22 Z9 22 U1 6 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 12 PY 2011 VL 6 IS 7 AR e22140 DI 10.1371/journal.pone.0022140 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791WM UT WOS:000292699000025 PM 21765944 ER PT J AU Tucker, JD Chang, H Brandt, A Gao, X Lin, M Luo, J Song, P Sun, K Zhang, XX AF Tucker, Joseph D. Chang, Helena Brandt, Allison Gao, Xing Lin, Margaret Luo, Jing Song, Philip Sun, Kai Zhang, Xiaoxi TI An Empirical Analysis of Overlap Publication in Chinese Language and English Research Manuscripts SO PLOS ONE LA English DT Article ID DUPLICATE PUBLICATION; ERROR MANAGEMENT; CITATIONS; JOURNALS; ICEBERG; TIP AB Background: There are a number of sound justifications for publishing nearly identical information in Chinese and English medical journals, assuming several conditions are met. Although overlap publication is perceived as undesirable and ethically questionable in Europe and North America, it may serve an important function in some regions where English is not the native tongue. There is no empirical data on the nature and degree of overlap publication in English and Chinese language journals. Methods/Principal Findings: A random sample of 100 English manuscripts from Chinese institutions was selected from PubMed. Key words and institutions were searched in the China National Knowledge Infrastructure, a comprehensive Chinese language research database. Unacknowledged overlap was a priori defined according to International Committee of Medical Journal Editor (ICMJE) guidelines following examination by two individuals. 19% (95% CI 11-27) of English manuscripts from Chinese institutions were found to have substantial overlap with Chinese published work based on full text examination. None of the manuscripts met all of the criteria established by the ICMJE for an acknowledged overlap publication. Individual-level, journal-level, and institutional factors seem to influence overlap publication. Manuscripts associated with an institution outside of China and with more than one institution were significantly less likely to have substantial overlap (p<0.05). Conclusions/Significance: Overlap publication was common in this context, but instances of standard ICMJE notations to acknowledge this practice were rare. This research did not cite the identified overlap manuscripts with the hope that these empirical data will inform journal policy changes and structural initiatives to promote clearer policies and manuscripts. C1 [Tucker, Joseph D.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Tucker, Joseph D.; Chang, Helena] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Chang, Helena] Univ Wisconsin, Dept Med, Madison, WI USA. [Brandt, Allison] Univ Oxford, Dept Int Dev, Oxford, England. [Gao, Xing] US Ctr Dis Control, Beijing, Peoples R China. [Lin, Margaret; Sun, Kai] Washington Univ, Dept Med, St Louis, MO USA. [Luo, Jing] Univ Illinois, Dept Med, Chicago, IL USA. [Song, Philip] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Zhang, Xiaoxi] UCL, Dept Med, London WC1E 6BT, England. RP Tucker, JD (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM jtucker4@partners.org NR 34 TC 2 Z9 2 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 JUL 12 PY 2011 VL 6 IS 7 AR e22149 DI 10.1371/journal.pone.0022149 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791WM UT WOS:000292699000026 PM 21765946 ER PT J AU Linefsky, JP O'Brien, KD Katz, R de Boer, IH Barasch, E Jenny, NS Siscovick, DS Kestenbaum, B AF Linefsky, Jason P. O'Brien, Kevin D. Katz, Ronit de Boer, Ian H. Barasch, Eddy Jenny, Nancy S. Siscovick, David S. Kestenbaum, Bryan TI Association of Serum Phosphate Levels With Aortic Valve Sclerosis and Annular Calcification The Cardiovascular Health Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aortic valve; calcification; epidemiology; mitral valve; phosphate ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; VITAMIN-D LEVELS; PARATHYROID-HORMONE; VALVULAR CALCIFICATION; KIDNEY-FUNCTION; RENAL-FUNCTION; FETUIN-A; STENOSIS; ATHEROSCLEROSIS AB Objectives This study was conducted to evaluate mineral metabolism markers as potential risk factors for calcific aortic valve disease. Background Mineral metabolism disturbances are common among older people and may contribute to cardiac valvular calcification. Associations of serum mineral metabolism markers with cardiac valvular calcification have not been evaluated in a well-characterized general population of older adults. Methods We measured serum levels of phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D in 1,938 Cardiovascular Health Study participants who were free of clinical cardiovascular disease and who underwent echo-cardiographic measurements of aortic valve sclerosis (AVS), mitral annular calcification (MAC), and aortic annular calcification (AAC). We used logistic regression models to estimate associations of mineral metabolism markers with AVS, MAC, and AAC after adjustment for relevant confounding variables, including kidney function. Results The respective prevalences of AVS, MAC, and AAC were 54%, 39%, and 44%. Each 0.5 mg/dl higher serum phosphate concentration was associated with greater adjusted odds of AVS (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.04 to 1.31, p = 0.01), MAC (OR: 1.12, 95% CI: 1.00 to 1.26, p = 0.05), and AAC (OR: 1.12, 95% CI: 0.99 to 1.25, p = 0.05). In contrast, serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations were not associated with aortic or mitral calcification. Conclusions Higher serum phosphate levels within the normal range were associated with valvular and annular calcification in a community-based cohort of older adults. Phosphate may be a novel risk factor for calcific aortic valve disease and warrants further study. (J Am Coll Cardiol 2011;58:291-7) (C) 2011 by the American College of Cardiology Foundation C1 [Linefsky, Jason P.; O'Brien, Kevin D.] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Linefsky, Jason P.] Vet Affairs Puget Sound Hlth Care Syst, NW Ctr Excellence, Hlth Serv Res & Dev, Seattle, WA USA. [Katz, Ronit] Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [de Boer, Ian H.; Kestenbaum, Bryan] Univ Washington, Kidney Res Inst, Div Nephrol, Harborview Med Ctr, Seattle, WA 98195 USA. [Barasch, Eddy] St Francis Hosp, Dept Res & Educ, Roslyn, NY USA. [Jenny, Nancy S.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Siscovick, David S.] Univ Washington, Dept Med & Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. RP Linefsky, JP (reprint author), Univ Washington, Div Cardiol, 1959 NE Pacific St,Box 356422, Seattle, WA 98195 USA. EM linefsky@u.washington.edu FU National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295]; Department of Veterans Affairs Health Services Research and Development Service [TPM 61-034]; National Institutes of Health [R01 HL084443, R01 AG 027002] FX The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The research reported in this article was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133, and grant number U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additionally, the research reported here was supported by the Department of Veterans Affairs Health Services Research and Development Service, TPM 61-034. Funding for this study was also provided by National Institutes of Health R01 HL084443 and R01 AG 027002. Dr. O'Brien has received honoraria from Astra-Zeneca and Merck. The other authors have reported that they have no relationships to disclose. Dr. Linefsky is presently the post doc fellow at the Veterans Affairs Health Services Research and Development Northwest Center for Excellence. NR 47 TC 44 Z9 49 U1 0 U2 15 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 JUL 12 PY 2011 VL 58 IS 3 BP 291 EP 297 DI 10.1016/j.jacc.2010.11.073 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 788OB UT WOS:000292453200013 PM 21737022 ER PT J AU Sharma, S Findlay, GM Bandukwala, HS Oberdoerffer, S Baust, B Li, ZG Schmidt, V Hogan, PG Sacks, DB Rao, A AF Sharma, Sonia Findlay, Gregory M. Bandukwala, Hozefa S. Oberdoerffer, Shalini Baust, Beate Li, Zhigang Schmidt, Valentina Hogan, Patrick G. Sacks, David B. Rao, Anjana TI Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LONG NONCODING RNAS; GENE-EXPRESSION; CHROMATIN; IQGAP1; COACTIVATOR; CALCIUM; BINDING; FAMILY AB Nuclear factor of activated T cells (NFAT) proteins are Ca(2+)-regulated transcription factors that control gene expression in many cell types. NFAT proteins are heavily phosphorylated and reside in the cytoplasm of resting cells; when cells are stimulated by a rise in intracellular Ca(2+), NFAT proteins are dephosphorylated by the Ca(2+)/calmodulin-dependent phosphatase calcineurin and translocate to the nucleus to activate target gene expression. Here we show that phosphorylated NFAT1 is present in a large cytoplasmic RNA-protein scaffold complex that contains a long intergenic noncoding RNA (lincRNA), NRON [noncoding (RNA) repressor of NFAT]; a scaffold protein, IQ motif containing GTPase activating protein (IQGAP); and three NFAT kinases, casein kinase 1, glycogen synthase kinase 3, and dual specificity tyrosine phosphorylation regulated kinase. Combined knockdown of NRON and IQGAP1 increased NFAT dephosphorylation and nuclear import exclusively after stimulation, without affecting the rate of NFAT rephosphorylation and nuclear export; and both NRON-depleted T cells and T cells from IQGAP1-deficient mice showed increased production of NFAT-dependent cytokines. Our results provide evidence that a complex of lincRNA and protein forms a scaffold for a latent transcription factor and its regulatory kinases, and support an emerging consensus that lincRNAs that bind transcriptional regulators have a similar scaffold function. C1 [Sharma, Sonia; Findlay, Gregory M.; Bandukwala, Hozefa S.; Oberdoerffer, Shalini; Baust, Beate; Hogan, Patrick G.; Rao, Anjana] Harvard Univ, Sch Med, Immune Dis Inst, Dept Pathol, Boston, MA 02115 USA. [Sharma, Sonia; Findlay, Gregory M.; Bandukwala, Hozefa S.; Oberdoerffer, Shalini; Baust, Beate; Hogan, Patrick G.; Rao, Anjana] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Schmidt, Valentina] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA. RP Rao, A (reprint author), La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. EM arao@idi.harvard.edu OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health (NIH) [AI40127, AI84167, CA93645, DK62040]; American Cancer Society; Canadian Institutes of Health Research; Leukemia and Lymphoma Society; Lady Tata Memorial Fund; Children's Hospital, Boston FX We thank Danya Machnes for technical support and members of the Rao lab for valuable discussions. This work was funded by National Institutes of Health (NIH) grants AI40127 and AI84167 (to A. R.), NIH Grant CA93645 (to D. B. S.) and NIH Grant DK62040 and a Research Scholar Grant from the American Cancer Society (to V. S.), a Fellowship from the Canadian Institutes of Health Research and a Special Fellowship from the Leukemia and Lymphoma Society (S. S.), a fellowship from the Lady Tata Memorial Fund (H. S. B.), and a postdoctoral training grant from the Joint Program in Transfusion Biology and Medicine, Children's Hospital, Boston (S.O.). NR 34 TC 78 Z9 87 U1 3 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 JUL 12 PY 2011 VL 108 IS 28 BP 11381 EP 11386 DI 10.1073/pnas.1019711108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200024 PM 21709260 ER PT J AU Tornberg, J Sykiotis, GP Keefe, K Plummer, L Hoang, X Hall, JE Quinton, R Seminara, SB Hughes, V Van Vliet, G Van Uum, S Crowley, WF Habuchi, H Kimata, K Pitteloud, N Bulow, HE AF Tornberg, Janne Sykiotis, Gerasimos P. Keefe, Kimberly Plummer, Lacey Hoang, Xuan Hall, Janet E. Quinton, Richard Seminara, Stephanie B. Hughes, Virginia Van Vliet, Guy Van Uum, Stan Crowley, William F. Habuchi, Hiroko Kimata, Koji Pitteloud, Nelly Buelow, Hannes E. TI Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE heparan sulfotransferase; Kallmann syndrome ID GONADOTROPIN-RELEASING-HORMONE; HEPARAN-SULFATE 6-O-SULFOTRANSFERASE; KALLMANN-SYNDROME; FGF RECEPTOR; CAENORHABDITIS-ELEGANS; DEFICIENCY; MUTATIONS; SPECIFICITY; EXPRESSION; FAMILY AB Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner. C1 [Tornberg, Janne; Buelow, Hannes E.] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA. [Buelow, Hannes E.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA. [Sykiotis, Gerasimos P.; Keefe, Kimberly; Plummer, Lacey; Hoang, Xuan; Hall, Janet E.; Seminara, Stephanie B.; Hughes, Virginia; Crowley, William F.; Pitteloud, Nelly] Massachusetts Gen Hosp, Dept Med, Harvard Ctr Reprod Endocrine Sci, Boston, MA 02114 USA. [Quinton, Richard] Newcastle Univ, Inst Human Genet, Dept Endocrinol, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Van Vliet, Guy] Univ Montreal, Ctr Hosp Univ St Justine, Montreal, PQ H3T 1C5, Canada. [Van Uum, Stan] Univ Western Ontario, Lawson Hlth Res Inst, Dept Med, London, ON N6A 4V2, Canada. [Habuchi, Hiroko; Kimata, Koji] Aichi Med Univ, Res Complex Med Frontiers, Nagakute, Aichi 4801195, Japan. RP Pitteloud, N (reprint author), Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA. EM nelly.pitteloud@chuv.ch; buelow@einstein.yu.edu RI PITTELOUD, Nelly/K-2709-2014; OI Sykiotis, Gerasimos/0000-0002-9565-4941 FU National Institutes of Health [R01HD055380, R01HD055380-03S1, 5U54HD028138, 1R01HD056264, 1 UL1 RR025758-01, M01-RR-01066]; Academy of Finland FX We are indebted to patients, family members, and the Massachusetts General Hospital General Clinical Research Center nursing staff. We thank R. Townley for protein sequence alignments, molecular modeling studies, and discussions and M. Stern for egl-17 alleles. We are grateful to J. Brandler and P. Weinberg for technical assistance and to N. Baker, T. Boulin, S. Emmons, O. Hobert, B. Morrow, and members of the Pitteloud and Bulow laboratories for comments. This work was supported by National Institutes of Health Grants R01HD055380 and R01HD055380-03S1 (to H. E. B.) and Grants 5U54HD028138, 1R01HD056264, 1 UL1 RR025758-01, and M01-RR-01066 (to N. P.) and by a postdoctoral fellowship of the Academy of Finland (to J. T.). H. E. B. is an Alfred P. Sloan Fellow. NR 43 TC 59 Z9 71 U1 1 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2011 VL 108 IS 28 BP 11524 EP 11529 DI 10.1073/pnas.1102284108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200048 PM 21700882 ER PT J AU Dahirel, V Shekhar, K Pereyra, F Miura, T Artyomov, M Talsania, S Allen, TM Altfeld, M Carrington, M Irvine, DJ Walker, BD Chakraborty, AK AF Dahirel, Vincent Shekhar, Karthik Pereyra, Florencia Miura, Toshiyuki Artyomov, Mikita Talsania, Shiv Allen, Todd M. Altfeld, Marcus Carrington, Mary Irvine, Darrell J. Walker, Bruce D. Chakraborty, Arup K. TI Coordinate linkage of HIV evolution reveals regions of immunological vulnerability SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytotoxic T-lymphocyte response; elite controllers; random matrix theory ID T-CELL RESPONSES; IMMUNODEFICIENCY-VIRUS TYPE-1; ELITE CONTROLLERS; VACCINE DESIGN; RHESUS-MONKEYS; INFECTION; DETERMINANTS; ASSOCIATIONS; MUTATIONS; PROTEINS AB Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses. C1 [Dahirel, Vincent; Shekhar, Karthik; Pereyra, Florencia; Allen, Todd M.; Altfeld, Marcus; Carrington, Mary; Irvine, Darrell J.; Walker, Bruce D.; Chakraborty, Arup K.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02129 USA. [Dahirel, Vincent; Shekhar, Karthik; Pereyra, Florencia; Allen, Todd M.; Altfeld, Marcus; Carrington, Mary; Irvine, Darrell J.; Walker, Bruce D.; Chakraborty, Arup K.] Harvard Univ, Boston, MA 02129 USA. [Dahirel, Vincent; Shekhar, Karthik; Talsania, Shiv; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Dahirel, Vincent; Artyomov, Mikita; Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Irvine, Darrell J.; Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Artyomov, Mikita] Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119991, Russia. [Talsania, Shiv] Univ Loughborough, Dept Chem Engn, Loughborough LE11 3TU, Leics, England. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Irvine, Darrell J.; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Miura, Toshiyuki] Univ Tokyo, Inst Med Sci, Tokyo 1088639, Japan. RP Walker, BD (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02129 USA. EM bwalker@partners.org; arupc@mit.edu RI Allen, Todd/F-5473-2011 FU Ragon Institute; National Institutes of Health [RO130914, PO1 AI074415, HHSN261200800001E]; Howard Hughes Medical Institute; Mark and Lisa Schwartz Foundation; National Cancer Institute FX We thank D. Barouch and H. Eisen for valuable discussions. Financial support was provided by the Ragon Institute, a National Institutes of Health Director's Pioneer Award (to A. K. C.), National Institutes of Health Grants RO130914 (to B. D. W.) and PO1 AI074415 (to M. Altfeld and T. M. A.), The Howard Hughes Medical Institute (B. D. W.) and the Mark and Lisa Schwartz Foundation (B. D. W.) This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. NR 33 TC 92 Z9 92 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 JUL 12 PY 2011 VL 108 IS 28 BP 11530 EP 11535 DI 10.1073/pnas.1105315108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200049 PM 21690407 ER PT J AU Garkavtsev, I Chauhan, VP Wong, HK Mukhopadhyay, A Glicksman, MA Peterson, RT Jain, RK AF Garkavtsev, Igor Chauhan, Vikash P. Wong, Hon Kit Mukhopadhyay, Arpita Glicksman, Marcie A. Peterson, Randall T. Jain, Rakesh K. TI Dehydro-alpha-lapachone, a plant product with antivascular activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug discovery; angiogenesis ID UBIQUITIN-PROTEASOME SYSTEM; ZEBRAFISH FIN REGENERATION; IN-VIVO; ENDOTHELIAL PERMEABILITY; ANTIANGIOGENIC THERAPY; TUMOR VASCULATURE; TIGHT JUNCTIONS; BETA-LAPACHONE; RHO-GTPASES; ANGIOGENESIS AB Antivascular agents have become a standard of treatment for many malignancies. However, most of them target the VEGF pathway and lead to refractoriness. To improve the diversity of options for antivascular therapy, we applied a high-throughput screen for small molecules targeting cell adhesion. We then assayed the resulting antiadhesion hits in a transgenic zebrafish line with endothelial expression of EGFP (Tg(fli1:EGFP)(y1)) to identify nontoxic molecules with antivascular activity selective to neovasculature. This screen identified dehydro-alpha-lapachone (DAL), a natural plant product. We found that DAL inhibits vessel regeneration, interferes with vessel anastomosis, and limits plexus formation in zebrafish. Furthermore, DAL induces vascular pruning and growth delay in orthotopic mammary tumors in mice. We show that DAL targets cell adhesion by promoting ubiquitination of the Rho-GTPase Rac1, which is frequently up-regulated in many different cancers. C1 [Garkavtsev, Igor; Chauhan, Vikash P.; Wong, Hon Kit; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Garkavtsev, Igor; Chauhan, Vikash P.; Wong, Hon Kit; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Chauhan, Vikash P.] Harvard Univ, Harvard Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Mukhopadhyay, Arpita; Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Glicksman, Marcie A.] Brigham & Womens Hosp, Partners Ctr Drug Discovery, Cambridge, MA 02139 USA. [Glicksman, Marcie A.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. RP Garkavtsev, I (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. EM igorg@steele.mgh.harvard.edu RI Chauhan, Vikash/H-8172-2013; Wong, Hon-Kit/G-3944-2014 OI Chauhan, Vikash/0000-0001-9126-2302; Wong, Hon-Kit/0000-0003-0049-8454 FU Dyax; AstraZeneca; MedImmune; Roche; Astellas; SynDevRx; Regeneron; Genzyme; Morphosys; Noxxon Pharma; Department of Defense [W81XWH-10-1-0016]; National Institutes of Health [HL079267] FX R.K.J. received commercial research grants from Dyax, AstraZeneca, MedImmune and Roche; consultant fees from AstraZeneca, Dyax, Astellas, SynDevRx, Regeneron, Genzyme, Morphosys, and Noxxon Pharma; and a speaker honorarium from MPM Capital. R.K.J. owns stock in SynDevRx. No reagents or funding from these companies was used in these studies. There is no significant financial or other competing interest in the work.; We thank Brian Seed for his insightful input throughout this project, various members of the Steele Laboratory-Gang Cheng, Sergey Kozin, and Ned Kirkpatrick-for help with experiments, and Lance Munn and Dai Fukumura for the helpful comments and suggestions. This work was supported in part by Department of Defense Breast Cancer Research Innovator Award W81XWH-10-1-0016 (to R.K.J.), National Institutes of Health Grant HL079267 (to R. T. P.), and a grant from Partners (to I.G.). NR 35 TC 14 Z9 14 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2011 VL 108 IS 28 BP 11596 EP 11601 DI 10.1073/pnas.1104225108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200060 PM 21709229 ER PT J AU Bradley, SM Bryson, CL Maynard, C Maddox, TM Fihn, SD AF Bradley, Steven M. Bryson, Chris L. Maynard, Charles Maddox, Thomas M. Fihn, Stephan D. TI Recent hospitalization for Non-coronary events and use of preventive medications for coronary artery disease: An observational cohort study SO BMC CARDIOVASCULAR DISORDERS LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; LONG-TERM ADHERENCE; INFLUENZA VACCINATION RATES; OF-VETERANS-AFFAIRS; SECONDARY PREVENTION; FOLLOW-UP; CARE; QUALITY; RISK; GUIDELINES AB Background: High-quality systems have adopted a comprehensive approach to preventive care instead of diagnosis or procedure driven care. The current emphasis on prescribing medications to prevent complications of coronary artery disease (CAD) at discharge following an acute coronary syndrome (ACS) may exclude high-risk patients who are hospitalized with conditions other than ACS. Methods: Among a sample of patients with CAD treated at Veterans Affairs medical centers between January, 2005 and November, 2006, we investigated whether recent non-ACS hospitalization was associated with prescriptions of preventive medications as compared with patients recently hospitalized with ACS. Results: Of 13,211 patients with CAD, 58% received aspirin, 70% beta-blocker, 60% angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB), and 65% lipid-lowering therapy. Twenty-five percent of eligible patients were receiving all four medications. Having been hospitalized for a non-ACS event in the prior 6 months did not substantially affect the adjusted proportion on preventive medications. In contrast, among patients hospitalized for ACS in the prior 6 months, the adjusted proportion prescribed aspirin was 21% higher (p < 0.001), beta-blocker was 14% higher (p < 0.001), ACE-I or ARB was 9% higher (p < 0.001), lipid therapy was 12% higher (p < 0.001), and prescribed all four medications was 18% higher (p < 0.001) than among patients hospitalized for ACS more than 2 years earlier. Conclusions: Being hospitalized for a non-ACS condition did not appear to influence preventive medication use among patients with CAD and represents a missed opportunity to improve patient care. The same protocols employed to improve use of preventive medications in patients discharged for ACS might be extended to CAD patients discharged for other conditions as well. C1 [Bradley, Steven M.; Bryson, Chris L.; Maynard, Charles; Fihn, Stephan D.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev NW Ctr Excellence, Seattle, WA USA. [Bradley, Steven M.; Bryson, Chris L.; Maynard, Charles; Fihn, Stephan D.] Univ Washington, Seattle, WA 98195 USA. [Maddox, Thomas M.] Univ Colorado, Denver, CO 80202 USA. [Maddox, Thomas M.] VA Eastern Colorado Hlth Care Syst, Denver, CO USA. RP Bradley, SM (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev NW Ctr Excellence, Seattle, WA USA. EM Steve.Bradley@va.gov RI Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 FU Health Services Research and Development (HSRD); HSR&D's Quality Enhancement Research Initiative, Department of Veterans Affairs [IHD 98-001, MRC 03-334] FX This material is based upon work supported by Health Services Research and Development (HSR&D) and HSR&D's Quality Enhancement Research Initiative, Department of Veterans Affairs (Project#: IHD 98-001 and MRC 03-334). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 32 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 1471-2261 J9 BMC CARDIOVASC DISOR JI BMC Cardiovasc. Disord. PD JUL 9 PY 2011 VL 11 AR 42 DI 10.1186/1471-2261-11-42 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 799FX UT WOS:000293271900001 PM 21740591 ER PT J AU Ho, TJ Christiani, DC Ma, TC Jang, TR Lieng, CH Yeh, YC Lin, SZ Lin, JG Lai, JS Lan, TY AF Ho, Tsung-Jung Christiani, David C. Ma, Tso-Chiang Jang, Tsong-Rong Lieng, Chih-Hui Yeh, Yi-Chun Lin, Shinn-Zong Lin, Jaung-Geng Lai, Jim-Shoung Lan, Tzuo-Yun TI Effect of Qigong on quality of life: a cross-sectional population-based comparison study in Taiwan SO BMC PUBLIC HEALTH LA English DT Article DE General health; Qigong; quality of life; Waitankung ID HEALTH; CHI; SF-36 AB Background: Qigong, similar to Tai Chi Chuan, is beneficial to health. In Taiwan, Waitankung, a type of Qigong, is as popular as Tai Chi Chuan. This population-based comparison study compares the health-related quality of life between people practicing Waitankung and their comparable community residents. Methods: A total of 165 individuals practicing Waitankung were matched by age and sex with 660 general individuals for comparison. Information about health-related quality of life, measured by the SF-36, and other basic and health conditions was obtained from the questionnaires. This study used the linear mixed-effect regression model to examine the association between health-related quality of life and the practice of Waitankung. Results: Compared with either sedentary individuals or individuals practicing other types of exercise, the Waitankung group scored higher for eight and five out of ten SF-36 components, respectively. The Waitankung group scored better in general health, vitality, and physical component summary compared to individuals participating in other types of exercise, even when considering the energy expended by exercise. Conclusion: The results suggest that Waitankung exercising is significantly associated with health-related quality of life. Waitankung may serve as an exercise choice for middle-aged and older people to improve overall quality of life. C1 [Lieng, Chih-Hui; Yeh, Yi-Chun; Lai, Jim-Shoung; Lan, Tzuo-Yun] China Med Univ, Sch Publ Hlth, Taichung 404, Taiwan. [Ho, Tsung-Jung; Lin, Jaung-Geng] China Med Univ, Sch Chinese Med, Taichung 404, Taiwan. [Ho, Tsung-Jung] Cnina Med Univ, Beigang Hosp, Div Chinese Med, Beigang Town 651, Yunlin County, Taiwan. [Christiani, David C.] Harvard Univ, Environm & Occupat Med & Epidemiol Program, Sch Publ Hlth, Boston, MA 02115 USA. [Christiani, David C.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Ma, Tso-Chiang] China Med Univ, Dept Hlth Serv Adm, Taichung 404, Taiwan. [Jang, Tsong-Rong] Natl Taiwan Coll Phys Educ, Athlet Dept, Taichung 404, Taiwan. [Jang, Tsong-Rong] Natl Taiwan Coll Phys Educ, Grad Sch, Taichung 404, Taiwan. [Lan, Tzuo-Yun] Natl Hlth Res Inst, Inst Populat Hlth Sci, Zhunan Town 350, Miaoli County, Taiwan. [Lan, Tzuo-Yun] Natl Yang Ming Univ, Inst Hosp & Hlth Care Adm, Sch Med, Taipei 112, Taiwan. RP Lan, TY (reprint author), China Med Univ, Sch Publ Hlth, 91 Hsueh Shih Rd, Taichung 404, Taiwan. EM tylan@nhri.org.tw FU China Medical University [CMU94-025] FX The study was supported by the China Medical University (Grant No. CMU94-025). NR 15 TC 5 Z9 6 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JUL 9 PY 2011 VL 11 AR 546 DI 10.1186/1471-2458-11-546 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 800AN UT WOS:000293329100001 PM 21740594 ER PT J AU Takahashi, A Tsutsumi, R Kikuchi, I Obuse, C Saito, Y Seidl, A Karisch, R Fernandez, M Cho, T Ohnishi, N Rozenblatt-Rosen, O Meyerson, M Neel, BG Hatakeyama, M AF Takahashi, Atsushi Tsutsumi, Ryouhei Kikuchi, Ippei Obuse, Chikashi Saito, Yasuhiro Seidl, Azadeh Karisch, Robert Fernandez, Minerva Cho, Taewoo Ohnishi, Naomi Rozenblatt-Rosen, Orit Meyerson, Matthew Neel, Benjamin G. Hatakeyama, Masanori TI SHP2 Tyrosine Phosphatase Converts Parafibromin/Cdc73 from a Tumor Suppressor to an Oncogenic Driver SO MOLECULAR CELL LA English DT Article ID GROWTH-FACTOR RECEPTOR; PYLORI CAGA PROTEIN; HUMAN PAF1 COMPLEX; STEM-CELL; NOONAN-SYNDROME; K-RAS; CANCER; PATHWAY; TRANSCRIPTION; CATENIN AB Deregulation of SHP2 is associated with malignant diseases as well as developmental disorders. Although SHP2 is required for full activation of RAS signaling, other potential roles in cell physiology have not been elucidated. Here we show that SHP2 dephosphorylates parafibromin/Cdc73, a core component of the RNA polymerase II-associated factor (PAF) complex. Parafibromin is known to act as a tumor suppressor that inhibits cyclin D1 and c-myc by recruiting SUV39H1 histone methyltransferase. However, parafibromin can also act in the opposing direction by binding beta-catenin, thereby activating promitogenic/oncogenic Wnt signaling. We found that, on tyrosine dephosphorylation by SHP2, parafibromin acquires the ability to stably bind beta-catenin. The parafibromin/beta-catenin interaction overrides parafibromin/SUV39H1-mediated transrepression and induces expression of Wnt target genes, including cyclin D1 and c-myc. Hence, SHP2 governs the opposing functions of parafibromin, deregulation of which may cause the development of tumors or developmental malformations. C1 [Takahashi, Atsushi; Tsutsumi, Ryouhei; Kikuchi, Ippei; Saito, Yasuhiro; Seidl, Azadeh; Hatakeyama, Masanori] Univ Tokyo, Grad Sch Med, Div Microbiol, Tokyo 1130033, Japan. [Takahashi, Atsushi] Hokkaido Univ, Grad Sch Sci, Div Chem, Sapporo, Hokkaido 0600810, Japan. [Obuse, Chikashi] Hokkaido Univ, Grad Sch Life Sci, Div Mol Life Sci, Sapporo, Hokkaido 0010021, Japan. [Ohnishi, Naomi] Hokkaido Univ, Inst Med Genet, Res Ctr Infect Associated Canc, Sapporo, Hokkaido 0600185, Japan. [Karisch, Robert; Fernandez, Minerva; Cho, Taewoo; Neel, Benjamin G.] Ontario Canc Inst, Campbell Family Canc Res Inst, Toronto, ON M5G 1L7, Canada. [Karisch, Robert; Fernandez, Minerva; Cho, Taewoo; Neel, Benjamin G.] Univ Hlth Network, Princess Margaret Hosp, Toronto, ON M5G 1L7, Canada. [Karisch, Robert; Fernandez, Minerva; Cho, Taewoo; Neel, Benjamin G.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. [Rozenblatt-Rosen, Orit; Meyerson, Matthew] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rozenblatt-Rosen, Orit; Meyerson, Matthew] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Meyerson, Matthew] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Hatakeyama, M (reprint author), Univ Tokyo, Grad Sch Med, Div Microbiol, Tokyo 1130033, Japan. EM mhata@m.u-tokyo.ac.ip RI Meyerson, Matthew/E-7123-2012; OHNISHI, Naomi/F-6914-2012; Obuse, Chikashi/F-5273-2011; OI OHNISHI, Naomi/0000-0002-2382-3152; Tsutsumi, Ryouhei/0000-0002-1704-0362 FU Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; Princess Margaret Hospital Foundation; Ontario Ministry of Health and Long-Term Care; Canadian Institutes for Health Research; [R37CA39152] FX We thank Robert A. Weinberg for valuable discussions and comments. We also thank Akira Kikuchi, Mineo Kurokawa, Mitsuyasu Kato, Shinya Tanaka, and Yusuke Ohba for providing plasmids. We also thank Akiko Yano for help. This work was supported by Grants-in-Aid for the Scientific Research on Innovative Area from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (M.H.), by R37CA39152 (B.G.N.), and by the Princess Margaret Hospital Foundation and Ontario Ministry of Health and Long-Term Care. R.K. is the recipient of a graduate fellowship from the Canadian Institutes for Health Research. NR 50 TC 39 Z9 40 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 8 PY 2011 VL 43 IS 1 BP 45 EP 56 DI 10.1016/j.molcel.2011.05.014 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 792EN UT WOS:000292723400007 PM 21726809 ER PT J AU O'Brien, TR Everhart, JE Morgan, TR Lok, AS Chung, RT Shao, YW Shiffman, ML Dotrang, M Sninsky, JJ Bonkovsky, HL Pfeiffer, RM AF O'Brien, Thomas R. Everhart, James E. Morgan, Timothy R. Lok, Anna S. Chung, Raymond T. Shao, Yongwu Shiffman, Mitchell L. Dotrang, Myhanh Sninsky, John J. Bonkovsky, Herbert L. Pfeiffer, Ruth M. CA HALT-C Trial Grp TI An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C SO PLOS ONE LA English DT Article ID CHRONIC HCV INFECTION; LONG-TERM TREATMENT; INTERFERON-ALPHA; VIRUS-INFECTION; GENETIC-VARIATION; PEGYLATED INTERFERON; RIBAVIRIN; PEGINTERFERON; TELAPREVIR; THERAPY AB Background: Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables. Methods: HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC). Results: Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p <.0001); the model also included HCV RNA (log10 IU/ml), AST:ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p < 0.001). Subjects with a predicted probability of SVR < 10% had an observed SVR rate of 3.8%; subjects with a predicted probability > 10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study. Conclusion: A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC. C1 [O'Brien, Thomas R.; Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Everhart, James E.] NIDDKD, Div Digest Dis & Nutr, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Morgan, Timothy R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Lok, Anna S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Gastrointestinal Unit,Med Serv, Boston, MA USA. [Shao, Yongwu] Informat Management Serv Inc, Silver Spring, MD USA. [Shiffman, Mitchell L.] Bon Secours Hlth Syst, Liver Inst Virginia, Newport News, VA USA. [Dotrang, Myhanh] CSC, Rockville, MD USA. [Sninsky, John J.] Celera Corp, Alameda, CA USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Mol & Struct Biol, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. RP O'Brien, TR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Yang, Shuman/0000-0002-9638-0890 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute (NCI); National Center for Minority Health and Health Disparities; National Center for Research Resources, National Institutes of Health; Hoffmann-La Roche, Inc.; Celera Corporation through National Institutes of Health; National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; University of Massachusetts Medical Center, Worcester, MA [N01-DK-9-2326]; University of Connecticut Health Center, Farmington, CT [M01RR-06192]; Saint Louis University School of Medicine, St Louis, MO [N01-DK-w9-2324]; Massachusetts General Hospital, Boston, MA [N01-DK-9-2319, M01RR-01066, 1 UL1 RR025758-01]; University of Colorado Denver, School of Medicine, Aurora, CO [N01-DK-9-2327, M01RR-00051, 1 UL1 RR 025780-01]; University of California Irvine, Irvine, CA [N01-DK-9-2320, M01RR-00827]; University of Texas Southwestern Medical Center, Dallas, TX [N01-DK-9-2321, M01RR-00633, 1 UL1 RR024982-01]; University of Southern California, Los Angeles, CA [N01-DK-9-2325, M01RR-00043]; University of Michigan Medical Center, Ann Arbor, MI [N01-DK-9-2323, M01RR-00042, 1 UL1 RR024986]; Virginia Commonwealth University Health System, Richmond, VA [N01-DK-9-2322, M01RR-00065]; Vertex Pharmaceuticals; Merck; Schering Plough Corporation; WAKO Diagnostics; Bristol-Myers Squibb; Gilead and Eisai Pharmaceuticals; Novartis; Romark; Biolex; Conatus; Glaxo SmithKline; Globeimmune; Human Genome Sciences; Idenix; Roche; Tibotec; Valeant; Wyeth; Zymogenetics; Novartis Pharmaceuticals FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute (NCI), the National Center for Minority Health and Health Disparities, General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health. Employees of NIDDK and NCI played a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc., and Celera Corporation through Cooperative Research and Development Agreements (CRADA) with the National Institutes of Health. The present study was also supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. 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. Yongwu Shao was employed by Information Management Services, Silver Spring; Myhanh Dotrang by CSC, Rockville; and John J. Sninsky by Celera Corporation, Alameda. These authors played a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Contract and grant numbers: University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326); University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192); Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-w9-2324); Massachusetts General Hospital, Boston, MA: (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center); University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01); University of California Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827); University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative); University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043); University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research); Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065).; The authors wish to report the following relationships that might appear to represent a potential conflict: John J. Sninsky is employed by Celera Corporation, Alameda. T. R. Morgan is on the speaker's bureau and receives research support from Hoffmann-La Roche, Inc.; is a consultant, serves on an advisory board, and receives research support from Vertex Pharmaceuticals; serves on an advisory board for Gilead Sciences; and receives research support from Merck, Schering Plough Corporation, and WAKO Diagnostics. A. S. Lok is a consultant for Hoffmann-La Roche, Inc., Abbott and Gilead; and receives research support from Schering-Plough Corporation, Bristol-Myers Squibb, Gilead and Eisai Pharmaceuticals. R. T. Chung receives research support from Hoffmann-La Roche, Inc.; receives research support from Schering-Plough, Novartis, and Romark; and is a consultant for Vertex Pharmaceuticals, Merck, Pfizer, Astellas, Novartis, and Gilead. M. L. Shiffman is a consultant for Celera Corporation, Hoffmann-La Roche, Inc., and National Genome Sciences; has attended advisor meetings with Anadys, Biolex, Bristol-Myers-Squibb, Conatus, Globeimmune, Human Genome Sciences, Novartis, Roche, Romark, Pfizer, Schering-Plough, Valeant, Vertex and Zymogenetics; is a speaker for Roche and Schering-Plough; is on the data safety monitoring boards with Abbott and Anadys; and has received research support from Biolex, Conatus, Glaxo SmithKline, Globeimmune, Human Genome Sciences, Idenix, Roche, Romark, Tibotec, Valeant, Vertex, Wyeth and Zymogenetics. J. J. Sninsky is an employee of Celera Corporation. H. L. Bonkovsky receives research support from Hoffmann-La Roche, Inc.; is a consultant for Boehringer-Ingelheim; is a consultant and on the advisory board for Clinuvel, Inc.; is a consultant, advisory board member and receives research support from Novartis Pharmaceuticals; is a consultant and on the speakers' bureau for Lundbeck Pharmaceuticals; and receives research support from Vertex Pharmaceuticals. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. Authors with no financial relationships related to this project are: T. R. O'Brien, J. E. Everhart, Y. Shao, M. Dotrang, and R. M. Pfeiffer. NR 27 TC 18 Z9 19 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2011 VL 6 IS 7 AR e20904 DI 10.1371/journal.pone.0020904 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791IA UT WOS:000292657200005 PM 21760886 ER PT J AU Toombs, JA Liss, NM Cobble, KR Ben-Musa, Z Ross, ED AF Toombs, James A. Liss, Nathan M. Cobble, Kacy R. Ben-Musa, Zobaida Ross, Eric D. TI [PSI+] Maintenance Is Dependent on the Composition, Not Primary Sequence, of the Oligopeptide Repeat Domain SO PLOS ONE LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; CHAPERONE PROTEIN HSP104; INHERITED PRION DISEASE; PAIR GENE INSERTION; GUANIDINE-HYDROCHLORIDE; STRAIN VARIANTS; PROPAGATION; AGGREGATION; PSI(+); REGION AB [PSI+], the prion form of the yeast Sup35 protein, results from the structural conversion of Sup35 from a soluble form into an infectious amyloid form. The infectivity of prions is thought to result from chaperone-dependent fiber cleavage that breaks large prion fibers into smaller, inheritable propagons. Like the mammalian prion protein PrP, Sup35 contains an oligopeptide repeat domain. Deletion analysis indicates that the oligopeptide repeat domain is critical for [PSI+] propagation, while a distinct region of the prion domain is responsible for prion nucleation. The PrP oligopeptide repeat domain can substitute for the Sup35 oligopeptide repeat domain in supporting [PSI+] propagation, suggesting a common role for repeats in supporting prion maintenance. However, randomizing the order of the amino acids in the Sup35 prion domain does not block prion formation or propagation, suggesting that amino acid composition is the primary determinant of Sup35's prion propensity. Thus, it is unclear what role the oligopeptide repeats play in [PSI+] propagation: the repeats could simply act as a non-specific spacer separating the prion nucleation domain from the rest of the protein; the repeats could contain specific compositional elements that promote prion propagation; or the repeats, while not essential for prion propagation, might explain some unique features of [PSI+]. Here, we test these three hypotheses and show that the ability of the Sup35 and PrP repeats to support [PSI+] propagation stems from their amino acid composition, not their primary sequences. Furthermore, we demonstrate that compositional requirements for the repeat domain are distinct from those of the nucleation domain, indicating that prion nucleation and propagation are driven by distinct compositional features. C1 [Toombs, James A.; Liss, Nathan M.; Cobble, Kacy R.; Ross, Eric D.] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Ben-Musa, Zobaida; Ross, Eric D.] Colorado State Univ, Grad Program Cell & Mol Biol, Ft Collins, CO 80523 USA. RP Toombs, JA (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM eric.ross@colostate.edu FU National Sciences Foundation [MCB-1023771]; March of Dimes Basil O'Connor Award [5-FY07-104] FX This work was supported by National Sciences Foundation grant MCB-1023771 to EDR and a March of Dimes Basil O'Connor Award (#5-FY07-104) to EDR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 19 Z9 19 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2011 VL 6 IS 7 AR e21953 DI 10.1371/journal.pone.0021953 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791IA UT WOS:000292657200036 PM 21760933 ER PT J AU Zhuang, K Finzi, A Tasca, S Shakirzyanova, M Knight, H Westmoreland, S Sodroski, J Cheng-Mayer, C AF Zhuang, Ke Finzi, Andres Tasca, Silvana Shakirzyanova, Madina Knight, Heather Westmoreland, Susan Sodroski, Joseph Cheng-Mayer, Cecilia TI Adoption of an "Open" Envelope Conformation Facilitating CD4 Binding and Structural Remodeling Precedes Coreceptor Switch in R5 SHIV-Infected Macaques SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL DEPLETION; INCREASED NEUTRALIZATION SENSITIVITY; SYNCYTIUM-INDUCING PHENOTYPE; SOLUBLE CD4; MACROPHAGE-TROPISM; TYPE-1 INFECTION; HIV-1 INFECTION; IN-VIVO; ENTRY INHIBITORS AB A change in coreceptor preference from CCR5 to CXCR4 towards the end stage disease in some HIV-1 infected individuals has been well documented, but the reasons and mechanisms for this tropism switch remain elusive. It has been suggested that envelope structural constraints in accommodating amino acid changes required for CXCR4 usage is an obstacle to tropism switch, limiting the rate and pathways available for HIV-1 coreceptor switching. The present study was initiated in two R5 SHIV(SF162P3N)-infected rapid progressor macaques with coreceptor switch to test the hypothesis that an early step in the evolution of tropism switch is the adoption of a less constrained and more "open" envelope conformation for better CD4 usage, allowing greater structural flexibility to accommodate further mutational changes that confer CXCR4 utilization. We show that, prior to the time of coreceptor switch, R5 viruses in both macaques evolved to become increasingly sCD4-sensitive, suggestive of enhanced exposure of the CD4 binding site and an "open" envelope conformation, and this correlated with better gp120 binding to CD4 and with more efficient infection of CD4(low) cells such as primary macrophages. Moreover, significant changes in neutralization sensitivity to agents and antibodies directed against functional domains of gp120 and gp41 were seen for R5 viruses close to the time of X4 emergence, consistent with global changes in envelope configuration and structural plasticity. These observations in a simian model of R5-to-X4 evolution provide a mechanistic basis for the HIV-1 coreceptor switch. C1 [Zhuang, Ke; Tasca, Silvana; Shakirzyanova, Madina; Cheng-Mayer, Cecilia] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Finzi, Andres; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Pathol,Div AIDS, Boston, MA 02115 USA. [Knight, Heather; Westmoreland, Susan] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Comparat Pathol, Southborough, MA 01772 USA. RP Zhuang, K (reprint author), Aaron Diamond AIDS Res Ctr, New York, NY USA. EM cmayer@adarc.org FU NIH [RO1AI46980, R37AI41945] FX The work was supported by NIH grants RO1AI46980 and R37AI41945. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 119 TC 14 Z9 14 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 JUL 8 PY 2011 VL 6 IS 7 AR e21350 DI 10.1371/journal.pone.0021350 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791IA UT WOS:000292657200010 PM 21760891 ER PT J AU Mazzulli, JR Xu, YH Sun, Y Knight, AL McLean, PJ Caldwell, GA Sidransky, E Grabowski, GA Krainc, D AF Mazzulli, Joseph R. Xu, You-Hai Sun, Ying Knight, Adam L. McLean, Pamela J. Caldwell, Guy A. Sidransky, Ellen Grabowski, Gregory A. Krainc, Dimitri TI Gaucher Disease Glucocerebrosidase and alpha-Synuclein Form a Bidirectional Pathogenic Loop in Synucleinopathies SO CELL LA English DT Article ID PARKINSONS-DISEASE; FIBRIL FORMATION; MOUSE MODELS; MUTATIONS; NEURODEGENERATION; DEFICIENCY; MECHANISM; OLIGOMERS; CATECHOLS; ENZYME AB Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of alpha-synuclein (alpha-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified alpha-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that alpha-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of alpha-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies. C1 [Mazzulli, Joseph R.; McLean, Pamela J.; Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. [Xu, You-Hai; Sun, Ying; Grabowski, Gregory A.] Cincinnati Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Xu, You-Hai; Sun, Ying; Grabowski, Gregory A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA. [Knight, Adam L.; Caldwell, Guy A.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. [Caldwell, Guy A.] Univ Alabama, Ctr Neurodegenerat & Expt Therapeut, Dept Neurol, Birmingham, AL 35294 USA. [Caldwell, Guy A.] Univ Alabama, Ctr Neurodegenerat & Expt Therapeut, Dept Neurobiol, Birmingham, AL 35294 USA. [Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Krainc, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. EM krainc@mgh.helix.harvard.edu FU National Institutes of Health [R01NS051303, F32NS066730]; National Institute of Neurological Disorders and Stroke [R01DK36729]; National Human Genome Research Institute FX We thank Harry Ischiropoulos for pCDNA3.1 human alpha-syn plasmids and syn303 antibody, Benoit I. Giasson for the SNL-1 antibody, and Kimberly Kegel for technical advice on liposome formation. This work was supported by National Institutes of Health grants R01NS051303 (D.K.) and F32NS066730 (J.R.M.) from the National Institute of Neurological Disorders and Stroke, R01DK36729 (G.A.G.), and the Intramural Programs of the National Human Genome Research Institute and the National Institutes of Health (E.S.). NR 38 TC 356 Z9 361 U1 8 U2 37 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 8 PY 2011 VL 146 IS 1 BP 37 EP 52 DI 10.1016/j.cell.2011.06.001 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 789TN UT WOS:000292539300005 PM 21700325 ER PT J AU Eyler, CE Wu, QL Yan, K MacSwords, JM Chandler-Militello, D Misuraca, KL Lathia, JD Forrester, MT Lee, J Stamler, JS Goldman, SA Bredel, M McLendon, RE Sloan, AE Hjelmeland, AB Rich, JN AF Eyler, Christine E. Wu, Qiulian Yan, Kenneth MacSwords, Jennifer M. Chandler-Militello, Devin Misuraca, Katherine L. Lathia, Justin D. Forrester, Michael T. Lee, Jeongwu Stamler, Jonathan S. Goldman, Steven A. Bredel, Markus McLendon, Roger E. Sloan, Andrew E. Hjelmeland, Anita B. Rich, Jeremy N. TI Glioma Stem Cell Proliferation and Tumor Growth Are Promoted by Nitric Oxide Synthase-2 SO CELL LA English DT Article ID LYMPHOCYTIC-LEUKEMIA CELLS; HIGHLY SELECTIVE INHIBITOR; ACUTE MYELOID-LEUKEMIA; ISCHEMIC BRAIN-INJURY; MICE LACKING; IN-VIVO; HUMAN GLIOBLASTOMA; INITIATING CELLS; SEPTIC SHOCK; SELF-RENEWAL AB Malignant gliomas are aggressive brain tumors with limited therapeutic options, and improvements in treatment require a deeper molecular understanding of this disease. As in other cancers, recent studies have identified highly tumorigenic subpopulations within malignant gliomas, known generally as cancer stem cells. Here, we demonstrate that glioma stem cells (GSCs) produce nitric oxide via elevated nitric oxide synthase-2 (NOS2) expression. GSCs depend on NOS2 activity for growth and tumorigenicity, distinguishing them from non-GSCs and normal neural progenitors. Gene expression profiling identified many NOS2-regulated genes, including the cell-cycle inhibitor cell division autoantigen-1 (CDA1). Further, high NOS2 expression correlates with decreased survival in human glioma patients, and NOS2 inhibition slows glioma growth in a murine intracranial model. These data provide insight into how GSCs are mechanistically distinct from their less tumorigenic counterparts and suggest that NOS2 inhibition may be an efficacious approach to treating this devastating disease. C1 [Eyler, Christine E.; Wu, Qiulian; Yan, Kenneth; MacSwords, Jennifer M.; Lathia, Justin D.; Lee, Jeongwu; Hjelmeland, Anita B.; Rich, Jeremy N.] Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44195 USA. [Eyler, Christine E.; Misuraca, Katherine L.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Eyler, Christine E.] Duke Univ, Med Ctr, Med Scientist Training Program, Durham, NC 27710 USA. [McLendon, Roger E.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Chandler-Militello, Devin; Goldman, Steven A.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Forrester, Michael T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Stamler, Jonathan S.] Case Western Reserve Univ, Sch Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA. [Stamler, Jonathan S.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. [Sloan, Andrew E.] Case Western Reserve Univ, Sch Med, Dept Neurol Surg, Cleveland, OH 44106 USA. [Sloan, Andrew E.] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA. [Sloan, Andrew E.] Case Western Reserve Univ, Sch Med, Dept Translat Neurosci, Cleveland, OH 44106 USA. [Rich, Jeremy N.] Case Western Reserve Univ, Sch Med, Cleveland Clin Lerner Coll Med, Dept Mol Med, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Bredel, Markus] Univ Alabama, Ctr Comprehens Canc, Dept Radiat Oncol, Birmingham, AL 35249 USA. [Bredel, Markus] Univ Freiburg, Neuroctr, Dept Neurosurg, D-79106 Freiburg, Germany. [Bredel, Markus] Univ Freiburg, Ctr Comprehens Canc, D-79106 Freiburg, Germany. RP Hjelmeland, AB (reprint author), Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44195 USA. EM hjelmea@ccf.org; richj@ccf.org FU National Institutes of Health [F30NS063496, CA112958, CA116659, CA154130, CA151522, CA137443, NS063971, CA128269, CA101954, CA116257, CA142159, HL059130, HL091876,, HLO95463, CA108786, NS20023]; German Cancer Aid Grant Award [107714] FX We thank the sources of our funding, including National Institutes of Health grant F30NS063496 for C.E.E.; CA112958, CA116659, and CA154130 for J.N.R.; CA151522 for A.B.H.; CA137443, NS063971, CA128269, CA101954, and CA116257 for A.E.S.; CA142159 for J.D.L.; HL059130, HL091876, and HLO95463 for J.S.S.; and CA108786 and NS20023 for R.E.M. We also thank the Adelson Medical Research Foundation (S.A.G.), American Brain Tumor Association (J.D.L.), National Brain Tumor Society (A.B.H.), Ben and Catherine Ivy Foundation (A. E. S.), Damon Runyon Cancer Research Foundation (J.N.R.), German Cancer Aid Grant Award 107714 (M.B.), Goldhirsh Foundation (J.N.R.), James S. McDonnell Foundation (J.N.R. and S.A.G.), New York State Stem Cell Science Board (S. A. G.), Ohio Department of Development Tech 09-071 (A.E.S.), and Pediatric Brain Tumor Foundation of the United States (R.E.M.). We appreciate critical manuscript review by H. Suh; animal support provided by T. Myshrall, Y. Parker, and D. Lindner; M. Cook, B. Harvat, C. Shemo, and S. O'Bryant for flow cytometry assistance; D. Satterfield, L. Ehinger, J. Funkhouser, and J. Faison for technical assistance; the tissue provided by the Cleveland Clinic Foundation Tissue Procurement Service and S. Staugatis, R. Weil, and M. McGraw; and microarray analysis completed by P. Faber and W. Jones. NR 72 TC 115 Z9 116 U1 3 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 8 PY 2011 VL 146 IS 1 BP 53 EP 66 DI 10.1016/j.cell.2011.06.006 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 789TN UT WOS:000292539300006 PM 21729780 ER PT J AU Jeon, Y Lee, JT AF Jeon, Yesu Lee, Jeannie T. TI YY1 Tethers Xist RNA to the Inactive X Nucleation Center SO CELL LA English DT Article ID CHROMOSOME INACTIVATION; DOSAGE COMPENSATION; IN-VIVO; CELL-DIFFERENTIATION; BINDING PROTEIN; POLYMERASE-II; CTCF BINDING; POLYCOMB; GENE; MOUSE AB The long noncoding Xist RNA inactivates one X chromosome in the female mammal. Current models posit that Xist induces silencing as it spreads along X and recruits Polycomb complexes. However, the mechanisms for Xist loading and spreading are currently unknown. Here, we define the nucleation center for Xist RNA and show that YY1 docks Xist particles onto the X chromosome. YY1 is a "bivalent'' protein, capable of binding both RNA and DNA through different sequence motifs. Xist's exclusive attachment to the inactive X is determined by an epigenetically regulated trio of YY1 sites as well as allelic origin. Specific YY1-to-RNA and YY1-to-DNA contacts are required to load Xist particles onto X. YY1 interacts with Xist RNA through Repeat C. We propose that YY1 acts as adaptor between regulatory RNA and chromatin targets. C1 [Jeon, Yesu; Lee, Jeannie T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA. [Jeon, Yesu; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Lee, JT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu FU Korean Research Foundation; MGH ECOR Fund; NIH [RO1-GM090278] FX lWe thank K. Sarma, B. Del Rosario, and B. Payer for reading of the manuscript and all lab members for many helpful suggestions. We acknowledge K. Hochedlinger for Rosa26-M2rtTA mice, Y. Shi for His-YY1, and B. Del Rosario for purified His-GFP. This work was supported by a Korean Research Foundation grant and the MGH ECOR Fund to Y.J. and NIH RO1-GM090278 to J.T.L. J.T.L. is an Investigator of the Howard Hughes Medical Institute. NR 70 TC 202 Z9 218 U1 5 U2 29 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 8 PY 2011 VL 146 IS 1 BP 119 EP 133 DI 10.1016/j.cell.2011.06.026 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 789TN UT WOS:000292539300011 PM 21729784 ER PT J AU Chua, HN Roth, FP AF Chua, Hon Nian Roth, Frederick P. TI Discovering the Targets of Drugs Via Computational Systems Biology SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID MODE-OF-ACTION; INTERACTION NETWORKS; BIOACTIVE COMPOUNDS; EXPRESSION PROFILES; YEAST; GENOME; IDENTIFICATION; SCREEN; GENES; PREDICTION AB Computational systems biology is empowering the study of drug action. Studies on biological effects of chemical compounds have increased in scale and accessibility, allowing integration with other large-scale experimental data types. Here, we review computational approaches for elucidating the mechanisms of both intended and undesirable effects of drugs, with the collective potential to change the nature of drug discovery and pharmacological therapy. C1 [Chua, Hon Nian; Roth, Frederick P.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Roth, Frederick P.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. RP Roth, FP (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM fritz_roth@hms.harvard.edu RI Roth, Frederick/H-6308-2011; OI Roth, Frederick/0000-0002-6628-649X FU Agency of Science, Technology and Research, Singapore; National Institutes of Health [HG003224]; Canada Excellence Research Chairs Program; Canadian Institute for Advanced Research FX Supported by the Agency of Science, Technology and Research, Singapore.; Supported in part by National Institutes of Health Grant HG003224, the Canada Excellence Research Chairs Program, and a Canadian Institute for Advanced Research fellowship. To whom correspondence should be addressed. E-mail: fritz_roth@hms.harvard.edu. NR 54 TC 15 Z9 16 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 JUL 8 PY 2011 VL 286 IS 27 BP 23653 EP 23658 DI 10.1074/jbc.R110.174797 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786HO UT WOS:000292294900006 PM 21566122 ER PT J AU Ting, TC Miyazaki-Anzai, S Masuda, M Levi, M Demer, LL Tintut, Y Miyazaki, M AF Ting, Tabitha C. Miyazaki-Anzai, Shinobu Masuda, Masashi Levi, Moshe Demer, Linda L. Tintut, Yin Miyazaki, Makoto TI Increased Lipogenesis and Stearate Accelerate Vascular Calcification in Calcifying Vascular Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHRONIC KIDNEY-DISEASE; DESATURASE-1 DEFICIENCY PROTECTS; DENSITY-LIPOPROTEIN CHOLESTEROL; ENDOPLASMIC-RETICULUM STRESS; POLYUNSATURATED FATTY-ACIDS; TOLL-LIKE RECEPTOR-4; X-RECEPTOR; BETA-CELLS; GENE-EXPRESSION; INDUCED LIPOTOXICITY AB Vascular calcification is recognized as an independent predictor of cardiovascular mortality, particularly in subjects with chronic kidney disease. However, the pathways by which dysregulation of lipid and mineral metabolism simultaneously occur in this particular population remain unclear. We have shown that activation of the farnesoid X receptor (FXR) blocks mineralization of bovine calcifying vascular cells (CVCs) and in ApoE knock-out mice with 5/6 nephrectomy. In contrast to FXR, this study showed that liver X receptor (LXR) activation by LXR agonists and adenovirus-mediated LXR overexpression by VP16-LXR alpha and VP16-LXR beta accelerated mineralization of CVCs. Conversely, LXR inhibition by dominant negative (DN) forms of LXR alpha and LXR beta reduced calcium content in CVCs. The regulation of mineralization by FXR and LXR agonists was highly correlated with changes in lipid accumulation, fatty acid synthesis, and the expression of sterol regulatory element binding protein-1 (SREBP-1). The rate of lipogenesis in CVCs through the SREBP-1c dependent pathway was reduced by FXR activation, but increased by LXR activation. SREBP-1c overexpression augmented mineralization in CVCs, whereas SREBP-1c DN inhibited alkaline phosphatase activity and mineralization induced by LXR agonists. LXR and SREBP-1c activations increased, whereas FXR activation decreased, saturated and monounsaturated fatty acids derived from lipogenesis. In addition, we found that stearate markedly promoted mineralization of CVCs as compared with other fatty acids. Furthermore, inhibition of either acetyl-CoA carboxylase or acyl-CoA synthetase reduced mineralization of CVCs, whereas inhibition of stearoyl-CoA desaturase induced mineralization. Therefore, a stearate metabolite derived from lipogenesis might be a risk factor for the development of vascular calcification. C1 [Miyazaki, Makoto] Univ Colorado Denver, Dept Med, Div Renal Dis & Hypertens, Aurora, CO 80045 USA. [Ting, Tabitha C.; Miyazaki-Anzai, Shinobu; Masuda, Masashi; Levi, Moshe; Miyazaki, Makoto] Denver VA Med Ctr, Div Renal Dis & Hypertens, Dept Med, Aurora, CO 80045 USA. [Miyazaki, Makoto] Denver VA Med Ctr, Div Endocrinol Diabet & Metab, Dept Med, Aurora, CO 80045 USA. [Demer, Linda L.; Tintut, Yin] Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA. RP Miyazaki, M (reprint author), Univ Colorado Denver, Dept Med, Div Renal Dis & Hypertens, 12700 E 19th Ave,C281, Aurora, CO 80045 USA. EM Makoto.Miyazaki@ucdenver.edu RI Demer, Linda/I-5770-2013; OI Demer, Linda/0000-0002-9618-6895; Levi, Moshe/0000-0002-6225-946X FU National Institutes of Health [HL081202, DK081346]; American Heart Association [10BGIA458005]; Colorado Clinical Nutrition Research Unit (National Institutes of Health) [5P30DK048520]; UCHSC Diabetes and Endocrinology Research Center (National Institutes of Health) [P30DK57516]; NIGMS-IMSD [R25GM083333] FX This work was supported, in whole or in part, by National Institutes of Health Grants HL081202 and DK081346, the American Heart Association Grant 10BGIA458005, as well as the Colorado Clinical Nutrition Research Unit (National Institutes of Health Grant 5P30DK048520), and the UCHSC Diabetes and Endocrinology Research Center (National Institutes of Health Grant P30DK57516). T. C. T. was supported by NIGMS-IMSD #R25GM083333. NR 48 TC 13 Z9 14 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 8 PY 2011 VL 286 IS 27 BP 23938 EP 23949 DI 10.1074/jbc.M111.237065 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786HO UT WOS:000292294900036 PM 21596756 ER PT J AU Pereira, RI Wang, CCL Hosokawa, P Dickinson, LM Chonchol, M Krantz, MJ Steiner, JF Bessesen, DH Havranek, EP Long, CS AF Pereira, Rocio I. Wang, Cecilia C. L. Hosokawa, Patrick Dickinson, L. Miriam Chonchol, Michel Krantz, Mori J. Steiner, John F. Bessesen, Daniel H. Havranek, Edward P. Long, Carlin S. TI Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures SO BMC ENDOCRINE DISORDERS LA English DT Article ID BODY-FAT DISTRIBUTION; TYPE-2 DIABETIC-PATIENTS; INSULIN SENSITIVITY; MEXICAN-AMERICANS; ESSENTIAL-HYPERTENSION; AFRICAN-AMERICANS; PROTEIN ACRP30; PLASMA; OBESITY; RESISTANCE AB Background: Latinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance. Methods: We utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 +/- 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function. Results: Mean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non- Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA- IR were no longer observed after controlling for adiponectin levels. Conclusions: Among patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations. C1 [Pereira, Rocio I.; Krantz, Mori J.; Bessesen, Daniel H.; Havranek, Edward P.; Long, Carlin S.] Denver Hlth Med Ctr, Denver, CO 80204 USA. [Pereira, Rocio I.; Wang, Cecilia C. L.; Hosokawa, Patrick; Dickinson, L. Miriam; Chonchol, Michel; Bessesen, Daniel H.] Univ Colorado Denver, Aurora, CO 80045 USA. [Wang, Cecilia C. L.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. [Steiner, John F.] Kaiser Permanente, Inst Hlth Res, Denver, CO 80237 USA. RP Pereira, RI (reprint author), Denver Hlth Med Ctr, 660 Bannock St, Denver, CO 80204 USA. EM rocio.pereira@ucdenver.edu FU National Heart Lung and Blood Institute (NHLBI), component of the National Institutes of Health (NIH) [U01 HL079160, U01 HL079208]; National Center for Research Resources, component of the National Institutes of Health (NIH) [K23 RR0222238] FX The project described was supported by Grant Numbers U01 HL079160 and U01 HL079208 from the National Heart Lung and Blood Institute (NHLBI) and Grant Number K23 RR0222238 from the National Center for Research Resources, both components of the National Institutes of Health (NIH). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NCRR, NHLBI, or NIH. NR 36 TC 7 Z9 7 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6823 J9 BMC ENDOCR DISORD JI BMC Endocr. Disord. PD JUL 7 PY 2011 VL 11 AR 13 DI 10.1186/1472-6823-11-13 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 851SI UT WOS:000297290800001 PM 21736747 ER PT J AU Zimmer, SN Zhou, Q Zhou, T Cheng, ZM Abboud-Werner, SL Horn, D Lecocke, M White, R Krivtsov, AV Armstrong, SA Kung, AL Livingston, DM Rebel, VI AF Zimmer, Stephanie N. Zhou, Qing Zhou, Ting Cheng, Ziming Abboud-Werner, Sherry L. Horn, Diane Lecocke, Mike White, Ruth Krivtsov, Andrei V. Armstrong, Scott A. Kung, Andrew L. Livingston, David M. Rebel, Vivienne I. TI Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis SO BLOOD LA English DT Article ID RUBINSTEIN-TAYBI-SYNDROME; OLIGOMERIC MATRIX PROTEIN; ACUTE MYELOID-LEUKEMIA; HEMATOPOIETIC STEM; PROGENITOR CELLS; SELF-RENEWAL; MYELODYSPLASTIC SYNDROME; BINDING-PROTEIN; GENE-EXPRESSION; CBP GENES AB CREB-binding protein (CREBBP) is important for the cell-autonomous regulation of hematopoiesis, including the stem cell compartment. In the present study, we show that CREBBP plays an equally pivotal role in microenvironment-mediated regulation of hematopoiesis. We found that the BM microenvironment of Crebbp(+/-) mice was unable to properly maintain the immature stem cell and progenitor cell pools. Instead, it stimulates myeloid differentiation, which progresses into a myeloproliferation phenotype. Alterations in the BM microenvironment resulting from haploinsufficiency of Crebbp included a marked decrease in trabecular bone that was predominantly caused by increased osteoclastogenesis. Although CFU-fibroblast (CFU-F) and total osteoblast numbers were decreased, the bone formation rate was similar to that found in wild-type mice. At the molecular level, we found that the known hematopoietic modulators matrix metallopeptidase-9 (MMP9) and kit ligand (KITL) were decreased with heterozygous levels of Crebbp. Lastly, potentially important regulatory proteins, endothelial cell adhesion molecule 1 (ESAM1) and cadherin 5 (CDH5), were increased on Crebbp(+/-) endothelial cells. Our findings reveal that a full dose of Crebbp is essential in the BM microenvironment to maintain proper hematopoiesis and to prevent excessive myeloproliferation. (Blood. 2011;118(1):69-79) C1 [Zimmer, Stephanie N.; Zhou, Qing; Zhou, Ting; Cheng, Ziming; Rebel, Vivienne I.] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Zimmer, Stephanie N.; Rebel, Vivienne I.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Abboud-Werner, Sherry L.; Horn, Diane] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Lecocke, Mike] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Lecocke, Mike] St Marys Univ, Dept Math, San Antonio, TX USA. [White, Ruth] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR 97201 USA. [Krivtsov, Andrei V.; Armstrong, Scott A.] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. [Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Rebel, VI (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM rebel@uthscsa.edu OI Kung, Andrew/0000-0002-9091-488X FU National Cancer Institute Cancer Center [2P30 CA054174-17]; GCCRI; National Institutes of Health [AR042306] FX We thank Karla Moncada and Charles Thomas of the University of Texas Health Science Center Flow Cytometry Core (supported by National Cancer Institute Cancer Center Support Grant 2P30 CA054174-17) and Jennifer Rebeles of the GCCRI Shared Instrumentation Facility for assistance with FACS sorting and analysis, the GCCRI Laboratory Animal Resources for care of experimental mice, and Dr Thomas Prihoda for statistical analysis of the histomorphometric data.; This work was supported by funding from the GCCRI and from the National Institutes of Health (AR042306 to S.W). NR 50 TC 15 Z9 15 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 JUL 7 PY 2011 VL 118 IS 1 BP 69 EP 79 DI 10.1182/blood-2010-09-307942 PG 11 WC Hematology SC Hematology GA 789HI UT WOS:000292505900013 PM 21555743 ER PT J AU Delabie, J Holte, H Vose, JM Ullrich, F Jaffe, ES Savage, KJ Connors, JM Rimsza, L Harris, NL Muller-Hermelink, K Rudiger, T Coiffier, B Gascoyne, RD Berger, F Tobinai, K Au, WY Liang, R Montserrat, E Hochberg, EP Pileri, S Federico, M Nathwani, B Armitage, JO Weisenburger, DD AF Delabie, Jan Holte, Harald Vose, Julie M. Ullrich, Fred Jaffe, Elaine S. Savage, Kerry J. Connors, Joseph M. Rimsza, Lisa Harris, Nancy L. Mueller-Hermelink, Konrad Ruediger, Thomas Coiffier, Bertrand Gascoyne, Randy D. Berger, Francoise Tobinai, Kensei Au, Wing Y. Liang, Raymond Montserrat, Emili Hochberg, Ephraim P. Pileri, Stefano Federico, Massimo Nathwani, Bharat Armitage, James O. Weisenburger, Dennis D. TI Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project SO BLOOD LA English DT Article ID NON-HODGKIN-LYMPHOMA; CELIAC-DISEASE; INTESTINAL LYMPHOMAS; MALIGNANCY; MODEL; SPRUE AB Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options. (Blood. 2011;118(1):148-155) C1 [Delabie, Jan] Univ Hosp Oslo, Dept Pathol, Oslo, Norway. [Holte, Harald] Univ Hosp Oslo, Dept Oncol, Oslo, Norway. [Vose, Julie M.; Armitage, James O.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Ullrich, Fred] Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE USA. [Jaffe, Elaine S.] NCI, Dept Pathol, Bethesda, MD 20892 USA. [Savage, Kerry J.; Connors, Joseph M.] British Columbia Canc Agcy, Dept Med Oncol, Vancouver, BC V5Z 4E6, Canada. [Rimsza, Lisa] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Harris, Nancy L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mueller-Hermelink, Konrad] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Ruediger, Thomas] Stadt Klinikum Karlsruhe, Inst Pathol, Karlsruhe, Germany. [Coiffier, Bertrand] Ctr Hosp Lyon Sud, Dept Hematol, Lyon, France. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Berger, Francoise] Ctr Hosp Lyon Sud, Dept Pathol, Lyon, France. [Tobinai, Kensei] Natl Canc Ctr, Hematol & Stem Cell Transplantat Div, Tokyo, Japan. [Au, Wing Y.; Liang, Raymond] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Montserrat, Emili] Univ Barcelona Hosp, Inst Hematol & Oncol, Barcelona, Spain. [Hochberg, Ephraim P.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA USA. [Pileri, Stefano] Univ Bologna Hosp, Dept Pathol, Bologna, Italy. [Federico, Massimo] Univ Modena & Reggio Emilia, Dept Oncol & Haematol, Modena, Italy. [Nathwani, Bharat] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Nathwani, Bharat] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Weisenburger, Dennis D.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. RP Delabie, J (reprint author), Univ Oslo, Norwegian Radium Hosp, Dept Pathol, N-0310 Oslo, Norway. EM jan.delabie@medisin.uio.no RI Federico, Massimo/A-6801-2012; Federico, Massimo/J-5984-2014; OI Federico, Massimo/0000-0002-9889-3796; Federico, Massimo/0000-0002-5074-3262; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301 NR 34 TC 82 Z9 87 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 7 PY 2011 VL 118 IS 1 BP 148 EP 155 DI 10.1182/blood-2011-02-335216 PG 8 WC Hematology SC Hematology GA 789HI UT WOS:000292505900021 PM 21566094 ER PT J AU McMillin, DW Delmore, J Negri, J Ooi, M Klippel, S Miduturu, CV Gray, NS Richardson, PG Anderson, KC Kung, AL Mitsiades, CS AF McMillin, Douglas W. Delmore, Jake Negri, Joseph Ooi, Melissa Klippel, Steffen Miduturu, Chandrasekhar V. Gray, Nathanael S. Richardson, Paul G. Anderson, Kenneth C. Kung, Andrew L. Mitsiades, Constantine S. TI Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation SO PLOS ONE LA English DT Article ID ADVANCED SOLID TUMORS; GENE-EXPRESSION; BI 2536; MOLECULAR CLASSIFICATION; CHROMOSOMAL INSTABILITY; DRUG-RESISTANCE; CANCER-CELLS; PHASE-I; SURVIVAL; APOPTOSIS AB Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50,40 nM) and rapid (commitment to cell death,24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mousemodel. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers. C1 [McMillin, Douglas W.; Delmore, Jake; Negri, Joseph; Ooi, Melissa; Klippel, Steffen; Richardson, Paul G.; Anderson, Kenneth C.; Mitsiades, Constantine S.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol, Boston, MA 02115 USA. [McMillin, Douglas W.; Delmore, Jake; Negri, Joseph; Ooi, Melissa; Klippel, Steffen; Richardson, Paul G.; Anderson, Kenneth C.; Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Miduturu, Chandrasekhar V.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Dept Canc Biol, Boston, MA 02115 USA. [Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kung, Andrew L.] Childrens Hosp Boston, Boston, MA USA. RP McMillin, DW (reprint author), Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol, Boston, MA 02115 USA. EM Constantine_Mitsiades@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU Dana-Farber Cancer Institute; Chambers Medical Foundation; Stepanian Fund for Myeloma Research; Cobb Family Fellowship; NIH [R01CA050947]; Millennium; Celgene; Amgen Pharmaceuticals; AVEO Pharma; EMD Serono; Sunesis; Gloucester Pharmaceuticals; Johnson Johnson FX Supported in part by the "Dunkin Donuts Rising Stars" Program at the Dana-Farber Cancer Institute (C. S. M.), the Chambers Medical Foundation (P. G. R. and C. S. M.), the Stepanian Fund for Myeloma Research (P. G. R. and C. S. M.), the Cobb Family Fellowship (D. W. M.), and NIH grant R01CA050947 (C. S. M. and K. C. A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; D. W. M. is an equity holder in Axios Biosciences. J.D., J.N., M.O., S. K., C. V. M., N.S.G., and A. L. K. have nothing to disclose. P. G. R. has received honoraria from Millennium and Celgene. K. C. A. has received research grants and honoraria from Millennium and Celgene. C. S. M. has received in the past Consultant honoraria from Millennium Pharmaceuticals, Novartis Pharmaceuticals, Bristol-Myers Squibb, Merck & Co., Kosan Pharmaceuticals, Celgene and Pharmion, licensing royalties from PharmaMar, and research funding from Amgen Pharmaceuticals, AVEO Pharma, EMD Serono, Sunesis, Gloucester Pharmaceuticals, and Johnson & Johnson. NR 26 TC 21 Z9 22 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2011 VL 6 IS 7 AR e20226 DI 10.1371/journal.pone.0020226 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791HI UT WOS:000292655400001 PM 21750699 ER PT J AU Perera, RM Bardeesy, N AF Perera, Rushika M. Bardeesy, Nabeel TI CANCER When antioxidants are bad SO NATURE LA English DT Editorial Material ID C-MYC C1 [Perera, Rushika M.] Massachusetts Gen Hosp, Inst Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Perera, RM (reprint author), Massachusetts Gen Hosp, Inst Canc, Boston, MA 02114 USA. EM rperera@partners.org; bardeesy.nabeel@mgh.harvard.edu NR 10 TC 35 Z9 36 U1 4 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 7 PY 2011 VL 475 IS 7354 BP 43 EP 44 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 788RE UT WOS:000292461300039 PM 21734699 ER PT J AU O'Connor, CM Starling, RC Hernandez, AF Armstrong, PW Dickstein, K Hasselblad, V Heizer, GM Komajda, M Massie, BM McMurray, JJV Nieminen, MS Reist, CJ Rouleau, JL Swedberg, K Adams, KF Anker, SD Atar, D Battler, A Botero, R Bohidar, NR Butler, J Clausell, N Corbalan, R Costanzo, MR Dahlstrom, U Deckelbaum, LI Diaz, R Dunlap, ME Ezekowitz, JA Feldman, D Felker, GM Fonarow, GC Gennevois, D Gottlieb, SS Hill, JA Hollander, JE Howlett, JG Hudson, MP Kociol, RD Krum, H Laucevicius, A Levy, WC Mendez, GF Metra, M Mittal, S Oh, BH Pereira, NL Ponikowski, P Wilson, WH Tanomsup, S Teerlink, JR Triposkiadis, F Troughton, RW Voors, AA Whellan, DJ Zannad, F Califf, RM AF O'Connor, C. M. Starling, R. C. Hernandez, A. F. Armstrong, P. W. Dickstein, K. Hasselblad, V. Heizer, G. M. Komajda, M. Massie, B. M. McMurray, J. J. V. Nieminen, M. S. Reist, C. J. Rouleau, J. L. Swedberg, K. Adams, K. F., Jr. Anker, S. D. Atar, D. Battler, A. Botero, R. Bohidar, N. R. Butler, J. Clausell, N. Corbalan, R. Costanzo, M. R. Dahlstrom, U. Deckelbaum, L. I. Diaz, R. Dunlap, M. E. Ezekowitz, J. A. Feldman, D. Felker, G. M. Fonarow, G. C. Gennevois, D. Gottlieb, S. S. Hill, J. A. Hollander, J. E. Howlett, J. G. Hudson, M. P. Kociol, R. D. Krum, H. Laucevicius, A. Levy, W. C. Mendez, G. F. Metra, M. Mittal, S. Oh, B. -H. Pereira, N. L. Ponikowski, P. Wilson, W. H. Tanomsup, S. Teerlink, J. R. Triposkiadis, F. Troughton, R. W. Voors, A. A. Whellan, D. J. Zannad, F. Califf, R. M. TI Effect of Nesiritide in Patients with Acute Decompensated Heart Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; NATIONAL REGISTRY ADHERE; HOSPITALIZED-PATIENTS; OUTCOMES; POPULATION; DIURETICS; RISK AB Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (P = 0.005 for both assessments or Pd <= 0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. C1 [O'Connor, C. M.; Hernandez, A. F.; Hasselblad, V.; Heizer, G. M.; Reist, C. J.; Felker, G. M.; Kociol, R. D.; Califf, R. M.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [Adams, K. F., Jr.] Univ N Carolina, Heart Failure Program, Chapel Hill, NC USA. [Starling, R. C.; Wilson, W. H.] Cleveland Clin, Cleveland, OH USA. [Dunlap, M. E.] MetroHlth Med Ctr, Heart & Vasc Ctr, Cleveland, OH USA. [Rouleau, J. L.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Armstrong, P. W.; Ezekowitz, J. A.] Univ Alberta, Edmonton, AB, Canada. [Howlett, J. G.] Dalhousie Univ, Halifax, NS, Canada. [Dickstein, K.] Univ Bergen, Stavenger Univ Hosp, Bergen, Norway. [Komajda, M.] Univ Paris 06, Paris, France. [Komajda, M.] Hop La Pitie Salpetriere, Paris, France. [Massie, B. M.; Teerlink, J. R.] Univ Calif San Francisco, San Francisco Vet Affairs VA Hosp, San Francisco, CA 94143 USA. [Massie, B. M.; Teerlink, J. R.] San Francisco VA Med Ctr, San Francisco, CA USA. [McMurray, J. J. V.] Univ Glasgow, Western Infirm, Glasgow G11 6NT, Lanark, Scotland. [Nieminen, M. S.] Meilahti Hosp, Helsinki, Finland. [Swedberg, K.] Univ Gothenburg, Dept Emergency & Cardiovasc Med, Gothenburg, Sweden. [Dahlstrom, U.] Linkoping Univ, Div Cardiovasc Med, Dept Med & Hlth Sci, Linkoping, Sweden. [Anker, S. D.] IRCCS, Ctr Clin & Basic Res, Rome, Italy. [Anker, S. D.] Charite, Dept Cardiol, D-13353 Berlin, Germany. [Atar, D.] Aker Univ Hosp, Oslo, Norway. [Battler, A.] Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. [Botero, R.] Clin Medellin, Medellin, Colombia. [Bohidar, N. R.; Deckelbaum, L. I.] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ USA. [Butler, J.] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Clausell, N.] Hosp Clin Porto Alegre, Serv Cardiol, Porto Alegre, RS, Brazil. [Corbalan, R.] Pontificia Univ Catolica Chile, Div Cardiovasc, Santiago, Chile. [Costanzo, M. R.] Edward Heart Hosp, Naperville, IL USA. [Diaz, R.] Estudios Cardiol Latino Amer, Rosario, Santa Fe, Argentina. [Fonarow, G. C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Feldman, D.] Minneapolis Heart Inst, Minneapolis, MN USA. [Gennevois, D.] Janssen Alzheimer Immunotherapy, San Francisco, CA USA. [Gottlieb, S. S.] Univ Maryland Hosp, Div Cardiol, Baltimore, MD 21201 USA. [Hill, J. A.] Univ Florida, Gainesville, FL USA. [Hollander, J. E.] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Whellan, D. J.] Thomas Jefferson Univ, Jefferson Med Coll, Div Cardiol, Philadelphia, PA 19107 USA. [Hudson, M. P.] Edith & Benson Ford Heart & Vasc Inst, Detroit, MI USA. [Krum, H.] Monash Univ, Prahran, Vic, Australia. [Krum, H.] Alfred Hosp, Dept Epidemiol & Prevent Med, Prahran, Vic, Australia. [Laucevicius, A.] Vilnius Univ Hosp, Santariskiu Klin, Dept Cardiol & Angiol, Vilnius, Lithuania. [Levy, W. C.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Mendez, G. F.] Alta Especialidad Hosp Especialidades, Inst Mexicano Seguro Social 14, Unidades Med, Cordoba, Veracruz, Mexico. [Metra, M.] Univ Brescia, Dept Cardiol, Brescia, Italy. [Mittal, S.] Escorts Heart Inst & Res Ctr, Dept Cardiol, New Delhi, India. [Oh, B. -H.] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul Natl Univ Hosp, Seoul 151, South Korea. [Pereira, N. L.] Mayo Clin, Rochester, MN USA. [Ponikowski, P.] Med Univ, Dept Heart Dis, Wroclaw, Poland. [Tanomsup, S.] Mahidol Univ, Ramathibodi Hosp, Fac Med, Div Cardiol, Bangkok 10400, Thailand. [Triposkiadis, F.] Univ Hosp Larissa, Dept Cardiol, Larisa, Greece. [Troughton, R. W.] Univ Otago, Christchurch, New Zealand. [Voors, A. A.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Zannad, F.] Ctr Hosp Univ, INSERM, Ctr Invest Clin 9501, Nancy, France. [Zannad, F.] Ctr Hosp Univ, Inst Lorrain Coeur & Vaisseaux, U961, Nancy, France. RP O'Connor, CM (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Box 3356, Durham, NC 27710 USA. EM oconn002@mc.duke.edu RI Teerlink, John/D-2986-2012; Ezekowitz, Justin/C-4579-2013; Oh, Byung-Hee/G-9875-2011; Clausell, Nadine /C-7813-2016; Ponikowski, Piotr/O-6454-2015; Hernandez, Adrian F./A-7818-2016; OI Ezekowitz, Justin/0000-0002-2724-4086; Clausell, Nadine /0000-0003-4207-3809; Ponikowski, Piotr/0000-0002-3391-7064; Hollander, Judd/0000-0002-1318-2785; Hernandez, Adrian F./0000-0003-3387-9616; Metra, Marco/0000-0001-6691-8568; mcmurray, john/0000-0002-6317-3975 FU Scios FX Funded by Scios NR 26 TC 445 Z9 464 U1 1 U2 29 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 7 PY 2011 VL 365 IS 1 BP 32 EP 43 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 788QL UT WOS:000292459400007 PM 21732835 ER PT J AU Espana, S Paganetti, H AF Espana, Samuel Paganetti, Harald TI Uncertainties in planned dose due to the limited voxel size of the planning CT when treating lung tumors with proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID CALCULATION RESOLUTION; BEAM THERAPY; BRAGG PEAK; MODEL; DISTRIBUTIONS; ACCURACY; VOLUME AB Dose calculation for lung tumors can be challenging due to the low density and the fine structure of the geometry. The latter is not fully considered in the CT image resolution used in treatment planning causing the prediction of a more homogeneous tissue distribution. In proton therapy, this could result in predicting an unrealistically sharp distal dose falloff, i.e. an underestimation of the distal dose falloff degradation. The goal of this work was the quantification of such effects. Two computational phantoms resembling a two-dimensional heterogeneous random lung geometry and a swine lung were considered applying a variety of voxel sizes for dose calculation. Monte Carlo simulations were used to compare the dose distributions predicted with the voxel size typically used for the treatment planning procedure with those expected to be delivered using the finest resolution. The results show, for example, distal falloff position differences of up to 4 mm between planned and expected dose at the 90% level for the heterogeneous random lung (assuming treatment plan on a 2 x 2 x 2.5 mm(3) grid). For the swine lung, differences of up to 38 mm were seen when airways are present in the beam path when the treatment plan was done on a 0.8 x 0.8 x 2.4 mm(3) grid. The two-dimensional heterogeneous random lung phantom apparently does not describe the impact of the geometry adequately because of the lack of heterogeneities in the axial direction. The differences observed in the swine lung between planned and expected dose are presumably due to the poor axial resolution of the CT images used in clinical routine. In conclusion, when assigning margins for treatment planning for lung cancer, proton range uncertainties due to the heterogeneous lung geometry and CT image resolution need to be considered. C1 [Espana, Samuel] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Espana, S (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM hpaganetti@partners.org RI Espana, Samuel/E-9240-2010 OI Espana, Samuel/0000-0001-9092-4597 FU National Cancer Institute [P01CA021239] FX We would like to thank Dr George Chen for providing the swine lung CT scans. The project described was supported by Award Number P01CA021239 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors also thank the Partners Research Computing group at Massachusetts General Hospital for all their assistance with computing resources and Dr Alexei Trofimov for helpful comments and suggestions regarding this manuscript. NR 16 TC 6 Z9 6 U1 1 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2011 VL 56 IS 13 BP 3843 EP 3856 DI 10.1088/0031-9155/56/13/007 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 780OF UT WOS:000291866800009 PM 21628773 ER PT J AU Rinaldi, I Ferrari, A Mairani, A Paganetti, H Parodi, K Sala, P AF Rinaldi, I. Ferrari, A. Mairani, A. Paganetti, H. Parodi, K. Sala, P. TI An integral test of FLUKA nuclear models with 160 MeV proton beams in multi-layer Faraday cups SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MONTE-CARLO; RESIDUAL NUCLEI; DISTRIBUTIONS; THERAPY; PARTICLES; GEANT4; CODE AB Monte Carlo (MC) codes are useful tools to simulate the complex processes of proton beam interactions with matter. In proton therapy, nuclear reactions influence the dose distribution. Therefore, the validation of nuclear models adopted in MC codes is a critical requisite for their use in this field. A simple integral test can be performed using a multi-layer Faraday cup (MLFC). This method allows separation of the nuclear and atomic interaction processes, which are responsible for secondary particle emission and the finite primary proton range, respectively. In this work, the propagation of 160 MeV protons stopping in two MLFCs made of polyethylene and copper has been simulated by the FLUKA MC code. The calculations have been performed with and without secondary electron emission and transport, as well as charge sharing in the dielectric layers. Previous results with other codes neglected those two effects. The impact of this approximation has been investigated and found to be relevant only in the proximity of the Bragg peak. Longitudinal charge distributions computed with FLUKA with both approaches have been compared with experimental data from the literature. Moreover, the contribution of different processes to the measurable signal has been addressed. A thorough analysis of the results has demonstrated that the nuclear and electromagnetic models of FLUKA reproduce the two sets of experimental data reasonably well. C1 [Rinaldi, I.] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Rinaldi, I.; Mairani, A.; Parodi, K.] Heidelberg Ion Therapy Ctr, D-69120 Heidelberg, Germany. [Rinaldi, I.; Mairani, A.; Parodi, K.] Dept Radiat Oncol, D-69120 Heidelberg, Germany. [Ferrari, A.] CERN, CH-1211 Geneva 23, Switzerland. [Mairani, A.; Sala, P.] Ist Nazl Fis Nucl, I-20133 Milan, Italy. [Paganetti, H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Paganetti, H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Rinaldi, I (reprint author), German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM i.rinaldi@dkfz-heidelberg.de RI sala, paola/E-2868-2013 OI sala, paola/0000-0001-9859-5564 FU Helmholtz Association of German Research Centres (HGF) [VH-VI 303] FX Ilaria Rinaldi is supported by the Helmholtz Association of German Research Centres (HGF) in the 'Virtual Institut' project under the contract number VH-VI 303. We thank Oliver Jakel for supporting this work and his fruitful suggestions to the manuscript. NR 23 TC 9 Z9 10 U1 2 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2011 VL 56 IS 13 BP 4001 EP 4011 DI 10.1088/0031-9155/56/13/016 PG 11 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 780OF UT WOS:000291866800018 PM 21677365 ER PT J AU Zhu, XP Espana, S Daartz, J Liebsch, N Ouyang, JS Paganetti, H Bortfeld, TR El Fakhri, G AF Zhu, Xuping Espana, Samuel Daartz, Juliane Liebsch, Norbert Ouyang, Jinsong Paganetti, Harald Bortfeld, Thomas R. El Fakhri, Georges TI Monitoring proton radiation therapy with in-room PET imaging SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; BEAM RANGE VERIFICATION AB We used a mobile positron emission tomography (PET) scanner positioned within the proton therapy treatment room to study the feasibility of proton range verification with an in-room, stand-alone PET system, and compared with off-line equivalent studies. Two subjects with adenoid cystic carcinoma were enrolled into a pilot study in which in-room PET scans were acquired in list-mode after a routine fractionated treatment session. The list-mode PET data were reconstructed with different time schemes to generate in-room short, in-room long and off-line equivalent (by skipping coincidences from the first 15 min during the list-mode reconstruction) PET images for comparison in activity distribution patterns. A phantom study was followed to evaluate the accuracy of range verification for different reconstruction time schemes quantitatively. The in-room PET has a higher sensitivity compared to the off-line modality so that the PET acquisition time can be greatly reduced from 30 to < 5 min. Features in deep-site, soft-tissue regions were better retained with in-room short PET acquisitions because of the collection of (15)O component and lower biological washout. For soft tissue-equivalent material, the distal fall-off edge of an in-room short acquisition is deeper compared to an off-line equivalent scan, indicating a better coverage of the high-dose end of the beam. In-room PET is a promising low cost, high sensitivity modality for the in vivo verification of proton therapy. Better accuracy in Monte Carlo predictions, especially for biological decay modeling, is necessary. C1 [Zhu, Xuping; Ouyang, Jinsong; El Fakhri, Georges] Massachusetts Gen Hosp, Dept Imaging, Boston, MA 02114 USA. [Zhu, Xuping; Espana, Samuel; Daartz, Juliane; Liebsch, Norbert; Ouyang, Jinsong; Paganetti, Harald; Bortfeld, Thomas R.; El Fakhri, Georges] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Espana, Samuel; Daartz, Juliane; Liebsch, Norbert; Paganetti, Harald; Bortfeld, Thomas R.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP El Fakhri, G (reprint author), Massachusetts Gen Hosp, Dept Imaging, Boston, MA 02114 USA. EM elfakhri@pet.mgh.harvard.edu RI Espana, Samuel/E-9240-2010 OI Espana, Samuel/0000-0001-9092-4597 FU NIH/NCI [PO1 CA02139-29]; NIH/NIBIB [T32 EB002102] FX The research was supported by NIH/NCI PO1 CA02139-29 'Proton Therapy Research' and NIH/NIBIB T32 EB002102. NR 20 TC 43 Z9 44 U1 0 U2 8 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2011 VL 56 IS 13 BP 4041 EP 4057 DI 10.1088/0031-9155/56/13/019 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 780OF UT WOS:000291866800021 PM 21677366 ER PT J AU Khan, M Sakakima, H Dhammu, TS Shunmugavel, A Im, YB Gilg, AG Singh, AK Singh, I AF Khan, Mushfiquddin Sakakima, Harutoshi Dhammu, Tajinder S. Shunmugavel, Anandakumar Im, Yeong-Bin Gilg, Anne G. Singh, Avtar K. Singh, Inderjit TI S-Nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID FOCAL CEREBRAL-ISCHEMIA; NITRIC-OXIDE SYNTHASE; SPINAL-CORD-INJURY; NF-KAPPA-B; RECEPTOR AGONIST 8-OH-DPAT; THERAPEUTIC TIME WINDOW; CORTICAL IMPACT INJURY; ENDOTHELIAL DYSFUNCTION; EXPERIMENTAL STROKE; PROTECTS BRAIN AB Background: Traumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury in the neurovascular unit following TBI. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. Peroxynitrite has been implicated in blood brain barrier (BBB) leakage, altered metabolic function, and neurobehavioral impairment. S-nitrosoglutathione (GSNO), a nitrosylation-based signaling molecule, was reported not only to reduce brain levels of peroxynitrite and oxidative metabolites but also to improve neurological function in TBI, stroke, and spinal cord injury. Therefore, we investigated whether GSNO promotes the neurorepair process by reducing the levels of peroxynitrite and the degree of oxidative injury. Methods: TBI was induced by controlled cortical impact (CCI) in adult male rats. GSNO or 3-Morpholinosydnonimine (SIN-1) (50 mu g/kg body weight) was administered orally two hours following CCI. The same dose was repeated daily until endpoints. GSNO-treated (GSNO group) or SIN-1-treated (SIN-1 group) injured animals were compared with vehicle-treated injured animals (TBI group) and vehicle-treated sham-operated animals (Sham group) in terms of peroxynitrite, NO, glutathione (GSH), lipid peroxidation, blood brain barrier (BBB) leakage, edema, inflammation, tissue structure, axon/myelin integrity, and neurotrophic factors. Results: SIN-1 treatment of TBI increased whereas GSNO treatment decreased peroxynitrite, lipid peroxides/aldehydes, BBB leakage, inflammation and edema in a short-term treatment (4-48 hours). GSNO also reduced brain infarctions and enhanced the levels of NO and GSH. In a long-term treatment (14 days), GSNO protected axonal integrity, maintained myelin levels, promoted synaptic plasticity, and enhanced the expression of neurotrophic factors. Conclusion: Our findings indicate the participation of peroxynitrite in the pathobiology of TBI. GSNO treatment of TBI not only reduces peroxynitrite but also protects the integrity of the neurovascular unit, indicating that GSNO blunts the deleterious effects of peroxynitrite. A long-term treatment of TBI with the same low dose of GSNO promotes synaptic plasticity and enhances the expression of neurotrophic factors. These results support that GSNO reduces the levels of oxidative metabolites, protects the neurovascular unit, and promotes neurorepair mechanisms in TBI. C1 [Khan, Mushfiquddin; Sakakima, Harutoshi; Dhammu, Tajinder S.; Shunmugavel, Anandakumar; Im, Yeong-Bin; Gilg, Anne G.; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Singh, Avtar K.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Singh, Avtar K.] Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Singh, I (reprint author), Med Univ S Carolina, Dept Pediat, 171 Ashley Ave, Charleston, SC 29425 USA. EM singhi@musc.edu FU National Institutes of Health [NS-72511, NS-22576, NS-37766]; Betty L. Beatty Foundation; Guy E. Beatty Foundation; Veteran Administration; NIH National Center for Research Resources [C06 RR018823, C06 RR015455] FX These studies were supported by grants from National Institutes of Health (NS-72511, NS-22576 and NS-37766), Betty L. Beatty and Guy E. Beatty Foundations, and Veteran Administration merit awards. This work was also supported by the NIH, Grants C06 RR018823 and No C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources. We are grateful to Dr Tom Smith and Dr Melissa A Crofton from the MUSC Writing Center for their valuable editing and correction of the manuscript. We would like to thank Ms Joyce Bryan for procurement of animals and chemicals, and Ms Chara Williams for secretarial assistance. NR 97 TC 31 Z9 35 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JUL 6 PY 2011 VL 8 AR 78 DI 10.1186/1742-2094-8-78 PG 17 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 810UH UT WOS:000294152500001 PM 21733162 ER PT J AU Frei, CR Bell, AM Traugott, KA Jaso, TC Daniels, KR Mortensen, EM Restrepo, MI Oramasionwu, CU Ruiz, AD Mylchreest, WR Sikirica, V Raut, MR Fisher, A Schein, JR AF Frei, Christopher R. Bell, Allison M. Traugott, Kristi A. Jaso, Terry C. Daniels, Kelly R. Mortensen, Eric M. Restrepo, Marcos I. Oramasionwu, Christine U. Ruiz, Andres D. Mylchreest, William R. Sikirica, Vanja Raut, Monika R. Fisher, Alan Schein, Jeff R. TI A clinical pathway for community-acquired pneumonia: an observational cohort study SO BMC INFECTIOUS DISEASES LA English DT Article ID AZITHROMYCIN PLUS CEFTRIAXONE; STREPTOCOCCUS-PNEUMONIAE; HOSPITALIZED-PATIENTS; OPEN-LABEL; 500 MG; LEVOFLOXACIN; PHARMACODYNAMICS; MULTICENTER; CLARITHROMYCIN; GUIDELINES AB Background: Six hospitals instituted a voluntary, system-wide, pathway for community acquired pneumonia (CAP). We proposed this study to determine the impact of pathway antibiotics on patient survival, hospital length of stay (LOS), and total hospital cost. Methods: Data were collected for adults from six U. S. hospitals with a principal CAP discharge diagnosis code, a chest infiltrate, and medical notes indicative of CAP from 2005-2007. Pathway and non-pathway cohorts were assigned according to antibiotics received within 48 hours of admission. Pathway antibiotics included levofloxacin 750 mg monotherapy or ceftriaxone 1000 mg plus azithromycin 500 mg daily. Multivariable regression models assessed 90-day mortality, hospital LOS, total hospital cost, and total pharmacy cost. Results: Overall, 792 patients met study criteria. Of these, 505 (64%) received pathway antibiotics and 287 (36%) received non-pathway antibiotics. Adjusted means and p-values were derived from Least Squares regression models that included Pneumonia Severity Index risk class, patient age, heart failure, chronic obstructive pulmonary disease, and admitting hospital as covariates. After adjustment, patients who received pathway antibiotics experienced lower adjusted 90-day mortality (p = 0.02), shorter mean hospital LOS (3.9 vs. 5.0 days, p < 0.01), lower mean hospital costs ($2,485 vs. $3,281, p = 0.02), and similar mean pharmacy costs ($356 vs. $442, p = 0.11). Conclusions: Pathway antibiotics were associated with improved patient survival, hospital LOS, and total hospital cost for patients admitted to the hospital with CAP. C1 [Frei, Christopher R.; Bell, Allison M.; Traugott, Kristi A.; Jaso, Terry C.; Daniels, Kelly R.; Oramasionwu, Christine U.; Ruiz, Andres D.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Frei, Christopher R.; Bell, Allison M.; Traugott, Kristi A.; Daniels, Kelly R.; Oramasionwu, Christine U.; Ruiz, Andres D.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. [Traugott, Kristi A.] ALMD UTHSCSA, S Texas Vet Healthcare Syst, Dept Pharm, San Antonio, TX 78229 USA. [Jaso, Terry C.; Mylchreest, William R.] Seton Family Hosp, Austin, TX 78720 USA. [Daniels, Kelly R.; Ruiz, Andres D.] Oakdell Pharm Inc, San Antonio, TX 78229 USA. [Mortensen, Eric M.; Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Mortensen, Eric M.; Restrepo, Marcos I.] ALMD UTHSCSA, S Texas Vet Healthcare Syst, VERDICT, San Antonio, TX 78229 USA. [Sikirica, Vanja; Raut, Monika R.; Fisher, Alan; Schein, Jeff R.] Ortho McNeil Janssen Sci Affairs LLC, Raritan, NJ 08869 USA. RP Frei, CR (reprint author), Univ Texas Austin, Coll Pharm, 1 Univ Stn A1900, Austin, TX 78712 USA. EM freic@uthscsa.edu RI Restrepo, Marcos/H-4442-2014; OI Mortensen, Eric/0000-0002-3880-5563 FU NIH; AstraZeneca; Elan; Ortho McNeil Janssen Pharmaceuticals; Pfizer FX CRF has received research grants and/or served as a scientific consultant/advisor for the NIH, AstraZeneca, Elan, Ortho McNeil Janssen Pharmaceuticals, and Pfizer. MIR is on the speaker's bureaus of Ortho-McNeil Janssen, Johnson & Johnson, Pfizer, and BARD, Inc. He has also served on Advisory Boards for Forest, Ortho-McNeil Janssen, Johnson & Johnson, Pfizer, and BARD, Inc. VS, MRR, AF, and JRS are current or former employees of Ortho McNeil Janssen Scientific Affairs, LLC. AMB, KAT, TCJ, KRD, EMM, CUO, ADR, and WRM have nothing to disclose related to the content of this manuscript. NR 26 TC 5 Z9 5 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUL 6 PY 2011 VL 11 AR 188 DI 10.1186/1471-2334-11-188 PG 6 WC Infectious Diseases SC Infectious Diseases GA 795WJ UT WOS:000293008500001 PM 21733161 ER PT J AU Chmielecki, J Foo, J Oxnard, GR Hutchinson, K Ohashi, K Somwar, R Wang, L Amato, KR Arcila, M Sos, ML Socci, ND Viale, A de Stanchina, E Ginsberg, MS Thomas, RK Kris, MG Inoue, A Ladanyi, M Miller, VA Michor, F Pao, W AF Chmielecki, Juliann Foo, Jasmine Oxnard, Geoffrey R. Hutchinson, Katherine Ohashi, Kadoaki Somwar, Romel Wang, Lu Amato, Katherine R. Arcila, Maria Sos, Martin L. Socci, Nicholas D. Viale, Agnes de Stanchina, Elisa Ginsberg, Michelle S. Thomas, Roman K. Kris, Mark G. Inoue, Akira Ladanyi, Marc Miller, Vincent A. Michor, Franziska Pao, William TI Optimization of Dosing for EGFR-Mutant Non-Small Cell Lung Cancer with Evolutionary Cancer Modeling SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID TYROSINE KINASE INHIBITOR; ADVANCED SOLID TUMORS; ACQUIRED-RESISTANCE; PHASE-I; INCREASED SENSITIVITY; DRUG-RESISTANCE; T790M MUTATION; GEFITINIB; ERLOTINIB; ADENOCARCINOMA AB Non-small cell lung cancers (NSCLCs) that harbor mutations within the epidermal growth factor receptor (EGFR) gene are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Unfortunately, all patients treated with these drugs will acquire resistance, most commonly as a result of a secondary mutation within EGFR (T790M). Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance. To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors. We determined that the drug-sensitive and drug-resistant EGFR-mutant cells exhibited differential growth kinetics, with the drug-resistant cells showing slower growth. We incorporated these data into evolutionary mathematical cancer models with constraints derived from clinical data sets. This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance. C1 [Foo, Jasmine; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Foo, Jasmine; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Chmielecki, Juliann] Weill Cornell Grad Sch Med Sci, New York, NY 10021 USA. [Oxnard, Geoffrey R.; Kris, Mark G.; Miller, Vincent A.] Mem Sloan Kettering Canc Ctr, Dept Med, Thorac Oncol Serv, New York, NY 10065 USA. [Hutchinson, Katherine; Ohashi, Kadoaki; Amato, Katherine R.; Pao, William] Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37232 USA. [Somwar, Romel] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. [Wang, Lu; Arcila, Maria; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Sos, Martin L.; Thomas, Roman K.] Max Planck Gesell, Klaus Joachim Zulch Labs, Max Planck Inst Neurol Res, D-50931 Cologne, Germany. [Sos, Martin L.; Thomas, Roman K.] Fac Med, D-50931 Cologne, Germany. [Viale, Agnes] Mem Sloan Kettering Canc Ctr, Genom Core Lab, New York, NY 10065 USA. [de Stanchina, Elisa] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core Lab, New York, NY 10065 USA. [Ginsberg, Michelle S.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA. [Thomas, Roman K.] Univ Cologne, Dept Internal Med 1, D-50924 Cologne, Germany. [Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol Koln Bonn, D-50924 Cologne, Germany. [Thomas, Roman K.] Max Planck Gesell, Chem Genom Ctr, D-44227 Dortmund, Germany. [Inoue, Akira] Tohoku Univ Hosp, Dept Resp Med, Aoba Ku, Sendai, Miyagi 3831, Japan. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. RP Michor, F (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM michor@jimmy.harvard.edu; william.pao@vanderbilt.edu RI Inoue, Akihisa/E-5271-2015; OI Kris, Mark/0000-0002-7317-5341 FU NIH/National Cancer Institute (NCI) [R01-CA121210, P01-CA129243, U54-CA143798]; NCI Cancer Center [P30-CA008748]; Vanderbilt's SPORE in Lung Cancer [CA90949]; Vanderbilt-Ingram Cancer Center [P30-CA68485]; German Ministry of Science and Education [01GS08100]; Max Planck Society [M.I.F.A.NEUR8061]; Deutsche Forschungsgemeinschaft [SFB832, TP6]; Deutsche Krebshilfe [107954]; Fritz-Thyssen-Stiftung [10.08.2.175] FX Supported by NIH/National Cancer Institute (NCI) grants R01-CA121210 (W. P.), P01-CA129243 (M. G. K. and W. P.), and U54-CA143798 (F. M. and W. P.). The MSKCC Genomics Core is supported by an NCI Cancer Center Support Grant award to MSKCC (P30-CA008748). W. P. received additional support from Vanderbilt's SPORE in Lung Cancer grant (CA90949) and the Vanderbilt-Ingram Cancer Center Core grant (P30-CA68485). R. K. T. is supported by the German Ministry of Science and Education as part of the NGFNplus program (grant 01GS08100), Max Planck Society (M.I.F.A.NEUR8061), Deutsche Forschungsgemeinschaft through SFB832 (TP6), Deutsche Krebshilfe (grant 107954), and Fritz-Thyssen-Stiftung (grant 10.08.2.175). NR 56 TC 162 Z9 166 U1 0 U2 20 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 6 PY 2011 VL 3 IS 90 AR 90ra59 DI 10.1126/scitranslmed.3002356 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795NZ UT WOS:000292982200003 PM 21734175 ER PT J AU Taborsky, GJ AF Taborsky, Gerald J., Jr. TI Islets Have a Lot of Nerve! Or Do They? SO CELL METABOLISM LA English DT Editorial Material ID GLUCAGON-SECRETION; ENDOCRINE PANCREAS; ACTIVATION; HYPOGLYCEMIA; DOG C1 [Taborsky, Gerald J., Jr.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Taborsky, Gerald J., Jr.] Univ Washington, Seattle, WA 98108 USA. RP Taborsky, GJ (reprint author), VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. EM taborsky@u.washington.edu FU NIDDK NIH HHS [R01 DK050154] NR 10 TC 8 Z9 9 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JUL 6 PY 2011 VL 14 IS 1 BP 5 EP 6 DI 10.1016/j.cmet.2011.06.004 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 790JB UT WOS:000292583200003 PM 21723498 ER PT J AU Bertran, MT Sdelci, S Regue, L Avruch, J Caelles, C Roig, J AF Teresa Bertran, M. Sdelci, Sara Regue, Laura Avruch, Joseph Caelles, Carme Roig, Joan TI Nek9 is a Plk1-activated kinase that controls early centrosome separation through Nek6/7 and Eg5 SO EMBO JOURNAL LA English DT Article DE centrosome; Eg5; kinase; Nek; Plk1 ID MITOTIC SPINDLE FORMATION; NIMA-FAMILY KINASE; PROTEIN-KINASE; KINESIN EG5; CELL-CYCLE; POLO; CYTOKINESIS; MITOSIS; PLK1; MOTOR AB The NIMA-family kinases Nek9/Nercc1, Nek6 and Nek7 form a signalling module required for mitotic spindle assembly. Nek9, the upstream kinase, is activated during prophase at centrosomes although the details of this have remained elusive. We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. Furthermore, we show that Plk1 controls prophase centrosome separation through the activation of Nek9 and ultimately the phosphorylation of the mitotic kinesin Eg5 at Ser1033, a Nek6/7 site that together with the CDK1 site Thr926 we establish contributes to the accumulation of Eg5 at centrosomes and is necessary for subsequent centrosome separation and timely mitosis. Our results provide a basis to understand signalling downstream of Plk1 and shed light on the role of Eg5, Plk1 and the NIMA-family kinases in the control of centrosome separation and normal mitotic progression. The EMBO Journal (2011) 30, 2634-2647. doi: 10.1038/emboj.2011.179; Published online 3 June 2011 C1 [Teresa Bertran, M.; Sdelci, Sara; Regue, Laura; Caelles, Carme; Roig, Joan] Inst Res Biomed IRB Barcelona, Cell Signalling Res Grp, Program Mol Med, Barcelona 08028, Spain. [Avruch, Joseph] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Avruch, Joseph] Massachusetts Gen Hosp, Med Serv, Boston, MA USA. [Avruch, Joseph] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Caelles, Carme] Univ Barcelona, Dept Biochem & Mol Biol Pharm, Barcelona, Spain. RP Roig, J (reprint author), Inst Res Biomed IRB Barcelona, Cell Signalling Res Grp, Program Mol Med, Parc Cient Barcelona,C Baldiri & Reixac 10-12, Barcelona 08028, Spain. EM joan.roig@irbbarcelona.org OI Roig, Joan/0000-0002-3872-4712 FU NIH [DK17776]; Ramon y Cajal Program; MICINN, Spain [BFU2008-03441/BMC] FX We thank C Vila and other members of the extended Cell Signaling group as well as the staff of the IRB Barcelona Advanced Digital Microscopy Core Facility for their help. We also thank I Vernos (Centre de Regulacio Genomica, Barcelona, Spain) and J Luders (IRB Barcelona) for comments, A Fry (University of Leicester, Leicester, UK) for GFP-Nek2 and comments and A Groen, R Ohi and the Mitchison Laboratory (Harvard University, Boston, USA) for anti-centrin antibodies. JA acknowledges support from NIH grant DK17776 and institutional funds. JR acknowledges support from the Ramon y Cajal Program and the Plan Nacional I+D Grant BFU2008-03441/BMC (MICINN, Spain), and institutional funds. NR 42 TC 57 Z9 59 U1 0 U2 11 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 JUL 6 PY 2011 VL 30 IS 13 BP 2634 EP 2647 DI 10.1038/emboj.2011.179 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 791CJ UT WOS:000292638700013 PM 21642957 ER PT J AU Lysakowski, A Gaboyard-Niay, S Calin-Jageman, I Chatlani, S Price, SD Eatock, RA AF Lysakowski, Anna Gaboyard-Niay, Sophie Calin-Jageman, Irina Chatlani, Shilpa Price, Steven D. Eatock, Ruth Anne TI Molecular Microdomains in a Sensory Terminal, the Vestibular Calyx Ending SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PERIPHERAL INNERVATION PATTERNS; AXON INITIAL SEGMENT; EXTRACELLULAR-MATRIX MOLECULES; GATED SODIUM-CHANNELS; UTRICULAR HAIR-CELLS; K+ CHANNELS; GUINEA-PIG; SYNAPTIC PLASTICITY; SEMICIRCULAR CANALS; CRISTAE AMPULLARES AB Many primary vestibular afferents form large cup-shaped postsynaptic terminals (calyces) that envelope the basolateral surfaces of type I hair cells. The calyceal terminals both respond to glutamate released from ribbon synapses in the type I cells and initiate spikes that propagate to the afferent's central terminals in the brainstem. The combination of synaptic and spike initiation functions in these unique sensory endings distinguishes them from the axonal nodes of central neurons and peripheral nerves, such as the sciatic nerve, which have provided most of our information about nodal specializations. We show that rat vestibular calyces express an unusual mix of voltage-gated Na and K channels and scaffolding, cell adhesion, and extracellular matrix proteins, which may hold the ion channels in place. Protein expression patterns form several microdomains within the calyx membrane: a synaptic domain facing the hair cell, the heminode abutting the first myelinated internode, and one or two intermediate domains. Differences in the expression and localization of proteins between afferent types and zones may contribute to known variations in afferent physiology. C1 [Lysakowski, Anna; Price, Steven D.] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL 60605 USA. [Gaboyard-Niay, Sophie] Hop St Eloi, INSERM, U1051, F-34295 Montpellier, France. [Calin-Jageman, Irina] Dominican Univ, Dept Biol Sci, River Forest, IL 60305 USA. [Chatlani, Shilpa] Univ Chicago, Comm Neurobiol, Chicago, IL 60637 USA. [Eatock, Ruth Anne] Harvard Univ, Dept Otol & Laryngol, Sch Med, Boston, MA 02115 USA. [Eatock, Ruth Anne] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. RP Lysakowski, A (reprint author), Univ Illinois, Dept Anat & Cell Biol, 808 S Wood St, Chicago, IL 60605 USA. EM alysakow@uic.edu RI Lysakowski, Anna/F-9534-2010; Eatock, Ruth/F-6404-2013; OI Lysakowski, Anna/0000-0001-6259-0294; Calin-Jageman, Irina/0000-0002-2529-4223; Eatock, Ruth Anne/0000-0001-7547-2051; Gaboyard-Niay, Sophie/0000-0001-8256-8692 FU NIH [R01 DC-02521, R01 DC-02058, R01 DC-02290] FX This study was supported by NIH Grants R01 DC-02521, R01 DC-02058, and R01 DC-02290. The Electron Microscopic Facility of the Research Resources Center of the University of Illinois at Chicago provided equipment and assistance to conduct this study. We are grateful to Drs. Matt Rasband (NaV1.6, NaV1.2, Caspr1, beta IV spectrin, neurofascin 186, and pan-neurofascin), James Trimmer (pan-NaV), Elior Peles (Caspr3 and Caspr4), Edward Cooper (KCNQ2 and KCNQ3), Thomas Jentsch (KCNQ4 and KCNQ5), Rock Levinson (pan-NaV), Vann Bennett (ankyrinG and ankyrinB), and Michel Roux (H4, pan-dystrophin) for generous gifts of antibodies, and to Marcin Klapczynski for technical assistance. We thank Drs. Jay M. Goldberg, D. Kent Morest, and Matt Rasband for helpful discussions. NR 113 TC 47 Z9 47 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 6 PY 2011 VL 31 IS 27 BP 10101 EP 10114 DI 10.1523/JNEUROSCI.0521-11.2011 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 789OE UT WOS:000292524400034 PM 21734302 ER PT J AU Atilla-Gokcumen, GE Bedigian, AV Sasse, S Eggert, US AF Atilla-Gokcumen, G. E. Bedigian, A. V. Sasse, S. Eggert, U. S. TI Inhibition of Glycosphingolipid Biosynthesis Induces Cytokinesis Failure SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CLEAVAGE FURROW; MITOTIC CELLS; MEMBRANE; GLUCOSYLCERAMIDE; CYTOSKELETON; CURVATURE; CERAMIDE; DOMAINS; MOESIN; PHASE AB Although cells undergo dramatic shape changes during cytokinesis, the role of the plasma membrane and lipids is poorly understood. We report that inactivation of glucosyl ceramide synthase (GCS), either by RNAi or with the small molecule PPMP, causes failure of cleavage furrow ingression. Using mass-spectrometry-based global lipid profiling, we identify individual lipids that are enhanced or depleted due to GCS inhibition. We show that GCS inhibition results in the mislocalization of actin and the ERM proteins, key cytoskeletal proteins that connect the plasma membrane to the actin cortex. Our data suggest that ceramides participate in mediating the interactions between the membrane and the cortex. C1 [Atilla-Gokcumen, G. E.; Bedigian, A. V.; Sasse, S.; Eggert, U. S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Atilla-Gokcumen, G. E.; Bedigian, A. V.; Sasse, S.; Eggert, U. S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Sasse, S.] Univ Munster, Inst Neurobiol, Munster, Germany. [Eggert, U. S.] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England. RP Eggert, US (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM ulrike.eggert@kcl.ac.uk FU Taplin Funds for Discovery Program; Heinrich Hertz Foundation; Human Frontier Science Program; NIH [R01 GM082834]; Dana-Farber Cancer Institute FX We thank Alan Saghatelian, Tejia Zhang, Emma Doud, and members of the Eggert lab, especially Xin Zhang, for helpful discussions. LC/MS data were acquired on an Agilent 6520 Q-TOF spectrometer supported by the Taplin Funds for Discovery Program (PI, Suzanne Walker). We thank the Nikon Imaging Center at Harvard Medical School for help with light microscopy. This work was funded by the Heinrich Hertz Foundation (to S.S.), a Human Frontier Science Program Young Investigator Award (to U.E., Aurelien Roux, Kaori Sakurai, co-PIs), NIH grant R01 GM082834, and the Dana-Farber Cancer Institute. NR 29 TC 17 Z9 17 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 6 PY 2011 VL 133 IS 26 BP 10010 EP 10013 DI 10.1021/ja202804b PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 792BN UT WOS:000292715600017 PM 21668028 ER PT J AU Stany, MP Vathipadiekal, V Ozbun, L Stone, RL Mok, SC Xue, H Kagami, T Wang, YW McAlpine, JN Bowtell, D Gout, PW Miller, DM Gilks, CB Huntsman, DG Ellard, SL Wang, YZ Vivas-Mejia, P Lopez-Berestein, G Sood, AK Birrer, MJ AF Stany, Michael P. Vathipadiekal, Vinod Ozbun, Laurent Stone, Rebecca L. Mok, Samuel C. Xue, Hui Kagami, Takashi Wang, Yuwei McAlpine, Jessica N. Bowtell, David Gout, Peter W. Miller, Dianne M. Gilks, C. Blake Huntsman, David G. Ellard, Susan L. Wang, Yu-Zhuo Vivas-Mejia, Pablo Lopez-Berestein, Gabriel Sood, Anil K. Birrer, Michael J. TI Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; INTERFERING RNA DELIVERY; IN-VIVO; FACTOR EXPRESSION; GENE-EXPRESSION; ANTITUMOR-ACTIVITY; TYROSINE KINASE; FACTOR RECEPTOR; CARCINOMA AB Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients. C1 [Stany, Michael P.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Vathipadiekal, Vinod; Birrer, Michael J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Vathipadiekal, Vinod; Birrer, Michael J.] Harvard Univ, Sch Med, Boston, MA USA. [Ozbun, Laurent] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stone, Rebecca L.; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Mok, Samuel C.] Harvard Univ, Brigham & Womens Hosp, Sch Publ Hlth, Boston, MA 02115 USA. [Xue, Hui; Kagami, Takashi; Wang, Yuwei; Gout, Peter W.; Wang, Yu-Zhuo] British Columbia Canc Agcy, Living Tumor Lab, Vancouver, BC V5Z 4E6, Canada. [McAlpine, Jessica N.; Miller, Dianne M.] Univ British Columbia, Dept Obstet & Gynecol, Div Gynecol Oncol, Vancouver, BC V5Z 1M9, Canada. [Bowtell, David] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Gilks, C. Blake; Huntsman, David G.] British Columbia Canc Agcy, Ctr Translat & Appl Genom, Vancouver Gen Hosp, Dept Pathol,Genet Pathol Evaluat Ctr, Vancouver, BC V5Z 4E6, Canada. [Ellard, Susan L.] British Columbia Canc Agcy So Interior, Dept Med Oncol, Kelowna, BC, Canada. [Wang, Yu-Zhuo] Univ British Columbia, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada. [Wang, Yu-Zhuo] Univ British Columbia, Vancouver Prostate Ctr, Vancouver, BC V5Z 1M9, Canada. [Vivas-Mejia, Pablo; Lopez-Berestein, Gabriel] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Lopez-Berestein, Gabriel; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Lopez-Berestein, Gabriel; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77030 USA. RP Stany, MP (reprint author), Walter Reed Army Med Ctr, Washington, DC 20307 USA. EM mbirrer@partners.org RI Bowtell, David/H-1007-2016; OI Bowtell, David/0000-0001-9089-7525; Vathipadiekal, Vinod/0000-0002-8181-6890 FU National Cancer Institute at the National Institutes of the Health; OvCaRe (an initiative of the Vancouver General Hospital and University of BC Hospital Foundation and the BC Cancer Foundation); BC Cancer Foundation; Pfizer Canada FX This work was supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of the Health (MJB) and OvCaRe (an initiative of the Vancouver General Hospital and University of BC Hospital Foundation and the BC Cancer Foundation) (YZW), the BC Cancer Foundation and Pfizer Canada (Investigator-initiated project, SLE and YZW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 53 TC 37 Z9 37 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 6 PY 2011 VL 6 IS 7 AR e21121 DI 10.1371/journal.pone.0021121 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791AK UT WOS:000292632000007 PM 21754983 ER PT J AU Zafonte, R AF Zafonte, Ross TI Diagnosis and Management of Sports-Related Concussion A 15-Year-Old Athlete With a Concussion SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID TRAUMATIC-BRAIN-INJURY; PROFESSIONAL FOOTBALL PLAYERS; MILD HEAD-INJURY; HIGH-SCHOOL; RECURRENT CONCUSSION; NEUROCOGNITIVE PERFORMANCE; POSTTRAUMATIC MIGRAINE; INTELLECTUAL ABILITY; MAGNETIC-RESONANCE; POSTURAL STABILITY AB Concussion in youth athletes is a growing problem worldwide. During the past decade, significant progress has been made in standardization of the assessment of young athletes, and a growing appreciation of metabolic vulnerability, activity, and cognitive challenges has led to guidelines and suggestions for rest from the field as well as cognitive rest from school. Outcome data have begun to establish groups linked to symptom class, genetics, and sex who are at risk of worse outcomes from concussions. Decisions regarding return to activity are now based on at-rest symptoms, graded increases in activity, and neuropsychological testing. Using the case of Ms X, a 15-year-old otherwise healthy high school student who fell while skiing, evaluation, prognosis, and management of concussion are discussed. C1 [Zafonte, Ross] Spaulding Rehabil Hosp Network, Boston, MA 02114 USA. [Zafonte, Ross] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Zafonte, Ross] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zafonte, R (reprint author), Spaulding Rehabil Hosp Network, 125 Nashua St, Boston, MA 02114 USA. EM rzafonte@partners.org FU National Institutes of Health; National Institute on Disability and Rehabilitation Research; Department of Defense; US Food and Drug Administration FX The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Zafonte reports receiving research funding from the National Institutes of Health, the National Institute on Disability and Rehabilitation Research, and the Department of Defense. He is principal investigator on a study funded by the US Food and Drug Administration orphan drug program in collaboration with Neurohealing. He is a member of Neurohealing's scientific advisory board but receives no compensation. NR 81 TC 11 Z9 11 U1 3 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 6 PY 2011 VL 306 IS 1 BP 79 EP 86 DI 10.1001/jama.2011.819 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 787LV UT WOS:000292378700023 PM 21632470 ER PT J AU Sepucha, KR Stacey, D Clay, CF Chang, YC Cosenza, C Dervin, G Dorrwachter, J Feibelmann, S Katz, JN Kearing, SA Malchau, H Taljaard, M Tomek, I Tugwell, P Levin, CA AF Sepucha, Karen R. Stacey, Dawn Clay, Catharine F. Chang, Yuchiao Cosenza, Carol Dervin, Geoffrey Dorrwachter, Janet Feibelmann, Sandra Katz, Jeffrey N. Kearing, Stephen A. Malchau, Henrik Taljaard, Monica Tomek, Ivan Tugwell, Peter Levin, Carrie A. TI Decision quality instrument for treatment of hip and knee osteoarthritis: a psychometric evaluation SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE shared decision making; patient centered care; quality measurement; osteoarthritis; total joint replacement; decision quality ID INFORMED PATIENT CHOICE; REPLACEMENT SURGERY; ARTHROPLASTY; PREFERENCES; KNOWLEDGE; AIDS AB Background: A high quality decision requires that patients who meet clinical criteria for surgery are informed about the options (including non-surgical alternatives) and receive treatments that match their goals. The aim of this study was to evaluate the psychometric properties and clinical sensibility of a patient self report instrument, to measure the quality of decisions about total joint replacement for knee or hip osteoarthritis. Methods: The performance of the Hip/Knee Osteoarthritis Decision Quality Instrument (HK-DQI) was evaluated in two samples: (1) a cross-sectional mail survey with 489 patients and 77 providers (study 1); and (2) a randomized controlled trial of a patient decision aid with 138 osteoarthritis patients considering total joint replacement (study 2). The HK-DQI results in two scores. Knowledge items are summed to create a total knowledge score, and a set of goals and concerns are used in a logistic regression model to develop a concordance score. The concordance score measures the proportion of patients whose treatment matched their goals. Hypotheses related to acceptability, feasibility, reliability and validity of the knowledge and concordance scores were examined. Results: In study 1, the HK-DQI was completed by 382 patients (79%) and 45 providers (58%), and in study 2 by 127 patients (92%), with low rates of missing data. The DQI-knowledge score was reproducible (ICC = 0.81) and demonstrated discriminant validity (68% decision aid vs. 54% control, and 78% providers vs. 61% patients) and content validity. The concordance score demonstrated predictive validity, as patients whose treatments were concordant with their goals had more confidence and less regret with their decision compared to those who did not. Conclusions: The HK-DQI is feasible and acceptable to patients. It can be used to assess whether patients with osteoarthritis are making informed decisions about surgery that are concordant with their goals. C1 [Sepucha, Karen R.; Chang, Yuchiao] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA 02115 USA. [Stacey, Dawn; Taljaard, Monica] Univ Ottawa, Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Stacey, Dawn] Univ Ottawa, Fac Hlth Sci, Ottawa, ON, Canada. [Clay, Catharine F.] Dartmouth Hitchcock Med Ctr, Ctr Shared Decis Making, Lebanon, NH 03766 USA. [Cosenza, Carol] Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. [Dervin, Geoffrey] Ottawa Hosp, Div Orthopaed Surg, Ottawa, ON, Canada. [Malchau, Henrik] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthoped Surg, Boston, MA USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthoped Surg, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Kearing, Stephen A.] Dartmouth Med Sch, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Taljaard, Monica] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Tomek, Ivan] Dartmouth Med Sch, Dept Orthoped Surg, Lebanon, NH USA. [Tugwell, Peter] Ottawa Hosp, Dept Med, Ottawa, ON, Canada. [Levin, Carrie A.] Fdn Informed Med Decis Making, Boston, MA USA. RP Sepucha, KR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA 02115 USA. EM ksepucha@partners.org OI Tugwell, Peter/0000-0001-5062-0556 FU Foundation for Informed Medical Decision Making (FIMDM); NIH [K24 AR 02123, P60 AR 47782] FX The authors would like to thank the patients, providers and other respondents whose participation made this research possible. The work was supported by two grants from the Foundation for Informed Medical Decision Making (FIMDM) (one to K. S. and one to D. S.). The research involved collaboration between the Massachusetts General Hospital (MGH) research team/Ottawa research team and representatives from the funder. The research grant was awarded in compliance with MGH's policies which bar funder interference in scholarly work. During this research, Dr. Levin was Director of Research at the funder, the Foundation for Informed Medical Decision Making. She provided input on the research design, feedback on analyses, and constructive comments on manuscript drafts consistent with her listed co-authorship role. Dr. Katz has funding supported in part of NIH K24 AR 02123, NIH P60 AR 47782. NR 27 TC 18 Z9 18 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD JUL 5 PY 2011 VL 12 AR 149 DI 10.1186/1471-2474-12-149 PG 12 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 799NY UT WOS:000293294600002 PM 21729315 ER PT J AU Wu, J Zhu, AX AF Wu, Jennifer Zhu, Andrew X. TI Targeting insulin-like growth factor axis in hepatocellular carcinoma SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Review ID FACTOR-I RECEPTOR; FACTOR BINDING-PROTEINS; PROSTATE-CANCER CELLS; FACTOR-BETA; IGF-II; HUMAN HEPATOMA; BREAST-CANCER; HEPATITIS-B; INSULIN-LIKE-GROWTH-FACTOR-1 RECEPTOR; SUBSEQUENT RISK AB The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins. The essential role of IGF axis in hepatocellular carcinoma (HCC) has been illustrated in HCC cell lines and in animal xenograft models. Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC. Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation. This review describes the most up-to-date understanding of this complex axis in HCC, and provides relevant information on clinical trials targeting the IGF axis in HCC with a focus on anti-IGF-1R approach. IGF axis is increasingly recognized as one of the most relevant pathways in HCC and agents targeting this axis can potentially play an important role in the treatment of HCC. C1 [Wu, Jennifer] NYU Sch Med, NYU Canc Inst, Div Hematol & Med Oncol, New York, NY 10016 USA. [Zhu, Andrew X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol & Med Oncol,Canc Ctr, Boston, MA 02114 USA. RP Wu, J (reprint author), NYU Sch Med, NYU Canc Inst, Div Hematol & Med Oncol, New York, NY 10016 USA. EM jennifer.wu@nyumc.org NR 120 TC 51 Z9 53 U1 1 U2 9 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 JUL 5 PY 2011 VL 4 AR 30 DI 10.1186/1756-8722-4-30 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 795JL UT WOS:000292970400001 PM 21729319 ER PT J AU Brown, JD Oligino, E Rader, DJ Saghatelian, A Plutzky, J AF Brown, Jonathan D. Oligino, Eric Rader, Daniel J. Saghatelian, Alan Plutzky, Jorge TI VLDL Hydrolysis by Hepatic Lipase Regulates PPAR delta Transcriptional Responses SO PLOS ONE LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTORS; HUMAN ENDOTHELIAL-CELLS; LIPOPROTEIN-LIPASE; DEFICIENT MICE; FATTY-ACIDS; INSULIN SENSITIVITY; ALPHA ACTIVATORS; TRANSGENIC MICE; ATHEROSCLEROSIS; METABOLISM AB Background: PPARs (alpha,gamma,delta) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown. Methods/Principal Findings: Using PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL >> LDL, IDL) to activate PPAR delta preferentially over PPAR alpha or PPAR gamma, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPAR delta in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPAR delta target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPAR delta activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPARd activation and ADRP gene regulation in vitro. Conclusions: These data define a novel pathway involving HL hydrolysis of VLDL that activates PPARd through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription. C1 [Brown, Jonathan D.; Oligino, Eric; Plutzky, Jorge] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Brown, Jonathan D.] VA Boston Healthcare, W Roxbury, MA USA. [Oligino, Eric] Yale New Haven Med Ctr, Div Cardiol, New Haven, CT 06504 USA. [Rader, Daniel J.] Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Saghatelian, Alan] Harvard Univ, Dept Chem, Cambridge, MA 02138 USA. RP Brown, JD (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. EM jplutzky@rics.bwh.harvard.edu FU National Institutes of Health [NHBLI HL048743, NHLBI HL071745, NHLBI K08HL105678-01]; Sarnoff Cardiovascular Research Foundation; Searle Scholars Award FX This paper was supported by National Institutes of Health grants NHBLI HL048743 and NHLBI HL071745 (JP) and NHLBI K08HL105678-01 (JB), the Sarnoff Cardiovascular Research Foundation (JB, EO), and the Searle Scholars Award (AS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 9 Z9 9 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 5 PY 2011 VL 6 IS 7 AR e21209 DI 10.1371/journal.pone.0021209 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 789JO UT WOS:000292512000010 PM 21750705 ER PT J AU Wanyenze, RK Kamya, MR Fatch, R Mayanja-Kizza, H Baveewo, S Sawires, S Bangsberg, DR Coates, T Hahn, JA AF Wanyenze, Rhoda K. Kamya, Moses R. Fatch, Robin Mayanja-Kizza, Harriet Baveewo, Steven Sawires, Sharif Bangsberg, David R. Coates, Thomas Hahn, Judith A. TI Missed Opportunities for HIV Testing and Late-Stage Diagnosis among HIV-Infected Patients in Uganda SO PLOS ONE LA English DT Article ID ANTIRETROVIRAL THERAPY; SEXUAL-BEHAVIOR; TRANSMISSION; PREVENTION; STRATEGIES; DISCLOSURE; COUNTRIES; PROGRAMS; OUTCOMES; RISK AB Background: Late diagnosis of HIV infection is a major challenge to the scale-up of HIV prevention and treatment. In 2005 Uganda adopted provider-initiated HIV testing in the health care setting to ensure earlier HIV diagnosis and linkage to care. We provided HIV testing to patients at Mulago hospital in Uganda, and performed CD4 tests to assess disease stage at diagnosis. Methods: Patients who had never tested for HIV or tested negative over one year prior to recruitment were enrolled between May 2008 and March 2010. Participants who tested HIV positive had a blood draw for CD4. Late HIV diagnosis was defined as CD4 <= 250 cells/mm. Predictors of late HIV diagnosis were analyzed using multi-variable logistic regression. Results: Of 1966 participants, 616 (31.3%) were HIV infected; 47.6% of these (291) had CD4 counts <= 250. Overall, 66.7% (408) of the HIV infected participants had never received care in a medical clinic. Receiving care in a non-medical setting (home, traditional healer and drug stores) had a threefold increase in the odds of late diagnosis (OR = 3.2; 95% CI: 2.1-4.9) compared to receiving no health care. Conclusions: Late HIV diagnosis remains prevalent five years after introducing provider-initiated HIV testing in Uganda. Many individuals diagnosed with advanced HIV did not have prior exposure to medical clinics and could not have benefitted from the expansion of provider initiated HIV testing within health facilities. In addition to provider-initiated testing, approaches that reach individuals using non-hospital based encounters should be expanded to ensure early HIV diagnosis. C1 [Wanyenze, Rhoda K.] Makerere Univ, Sch Publ Hlth, Dept Dis Control & Environm Hlth, Kampala, Uganda. [Kamya, Moses R.; Mayanja-Kizza, Harriet; Baveewo, Steven] Makerere Univ, Sch Med, Dept Med, Kampala, Uganda. [Fatch, Robin; Baveewo, Steven; Hahn, Judith A.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA USA. [Sawires, Sharif; Coates, Thomas] Univ Calif Los Angeles, David Geffen Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. RP Wanyenze, RK (reprint author), Makerere Univ, Sch Publ Hlth, Dept Dis Control & Environm Hlth, Kampala, Uganda. EM rwanyenze@hotmail.com OI Mayanja-Kizza, Harriet/0000-0002-9297-6208 FU National Institute of Mental Health, Division of AIDS and Health and Behavior Research, Center for Mental Health Research on AIDS [1 R01 MH077512] FX This study was funded by National Institute of Mental Health (1 R01 MH077512), Division of AIDS and Health and Behavior Research, Center for Mental Health Research on AIDS. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 23 Z9 23 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 5 PY 2011 VL 6 IS 7 AR e21794 DI 10.1371/journal.pone.0021794 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 789JO UT WOS:000292512000024 PM 21750732 ER PT J AU Zhang, XQ Zhang, RL Raab, S Zheng, W Wang, J Liu, N Zhu, TG Xue, LF Song, ZT Mao, JM Li, KT Zhang, HL Zhang, Y Han, C Ding, Y Wang, H Hou, N Liu, YL Shang, SJ Li, CY Sebokova, E Cheng, HP Huang, PL AF Zhang, Xiuqin Zhang, Rongli Raab, Susanne Zheng, Wen Wang, Jue Liu, Na Zhu, Tiangang Xue, Lifang Song, Zhentao Mao, Jiaming Li, Kaitao Zhang, Huiliang Zhang, Yan Han, Chao Ding, Yi Wang, Hui Hou, Ning Liu, Yuli Shang, Shujiang Li, Chuanyun Sebokova, Elena Cheng, Heping Huang, Paul L. TI Rhesus Macaques Develop Metabolic Syndrome With Reversible Vascular Dysfunction Responsive to Pioglitazone SO CIRCULATION LA English DT Article DE metabolic X syndrome; primates; cardiovascular diseases; pathogenesis; peroxisome proliferator-activated receptors; agonists ID DIABETES-MELLITUS; NONHUMAN-PRIMATES; SCIENTIFIC STATEMENT; ROSIGLITAZONE STORY; DIETARY RESTRICTION; INSULIN-RESISTANCE; PROVISIONAL REPORT; BLOOD-INSTITUTE; HUMAN-DISEASE; MONKEYS AB Background-The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance. However, the concept remains controversial; it has been debated whether MetS represents nothing more than simultaneous co-occurrence of individual risk factors or whether there are common shared pathophysiological mechanisms that link the individual components. Methods and Results-To investigate the emergence of metabolic and cardiovascular components during the development of MetS, we identified MetS-predisposed animals (n = 35) in a large population of rhesus macaques (Macaca mulatta, 12.7 +/- 2.9 years old, n = 408), acclimated them to standardized conditions, and monitored the progression of individual component features over 18 months. In 18 MetS animals with recently developed fasting hyperinsulinemia, central obesity, hypertension, and atherogenic dyslipidemia, we found that individual metabolic and cardiovascular components track together during the transition from pre-MetS to onset of MetS; MetS was associated with a 60% impairment of flow-mediated dilation, establishing the mechanistic link with vascular dysfunction. Pioglitazone treatment (3 mg/kg body weight/d for 6 weeks), a peroxisome proliferator-activated receptor gamma agonist, reversibly improved atherogenic dyslipidemia and insulin resistance and fully restored flow-mediated dilation with persistent benefits. Conclusions-Coemergence of metabolic and cardiovascular components during MetS progression and complete normalization of vascular dysfunction with peroxisome proliferator-activated receptor gamma agonists suggest shared underlying mechanisms rather than separate processes, arguing for the benefit of early intervention of MetS components. Predictive nonhuman primate (NHP) models of MetS should be highly valuable in mechanistic and translational studies on the pathogenesis of MetS in relation to cardiovascular disease and diabetes mellitus. (Circulation. 2011;124:77-86.) C1 [Zhang, Xiuqin; Zhang, Rongli; Zheng, Wen; Wang, Jue; Liu, Na; Song, Zhentao; Mao, Jiaming; Li, Kaitao; Zhang, Huiliang; Zhang, Yan; Han, Chao; Ding, Yi; Wang, Hui; Hou, Ning; Liu, Yuli; Shang, Shujiang; Li, Chuanyun; Cheng, Heping] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Raab, Susanne; Sebokova, Elena] F Hoffmann La Roche Ltd, PRDM, Basel, Switzerland. [Zhu, Tiangang; Xue, Lifang] Peking Univ, Peoples Hosp, Dept Med Ultrason, Beijing 100871, Peoples R China. [Huang, Paul L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Huang, Paul L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. RP Cheng, HP (reprint author), Peking Univ, Inst Mol Med, 5 Yiheyuan Rd, Beijing 100871, Peoples R China. EM chengp@pku.edu.cn RI wang, jue/B-1348-2012; Zhang, Yan/B-2831-2012; cheng, heping/A-7299-2011 FU F. Hoffmann-La Roche Ltd; National Basic Research Program of China [2007CB512100]; National Natural Science Foundation of China [30973584, 30870996] FX The present study was supported by F. Hoffmann-La Roche Ltd, the National Basic Research Program of China grant 2007CB512100, and the National Natural Science Foundation of China (grants 30973584 and 30870996). NR 44 TC 17 Z9 19 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 5 PY 2011 VL 124 IS 1 BP 77 EP U176 DI 10.1161/CIRCULATIONAHA.110.990333 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 787KO UT WOS:000292375200022 PM 21690491 ER PT J AU Dugast, AS Tonelli, A Berger, CT Ackerman, ME Sciaranghella, G Liu, QQ Sips, M Toth, I Piechocka-Trocha, A Ghebremichael, M Alter, G AF Dugast, Anne-Sophie Tonelli, Andrew Berger, Christoph T. Ackerman, Margaret E. Sciaranghella, Gaia Liu, Qingquan Sips, Magdalena Toth, Ildiko Piechocka-Trocha, Alicja Ghebremichael, Musie Alter, Galit TI Decreased Fc receptor expression on innate immune cells is associated with impaired antibody-mediated cellular phagocytic activity in chronically HIV-1 infected individuals SO VIROLOGY LA English DT Article DE Innate immunity; Fc receptors; Antibody-dependent cellular phagocytosis; HIV-1 ID MONOCYTE-DERIVED MACROPHAGES; PERIPHERAL-BLOOD MONOCYTES; NATURAL-KILLER-CELLS; VIRUS HIV INFECTION; GAMMA-R; IN-VIVO; IMMUNODEFICIENCY; IGG; CYTOTOXICITY; MODULATION AB In addition to neutralization, antibodies mediate other antiviral activities including antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), as well as complement deposition. While it is established that progressive HIV infection is associated with reduced ADCC and ADCP, the underlying mechanism for this loss of function is unknown. Here we report considerable changes in FcR expression over the course of HIV infection on both mDCs and monocytes, including elevated Fc gamma RI expression in acute HIV infection and reduced expression of Fc gamma RII and Fc gamma RIIIa in chronic HIV infection. Furthermore, selective blockade of Fc gamma RII alone was associated with a loss in ADCP activity, suggesting that Fc gamma RII plays a central role in modulating ADCP. Overall, HIV infection is associated with a number of changes in FcR expression on phagocytic cells that are associated with changes in their ability to respond to antibody-opsonized targets, potentially contributing to a failure in viral clearance in progressive HIV-1 infection. (C) 2011 Elsevier Inc. All rights reserved. C1 [Dugast, Anne-Sophie; Tonelli, Andrew; Berger, Christoph T.; Ackerman, Margaret E.; Sciaranghella, Gaia; Liu, Qingquan; Sips, Magdalena; Toth, Ildiko; Piechocka-Trocha, Alicja; Ghebremichael, Musie; Alter, Galit] Harvard Univ, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02163 USA. [Dugast, Anne-Sophie; Tonelli, Andrew; Berger, Christoph T.; Ackerman, Margaret E.; Sciaranghella, Gaia; Liu, Qingquan; Sips, Magdalena; Toth, Ildiko; Piechocka-Trocha, Alicja; Ghebremichael, Musie; Alter, Galit] MIT, Boston, MA USA. [Ghebremichael, Musie] Dana Farber Canc Inst Boston, Boston, MA 02115 USA. RP Alter, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02163 USA. EM galter@partners.org RI Ackerman, Margaret/B-5944-2012; Dugast, AnneSophie/L-9541-2015 FU National Institute of Health [R01 A1080289] FX This work was supported by the National Institute of Health (R01 A1080289). NR 47 TC 34 Z9 34 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL 5 PY 2011 VL 415 IS 2 BP 160 EP 167 DI 10.1016/j.virol.2011.03.012 PG 8 WC Virology SC Virology GA 778OH UT WOS:000291713500010 PM 21565376 ER PT J AU Zile, MR Gaasch, WH AF Zile, Michael R. Gaasch, William H. TI Abnormal Calcium Homeostasis One Mechanism in Diastolic Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE calcium; diastole; heart failure; hypertrophy; tachycardia ID VENTRICULAR EJECTION FRACTION; DISEASE; INSIGHTS C1 [Zile, Michael R.] Med Univ S Carolina, Div Cardiol, Charleston, SC 29425 USA. [Zile, Michael R.] Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. [Gaasch, William H.] Lahey Clin Fdn, Dept Cardiovasc Med, Burlington, MA USA. RP Zile, MR (reprint author), Med Univ S Carolina, Div Cardiol, Ashley River Towers,Room 7067,25 Courtenay Dr, Charleston, SC 29425 USA. EM zilem@musc.edu NR 13 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 5 PY 2011 VL 58 IS 2 BP 155 EP 157 DI 10.1016/j.jacc.2010.10.068 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 784WN UT WOS:000292189300010 PM 21718912 ER PT J AU Grover, WH Bryan, AK Diez-Silva, M Suresh, S Higgins, JM Manalis, SR AF Grover, William H. Bryan, Andrea K. Diez-Silva, Monica Suresh, Subra Higgins, John M. Manalis, Scott R. TI Measuring single-cell density SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell size; apoptosis; hematology; biosensor; suspended microchannel resonator ID GRADIENT CENTRIFUGATION; PLASMODIUM-FALCIPARUM; APOPTOSIS; VOLUME; ERYTHROCYTES; BIOMECHANICS; SEPARATION; PERCOLL; MALARIA; DISEASE AB We have used a microfluidic mass sensor to measure the density of single living cells. By weighing each cell in two fluids of different densities, our technique measures the single-cell mass, volume, and density of approximately 500 cells per hour with a density precision of 0.001 gmL(-1). We observe that the intrinsic cell-to-cell variation in density is nearly 100-fold smaller than the mass or volume variation. As a result, we can measure changes in cell density indicative of cellular processes that would be otherwise undetectable by mass or volume measurements. Here, we demonstrate this with four examples: identifying Plasmodium falciparum malaria-infected erythrocytes in a culture, distinguishing transfused blood cells from a patient's own blood, identifying irreversibly sickled cells in a sickle cell patient, and identifying leukemia cells in the early stages of responding to a drug treatment. These demonstrations suggest that the ability to measure single-cell density will provide valuable insights into cell state for a wide range of biological processes. C1 [Grover, William H.; Bryan, Andrea K.; Manalis, Scott R.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Grover, William H.; Bryan, Andrea K.; Suresh, Subra; Manalis, Scott R.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Diez-Silva, Monica; Suresh, Subra] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Higgins, John M.; Manalis, Scott R.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Suresh, Subra] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Higgins, John M.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Higgins, John M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Higgins, John M.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Manalis, SR (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM scottm@media.mit.edu RI Grover, William/E-6995-2011; OI Grover, William/0000-0001-6854-8951 FU EUREKA [R01GM085457]; US National Institutes of Health [P50GM68762]; US Army Research Office [W911NF-09-D-0001]; Whitaker Health Sciences Graduate Fellowship; National Institutes of Health [R01HL094270]; National Institute of Diabetes and Digestive and Kidney Diseases [DK083242] FX We thank Prof. Marc Kirschner and Dr. Amit Tzur for the L1210 cells and cell culture expertise, and Dr. Paul Jorgensen for many helpful discussions. Funding was provided by EUREKA (R01GM085457) and a Center for Cell Decision Process Grant (P50GM68762) from the US National Institutes of Health and by an Institute for Collaborative Biotechnologies Grant (W911NF-09-D-0001) from the US Army Research Office. A. K. B. is supported by a Whitaker Health Sciences Graduate Fellowship. M.D.-S. and S. S. are funded by National Institutes of Health Grant R01HL094270. J.M.H. is funded by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK083242. NR 23 TC 94 Z9 95 U1 1 U2 42 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 5 PY 2011 VL 108 IS 27 BP 10992 EP 10996 DI 10.1073/pnas.1104651108 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 787LC UT WOS:000292376700020 PM 21690360 ER PT J AU Burton, DR Hessell, AJ Keele, BF Klasse, PJ Ketas, TA Moldt, B Dunlop, DC Poignard, P Doyle, LA Cavacini, L Veazey, RS Moore, JP AF Burton, Dennis R. Hessell, Ann J. Keele, Brandon F. Klasse, Per Johan Ketas, Thomas A. Moldt, Brian Dunlop, D. Cameron Poignard, Pascal Doyle, Lara A. Cavacini, Lisa Veazey, Ronald S. Moore, John P. TI Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE binding antibodies; passive immunization ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; RHESUS MACAQUES; ENVELOPE GLYCOPROTEIN; HIV VACCINES; IN-VITRO; INFECTION; BINDING; TRANSMISSION; MONKEYS AB To guide vaccine design, we assessed whether human monoclonal antibodies (MAbs) b12 and b6 against the CD4 binding site (CD4bs) on HIV-1 gp120 and F240 against an immundominant epitope on gp41 could prevent vaginal transmission of simian HIV (SHIV)-162P4 to macaques. The two anti-gp120 MAbs have similar monomeric gp120-binding properties, measured in vitro, but b12 is strongly neutralizing and b6 is not. F240 is nonneutralizing. Applied vaginally at a high dose, the strongly neutralizing MAb b12 provided sterilizing immunity in seven of seven animals, b6 in zero of five animals, and F240 in two of five animals. Compared with control animals, the protection by b12 achieved statistical significance, whereas that caused by F240 did not. For two of three unprotected F240-treated animals there was a trend toward lowered viremia. The potential protective effect of F240 may relate to the relatively strong ability of this antibody to capture infectious virions. Additional passive transfer experiments also indicated that the ability of the administered anti-gp120 MAbs to neutralize the challenge virus was a critical influence on protection. Furthermore, when data from all of the experiments were combined, there was a significant increase in the number of founder viruses establishing infection in animals receiving MAb b6, compared with other nonprotected macaques. Thus, a gp120-binding, weakly neutralizing MAb to the CD4bs was, at best, completely ineffective at protection. A nonneutralizing antibody to gp41 may have a limited capacity to protect, but the results suggest that the central focus of HIV-1 vaccine research should be on the induction of potently neutralizing antibodies. C1 [Burton, Dennis R.; Hessell, Ann J.; Moldt, Brian; Dunlop, D. Cameron; Poignard, Pascal] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.; Hessell, Ann J.; Moldt, Brian; Dunlop, D. Cameron; Poignard, Pascal] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Burton, Dennis R.; Dunlop, D. Cameron] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA 02114 USA. [Hessell, Ann J.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. [Keele, Brandon F.] NCI, AIDS & Canc Virus Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Klasse, Per Johan; Ketas, Thomas A.; Moore, John P.] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. [Doyle, Lara A.; Veazey, Ronald S.] Tulane Univ, Sch Med, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. [Cavacini, Lisa] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM burton@scripps.edu; jpm2003@med.cornell.edu RI poignard, pascal/N-6678-2013 FU International AIDS Vaccine Initiative; National Institutes of Health [U19 AI76982, R37 AI36082, AI33292, AI1055332]; National Cancer Institute, National Institutes of Health [HHSN266200400088C]; Alfred Benzon Foundation FX We thank Athe Tsibris and Steven Wolinsky for contributing founder virus data for the gel control group (Fig. 4); Leo Stamatatos for the SHIV-162P4 challenge stock; and Kelsi Rasmussen and Janell LeBlanc for their technical support. The animal studies were funded by the International AIDS Vaccine Initiative, with additional support by National Institutes of Health Cooperative Agreement U19 AI76982 (to J.P.M.); in vitro studies were also supported by National Institutes of Health Grants R37 AI36082 (to J.P.M.) and AI33292 and AI1055332 (to D.R.B.); sequencing and founder virus analysis was performed with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN266200400088C. B.M. was supported by the Alfred Benzon Foundation. NR 43 TC 149 Z9 150 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 5 PY 2011 VL 108 IS 27 BP 11181 EP 11186 DI 10.1073/pnas.1103012108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 787LC UT WOS:000292376700053 PM 21690411 ER PT J AU Lesser, CF Leong, JM AF Lesser, Cammie F. Leong, John M. TI Bacterial Scaffolds Assemble Novel Higher-Order Complexes to Reengineer Eukaryotic Cell Processes SO SCIENCE SIGNALING LA English DT Article ID ENTEROPATHOGENIC ESCHERICHIA-COLI; III SECRETION EFFECTORS; N-WASP; PEDESTAL FORMATION; ACTIVATION; FAMILY; ESPF(U); PROTEIN; LINKS; TIR AB Many microbial pathogens use specialized secretion systems to inject proteins referred to as effectors directly into eukaryotic host cells. These effectors directly target various eukaryotic signaling pathways and cellular processes, often by mimicking the activity of host cell proteins. Effectors of pathogenic Escherichia coli and Salmonella typhimurium can also act as molecular scaffolds that not only recruit but also directly regulate the activity and localization of multiple eukaryotic proteins. By assembling and localizing disparate signaling pathways, the bacteria can reengineer host cell processes to generate novel processes not previously observed in eukaryotic cells. C1 [Lesser, Cammie F.] Massachusetts Gen Hosp, Dept Med Microbiol & Mol Genet, Div Infect Dis, Cambridge, MA 02139 USA. [Lesser, Cammie F.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Leong, John M.] Univ Massachusetts, Dept Microbiol & Physiol Syst, Sch Med, Worcester, MA 01655 USA. RP Lesser, CF (reprint author), Massachusetts Gen Hosp, Dept Med Microbiol & Mol Genet, Div Infect Dis, 65 Landsdowne St, Cambridge, MA 02139 USA. EM clesser@partners.org FU NIH [R01 64285, R01 AI46454] FX This work was supported by NIH R01 64285 to C.F.L. and NIH R01 AI46454 to J.M.L. NR 31 TC 0 Z9 0 U1 0 U2 2 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 JUL 5 PY 2011 VL 4 IS 180 AR pe32 DI 10.1126/scisignal.2002252 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 787MQ UT WOS:000292381100003 PM 21730324 ER PT J AU Kometani, K Yamada, T Sasaki, Y Yokosuka, T Saito, T Rajewsky, K Ishiai, M Hikida, M Kurosaki, T AF Kometani, Kohei Yamada, Takayuki Sasaki, Yoshiteru Yokosuka, Tadashi Saito, Takashi Rajewsky, Klaus Ishiai, Masamichi Hikida, Masaki Kurosaki, Tomohiro TI CIN85 drives B cell responses by linking BCR signals to the canonical NF-kappa B pathway SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ADAPTER PROTEIN; DOWN-REGULATION; POSITIVE SELECTION; KINASE-BETA; PKC-BETA; IN-VIVO; C-CBL; RECEPTOR; ACTIVATION; UBIQUITIN AB CIN85, an adaptor protein which binds the C-terminal domain of tyrosine phosphorylated Cbl and Cbl-b, has been thought to be involved in the internalization and subsequent degradation of receptors. However, its physiological function remains unclear. To determine its role in B cells, we used Mb1-cre to generate mice with a B cell-specific deletion of CIN85. These mice had impaired T cell-independent type II antibody responses in vivo and diminished IKK-beta activation and cellular responses to B cell receptor (BCR) cross-linking in vitro. Introduction of a constitutively active IKK-beta construct corrected the defective antibody responses as well as cellular responses in the mutant mice. Together, our results suggest that CIN85 links the BCR to IKK-beta activation, thereby contributing to T cell-independent immune responses. C1 [Kometani, Kohei; Yamada, Takayuki; Hikida, Masaki; Kurosaki, Tomohiro] RIKEN Res Ctr Allergy & Immunol, Turumi Ku, Lab Lymphocyte Differentiat, Kanagawa 2300045, Japan. [Yokosuka, Tadashi; Saito, Takashi] RIKEN Res Ctr Allergy & Immunol, Turumi Ku, Lab Cell Signaling, Kanagawa 2300045, Japan. [Yamada, Takayuki; Ishiai, Masamichi; Hikida, Masaki; Kurosaki, Tomohiro] Kansai Med Univ, Inst Liver Res, Dept Mol Genet, Osaka 5708506, Japan. [Sasaki, Yoshiteru; Rajewsky, Klaus] Harvard Univ, Childrens Hosp, Program Mol & Cellular Med, Sch Med, Boston, MA 02115 USA. [Sasaki, Yoshiteru; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Kurosaki, Tomohiro] Osaka Univ, WPI Immunol Frontier Res Ctr, Lab Lymphocyte Differentiat, Suita, Osaka 5650871, Japan. RP Kurosaki, T (reprint author), RIKEN Res Ctr Allergy & Immunol, Turumi Ku, Lab Lymphocyte Differentiat, Kanagawa 2300045, Japan. EM kurosaki@rcai.riken.jp RI Kurosaki, Tomohiro/D-1306-2009; Saito, Takashi/C-9684-2009 OI Kurosaki, Tomohiro/0000-0002-6352-304X; Saito, Takashi/0000-0001-9495-3547 FU Ministry of Education, Culture, Sports, Science, and Technology in Japan; Japan Science and Technology Agency, Core Research of Evolutional Science and Technology; RIKEN FX This work was supported by grant-in-Aid to T. Kurosaki from the Ministry of Education, Culture, Sports, Science, and Technology in Japan and by a grant to T. Kurosaki from Japan Science and Technology Agency, Core Research of Evolutional Science and Technology. This work was also supported by RIKEN Special Postdoctoral Researchers Program to K. Kometani. NR 51 TC 13 Z9 13 U1 1 U2 5 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 JUL 4 PY 2011 VL 208 IS 7 BP 1447 EP 1457 DI 10.1084/jem.20102665 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 791BZ UT WOS:000292637000011 PM 21708930 ER PT J AU Daniel, C Weigmann, B Bronson, R von Boehmer, H AF Daniel, Carolin Weigmann, Benno Bronson, Roderick von Boehmer, Harald TI Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID REGULATORY T-CELLS; NOD MICE; IN-VIVO; FOXP3 EXPRESSION; PEPTIDE; TOLERANCE; ANTIGEN; INDUCTION; EPITOPE; SUPPRESSION AB Type 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic. cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-A(g7) molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3(+) regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease. C1 [Daniel, Carolin; von Boehmer, Harald] Dana Farber Canc Inst, Lab Lymphocyte Biol, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [von Boehmer, Harald] Harvard Univ, Harvard Fac Arts & Sci, Cambridge, MA 02138 USA. [Weigmann, Benno] Univ Erlangen Nurnberg, Med Clin 1, D-91052 Erlangen, Germany. [Daniel, Carolin; Bronson, Roderick] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP von Boehmer, H (reprint author), Dana Farber Canc Inst, Lab Lymphocyte Biol, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM harald_von_boehmer@dfci.harvard.edu RI Daniel, Carolin/M-4624-2014 OI Daniel, Carolin/0000-0003-4698-7069 FU National Institutes of Health [AI-53102]; BMBF-LPD [9901/8-184]; Federal State of Hessen, Germany FX The studies were supported by National Institutes of Health grant AI-53102 (to H. von Boehmer). C. Daniel was supported by a Leopoldina research fellowship (BMBF-LPD 9901/8-184) and by the LOEWE (LipidSignaling Forschungszentrum Frankfurt) program of the Federal State of Hessen, Germany. NR 54 TC 54 Z9 56 U1 0 U2 7 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 JUL 4 PY 2011 VL 208 IS 7 BP 1501 EP 1510 DI 10.1084/jem.20110574 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 791BZ UT WOS:000292637000015 PM 21690251 ER PT J AU Kabrhel, C Varraso, R Goldhaber, SZ Rimm, E Camargo, CA AF Kabrhel, Christopher Varraso, Raphaelle Goldhaber, Samuel Z. Rimm, Eric Camargo, Carlos A., Jr. TI Physical inactivity and idiopathic pulmonary embolism in women: prospective study SO BRITISH MEDICAL JOURNAL LA English DT Article ID DEEP-VEIN THROMBOSIS; CARDIOVASCULAR RISK-FACTORS; VENOUS-BLOOD FLOW; THROMBOEMBOLISM; EXERCISE; DISEASE; POPULATION; FIBRINOLYSIS; HEMOSTASIS; FIBRINOGEN AB Objectives To determine the association between physical inactivity (that is, a sedentary lifestyle) and incident idiopathic pulmonary embolism. Design Prospective cohort study. Setting Nurses' Health Study. Participants 69 950 female nurses who completed biennial questionnaires from 1990 to 2008. Main outcome measures The primary outcome was idiopathic pulmonary embolism confirmed in medical records. Multivariable Cox proportional hazards models controlled for age, body mass index (BMI), energy intake, smoking, pack years, race, spouse's educational attainment, parity, menopause, non-aspirin non-steroidal anti-inflammatory drugs, warfarin, multivitamin supplements, hypertension, coronary heart disease, rheumatological disease, and dietary patterns. The primary exposure was physical inactivity, measured in hours of sitting each day. The secondary exposure was physical activity, measured in metabolic equivalents a day. Results Over the 18 year study period, there were 268 cases of incident idiopathic pulmonary embolism. There was an association between time of sitting and risk of idiopathic pulmonary embolism (41/104 720 v 16/14 565 cases in most inactive v least inactive in combined data; P<0.001 for trend). The risk of pulmonary embolism was more than twofold in women who spent the most time sitting compared with those who spent the least time sitting (multivariable hazard ratio 2.34, 95% confidence interval 1.30 to 4.20). There was no association between physical activity and pulmonary embolism (P=0.53 for trend). Conclusions Physical inactivity is associated with incident pulmonary embolism in women. Interventions that decrease time sitting could lower the risk of pulmonary embolism. C1 [Kabrhel, Christopher; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Goldhaber, Samuel Z.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc,Dept Med, Boston, MA 02115 USA. [Varraso, Raphaelle] INSERM, CESP Ctr Res Epidemiol & Populat Hlth, U1018, Resp & Environm Epidemiol Team, F-94807 Villejuif, France. [Varraso, Raphaelle] Univ Paris 11, UMRS 1018, F-94807 Villejuif, France. [Rimm, Eric] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rimm, Eric] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Rimm, Eric; Camargo, Carlos A., Jr.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. RP Kabrhel, C (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM ckabrhel@partners.org RI Varraso, Raphaelle/R-8740-2016; OI Varraso, Raphaelle/0000-0002-3338-7825; Kabrhel, Christopher/0000-0002-8699-7176 FU National Institute on Aging, National Institutes of Health, Bethesda, MD [R21AG031079, P01CA87969, R01HL034594] FX This study was funded by the National Institute on Aging, National Institutes of Health, Bethesda, MD (R21AG031079, P01CA87969, and R01HL034594). The funding source had no role in design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript. NR 40 TC 25 Z9 25 U1 0 U2 9 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUL 4 PY 2011 VL 343 AR d3867 DI 10.1136/bmj.d3867 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 791RR UT WOS:000292682800005 PM 21727169 ER PT J AU Aujesky, D Roy, PM Verschuren, F Righini, M Osterwalder, J Egloff, M Renaud, B Verhamme, P Stone, RA Legal, C Sanchez, O Pugh, NA N'gako, A Cornuz, J Hugii, O Beer, HJ Perrier, A Fine, MJ Yealy, DM AF Aujesky, Drahomir Roy, Pierre-Marie Verschuren, Franck Righini, Marc Osterwalder, Joseph Egloff, Michael Renaud, Bertrand Verhamme, Peter Stone, Roslyn A. Legal, Catherine Sanchez, Olivier Pugh, Nathan A. N'gako, Alfred Cornuz, Jacques Hugii, Olivier Beer, Hans-Juerg Perrier, Arnaud Fine, Michael J. Yealy, Donald M. TI Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial SO LANCET LA English DT Article ID MOLECULAR-WEIGHT HEPARIN; DEEP-VEIN THROMBOSIS; INTRAVENOUS UNFRACTIONATED HEPARIN; VENOUS THROMBOEMBOLIC DISEASE; CLINICAL PROGNOSTIC MODEL; LOW-RISK PATIENTS; EARLY DISCHARGE; ANTICOAGULANT-THERAPY; INITIAL TREATMENT; SEVERITY INDEX AB Background Although practice guidelines recommend outpatient care for selected, haemodynamically stable patients with pulmonary embolism, most treatment is presently inpatient based. We aimed to assess non-inferiority of outpatient care compared with inpatient care. Methods We undertook an open-label, randomised non-inferiority trial at 19 emergency departments in Switzerland, France, Belgium, and the USA. We randomly assigned patients with acute, symptomatic pulmonary embolism and a low risk of death (pulmonary embolism severity index risk classes I or II) with a computer-generated randomisation sequence (blocks of 2-4) in a 1:1 ratio to initial outpatient (ie, discharged from hospital <= 24 h after randomisation) or inpatient treatment with subcutaneous enoxaparin (>= 5 days) followed by oral anticoagulation (>= 90 days). The primary outcome was symptomatic, recurrent venous thromboembolism within 90 days; safety outcomes included major bleeding within 14 or 90 days and mortality within 90 days. We used a non-inferiority margin of 4% for a difference between inpatient and outpatient groups. We included all enrolled patients in the primary analysis, excluding those lost to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00425542. Findings Between February, 2007, and June, 2010, we enrolled 344 eligible patients. In the primary analysis, one (0.6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2-7%; p=0.011). Only one (0.6%) patient in each treatment group died within 90 days (95% UCL 2.1%; p=0.005), and two (1.2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3.6%; p=0.031). By 90 days, three (1.8%) outpatients but no inpatients had developed major bleeding (95% UCL 4.5%; p=0.086). Mean length of stay was 0.5 days (SD 1.0) for outpatients and 3.9 days (SD 3.1) for inpatients. Interpretation In selected low-risk patients with pulmonary embolism, outpatient care can safely and effectively be used in place of inpatient care. C1 [Aujesky, Drahomir] Univ Hosp Bern, Univ Klin Allgemeine Innere Med, Inselspital, CH-3010 Bern, Switzerland. [Roy, Pierre-Marie] LUNAM Univ, Angers, France. [Roy, Pierre-Marie] Univ Angers, Angers, France. [Verschuren, Franck] Univ Louvain, Brussels, Belgium. [Righini, Marc; Perrier, Arnaud] Univ Geneva, Geneva, Switzerland. [Osterwalder, Joseph] Cantonal Hosp St Gallen, St Gallen, Switzerland. [Egloff, Michael; Beer, Hans-Juerg] Cantonal Hosp Baden, Baden, Switzerland. [Renaud, Bertrand; N'gako, Alfred] Univ Hosp Henri Mondor, Creteil, France. [Verhamme, Peter] Univ Louvain, Louvain, Belgium. [Fine, Michael J.] Univ Pittsburgh, VA Ctr Hlth Equity Res & Promot, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Fine, Michael J.] Univ Pittsburgh, Div Gen Internal Med, Sch Med, Pittsburgh, PA 15260 USA. [Stone, Roslyn A.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15260 USA. [Yealy, Donald M.] Univ Pittsburgh, Dept Emergency Med, Pittsburgh, PA 15260 USA. [Legal, Catherine] Univ Argenteuil, Argenteuil, France. [Sanchez, Olivier] Hop Europeen Georges Pompidou, Paris, France. [Cornuz, Jacques; Hugii, Olivier] Univ Lausanne, Lausanne, Switzerland. RP Aujesky, D (reprint author), Univ Hosp Bern, Univ Klin Allgemeine Innere Med, Inselspital, CH-3010 Bern, Switzerland. EM drahomir.aujesky@insel.ch RI Perrier, Arnaud/M-2263-2014; OI Hugli, Olivier/0000-0003-2312-1625 FU Swiss National Science Foundation [3200B0-1121]; Programme Hospitalier de Recherche Clinique [21-03]; US National Heart, Lung, and Blood Institute [1R01HL085565-01A2]; GlaxoSmithKline; Sanofi-Aventis; Bayer; Biomerieux; Boehringer Ingelheim; Eli Lilly; LFB Biomedicaments; Daiichi-Sankyo; ThromboGenics; Leo; Pfizer; MSD; Menarini FX Swiss National Science Foundation, Programme Hospitalier de Recherche Clinique, and the US National Heart, Lung, and Blood Institute. Sanofi-Aventis provided free drug supply in the participating European centres.; DA has received honoraria from Sanofi-Aventis and Bayer. PM R has received grants, honoraria, consultancy fees, and payments from GlaxoSmithKline, Sanofi-Aventis, Bayer, Biomerieux, Boehringer Ingelheim, Eli Lilly, and LFB Biomedicaments. PV has received grants, consultancy fees, and payments from Sanofi-Aventis, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, ThromboGenics, Leo, and Pfizer. OH has received grants from Pfizer and MSD. HJB has received honoraria from Sariofi-Aventis, Bayer, Boehringer Ingelheim, Menarini, and GlaxoSmithKline.; This study was supported by grants from the Swiss National Science Foundation (3200B0-1121), the Programme Hospitalier de Recherche Clinique 2007 (21-03), and the US National Heart, Lung, and Blood Institute (1R01HL085565-01A2). Sanofi-Aventis provided free drug supply in the participating European centres. We thank Emmanuelle Le Moigne (Brest, France), David Elkharrat (Boulogne, France), Dominique Elkouri (Nantes, France), Mark Courtney (Chicago, IL, USA), Didier Honnart (Dijon, France), Jeannot Schmidt (Clermont-Ferrand, France), Jeffrey Kline (Charlotte, NC, USA), Yves Poitrineau (Thiers, France), and Bertrand Yersin (Lausanne, Switzerland). NR 43 TC 187 Z9 189 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUL 2 PY 2011 VL 378 IS 9785 BP 41 EP 48 DI 10.1016/S0140-6736(11)60824-6 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 791IU UT WOS:000292659700032 PM 21703676 ER PT J AU Deckersbach, T Stange, JP Nierenberg, AA AF Deckersbach, Thilo Stange, Jonathan P. Nierenberg, Andrew A. TI Norms for Performance in the Workplace in Healthy People: Data from the National Comorbidity Survey Replication Study SO CNS SPECTRUMS LA English DT Article ID WORK PERFORMANCE; REPRESENTATIVE SAMPLE; PSYCHIATRIC-DISORDERS; ORGANIZATION HEALTH; QUESTIONNAIRE HPQ; MOOD DISORDERS; NCS-R; PRODUCTIVITY; VERSION; CIDI AB Introduction: Psychiatric conditions affect multiple areas of psychosocial functioning, including functioning in the workplace. The purpose of this study was to establish norms for absenteeism (work days missed due to mental or physical illness) and work performance (quality of work performed when at work) for healthy individuals. Methods: We selected 300 individuals without psychiatric or medical conditions from the National Comorbidity Survey Replication study (NCS-R). Absenteeism and work performance were assessed using the NCS-R version of the Health and Work Performance Questionnaire (HPQ). Results: Employees missed an average of 5.1 days of work in the past year. Absenteeism varied across occupations, with performers of routine tasks, office clerks, and professionals exhibiting the greatest variance in days missed. Work performance ratings were skewed toward high performance ratings and did not differ across occupations. Gender, age, race/ethnicity, and education level did not substantially moderate absenteeism and work performance norms. Discussion: Skewed ratings for work performance are consistent with previous findings using the HPQ. This may reflect a general tendency that individuals rate themselves favorably when they compare themselves to others. Conclusion: This study provides normative tables for absenteeism and work performance in individuals without psychiatric or medical conditions, against which individuals with such conditions may be compared. C1 [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Depress Clin & Res Program, Boston, MA 02114 USA. [Deckersbach, Thilo; Nierenberg, Andrew A.] Harvard Univ, Sch Med, Boston, MA USA. [Stange, Jonathan P.] Temple Univ, Philadelphia, PA 19122 USA. RP Deckersbach, T (reprint author), Massachusetts Gen Hosp, Bipolar Clin & Res Program, Depress Clin & Res Program, Boston, MA 02114 USA. EM tdeckersbach@partners.org FU Cederroth; Cyberonics; Forest; Medtronics; National Alliance for Research on Schizophrenia and Depression; National Institute of Mental Health; Ortho-McNeil-Janssen; Pamlab; Pfizer; Shire; Stanley Foundation through the Broad Institute; Bristol-Myers Squibb; Eli Lilly; GlaxoSmithKline; Janssen; Lictwer Pharma; Wyeth; AstraZeneca; Cambridge University Press; Belvoir Publishing; National Institute of Mental Health (NIMH) [K-23] FX Dr. Deckersbach has been a consultant to BrainCells, Catalan Agency for Health Technology Assessment and Research, Medacorp, National Association of Social Workers Massachusetts, Oxford University Press, and Systems Research and Applications Corporation. Mr. Stange reports no affiliations with or financial interest in any organization that may pose a conflict of interest. Dr. Nierenberg consulted to or served on the advisory boards of Abbott, Appliance Computing, Brain Cells, Bristol-Myers Squibb, Eli Lilly, EpiQ, Forest, GlaxoSmithKline, Janssen, Jazz, Merck, Novartis, Pamlab, Pfizer, PGx Health, Pharmaceutica, Schering-Plough, Sepracor, Shire, Somerset, Takeda, and Targacept; has received research support from Cederroth, Cyberonics, Forest, Medtronics, the National Alliance for Research on Schizophrenia and Depression, the National Institute of Mental Health, Ortho-McNeil-Janssen, Pamlab, Pfizer, Shire, and the Stanley Foundation through the Broad Institute; has received past support from Bristol-Myers Squibb, Cederroth, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Lictwer Pharma, Pfizer, and Wyeth; has received honoraria from the MGH Psychiatry Academy (MGHPA activities are supported through Independent Medical Education grants from AstraZeneca, Eli Lilly, and Janssen); earns fees for editorial functions for CNS Spectrums through MBL Communications, and Psychiatric Annals through Slack; receives honoraria as a CME executive director for the Journal of Clinical Psychiatry through Physicians Postgraduate Press; has been on the speaker's bureaus of Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, and Wyeth; has received royalties from Cambridge University Press and Belvoir Publishing; owns stock options in Appliance Computing; and owns the copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery Asberg Depression Scale, exclusively licensed to the MGH Clinical Trials Network and Institute.; This work was supported by a K-23 Award from the National Institute of Mental Health (NIMH) to Dr. Deckersbach. Parts of this research have been presented at the annual meeting of the MGH Clinical Research Day, Boston, 2010, and at the annual meeting of the Association for Behavioral and Cognitive Therapies, San Francisco, 2010. NR 33 TC 1 Z9 1 U1 1 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD JUL PY 2011 VL 16 IS 7 BP 143 EP 152 DI 10.1017/S1092852912000314 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 951KI UT WOS:000304719000001 PM 24725499 ER PT J AU Tucker, J Peng, H Wang, K Chang, H Yang, LG Zhang, S Yang, B AF Tucker, J. Peng, H. Wang, K. Chang, H. Yang, L. G. Zhang, S. Yang, B. TI SEX WORKER COLLECTIVE ORGANIZATION IN THE ABSENCE OF NGOS: A QUALITATIVE ANALYSIS OF FEMALE SEX WORKER HOMETOWN SOCIAL NETWORKS IN SOUTH CHINA SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Tucker, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Peng, H.; Yang, L. G.; Zhang, S.; Yang, B.] Guangdong Prov STI Control Ctr, Guangzhou, Guangdong, Peoples R China. [Wang, K.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Chang, H.] Univ Wisconsin Madison, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2011 VL 87 SU 1 BP A231 EP A231 DI 10.1136/sextrans-2011-050108.306 PG 1 WC Infectious Diseases SC Infectious Diseases GA 926ZQ UT WOS:000302874201202 ER PT J AU Kozin, SV Duda, DG Munn, LL Jain, RK AF Kozin, Sergey V. Duda, Dan G. Munn, Lance L. Jain, Rakesh K. TI Is vasculogenesis crucial for the regrowth of irradiated tumours? SO NATURE REVIEWS CANCER LA English DT Letter ID STEM-LIKE CELLS; GLIOBLASTOMA; ANGIOGENESIS C1 [Kozin, Sergey V.; Duda, Dan G.; Munn, Lance L.; Jain, Rakesh K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Steele Lab Tumor Biol,Dept Radiat Oncol, Boston, MA 02114 USA. RP Jain, RK (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Steele Lab Tumor Biol,Dept Radiat Oncol, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu RI Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 FU NCI NIH HHS [R01 CA159258, P01 CA080124, R01 CA149285, R21 CA139168, R01 CA115767] NR 13 TC 9 Z9 10 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD JUL PY 2011 VL 11 IS 7 BP 532 EP 532 DI 10.1038/nrc3007-c1 PG 1 WC Oncology SC Oncology GA 782RP UT WOS:000292028300018 PM 21701514 ER PT J AU Carp, SA Roche-Labarbe, N Franceschini, MA Srinivasan, VJ Sakadzic, S Boas, DA AF Carp, Stefan A. Roche-Labarbe, Nadege Franceschini, Maria-Angela Srinivasan, Vivek J. Sakadzic, Sava Boas, David A. TI Due to intravascular multiple sequential scattering, Diffuse Correlation Spectroscopy of tissue primarily measures relative red blood cell motion within vessels SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID WAVE SPECTROSCOPY; FLOW; HEMATOCRIT; ARTERIAL; BRAIN; MODEL AB We suggest that Diffuse Correlation Spectroscopy (DCS) measurements of tissue blood flow primarily probe relative red blood cell (RBC) motion, due to the occurrence of multiple sequential scattering events within blood vessels. The magnitude of RBC shear-induced diffusion is known to correlate with flow velocity, explaining previous reports of linear scaling of the DCS "blood flow index" with tissue perfusion despite the observed diffusion-like auto-correlation decay. Further, by modeling RBC mean square displacement using a formulation that captures the transition from ballistic to diffusive motion, we improve the fit to experimental data and recover effective diffusion coefficients and velocity de-correlation time scales in the range expected from previous blood rheology studies. (C) 2011 Optical Society of America C1 [Carp, Stefan A.; Roche-Labarbe, Nadege; Franceschini, Maria-Angela; Srinivasan, Vivek J.; Sakadzic, Sava; Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Carp, SA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Bldg 149,13th St, Charlestown, MA 02129 USA. EM carp@nmr.mgh.harvard.edu RI Roche-Labarbe, Nadege/N-9101-2015 OI Roche-Labarbe, Nadege/0000-0002-5010-0400 FU NIH [K99EB011889, R01HD042908, P41RR14075, K99NS067050] FX The authors acknowledge funding from NIH grants K99EB011889, R01HD042908, P41RR14075 and K99NS067050. NR 24 TC 17 Z9 17 U1 0 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUL 1 PY 2011 VL 2 IS 7 BP 2047 EP 2054 PG 8 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886UN UT WOS:000299879500023 PM 21750779 ER PT J AU Peters, AT Nierenberg, AA Deckersbach, T AF Peters, Amy T. Nierenberg, Andrew A. Deckersbach, Thilo TI A 32-Year-Old Male with Mania, Leg Pain, Migraines SO PSYCHIATRIC ANNALS LA English DT Article ID BIPOLAR-I DISORDER; ANTIPSYCHOTIC-INDUCED AKATHISIA; ANXIETY DISORDERS; COMORBIDITY; ILLNESS; IMPACT; PREVALENCE; SCHIZOPHRENIA; EPIDEMIOLOGY; METAANALYSIS C1 [Peters, Amy T.; Nierenberg, Andrew A.; Deckersbach, Thilo] Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. [Peters, Amy T.; Nierenberg, Andrew A.; Deckersbach, Thilo] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. [Nierenberg, Andrew A.; Deckersbach, Thilo] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Peters, AT (reprint author), Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. NR 37 TC 0 Z9 0 U1 2 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JUL PY 2011 VL 41 IS 7 BP 363 EP 366 DI 10.3928/00485713-20110627-09 PG 4 WC Psychiatry SC Psychiatry GA 885HB UT WOS:000299768500015 ER PT J AU Dai, TH Kharkwal, GB Tanaka, M Huang, YY de Arce, VJB Hamblin, MR AF Dai, Tianhong Kharkwal, Gitika B. Tanaka, Masamitsu Huang, Ying-Ying de Arce, Vida J. Bil Hamblin, Michael R. TI Animal models of external traumatic wound infections SO VIRULENCE LA English DT Review DE animal models; wounds; burns; infection; bacteria; fungi ID RESISTANT STAPHYLOCOCCUS-AUREUS; BIOLUMINESCENT ESCHERICHIA-COLI; SURGICAL SITE INFECTION; FOREIGN-BODY INFECTION; BURNED MOUSE MODEL; GUINEA-PIG MODEL; PSEUDOMONAS-AERUGINOSA INFECTION; ANTIMICROBIAL PEPTIDE D2A21; CHITOSAN ACETATE BANDAGE; FULL-THICKNESS BURN AB Background: Despite advances in traumatic wound care and management, infections remain a leading cause of mortality, morbidity and economic disruption in millions of wound patients around the world. Animal models have become standard tools for studying a wide array of external traumatic wound infections and testing new antimicrobial strategies. Results: Animal models of external traumatic wound infections reported by different investigators vary in animal species used, microorganism strains, the number of microorganisms applied, the size of the wounds and for burn infections, the length of time the heated object or liquid is in contact with the skin. Methods: This review covers experimental infections in animal models of surgical wounds, skin abrasions, burns, lacerations, excisional wounds and open fractures. Conclusions: As antibiotic resistance continues to increase, more new antimicrobial approaches are urgently needed. These should be tested using standard protocols for infections in external traumatic wounds in animal models. C1 [Dai, Tianhong; Kharkwal, Gitika B.; Tanaka, Masamitsu; Huang, Ying-Ying; de Arce, Vida J. Bil; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Dai, Tianhong; Kharkwal, Gitika B.; Huang, Ying-Ying; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Tanaka, Masamitsu] Natl Def Med Coll, Dept Orthoped Surg, Saitama, Japan. [Huang, Ying-Ying] Guangxi Med Univ, Aesthet & Plast Ctr, Nanning, Peoples R China. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI Huang, Ying-ying/G-3153-2011; OI Huang, Ying-ying/0000-0003-3066-6981; Hamblin, Michael/0000-0001-6431-4605 FU NIH [RO1AI050875]; US Air Force MFEL [FA9550-04-1-0079]; Bullock-Wellman Fellowship; Airlift Research Foundation [109421] FX Research in the Hamblin laboratory is supported by the NIH (grant RO1AI050875) and the US Air Force MFEL program (contract FA9550-04-1-0079). T. D. was partially supported by a Bullock-Wellman Fellowship Award and an Airlift Research Foundation Extremity Trauma Research Grant (grant #109421). NR 149 TC 29 Z9 30 U1 4 U2 22 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD JUL-AUG PY 2011 VL 2 IS 4 BP 296 EP 315 DI 10.4161/viru.2.4.16840 PG 20 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 878LB UT WOS:000299257400005 PM 21701256 ER PT J AU Ndung'u, T AF Ndung'u, Thumbi TI TRIM E3 ligases in HIV infection Can these intrinsic immunity factors be harnessed for novel antiviral strategies? SO VIRULENCE LA English DT Article DE TRIM5a; TRIM22; TRIM E3 ligases; type 1 interferon; HIV; innate immunity; antiviral mechanisms; HIV pathogenesis ID IMMUNODEFICIENCY-VIRUS-INFECTION; RESTRICTION FACTOR TRIM5-ALPHA; RETROVIRAL RESTRICTION; PRIMATE TRIM5-ALPHA; MONKEY TRIM5-ALPHA; FAMILY PROTEINS; INNATE IMMUNITY; AIDS VACCINE; MOTIF; CELLS AB Tripartite motif-containing (TRIM) E3 ligases are a recently identified family of proteins with potent antiviral activity in mammalian cells. The prototype TRIM E3 ligase, TRIM5a was initially identified as a species-specific antiviral restriction factor in Old World monkeys but subsequent studies suggest some antiviral activity by several TRIM E3 ligases in human cells. However, the mechanisms of antiviral activity by these proteins and their transcriptional, translational and post-translational regulation are poorly understood. Furthermore, the contribution of TRIM E3 ligases to relative resistance or viral control in vivo is largely unknown. Emerging data from our laboratory and other groups suggest that these proteins may have antiviral activity in vivo and contribute to HIV pathogenesis. Considering the significant difficulties so far encountered in developing an effective HIV vaccine and with the use of antiretroviral therapies, it will be important to further investigate the potential of TRIM E3 ligases as novel prophylactics or therapies. C1 [Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Nelson R Mandela Sch Med, Durban, South Africa. [Ndung'u, Thumbi] Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Ndung'u, Thumbi] MIT, Boston, MA USA. [Ndung'u, Thumbi] Harvard Univ, Boston, MA 02115 USA. RP Ndung'u, T (reprint author), Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Nelson R Mandela Sch Med, Durban, South Africa. EM ndungu@ukzn.ac.za NR 63 TC 3 Z9 3 U1 3 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD JUL-AUG PY 2011 VL 2 IS 4 BP 360 EP 366 DI 10.4161/viru.2.4.16372 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 878LB UT WOS:000299257400011 PM 21758007 ER PT J AU Chiang, S Fazlollahi, L Nguyen, A Betensky, RA Roberts, DJ Iafrate, AJ AF Chiang, Sarah Fazlollahi, Ladan Anhthu Nguyen Betensky, Rebecca A. Roberts, Drucilla J. Iafrate, A. John TI Diagnosis of Hydatidiform Moles by Polymorphic Deletion Probe Fluorescence in Situ Hybridization SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID GESTATIONAL TROPHOBLASTIC DISEASE; MOLAR PREGNANCY; SUBSEQUENT PREGNANCY; HUMAN GENOME; P57 IMMUNOHISTOCHEMISTRY; P57(KIP2); NEOPLASIA; RISK AB Because products of conception often contain maternal and vinous tissues, the determination of maternal and vinous genotypes based on genetic polymorphisms can help discern maternal and paternal chromosomal contribution and aid in the diagnosis of hydatidiform moles. Polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes based on copy number variants are highly polymorphic and allow in situ determination of genetic identity. By using three informative PDPs on chromosomes 2p, 4q, and 8p, we compared maternal with vinous genotypes and determined the ploidy of vinous tissue. PDP FISH was performed on 13 complete moles, 13 partial moles, 13 nonmolar abortions, and an equivocal hydropic abortion. PDP FISH permitted definitive diagnosis of complete moles in five of 13 cases for which maternal and vinous genotypes were mutually exclusive. A complete mole was highly suspected when all three PDP loci showed homozygous vinous genotypes. The diagnosis of a complete mole by PDP FISH yielded a theoretical test sensitivity of 87.5%, specificity of 91.8%, an observed test sensitivity of 100%, and specificity of 92.3%. Triploidy was observed in all partial moles, in which diandric triploidy was confirmed in six cases. In the equivocal hydropic abortion, PDP FISH combined with p57 immunofluorescence revealed placental androgenetic/biparental mosaicism. PDP FISH can be used in clinical practice and research studies to subclassify hydatidiform moles and evaluate unusual products of conception. (J Mol Diagn 2011, 13:406-415; DOI: 10.1016/j.jmoldx.2011.02.002) C1 [Iafrate, A. John] Harvard Univ, Massachusetts Gen Hosp, Mol Diagnost Lab, Dept Pathol,Med Sch, Boston, MA 02114 USA. [Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Iafrate, AJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Mol Diagnost Lab, Dept Pathol,Med Sch, 55 Fruit St,Warren 501c, Boston, MA 02114 USA. EM aiafrate@partners.org NR 38 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD JUL PY 2011 VL 13 IS 4 BP 406 EP 415 DI 10.1016/j.jmoldx.2011.02.002 PG 10 WC Pathology SC Pathology GA 865JF UT WOS:000298306500008 PM 21704275 ER PT J AU Buxbaum, LU DeRitis, PC Chu, NS Conti, PA AF Buxbaum, Laurence U. DeRitis, Pierina C. Chu, Niansheng Conti, Pierre A. TI Eliminating Murine Norovirus by Cross-Fostering SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID MICE; INFECTION; VIRUS; ERADICATION; PREVALENCE; IMMUNITY AB Murine norovirus (MNV) is a newly discovered and extremely prevalent pathogen of laboratory mouse colonies. MNV causes severe disease in some immunocompromised mouse strains and can cause persistent infections even in immunocompetent mice. Despite the fact that immunocompetent mice are generally asymptomatic, the possibility that MNV infection might alter immune responses makes its eradication a potentially useful goal for many facilities. Initial attempts by others to use a strategy of testing and culling were unsuccessful, whereas complete depopulation and facility decontamination was successful. However, these measures may be impractical, and finding less drastic approaches seemed prudent. Based on a report that cross-fostering of pups from MNV-positive mothers to MNV-negative ones could be successful in experimental MNV infection, we undertook a comprehensive fostering program using Swiss Webster mothers, careful sanitary measures, and fecal PCR testing to eradicate the virus from a mouse colony recently infected with MNV. We successfully decontaminated 17 of 18 (94%) litters and managed to prevent spread when a new MNV-infected mouse strain entered quarantine at our facility. These results suggest that cross-fostering, when performed in a setting of excellent sanitary procedures, may be practical for the large number of mouse facilities in which MNV is endemic. C1 [Buxbaum, Laurence U.; DeRitis, Pierina C.; Chu, Niansheng; Conti, Pierre A.] Univ Penn, Sch Med, Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Buxbaum, Laurence U.; Chu, Niansheng] Univ Penn, Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. RP Buxbaum, LU (reprint author), Univ Penn, Sch Med, Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. EM buxbaum@mail.med.upenn.edu FU Veterans Affairs Merit Award; Veterans Affairs Medical Center FX This work was funded by a Veterans Affairs Merit Award and by Veterans Affairs Medical Center facilities funding. We thank the Animal Research Facility staff for their careful attention to protocol in allowing our efforts to be successful. We also thank Dr Susan R Compton for advice on fostering procedures. The content of this article does not necessarily reflect the views of the Department of Veterans Affairs or of the US Government. NR 13 TC 6 Z9 6 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD JUL PY 2011 VL 50 IS 4 BP 495 EP 499 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 875JP UT WOS:000299026500011 PM 21838978 ER PT J AU Hu, YY Weeks, CM In, H Dodgion, CM Golshan, M Chun, YS Hassett, MJ Corso, KA Gu, XM Lipsitz, SR Greenberg, CC AF Hu, Yue-Yung Weeks, Christine M. In, Haejin Dodgion, Christopher M. Golshan, Mehra Chun, Yoon S. Hassett, Michael J. Corso, Katherine A. Gu, Xiangmei Lipsitz, Stuart R. Greenberg, Caprice C. TI Impact of Neoadjuvant Chemotherapy on Breast Reconstruction SO CANCER LA English DT Article DE neoadjuvant chemotherapy; breast reconstruction; breast cancer; mastectomy; postoperative complications ID IMMEDIATE RECONSTRUCTION; ADJUVANT CHEMOTHERAPY; PREOPERATIVE CHEMOTHERAPY; PSYCHOSOCIAL OUTCOMES; WOUND COMPLICATIONS; FOLLOW-UP; TRAM FLAP; MASTECTOMY; CANCER; CARCINOMA AB BACKGROUND: With advances in oncologic treatment, cosmesis after mastectomy has assumed a pivotal role in patient and provider decision making. Multiple studies have confirmed the safety of both chemotherapy before breast surgery and immediate reconstruction. Little has been written about the effect of neoadjuvant chemotherapy on decisions about reconstruction. METHODS: The authors identified 665 patients with stage I through III breast cancer who received chemotherapy and underwent mastectomy at Dana-Farber/Brigham & Women's Cancer Center from 1997 to 2007. By using multivariate logistic regression, reconstruction rates were compared between patients who received neoadjuvant chemotherapy (n = 180) and patients who underwent mastectomy before chemotherapy (n = 485). The rate of postoperative complications after mastectomy was determined for patients who received neoadjuvant chemotherapy compared with those who did not. RESULTS: Reconstruction was performed immediately in 44% of patients who did not receive neoadjuvant chemotherapy but in only 23% of those who did. Twenty-one percent of neoadjuvant chemotherapy recipients and 14% of adjuvant-only chemotherapy recipients underwent delayed reconstruction. After controlling for age, receipt of radiotherapy, and disease stage, neoadjuvant recipients were less likely to undergo immediate reconstruction (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.37, 0.87) but were no more likely to undergo delayed reconstruction (OR, 1.29; 95% CI, 0.75, 2.20). Surgical complications occurred in 30% of neoadjuvant chemotherapy recipients and in 31% of adjuvant chemotherapy recipients. CONCLUSIONS: The current results suggest that patients who receive neoadjuvant chemotherapy are less likely to undergo immediate reconstruction and are no more likely to undergo delayed reconstruction than patients who undergo surgery before they receive chemotherapy. Cancer 2011;117:2833-41. (C) 2011 American Cancer Society C1 [Hu, Yue-Yung; Weeks, Christine M.; In, Haejin; Dodgion, Christopher M.; Corso, Katherine A.; Gu, Xiangmei; Lipsitz, Stuart R.; Greenberg, Caprice C.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Dept Surg, Boston, MA 02115 USA. [Hu, Yue-Yung] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Golshan, Mehra; Greenberg, Caprice C.] Brigham & Womens Hosp, Div Surg Oncol, Boston, MA 02115 USA. [Chun, Yoon S.] Brigham & Womens Hosp, Div Plast & Reconstruct Surg, Boston, MA 02115 USA. [Hassett, Michael J.; Greenberg, Caprice C.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. RP Greenberg, CC (reprint author), Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Dept Surg, 1 Brigham Circle,1620 Tremont St,Suite 4-020, Boston, MA 02115 USA. EM ccgreenberg@partners.org RI Dodgion, Chris/A-2877-2016 OI Dodgion, Chris/0000-0002-5789-7731 FU NCI NIH HHS [L30 CA123695, R25 CA092203, R25 CA092203-09, T32 CA009535, T32 CA009535-23, T32 CA090217]; NCRR NIH HHS [L30 RR031458-01]; NIDDK NIH HHS [T32 DK007754-12, T32 DK007754] NR 36 TC 16 Z9 18 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 1 PY 2011 VL 117 IS 13 BP 2833 EP 2841 DI 10.1002/cncr.25872 PG 9 WC Oncology SC Oncology GA 783BJ UT WOS:000292056200005 PM 21264833 ER PT J AU Lee, CG Boyko, EJ Strotmeyer, ES Lewis, CE Cawthon, PM Hoffman, AR Everson-Rose, SA Barrett-Connor, E Orwoll, ES AF Lee, Christine G. Boyko, Edward J. Strotmeyer, Elsa S. Lewis, Cora E. Cawthon, Peggy Mannen Hoffman, Andrew R. Everson-Rose, Susan A. Barrett-Connor, Elizabeth Orwoll, Eric S. CA Osteoporotic Fractures Men Study TI Association Between Insulin Resistance and Lean Mass Loss and Fat Mass Gain in Older Men without Diabetes Mellitus SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE older men; lean mass; fat mass; insulin resistance; body composition ID HOMEOSTASIS MODEL ASSESSMENT; HIGH FASTING INSULIN; BODY-COMPOSITION; WEIGHT-GAIN; OSTEOPOROTIC FRACTURES; METABOLIC SYNDROME; GLUCOSE-TOLERANCE; ELDERLY-MEN; LOWER RATES; AMINO-ACID AB OBJECTIVES: To examine the associations between insulin resistance and changes in body composition in older men without diabetes mellitus. DESIGN: Longitudinal cohort study of older men participating in the Osteoporotic Fractures in Men (MrOS) study. SETTING: Six U.S. clinical centers. PARTICIPANTS: Three thousand one hundred thirty-two ambulatory men aged 65 and older at baseline. MEASUREMENTS: Baseline insulin resistance was calculated for men without diabetes mellitus using the homeostasis model assessment of insulin resistance (HOMA-IR). Total lean, appendicular lean, total fat, and truncal fat mass were measured using dual energy X-ray absorptiometry scans at baseline and 4.6 perpendicular to 0.3 years later in 3,132 men with HOMA-IR measurements. RESULTS: There was greater loss of weight, total lean mass, and appendicular lean mass and less gain in total fat mass and truncal fat mass with increasing quartiles of HOMA-IR (P<.001 for trend). Insulin-resistant men in the highest quartile had higher odds of 5% or more loss of weight (odds ratio (OR) = 1.88, 95% confidence interval (CI) = 1.46-2.43), total lean mass (OR = 2.09, 95% CI = 1.60-2.73) and appendicular lean mass (OR = 1.57, 95% CI = 1.27-1.95) and lower odds of 5% or more gain in total fat mass (OR = 0.56, 95% CI = 0.45-0.68) and truncal fat mass (OR = 0.52, 95% CI = 0.42-0.64) than those in the lowest quartile. These findings remained significant after accounting for age, site, baseline weight, physical activity, and change in physical activity. These associations were also independent of other metabolic syndrome features and medications. CONCLUSION: Greater lean mass loss and lower fat mass gain occurred in insulin-resistant men without diabetes mellitus than in insulin-sensitive men. Insulin resistance may accelerate age-related sarcopenia. J Am Geriatr Soc 59:1217-1224, 2011. C1 [Lee, Christine G.; Orwoll, Eric S.] Oregon Hlth & Sci Univ, Dept Med, Div Endocrinol Diabet & Clin Nutr, Portland, OR 97239 USA. [Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Gen Internal Med, Seattle, WA USA. [Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Lewis, Cora E.] Univ Alabama, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Cawthon, Peggy Mannen] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Hoffman, Andrew R.] Stanford Univ, Dept Med, Div Endocrinol Gerontol & Metab, Palo Alto, CA 94304 USA. [Everson-Rose, Susan A.] Univ Minnesota, Dept Med, Div Gen Internal Med, Minneapolis, MN 55455 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family & Prevent Med, Div Epidemiol, La Jolla, CA 92093 USA. RP Lee, CG (reprint author), Oregon Hlth & Sci Univ, Dept Med, Div Endocrinol Diabet & Clin Nutr, 3181 SW Sam Jackson Pk Rd,CR 113, Portland, OR 97239 USA. EM leechr@ohsu.edu RI Strotmeyer, Elsa/F-3015-2014; OI Strotmeyer, Elsa/0000-0002-4093-6036; Orwoll, Eric/0000-0002-8520-7355 FU National Institutes of Health [P30DK17047]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute on Aging (NIA); National Center for Research Resources (NCRR); NIH Roadmap for Medical Research [U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01 AG027810, UL1 RR024140]; American Diabetes Association [1-04-JF-46] FX MrOS is supported by funding from the National Institutes of Health. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute on Aging (NIA), the National Center for Research Resources (NCRR), and NIH Roadmap for Medical Research under Grants U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01 AG027810, and UL1 RR024140. Additional support was provided by the Veterans Affairs Puget Sound and Diabetes Endocrinology Research Center at the University of Washington supported by NIH Grant P30DK17047 to E.J.B. and American Diabetes Association Grant 1-04-JF-46 to E.S.S. NR 38 TC 44 Z9 45 U1 2 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2011 VL 59 IS 7 BP 1217 EP 1224 DI 10.1111/j.1532-5415.2011.03472.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 791VT UT WOS:000292696100007 PM 21718263 ER PT J AU Teles, R Wang, CY AF Teles, R. Wang, C-Y TI Mechanisms involved in the association between peridontal diseases and cardiovascular disease SO ORAL DISEASES LA English DT Review DE cardiovascular disease; atherosclerosis; periodontal diseases; infection; periodontal pathogens; bacteremia; inflammatory response; systemic biomarkers; C-reactive protein ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; AORTIC ENDOTHELIAL-CELLS; FIMBRIA-DEPENDENT ACTIVATION; CHRONIC PERIODONTITIS PATIENTS; CHRONIC ADULT PERIODONTITIS; HEALTH-CARE PROFESSIONALS; GINGIVAL CREVICULAR FLUID; NECROSIS-FACTOR-ALPHA; TOTAL PATHOGEN BURDEN AB It is now well accepted that besides the cholesterol associated mechanisms of atherogenesis, inflammation plays a crucial role in all stages of the development of the atherosclerotic lesion. This 'inflammation hypothesis' raises the possibility that through systemic elevations of pro-inflammatory cytokines, periodontal diseases might also contribute to systemic inflammation and, therefore, to atherogenesis. In fact, there is evidence that periodontal diseases are associated with higher systemic levels of high-sensitivity C-reactive protein and a low grade systemic inflammation. This phenomenon has been explained based on mechanisms associated with either the infectious or the inflammatory nature of periodontal diseases. The purposes of this article were to review (1) the evidence suggesting a role for oral bacterial species, particularly periodontal pathogens, in atherogenesis; (2) the potential mechanisms explaining an etiological role for oral bacteria in atherosclerosis; (3) the evidence suggesting that periodontal infections are accompanied by a heightened state of systemic inflammation; (4) the potential sources of systemic inflammatory biomarkers associated with periodontal diseases; and (5) the effects of periodontal therapy on systemic inflammatory biomarkers and cardiovascular risk. C1 [Teles, R.] Forsyth Inst, Dept Periodontol, Cambridge, MA 02142 USA. [Teles, R.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Wang, C-Y] UCLA Dent, Lab Mol Signaling, Div Oral Biol & Med, Los Angeles, CA USA. RP Teles, R (reprint author), Forsyth Inst, Dept Periodontol, 245 1st St, Cambridge, MA 02142 USA. EM rteles@forsyth.org FU NIDCR [R01 DE017400, U01 DE021127, R01DE16513, R01DE017684, R01DE019412] FX This work was supports by NIDCR grants R01 DE017400 and U01 DE021127 to RT and R01DE16513, R01DE017684 and R01DE019412 to CYW. NR 136 TC 35 Z9 35 U1 1 U2 24 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 JUL PY 2011 VL 17 IS 5 BP 450 EP 461 DI 10.1111/j.1601-0825.2010.01784.x PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 772GY UT WOS:000291223500002 PM 21223455 ER PT J AU Conti, CM Angelucci, D Ferri, M Maccauro, G Caraffa, A Doyle, R Fulcheri, M Cianchetti, E AF Conti, C. M. Angelucci, D. Ferri, M. Maccauro, G. Caraffa, A. Doyle, R. Fulcheri, M. Cianchetti, E. TI RELATIONSHIP BETWEEN CANCER AND PSYCHOLOGY: AN UPDATED HISTORY SO JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS LA English DT Editorial Material DE oral inflammation; periodontitis; systemic diseases ID RHEUMATOID-ARTHRITIS; INFLAMMATORY CYTOKINES; MULTIPLE-SCLEROSIS; GENE POLYMORPHISMS; SYSTEMIC-SCLEROSIS; TNF-ALPHA; IN-VITRO; STRESS; CELLS; EXPRESSION AB The mechanism and formation of cancer have always been topics of interest for scientists, even for doctors in ancient times. Nowadays a great role for cancer is played by psychological stress which promotes relevant changes in neuronal activity and gene regulations across the different brain areas. It has been reported by many authors that stress can have an important role in the immune system and may be relevant in the formation of cancer. Our observations, in accordance with other research studies, confirm the importance of the influence of depression, linked to neuroendocrine stress, on the enhancement of cancer pathogenesis by inhibiting anti-tumor immune responses. In this article we review the past and present history of the relationship between cancer and psychology. C1 [Conti, C. M.; Ferri, M.; Fulcheri, M.] Univ G dAnnunzio, Clin Psychol Div, I-66013 Chieti, Italy. [Angelucci, D.] Univ G dAnnunzio, AnatomoPathol Div, I-66013 Chieti, Italy. [Maccauro, G.] Univ Cattolica Sacro Cuore, Orthopaed Div, Rome, Italy. [Caraffa, A.] Univ Perugia, Orthopaed Div, I-06100 Perugia, Italy. [Doyle, R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Psychiat, Boston, MA USA. RP Conti, CM (reprint author), Univ G dAnnunzio, Clin Psychol Div, I-66013 Chieti, Italy. EM cconti@unich.it OI Fulcheri, Mario/0000-0002-2389-9800; MACCAURO, Giulio/0000-0002-7359-268X NR 77 TC 3 Z9 5 U1 0 U2 8 PU BIOLIFE SAS PI SILVA MARINA (TE) PA VIA S STEFANO 39 BIS, 64029 SILVA MARINA (TE), ITALY SN 0393-974X EI 1724-6083 J9 J BIOL REG HOMEOS AG JI J. Biol. Regul. Homeost. Agents PD JUL-SEP PY 2011 VL 25 IS 3 BP 331 EP 339 PG 9 WC Endocrinology & Metabolism; Immunology; Medicine, Research & Experimental; Physiology SC Endocrinology & Metabolism; Immunology; Research & Experimental Medicine; Physiology GA 838DY UT WOS:000296268200004 PM 22023757 ER PT J AU Manchikanti, L Falco, FJE Singh, V Benyamin, RM Hirsch, JA AF Manchikanti, Laxmaiah Falco, Frank J. E. Singh, Vijay Benyamin, Ramsin M. Hirsch, Joshua A. TI The Independent Payment Advisory Board SO PAIN PHYSICIAN LA English DT Review DE Independent Payment Advisory Board (IPAB); Patient-Centered Outcomes Research Institute (PCORI); Congressional Budget Office (CBO); National Institute for Health and Clinical Excellence (NICE); Patient Protection and Affordable Care Act (ACA); interventional pain management; interventional techniques ID LOW-BACK-PAIN; CAUDAL EPIDURAL INJECTIONS; EVIDENCE-BASED MEDICINE; CHRONIC SPINAL PAIN; ACTIVE CONTROLLED-TRIAL; LUMBAR SURGERY SYNDROME; MEDIAL BRANCH BLOCKS; EQUIVALENCE CONTROLLED-TRIAL; CLINICAL-PRACTICE GUIDELINES; FACET JOINT INTERVENTIONS AB The Independent Payment Advisory Board (IPAB) is a vastly powerful component of the president's health care reform law, with authority to issue recommendations to reduce the growth in Medicare spending, providing recommendations to be considered by Congress and implemented by the administration on a fast track basis. Ever since its inception, IPAB has been one of the most controversial issues of the Patient Protection and Affordable Care Act (ACA), even though the powers of IPAB are restricted and multiple sectors of health care have been protected in the law. IPAB works by recommending policies to Congress to help Medicare provide better care at a lower cost, which would include ideas on coordinating care, getting rid of waste in the system, providing incentives for best practices, and prioritizing primary care. Congress then has the power to accept or reject these recommendations. However, Congress faces extreme limitations, either to enact policies that achieve equivalent savings, or let the Secretary of Health and Human Services (HHS) follow IPAB's recommendations. IPAB has strong supporters and opponents, leading to arguments in favor of or against to the extreme of introducing legislation to repeal IPAB. The origins of IPAB are found in the ideology of the National Institute for Health and Clinical Excellence (NICE) and the impetus of exploring health care costs, even though IPAB's authority seems to be limited to Medicare only. The structure and operation of IPAB differs from Medicare and has been called the Medicare Payment Advisory Commission (MedPAC) on steroids. The board membership consists of 15 full-time members appointed by the president and confirmed by the Senate with options for recess appointments. The IPAB statute sets target growth rates for Medicare spending. The applicable percent for maximum savings appears to be 0.5% for year 2015, 1% for 2016, 1.25% for 2017, and 1.5% for 2018 and later. The IPAB Medicare proposal process involves mandatory recommendations and advisory recommendations with multiple reporting requirements. However, although IPAB has been described as having limited authority, some believe that it has unlimited authority due to the lack of judicial review and the requirement of two-thirds of the Congress to override any recommendations by IPAB. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys Newark, Newark, DE USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Falco, Frank J. E.] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Falco, Frank J. E.] Temple Univ, Sch Med, Dept PM&R, Philadelphia, PA 19122 USA. [Benyamin, Ramsin M.] Univ Illinois, Coll Med, Urbana, IL 61801 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 156 TC 15 Z9 15 U1 0 U2 2 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 JUL-AUG PY 2011 VL 14 IS 4 BP E313 EP E342 PG 30 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 829VR UT WOS:000295613500001 PM 21785484 ER PT J AU Jakobiec, FA Stacy, RC Thakker, MM AF Jakobiec, Frederick A. Stacy, Rebecca C. Thakker, Manoj M. TI Blue Nevus of the Tarsus as the Predominant Component of a Combined Nevus of the Eyelid SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID MELANOCYTIC NEVI; CONJUNCTIVA AB A 40-year-old man presented with a pigmented lesion of the palpebral conjunctiva and margin of the right lower eyelid. Because of suspicion of melanoma, the lesion was resected. Microscopic examination revealed 2 distinct components: a dominant blue nevus in the tarsus consisting of bland pigmented spindle and epithelioid cells that dissected among the orbicularis muscle fibers and meibomian glands, and a small subepithelial nevomelanocytic component with no overlying junctional activity. The diagnosis of a combined nevus was supported by minimal Ki-67 nuclear immunoreactivity. While the current lesion was proved to be an atypical nevus, all palpebral pigmented lesions should be routinely excised because many are melanomas. C1 [Jakobiec, Frederick A.; Stacy, Rebecca C.] Harvard Univ, Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Sch Med, Boston, MA 02114 USA. [Thakker, Manoj M.] Harvard Univ, Sch Med, Oculoplast Serv, Dept Ophthalmol, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu FU Heed Foundation FX None of the authors has any financial conflicts of interest. Dr. Stacy is supported in part by the Heed Foundation. NR 17 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD JUL-AUG PY 2011 VL 27 IS 4 BP E94 EP E96 DI 10.1097/IOP.0b013e3181f0b6d5 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 791BB UT WOS:000292633700007 PM 20940655 ER PT J AU Nardella, C Lunardi, A Patnaik, A Cantley, LC Pandolfi, PP AF Nardella, Caterina Lunardi, Andrea Patnaik, Akash Cantley, Lewis C. Pandolfi, Pier Paolo TI The APL Paradigm and the "Co-Clinical Trial" Project SO CANCER DISCOVERY LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; PML-RAR-ALPHA; TRANSGENIC MICE; PML/RAR-ALPHA; HISTONE DEACETYLASE; RETINOIC ACID; CELLS; TRANSCRIPTION; THERAPY; MODELS AB Tremendous advances in technologies have allowed the attainment of powerful insights into the molecular and genetic determinants that drive human cancers. However, this acquired knowledge has been translated into effective therapeutics very slowly, in part due to difficulty in predicting which drug or drug combination is likely to be effective in the complex mutational background of human cancers. To address this difficulty we have proposed and initiated the "co-clinical trial" project, in which we exploit mouse models that faithfully replicate the variety of mutational events observed in human cancers, to conduct preclinical trials that parallel ongoing human phase I/II clinical trials. Here, we focus on concepts relevant to the application of this novel paradigm and the essential components required for its implementation to ultimately achieve the rational and rapid development of new therapeutic treatments. Cancer Discovery; 1(2); 108-16. (C)2011 AACR. C1 [Nardella, Caterina; Lunardi, Andrea; Pandolfi, Pier Paolo] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med & Pathol,Div Genet,Canc Genet Program, Boston, MA 02215 USA. [Nardella, Caterina] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Genet,Dept Med,Preclin Murline Pharmacogenet, Boston, MA 02215 USA. [Patnaik, Akash] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Hematol Oncol,Dept Med, Boston, MA 02215 USA. [Patnaik, Akash; Cantley, Lewis C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Signal Transduct,Dept Med, Boston, MA 02215 USA. [Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02215 USA. RP Pandolfi, PP (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med & Pathol,Div Genet,Canc Genet Program, 330 Brookline Ave,CLS401, Boston, MA 02215 USA. EM ppandolf@bidmc.harvard.edu RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU NCI NIH HHS [RC2 CA147940, RC2 CA147940-01, RC2 CA147940-02] NR 17 TC 53 Z9 53 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD JUL PY 2011 VL 1 IS 2 BP 108 EP 116 DI 10.1158/2159-8290.CD-11-0061 PG 9 WC Oncology SC Oncology GA 832DK UT WOS:000295781800013 PM 22116793 ER PT J AU Ying, HQ Elpek, KG Vinjamoori, A Zimmerman, SM Chu, GC Yan, HY Fletcher-Sananikone, E Zhang, HL Liu, YC Wang, W Ren, XJ Zheng, HW Kimmelman, AC Paik, JH Lim, C Perry, SR Jiang, S Malinn, B Protopopov, A Colla, S Xiao, YH Hezel, AF Bardeesy, N Turley, SJ Wang, YAA Chin, L Thayer, SP DePinho, RA AF Ying, Haoqiang Elpek, Kutlu G. Vinjamoori, Anant Zimmerman, Stephanie M. Chu, Gerald C. Yan, Haiyan Fletcher-Sananikone, Eliot Zhang, Hailei Liu, Yingchun Wang, Wei Ren, Xiaojia Zheng, Hongwu Kimmelman, Alec C. Paik, Ji-hye Lim, Carol Perry, Samuel R. Jiang, Shan Malinn, Brian Protopopov, Alexei Colla, Simona Xiao, Yonghong Hezel, Aram F. Bardeesy, Nabeel Turley, Shannon J. Wang, Y. Alan Chin, Lynda Thayer, Sarah P. DePinho, Ronald A. TI PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-kappa B-Cytokine Network SO CANCER DISCOVERY LA English DT Article ID K-RAS; MOUSE MODEL; PHOSPHATIDYLINOSITOL 3-KINASE; MALIGNANT-TRANSFORMATION; CANCER DEVELOPMENT; CELLS; EXPRESSION; PROGRESSION; MUTATIONS; SUBUNIT AB Initiation of pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS mutation, and disease progression is associated with frequent loss of tumor suppressors. In this study, human PDAC genome analyses revealed frequent deletion of the PTEN gene as well as loss of expression in primary tumor specimens. A potential role for PTEN as a haploinsufficient tumor suppressor is further supported by mouse genetic studies. The mouse PDAC driven by oncogenic Kras mutation and Pten deficiency also sustains spontaneous extinction of Ink4a expression and shows prometastatic capacity. Unbiased transcriptomic analyses established that combined oncogenic Kras and Pten loss promotes marked NF-kappa B activation and its cytokine network, with accompanying robust stromal activation and immune cell infiltration with known tumor-promoting properties. Thus, PTEN/phosphoinositide 3-kinase (PI3K) pathway alteration is a common event in PDAC development and functions in part to strongly activate the NF-kappa B network, which may serve to shape the PDAC tumor microenvironment. SIGNIFICANCE: Detailed molecular genetics studies established that PTEN operates as a haploinsufficient tumor suppressor to promote metastatic PDAC development. The strong activation of the NF-kappa B-cytokine program in Pten-deficient tumors provides additional avenues for targeted therapies in tumors with altered PI3K regulation. Cancer Discovery; 1(2); 158-69. (C)2011 AACR. C1 [Ying, Haoqiang; Chu, Gerald C.; Yan, Haiyan; Fletcher-Sananikone, Eliot; Zhang, Hailei; Liu, Yingchun; Wang, Wei; Ren, Xiaojia; Zheng, Hongwu; Paik, Ji-hye; Lim, Carol; Perry, Samuel R.; Jiang, Shan; Malinn, Brian; Protopopov, Alexei; Colla, Simona; Xiao, Yonghong; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Ying, Haoqiang; Vinjamoori, Anant; Chu, Gerald C.; Yan, Haiyan; Fletcher-Sananikone, Eliot; Wang, Wei; Zheng, Hongwu; Paik, Ji-hye; Lim, Carol; Perry, Samuel R.; Jiang, Shan; Malinn, Brian; Colla, Simona; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Elpek, Kutlu G.; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Kimmelman, Alec C.] Dana Farber Canc Inst, Div Genom Stabil & DNA Repair, Boston, MA 02215 USA. [Kimmelman, Alec C.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Chu, Gerald C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wang, Wei] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Zimmerman, Stephanie M.; Chin, Lynda] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Hezel, Aram F.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Thayer, Sarah P.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA 02115 USA. [Hezel, Aram F.] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, 450 Brookline Ave,HIM208, Boston, MA 02215 USA. EM ron_depinho@dfci.harvard.edu OI Zheng, Hongwu/0000-0002-5823-4913 FU NIH [P50 CA127003-03, T32 CA009382-26, P01 CA117969]; AACR; Dana-Farber Cancer Institute; Kimmel Scholar Award; Harvard Stem Cell Institute; Robert A. and Renee E. Belfer Foundation FX Grant support derives from NIH Grants P50 CA127003-03 (DF/HCC SPORE in Gastrointestinal Cancer, H. Ying and R. A. DePinho), T32 CA009382-26 (H. Ying), P01 CA117969 (N. Bardeesy, S. P. Thayer, L. Chin, and R. A. DePinho). In addition, K. G. Elpek is supported by an AACR Centennial postdoctoral fellowship in cancer research; A.C. Kimmelman is supported by the Dana-Farber Cancer Institute, the Kimmel Scholar Award, and the AACR-PanCAN Career Development Award; and R. A. Depinho is supported by the Harvard Stem Cell Institute Cancer Program Pilot Grant and the Robert A. and Renee E. Belfer Foundation. NR 50 TC 72 Z9 75 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD JUL PY 2011 VL 1 IS 2 BP 158 EP 169 DI 10.1158/2159-8290.CD-11-0031 PG 12 WC Oncology SC Oncology GA 832DK UT WOS:000295781800018 PM 21984975 ER PT J AU Cheung, LWT Hennessy, BT Li, J Yu, SX Myers, AP Djordjevic, B Lu, YL Stemke-Hale, K Dyer, MD Zhang, F Ju, ZL Cantley, LC Scherer, SE Liang, H Lu, KH Broaddus, RR Mills, GB AF Cheung, Lydia W. T. Hennessy, Bryan T. Li, Jie Yu, Shuangxing Myers, Andrea P. Djordjevic, Bojana Lu, Yiling Stemke-Hale, Katherine Dyer, Mary D. Zhang, Fan Ju, Zhenlin Cantley, Lewis C. Scherer, Steven E. Liang, Han Lu, Karen H. Broaddus, Russell R. Mills, Gordon B. TI High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability SO CANCER DISCOVERY LA English DT Article ID DNA MISMATCH REPAIR; PHOSPHOINOSITIDE 3-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; SOMATIC MUTATIONS; SUBUNIT P85-ALPHA; SEROUS CARCINOMA; BREAST-CANCER; RAS; PATHWAY; GENE AB We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85 alpha) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85 beta), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85 alpha dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target. SIGNIFICANCE: Our data indicate that the PI3K pathway is targeted in the vast majority of endometrioid endometrial cancers leading to PI3K pathway activation. Frequent oncogenic mutations in PIK3R1 and PIK3R2 provide evidence for their role in endometrial cancer pathophysiology with patient-specific mutations revealing a novel mechanism by which p85 alpha regulates the PI3K pathway through stabilizing PTEN. Cancer Discovery; 1(2); 170-85. (C)2011 AACR. C1 [Cheung, Lydia W. T.; Li, Jie; Yu, Shuangxing; Lu, Yiling; Stemke-Hale, Katherine; Dyer, Mary D.; Zhang, Fan; Ju, Zhenlin; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77054 USA. [Ju, Zhenlin; Liang, Han] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77054 USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77054 USA. [Broaddus, Russell R.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77054 USA. [Scherer, Steven E.] Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Hennessy, Bryan T.] Beaumont Hosp, Dept Med Oncol, Dublin, Ireland. [Hennessy, Bryan T.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Myers, Andrea P.] Dana Farber Canc Inst, Div Womens Cancers, Dept Med Oncol, Boston, MA USA. [Myers, Andrea P.; Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Dept Med, Boston, MA USA. [Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Djordjevic, Bojana] Univ Ottawa, Dept Pathol & Lab Med, Ottawa, ON, Canada. RP Cheung, LWT (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, 7435 Fannin St,Suite 2SCR3-2211, Houston, TX 77054 USA. EM wcheung@mdanderson.org RI Stemke-Hale, Katherine/K-9113-2013; Cantley, Lewis/D-1800-2014; OI Stemke-Hale, Katherine/0000-0002-1231-4192; Cantley, Lewis/0000-0002-1298-7653; Liang, Han/0000-0001-7633-286X FU AstraZeneca; GlaxoSmithKline; Celgene; Exelixis; Roche; Wyeth/Pfizer; NCI [CA16672]; Stand Up to Cancer grant; NIH/NCI [P50 CA098258]; Conquer Cancer Foundation of the American Society of Clinical Oncology FX G.B. Mills received commercial research grants from AstraZeneca, GlaxoSmithKline, Celgene, Exelixis, Roche, and Wyeth/Pfizer, and served as consultant to AstraZeneca, Celgene, Enzon, Novartis, and Wyeth/Pfizer. The other authors disclosed no potential conflicts of interest.; We thank Drs. Lynda Chin and Peter Vogt for providing p85 alpha plasmids; and CCSG DNA analysis facility, RPPA core, and characterized cell line core (funded by NCI CA16672) in the MD Anderson Cancer Center. We wish to acknowledge the contributions of the Baylor College of Medicine Human Genome Sequencing Center and in particular, Dr. Richard Gibbs, director, Donna Muzny, Dr. David Wheeler, Lora Lewis, Robert Ruth, Kyle Chang, Humeira Akbar, and Shannon Gross.; This work was supported by a Stand Up to Cancer grant to L. C. Cantley, A. P. Myers, and G. B. Mills; a Uterine Cancer SPORE grant (NIH/NCI P50 CA098258) to R. R. Broaddus, K. H. Lu, and G. B. Mills; and a Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology to B. T. Hennessy. NR 50 TC 148 Z9 149 U1 2 U2 23 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD JUL PY 2011 VL 1 IS 2 BP 170 EP 185 DI 10.1158/2159-8290.CD-11-0039 PG 16 WC Oncology SC Oncology GA 832DK UT WOS:000295781800019 PM 21984976 ER PT J AU Leclercq, C Singh, JP AF Leclercq, Christophe Singh, Jagmeet P. TI Cardiac resynchronization therapy: from treatment to prevention SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID LEFT-VENTRICULAR DYSFUNCTION; HEART-FAILURE; COST-EFFECTIVENESS; DEFIBRILLATOR; GUIDELINES; TRIAL C1 [Leclercq, Christophe] CHU Rennes, Serv Cardiol & Malad Vasc, INSERM, CIC IT, F-35000 Rennes, France. [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA USA. RP Leclercq, C (reprint author), CHU Rennes, Serv Cardiol & Malad Vasc, INSERM, CIC IT, F-35000 Rennes, France. EM christophe.leclercq@chu-rennes.fr 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 0195-668X J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2011 VL 32 IS 13 BP 1580 EP 1582 DI 10.1093/eurheartj/ehr016 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 830TD UT WOS:000295679200006 PM 21324935 ER PT J AU Natarajan, P Cannon, CP AF Natarajan, Pradeep Cannon, Christopher P. TI Myocardial infarction vaccine? Evidence supporting the influenza vaccine for secondary prevention SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; INFECTION; AZITHROMYCIN; EVENTS; TRIAL C1 [Cannon, Christopher P.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiovasc Div,TIMI Study Grp, Harvard, MA 01451 USA. [Natarajan, Pradeep] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Harvard, MA USA. RP Cannon, CP (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiovasc Div,TIMI Study Grp, Harvard, MA 01451 USA. EM cpcannon@partners.org OI Natarajan, Pradeep/0000-0001-8402-7435 NR 17 TC 3 Z9 3 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2011 VL 32 IS 14 BP 1701 EP 1703 DI 10.1093/eurheartj/ehr053 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 830TE UT WOS:000295679300008 PM 21406438 ER PT J AU Ohishi, M Schipani, E AF Ohishi, M. Schipani, E. TI PTH and stem cells SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Review DE Bone marrow; PTH; stem cells; stroma ID BONE-MARROW FIBROSIS; HEMATOPOIETIC STEM; PARATHYROID-HORMONE; SKELETAL PROGENITORS; PTH/PTHRP RECEPTOR; MEDICAL THERAPY; NICHE; DYSPLASIA; ALENDRONATE; HYPERPARATHYROIDISM AB At least 2 different types of cells, hematopoietic and mesenchymal, are present in the adult bone marrow, in addition to endothelial cells. Hematopoietic and mesenchymal cells are believed to originate from hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC), respectively. The bone marrow stroma, a cellular microenvironment that supports HSC, is composed of non-hematopoietic cells and contains MSC. A unique expansion of the bone marrow stroma, also known as marrow fibrosis, is the hallmark of a variety of disorders including hyperparathyroidism and fibrous dysplasia. PTH is the first bone anabolic agent approved by US Food and Drug Administration for the treatment of osteoporosis. Recent studies have suggested that PTH treatment may affect the number of hematopoietic stem cells in the bone marrow and their mobilization into the bloodstream. In addition, cells with classical features of mesenchymal stem cells/progenitors have been shown to express receptors for PTH, and to increase in number and undergo redistribution in the adult bone marrow upon PTH treatment. In this review, we will summarize the up-to-date knowledge on PTH and its relation to stem cells. We will also discuss the contribution of different cell types to the development of marrow fibrosis and the involvement of PTH signaling in this pathology. (J. Endocrinol. Invest. 34: 552-556, 2011) (C) 2011, Editrice Kurtis C1 [Ohishi, M.; Schipani, E.] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Ohishi, M.; Schipani, E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ohishi, M.] Kyushu Univ, Grad Sch Med, Fac Med Sci, Dept Orthopaed Surg, Fukuoka 812, Japan. RP Schipani, E (reprint author), Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. EM schipani@helix.mgh.harvard.edu NR 53 TC 9 Z9 9 U1 0 U2 2 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD JUL-AUG PY 2011 VL 34 IS 7 BP 552 EP 556 DI 10.3275/7620 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 829EY UT WOS:000295562600012 PM 21427529 ER PT J AU Chung, B Dopheide, JA Gregerson, P AF Chung, Bosun Dopheide, Julie A. Gregerson, Paul TI Psychiatric Pharmacist and Primary Care Collaboration at a Skid-Row Safety-Net Clinic SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE primary care; psychiatry; pharmacist; safety-net practices ID OUTCOMES; SERVICES; IMPACT AB Purpose: There is limited access to psychiatric medication follow-up services at safety-net clinics serving the largely homeless minority population of Los Angeles' skid-row district. This paper describes the process of establishing a pharmacist-run psychiatric medication management service, the types of interventions provided by the psychiatric pharmacist, and patient and provider satisfaction with the service. Methods: The establishment of a collaborative practice agreement between primary care physicians and psychiatric pharmacists is described along with the patient demographics and types of pharmacist interventions. Primary care physicians were surveyed regarding their comfort level with managing psychiatric illness and prescribing psychotropic medications. They were also asked about their opinion of psychiatric pharmacist medication management services. An anonymous patient satisfaction survey was also administered. Results: The development of psychiatric pharmacy services is described. The types of interventions included initiating drug therapy, adjusting dosages, discontinuing drug therapy, and providing medication education. Primary care providers were not comfortable in providing psychiatric medication follow-up for patients beyond uncomplicated depression and anxiety disorders. They expressed an overall positive view of psychiatric pharmacist services for their patients with established psychiatric diagnoses. Patient satisfaction ratings were high. Conclusions: A psychiatric pharmacist-run medication management service in collaboration with primary care providers can improve access to mental health services in safety-net clinics with good provider and patient satisfaction. C1 [Chung, Bosun; Dopheide, Julie A.] Univ So Calif, Sch Pharm, Los Angeles, CA 90089 USA. [Chung, Bosun] Healthcare, Vet Adm Greater Los Angeles, Los Angeles, CA USA. [Gregerson, Paul] JWCH Inc Weingart, Ctr Community Hlth, Los Angeles, CA USA. RP Dopheide, JA (reprint author), Univ So Calif, Sch Pharm, 1985 Zonal Ave, Los Angeles, CA 90089 USA. EM dopheide@usc.edu NR 12 TC 1 Z9 1 U1 1 U2 3 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 JUL PY 2011 VL 103 IS 7 BP 567 EP 574 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 829SY UT WOS:000295605800003 PM 21999031 ER PT J AU Hazin, R Giles, CA AF Hazin, Ribhi Giles, Cheryl A. TI Is There a Color Line in Death? An Examination of End-of-Life Care in the African American Community SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE end-of-life care; palliative therapy; cancer; pain management; African Americans; hospice ID EMERGENCY-DEPARTMENT; SOCIOECONOMIC-STATUS; ETHNIC-DIFFERENCES; RACIAL-DIFFERENCES; NONMALIGNANT PAIN; HEALTH OUTCOMES; CANCER-PATIENTS; NURSING-HOME; PATIENT; RACE AB Although the goals of end-of-life care and hospice are to mitigate suffering and improve quality of life for patients with terminal illnesses, they remain underutilized by a significant number of African Americans. While sociocultural issues play a role in the underutilization of these resources among African Americans, other confounding factors affect the ability of African Americans to adequately access quality care at the end of life. Here, the authors examine the various barriers preventing increased use of hospice care and palliative therapy among African Americans. A particular focus of this examination will revolve around suggestions for increasing the use of end-of-life care among African Americans in the future. C1 [Hazin, Ribhi] Harvard Univ, Fac Arts & Sci, Cambridge, MA 02138 USA. [Giles, Cheryl A.] Harvard Univ, Sch Divin, Cambridge, MA 02138 USA. [Hazin, Ribhi] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Hazin, R (reprint author), Harvard Univ, Fac Arts & Sci, 41 Garden St, Cambridge, MA 02138 USA. EM rhazin@mail.harvard.edu NR 54 TC 0 Z9 0 U1 1 U2 6 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 JUL PY 2011 VL 103 IS 7 BP 609 EP 613 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 829SY UT WOS:000295605800008 PM 21999036 ER PT J AU Clements, JL Dana, R AF Clements, John L. Dana, Reza TI Inflammatory Corneal Neovascularization: Etiopathogenesis SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE angiogenesis; cornea; corneal transplantation; hemangiogenesis; inflammation ID ENDOTHELIAL GROWTH-FACTOR; CONTACT-LENS WEAR; EPITHELIUM-DERIVED FACTOR; HERPETIC STROMAL KERATITIS; ANGIOGENESIS IN-VIVO; FACTOR VEGF; MATRIX METALLOPROTEINASES; CELL PROLIFERATION; TUMOR-GROWTH; PSEUDOMONAS-AERUGINOSA AB There is a delicate balance between pro-angiogenic stimuli and anti-angiogenic stimuli in the normal cornea. This balance allows the cornea to normally exist in a relatively avascular state, which is needed for optical clarity and vision. However, in the setting of inflammation, this balance may be shifted in favor of neovascularization. This paper reviews the literature on corneal inflammatory neovascularization beginning with the pro-angiogenic factors, such as Vascular Endothelial Growth Factor and Fibroblast Growth Factor, which help to facilitate the development of new corneal vessels. Subsequently the anti-angiogenic factors and their role in preventing neovascularization in the normal cornea are reviewed. Finally, a review of several etiologies of inflammatory neovascularization is presented with attention to the processes that allow the pro-angiogenic stimuli to overwhelm the anti-angiogenic factors. C1 [Clements, John L.; Dana, Reza] Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, Boston, MA 02114 USA. RP Clements, JL (reprint author), Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. EM john_clements@meei.harvard.edu NR 119 TC 20 Z9 20 U1 0 U2 4 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 235 EP 245 DI 10.3109/08820538.2011.588652 PG 11 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800001 PM 21958169 ER PT J AU Yoo, JH Chodosh, J Dana, R AF Yoo, Janie H. Chodosh, James Dana, Reza TI Relapsing Polychondritis: Systemic and Ocular Manifestations, Differential Diagnosis, Management, and Prognosis SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE autoimmune disease; cartilage; vasculitis; episcleritis; scleritis ID OF-THE-LITERATURE; II COLLAGEN; SUSTAINED RESPONSE; EYE DISEASE; PATIENT; INFLIXIMAB; CARTILAGE; MATRILIN-1; VASCULITIS; KERATITIS AB Relapsing polychondritis (RP) is a rare systemic autoimmune disease characterized by episodic inflammation of cartilaginous tissues throughout the body. It is distinguished by recurrent bouts of inflammation, which lead to the permanent destruction of the involved structures. It can be a life-threatening, debilitating, and frightening disease and is often difficult to diagnose in its early stages. Ocular manifestations have been reported to occur in up to 65% of cases and include proptosis, eyelid edema, extraocular muscles palsy, episcleritis, scleritis, conjunctivitis, corneal infiltrate, peripheral ulcerative keratitis, corneal thinning or perforation, iridocyclitis, cataract, retinopathy, exudative retinal detachment, and optic neuritis. Corticosteroids remain the mainstay of treatment for RP; however, other treatment modalities include nonsteroidal anti-inflammatory drugs, colchicine, dapsone, and immunomodulatory drugs. This article reviews the literature and summarizes the epidemiology, pathogenesis, clinical features, treatment, and prognosis of the systemic and ocular manifestations of RP. C1 [Yoo, Janie H.] Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, Boston, MA 02114 USA. RP Yoo, JH (reprint author), Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. EM jknee23@yahoo.com NR 56 TC 13 Z9 15 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 261 EP 269 DI 10.3109/08820538.2011.588653 PG 9 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800004 PM 21958172 ER PT J AU Kirzhner, M Jakobiec, FA AF Kirzhner, Maria Jakobiec, Frederick A. TI Ocular Cicatricial Pemphigoid: A Review of Clinical Features, Immunopathology, Differential Diagnosis, and Current Management SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE ocular cicatricial pemphigoid; mucous membrane pemphigoid; differential diagnosis; immunomodulatory treatment; review ID INTRAVENOUS IMMUNOGLOBULIN THERAPY; CHRONIC CICATRIZING CONJUNCTIVITIS; IMMUNOSUPPRESSIVE THERAPY; MANIFESTATIONS; SYMBLEPHARON; AUTOIMMUNE; VULGARIS; DISEASE; GRANULOMATOSIS; SARCOIDOSIS AB Ocular cicatricial pemphigoid is a devastating autoimmune blistering disorder mainly affecting the conjunctiva but frequently associated with systemic mucosal findings. This article is an update of the pathogenesis, ocular findings, differential diagnosis, and approaches to treatment. C1 [Jakobiec, Frederick A.] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Dept Ophthalmol, Boston, MA 02114 USA. [Kirzhner, Maria; Jakobiec, Frederick A.] Harvard Univ, Sch Med, Boston, MA USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Dept Ophthalmol, Suite 321,243 Charles St,Room 321, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 43 TC 16 Z9 17 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 270 EP 277 DI 10.3109/08820538.2011.588660 PG 8 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800005 PM 21958173 ER PT J AU Shazly, TA Aljajeh, M Latina, MA AF Shazly, Tarek A. Aljajeh, Mouhab Latina, Mark A. TI Autoimmune Basis of Glaucoma SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE glaucoma; retinal ganglion cell; glia; oxidative stress; immune system; aging ID OPTIC-NERVE HEAD; OPEN-ANGLE GLAUCOMA; ELEVATED INTRAOCULAR-PRESSURE; NORMAL-TENSION GLAUCOMA; SERUM AUTOANTIBODIES; SHOCK PROTEINS; PROGRESSION; ANTIBODIES; TRIAL; VACCINATION AB Glaucoma is one of the leading causes of blindness worldwide. The current view of glaucoma is that it is a multifactorial disease. Elevated IOP is a recognized etiologic factor which can trigger initial damage through biomechanical and ischemic injury to the retinal ganglion cells. However, elevated intraocular pressure cannot be entirely responsible for the development of glaucoma. Accumulating evidence suggests that abnormal immunity may be contributing to the glaucomatous optic neuropathy. Autoimmunity may be responsible for initiating or exacerbating glaucoma. This review provides an evaluation of the potential role of autoimmunity in some patients with glaucoma. C1 [Shazly, Tarek A.; Aljajeh, Mouhab; Latina, Mark A.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Shazly, Tarek A.] Assiut Univ Hosp, Dept Ophthalmol, Assiut, Egypt. RP Latina, MA (reprint author), 20 Pond Meadow Dr,Ste 203, Reading, MA 01867 USA. EM shazlyt@gmail.com OI A Shazly, Tarek/0000-0002-4561-1871 NR 39 TC 5 Z9 6 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 278 EP 281 DI 10.3109/08820538.2011.588649 PG 4 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800006 PM 21958174 ER PT J AU Shazly, TA Aljajeh, M Latina, MA AF Shazly, Tarek A. Aljajeh, Mouhab Latina, Mark A. TI Posner-Schlossman Glaucomatocyclitic Crisis SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE glaucoma; trabecular meshwork; aqueous humor; trabeculitis; immune system; Posner-Schlossman; glaucomatocyclitic crisis ID OPEN-ANGLE GLAUCOMA; ETIOLOGY; CYTOMEGALOVIRUS; UVEITIS; VIRUS AB In 1948, Posner and Schlossman first reported glaucomatocyclitic crisis, an uncommon form of glaucoma characterized by recurrent unilateral episodes of markedly elevated intraocular pressure (IOP) with mild idiopathic anterior chamber inflammation. The exact etiology of glaucomatocyclitic crisis is not clear. Although it is typically a self-limited condition, some cases with advanced optic nerve cupping and associated visual field loss have been reported. Diagnosis of Posner-Schlossman syndrome is difficult, and it may mimic a variety of ocular disorders. Treatment of this syndrome is directed towards controlling the inflammation and associated IOP elevation. C1 [Shazly, Tarek A.; Aljajeh, Mouhab; Latina, Mark A.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Shazly, Tarek A.] Assiut Univ Hosp, Dept Ophthalmol, Assiut, Egypt. [Latina, Mark A.] Tufts Univ, Dept Ophthalmol, Boston, MA 02111 USA. RP Shazly, TA (reprint author), 20 Pond Meadow Dr,Ste 203, Reading, MA 01867 USA. EM shazlyt@gmail.com OI A Shazly, Tarek/0000-0002-4561-1871 NR 23 TC 5 Z9 7 U1 1 U2 8 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 282 EP 284 DI 10.3109/08820538.2011.605821 PG 3 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800007 PM 21958175 ER PT J AU Horsley, MB Chen, TC AF Horsley, Michael B. Chen, Teresa C. TI The Use of Prostaglandin Analogs in the Uveitic Patient SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE prostaglandin analogs; uveitis; cystoid macular edema; Herpes simplex keratitis ID CYSTOID MACULAR EDEMA; ELEVATED INTRAOCULAR-PRESSURE; BLOOD-AQUEOUS BARRIER; OCULAR HERPES-SIMPLEX; ANTERIOR UVEITIS; CATARACT-EXTRACTION; UVEOSCLERAL OUTFLOW; CYNOMOLGUS MONKEY; HUMOR DYNAMICS; LATANOPROST AB Glaucoma is a disease process characterized by progressive optic nerve damage and corresponding visual field loss. It may be further categorized into either primary open-angle glaucoma or secondary glaucoma. These secondary glaucomas include glaucomas associated with uveitis and inflammation. Prostaglandin analogs (PGA) have been used to help lower intraocular pressure (IOP) in these often difficult to manage eyes. However, controversy exists concerning their use in uveitic patients due to the theoretically higher risk of anterior uveitis, development of cystoid macular edema (CME), and reactivation of herpes simplex keratitis (HSK). There is little evidence that PGA disrupt the blood-aqueous barrier and only anecdotal evidence suggesting an increased risk of these rare findings. PGA may be used in uveitic glaucoma when other topical treatments have not lowered IOP to the patient's target range. C1 [Horsley, Michael B.; Chen, Teresa C.] Harvard Univ, Glaucoma Serv, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Horsley, MB (reprint author), Harvard Univ, Glaucoma Serv, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM horsley@sweye.com NR 53 TC 10 Z9 10 U1 1 U2 2 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 285 EP 289 DI 10.3109/08820538.2011.588650 PG 5 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800008 PM 21958176 ER PT J AU Benitah, NR Sobrin, L Papaliodis, GN AF Benitah, Nicole R. Sobrin, Lucia Papaliodis, George N. TI The Use of Biologic Agents in the Treatment of Ocular Manifestations of Behcet's Disease SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE adalimumab; etanercept; infliximab; interferon; rituximab; uveitis ID REFRACTORY POSTERIOR UVEITIS; INTERFERON-ALPHA TREATMENT; SIGHT-THREATENING UVEITIS; LONG-TERM EFFICACY; OPEN-LABEL TRIAL; INFLIXIMAB THERAPY; TNF-ALPHA; RETINAL VASCULITIS; FOLLOW-UP; SAFETY AB Behcet's Disease (BD) is a multisystem inflammatory disorder of uncertain etiology with a variety of potential manifestations throughout the body, and its ocular complications are some of its most devastating. Treatment with immunosuppressive agents has improved outcomes, but many patients suffer from disease that responds poorly to conventional therapies. Because of this, therapy with a variety of biological response modifiers has been employed. The earliest was interferon-alpha, and a multitude of reports have described its benefits for the uveitis associated with Behcet's Disease. Many patients enjoy durable remissions of their ocular inflammatory disease even after discontinuation of therapy, but side-effects are almost universal and some can be dangerous. Of the newer biological response modifiers, infliximab, a monoclonal antibody to TNF-alpha, has been most extensively studied. It is reported to be rapidly effective in many cases of Behcet's Disease uveitis, though with conflicting data as to the ability to induce durable remission after cessation of treatment. Side-effects are relatively rare, but may be serious. Several reports have been published on the use of other biologic agents, including adalimumab (a humanized antibody to TNF-alpha), etanercept (a molecule that resembles the TNF-alpha receptor), and rituximab (an antibody to CD20 that depletes the body of CD20-positive B cells). Of the three of these, adalimumab has the most promising initial evidence, etanercept has very few positive reports in patients with BD uveitis (and is likely ineffective in uveitis in general), and rituximab is lacking data. Although randomized controlled trials are almost completely lacking, currently available evidence is promising that biologic agents can prove an invaluable addition to the armamentarium of the practitioner treating patients with BD uveitis. C1 [Papaliodis, George N.] Harvard Univ, Ocular Immunol & Uveitis Serv, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Med Sch, Boston, MA 02114 USA. RP Papaliodis, GN (reprint author), Harvard Univ, Ocular Immunol & Uveitis Serv, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Med Sch, 243 Charles St, Boston, MA 02114 USA. EM George_Papaliodis@meei.harvard.edu NR 55 TC 19 Z9 20 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 295 EP 303 DI 10.3109/08820538.2011.588665 PG 9 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800010 PM 21958178 ER PT J AU Fazelat, A Bahrani, H Buzney, S Lashkari, K Weiter, JJ AF Fazelat, Ahad Bahrani, Hasan Buzney, Sheldon Lashkari, Kameran Weiter, John J. TI Autoimmunity and Age-related Macular Degeneration: A Review of the Literature SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Drusen; Choroidal Neovascular Membranes; Autoantibodies; Autoimmunity; Complement; Inflammation ID FACTOR-H POLYMORPHISM; CHOROIDAL NEOVASCULARIZATION; EPITHELIAL-CELLS; ANIMAL-MODEL; RISK-FACTORS; DRUSEN; INFLAMMATION; AUTOANTIBODIES; ACTIVATION; ANTIBODIES C1 [Fazelat, Ahad; Bahrani, Hasan; Buzney, Sheldon; Weiter, John J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Lashkari, Kameran] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. RP Fazelat, A (reprint author), 2285 Massachusetts Ave, Cambridge, MA USA. EM Ahad_Fazelat@meei.harvard.edu NR 40 TC 2 Z9 2 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 304 EP 311 DI 10.3109/08820538.2011.588666 PG 8 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800011 PM 21958179 ER PT J AU Pan, D Hirose, T AF Pan, David Hirose, Tatsuo TI Vogt-Koyanagi-Harada Syndrome: Review of Clinical Features SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE choroiditis; inflammation; pleocytosis; sunset glow fundus; uveitis ID PERIPHERAL IRIS DEPIGMENTATION; OCULAR HYPOTONY; DISEASE; INVOLVEMENT; THERAPY AB Vogt-Koyanagi-Harada syndrome is a bilateral, chronic, diffuse granulomatous panuveitis associated with poliosis, vitiligo, and central nervous system and auditory signs. Increasing reports have been published to describe the clinical features of Vogt-Koyanagi-Harada syndrome. These manifestations are variable. This article presents a review of the clinical features. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. Harvard Univ, Schepens Eye Res Inst, Sch Med, Boston, MA USA. RP Pan, D (reprint author), 7150 Holmes Pk Rd,Apt 301, Lincoln, NE 68506 USA. EM pandsw@yahoo.com NR 28 TC 12 Z9 12 U1 1 U2 5 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 312 EP 315 DI 10.3109/08820538.2011.588654 PG 4 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800012 PM 21958180 ER PT J AU Chang, GC Young, LH AF Chang, Grace C. Young, Lucy H. TI Sympathetic Ophthalmia SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE autoimmune disease; Dalen-Fuchs nodules; granulomatous uveitis; trauma; inflammation ID INTRAVITREAL TRIAMCINOLONE ACETONIDE; KOYANAGI-HARADA DISEASE; DALEN-FUCHS NODULES; ELECTRON-MICROSCOPY; UVEITIS; EYE; THERAPY; CHLORAMBUCIL; INJECTIONS; MELANOMA AB Sympathetic ophthalmia is a rare, bilateral granulomatous panuveitis following accidental or surgical trauma to one eye. The pathophysiology is not clearly understood, but is believed to be a T-cell mediated autoimmune response. Clinical presentation most often occurs within the first year after trauma; anteriorly it manifests as a chronic or acute uveitis with mutton-fat keratic precipitates, while posteriorly it is often accompanied by yellowish-white choroidal lesions or Dalen-Fuchs nodules. The mainstay of treatment consists of systemic anti-inflammatory agents such as oral corticosteroids, or other immunosuppressive agents. Newer treatments include intravitreal injections of steroids in combination with systemic therapy, periocular injections of steroids without systemic therapy, and injections of infliximab, an anti-vascular endothelial growth factor. C1 [Chang, Grace C.; Young, Lucy H.] Harvard Univ, Retina Serv, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Young, LH (reprint author), Harvard Univ, Retina Serv, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM lucy_young@meei.harvard.edu NR 64 TC 7 Z9 8 U1 1 U2 5 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 316 EP 320 DI 10.3109/08820538.2011.588658 PG 5 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800013 PM 21958181 ER PT J AU Shildkrot, Y Sobrin, L Gragoudas, ES AF Shildkrot, Yevgeniy Sobrin, Lucia Gragoudas, Evangelos S. TI Cancer-Associated Retinopathy: Update on Pathogenesis and Therapy SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE paraneoplastic retinopathy; autoimmune retinopathy; CAR; recoverin; cytotoxic T-lymphocyte; immune therapy ID RECOVERIN-ASSOCIATED RETINOPATHY; ABERRANTLY EXPRESSED RECOVERIN; ANTIRETINAL ANTIBODY DETECTION; CALCIUM-BINDING PROTEIN; CELL LUNG-CANCER; PARANEOPLASTIC RETINOPATHY; AUTOIMMUNE RETINOPATHY; PHOTORECEPTOR DEGENERATION; RETINAL DYSFUNCTION; ENDOMETRIAL CANCER AB Paraneoplastic retinopathies comprise a diverse group of immune-mediated conditions affecting the eye. Cancer-associated retinopathy (CAR) typically has a sudden onset of severe visual loss and an ominous association with an occult malignancy. CAR is one of the best studied and better understood conditions in the multifarious group of autoimmune retinopathies. Recent developments have correlated the disease presentation, course, and therapeutic response to the underlying immune mediators and the inciting antigens. Signaling involving cytotoxic T-lymphocytes antigen 4 (CTLA-4) and vascular endothelial growth factor (VEGF) receptor-1 appears to play a role in the pathogenesis and may offer novel avenues for therapeutic intervention in CAR. Future developments in rapid identification and longitudinal quantification of antibody levels would enable individualized management in these patients. The goal of this review is to analyze the clinical features of diagnosis and management of retinopathy in the context of recent advances in the elucidation of CAR pathogenesis. C1 [Shildkrot, Yevgeniy; Sobrin, Lucia; Gragoudas, Evangelos S.] Harvard Univ, Retina Serv, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Shildkrot, Y (reprint author), Harvard Univ, Retina Serv, Sch Med, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM eugene_shildkrot@meei.harvard.edu NR 81 TC 10 Z9 12 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 321 EP 328 DI 10.3109/08820538.2011.588657 PG 8 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800014 PM 21958182 ER PT J AU Comander, J Loewenstein, J Sobrin, L AF Comander, Jason Loewenstein, John Sobrin, Lucia TI Diagnostic Testing and Disease Monitoring in Birdshot Chorioretinopathy SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE birdshot chorioretinopathy; birdshot retinochoroidopathyelectroretinogram; HLA-A29; posterior uveitis ID INDOCYANINE GREEN ANGIOGRAPHY; OPTICAL COHERENCE TOMOGRAPHY; TERM-FOLLOW-UP; LONGITUDINAL COHORT; BASE-LINE; VISUAL-FIELD; RETINOCHOROIDOPATHY AB Birdshot chorioretinopathy (BSCR) is a rare form of posterior uveitis in which hypopigmented choroidal lesions are scattered throughout the posterior pole. In order to avoid the poor natural history of BSCR, many practitioners would argue that it is critical to diagnose and carefully monitor the often subtle activity of this disease; BSCR can progress insidiously in a white and painless eye, and treatment algorithms based on visual acuity, vitreous inflammation, and retinal vascular leakage of fluorescein alone have been ineffective. This article reviews the various modalities that can be used to diagnose and monitor BSCR, including the clinical and ophthalmoscopic features, diagnostic criteria, electroretinography (ERG-full field, multifocal, and pattern), fluorescein angiography (FA), indocyanine green (ICG) angiography, optical coherence tomography (OCT), fundus autofluorescence (AF), visual fields, HLA A29 testing, and other laboratory testing. HLA-A29 testing can be useful in diagnostically borderline cases, but a positive test is not as useful as one might think in cases where the clinical suspicion for BSCR is low. Out of all the testing modalities, the ERG has been studied most extensively in its relationship to successful treatment. The key parameter is the 30 Hz flicker implicit time, which is abnormal in 70% of patients at baseline. A normal implicit time is correlated with the chance that a patient can be successfully tapered from systemic immunomodulatory therapy without recurrence. Alternatively, some practitioners use ICG angiography or visual field testing for adjunctive monitoring. OCT is used most commonly to follow macular edema. While there is no consensus on how to best monitor disease activity, our institution uses serial ERGs as an adjunct to the normal exam. C1 [Comander, Jason] Massachusetts Eye & Ear Infirm, Retina Dept, Boston, MA 02114 USA. RP Comander, J (reprint author), Massachusetts Eye & Ear Infirm, Retina Dept, 243 Charles St, Boston, MA 02114 USA. EM jason_comander@meei.harvard.edu OI Comander, Jason/0000-0002-4257-7145 NR 38 TC 13 Z9 14 U1 0 U2 2 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 329 EP 336 DI 10.3109/08820538.2011.588661 PG 8 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800015 PM 21958183 ER EF