FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Saag, MS Masur, H AF Saag, Michael S. Masur, Henry TI HIV/AIDS Preface SO INFECTIOUS DISEASE CLINICS OF NORTH AMERICA LA English DT Editorial Material C1 [Saag, Michael S.] Univ Alabama Birmingham, Ctr AIDS Res, Birmingham, AL 35294 USA. [Masur, Henry] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Saag, MS (reprint author), Univ Alabama Birmingham, Ctr AIDS Res, 845 19th St South BBRB 256, Birmingham, AL 35294 USA. EM msaag@uab.edu; hmasur@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0891-5520 EI 1557-9824 J9 INFECT DIS CLIN N AM JI Infect. Dis. Clin. North Am. PD SEP PY 2014 VL 28 IS 3 BP 17 EP 18 DI 10.1016/j.idc.2014.07.001 PN 1 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP2JS UT WOS:000341899100003 PM 25151570 ER PT J AU Pau, AK George, JM AF Pau, Alice K. George, Jomy M. TI Antiretroviral Therapy Current Drugs SO INFECTIOUS DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE HIV; Antiretroviral therapy; Nucleoside/nucleotide reverse transcriptase inhibitors; Non-nucleoside reverse transcriptase inhibitors; Protease inhibitors; Integrase strand transfer inhibitors; Fusion inhibitor; CCR5 antagonist ID HIV-INFECTED PATIENTS; RITONAVIR-BOOSTED ATAZANAVIR; MYOCARDIAL-INFARCTION; INHIBITOR; ABACAVIR; HYPERSENSITIVITY; RALTEGRAVIR; EFAVIRENZ; EFFICACY; COHORT AB The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus' replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date. C1 [Pau, Alice K.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [George, Jomy M.] Univ Sci Philadelphia, Philadelphia Coll Pharm, Dept Pharm Practice & Adm, Philadelphia, PA 19104 USA. RP Pau, AK (reprint author), NIAID, Div Clin Res, NIH, Bldg 10,Room 11C103,MSC 1880, Bethesda, MD 20892 USA. EM apau@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 61 TC 12 Z9 12 U1 2 U2 22 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0891-5520 EI 1557-9824 J9 INFECT DIS CLIN N AM JI Infect. Dis. Clin. North Am. PD SEP PY 2014 VL 28 IS 3 BP 371 EP + DI 10.1016/j.idc.2014.06.001 PN 1 PG 33 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP2JS UT WOS:000341899100007 PM 25151562 ER PT J AU Prasanna, PGS Ahmed, MM Stone, HB Vikram, B Mehta, MP Coleman, CN AF Prasanna, Pataje G. S. Ahmed, Mansoor M. Stone, Helen B. Vikram, Bhadrasain Mehta, Minesh P. Coleman, C. Norman TI Radiation-induced brain damage, impact of Michael Robbins' work and the need for predictive biomarkers SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Review DE Radiotherapy; radiation-induced brain damage; mechanisms; radiation mitigator; predictive biomarkers ID ANGIOTENSIN-CONVERTING ENZYME; INDUCED COGNITIVE IMPAIRMENT; PROPHYLACTIC CRANIAL IRRADIATION; CENTRAL-NERVOUS-SYSTEM; STEM-CELL TRANSPLANTATION; NEURAL PRECURSOR CELLS; WHITE-MATTER INTEGRITY; NORMAL TISSUE-INJURY; PPAR-ALPHA AGONIST; NF-KAPPA-B AB Purpose: To review the literature on radiation-induced normal tissue injury in the context of treatment of primary and metastatic brain tumors with a focus on Michael Robbins' work on mechanisms of injury and approaches to mitigation, and also to identify other potential opportunities to improve treatment outcome and quality of life (QOL). Background: Brain tumors remain a significant challenge for patients, their families, the physicians treating them, and researchers seeking more effective treatments. Current treatment of brain tumors involves combinations of radiotherapy with surgery, chemotherapy, and molecularly targeted agents. As patient survival improves with advances in treatment there is an increasing concern for the cognitive deficits that may become apparent months or years after treatment some of which are related to radiation-induced brain damage. One area of Michael Robbins' research was unraveling the mechanisms of radiation-induced cognitive deficits, which formed the basis for the development of some mitigators of radiation injury. Extrapolating from this, new opportunities to identify and develop putative predictive biomarkers of radiation-induced brain damage can be explored. Conclusions: Predictive biomarkers of radiation-induced brain injury may enable stratifying patients for customization of treatment and thus aid in improving the QOL and possibly prolonging survival. Here we discuss the challenges involved in leveraging recent advances in radiation-specific biomarker research and translating them to radiotherapy, which for the foreseeable future is likely to remain a cornerstone of the treatment of brain tumors. C1 [Prasanna, Pataje G. S.; Ahmed, Mansoor M.; Stone, Helen B.; Vikram, Bhadrasain; Coleman, C. Norman] NCI, Div Canc Treatment & Diag, Radiat Res Program, Bethesda, MD 20892 USA. [Mehta, Minesh P.] Univ Maryland, Med Ctr, Dept Radiat Oncol, Baltimore, MD 21201 USA. RP Prasanna, PGS (reprint author), NCI, Div Canc Treatment & Diag, Radiat Res Program, 9609 Med Ctr Dr,MSC 9727, Bethesda, MD 20892 USA. EM Pat.Prasanna@nih.gov OI mehta, minesh/0000-0002-4812-5713 FU National Cancer Institute's Radiation Research Program FX The authors appreciate insightful discussions with late Dr Michael Robbins, Wake Forest University and Dr Eric Bernhard, National Cancer Institute. National Cancer Institute's Radiation Research Program supported the manuscript preparation. The work is the opinion of the authors and not of the National Cancer Institute or Department of Health and Human Services. NR 133 TC 5 Z9 5 U1 1 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0955-3002 EI 1362-3095 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD SEP PY 2014 VL 90 IS 9 BP 742 EP 752 DI 10.3109/09553002.2014.925607 PG 11 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 AP6DD UT WOS:000342166800003 PM 24844376 ER PT J AU Koroshetz, WJ Landis, S AF Koroshetz, Walter J. Landis, Story TI Neurology's Stake in Foundational Neuroscience Research SO JAMA NEUROLOGY LA English DT Editorial Material C1 [Koroshetz, Walter J.; Landis, Story] NINDS, NIH, Bethesda, MD 20892 USA. RP Koroshetz, WJ (reprint author), NINDS, NIH, 31 Ctr Dr,MSC 2540,Bldg 31,Room 8A52, Bethesda, MD 20892 USA. EM koroshetzw@ninds.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD SEP PY 2014 VL 71 IS 9 BP 1081 EP 1082 DI 10.1001/jamaneurol.2014.1496 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AP3LK UT WOS:000341977300001 PM 25003493 ER PT J AU Fitzgerald, KC O'Reilly, EJ Falcone, GJ McCullough, ML Park, Y Kolonel, LN Ascherio, A AF Fitzgerald, Kathryn C. O'Reilly, EIlis J. Falcone, Guido J. McCullough, Marjorie L. Park, Yikyung Kolonel, Laurence N. Ascherio, Alberto TI Dietary omega-3 Polyunsaturated Fatty Acid Intake and Risk for Amyotrophic Lateral Sclerosis SO JAMA NEUROLOGY LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; SOCIETY CANCER PREVENTION; BASE-LINE CHARACTERISTICS; RETIRED-PERSONS DIET; MOTOR-NEURON DISEASE; VITAMIN-E INTAKE; NATIONAL-INSTITUTES; POOLED ANALYSIS; LINOLENIC ACID AB IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a severe progressive disease that cannot be prevented or cured. Diet-derived long-chain polyunsaturated fatty acids (PUFAs) are incorporated in brain lipids and modulate oxidative and inflammatory processes and could thus affect ALS risk and progression. OBJECTIVE To examine the association between omega-6 and omega-3 PUFA consumption and ALS risk. DESIGN, SETTING, AND PARTICIPANTS Longitudinal analyses based on 1 002 082 participants (479 114 women and 522 968 men) in 5 prospective cohorts: the National Institutes of Health-AARP Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Health Professionals Follow-up Study, the Multiethnic Cohort Study, and the Nurses' Health Study. Diet was assessed via food frequency questionnaire developed or modified for each cohort. Participants were categorized into cohort-specific quintiles of intake of energy-adjusted dietary variables. MAIN OUTCOMES AND MEASURES Cohort-specific multivariable-adjusted risk ratios (RRs) of ALS incidence or death estimated by Cox proportional hazards regression and pooled using random-effects methods. RESULTS A total of 995 ALS cases were documented during the follow-up. A greater omega-3 PUFA intake was associated with a reduced risk for ALS. The pooled, multivariable-adjusted RR for the highest to the lowest quintile was 0.66 (95% CI, 0.53-0.81; P < .001 for trend). Consumption of both a-linolenic acid (RR, 0.73; 95% CI, 0.59-0.89; P = .003 for trend) and marine omega-3 PUFAs (RR, 0.84; 95% CI, 0.65-1.08; P = .03 for trend) contributed to this inverse association. Intakes of omega-6 PUFA were not associated with ALS risk. CONCLUSIONS AND RELEVANCE Consumption of foods high in omega-3 PUFAs may help prevent or delay the onset of ALS. C1 [Fitzgerald, Kathryn C.; O'Reilly, EIlis J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Falcone, Guido J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [O'Reilly, EIlis J.; Ascherio, Alberto] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [O'Reilly, EIlis J.; Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Fitzgerald, KC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,3rd Floor, Boston, MA 02115 USA. EM hpkcf@channing.harvard.edu RI Falcone, Guido/L-2287-2016 OI Falcone, Guido/0000-0002-6407-0302 FU National Institute of Neurological Diseases and Stroke [R01 NS045893]; National Cancer Institute [P01 CA87969, P01 CA055075]; ALS Therapy Alliance Foundation FX This work was supported by grant R01 NS045893 from the National Institute of Neurological Diseases and Stroke, grants P01 CA87969 and P01 CA055075 from the National Cancer Institute, and a grant from the ALS Therapy Alliance Foundation. NR 51 TC 20 Z9 21 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD SEP PY 2014 VL 71 IS 9 BP 1102 EP 1110 DI 10.1001/jamaneurol.2014.1214 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AP3LK UT WOS:000341977300006 PM 25023276 ER PT J AU Keller, MF Ferrucci, L Singleton, AB Tienari, PJ Laaksovirta, H Restagno, G Chio, A Traynor, BJ Nalls, MA AF Keller, Margaux F. Ferrucci, Luigi Singleton, Andrew B. Tienari, Pentti J. Laaksovirta, Hannu Restagno, Gabriella Chio, Adriano Traynor, Bryan J. Nalls, Michael A. TI Genome-Wide Analysis of the Heritability of Amyotrophic Lateral Sclerosis SO JAMA NEUROLOGY LA English DT Article ID SPORADIC ALS; HEXANUCLEOTIDE REPEAT; SUSCEPTIBILITY LOCI; GENETIC-VARIATION; COMMON SNPS; ASSOCIATION; POPULATION; ONSET; STRATIFICATION; EPIDEMIOLOGY AB IMPORTANCE Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations. OBJECTIVE To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies. DESIGN, SETTING, AND PARTICIPANTS We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the In CHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland. MAIN OUTCOMES AND MEASURES A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability. RESULTS With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0%(95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk. CONCLUSIONS AND RELEVANCE We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS. C1 [Keller, Margaux F.; Singleton, Andrew B.; Nalls, Michael A.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Keller, Margaux F.] Temple Univ, Dept Biol Anthropol, Philadelphia, PA 19122 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Tienari, Pentti J.; Laaksovirta, Hannu] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Tienari, Pentti J.; Laaksovirta, Hannu] Univ Helsinki, Biomedicum, Res Programs Unit, Helsinki, Finland. [Restagno, Gabriella] ASO OIRM St Anna, Dept Clin Pathol, Mol Genet Unit, Turin, Italy. [Chio, Adriano] Univ Turin, Rita Levi Montalcini Dept Neurosci, Turin, Italy. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Keller, MF (reprint author), NIA, Mol Genet Sect, Neurogenet Lab, NIH, 35 Convent Dr,Room 1A-1008, Bethesda, MD 20892 USA. EM kellermf@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Tienari, Pentti/A-4893-2012 OI Chio, Adriano/0000-0001-9579-5341; FU National Institute on Aging [Z01AG000949-02]; NINDS; National Institute of Mental Health; ALS Association; Packard Center; Istituto Superiore di Sanita [2005-10]; Regione Piemonte [PF A15]; Medical Research Council FX This work was supported by the intramural programmes of the National Institute on Aging, the NINDS, and the National Institute of Mental Health, as well as by grants from the ALS Association and the Packard Center for ALS Research at Johns Hopkins. This work was also supported by the Intramural Research Program of the National Institute on Aging (project Z01AG000949-02), the NINDS, Istituto Superiore di Sanita (grant 2005-10 to Dr Ferruci), PF A15 Regione Piemonte (to Dr Restagno), and the Medical Research Council. NR 49 TC 14 Z9 14 U1 0 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD SEP PY 2014 VL 71 IS 9 BP 1123 EP 1133 DI 10.1001/jamaneurol.2014.1184 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA AP3LK UT WOS:000341977300008 PM 25023141 ER PT J AU Kara, E Kiely, AP Proukakis, C Giffin, N Love, S Hehir, J Rantell, K Pandraud, A Hernandez, DG Nacheva, E Pittman, AM Nalls, MA Singleton, AB Revesz, T Bhatia, KP Quinn, N Hardy, J Holton, JL Houlden, H AF Kara, Eleanna Kiely, Aoife P. Proukakis, Christos Giffin, Nicola Love, Seth Hehir, Jason Rantell, Khadija Pandraud, Amelie Hernandez, Dena G. Nacheva, Elizabeth Pittman, Alan M. Nalls, Mike A. Singleton, Andrew B. Revesz, Tamas Bhatia, Kailash P. Quinn, Niall Hardy, John Holton, Janice L. Houlden, Henry TI A 6.4 Mb Duplication of the alpha-Synuclein Locus Causing Frontotemporal Dementia and Parkinsonism Phenotype-Genotype Correlations SO JAMA NEUROLOGY LA English DT Article ID GENE DUPLICATION; SNCA DUPLICATION; LEWY BODIES; DISEASE; GENOME; MUTATIONS; ASSOCIATION; HETEROGENEITY; INSTABILITY; DISCORDANT AB IMPORTANCE alpha-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown. OBJECTIVES To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. DESIGN, SETTING, AND PARTICIPANTS We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. MAIN OUTCOMES AND MEASURES We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. RESULTS We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive alpha-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively. CONCLUSIONS AND RELEVANCE These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in alpha-synuclein aggregation. C1 [Kara, Eleanna; Kiely, Aoife P.; Hehir, Jason; Pandraud, Amelie; Hernandez, Dena G.; Pittman, Alan M.; Revesz, Tamas; Hardy, John; Holton, Janice L.; Houlden, Henry] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Kiely, Aoife P.; Revesz, Tamas; Holton, Janice L.] UCL Inst Neurol, Queen Sq Brain Bank, London WC1N 3BG, England. [Proukakis, Christos] UCL Inst Neurol, Dept Clin Neurosci, London WC1N 3BG, England. [Giffin, Nicola] Frenchay Hosp, Dept Neurol, Bristol BS16 1LE, Avon, England. [Love, Seth] Frenchay Hosp, Dept Neuropathol, Bristol BS16 1LE, Avon, England. [Rantell, Khadija] UCL, Biomed Res Ctr, London, England. [Rantell, Khadija] UCL Inst Neurol, Educ Unit, London WC1N 3BG, England. [Hernandez, Dena G.; Nalls, Mike A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Nacheva, Elizabeth] UCL, Dept Acad Hematol, London, England. [Bhatia, Kailash P.; Quinn, Niall] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Houlden, Henry] UCL Inst Neurol, MRC, Ctr Neuromuscular Dis, London WC1N 3BG, England. RP Houlden, H (reprint author), UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England. EM h.houlden@ucl.ac.uk RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Pittman, Alan/D-6231-2012; Houlden, Henry/C-1532-2008; Revesz, Tamas/A-8732-2010 OI Houlden, Henry/0000-0002-2866-7777; Revesz, Tamas/0000-0003-2501-0259 FU Parkinson's Disease Foundation; Wellcome Trust/Medical Research Council [WT089698]; Reta Lila Weston Institute for Neurological Studies; Multiple System Atrophy Trust; Alzheimer's Research United Kingdom; Parkinson's United Kingdom [G-1009]; Dystonia Coalition; Department of Health and Human Services [ZO1 AG000949-08]; National Institute for Health Research; Intramural Research Program of the National Institute on Aging, National Institutes of Health; UCL Hospitals Biomedical Research Centre FX This study was supported by the Parkinson's Disease Foundation and grant WT089698 from the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration received by the United Kingdom Parkinson's Disease Consortium whose members are from the UCL Institute of Neurology, the University of Sheffeld, and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. Dr Holton is supported by the Reta Lila Weston Institute for Neurological Studies, the Multiple System Atrophy Trust, Alzheimer's Research United Kingdom, and Parkinson's United Kingdom. Dr Kiely is supported by the Multiple System Atrophy Trust. Dr Bhatia received grant G-1009 from Parkinson's United Kingdom and a grant from the Dystonia Coalition. This study was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, project ZO1 AG000949-08 from the Department of Health and Human Services and the National Institute for Health Research, UCL Hospitals Biomedical Research Centre. NR 54 TC 15 Z9 15 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD SEP PY 2014 VL 71 IS 9 BP 1162 EP 1171 DI 10.1001/jamaneurol.2014.994 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AP3LK UT WOS:000341977300013 PM 25003242 ER PT J AU Frohman, EM Douek, D Major, EO AF Frohman, Elliot M. Douek, Daniel Major, Eugene O. TI Relevance of CD34+ Cells as a Reservoir for JC Virus in Patients With Multiple Sclerosis Reply SO JAMA NEUROLOGY LA English DT Letter ID NATALIZUMAB C1 [Frohman, Elliot M.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Douek, Daniel; Major, Eugene O.] NIH, Bethesda, MD 20892 USA. RP Frohman, EM (reprint author), Univ Texas SW Med Ctr Dallas, Dept Neurol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM elliot.frohman@utsouthwestern.edu NR 4 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD SEP PY 2014 VL 71 IS 9 BP 1192 EP 1193 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA AP3LK UT WOS:000341977300024 PM 25200546 ER PT J AU Subramaniam, GA Volkov, ND AF Subramaniam, Geetha A. Volkov, Nora D. TI Substance Misuse Among Adolescents To Screen or Not to Screen? SO JAMA PEDIATRICS LA English DT Editorial Material C1 [Subramaniam, Geetha A.; Volkov, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Subramaniam, GA (reprint author), NIDA, 6001 Executive Blvd,Room 3119,MSC 9557, Bethesda, MD 20892 USA. EM geetha.subramaniam@nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 4 TC 6 Z9 6 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD SEP PY 2014 VL 168 IS 9 BP 798 EP 799 DI 10.1001/jamapediatrics.2014.958 PG 2 WC Pediatrics SC Pediatrics GA AO8AS UT WOS:000341575200006 PM 25069987 ER PT J AU Guasch, L Sitzmann, M Nicklaus, MC AF Guasch, Laura Sitzmann, Markus Nicklaus, Marc C. TI Enumeration of Ring-Chain Tautomers Based on SMIRKS Rules SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID LARGE DATABASES; INFORMATION; DERIVATIVES; PRODUCTS; WARFARIN; CONDENSATION; ADDUCTS; DESIGN AB A compound exhibits (prototropic) tautomerism if it can be represented by two or more structures that are related by a formal intramolecular movement of a hydrogen atom from one heavy atom position to another. When the movement of the proton is accompanied by the opening or closing of a ring it is called ring-chain tautomerism. This type of tautomerism is well observed in carbohydrates, but it also occurs in other molecules such as warfarin. In this work, we present an approach that allows for the generation of all ring-chain tautomers of a given chemical structure. Based on Baldwin's Rules estimating the likelihood of ring closure reactions to occur, we have defined a set of transform rules covering the majority of ring-chain tautomerism cases. The rules automatically detect substructures in a given compound that can undergo a ring- chain tautomeric transformation. Each transformation is encoded in SMIRKS line notation. All work was implemented in the chemoinformatics toolkit CACTVS. We report on the application of our ring chain tautomerism rules to a large database of commercially available screening samples in order to identify ring-chain tautomers. C1 [Guasch, Laura; Sitzmann, Markus; Nicklaus, Marc C.] NCI, Biol Chem Lab, Ctr Canc Res, NIH,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Nicklaus, MC (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM mn1@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 NR 50 TC 4 Z9 4 U1 2 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD SEP PY 2014 VL 54 IS 9 BP 2423 EP 2432 DI 10.1021/ci500363p PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA AP6IH UT WOS:000342180400004 PM 25158156 ER PT J AU Greenstein, D Kataria, R Gochman, P Dasgupta, A Malley, JD Rapoport, J Gogtay, N AF Greenstein, Deanna Kataria, Rachna Gochman, Peter Dasgupta, Abhijit Malley, James D. Rapoport, Judith Gogtay, Nitin TI Looking for Childhood-Onset Schizophrenia: Diagnostic Algorithms for Classifying Children and Adolescents with Psychosis SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID PATTERN-CLASSIFICATION; BIRTH-COHORT; RELIABILITY; SYMPTOMS; REGRESSION; DISORDER; PERFORMANCE; IMPAIRMENT; SELECTION; EVENTS AB Objective: Among children <13 years of age with persistent psychosis and contemporaneous decline in functioning, it is often difficult to determine if the diagnosis of childhood onset schizophrenia (COS) is warranted. Despite decades of experience, we have up to a 44% false positive screening diagnosis rate among patients identified as having probable or possible COS; final diagnoses are made following inpatient hospitalization and medication washout. Because our lengthy medication-free observation is not feasible in clinical practice, we constructed diagnostic classifiers using screening data to assist clinicians practicing in the community or academic centers. Methods: We used cross-validation, logistic regression, receiver operating characteristic (ROC) analysis, and random forest to determine the best algorithmfor classifying COS (n = 85) versus histories of psychosis and impaired functioning in children and adolescents who, at screening, were considered likely to have COS, but who did not meet diagnostic criteria for schizophrenia after medication washout and inpatient observation (n = 53). We used demographics, clinical history measures, intelligence quotient (IQ) and screening rating scales, and number of typical and atypical antipsychotic medications as our predictors. Results: Logistic regression models using nine, four, and two predictors performed well with positive predictive values > 90%, overall accuracy > 77%, and areas under the curve (AUCs) > 86%. Conclusions: COS can be distinguished from alternate disorders with psychosis in children and adolescents; greater levels of positive and negative symptoms and lower levels of depression combine to make COS more likely. Weinclude a worksheet so that clinicians in the community and academic centers can predict the probability that a young patient may be schizophrenic, using only two ratings. C1 [Greenstein, Deanna; Kataria, Rachna; Gochman, Peter; Rapoport, Judith; Gogtay, Nitin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Dasgupta, Abhijit] NIAMSD, NIAMS, NIH, Bethesda, MD 20892 USA. [Malley, James D.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Greenstein, D (reprint author), 10 Ctr Dr Room 3N202, Bethesda, MD 20892 USA. EM dede.greenstein@nih.gov RI Gogtay, Nitin/A-3035-2008 NR 39 TC 1 Z9 1 U1 1 U2 12 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD SEP PY 2014 VL 24 IS 7 BP 366 EP 373 DI 10.1089/cap.2013.0139 PG 8 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA AP6CD UT WOS:000342164200002 PM 25019955 ER PT J AU Rid, A Abdoler, E Roberson-Nay, R Pine, DS Wendler, D AF Rid, Annette Abdoler, Emily Roberson-Nay, Roxann Pine, Daniel S. Wendler, David TI Evaluating the Risks of Clinical Research: Direct Comparative Analysis SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID DENTAL ANXIETY SCALE; PANIC DISORDER; CARBON-DIOXIDE; CHILDHOOD ANXIETY; TELEVISION-NEWS; CHILDREN; FEAR; RELIABILITY; PARENTS; PAIN AB Objectives: Many guidelines and regulations allow children and adolescents to be enrolled in research without the prospect of clinical benefit when it poses minimal risk. However, few systematic methods exist to determine when research risks are minimal. This situation has led to significant variation in minimal risk judgments, raising concern that some children are not being adequately protected. To address this concern, we describe a new method for implementing the widely endorsed "risks of daily life'' standard for minimal risk. This standard defines research risks as minimal when they do not exceed the risks posed by daily life activities or routine examinations. Methods: This study employed a conceptual and normative analysis, and use of an illustrative example. Results: Different risks are composed of the same basic elements: Type, likelihood, and magnitude of harm. Hence, one can compare the risks of research and the risks of daily life by comparing the respective basic elements with each other. We use this insight to develop a systematic method, direct comparative analysis, for implementing the "risks of daily life'' standard for minimal risk. The method offers a way of evaluating research procedures that pose the same types of risk as daily life activities, such as the risk of experiencing anxiety, stress, or other psychological harm. We thus illustrate how direct comparative analysis can be applied in practice by using it to evaluate whether the anxiety induced by a respiratory CO2 challenge poses minimal or greater than minimal risks in children and adolescents. Conclusions: Direct comparative analysis is a systematic method for applying the "risks of daily life'' standard for minimal risk to research procedures that pose the same types of risk as daily life activities. It thereby offers a method to protect children and adolescents in research, while ensuring that important studies are not blocked because of unwarranted concerns about research risks. C1 [Rid, Annette] Kings Coll London, Dept Social Sci Hlth & Med, London WC2R 2LS, England. [Rid, Annette] Univ Zurich, Inst Biomed Eth, Zurich, Switzerland. [Abdoler, Emily] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Roberson-Nay, Roxann] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Rid, A (reprint author), Kings Coll London, Dept Social Sci Hlth & Med, East Wing Bldg, London WC2R 2LS, England. EM annette.rid@kcl.ac.uk FU University of Zurich (Nachwuchsforderungskredit) FX Dr. Rid received funding from the University of Zurich (Nachwuchsforderungskredit) for this project. The sponsor had no 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. NR 56 TC 0 Z9 0 U1 3 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD SEP PY 2014 VL 24 IS 7 BP 390 EP 398 DI 10.1089/cap.2014.0039 PG 9 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA AP6CD UT WOS:000342164200005 PM 25210944 ER PT J AU Edwards, JP Thornton, AM Shevach, EM AF Edwards, Justin P. Thornton, Angela M. Shevach, Ethan M. TI Release of Active TGF-beta 1 from the Latent TGF-beta 1/GARP Complex on T Regulatory Cells Is Mediated by Integrin beta(8) SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; TGF-BETA; DENDRITIC CELLS; IN-VIVO; TRANSFORMING GROWTH-FACTOR-BETA-1; ACTIVATION; EXPRESSION; ALPHA-V-BETA-8; MICE; INFLAMMATION AB Activated T regulatory cells (Tregs) express latent TGF-beta 1 on their cell surface bound to GARP. Although integrins have been implicated in mediating the release of active TGF-beta 1 from the complex of latent TGF-b1 and latent TGF-beta 1 binding protein, their role in processing latent TGF-beta 1 from the latent TGF-beta 1/GARP complex is unclear. Mouse CD4(+)Foxp3(+) Treg, but not CD4(+) Foxp3(-) T cells, expressed integrin beta(8) (Itgb8) as detected by quantitative RT-PCR. Itgb8 expression was a marker of thymically derived (t)Treg, because it could not be detected on Foxp3(+)Helios(-) Tregs or on Foxp3(+) T cells induced in vitro. Tregs from Itgb8 conditional knockouts exhibited normal suppressor function in vitro and in vivo in a model of colitis but failed to provide TGF-beta 1 to drive Th17 or induced Treg differentiation in vitro. In addition, Itgb8 knockout Tregs expressed higher levels of latent TGF-beta 1 on their cell surface consistent with defective processing. Thus, integrin alpha(v)beta(8) is a marker of tTregs and functions in a cell intrinsic manner in mediating the processing of latent TGF-beta 1 from the latent TGF-beta 1/GARP complex on the surface of tTregs. C1 [Edwards, Justin P.; Thornton, Angela M.; Shevach, Ethan M.] NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM ESHEVACH@niaid.nih.gov OI Edwards, Justin/0000-0001-8936-2136 FU Intramural Program of the National Institute of Allergy and Infectious Diseases FX This work was supported by funds from the Intramural Program of the National Institute of Allergy and Infectious Diseases. NR 22 TC 12 Z9 14 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP PY 2014 VL 193 IS 6 BP 2843 EP 2849 DI 10.4049/jimmunol.1401102 PG 7 WC Immunology SC Immunology GA AP1VJ UT WOS:000341859700024 PM 25127859 ER PT J AU Joedicke, JJ Myers, L Carmody, AB Messer, RJ Wajant, H Lang, KS Lang, PA Mak, TW Hasenkrug, KJ Dittmer, U AF Joedicke, Jara J. Myers, Lara Carmody, Aaron B. Messer, Ronald J. Wajant, Harald Lang, Karl S. Lang, Philipp A. Mak, Tak W. Hasenkrug, Kim J. Dittmer, Ulf TI Activated CD8+ T Cells Induce Expansion of V beta 5(+) Regulatory T Cells via TNFR2 Signaling SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; FRIEND RETROVIRUS INFECTION; IMMUNOLOGICAL SELF-TOLERANCE; FACTOR RECEPTOR; EFFECTOR FUNCTION; IMMUNE-RESPONSES; VIRAL-INFECTION; ANTI-TNF; IN-VIVO; VIRUS AB V beta 5(+) regulatory T cells (Tregs), which are specific for a mouse endogenous retroviral superantigen, become activated and proliferate in response to Friend virus (FV) infection. We previously reported that FV-induced expansion of this Treg subset was dependent on CD8(+) T cells and TNF-alpha, but independent of IL-2. We now show that the inflammatory milieu associated with FV infection is not necessary for induction of V beta 5(+) Treg expansion. Rather, it is the presence of activated CD8(+) T cells that is critical for their expansion. The data indicate that the mechanism involves signaling between the membrane-bound form of TNF-alpha on activated CD8(+) T cells and TNFR2 on Tregs. CD8(+) T cells expressing membrane-bound TNF-alpha but no soluble TNF-alpha remained competent to induce strong V beta 5(+) Treg expansion in vivo. In addition, V beta 5(+) Tregs expressing only TNFR2 but no TNFR1 were still responsive to expansion. Finally, treatment of naive mice with soluble TNF-alpha did not induce V beta 5(+) Treg expansion, but treatment with a TNFR2-specific agonist did. These results reveal a new mechanism of intercellular communication between activated CD8(+) T cell effectors and Tregs that results in the activation and expansion of a Treg subset that subsequently suppresses CD8(+) T cell functions. C1 [Joedicke, Jara J.; Dittmer, Ulf] Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, D-45147 Essen, Germany. [Myers, Lara; Messer, Ronald J.; Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Carmody, Aaron B.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Wajant, Harald] Univ Hosp Wurzburg, Div Mol Internal Med, Dept Internal Med 2, D-97080 Wurzburg, Germany. [Lang, Karl S.] Univ Duisburg Essen, Univ Hosp Essen, Inst Immunol, D-45147 Essen, Germany. [Lang, Philipp A.] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infect Dis, D-40225 Dusseldorf, Germany. [Lang, Philipp A.] Univ Dusseldorf, Dept Mol Med 2, D-40225 Dusseldorf, Germany. [Mak, Tak W.] Univ Toronto, Univ Hlth Network, Ontario Canc Inst, Dept Med Biophys & Immunol,Campbell Family Inst B, Toronto, ON, Canada. RP Hasenkrug, KJ (reprint author), NIAID, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM khasenkrug@nih.gov; ulf.dittmer@uni-due.de RI Lang, Karl/R-2505-2016; Wajant, Harald/A-3020-2017 OI Wajant, Harald/0000-0002-2005-3949 FU National Institute of Allergy and Infectious Diseases/National Institutes of Health and Deutsche Forschungsgemeinschaft [Transregio 60, GK1045] FX This work was supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases/National Institutes of Health and Deutsche Forschungsgemeinschaft Transregio 60 Project B4 and Graduate School Grant GK1045. NR 75 TC 5 Z9 5 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP PY 2014 VL 193 IS 6 BP 2952 EP 2960 DI 10.4049/jimmunol.1400649 PG 9 WC Immunology SC Immunology GA AP1VJ UT WOS:000341859700035 PM 25098294 ER PT J AU Shi, CS Qi, HY Boularan, C Huang, NN Abu-Asab, M Shelhamer, JH Kehrl, JH AF Shi, Chong-Shan Qi, Hai-Yan Boularan, Cedric Huang, Ning-Na Abu-Asab, Mones Shelhamer, James H. Kehrl, John H. TI SARS-Coronavirus Open Reading Frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACUTE RESPIRATORY SYNDROME; ANTIVIRAL SIGNALING PROTEIN; HEPATITIS-C-VIRUS; ADAPTER MAVS; AUTOPHAGY; DEGRADATION; ACTIVATION; IDENTIFICATION; LOCALIZATION; PATHOGENESIS AB Coronaviruses (CoV) have recently emerged as potentially serious pathogens that can cause significant human morbidity and death. The severe acute respiratory syndrome (SARS)-CoV was identified as the etiologic agent of the 2002-2003 international SARS outbreak. Yet, how SARS evades innate immune responses to cause human disease remains poorly understood. In this study, we show that a protein encoded by SARS-CoV designated as open reading frame-9b (ORF-9b) localizes to mitochondria and causes mitochondrial elongation by triggering ubiquitination and proteasomal degradation of dynamin-like protein 1, a host protein involved in mitochondrial fission. Also, acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. This severely limits host cell IFN responses. Reducing either PCBP2 or AIP4 expression substantially reversed the ORF-9b-mediated reduction of MAVS and the suppression of antiviral transcriptional responses. Finally, transient ORF-9b expression led to a strong induction of autophagy in cells. The induction of autophagy depended upon ATG5, a critical autophagy regulator, but the inhibition of MAVS signaling did not. These results indicate that SARS-CoV ORF-9b manipulates host cell mitochondria and mitochondrial function to help evade host innate immunity. This study has uncovered an important clue to the pathogenesis of SARS-CoV infection and illustrates the havoc that a small ORF can cause in cells. C1 [Shi, Chong-Shan; Boularan, Cedric; Huang, Ning-Na; Kehrl, John H.] NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Qi, Hai-Yan; Shelhamer, James H.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Abu-Asab, Mones] NEI, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11B08,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov FU National Institutes of Health (National Institute of Allergy and Infectious Diseases) FX This work was supported by the Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases). NR 48 TC 23 Z9 25 U1 2 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP PY 2014 VL 193 IS 6 BP 3080 EP 3089 DI 10.4049/jimmunol.1303196 PG 10 WC Immunology SC Immunology GA AP1VJ UT WOS:000341859700047 PM 25135833 ER PT J AU Li, QS Zeng, M Duan, LJ Voss, JE Smith, AJ Pambuccian, S Shang, L Wietgrefe, S Southern, PJ Reilly, CS Skinner, PJ Zupancic, ML Carlis, JV Piatak, M Waterman, D Reeves, RK Masek-Hammerman, K Derdeyn, CA Alpert, MD Evans, DT Kohler, H Muller, S Robinson, J Lifson, JD Burton, DR Johnson, RP Haase, AT AF Li, Qingsheng Zeng, Ming Duan, Lijie Voss, James E. Smith, Anthony J. Pambuccian, Stefan Shang, Liang Wietgrefe, Stephen Southern, Peter J. Reilly, Cavan S. Skinner, Pamela J. Zupancic, Mary L. Carlis, John V. Piatak, Michael, Jr. Waterman, Diane Reeves, R. Keith Masek-Hammerman, Katherine Derdeyn, Cynthia A. Alpert, Michael D. Evans, David T. Kohler, Heinz Mueller, Sybille Robinson, James Lifson, Jeffrey D. Burton, Dennis R. Johnson, R. Paul Haase, Ashley T. TI Live Simian Immunodeficiency Virus Vaccine Correlate of Protection: Local Antibody Production and Concentration on the Path of Virus Entry SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NEONATAL FC-RECEPTOR; ATTENUATED SIV; RHESUS MACAQUES; MONOCLONAL-ANTIBODIES; CONTROL REPLICATION; IMMUNE-RESPONSES; RESERVE CELLS; T-CELLS; INFECTION; HIV AB We sought design principles for a vaccine to prevent HIV transmission to women by identifying correlates of protection conferred by a highly effective live attenuated SIV vaccine in the rhesus macaque animal model. We show that SIVmac239 Delta nef vaccination recruits plasma cells and induces ectopic lymphoid follicle formation beneath the mucosal epithelium in the rhesus macaque female reproductive tract. The plasma cells and ectopic follicles produce IgG Abs reactive with viral envelope glycoprotein gp41 trimers, and these Abs are concentrated on the path of virus entry by the neonatal FcR in cervical reserve epithelium and in vaginal epithelium. This local Ab production and delivery system correlated spatially and temporally with the maturation of local protection against high-dose pathogenic SIV vaginal challenge. Thus, designing vaccines to elicit production and concentration of Abs at mucosal frontlines could aid in the development of an effective vaccine to protect women against HIV-1. C1 [Li, Qingsheng; Zeng, Ming; Duan, Lijie; Smith, Anthony J.; Shang, Liang; Wietgrefe, Stephen; Southern, Peter J.; Zupancic, Mary L.; Haase, Ashley T.] Univ Minnesota, Sch Med, Dept Microbiol, Minneapolis, MN 55455 USA. [Voss, James E.; Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Voss, James E.; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Design, La Jolla, CA 92037 USA. [Voss, James E.; Burton, Dennis R.] MIT, Ragon Inst MGH, Charlestown, MA 02129 USA. [Voss, James E.; Burton, Dennis R.] Harvard Univ, Charlestown, MA 02129 USA. [Pambuccian, Stefan] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Reilly, Cavan S.] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Skinner, Pamela J.] Univ Minnesota, Coll Vet Med, Dept Vet & Biomed Sci, St Paul, MN 55108 USA. [Carlis, John V.] Univ Minnesota, Coll Sci & Engn, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] Sci Applicat Int Corp Frederick Inc, Natl Canc Inst, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Waterman, Diane] ZeptoMetrix Corp, Buffalo, NY 14202 USA. [Reeves, R. Keith; Masek-Hammerman, Katherine; Alpert, Michael D.; Evans, David T.] Harvard Univ, New England Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. [Reeves, R. Keith; Masek-Hammerman, Katherine] Massachusetts Gen Hosp, Dept Med, Infect Dis Unit, Boston, MA 02115 USA. [Derdeyn, Cynthia A.] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30329 USA. [Derdeyn, Cynthia A.] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30329 USA. [Alpert, Michael D.; Evans, David T.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Kohler, Heinz] Univ Kentucky, Dept Microbiol & Immunol & Mol Genet, Lexington, KY 40536 USA. [Mueller, Sybille] ImmPheron Inc, Lexington, KY 40509 USA. [Robinson, James] Tulane Univ, Ctr Infect Dis, Dept Pediat, New Orleans, LA 70112 USA. RP Haase, AT (reprint author), Univ Minnesota, Sch Med, Dept Microbiol, MMC 196,420 Delaware St SE, Minneapolis, MN 55455 USA. EM haase001@umn.edu OI Skinner, Pamela/0000-0003-3388-1687 FU International AIDS Vaccine Initiative; National Institutes of Health [AI 086922, AI 071306, RR00168, AI095985, AI 055332, 1UM1AI100663]; Center for HIV/AIDS Vaccine Immunology/HIV Vaccine Trials Network; Ragon Fellowship; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health/National Institute of Allergy and Infectious Diseases Reagent Resource Support Program for AIDS Vaccine Development, Quality Biological, Inc., Gaithersburg, MD (National [HHSN272201100023C]; [U19 AI 067854] FX This work was supported by a grant from the International AIDS Vaccine Initiative (to A.T.H.); National Institutes of Health Grants AI 086922 (to A.T.H.), AI 071306 and RR00168 (to R.P.J.), AI095985 (to R.P.J. and A.T.H.), and AI 055332 and 1UM1AI100663 (to D.R.B.); a Center for HIV/AIDS Vaccine Immunology/HIV Vaccine Trials Network Early Stage Investigator award and Grant U19 AI 067854 (to R.K.R.); a Ragon Fellowship (to J.E.V.); and by federal funds from the National Cancer Institute, National Institutes of Health under Contract HHSN261200800001E and the National Institutes of Health/National Institute of Allergy and Infectious Diseases Reagent Resource Support Program for AIDS Vaccine Development, Quality Biological, Inc., Gaithersburg, MD (National Institute of Allergy and Infectious Diseases Division of AIDS Contract HHSN272201100023C). NR 46 TC 28 Z9 28 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP PY 2014 VL 193 IS 6 BP 3113 EP 3125 DI 10.4049/jimmunol.1400820 PG 13 WC Immunology SC Immunology GA AP1VJ UT WOS:000341859700050 PM 25135832 ER PT J AU Rose, SR Vallabhajosyula, S Velez, MG Fedorko, DP VanRaden, MJ Gea-Banacloche, JC Lionakis, MS AF Rose, Stacey R. Vallabhajosyula, Saraschandra Velez, Miguel G. Fedorko, Daniel P. VanRaden, Mark J. Gea-Banacloche, Juan C. Lionakis, Michail S. TI The utility of bronchoalveolar lavage beta-D-glucan testing for the diagnosis of invasive fungal infections SO JOURNAL OF INFECTION LA English DT Article DE Invasive fungal infection; Aspergillosis; Beta-D-glucan; Galactomannan; Bronchoalveolar lavage ID PNEUMOCYSTIS-JIROVECII PNEUMONIA; MYCOSES STUDY-GROUP; EUROPEAN-ORGANIZATION; METAANALYSIS; ASSAY; ASPERGILLOSIS; DISEASES AB Objectives: To investigate the utility of beta-D-glucan (BDG) testing in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive fungal infection (IFI), as compared to BAL galactomannan (GM). Methods: We retrospectively reviewed medical records of 132 consecutive patients at the National Institutes of Health (NIH) in whom BAL BDG testing was performed for diagnosis of pneumonia. Using the European Organization for Research and Treatment of Cancer/Mycoses Study Group guidelines, we determined which patients had proven or probable IFI, and assessed the diagnostic performance of BAL BDG testing, relative to BAL GM. We also determined the reproducibility of the BDG assay in BAL via repeat testing of patient samples. Results: Ten patients had Pneumocystis pneumonia, and 34 patients had proven/probable IFI, including 14 with invasive aspergillosis (IA). BAL BDG was 100% sensitive for Pneumocystis. Although BAL BDG had similar sensitivity to BAL GM for the diagnosis of IA and IFI, it exhibited inferior specificity. Repeat testing demonstrated poor reproducibility of the BDG assay in BAL but not in serum. Conclusions: BDG testing exhibits poor specificity and reproducibility in BAL. Identification of the BAL-specific factors that may interfere with the performance of the assay could improve the clinical usefulness of BAL BDG testing. Published by Elsevier Ltd on behalf of The British Infection Association. C1 [Rose, Stacey R.; Vallabhajosyula, Saraschandra; Velez, Miguel G.; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Fedorko, Daniel P.] Off Device Evaluat Food & Drug Adm, Silver Spring, MD 20993 USA. [VanRaden, Mark J.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20817 USA. [Gea-Banacloche, Juan C.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, NIH, 9000 Rockville Pike,Bldg 10,Room 11 C 102, Bethesda, MD 20892 USA. EM Stacey.rose@nih.gov; lionakism@niaid.nih.gov OI Vallabhajosyula, Saraschandra/0000-0002-1631-8238 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. Results were presented in part at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy in Denver, Colo-rado, 2013. NR 13 TC 13 Z9 13 U1 1 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 EI 1532-2742 J9 J INFECTION JI J. Infect. PD SEP PY 2014 VL 69 IS 3 BP 278 EP 283 DI 10.1016/j.jinf.2014.04.008 PG 6 WC Infectious Diseases SC Infectious Diseases GA AP3PF UT WOS:000341988500009 PM 24797077 ER PT J AU Benjamini, D Komlosh, ME Basser, PJ Nevo, U AF Benjamini, Dan Komlosh, Michal E. Basser, Peter J. Nevo, Uri TI Nonparametric pore size distribution using d-PFG: Comparison to s-PFG and migration to MRI SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE MRI; Double pulsed field gradient; Pore size distribution; NMR; Nonparametric; Empirical ID COMPARTMENT SHAPE ANISOTROPY; FIELD GRADIENT MR; DIFFUSION-DIFFRACTION; NMR DIFFUSION; WHITE-MATTER; WATER; SCLEROSIS; FRAMEWORK; POROSITY AB Here we present the successful translation of a pore size distribution (PSD) estimation method from NMR to MRI. This approach is validated using a well-characterized MRI phantom consisting of stacked glass capillary arrays (GCA) having different diameters. By employing a double pulsed-field gradient (d-PFG) MRI sequence, this method overcomes several important theoretical and experimental limitations of previous single-PFG (s-PFG) based MRI methods by allowing the relative diffusion gradients' direction to vary. This feature adds an essential second dimension in the parameters space, which can potentially improve the reliability and stability of the PSD estimation. To infer PSDs from the MRI data in each voxel an inverse linear problem is solved in conjunction with the multiple correlation function (MCF) framework, which can account for arbitrary experimental parameters (e.g., long diffusion pulses). This scheme makes no a priori assumptions about the functional form of the underlying PSD. Creative use of region of interest (ROI) analysis allows us to create different underlying PSDs using the same GCA MRI phantom. We show that an s-PFG experiment on the GCA phantom fails to accurately reconstruct the size distribution, thus demonstrating the superiority of the d-PFG experiment. In addition, signal simulations corrupted by different noise levels were used to generate continuous and complex PSDs, which were then successfully reconstructed. Finally, owing to the reduced q- or b- values required to measure microscopic PSDs via d-PFG MRI, this method will be better suited to biomedical and clinical applications, in which gradient strength of scanners is limited. (C) 2014 Elsevier Inc. All rights reserved. C1 [Benjamini, Dan; Komlosh, Michal E.; Basser, Peter J.] NICHHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. [Benjamini, Dan; Nevo, Uri] Tel Aviv Univ, Iby & Aladar Fleischman Fac Engn, Dept Biomed Engn, IL-69978 Tel Aviv, Israel. [Komlosh, Michal E.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Nevo, U (reprint author), Tel Aviv Univ, Iby & Aladar Fleischman Fac Engn, Dept Biomed Engn, IL-69978 Tel Aviv, Israel. EM nevouri@eng.tau.ac.il FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Center for Neuroregenerative Medicine (CNRM) under the Henry Jackson Foundation (HJF) FX This work was supported by funds provided by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the Center for Neuroregenerative Medicine (CNRM) under the auspices of the Henry Jackson Foundation (HJF). The authors would like to thank Liz Salak for editing the manuscript. NR 41 TC 5 Z9 5 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD SEP PY 2014 VL 246 BP 36 EP 45 DI 10.1016/j.jmr.2014.06.017 PG 10 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA AP5LK UT WOS:000342120500007 PM 25064269 ER PT J AU Zaborskis, A Moceviciene, R Iannotti, RJ AF Zaborskis, Apolinaras Moceviciene, Reda Iannotti, Ronald J. TI The Influence of Chronological Period of Data Collection on Differences in Reported Dietary Intake Among School-Aged Children Surveyed in 39 Countries SO JOURNAL OF NUTRITION EDUCATION AND BEHAVIOR LA English DT Article DE children; diet surveys; time of year variation; multilevel analysis ID SEASONAL-VARIATION; HEALTH BEHAVIOR; FOOD FREQUENCY; CONSUMPTION; ADOLESCENTS; FRUIT AB Objective: To examine whether dietary intake reported by school-aged children relates to the chronological period of data collection. Design: Cross-sectional surveys in 39 countries in different monthly periods of the 2009-2010 school year. Settings: Questionnaires were completed in schools anonymously. Participants: Children from 39 countries, aged 11, 13, and 15 years (n = 209,320). Main Outcome Measures: Daily consumption of fruits, vegetables, sweets, and soft drinks, derived from a food frequency questionnaire. Analysis: Multivariate logistic regression (applied for 3 countries); 2-level random intercept logistic regression (applied for 36 countries). Results: Monthly variations in food intake among students from Canada, England, and Norway, where data collection took place almost all months of the school year, revealed significantly lower daily consumption of food items in January to February. A 2-level random intercept logistic regression model for 36 countries, where questionnaires were administered in relatively shorter periods, indicated the lowest likelihood of fruit and soft drink consumption when the data were collected in March to April (beta = -0.30; P = .006, compared with October to December) and in January to February (beta = -0.65; P = .018, compared with May to June), respectively. Conclusions and Implications: The chronological period of data collection must be considered when comparing children's reported food consumption, but this effect is small relative to cross-national variations in dietary patterns. C1 [Zaborskis, Apolinaras; Moceviciene, Reda] Lithuanian Univ Hlth Sci, Fac Publ Hlth, Med Acad, LT-49264 Kaunas, Lithuania. [Iannotti, Ronald J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Washington, DC USA. RP Zaborskis, A (reprint author), Lithuanian Univ Hlth Sci, Fac Publ Hlth, Med Acad, Siaures Pr 57, LT-49264 Kaunas, Lithuania. EM apolinaras.zaborskis@lsmuni.lt FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The HBSC Survey is a World Health Organization Regional Office for Europe collaborative study. The International Coordinator of the 2009-2010 HBSC survey was Candace Currie, University of St Andrews School of Medicine, United Kingdom; and the Data Bank Manager was Oddrun Samdal, University of Bergen, Norway. The authors thank the Principal Investigators of the study in the different countries for permitting access to the regional data. Data collection was funded by each of the participating countries and regions separately. The contribution of Ronald J. Iannotti was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 28 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1499-4046 EI 1878-2620 J9 J NUTR EDUC BEHAV JI J. Nutr. Educ. Behav. PD SEP-OCT PY 2014 VL 46 IS 5 BP 359 EP 369 DI 10.1016/j.jneb.2013.11.017 PG 11 WC Education, Scientific Disciplines; Nutrition & Dietetics SC Education & Educational Research; Nutrition & Dietetics GA AP5RT UT WOS:000342137100011 PM 24502964 ER PT J AU Friedl, KE Rowe, S Bellows, LL Johnson, SL Hetherington, MM de Froidmont-Gortz, I Lammens, V Hubbard, VS AF Friedl, Karl E. Rowe, Sylvia Bellows, Laura L. Johnson, Susan L. Hetherington, Marion M. de Froidmont-Goertz, Isabelle Lammens, Veerle Hubbard, Van S. TI Report of an EU-US Symposium on Understanding Nutrition-Related Consumer Behavior: Strategies to Promote a Lifetime of Healthy Food Choices SO JOURNAL OF NUTRITION EDUCATION AND BEHAVIOR LA English DT Article DE Obesity; food behavior; eating practices; purchasing behavior ID OBESITY PREVENTION; CHILDREN; INFANTS; SALT; FRAMEWORK; EXPOSURE; CAMPAIGN; POLICIES; PROGRAM; WOMEN AB This report summarizes an EU-US Task Force on Biotechnology Research symposium on healthy food choices and nutrition-related purchasing behaviors. This meeting was unique in its transdisciplinary approach to obesity and in bringing together scientists from academia, government, and industry. Discussion relevant to funders and researchers centered on (1) increased use of public-private partnerships, (2) the complexity of food behaviors and obesity risk and multilevel aspects that must be considered, and (3) the importance of transatlantic cooperation and collaboration that could accelerate advances in this field. A call to action stressed these points along with a commitment to enhanced communication strategies. C1 [Friedl, Karl E.; Hubbard, Van S.] Natl Inst Hlth, Div Nutr Res Coordinat, Bethesda, MD USA. [Rowe, Sylvia] SR Strategy LLC, Washington, DC USA. [Bellows, Laura L.] Colorado State Univ, Dept Food Sci & Human Nutr, Ft Collins, CO 80523 USA. [Johnson, Susan L.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Johnson, Susan L.] Univ Colorado, Sch Med, Childrens Eating Lab, Aurora, CO USA. [Hetherington, Marion M.] Univ Leeds, Inst Psychol Sci, Leeds, W Yorkshire, England. [de Froidmont-Goertz, Isabelle; Lammens, Veerle] European Commiss, Unit Agri Food Chain F3, Brussels, Belgium. RP Friedl, KE (reprint author), 8616 Longwood Circle, Frederick, MD 21704 USA. EM karl.friedl@nih.gov OI Hetherington, Marion/0000-0001-8677-5234 FU Coca-Cola Company; General Mills; Mars Global Scientific and Regulatory Affairs; Monsanto Company; Nestle Nutrition; PepsiCo FX This meeting was partially supported by the Foundation for the National Institutes of Health through unrestricted funding from the Coca-Cola Company, General Mills, Mars Global Scientific and Regulatory Affairs, Monsanto Company, Nestle Nutrition, and PepsiCo. This report is a summary of a workshop organized by the National Institutes of Health and the European Commission in association with the EU and US Task Force on Biotechnology Research. The authors are grateful to Drs Christine Hunter (NIDDK), Susan Czajkowski (NHLBI), and Robert Kuczmarski (NIDDK) for constructive suggestions regarding the manuscript. NR 35 TC 4 Z9 4 U1 3 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1499-4046 EI 1878-2620 J9 J NUTR EDUC BEHAV JI J. Nutr. Educ. Behav. PD SEP-OCT PY 2014 VL 46 IS 5 BP 445 EP 450 DI 10.1016/j.jneb.2014.05.002 PG 6 WC Education, Scientific Disciplines; Nutrition & Dietetics SC Education & Educational Research; Nutrition & Dietetics GA AP5RT UT WOS:000342137100025 PM 24974355 ER PT J AU Hernandez-Andrade, E Aurioles-Garibay, A Garcia, M Korzeniewski, SJ Schwartz, AG Ahn, H Martinez-Varea, A Yeo, L Chaiworapongsa, T Hassan, SS Romero, R AF Hernandez-Andrade, Edgar Aurioles-Garibay, Alma Garcia, Maynor Korzeniewski, Steven J. Schwartz, Alyse G. Ahn, Hyunyoung Martinez-Varea, Alicia A Yeo, Lami Chaiworapongsa, Tinnakorn Hassan, Sonia S. Romero, Roberto TI Effect of depth on shear-wave elastography estimated in the internal and external cervical os during pregnancy SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Cervical elasticity; cervical length; short cervix; strain, elastic Young's modulus ID ACOUSTIC RADIATION FORCE; SONOGRAPHIC SHORT CERVIX; HUMAN UTERINE CERVIX; SPONTANEOUS PRETERM DELIVERY; LIGHT-INDUCED FLUORESCENCE; IN-VIVO; TRANSIENT ELASTOGRAPHY; VAGINAL PROGESTERONE; BIOMECHANICAL PROPERTIES; NONINVASIVE ASSESSMENT AB Aim: To investigate the effect of depth on cervical shear-wave elastography. Methods: Shear-wave elastography was applied to estimate the velocity of propagation of the acoustic force impulse (shear wave) in the cervix of 154 pregnant women at 11-36 weeks of gestation. Shear-wave speed (SWS) was evaluated in cross-sectional views of the internal and external cervical os in five regions of interest: anterior, posterior, lateral right, lateral left, and endocervix. Distance from the center of the ultrasound (US) transducer to the center of each region of interest was registered. Results: In all regions, SWS decreased significantly with gestational age (P=0.006). In the internal os, SWS was similar among the anterior, posterior, and lateral regions and lower in the endocervix. In the external os, the endocervix and anterior regions showed similar SWS values, lower than those from the posterior and lateral regions. In the endocervix, these differences remained significant after adjustment for depth, gestational age, and cervical length. SWS estimations in all regions of the internal os were higher than those of the external os, suggesting denser tissue. Conclusion: Depth from the US probe to different regions in the cervix did not significantly affect the SWS estimations. C1 [Hernandez-Andrade, Edgar; Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Hernandez-Andrade, Edgar; Aurioles-Garibay, Alma; Garcia, Maynor; Korzeniewski, Steven J.; Schwartz, Alyse G.; Ahn, Hyunyoung; Martinez-Varea, Alicia A; Yeo, Lami; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Hernandez-Andrade, Edgar; Aurioles-Garibay, Alma; Garcia, Maynor; Korzeniewski, Steven J.; Schwartz, Alyse G.; Ahn, Hyunyoung; Yeo, Lami; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Romero, Roberto] Wayne State Univ, Sch Med, Dept Obstet Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM ehernand@med.wayne.edu; romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HHSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH), and, in part, with Federal funds from NICHD, NIH under contract no. HHSN275201300006C. The ultrasound experience and technical support of senior Registered Diagnostic Medical Sonographers (RDMS), Catherine Ducharme, Denise Haggerty, and Cara Staszewski are gratefully acknowledged. NR 85 TC 9 Z9 12 U1 0 U2 2 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD SEP PY 2014 VL 42 IS 5 BP 549 EP 557 DI 10.1515/jpm-2014-0073 PG 9 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AP1XQ UT WOS:000341866000003 PM 25029081 ER PT J AU Hsing, AW Yeboah, E Biritwum, R Tettey, Y De Marzo, AM Adjei, A Netto, GJ Yu, K Li, Y Chokkalingam, AP Chu, LW Chia, D Partin, A Thompson, IM Quraishi, SM Niwa, S Tarone, R Hoover, RN AF Hsing, Ann W. Yeboah, Edward Biritwum, Richard Tettey, Yao De Marzo, Angelo M. Adjei, Andrew Netto, George J. Yu, Kai Li, Yan Chokkalingam, Anand P. Chu, Lisa W. Chia, David Partin, Alan Thompson, Ian M. Quraishi, Sabah M. Niwa, Shelley Tarone, Robert Hoover, Robert N. TI High Prevalence of Screen Detected Prostate Cancer in West Africans: Implications for Racial Disparity of Prostate Cancer SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; prostate-specific antigen; mass screening; African Americans; Africa ID GENOME-WIDE ASSOCIATION; AMERICAN MEN; SUSCEPTIBILITY LOCUS; RISK LOCUS; IDENTIFICATION; EPIDEMIOLOGY; TRENDS; 8Q24; PATTERNS; ANTIGEN AB Purpose: To our knowledge the reasons for the high rates of prostate cancer in black American men are unknown. Genetic and lifestyle factors have been implicated. Better understanding of prostate cancer rates in West African men would help clarify why black American men have such high rates since the groups share genetic ancestry and yet have different lifestyles and screening practices. To estimate the prostate cancer burden in West African men we performed a population based screening study with biopsy confirmation in Ghana. Materials and Methods: We randomly selected 1,037 healthy men 50 to 74 years old from Accra, Ghana for prostate cancer screening with prostate specific antigen testing and digital rectal examination. Men with a positive screen result (positive digital rectal examination or prostate specific antigen greater than 2.5 ng/ml) underwent transrectal ultrasound guided biopsies. Results: Of the 1,037 men 154 (14.9%) had a positive digital rectal examination and 272 (26.2%) had prostate specific antigen greater than 2.5 ng/ml, including 166 with prostate specific antigen greater than 4.0 ng/ml. A total of 352 men (33.9%) had a positive screen by prostate specific antigen or digital rectal examination and 307 (87%) underwent biopsy. Of these men 73 were confirmed to have prostate cancer, yielding a 7.0% screen detected prostate cancer prevalence (65 patients), including 5.8% with prostate specific antigen greater than 4.0 ng/ml. Conclusions: In this relatively unscreened population in Africa the screen detected prostate cancer prevalence is high, suggesting a possible role of genetics in prostate cancer etiology and the disparity in prostate cancer risk between black and white American men. Further studies are needed to confirm the high prostate cancer burden in African men and the role of genetics in prostate cancer etiology. C1 [Hsing, Ann W.; Chu, Lisa W.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Hsing, Ann W.; Chu, Lisa W.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [Hsing, Ann W.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Chokkalingam, Anand P.] Univ Calif Berkeley, Dept Epidemiol, Berkeley, CA 94720 USA. [Chia, David] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Hsing, Ann W.; Yu, Kai; Li, Yan; Quraishi, Sabah M.; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [De Marzo, Angelo M.; Netto, George J.; Partin, Alan] Johns Hopkins Univ, Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Dept Pathol & Oncol, Baltimore, MD USA. [Niwa, Shelley] Westat Corp, Rockville, MD USA. [Tarone, Robert] Int Epidemiol Inst, Rockville, MD USA. [Yeboah, Edward; Biritwum, Richard; Tettey, Yao; Adjei, Andrew] Univ Ghana, Sch Med, Accra, Ghana. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Hsing, AW (reprint author), Canc Prevent Inst Calif, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA. EM ann.hsing@cpic.org FU National Institutes of Health Intramural Research Program (National Cancer Institute); National Center on Minority Health; Center to Reduce Cancer Disparities (National Cancer Institute) FX Supported by the National Institutes of Health Intramural Research Program (National Cancer Institute), National Center on Minority Health and Center to Reduce Cancer Disparities (National Cancer Institute). NR 29 TC 10 Z9 10 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD SEP PY 2014 VL 192 IS 3 BP 730 EP 735 DI 10.1016/j.juro.2014.04.017 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA AP5FR UT WOS:000342105600028 PM 24747091 ER PT J AU Kilpatrick, LA Kutch, JJ Tillisch, K Naliboff, BD Labus, JS Jiang, Z Farmer, MA Apkarian, AV Mackey, S Martucci, KT Clauw, DJ Harris, RE Deutsch, G Ness, TJ Yang, CC Maravilla, K Mullins, C Mayer, EA AF Kilpatrick, Lisa A. Kutch, Jason J. Tillisch, Kirsten Naliboff, Bruce D. Labus, Jennifer S. Jiang, Zhiguo Farmer, Melissa A. Apkarian, A. Vania Mackey, Sean Martucci, Katherine T. Clauw, Daniel J. Harris, Richard E. Deutsch, Georg Ness, Timothy J. Yang, Claire C. Maravilla, Kenneth Mullins, Chris Mayer, Emeran A. TI Alterations in Resting State Oscillations and Connectivity in Sensory and Motor Networks in Women with Interstitial Cystitis/Painful Bladder Syndrome SO JOURNAL OF UROLOGY LA English DT Article DE urinary bladder; cystitis, interstitial; magnetic resonance imaging; brain mapping; pain ID MICTURITION; PREVALENCE; FMRI AB Purpose: The pathophysiology of interstitial cystitis/painful bladder syndrome remains incompletely understood but is thought to involve central disturbance in the processing of pain and viscerosensory signals. We identified differences in brain activity and connectivity between female patients with interstitial cystitis/painful bladder syndrome and healthy controls to advance clinical phenotyping and treatment efforts for interstitial cystitis/painful bladder syndrome. Materials and Methods: We examined oscillation dynamics of intrinsic brain activity in a large sample of well phenotyped female patients with interstitial cystitis/painful bladder syndrome and female healthy controls. Data were collected during 10-minute resting functional magnetic resonance imaging as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network project. The blood oxygen level dependent signal was transformed to the frequency domain. Relative power was calculated for multiple frequency bands. Results: Results demonstrated altered frequency distributions in viscerosensory (post insula), somatosensory (postcentral gyrus) and motor regions (anterior paracentral lobule, and medial and ventral supplementary motor areas) in patients with interstitial cystitis/painful bladder syndrome. Also, the anterior paracentral lobule, and medial and ventral supplementary motor areas showed increased functional connectivity to the midbrain (red nucleus) and cerebellum. This increased functional connectivity was greatest in patients who reported pain during bladder filling. Conclusions: Findings suggest that women with interstitial cystitis/painful bladder syndrome have a sensorimotor component to the pathological condition involving an alteration in intrinsic oscillations and connectivity in a cortico-cerebellar network previously associated with bladder function. C1 [Kilpatrick, Lisa A.; Tillisch, Kirsten; Naliboff, Bruce D.; Labus, Jennifer S.; Jiang, Zhiguo; Mayer, Emeran A.] Univ Calif Los Angeles, David Geffen Sch Med, Gail & Gerald Oppenheimer Family Ctr Neurobiol St, Los Angeles, CA 90095 USA. [Kutch, Jason J.] Univ So Calif, Div Biokinesiol & Phys Therapy, Los Angeles, CA USA. [Mackey, Sean; Martucci, Katherine T.] Stanford Univ, Ctr Med, Dept Anesthesiol Perioperat & Pain Med, Div Pain Med, Stanford, CA 94305 USA. [Jiang, Zhiguo] Kessler Fdn, Res Ctr, Human Performance & Engn Lab, W Orange, NJ USA. [Jiang, Zhiguo] New Jersey Inst Technol, Dept Biomed Engn, Newark, NJ 07102 USA. [Farmer, Melissa A.; Apkarian, A. Vania] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL USA. [Clauw, Daniel J.; Harris, Richard E.] Univ Michigan, Chron Pain & Fatigue Res Ctr, Dept Anesthesiol, Ann Arbor, MI USA. [Deutsch, Georg; Ness, Timothy J.] Univ Alabama Birmingham, Birmingham Med Ctr, Dept Radiol, Birmingham, AL USA. [Deutsch, Georg; Ness, Timothy J.] Univ Alabama Birmingham, Birmingham Med Ctr, Dept Anesthesiol, Birmingham, AL USA. [Yang, Claire C.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Martucci, Katherine T.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Mullins, Chris] NIDDK, NIH, Bethesda, MD 20892 USA. RP Mayer, EA (reprint author), Univ Calif Los Angeles, Ctr Neurobiol Stress, CHS 47-122,10833 Conte Ave, Los Angeles, CA 90095 USA. EM emayer@ucla.edu RI Kilpatrick, Lisa/E-6995-2015; OI Apkarian, A. Vania/0000-0002-9788-7458; Ness, Timothy/0000-0002-7908-4459 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health [DK82370, DK82342, DK82315, DK82344, DK82325, DK82345, DK82333, DK82316]; [R01 DK04835]; [K01 DK085133] FX Supported by a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases, and National Institutes of Health Grants DK82370, DK82342, DK82315, DK82344, DK82325, DK82345, DK82333 and DK82316 (MAPP Research Network), and R01 DK04835 and K01 DK085133. NR 29 TC 29 Z9 29 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD SEP PY 2014 VL 192 IS 3 BP 947 EP 955 DI 10.1016/j.juro.2014.03.093 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AP5FR UT WOS:000342105600109 PM 24681331 ER PT J AU Nguyen, P Lee, S Lorang-Leins, D Trepel, J Smart, DK AF Nguyen, Phuongmai Lee, Sunmin Lorang-Leins, Dominique Trepel, Jane Smart, DeeDee K. TI SIRT2 Interacts with beta-Catenin to Inhibit Wnt Signaling Output in Response to Radiation-Induced Stress SO MOLECULAR CANCER RESEARCH LA English DT Article ID CELL-MIGRATION; STEM-CELLS; DIFFERENTIATION; CANCER; OVEREXPRESSION; DEACETYLATION; TUMORIGENESIS; EXPRESSION; INSIGHTS; PATHWAY AB Wnt signaling is critical to maintaining cellular homeostasis via regulation of cell division, mitigation of cell stress, and degradation. Aberrations in Wnt signaling contribute to carcinogenesis and metastasis, whereas sirtuins have purported roles in carcinogenesis, aging, and neurodegeneration. Therefore, the hypothesis that sirtuin 2 (SIRT2) directly interacts with beta-catenin and whether this interaction alters the expression of Wnt target genes to produce an altered cellular phenotype was tested. Coimmunoprecipitation studies, using mouse embryonic fibroblasts (MEF) from Sirt2 wild-type and genomic knockout mice, demonstrate that beta-catenin directly binds SIRT2. Moreover, this interaction increases in response to oxidative stress induced by ionizing radiation. In addition, this association inhibits the expression of important Wnt target genes such as survivin (BIRC5), cyclin D1 (CCND1), and c-myc (MYC). In Sirt2 null MEFs, an upregulation of matrix metalloproteinase 9 (MMP9) and decreased E-cadherin (CDH1) expression is observed that produces increased cellular migration and invasion. Together, these data demonstrate that SIRT2, a tumor suppressor lost in multiple cancers, inhibits the Wnt signaling pathway in nonmalignant cells by binding to beta-catenin and that SIRT2 plays a critical role in the response to oxidative stress from radiation. C1 [Nguyen, Phuongmai; Lorang-Leins, Dominique; Smart, DeeDee K.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Sunmin; Trepel, Jane] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Smart, DK (reprint author), NCI, Radiat Oncol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM smartd@mail.nih.gov FU Intramural Research Program of the NIH; NCI; Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, NCI, and Center for Cancer Research. NR 33 TC 8 Z9 8 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD SEP PY 2014 VL 12 IS 9 BP 1244 EP 1253 DI 10.1158/1541-7786.MCR-14-0223-T PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AP5TQ UT WOS:000342142000006 PM 24866770 ER PT J AU Chen, HL Huang, XM Guo, XG Peddada, S AF Chen, Honglei Huang, Xuemei Guo, Xuguang Peddada, Shyamal TI Individual and Joint Prevalence of Three Nonmotor Symptoms of PD in the US General Population SO MOVEMENT DISORDERS LA English DT Article DE constipation; daytime sleepiness; depression; nonmotor symptoms; Parkinson's disease; prevalence ID SLEEP BEHAVIOR DISORDER; BOWEL MOVEMENT FREQUENCY; PARKINSONS-DISEASE; RISK; DEPRESSION; START AB Background: Some nonmotor symptoms may precede the clinical diagnosis of Parkinson's disease (PD) by years. Methods: We examined the individual and joint prevalence of depression, daytime sleepiness, and infrequent bowel movement among 10,477 participants of the US National Health and Nutrition Examination Surveys 2005-2008. Results: For all symptoms, the prevalence was higher in women than in men. Importantly, few participants had two or more symptoms: 1.3% at ages 20 to 29, 1.0% at 30 to 39, 1.2% at 40 to 49, 3.5% at 50 to 59, 1.7% at 60 to 69, 1.1% at 70 to 79, and 1.2% at ages 80 years or older in men; the corresponding prevalence in women was 3.1%, 5.2%, 5.7%, 4.1%, 3.1%, 2.3%, and 1.2%, respectively. In both men and women, depression was correlated with infrequent bowel movement and daytime sleepiness, but the latter two were mutually independent. Conclusion: The presence of multiple nonmotor symptoms was uncommon in the general population and the prevalence was higher in women than in men. (C) 2014 International Parkinson and Movement Disorder Society C1 [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. [Guo, Xuguang] Westat Corp, Durham, NC USA. [Peddada, Shyamal] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Chen, HL (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr POB 12233 Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov OI Chen, Honglei/0000-0003-3446-7779 FU NIH, National Institute of Environmental Health Sciences FX This study was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 21 TC 6 Z9 6 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2014 VL 29 IS 10 BP 1316 EP 1319 DI 10.1002/mds.25950 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA AP6CH UT WOS:000342164600045 PM 24985078 ER PT J AU Babcock, D St Hillaire-Clarke, C Gwinn, KA Sieber, BA Baker, S Linde, J McAuliffe, M Koroshetz, WA Sutherland, M AF Babcock, D. St Hillaire-Clarke, C. Gwinn, K. A. Sieber, B-A. Baker, S. Linde, J. McAuliffe, M. Koroshetz, W. A. Sutherland, M. TI The NINDS Parkinson's Disease Biomarkers Program. SO MOVEMENT DISORDERS LA English DT Meeting Abstract CT 28th Annual Symposium on Etiology, Pathogenesis, and Treatment of Parkinson Disease and Other Movement Disorders CY SEP 19, 2014 CL St Louis, MO C1 [Babcock, D.; St Hillaire-Clarke, C.; Gwinn, K. A.; Sieber, B-A.; Koroshetz, W. A.; Sutherland, M.] NINDS, Bethesda, MD 20892 USA. [Baker, S.; Linde, J.; McAuliffe, M.] Ctr Informat Technol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2014 VL 29 IS 10 BP E6 EP E6 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AP6CH UT WOS:000342164600016 ER PT J AU Butterfield, RJ Bonnemann, C Weiss, RB AF Butterfield, R. J. Bonnemann, C. Weiss, R. B. TI TRANSCRIPTOME PROFILING IDENTIFIES KEY DIFFERENCES BETWEEN PATIENTS WITH RECESSIVE OR DOMINANT NEGATIVE MUTATIONS IN COLLAGEN VI RELATED MYOPATHIES SO MUSCLE & NERVE LA English DT Meeting Abstract CT Muscle-Study-Group Meeting on Economic Considerations in the Development of New Treatments for Neuromuscular Diseases CY SEP 21-23, 2014 CL New York, NY SP Muscle Study Grp C1 [Butterfield, R. J.; Weiss, R. B.] Univ Utah, Salt Lake City, UT USA. [Bonnemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD SEP PY 2014 VL 50 SU 1 MA 13 BP S4 EP S5 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AP6HP UT WOS:000342178600014 ER PT J AU Zhu, XG Zhao, L Park, JW Willingham, MC Cheng, SY AF Zhu, Xuguang Zhao, Li Park, Jeong Won Willingham, Mark C. Cheng, Sheue-Yann TI Synergistic Signaling of KRAS and Thyroid Hormone Receptor beta Mutants Promotes Undifferentiated Thyroid Cancer through MYC Up-Regulation SO NEOPLASIA LA English DT Article ID C-MYC; MOUSE MODEL; SELECTIVE-INHIBITION; TARGETED MUTATION; TUMOR PROGRESSION; RESISTANCE; MICE; GENE; DIFFERENTIATION; EXPRESSION AB Undifferentiated thyroid carcinoma is one of the most aggressive human cancers with frequent RAS mutations. How mutations of the RAS gene contribute to undifferentiated thyroid cancer remains largely unknown. Mice harboring a potent dominant negative mutant thyroid hormone receptor beta, TR beta PV (Thrb(PV/PV)), spontaneously develop well-differentiated follicular thyroid cancer similar to human cancer. We genetically targeted the Kras(G12D) mutation to thyroid epithelial cells of Thrb(PV/PV) mice to understand how Kras(G12D) mutation could induce undifferentiated thyroid cancer in Thrb(PV/PV)Kras(G12D) mice. Thrb(PV/PV)Kras(G12D) mice exhibited poorer survival due to more aggressive thyroid tumors with capsular invasion, vascular invasion, and distant metastases to the lung occurring at an earlier age and at a higher frequency than Thrb(PV/PV) mice did. Importantly, Thrb(PV/PV)Kras(G12D) mice developed frequent anaplastic foci with complete loss of normal thyroid follicular morphology. Within the anaplastic foci, the thyroid-specific transcription factor paired box gene 8 (PAX8) expression was virtually lost and the loss of PAX8 expression was inversely correlated with elevated MYC expression. Consistently, co-expression of KRAS(G12D) with TR beta PV upregulated MYC levels in rat thyroid pccl3 cells, and MYC acted to enhance the TR beta PV-mediated repression of the Pax8 promoter activity of a distant upstream enhancer, critical for thyroid-specific Pax8 expression. Our findings indicated that synergistic signaling of KRAS(G12D) and TR beta PV led to increased MYC expression. Upregulated MYC contributes to the initiation of undifferentiated thyroid cancer, in part, through enhancing TR beta PV-mediated repression of the Pax8 expression. Thus, MYC might serve as a potential target for therapeutic intervention. C1 [Zhu, Xuguang; Zhao, Li; Park, Jeong Won; Willingham, Mark C.; Cheng, Sheue-Yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research; National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Disclosure of potential conflicts of interest: The authors declare no conflicts of interest. NR 49 TC 12 Z9 12 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1522-8002 EI 1476-5586 J9 NEOPLASIA JI Neoplasia PD SEP PY 2014 VL 16 IS 9 BP 757 EP 769 DI 10.1016/j.neo.2014.08.003 PG 13 WC Oncology SC Oncology GA AP4WB UT WOS:000342079000007 PM 25246276 ER PT J AU Lee, KA Meek, P Grady, PA AF Lee, Kathryn A. Meek, Paula Grady, Patricia A. TI Advancing symptom science: Nurse researchers lead the way SO NURSING OUTLOOK LA English DT Editorial Material C1 [Lee, Kathryn A.] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. [Meek, Paula] Univ Colorado, Coll Nursing, Denver, CO 80202 USA. [Grady, Patricia A.] NINR, Bethesda, MD 20892 USA. RP Lee, KA (reprint author), Univ Calif San Francisco, Sch Nursing, 2 Kirkham, San Francisco, CA 94143 USA. EM kathryn.lee@ucsf.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD SEP-OCT PY 2014 VL 62 IS 5 BP 301 EP 302 DI 10.1016/j.outlook.2014.05.010 PG 2 WC Nursing SC Nursing GA AP5KE UT WOS:000342117300001 PM 25218079 ER PT J AU Bevans, M Ross, A Cella, D AF Bevans, Margaret Ross, Alyson Cella, David TI Patient-Reported Outcomes Measurement Information System (PROMIS): Efficient, standardized tools to measure self-reported health and quality of life SO NURSING OUTLOOK LA English DT Article DE Item response theory; Measurements; Patient-centered outcomes; Web-based data collection ID CLINICAL-PRACTICE; CANCER-PATIENTS; ITEM RESPONSE; NIH ROADMAP; IMPACT; TRIALS; COMMUNICATION; ASSESSMENTS; DEPRESSION; MANAGEMENT AB All nurses are interested in the effects of diseases and treatments on individuals. Patient-reported outcome (PRO) measures are used to obtain self-reported information about symptoms, function, perceptions, and experiences. However, there are challenges to their use, including multiple measures of the same concept, widely varying quality, excessive length and complexity, and difficulty comparing findings across studies and conditions. To address these challenges, the National Institutes of Health funded the Patient-Reported Outcomes Measurement Information System (PROMIS), a web-based repository of valid and reliable PRO measures of health concepts relevant to clinician and researchers. Through the PROMIS Assessment Center, clinicians and researchers can access PRO measures, administer computerized adaptive tests, collect self-report data, and report instant health assessments. The purpose of this article was to summarize the development and validation of the PROMIS measures and to describe its current functionality as it relates to nursing science. C1 [Bevans, Margaret; Ross, Alyson] NIH, Dept Nursing, Ctr Clin, Bethesda, MD 20892 USA. [Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Cella, David] Inst Publ Hlth & Med, Ctr Patient Ctr Outcomes, Chicago, IL USA. RP Bevans, M (reprint author), NIH, Dept Nursing, Ctr Clin, 10 Ctr Dr,Room 2B13 MSC 1151, Bethesda, MD 20892 USA. EM mbevans@cc.nih.gov FU NIH Clinical Center Intramural Research Program; PROMIS Statistical Center [U54AR057951] FX Support provided to Drs. Bevans and Ross by the NIH Clinical Center Intramural Research Program and Dr. Cella by the U54AR057951 PROMIS Statistical Center. NR 37 TC 9 Z9 9 U1 5 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD SEP-OCT PY 2014 VL 62 IS 5 BP 339 EP 345 DI 10.1016/j.outlook.2014.05.009 PG 7 WC Nursing SC Nursing GA AP5KE UT WOS:000342117300007 PM 25015409 ER PT J AU Grady, PA Gullatte, M AF Grady, Patricia A. Gullatte, Mary TI The 2014 National Nursing Research Roundtable: The science of caregiving SO NURSING OUTLOOK LA English DT Article DE Caregivers; Caregiver/psychology; Chronic illnesses; Nursing research ID C-REACTIVE PROTEIN; FAMILY CAREGIVERS; DEPRESSED MOOD; INTERVENTIONS; METAANALYSIS; INFLAMMATION; CANCER; MORTALITY; DEMENTIA AB The National Nursing Research Roundtable (NNRR) meets annually to provide an opportunity for the leaders of nursing organizations with a research mission to discuss and disseminate research findings. to improve health outcomes. In 2014, the NNRR addressed the science of caregiving, a topic of increasing importance given that more people are living with chronic conditions and that managing chronic illness is shifting from providers to individuals, their families, and the communities where they live. The NNRR consisted of scientific presentations in which leading researchers discussed the latest advances in caregiving science across the life span and breakout sessions where specific questions were discussed. The questions focused on the policy and practice implications of caregiving science and provided an opportunity for nursing leaders to discuss ways to advance caregiving science. The nursing community is ideally positioned to design and test caregiver health interventions and to implement these interventions in clinical and community settings. C1 [Grady, Patricia A.] NINR, NIH, Bethesda, MD 20892 USA. [Gullatte, Mary] Oncol Nursing Soc, Pittsburgh, PA USA. RP Grady, PA (reprint author), Care of Rosenbaum LM, NINR, NIH, 6701 Democracy Blvd,Suite 710, Bethesda, MD 20817 USA. EM info@ninr.nih.gov FU Intramural NIH HHS [Z99 NR999999] NR 26 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD SEP-OCT PY 2014 VL 62 IS 5 BP 362 EP 365 DI 10.1016/j.outlook.2014.05.007 PG 4 WC Nursing SC Nursing GA AP5KE UT WOS:000342117300010 PM 25015405 ER PT J AU Hwang, HW Baxter, LL Loftus, SK Cronin, JC Trivedi, NS Borate, B Pavan, WJ AF Hwang, Hun-Way Baxter, Laura L. Loftus, Stacie K. Cronin, Julia C. Trivedi, Niraj S. Borate, Bhavesh Pavan, William J. TI Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanoma; miRNA; hypoxia; HIF1; Bnip3 ID IN-VIVO; HYPOXIA; CANCER; PHENOTYPE; CELLS; PROGRESSION; METASTASIS; BIOGENESIS; PROFILES; INVASION AB The complex genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, including transcripts regulated by either transforming growth factor, beta 1 (TGF1) pathways, or microphthalmia-associated transcription factor (MITF)/SRY-box containing gene 10 (SOX10) pathways. We extended this knowledge by discovering that melanoma cell lines with these two expression programs exhibit distinctive microRNA (miRNA) expression patterns. We also demonstrated that hypoxia-inducible factor 1 alpha (HIF1A) is increased in TGF1 pathway-expressing melanoma cells and that HIF1A upregulates miR-210, miR-218, miR-224, and miR-452. Reduced expression of these four miRNAs in TGF1 pathway-expressing melanoma cells arrests the cell cycle, while their overexpression in mouse melanoma cells increases the expression of the hypoxic response gene Bnip3. Taken together, these data suggest that HIF1A may regulate some of the gene expression and biological behavior of TGF1 pathway-expressing melanoma cells, in part via alterations in these four miRNAs. C1 [Hwang, Hun-Way; Baxter, Laura L.; Loftus, Stacie K.; Cronin, Julia C.; Pavan, William J.] NHGRI, Genet Dis Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Trivedi, Niraj S.; Borate, Bhavesh] NHGRI, Genome Technol Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov OI Hwang, Hun-Way/0000-0003-0522-1577 FU National Human Genome Research Institute's Intramural Research Program at the National Institutes of Health FX The authors would like to thank Stacie Anderson for outstanding support in cell sorting and analysis by flow cytometry, Dr. Wendy Westbroek for help with primary human melanocyte culture, and Dr. Chi-Ping Day for providing lentiviral vectors. Hun-Way Hwang is an HHMI Fellow of the Life Sciences Research Foundation. Funding of this research was provided by the National Human Genome Research Institute's Intramural Research Program at the National Institutes of Health. NR 44 TC 15 Z9 15 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD SEP PY 2014 VL 27 IS 5 BP 777 EP 787 DI 10.1111/pcmr.12255 PG 11 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA AP0TV UT WOS:000341778700016 PM 24767210 ER PT J AU Mantsyzov, AB Maltsev, AS Ying, JF Shen, Y Hummer, G Bax, A AF Mantsyzov, Alexey B. Maltsev, Alexander S. Ying, Jinfa Shen, Yang Hummer, Gerhard Bax, Ad TI A maximum entropy approach to the study of residue-specific backbone angle distributions in alpha-synuclein, an intrinsically disordered protein SO PROTEIN SCIENCE LA English DT Article DE diffusion anisotropy; intrinsically disordered proteins; Karplus curve; random coil; short-range NOE ID NMR CHEMICAL-SHIFTS; MOLECULAR-DYNAMICS SIMULATIONS; CHAIN TORSION ANGLES; LONG-RANGE ORDER; DIPOLAR COUPLINGS; UNFOLDED STATE; SECONDARY STRUCTURE; RANDOM COIL; CONFORMATIONAL PROPERTIES; STAPHYLOCOCCAL NUCLEASE AB alpha-Synuclein is an intrinsically disordered protein of 140 residues that switches to an alpha-helical conformation upon binding phospholipid membranes. We characterize its residue-specific backbone structure in free solution with a novel maximum entropy procedure that integrates an extensive set of NMR data. These data include intraresidue and sequential H-N-H-alpha and H-N-H-N NOEs, values for (3)J(HNH alpha), (1)J(H alpha C alpha), (2)J(C alpha N), and (1)J(C alpha N), as well as chemical shifts of N-15, C-13(alpha), and C-13' nuclei, which are sensitive to backbone torsion angles. Distributions of these torsion angles were identified that yield best agreement to the experimental data, while using an entropy term to minimize the deviation from statistical distributions seen in a large protein coil library. Results indicate that although at the individual residue level considerable deviations from the coil library distribution are seen, on average the fitted distributions agree fairly well with this library, yielding a moderate population (20-30%) of the PPII region and a somewhat higher population of the potentially aggregation-prone beta region (20-40%) than seen in the database. A generally lower population of the alpha(R) region (10-20%) is found. Analysis of H-1-H-1 NOE data required consideration of the considerable backbone diffusion anisotropy of a disordered protein. C1 [Mantsyzov, Alexey B.; Maltsev, Alexander S.; Ying, Jinfa; Shen, Yang; Hummer, Gerhard; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Hummer, Gerhard] Max Planck Inst Biophys, D-60438 Frankfurt, Germany. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Shen, Yang/C-3064-2008; Hummer, Gerhard/A-2546-2013 OI Shen, Yang/0000-0003-1408-8034; Hummer, Gerhard/0000-0001-7768-746X NR 94 TC 15 Z9 15 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2014 VL 23 IS 9 BP 1275 EP 1290 DI 10.1002/pro.2511 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP6TD UT WOS:000342209700009 PM 24976112 ER PT J AU Yates, JR Gay, EA Heyes, MP Blight, AR AF Yates, J. R. Gay, E. A. Heyes, M. P. Blight, A. R. TI Effects of methylprednisolone and 4-chloro-3-hydroxyanthranilic acid in experimental spinal cord injury in the guinea pig appear to be mediated by different and potentially complementary mechanisms SO SPINAL CORD LA English DT Article ID NEUROTOXIN QUINOLINIC ACID; CONVERT L-TRYPTOPHAN; CONTROLLED-TRIAL; RAT; ACCUMULATION; MACROPHAGES; BRAIN; BLOOD; QUANTIFICATION; INTERFERON AB Study design: Blinded, placebo-controlled, parallel treatment group studies of the effects of methylprednisolone (MP) or 4-chloro-3-hydroxyanthranilate (4-Cl-3-HAA) on behavioral outcome and quinolinic acid tissue levels from experimental thoracic spinal cord injury in adult guinea pigs. Objectives: To compare the effects of treatment with high-dose MP, a corticosteroid, and 4-Cl-3-HAA, a compound that inhibits synthesis of the neurotoxin quinolinic acid (QUIN) by activated macrophages. To explore the effect of different times of treatment using these two approaches to ameliorating secondary tissue damage. Setting: Laboratory animal studies at the University of North Carolina, Chapel Hill, NC, USA. Methods: Standardized spinal cord injuries were produced in anesthetized guinea pigs, using lateral compression of the spinal cord. Behavioral impairment and recovery were measured by placing and toe-spread responses (motor function), cutaneus trunci muscle reflex receptive field areas and somatosensory-evoked potentials (sensory function). Tissue quinolinic acid levels were measured by gas chromatograph/mass spectrometry. Results: The current experiments showed a reduction in delayed loss of motor and sensory function in the guinea pig with MP (150 mg kg(-1), intraperitoneally in split doses between 0.5 and 6 h), but no significant reduction in tissue QUIN. Improved sensory function was seen with a single dose of 60 mg kg(-1) MP intraperitoneally at 5 h after injury, but not at 10 h after injury. A single dose of 4-Cl-3-HAA at 5 h in the guinea pig did not produce the sensory and motor improvements seen in previous studies with 12 days of dosing, beginning at 5 h. Conclusion: These studies, together with earlier findings, indicate that both drugs can attenuate secondary pathologic damage after SCI, but through separate mechanisms. These are most likely an acute reduction by MP of oxidative processes and reduction by 4-Cl-3-HAA of QUIN synthesis. C1 [Yates, J. R.; Gay, E. A.; Blight, A. R.] Univ N Carolina, Curriculum Neurobiol, Chapel Hill, NC USA. [Yates, J. R.; Gay, E. A.; Blight, A. R.] Univ N Carolina, Div Neurosurg, Chapel Hill, NC USA. [Yates, J. R.; Blight, A. R.] Acorda Therapeut Inc, Ardsley, NY USA. [Yates, J. R.] Ohio Wesleyan Univ, Dept Psychol, Delaware, OH 43015 USA. [Heyes, M. P.] NIMH, Lab Neurotoxicol, Chapel Hill, NC USA. RP Yates, JR (reprint author), Ohio Wesleyan Univ, Dept Psychol, 61 South Sandusky St, Delaware, OH 43015 USA. EM jryates@owu.edu FU NIH, NINDS [NS-33687]; Spinal Cord Research Foundation of the Paralyzed Veterans of America [1793]; American Paralysis Association [BA2-9701] FX This work was supported in part by Grant NS-33687 from NIH, NINDS, by Grant 1793 from the Spinal Cord Research Foundation of the Paralyzed Veterans of America and by research contract BA2-9701 from the American Paralysis Association. NR 28 TC 0 Z9 1 U1 0 U2 8 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 SEP PY 2014 VL 52 IS 9 BP 662 EP 666 DI 10.1038/sc.2014.118 PG 5 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA AP3OP UT WOS:000341986400004 PM 25047053 ER PT J AU Canet-Aviles, R Lomax, GP Feigal, EG Priest, C AF Canet-Aviles, Rosa Lomax, Geoffrey P. Feigal, Ellen G. Priest, Catherine TI Proceedings: Cell Therapies for Parkinson's Disease From Discovery to Clinic SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Parkinson's disease; Cell therapies; Clinical trials; Experimental models ID PLURIPOTENT STEM-CELLS; DEEP-BRAIN-STIMULATION; MIDBRAIN DOPAMINERGIC-NEURONS; FETAL NIGRAL TRANSPLANTATION; FAMILIAL ALZHEIMERS-DISEASE; LONG-TERM SURVIVAL; ALPHA-SYNUCLEIN; MESENCEPHALIC TISSUE; SUBTHALAMIC NUCLEUS; INDUCED DYSKINESIAS AB In March 2013, the California Institute for Regenerative Medicine, in collaboration with the NIH Center for Regenerative Medicine, held a 2-day workshop on cell therapies for Parkinson's disease (PD), with the goals of reviewing the state of stem cell research for the treatment of PD and discussing and refining the approach and the appropriate patient populations in which to plan and conduct new clinical trials using stem cell-based therapies for PD. Workshop participants identified priorities for research, development, and funding; discussed existing resources and initiatives; and outlined a path to the clinic for a stem cell-based therapy for PD. A consensus emerged among participants that the development of cell replacement therapies for PD using stem cell-derived products could potentially offer substantial benefits to patients. As with all stem cell-based therapeutic approaches, however, there are many issues yet to be resolved regarding the safety, efficacy, and methodology of transplanting cell therapies into patients. Workshop participants agreed that designing an effective stem cell-based therapy for PD will require further research and development in several key areas. This paper summarizes the meeting. C1 [Canet-Aviles, Rosa; Lomax, Geoffrey P.; Feigal, Ellen G.; Priest, Catherine] Calif Inst Regenerat Med, San Francisco, CA USA. RP Canet-Aviles, R (reprint author), Fdn Natl Inst Hlth, 9650 Rockville Pike, Bethesda, MD 20814 USA. EM rcanet-aviles@fnih.org NR 116 TC 1 Z9 1 U1 3 U2 19 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD SEP PY 2014 VL 3 IS 9 BP 979 EP 991 DI 10.5966/sctm.2014-0146 PG 13 WC Cell & Tissue Engineering SC Cell Biology GA AP6LJ UT WOS:000342189000015 PM 25150264 ER PT J AU West, KA Leitman, SF Flegel, WA AF West, Kamille A. Leitman, Susan F. Flegel, Willy A. TI Muddy waters in therapeutic plasma exchange SO TRANSFUSION LA English DT Editorial Material C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP West, KA (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bldg 10,Room 1C711 MSC 1184,10 Ctr Dr, Bethesda, MD 20892 USA. EM kamille.west@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 1 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 IS 9 BP 2157 EP 2157 DI 10.1111/trf.12601 PG 1 WC Hematology SC Hematology GA AP5TJ UT WOS:000342141300005 PM 25212424 ER PT J AU Srivastava, K Almarry, NS Flegel, WA AF Srivastava, Kshitij Almarry, Noorah Salman Flegel, Willy A. TI Genetic variation of the whole ICAM4 gene in Caucasians and African Americans SO TRANSFUSION LA English DT Article ID LW BLOOD-GROUP; ACQUIRED HEMOLYTIC-ANEMIA; AMINO-ACID SUBSTITUTIONS; ANTI-LW; MISSENSE MUTATIONS; BINDING-SITES; GROUP PROTEIN; HUMAN GENOME; PREDICTION; ADHESION AB BackgroundLandsteiner-Wiener (LW) is the human blood group system Number 16, which comprises two antithetical antigens, LWa and LWb and the high-prevalence antigen LWab. LW is encoded by the intracellular adhesion molecule 4 (ICAM4) gene. The ICAM4 protein is part of the Rhesus complex in the red cell membrane and is involved in cell-cell adhesion. Study Design and MethodsWe developed a method to sequence the whole 1.9-kb ICAM4 gene from genomic DNA in one amplicon. We determined the nucleotide sequence of Exons 1 to 3, the two introns, and 402-bp 5-untranslated region (UTR) and 347-bp 3-UTR in 97 Caucasian and 91 African American individuals. ResultsSeven variant ICAM4 alleles were found, distinct from the wild-type ICAM4 allele (GenBank KF712272), known as LW*05 and encoding LWa. An effect of the LWa/LWb amino acid substitution on the protein structure was predicted by two of the three computational modeling programs used. ConclusionsWe describe a practical approach for sequencing and determining the ICAM4 alleles using genomic DNA. LW*05 is the ancestral allele, which had also been observed in a Neanderthal sample. All seven variant alleles are immediate derivatives of the prevalent LW*05 and caused by one single-nucleotide polymorphism (SNP) in each allele. Our data were consistent with the NHLBI GO Exome Sequencing Project (ESP) and the dbSNP databases, as all SNPs had been observed previously. Our study has the advantage over the other databases in that it adds haplotype (allele) information for the ICAM4 gene, clinically relevant in the field of transfusion medicine. C1 [Srivastava, Kshitij; Almarry, Noorah Salman; Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Almarry, Noorah Salman] Georgetown Univ, Sch Med, Dept Biochem & Mol & Cellular Biol, Washington, DC USA. RP Flegel, WA (reprint author), NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov FU Intramural Research Program of the NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 51 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 IS 9 BP 2315 EP 2324 DI 10.1111/trf.12615 PG 10 WC Hematology SC Hematology GA AP5TJ UT WOS:000342141300023 PM 24673173 ER PT J AU Martins, AJ Tsang, JS AF Martins, Andrew J. Tsang, John S. TI Random yet deterministic: convergent immunoglobulin responses to influenza SO TRENDS IN MICROBIOLOGY LA English DT Editorial Material AB B cell clonal expansion is a hallmark of host-defense and vaccination responses. Given the vast immunoglobulin repertoire, individuals may expand B cells carrying largely distinct immunoglobulin genes following antigenic challenge. Using immunoglobulin-repertoire sequencing to dynamically track responses to influenza vaccination, Jackson et al find evidence of convergent immunoglobulin responses across individuals. C1 [Martins, Andrew J.; Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Tsang, John S.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. RP Tsang, JS (reprint author), NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM john.tsang@nih.gov FU Intramural NIH HHS [ZIA AI001152-02, ZIA AI001152-01, Z99 AI999999, ZIA AI001152-03] NR 10 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD SEP PY 2014 VL 22 IS 9 BP 488 EP 489 DI 10.1016/j.tim.2014.07.005 PG 2 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AP7KZ UT WOS:000342257500003 PM 25179798 ER PT J AU Torres, OB Jalah, R Rice, KC Li, FY Antoline, JFG Iyer, MR Jacobson, AE Boutaghou, MN Alving, CR Matyas, GR AF Torres, Oscar B. Jalah, Rashmi Rice, Kenner C. Li, Fuying Antoline, Joshua F. G. Iyer, Malliga R. Jacobson, Arthur E. Boutaghou, Mohamed Nazim Alving, Carl R. Matyas, Gary R. TI Characterization and optimization of heroin hapten-BSA conjugates: method development for the synthesis of reproducible hapten-based vaccines SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Hapten density; Drugs of abuse vaccines; TNBS; Ellman's test; MALDI-TOFMS; ELISA ID IONIZATION-MASS-SPECTROMETRY; SIMPLE CHEMICAL-COMPOUNDS; ANTIBODY REACTIONS; PROTEINS; BINDING; MORPHINE; ANTIGEN; ACID; SENSITIZATION; KINETICS AB A potential new treatment for drug addiction is immunization with vaccines that induce antibodies that can abrogate the addictive effects of the drug of abuse. One of the challenges in the development of a vaccine against drugs of abuse is the availability of an optimum procedure that gives reproducible and high yielding hapten-protein conjugates. In this study, a heroin/morphine surrogate hapten (MorHap) was coupled to bovine serum albumin (BSA) using maleimide-thiol chemistry. MorHap-BSA conjugates with 3, 5, 10, 15, 22, 28, and 34 haptens were obtained using different linker and hapten ratios. Using this optimized procedure, MorHap-BSA conjugates were synthesized with highly reproducible results and in high yields. The number of haptens attached to BSA was compared by 2,4,6-trinitrobenzenesulfonic acid (TNBS) assay, modified Ellman's test and matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Among the three methods, MALDI-TOF MS discriminated subtle differences in hapten density. The effect of hapten density on enzyme-linked immunosorbent assay (ELISA) performance was evaluated with seven MorHap-BSA conjugates of varying hapten densities, which were used as coating antigens. The highest antibody binding was obtained with MorHap-BSA conjugates containing 3-5 haptens. This is the first report that rigorously analyzes, optimizes and characterizes the conjugation of haptens to proteins that can be used for vaccines against drugs of abuse. The effect of hapten density on the ELISA detection of antibodies against haptens demonstrates the importance of careful characterization of the hapten density by the analytical techniques described. C1 [Torres, Oscar B.; Jalah, Rashmi; Alving, Carl R.; Matyas, Gary R.] US Mil HIV Res Program, Lab Adjuvant & Antigen Res, Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Rice, Kenner C.; Li, Fuying; Antoline, Joshua F. G.; Jacobson, Arthur E.] NIDA, US Dept HHS, Drug Design & Synth Sect, Chem Biol Res Branch,NIH, Bethesda, MD 20892 USA. [Rice, Kenner C.; Li, Fuying; Antoline, Joshua F. G.; Iyer, Malliga R.; Jacobson, Arthur E.] NIAAA, NIH, Bethesda, MD 20892 USA. [Torres, Oscar B.; Jalah, Rashmi] US Mil HIV Res Program, Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20817 USA. [Boutaghou, Mohamed Nazim] Shimadzu Sci Instrument, Columbia, MD 21046 USA. RP Matyas, GR (reprint author), US Mil HIV Res Program, Lab Adjuvant & Antigen Res, Walter Reed Army Inst Res, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM gmatyas@hivresearch.org OI Matyas, Gary/0000-0002-2074-2373 FU Henry M. Jackson Foundation for the Advancement of Military Medicine [W81XWH-07-2-067]; US Army Medical Research and Materiel Command (MRMC) [W81XWH-07-2-067]; National Institute on Drug Abuse (NIH) [1DP1DA034787-01]; NIH Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS FX This work was supported through a Cooperative Agreement Award (no. W81XWH-07-2-067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Army Medical Research and Materiel Command (MRMC). The work was partially supported by an Avant Garde award to GRM from the National Institute on Drug Abuse (NIH grant no. 1DP1DA034787-01). The work of FL, JFGA, MRI, AEJ, and KCR was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS. NR 39 TC 6 Z9 7 U1 6 U2 40 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD SEP PY 2014 VL 406 IS 24 BP 5927 EP 5937 DI 10.1007/s00216-014-8035-x PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AP1MN UT WOS:000341834500018 PM 25084736 ER PT J AU You, J Du, CW Volkow, ND Pan, YT AF You, Jiang Du, Congwu Volkow, Nora D. Pan, Yingtian TI Optical coherence Doppler tomography for quantitative cerebral blood flow imaging SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID VELOCITY; BRAIN; ANGIOGRAPHY; MICROSCOPY; SPEED; OCT; MICROVASCULATURE; BANDWIDTH; SHIFT; ANGLE AB Optical coherence Doppler tomography (ODT) is a promising neurotechnique that permits 3D imaging of the cerebral blood flow (CBF) network; however, quantitative CBF velocity (CBFv) imaging remains challenging. Here we present a simple phase summation method to enhance slow capillary flow detection sensitivity without sacrificing dynamic range for fast flow and vessel tracking to improve angle correction for absolute CBFv quantification. Flow phantom validation indicated that the CBFv quantification accuracy increased from 15% to 91% and the coefficient of variation (CV) decreased 9.3-fold; in vivo mouse brain validation showed that CV decreased 4.4-/10.8- fold for venular/arteriolar flows. ODT was able to identify cocaine-elicited microischemia and quantify CBFv disruption in branch vessels and capillaries that otherwise would not have been possible. (C) 2014 Optical Society of America C1 [You, Jiang; Du, Congwu; Pan, Yingtian] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. RP You, J (reprint author), SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. EM yingtian.pan@stonybrook.edu FU National Institutes of Health (NIH) [R21DA032228, 1R01DA029718, K25 DA021200]; NIH's Intramural Program FX This work was supported in part by National Institutes of Health (NIH) grants R21DA032228 (YP/CD), 1R01DA029718 (CD/YP), K25 DA021200 (CD) and NIH's Intramural Program (NV). K. Park helped on animal surgery and preparation, Dr. Z. Yuan participated in the early programming work. NR 38 TC 10 Z9 10 U1 1 U2 12 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 SEP 1 PY 2014 VL 5 IS 9 BP 3217 EP 3230 DI 10.1364/BOE.5.003217 PG 14 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA AO9BQ UT WOS:000341650900030 PM 25401033 ER PT J AU Zustiak, MP Jose, L Xie, YQ Zhu, JW Betenbaugh, MJ AF Zustiak, Matthew P. Jose, Lisa Xie, Yueqing Zhu, Jianwei Betenbaugh, Micheal J. TI Enhanced transient recombinant protein production in CHO cells through the co-transfection of the product gene with Bcl-x(L) SO BIOTECHNOLOGY JOURNAL LA English DT Article DE Anti-apoptosis; CHO cells; Polyethyleneimine (PEI); Transient gene expression ID HAMSTER OVARY CELLS; HUMANIZED ANTIBODY-PRODUCTION; MAMMALIAN-CELLS; HIGH-LEVEL; MONOCLONAL-ANTIBODIES; EBNA1 CELLS; EXPRESSION; TRANSFECTION; APOPTOSIS; CULTURE AB Transient gene expression is gaining popularity as a method to rapidly produce recombinant proteins in mammalian cells. Although significant improvements have been made, in terms of expression, more improvements are needed to compete with the yields achievable in stable gene expression. Much progress has come from optimization of transfection media and parameters, as well as altering culturing conditions to enhance productivity. Recent studies have included cell lines engineered for apoptosis resistance through the constitutive expression of an anti-apoptotic protein, Bcl-x(L). In this study, we examine an alternative method of using the benefits of anti-apoptotic gene expression to enhance the transient expression of biotherapeutics, namely, through the co-transfection of Bcl-x(L) and the product-coding gene. CHO-S cells were co-transfected with the product-coding gene and a vector containing Bcl-x(L) using polyethylenimine. Cells co-transfected with Bcl-x(L) showed reduced levels of apoptosis, increased specific productivity, and an overall increase in product yield of approximately 100%. Similar results were produced by employing another antiapoptotic protein, Bcl-2 delta, in CHO cells, or through the co-transfection with Bcl-x(L) using HEK-293E cells. This work provides an alternative method for increasing yields of therapeutic proteins in TGE applications without generating a stable cell line and subsequent screening, which are both time- and resource-consuming. C1 [Zustiak, Matthew P.; Betenbaugh, Micheal J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD USA. [Zustiak, Matthew P.; Jose, Lisa; Xie, Yueqing; Zhu, Jianwei] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Biopharmaceut Dev Program, Frederick, MD 21702 USA. RP Zhu, JW (reprint author), SAIC Frederick Inc, Frederick Natl Lab Canc Res, Biopharmaceut Dev Program, POB B, Frederick, MD 21702 USA. EM jianweiz@hotmail.com; beten@jhu.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors would like to thank Dr. Terry Strom for the product-coding cDNA Staffs in the Early Process Sciences department of the Biopharmaceutical Development Program including Wei Cheng, Jane Wu, David Williams, and Dr. Vinay Vyas provided numerous assistances in various experiments and technical discussions. Drs. George Mitra and John Gilly provided managerial and administrative over view of the project. Finally, we like to thank the support from Drs. Steve Creekmore and Toby Hecht at National Cancer Institute. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract #HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mentioned of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 42 TC 7 Z9 7 U1 1 U2 22 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1860-6768 EI 1860-7314 J9 BIOTECHNOL J JI Biotechnol. J. PD SEP PY 2014 VL 9 IS 9 SI SI BP 1164 EP 1174 DI 10.1002/biot.201300468 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA AO9RO UT WOS:000341694200008 PM 24604826 ER PT J AU Downey, RF Wallace, T Sullivan, FJ Wang-Johanning, F Walsh, K Durkan, G Rogers, E Goldman, R Ambs, S Glynn, SA AF Downey, Ronan F. Wallace, Tiffany Sullivan, Francis J. Wang-Johanning, Feng Walsh, Kilian Durkan, Garrett Rogers, Eamonn Goldman, Radoslav Ambs, Stefan Glynn, Sharon A. TI Human Endogenous Retrovirus K Expression Predicts a Prostate Cancer Diagnosis SO BJU INTERNATIONAL LA English DT Meeting Abstract CT Annual Scientific Meeting of the Irish-Society-of-Urology CY SEP 25-26, 2014 CL Killarney, IRELAND SP Irish Soc Urol C1 [Downey, Ronan F.; Sullivan, Francis J.; Glynn, Sharon A.] Natl Univ Ireland, Prostate Canc Inst, Galway, Ireland. [Wallace, Tiffany; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Sullivan, Francis J.] Galway Univ Hosp, Dept Radiat Oncol, Galway, Ireland. [Wang-Johanning, Feng] SRI Int, Menlo Pk, CA 94025 USA. [Walsh, Kilian; Durkan, Garrett; Rogers, Eamonn] Galway Univ Hosp, Dept Urol, Galway, Ireland. [Goldman, Radoslav] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. RI Glynn, Sharon/D-7136-2013 OI Glynn, Sharon/0000-0003-1459-2580 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD SEP PY 2014 VL 114 SU 2 SI SI BP 19 EP 19 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AO9NG UT WOS:000341681800007 ER PT J AU Fleischhauer, K Fernandez-Vina, MA Wang, T Haagenson, M Battiwalla, M Baxter-Lowe, LA Ciceri, F Dehn, J Gajewski, J Hale, GA Heemskerk, MBA Marino, SR McCarthy, PL Miklos, D Oudshoorn, M Pollack, MS Reddy, V Senitzer, D Shaw, BE Waller, EK Lee, SJ Spellman, SR AF Fleischhauer, K. Fernandez-Vina, M. A. Wang, T. Haagenson, M. Battiwalla, M. Baxter-Lowe, L. A. Ciceri, F. Dehn, J. Gajewski, J. Hale, G. A. Heemskerk, M. B. A. Marino, S. R. McCarthy, P. L. Miklos, D. Oudshoorn, M. Pollack, M. S. Reddy, V. Senitzer, D. Shaw, B. E. Waller, E. K. Lee, S. J. Spellman, S. R. TI Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1 SO BONE MARROW TRANSPLANTATION LA English DT Article ID VERSUS-HOST-DISEASE; HLA-DP; MARROW-TRANSPLANTATION; LYMPHOCYTE INFUSION; DONOR; LEUKEMIA; ALLELES; MISMATCHES; DISPARITY; SELECTION AB HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06-1.53; P = 0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37-0.80; P = 0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence. C1 [Fleischhauer, K.] Essen Univ Hosp, Inst Expt Cellular Therapy, D-45122 Essen, Germany. [Fleischhauer, K.] Ist Sci San Raffaele, Unit Mol & Funct Immunogenet, I-20132 Milan, Italy. [Fernandez-Vina, M. A.] Stanford Univ, Sch Med, Histocompatibil Immunogenet & Dis Profiling Lab, Stanford, CA 94305 USA. [Wang, T.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Haagenson, M.; Spellman, S. R.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Battiwalla, M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Baxter-Lowe, L. A.] Univ Calif San Francisco, Med Ctr, Immunogent & Transplantat Lab, San Francisco, CA USA. [Ciceri, F.] Ist Sci San Raffaele, Hematol & Bone Marrow Transplantat Unit, I-20132 Milan, Italy. [Dehn, J.] Natl Marrow Donor Program, Minneapolis, MN USA. [Gajewski, J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Hale, G. A.] Univ S Florida, All Childrens Hosp, Pediat Hematol Oncol BMT, St Petersburg, FL 33701 USA. [Heemskerk, M. B. A.] Dutch Transplant Fdn, Leiden, Netherlands. [Marino, S. R.] Univ Chicago Hosp, Dept Pathol, Chicago, IL 60637 USA. [McCarthy, P. L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Miklos, D.] Stanford Hosp & Clin, Dept Med Bone Marrow Transplant, Stanford, CA USA. [Oudshoorn, M.] Leiden Univ, Med Ctr, Europdonor Fdn, Leiden, Netherlands. [Pollack, M. S.] Univ Texas Hlth Care Syst, Dept Pathol, San Antonio, TX USA. [Reddy, V.] Univ Florida, Dept Hemaotol Oncol, Gainesville, FL USA. [Senitzer, D.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Shaw, B. E.] Anthony Nolan Res Inst, London, England. [Waller, E. K.] Emory Univ Hosp, Bone Marrow & Stem Cell Transplant Ctr, Atlanta, GA 30322 USA. [Lee, S. J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Fleischhauer, K (reprint author), Essen Univ Hosp, Inst Expt Cellular Therapy, Hufelandstr 55, D-45122 Essen, Germany. EM katharina.fleischhauer@uk-essen.de OI Heemskerk, Martin/0000-0002-9432-7623 FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG12042]; National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Allos, Inc.; Amgen, Inc.; Angioblast FX This work was supported by a grant (no. IG12042) from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to KF. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two grants, N00014-12-1-0142 and N00014-13-1-0039, from the Office of Naval Research; grants from Allos, Inc., Amgen, Inc., Angioblast; anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; THERAKOS, Inc.; and Wellpoint, Inc. NR 18 TC 11 Z9 11 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD SEP PY 2014 VL 49 IS 9 BP 1176 EP 1183 DI 10.1038/bmt.2014.122 PG 8 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA AP0WN UT WOS:000341786700007 PM 24955785 ER PT J AU Gandini, S Puntoni, M Heckman-Stoddard, BM Dunn, BK Ford, L DeCensi, A Szabo, E AF Gandini, Sara Puntoni, Matteo Heckman-Stoddard, Brandy M. Dunn, Barbara K. Ford, Leslie DeCensi, Andrea Szabo, Eva TI Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and Confounders SO CANCER PREVENTION RESEARCH LA English DT Article ID TYPE-2 DIABETES-MELLITUS; POPULATION-BASED COHORT; GLUCOSE-LOWERING THERAPIES; BREAST-CANCER; PROSTATE-CANCER; HEPATOCELLULAR-CARCINOMA; PANCREATIC-CANCER; LUNG-CANCER; COLORECTAL-CANCER; INCIDENT CANCER AB Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52-0.90], although between-study heterogeneity was considerable (I 2 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54-0.81; I-2 = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70-0.96 with I-2 = 76% and SRR, 0.90; 95% CI, 0.89-0.91 with I-2 = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites. (C) 2014 AACR. C1 [Gandini, Sara] European Inst Oncol, Div Epidemiol & Biostat, Milan, Italy. [Puntoni, Matteo] EO Osped Galliera, Off Sci Director, Clin Trials Off, Genoa, Italy. [Heckman-Stoddard, Brandy M.] NCI, Canc Prevent Div, Breast & Gynecol Canc Res Grp, Bethesda, MD 20892 USA. [Dunn, Barbara K.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. [Ford, Leslie] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [DeCensi, Andrea] EO Osped Galliera, Div Med Oncol, Genoa, Italy. [Szabo, Eva] NCI, Canc Prevent Div, Lung & Upper Aerodigest Canc Res Grp, Bethesda, MD 20892 USA. RP Szabo, E (reprint author), NCI, Canc Prevent Div, Lung & Upper Aerodigest Canc Res Grp, NIH, 9609 Med Ctr Dr,Room 5E-102, Bethesda, MD 20892 USA. EM szaboe@mail.nih.gov RI Puntoni, Matteo/J-5440-2016; OI Puntoni, Matteo/0000-0002-7908-0626; Gandini, Sara/0000-0002-1348-4548 FU Italian Association for Cancer Research AIRC [IG 12072]; Italian Ministry of Health [RF-2009-1532226]; Italian League Against Cancer [14/08] FX The study was supported by grants from the Italian Association for Cancer Research AIRC (IG 12072), the Italian Ministry of Health (RF-2009-1532226), and the Italian League Against Cancer (14/08) to A. DeCensi. A. DeCensi's work was partially performed during a sabbatical at the Division of Cancer Prevention, National Cancer Institute, NIH. NR 106 TC 66 Z9 67 U1 2 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2014 VL 7 IS 9 BP 867 EP 885 DI 10.1158/1940-6207.CAPR-13-0424 PG 19 WC Oncology SC Oncology GA AP0XB UT WOS:000341788300001 PM 24985407 ER PT J AU Albanes, D Till, C Klein, EA Goodman, PJ Mondul, AM Weinstein, SJ Taylor, PR Parnes, HL Gaziano, JM Song, XL Fleshner, NE Brown, PH Meyskens, FL Thompson, IM AF Albanes, Demetrius Till, Cathee Klein, Eric A. Goodman, Phyllis J. Mondul, Alison M. Weinstein, Stephanie J. Taylor, Philip R. Parnes, Howard L. Gaziano, J. Michael Song, Xiaoling Fleshner, Neil E. Brown, Powel H. Meyskens, Frank L., Jr. Thompson, Ian M. TI Plasma Tocopherols and Risk of Prostate Cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) SO CANCER PREVENTION RESEARCH LA English DT Article ID SERUM ALPHA-TOCOPHEROL; GAMMA-TOCOPHEROL; BETA-CAROTENE; FOLLOW-UP; ASSOCIATION; RETINOL; COHORT; MEN; SUPPLEMENTATION; MICRONUTRIENTS AB The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose alpha-tocopherol. We, therefore, examined whether presupplementation plasma alpha-tocopherol or gamma-tocopherol was associated with overall or high-grade prostate cancer. A stratified case-cohort sample that included 1,746 incident prostate cancer cases diagnosed through June 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry from 2001 to 2004, and median follow-up was 5.5 years (range, 0-7.9 years). Incidence of prostate cancer as a function of plasma a-tocopherol, g-tocopherol, and supplementation with alpha-tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma gamma-tocopherol was not associated with prostate cancer. Men with higher alpha-tocopherol concentrations seemed to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21; 95 % confidence interval (CI), 0.88-1.66; P-trend = 0.24; in the trial placebo arm, Q5 HR, 0.85; 95% CI, 0.44-1.62; P-trend = 0.66]. We found a strong positive plasma alpha-tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04; 95% CI, 1.29-3.22; P-trend = 0.005]. A positive plasma a-tocopherol-prostate cancer association also seemed limited to high-grade disease (Gleason grade, 7-10; overall Q5 HR, 1.59; 95% CI, 1.13-2.24; P-trend = 0.001; among men receiving selenomethionine, Q5 HR, 2.12; 95% CI, 1.32-3.40; P-trend = 0.0002). Our findings indicate that higher plasma a-tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biologic interaction between a-tocopherol and selenium itself or selenomethionine. (C) 2014 AACR. C1 [Albanes, Demetrius; Mondul, Alison M.; Weinstein, Stephanie J.; Taylor, Philip R.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Till, Cathee; Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44106 USA. [Parnes, Howard L.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Res & Informat Ctr, Boston, MA USA. [Song, Xiaoling] Fred Hutchinson Canc Res Ctr, Biomarker Lab, Seattle, WA 98104 USA. [Fleshner, Neil E.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Brown, Powel H.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Meyskens, Frank L., Jr.] Univ Calif Irvine, Dept Med, Orange, CA 92668 USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. RP Albanes, D (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E342, Bethesda, MD 20892 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015 OI Mondul, Alison/0000-0002-8843-1416; FU National Cancer Institute [7U10CA037429-29]; Intramural Program of the U.S. Public Health Service, NIH, National Cancer Institute; National Center for Complementary and Alternative Medicine National Institutes of Health, NIH, Department of Health and Human Services FX This work was supported in part by Public Health Service Cooperative Agreement grant 7U10CA037429-29 awarded by the National Cancer Institute in cooperation with the National Center for Complementary and Alternative Medicine National Institutes of Health, NIH, Department of Health and Human Services (to C. Till, E.A. Klein, P.J. Goodman, F.L. Meyskens Jr, and I.M. Thompson), and by the Intramural Program of the U.S. Public Health Service, NIH, National Cancer Institute (to D. Albanes, A. Mondul, S.J. Weinstein, and P.R. Taylor). Study agents and packaging were provided by Perrigo Company (Allegan, MI), Sabinsa Corporation (Piscataway, NJ), Tishcon Corporation (Westbury, NY), and DSM Nutritional Products, Inc. (Parsipanny, NJ). NR 44 TC 16 Z9 17 U1 2 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2014 VL 7 IS 9 BP 886 EP 895 DI 10.1158/1940-6207.CAPR-14-0058 PG 10 WC Oncology SC Oncology GA AP0XB UT WOS:000341788300002 PM 24961880 ER PT J AU Blagoev, KB Wilkerson, J Stein, WD Yang, J Bates, SE Fojo, T AF Blagoev, Krastan B. Wilkerson, Julia Stein, Wilfred D. Yang, James Bates, Susan E. Fojo, Tito TI Therapies with Diverse Mechanisms of Action Kill Cells by a Similar Exponential Process in Advanced Cancers SO CANCER RESEARCH LA English DT Article ID PHASE-II TRIAL; INDEPENDENT PROSTATE-CANCER; GROWTH-RATE CONSTANTS; INTERFERON-ALPHA; CARCINOMA; SURVIVAL; BEVACIZUMAB; SUNITINIB; THALIDOMIDE; DOCETAXEL AB Successful cancer treatments are generally defined as those that decrease tumor quantity. In many cases, this decrease occurs exponentially, with deviations from a strict exponential being attributed to a growing fraction of drug-resistant cells. Deviations from an exponential decrease in tumor quantity can also be expected if drugs have a nonuniform spatial distribution inside the tumor, for example, because of interstitial pressure inside the tumor. Here, we examine theoretically different models of cell killing and analyze data from clinical trials based on these models. We show that the best description of clinical outcomes is by first-order kinetics with exponential decrease of tumor quantity. We analyzed the total tumor quantity in a diverse group of clinical trials with various cancers during the administration of different classes of anticancer agents and in all cases observed that the models that best fit the data describe the decrease of the sensitive tumor fraction exponentially. The exponential decrease suggests that all drug-sensitive cancer cells have a single rate-limiting step on the path to cell death. If there are intermediate steps in the path to cell death, they are not rate limiting in the observational time scale utilized in clinical trials-tumor restaging at 6- to 8-week intervals. On shorter time scales, there might be intermediate steps, but the rate-limiting step is the same. Our analysis, thus, points to a common pathway to cell death for cancer cells in patients. (C) 2014 AACR. C1 [Blagoev, Krastan B.] Natl Sci Fdn, Arlington, VA 22230 USA. [Blagoev, Krastan B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Blagoev, Krastan B.] Antinula Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Wilkerson, Julia; Stein, Wilfred D.; Bates, Susan E.; Fojo, Tito] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stein, Wilfred D.] Hebrew Univ Jerusalem, Jerusalem, Israel. [Yang, James] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Blagoev, KB (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Bldg 149,13th St, Charlestown, MA 02129 USA. EM kblagoev@nsf.gov OI Wilkerson, Julia/0000-0002-6965-0867 FU National Science Foundation FX The National Science Foundation supported the work of K.B. Blagoev. NR 21 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2014 VL 74 IS 17 BP 4653 EP 4662 DI 10.1158/0008-5472.CAN-14-0420 PG 10 WC Oncology SC Oncology GA AP1MC UT WOS:000341833300009 PM 25183789 ER PT J AU Lee, YH Seo, D Choi, KJ Andersen, JB Won, MA Kitade, M Gomez-Quiroz, LE Judge, AD Marquardt, JU Raggi, C Conner, EA MacLachlan, I Factor, VM Thorgeirsson, SS AF Lee, Yun-Han Seo, Daekwan Choi, Kyung-Ju Andersen, Jesper B. Won, Min-Ah Kitade, Mitsuteru Gomez-Quiroz, Luis E. Judge, Adam D. Marquardt, Jens U. Raggi, Chiara Conner, Elizabeth A. MacLachlan, Ian Factor, Valentina M. Thorgeirsson, Snorri S. TI Antitumor Effects in Hepatocarcinoma of lsoform-Selective Inhibition of HDAC2 SO CANCER RESEARCH LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTOR; HUMAN HEPATOCELLULAR-CARCINOMA; HISTONE DEACETYLASE INHIBITORS; THERAPEUTIC TARGET; RNA INTERFERENCE; SYNTHETIC SIRNA; GENE-EXPRESSION; CANCER-THERAPY; IN-VIVO; POTENT AB Ilistone deacetylase 2 (IIDAC2) is a chromatin modifier involved in epigenetic regulation of cell cycle, apoptosis, and differentiation that is upregulated commonly in human hepatocellular carcinoma (HCC). In this study, we show that specific targeting of this HDAC isoforrn is sufficient to inhibit HCC progression. siRNA-mediated silencing of HDAC inhibited HCC cell growth by blocking cell-cycle progression and inducing apoptosis. These effects were associated with deregulation of HDAC-regulated genes that control cell cycle, apoptosis, and lipid metabolism, specifically, by upregulation of p27 and acetylated p53 and by downregulation of CDK6 and BCL2. We found that HDAC2 silencing in HCC cells also strongly inhibited PPARy signaling and other regulators of glycolysis (ChREBRY and GLUT4) and lipogenesis (SREBP1C and FAS), eliciting a marked decrease in fat: accumulation. Notably, systemic delivery of LIDAC2 siRNA encapsulated in lipid nanoparticles was sufficient to blunt the growth of human LICC in a murine xenograft model. Our findings offer preclinical proof-of-concept for LIDAC2 blockade as a systemic therapy for liver cancer. (C) 2014 AACR. C1 [Lee, Yun-Han; Seo, Daekwan; Andersen, Jesper B.; Kitade, Mitsuteru; Gomez-Quiroz, Luis E.; Marquardt, Jens U.; Raggi, Chiara; Conner, Elizabeth A.; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Yun-Han; Choi, Kyung-Ju; Won, Min-Ah] Yonsei Univ, Coll Med, Dept Radiat Oncol, Seoul, South Korea. [Judge, Adam D.; MacLachlan, Ian] Tekmira Pharmaceut Corp, Burnaby, BC, Canada. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr Dr MSC 4262,Room 4146A, Bethesda, MD 20892 USA. EM yhlee87@yuhs.ac; snorri_thorgeirsson@nih.gov FU Intramural Research Program of the Center for Cancer Research, NCI; Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A121982] FX This project was supported by the Intramural Research Program of the Center for Cancer Research, NCI, and by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A121982). NR 47 TC 21 Z9 22 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2014 VL 74 IS 17 BP 4752 EP 4761 DI 10.1158/0008-5472.CAN-13-3531 PG 10 WC Oncology SC Oncology GA AP1MC UT WOS:000341833300019 PM 24958469 ER PT J AU Chow, KH Shin, DM Jenkins, MH Miller, EE Shih, DJ Choi, S Low, BE Philip, V Rybinski, B Bronson, RT Taylor, MD Yun, K AF Chow, Kin-Hoe Shin, Dong-Mi Jenkins, Molly H. Miller, Emily E. Shih, David J. Choi, Seungbum Low, Benjamin E. Philip, Vivek Rybinski, Brad Bronson, Roderick T. Taylor, Michael D. Yun, Kyuson TI Epigenetic States of Cells of Origin and Tumor Evolution Drive Tumor-Initiating Cell Phenotype and Tumor Heterogeneity SO CANCER RESEARCH LA English DT Article ID CANCER STEM-CELLS; MOUSE MODEL; MOLECULAR SUBGROUPS; MEDULLOBLASTOMA; MICE; PATHWAY; IDENTIFICATION; GENERATION; MUTATIONS; DISTINCT AB A central confounding factor in the development of targeted therapies is tumor cell heterogeneity, particularly in tumor-initiating cells (TIC), within clinically identical tumors. Here, we show how activation of the Sonic Hedgehog (SHH) pathway in neural stem and progenitor cells creates a foundation for tumor cell evolution to heterogeneous states that are histologically indistinguishable but molecularly distinct. In spontaneous medulloblastomas that arise in Patched (Ptch)(+/-) mice, we identified three distinct tumor subtypes. Through cell type-specific activation of the SHH pathway in vivo, we determined that different cells of origin evolved in unique ways to generate these subtypes. Moreover, TICs in each subtype had distinct molecular and cellular phenotypes. At the bulk tumor level, the three tumor subtypes could be distinguished by a 465-gene signature and by differential activation levels of the ERK and AKT pathways. Notably, TICs from different subtypes were differentially sensitive to SHH or AKT pathway inhibitors, highlighting new mechanisms of resistance to targeted therapies. In summary, our results show how evolutionary processes act on distinct cells of origin to contribute to tumoral heterogeneity, at both bulk tumor and TIC levels. (C) 2014 AACR. C1 [Chow, Kin-Hoe; Jenkins, Molly H.; Miller, Emily E.; Choi, Seungbum; Low, Benjamin E.; Philip, Vivek; Rybinski, Brad; Yun, Kyuson] Jackson Lab, Bar Harbor, ME 04609 USA. [Shin, Dong-Mi] NIAID, Immunogenet Lab, NIH, Bethesda, MD USA. [Shin, Dong-Mi] Seoul Natl Univ, Dept Food & Nutr, Seoul, South Korea. [Shih, David J.; Taylor, Michael D.] Hosp Sick Children, Div Neurosurg, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada. [Bronson, Roderick T.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Yun, K (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM Kyuson.yun@jax.org RI Shih, David/H-3186-2011; OI Shih, David/0000-0002-9802-4937; Rybinski, Brad/0000-0002-3180-4496; Philip, Vivek/0000-0001-5126-707X FU National Cancer Institute Center [P30CA034196] FX This work was supported in part by the National Cancer Institute Center Support Grant P30CA034196 and a gift from Walter and Dorsey Cabot (to K. Yun). NR 31 TC 8 Z9 8 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2014 VL 74 IS 17 BP 4864 EP 4874 DI 10.1158/0008-5472.CAN-13-3293 PG 11 WC Oncology SC Oncology GA AP1MC UT WOS:000341833300029 PM 25136069 ER PT J AU Rajagopalan, S AF Rajagopalan, Sumati TI HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE cellular senescence; HLA-G; KIR2DL4; natural killer cells; pregnancy ID NATURAL-KILLER-CELLS; RECEPTOR KIR2DL4 CD158D; IFN-GAMMA PRODUCTION; CLASS-I MOLECULES; INHIBITORY RECEPTORS; ACTIVATING RECEPTOR; ADAPTIVE IMMUNITY; CUTTING EDGE; FETAL-GROWTH; UTERINE AB The uterus in early pregnancy is a non-lymphoid organ that is enriched in natural killer (NK) cells. Studies to address the role of these abundant human NK cells at the maternal/fetal interface have focused on their response to the major histocompatibility complex (MHC) molecules on fetal trophoblast cells that they contact. The interaction of maternal NK cell receptors belonging to the killer cell immunoglobulin-like receptor (KIR) family with trophoblast MHC class I molecules in pregnancy can regulate NK cell activation for secretion of pro-angiogenic factors that promote placental development. This review will cover the role of KIR at the maternal/fetal interface and focus on KIR2DL4, a KIR family member that is uniquely poised to play a role in pregnancy due to the restricted expression of its ligand, human leukocyte antigen (HLA)-G, by fetal trophoblast cells early in pregnancy. The pathways by which KIR2DL4-HLA-G interactions induce the cellular senescence of NK cells and the role of the resulting senescence-associated secretory phenotype (SASP) in vascular remodeling will be discussed in the context of reproduction. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Rajagopalan, S (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM sumi@nih.gov FU NIAID, NIH FX I thank Dr E O Long for his support. This work was supported by the Intramural Research Program of the NIAID, NIH. NR 67 TC 16 Z9 17 U1 3 U2 9 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD SEP PY 2014 VL 11 IS 5 BP 460 EP 466 DI 10.1038/cmi.2014.53 PG 7 WC Immunology SC Immunology GA AP1IT UT WOS:000341823000007 PM 24998350 ER PT J AU Cohen, JI Ali, MA Bayat, A Steinberg, SP Park, H Gershon, AA Burbelo, PD AF Cohen, Jeffrey I. Ali, Mir A. Bayat, Ahmad Steinberg, Sharon P. Park, Hosun Gershon, Anne A. Burbelo, Peter D. TI Detection of Antibodies to Varicella-Zoster Virus in Recipients of the Varicella Vaccine by Using a Luciferase Immunoprecipitation System Assay SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; MEMBRANE-ANTIGEN; FLUORESCENT-ANTIBODY; IMMUNITY; IMMUNOFLUORESCENCE AB A high-throughput test to detect varicella-zoster virus (VZV) antibodies in varicella vaccine recipients is not currently available. One of the most sensitive tests for detecting VZV antibodies after vaccination is the fluorescent antibody to membrane antigen (FAMA) test. Unfortunately, this test is labor-intensive, somewhat subjective to read, and not commercially available. Therefore, we developed a highly quantitative and high-throughput luciferase immunoprecipitation system (LIPS) assay to detect antibody to VZV glycoprotein E (gE). Tests of children who received the varicella vaccine showed that the gE LIPS assay had 90% sensitivity and 70% specificity, a viral capsid antigen enzyme-linked immunosorbent assay (ELISA) had 67% and 87% specificity, and a glycoprotein ELISA (not commercially available in the United States) had 94% sensitivity and 74% specificity compared with the FAMA test. The rates of antibody detection by the gE LIPS and glycoprotein ELISA were not statistically different. Therefore, the gE LIPS assay may be useful for detecting VZV antibodies in varicella vaccine recipients. C1 [Cohen, Jeffrey I.; Ali, Mir A.] Natl Inst Allergy & Infect Dis, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD USA. [Bayat, Ahmad] Ctr Clin, Dept Perioperat Med, NIH, Bethesda, MD USA. [Steinberg, Sharon P.; Gershon, Anne A.] Columbia Univ, Coll Phys & Surg, Dept Pediat, Div Pediat Infect Dis, New York, NY USA. [Park, Hosun] Yeungnam Univ, Coll Med, Dept Microbiol, Taegu, South Korea. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Cohen, JI (reprint author), Natl Inst Allergy & Infect Dis, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Disease; National Institute of Dental and Craniofacial Research FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research. NR 13 TC 6 Z9 6 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD SEP PY 2014 VL 21 IS 9 BP 1288 EP 1291 DI 10.1128/CVI.00250-14 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AO8SO UT WOS:000341624800013 PM 24990909 ER PT J AU Suryani, S Carol, H Chonghaile, TN Frismantas, V Sarmah, C High, L Bornhauser, B Cowley, MJ Szymanska, B Evans, K Boehm, I Tonna, E Jones, L Manesh, DM Kurmasheva, RT Billups, C Kaplan, W Letai, A Bourquin, JP Houghton, PJ Smith, MA Lock, RB AF Suryani, Santi Carol, Hernan Chonghaile, Triona Ni Frismantas, Viktoras Sarmah, Chintanu High, Laura Bornhauser, Beat Cowley, Mark J. Szymanska, Barbara Evans, Kathryn Boehm, Ingrid Tonna, Elise Jones, Luke Manesh, Donya Moradi Kurmasheva, Raushan T. Billups, Catherine Kaplan, Warren Letai, Anthony Bourquin, Jean-Pierre Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI Cell and Molecular Determinants of In Vivo Efficacy of the BH3 Mimetic ABT-263 against Pediatric Acute Lymphoblastic Leukemia Xenografts SO CLINICAL CANCER RESEARCH LA English DT Article ID PRECLINICAL TESTING PROGRAM; GENE-EXPRESSION; ANTITUMOR-ACTIVITY; ABT-737 TARGETS; BCL-2 PROTEINS; CANCER-CELLS; MCL-1; APOPTOSIS; RESISTANCE; INHIBITOR AB Purpose: Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vivo ABT-263 sensitivity. Experimental Design: The in vivo efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts composed of MLL-, BCP-, and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An in vitro coculture assay with immortalized human mesenchymal cells was utilized to build a predictive model of in vivo ABT-263 sensitivity. Results: ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among BCL2 family members, in vivo ABT-263 sensitivity correlated best with low MCL1 mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an in vitro coculture assay, a predictive model of in vivo ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted in vivo ABT-263 responses with high sensitivity (50%) and specificity (100%). Conclusion: These results highlight the in vivo efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of in vitro functional assays can be used to predict its in vivo efficacy. (C) 2014 AACR. C1 [Suryani, Santi; Carol, Hernan; Sarmah, Chintanu; High, Laura; Szymanska, Barbara; Evans, Kathryn; Boehm, Ingrid; Tonna, Elise; Jones, Luke; Manesh, Donya Moradi; Lock, Richard B.] UNSW, Lowy Canc Res Ctr, Childrens Canc Inst Australia Med Res, Randwick, NSW 2031, Australia. [Chonghaile, Triona Ni; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Frismantas, Viktoras; Bornhauser, Beat; Bourquin, Jean-Pierre] Univ Childrens Hosp, Div Pediat Oncol, Zurich, Switzerland. [Cowley, Mark J.; Kaplan, Warren] St Vincents Hosp, Garvan Inst Med Res, Peter Wills Bioinformat Ctr, Darlinghurst, NSW 2010, Australia. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Ctr Childhood Canc, Columbus, OH USA. [Billups, Catherine] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. RP Lock, RB (reprint author), UNSW, Lowy Canc Res Ctr, Childrens Canc Inst Australia Med Res, POB 81, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Bornhauser, Beat/M-4437-2014; Ni Chonghaile, Triona/L-9418-2015; Lock, Richard/G-4253-2013; OI Ni Chonghaile, Triona/0000-0002-3041-4031; Cowley, Mark/0000-0002-9519-5714 FU National Cancer Institute [NOI-CM-42216, NOI-CM-91001-03]; Leukaemia Foundation of Australia; Cancer Council New South Wales; Krebsliga Zurich; Foundation Kind und Krebs; Hanne Liebermann Stiftung; Swiss National Research Foundation; Cure Cancer Australia Foundation; Cancer Institute NSW; National Health and Medical Research Council FX This research was funded by grants from the National Cancer Institute (NOI-CM-42216 and NOI-CM-91001-03); the Leukaemia Foundation of Australia the Cancer Council New South Wales; the Krebsliga Zurich to B. Bornhauser, and the Foundation Kind und Krebs, the Hanne Liebermann Stiftung, and the Swiss National Research Foundation to J.-P. Bourquin. S. Suryani is supported by Postdoctoral Fellowships from the Leukaemia Foundation of Australia and the Cure Cancer Australia Foundation, and an Early Career Fellowship from the Cancer Institute NSW. R. B. Lock is supported by a Fellowship from the National Health and Medical Research Council. NR 50 TC 22 Z9 22 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 SEP 1 PY 2014 VL 20 IS 17 BP 4520 EP 4531 DI 10.1158/1078-0432.CCR-14-0259 PG 12 WC Oncology SC Oncology GA AP1MV UT WOS:000341835500013 PM 25013123 ER PT J AU Lu, K Cheng, MCJ Ge, XY Berger, A Xu, DH Kato, GJ Minniti, CP AF Lu, Kit Cheng, Mok-Chung Jennifer Ge, Xiaoying Berger, Ann Xu, Dihua Kato, Gregory J. Minniti, Caterina P. TI A Retrospective Review of Acupuncture Use for the Treatment of Pain in Sickle Cell Disease Patients Descriptive Analysis From a Single Institution SO CLINICAL JOURNAL OF PAIN LA English DT Review DE sickle cell; acupuncture; pain management; acute pain; chronic pain ID MANAGEMENT; GUIDELINES; MECHANISM; ADULTS AB Objectives: This retrospective study describes the use of acupuncture for adult sickle cell patients in a single institution. Materials and Methods: We identified 47 sickle cell disease patients referred for acupuncture at the National Institutes of Health between January 2005 and September 2011. All patients were enrolled in a Study of the Natural History of sickle cell disease and signed consent. We reviewed patient demographics, location of acupuncture treatment sessions (inpatient vs. outpatient), number of sessions received, sites of pain, patient pain reporting, and the use of other complementary therapies. Results: Of the 47 patients (60% women, median age 36 y) referred for acupuncture, 42 had homozygous SS disease (89%) and 5 had SC disease (11%). Over half of the patients (51%) reported > 3 sites of pain. Only 24 patients (51%) underwent acupuncture treatment. Of those who elected not to receive acupuncture, a majority (87%) accepted some other forms of complementary therapies. Nine patients underwent only inpatient acupuncture for acute vaso-occlusive crisis. Eleven patients received only outpatient acupuncture treatment for chronic pain, and 4 patients received both inpatient and outpatient treatments. For the patients who received inpatient acupuncture treatment for acute vaso-occlusive crisis, there was a significant reduction of reported pain score immediately after acupuncture treatment with an average pain reduction of 2.1 points on the numeric pain scale (P < 0.0001). Excluding the 2 outliers, 75% of patients (n = 13) in the outpatient setting described their pain as improved compared with prior session. Discussion: To our knowledge, this is the largest retrospective review of acupuncture use in the sickle cell population. This analysis describes the use of acupuncture and raises the possibility of its use as an adjuvant for pain management in this population. Future clinical trials are needed to evaluate acupuncture's efficacy and effectiveness for pain management in different treatment settings and for various types of pain etiologies among the sickle cell population. C1 [Lu, Kit] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Cheng, Mok-Chung Jennifer; Ge, Xiaoying; Berger, Ann] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Xu, Dihua; Minniti, Caterina P.] NHLBI, Sickle Cell Vasc Dis Sect, Hematol Branch, Bethesda, MD 20892 USA. [Kato, Gregory J.; Minniti, Caterina P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Minniti, CP (reprint author), NHLBI, Sickle Cell Vasc Dis Sect, Hematol Branch, Bldg 10CRC,Room 5-5140, Bethesda, MD 20892 USA. EM minnitic@nhlbi.nih.gov FU National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, MD [1 ZIA HL006014-04] FX The authors declare no conflict of interest. Supported by the National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, MD 20892 (1 ZIA HL006014-04). NR 26 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-8047 EI 1536-5409 J9 CLIN J PAIN JI Clin. J. Pain PD SEP PY 2014 VL 30 IS 9 BP 825 EP 830 PG 6 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AP1MM UT WOS:000341834400011 PM 24322996 ER PT J AU Lamm, C Walker, OL Degnan, KA Henderson, HA Pine, DS McDermott, JM Fox, NA AF Lamm, Connie Walker, Olga L. Degnan, Kathryn A. Henderson, Heather A. Pine, Daniel S. McDermott, Jennifer Martin Fox, Nathan A. TI Cognitive control moderates early childhood temperament in predicting social behavior in 7-year-old children: an ERP study SO DEVELOPMENTAL SCIENCE LA English DT Article ID EMOTION REGULATION; ANXIETY DISORDERS; NEURAL MECHANISMS; GO/NOGO TASK; NEGATIVITY ERN; INHIBITION; ATTENTION; GO; QUESTIONNAIRE; ACTIVATION AB Behavioral inhibition (BI) is a temperament associated with heightened vigilance and fear of novelty in early childhood, and social reticence and increased risk for anxiety problems later in development. However, not all behaviorally inhibited children develop signs of anxiety. One mechanism that might contribute to the variability in developmental trajectories is the recruitment of cognitive-control resources. The current study measured N2 activation, an ERP (event-related potential) associated with cognitive control, and modeled source-space activation (LORETA; Low Resolution Brain Electromagnetic Tomography) at 7years of age while children performed a go/no-go task. Activation was estimated for the entire cortex and then exported for four regions of interest: ventromedial prefrontal cortex (VMPFC), ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dorsal ACC), and dorsal lateral prefrontal cortex (DLPFC). BI was measured in early childhood (ages 2 and 3years). Anxiety problems and social reticence were measured at 7years of age to ascertain stability of temperamental style. Results revealed that BI was associated with increased performance accuracy, longer reaction times, greater (more negative) N2 activation, and higher estimated dorsal ACC and DLPFC activation. Furthermore, early BI was only associated with social reticence at age 7 at higher (more negative) levels of N2 activation or higher estimated dorsal ACC or DLPFC activation. Results are discussed in the context of overcontrolled behavior contributing to social reticence and signs of anxiety in middle childhood. C1 [Lamm, Connie] Univ New Orleans, Dept Psychol, New Orleans, LA 70148 USA. [Walker, Olga L.; Degnan, Kathryn A.; Fox, Nathan A.] Univ Maryland, Child Dev Lab, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Henderson, Heather A.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Pine, Daniel S.] NIMH, Bethesda, MD USA. [McDermott, Jennifer Martin] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. RP Lamm, C (reprint author), Univ New Orleans, Dept Psychol, 2001 Geol & Psychol Bldg, New Orleans, LA 70148 USA. EM clamm@uno.edu FU NICHD NIH HHS [R37 HD017899, R37HD17899]; NIMH NIH HHS [P50 MH078105, P50MH078105, U01 MH093349, R01MH093349] NR 51 TC 13 Z9 13 U1 1 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1363-755X EI 1467-7687 J9 DEVELOPMENTAL SCI JI Dev. Sci. PD SEP PY 2014 VL 17 IS 5 BP 667 EP 681 DI 10.1111/desc.12158 PG 15 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA AO7DG UT WOS:000341511600004 PM 24754610 ER PT J AU McHugh, CA Fontana, J Nemecek, D Cheng, NQ Aksyuk, AA Heymann, JB Winkler, DC Lam, AS Wall, JS Steven, AC Hoiczyk, E AF McHugh, Colleen A. Fontana, Juan Nemecek, Daniel Cheng, Naiqian Aksyuk, Anastasia A. Heymann, J. Bernard Winkler, Dennis C. Lam, Alan S. Wall, Joseph S. Steven, Alasdair C. Hoiczyk, Egbert TI A virus capsid-like nanocompartment that stores iron and protects bacteria from oxidative stress SO EMBO JOURNAL LA English DT Article DE cryo-electron microscopy; encapsulin; ferritin; HK97 fold; oxidative stress ID TRANSMISSION ELECTRON-MICROSCOPY; MYXOCOCCUS-XANTHUS; CRYSTAL-STRUCTURE; COMMON ANCESTRY; MASS ANALYSIS; MATURATION; PROTEINS; EVOLUTION; MICROCOMPARTMENTS; FERRITIN AB Living cells compartmentalize materials and enzymatic reactions to increase metabolic efficiency. While eukaryotes use membrane-bound organelles, bacteria and archaea rely primarily on protein-bound nanocompartments. Encapsulins constitute a class of nanocompartments widespread in bacteria and archaea whose functions have hitherto been unclear. Here, we characterize the encapsulin nanocompartment from Myxococcus xanthus, which consists of a shell protein (EncA, 32.5 kDa) and three internal proteins (EncB, 17 kDa; EncC, 13 kDa; EncD, 11 kDa). Using cryo-electron microscopy, we determined that EncA self-assembles into an icosahedral shell 32 nm in diameter (26 nm internal diameter), built from 180 subunits with the fold first observed in bacteriophage HK97 capsid. The internal proteins, of which EncB and EncC have ferritin-like domains, attach to its inner surface. Native nanocompartments have dense iron-rich cores. Functionally, they resemble ferritins, cage-like iron storage proteins, but with a massively greater capacity (similar to 30,000 iron atoms versus similar to 3,000 in ferritin). Physiological data reveal that few nanocompartments are assembled during vegetative growth, but they increase fivefold upon starvation, protecting cells from oxidative stress through iron sequestration. C1 [McHugh, Colleen A.; Lam, Alan S.; Hoiczyk, Egbert] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Fontana, Juan; Nemecek, Daniel; Cheng, Naiqian; Aksyuk, Anastasia A.; Heymann, J. Bernard; Winkler, Dennis C.; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, Bethesda, MD 20892 USA. [Wall, Joseph S.] Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov; ehoiczyk@jhsph.edu RI Fontana, Juan/A-9138-2009 OI Fontana, Juan/0000-0002-9084-2927 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; Ruth L. Kirschstein National Research Service Award [T32 ES07141]; National Institutes of Health, National Institute of General Medical Sciences [R01 GM085024] FX We thank G. Ketner, I. Coppens, K. McLean, D. Sullivan, A. Rule, D. Zusman, H. Engelhardt, and J. Kellermann for contributions of reagents and advice and P. Afonine for advice on the use of phenix.refine and phenix.map_to_structure_factors programs. Funding for this work was provided by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (ACS), a Ruth L. Kirschstein National Research Service Award T32 ES07141 (CAM), and National Institutes of Health, National Institute of General Medical Sciences grant R01 GM085024 (EH). NR 76 TC 14 Z9 14 U1 3 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD SEP 1 PY 2014 VL 33 IS 17 BP 1896 EP 1911 DI 10.15252/embj.201488566 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AP1OF UT WOS:000341839500008 PM 25024436 ER PT J AU Makarova, KS Wolf, YI Forterre, P Prangishvili, D Krupovic, M Koonin, EV AF Makarova, Kira S. Wolf, Yuri I. Forterre, Patrick Prangishvili, David Krupovic, Mart Koonin, Eugene V. TI Dark matter in archaeal genomes: a rich source of novel mobile elements, defense systems and secretory complexes SO EXTREMOPHILES LA English DT Article DE Archaeal genomes; ORFans; Genomic islands; Integration; Viruses; Defense ID CRISPR-CAS SYSTEMS; SHAPED VIRUS 1; STRUCTURE PREDICTION; REPLICATION PROTEIN; PRIMASE-POLYMERASE; ADAPTIVE IMMUNITY; BACTERIAL GENOMES; ORTHOLOGOUS GENES; TAILED VIRUSES; EVOLUTION AB Microbial genomes encompass a sizable fraction of poorly characterized, narrowly spread fast-evolving genes. Using sensitive methods for sequences comparison and protein structure prediction, we performed a detailed comparative analysis of clusters of such genes, which we denote "dark matter islands", in archaeal genomes. The dark matter islands comprise up to 20 % of archaeal genomes and show remarkable heterogeneity and diversity. Nevertheless, three classes of entities are common in these genomic loci: (a) integrated viral genomes and other mobile elements; (b) defense systems, and (c) secretory and other membrane-associated systems. The dark matter islands in the genome of thermophiles and mesophiles show similar general trends of gene content, but thermophiles are substantially enriched in predicted membrane proteins whereas mesophiles have a greater proportion of recognizable mobile elements. Based on this analysis, we predict the existence of several novel groups of viruses and mobile elements, previously unnoticed variants of CRISPR-Cas immune systems, and new secretory systems that might be involved in stress response, intermicrobial conflicts and biogenesis of novel, uncharacterized membrane structures. C1 [Makarova, Kira S.; Wolf, Yuri I.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Forterre, Patrick; Prangishvili, David; Krupovic, Mart] Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Krupovic, Mart/I-4209-2012 OI Krupovic, Mart/0000-0001-5486-0098 FU US Department of Health and Human Services; European Union [340440]; European Molecular Biology Organization [ASTF 82-2014] FX KSM, YIW and EVK are supported by intramural funds of the US Department of Health and Human Services (to National Library of Medicine); PF is supported by the European Union's Seventh Framework Programme (FP/2007-2013)/Project EVOMOBIL-ERC Grant Agreement no. 340440; MK was partly supported by the European Molecular Biology Organization (ASTF 82-2014). NR 72 TC 17 Z9 18 U1 1 U2 22 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 1431-0651 EI 1433-4909 J9 EXTREMOPHILES JI Extremophiles PD SEP PY 2014 VL 18 IS 5 BP 877 EP 893 DI 10.1007/s00792-014-0672-7 PG 17 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AP1WQ UT WOS:000341863200008 PM 25113822 ER PT J AU Murphy, G Michel, A Taylor, PR Albanes, D Weinstein, SJ Virtamo, J Parisi, D Snyder, K Butt, J McGlynn, KA Koshiol, J Pawlita, M Lai, GY Abnet, CC Dawsey, SM Freedman, ND AF Murphy, G. Michel, A. Taylor, P. R. Albanes, D. Weinstein, S. J. Virtamo, J. Parisi, D. Snyder, K. Butt, J. McGlynn, K. A. Koshiol, J. Pawlita, M. Lai, G. Y. Abnet, C. C. Dawsey, S. M. Freedman, N. D. TI SEROLOGICAL ASSOCIATION OF HELICOBACTER PYLORI PROTEINS AND BILIARY TRACT CANCER IN THE ATBC STUDY SO HELICOBACTER LA English DT Meeting Abstract CT European-Helicobacter-Study-Group 27th International Workshop on Helicobacter and Microbiota in Chronic Digestive Inflammation and Gastric Cancer CY SEP 11-13, 2014 CL Rome, ITALY SP European Helicobacter Study Grp C1 [Murphy, G.; Taylor, P. R.; Albanes, D.; Weinstein, S. J.; McGlynn, K. A.; Koshiol, J.; Lai, G. Y.; Abnet, C. C.; Dawsey, S. M.; Freedman, N. D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Michel, A.; Butt, J.; Pawlita, M.] German Canc Res Ctr, Res Program Infect & Canc F020, Heidelberg, Germany. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Parisi, D.; Snyder, K.] Informat Management Serv Inc, Rockville, MD USA. RI Albanes, Demetrius/B-9749-2015; Freedman, Neal/B-9741-2015; Abnet, Christian/C-4111-2015; Waterboer, Tim/G-1252-2010 OI Freedman, Neal/0000-0003-0074-1098; Abnet, Christian/0000-0002-3008-7843; NR 0 TC 0 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-4389 EI 1523-5378 J9 HELICOBACTER JI Helicobacter PD SEP PY 2014 VL 19 SU 1 SI SI MA W6.3 BP 87 EP 87 PG 1 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA AO8SG UT WOS:000341623900045 ER PT J AU Butt, J Michel, A Willhauck-Fleckenstein, M Nicklas, W Fox, JG Murphy, G Freedman, N Albanes, D Weinstein, SJ Virtamo, J Pawlita, M AF Butt, J. Michel, A. Willhauck-Fleckenstein, M. Nicklas, W. Fox, J. G. Murphy, G. Freedman, N. Albanes, D. Weinstein, S. J. Virtamo, J. Pawlita, M. TI HEPATOBILIARY TRACT CANCER AND SEROPOSITIVITY TO HELICOBACTER SPP. IN THE ATBC STUDY SO HELICOBACTER LA English DT Meeting Abstract CT European-Helicobacter-Study-Group 27th International Workshop on Helicobacter and Microbiota in Chronic Digestive Inflammation and Gastric Cancer CY SEP 11-13, 2014 CL Rome, ITALY SP European Helicobacter Study Grp C1 [Butt, J.; Michel, A.; Willhauck-Fleckenstein, M.; Pawlita, M.] German Canc Res Ctr, Infect & Canc Program, Heidelberg, Germany. [Nicklas, W.] German Canc Res Ctr, Cent Anim Labs, Heidelberg, Germany. [Fox, J. G.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Murphy, G.; Freedman, N.; Albanes, D.; Weinstein, S. J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015; Waterboer, Tim/G-1252-2010 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-4389 EI 1523-5378 J9 HELICOBACTER JI Helicobacter PD SEP PY 2014 VL 19 SU 1 SI SI MA P16.04 BP 157 EP 157 PG 1 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA AO8SG UT WOS:000341623900296 ER PT J AU Ying, JF Li, F Lee, JH Bax, A AF Ying, Jinfa Li, Fang Lee, Jung Ho Bax, Ad TI C-13(alpha) decoupling during direct observation of carbonyl resonances in solution NMR of isotopically enriched proteins SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE C-13 direct detection; alpha-Synuclein; Composite pulse decoupling; Dark state; IPAP; Lipid binding; NCO; Three-spin effect ID INTRINSICALLY DISORDERED PROTEINS; SOLID-STATE NMR; ALPHA-SYNUCLEIN; HOMONUCLEAR; SPECTROSCOPY; SPECTRA; ASSIGNMENT; RESOLUTION; SENSITIVITY; ACQUISITION AB Direct detection of C-13 can be advantageous when studying uniformly enriched proteins, in particular for paramagnetic proteins or when hydrogen exchange with solvent is fast. A scheme recently introduced for long-observation-window band-selective homonuclear decoupling in solid state NMR, LOW-BASHD (Struppe et al. in J Magn Reson 236:89-94, 2013) is shown to be effective for C-13(alpha) decoupling during direct C-13' observation in solution NMR experiments too. For this purpose, adjustment of the decoupling pulse parameters and delays is demonstrated to be important for increasing spectral resolution, to reduce three-spin effects, and to decrease the intensity of decoupling side-bands. LOW-BASHD then yields C-13' line widths comparable to those obtained with the popular IPAP method, while enhancing sensitivity by ca 35 %. As a practical application of LOW-BASHD decoupling, requiring quantitative intensity measurement over a wide dynamic range, the impact of lipid binding on the C-13'-detected NCO spectrum of the intrinsically disordered protein alpha-synuclein is compared with that on the H-1-detected H-1-N-15 HSQC spectrum. Results confirm that synuclein's "dark state" behavior is not caused by paramagnetic relaxation or rapid hydrogen exchange. C1 [Ying, Jinfa; Li, Fang; Lee, Jung Ho; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM bax@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH; KVSTA Fellowship; China Scholarship Council FX This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. J.H. Lee is the recipient of a KVSTA Fellowship and F. Li acknowledges financial support from the China Scholarship Council. NR 38 TC 8 Z9 8 U1 4 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD SEP PY 2014 VL 60 IS 1 BP 15 EP 21 DI 10.1007/s10858-014-9853-z PG 7 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA AO9OT UT WOS:000341685800003 PM 25129622 ER PT J AU Dracup, K Moser, DK Pelter, MM Nesbitt, T Southard, J Paul, SM Robinson, S Hemsey, JZ Cooper, L AF Dracup, Kathleen Moser, Debra K. Pelter, Michele M. Nesbitt, Thomas Southard, Jeffrey Paul, Steven M. Robinson, Susan Hemsey, Jessica Zegre Cooper, Lawton TI Rural Patients' Knowledge About Heart Failure SO JOURNAL OF CARDIOVASCULAR NURSING LA English DT Article DE heart failure; patient education; rural ID HEALTH LITERACY; MEDICARE BENEFICIARIES; SELF-CARE; HOSPITALIZATION; POVERTY; PEOPLE; AREAS; US AB Background: Heart failure (HF) is a potentially disabling condition requiring significant patient knowledge to manage the requirements of self-care. The need for self-care is important for all patients but particularly for those living in rural areas that are geographically remote from healthcare services. Objective: The aim of this study was to identify the level of knowledge of rural patients with HF and the clinical and demographic characteristics associated with low levels of HF knowledge. Methods: Baseline data from 612 patients with HF enrolled in the Rural Education to Improve Outcomes in Heart Failure trial were analyzed using the Heart Failure Knowledge Scale, the Short Test of Functional Health Literacy in Adults, and the anxiety subscale of the Brief Symptom Inventory. Multiple linear regression was used to explore the contribution of sociodemographic and clinical variables to levels of HF knowledge. Results: The mean (SD) age was 66 (13) years; 59% were men, and 50.5% had an ejection fraction of less than 40%. The mean (SD) percent correct on the Heart Failure Knowledge Scale was 69.5% (13%; range, 25%-100%), with the most frequent incorrect items related to symptoms of HF and the need for daily weights. The men and the older patients scored significantly lower in HF knowledge than did the women and the younger patients (P = 0.002 and 0.011, respectively). The patients with preserved systolic function also scored significantly lower than those with systolic HF (P = 0.030). Conclusions: Patients who are at risk for poor self-care because of low levels of HF knowledge can be identified. Older patients, men, and, patients with HF with preserved systolic function may require special educational strategies to gain the knowledge required for effective self-care. C1 [Dracup, Kathleen] Univ Calif San Francisco, Sch Nursing, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Moser, Debra K.] Univ Kentucky, Coll Nursing, Lexington, KY 40506 USA. [Pelter, Michele M.] Univ Nevada, Orvis Sch Nursing, Reno, NV 89557 USA. [Nesbitt, Thomas; Southard, Jeffrey] Univ Calif Davis, Sch Med, Davis, CA 95616 USA. [Paul, Steven M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Robinson, Susan; Hemsey, Jessica Zegre] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Cooper, Lawton] NHLBI, Bethesda, MD 20892 USA. RP Dracup, K (reprint author), Univ Calif San Francisco, Sch Nursing, 2 Koret Way,N611E, San Francisco, CA 94143 USA. EM kathy.dracup@nursing.ucsf.edu FU National Heart, Lung and Blood Institute; National Institute of Nursing Research [5R01HL83176] FX This study was funded by the National Heart, Lung and Blood Institute and the National Institute of Nursing Research: 5R01HL83176. NR 24 TC 7 Z9 7 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0889-4655 EI 1550-5049 J9 J CARDIOVASC NURS JI J. Cardiovasc. Nurs. PD SEP-OCT PY 2014 VL 29 IS 5 BP 423 EP 428 DI 10.1097/JCN.0b013e31829cbcf3 PG 6 WC Cardiac & Cardiovascular Systems; Nursing SC Cardiovascular System & Cardiology; Nursing GA AO6XL UT WOS:000341496000055 PM 23839575 ER PT J AU Jovic, M Kean, MJ Dubankova, A Boura, E Gingras, AC Brill, JA Balla, T AF Jovic, Marko Kean, Michelle J. Dubankova, Anna Boura, Evzen Gingras, Anne-Claude Brill, Julie A. Balla, Tamas TI Endosomal sorting of VAMP3 is regulated by PI4K2A SO JOURNAL OF CELL SCIENCE LA English DT Article DE PI4K2A; VAMP3; PtdIns4P; Vesicle fusion; Sorting; SNARE ID PHOSPHATIDYLINOSITOL 4-KINASE; MEMBRANE-FUSION; SNARE COMPLEXES; II-ALPHA; IN-VITRO; R-SNARES; GOLGI; CELLUBREVIN; SPECIFICITY; TRAFFICKING AB Specificity of membrane fusion in vesicular trafficking is dependent on proper subcellular distribution of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Although SNARE complexes are fairly promiscuous in vitro, substantial specificity is achieved in cells owing to the spatial segregation and shielding of SNARE motifs prior to association with cognate Q-SNAREs. In this study, we identified phosphatidylinositol 4-kinase II alpha (PI4K2A) as a binding partner of vesicle-associated membrane protein 3 (VAMP3), a small R-SNARE involved in recycling and retrograde transport, and found that the two proteins co-reside on tubulo-vesicular endosomes. PI4K2A knockdown inhibited VAMP3 trafficking to perinuclear membranes and impaired the rate of VAMP3-mediated recycling of the transferrin receptor. Moreover, depletion of PI4K2A significantly decreased association of VAMP3 with its cognate Q-SNARE Vti1a. Although binding of VAMP3 to PI4K2A did not require kinase activity, acute depletion of phosphatidylinositol 4-phosphate (PtdIns4P) on endosomes significantly delayed VAMP3 trafficking. Modulation of SNARE function by phospholipids had previously been proposed based on in vitro studies, and our study provides mechanistic evidence in support of these claims by identifying PI4K2A and PtdIns4P as regulators of an R-SNARE in intact cells. C1 [Jovic, Marko; Balla, Tamas] NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Kean, Michelle J.; Gingras, Anne-Claude] Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Kean, Michelle J.; Gingras, Anne-Claude; Brill, Julie A.] Univ Toronto, Kings Coll Circle 1, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Dubankova, Anna; Boura, Evzen] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Vvi, CR-16610 Prague 6, Czech Republic. [Brill, Julie A.] PGCRL, Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 0A4, Canada. RP Jovic, M (reprint author), NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM jovicm@mail.nih.gov RI Gingras, Anne-Claude/E-9982-2010; Boura, Evzen/G-5275-2014; OI Gingras, Anne-Claude/0000-0002-6090-4437; Balla, Tamas/0000-0002-9077-3335; Brill, Julie/0000-0002-5925-9901 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health; Canadian Institutes of Health Research (CHIR) [MOP-119483, MOP-84314]; CIHR FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (M.J. and T.B.); and in part by operating grants from Canadian Institutes of Health Research (CHIR) [grant numbers MOP-119483 to J.A.B., MOP-84314 to A.C.G.]. M.J.K. was supported by CIHR through a Banting and Best Canada Graduate Scholarship. Deposited in PMC for release after 12 months. NR 51 TC 13 Z9 13 U1 0 U2 13 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD SEP 1 PY 2014 VL 127 IS 17 BP 3745 EP 3756 DI 10.1242/jcs.148809 PG 12 WC Cell Biology SC Cell Biology GA AO9SY UT WOS:000341698300011 PM 25002402 ER PT J AU Thornton, B Cohen, B Copeland, W Maria, BL AF Thornton, Ben Cohen, Bruce Copeland, William Maria, Bernard L. TI Mitochondrial Disease: Clinical Aspects, Molecular Mechanisms, Translational Science, and Clinical Frontiers SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE mitochondrial disease ID MTDNA AB Mitochondrial medicine provides a metabolic perspective on the pathology of conditions linked with inadequate oxidative phosphorylation. Dysfunction in the mitochondrial machinery can result in improper energy production, leading to cellular injury or even apoptosis. Clinical presentations are often subtle, so clinicians must have a high index of suspicion to make early diagnoses. Symptoms could include muscle weakness and pain, seizures, loss of motor control, decreased visual and auditory functions, metabolic acidosis, acute developmental regression, and immune system dysfunction. The 2013 Neurobiology of Disease in Children Symposium, held in conjunction with the 42nd Annual Meeting of the Child Neurology Society, aimed to (1) describe accepted clinical phenotypes of mitochondrial disease produced from various mitochondrial mutations, (2) discuss contemporary understanding of molecular mechanisms that contribute to disease pathology, (3) highlight the systemic effects produced by dysfunction within the mitochondrial machinery, and (4) introduce current strategies that are being translated from bench to bedside as potential therapeutics. C1 [Thornton, Ben; Maria, Bernard L.] Georgia Regents Univ, Dept Pediat, Augusta, GA USA. [Cohen, Bruce] Akron Childrens Hosp, Akron, OH USA. [Copeland, William] NIEHS, Res Triangle Pk, NC 27709 USA. RP Maria, BL (reprint author), Georgia Regents Univ, Med Coll Georgia, Dept Pediat, 1446 Harper St,BT-1850, Augusta, GA 30912 USA. EM bmaria@gru.edu FU Intramural NIH HHS [Z01 ES065078-14] NR 5 TC 2 Z9 2 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD SEP PY 2014 VL 29 IS 9 SI SI BP 1179 EP 1207 DI 10.1177/0883073814537379 PG 29 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AP1FK UT WOS:000341812400012 PM 24916430 ER PT J AU Copeland, WC AF Copeland, William C. TI Defects of Mitochondrial DNA Replication SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE Alpers syndrome; ataxia-neuropathy; DNA polymerase; mitochondrial DNA depletion syndrome; mitochondrial DNA replication; POLG; progressive external ophthalmoplegia ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; RECESSIVE TWINKLE MUTATIONS; MULTIPLE MTDNA DELETIONS; P55 ACCESSORY SUBUNIT; POLYMERASE-GAMMA; SACCHAROMYCES-CEREVISIAE; DISEASE MUTATIONS; ALPERS-SYNDROME; POLG MUTATIONS; MAMMALIAN EMBRYOGENESIS AB Mitochondrial DNA is replicated by DNA polymerase in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, and initiating factors. Defects in mitochondrial DNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mitochondrial DNA deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mitochondrial DNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mitochondrial DNA deletion disorders, such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. This review focuses on our current knowledge of genetic defects of mitochondrial DNA replication (POLG, POLG2, C10orf2, and MGME1) that cause instability of mitochondrial DNA and mitochondrial disease. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health [ES 065078, ES 065080]; National Institute of Neurological Disorders and Stroke [R13NS04925] FX The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by intramural funds from the National Institute of Environmental Health Sciences, National Institutes of Health (ES 065078 and ES 065080), and the National Institute of Neurological Disorders and Stroke (R13NS04925). NR 78 TC 12 Z9 12 U1 3 U2 21 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD SEP PY 2014 VL 29 IS 9 SI SI BP 1216 EP 1224 DI 10.1177/0883073814537380 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AP1FK UT WOS:000341812400014 PM 24985751 ER PT J AU Prahlad, J Hauser, DN Milkovic, NM Cookson, MR Wilson, MA AF Prahlad, Janani Hauser, David N. Milkovic, Nicole M. Cookson, Mark R. Wilson, Mark A. TI Use of cysteine-reactive cross-linkers to probe conformational flexibility of human DJ-1 demonstrates that Glu18 mutations are dimers SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE cysteine oxidation; DJ-1; PARK7; Parkinson disease; parkinsonism; structure ID ONSET PARKINSONS-DISEASE; OXIDATIVE STRESS; CRYSTAL-STRUCTURE; MITOCHONDRIAL-FUNCTION; PROTEIN DJ-1; DOPAMINERGIC-NEURONS; DROSOPHILA DJ-1; SULFINIC ACID; GENE DJ-1; IN-VIVO AB The oxidation of a key cysteine residue (Cys106) in the parkinsonism-associated protein DJ-1 regulates its ability to protect against oxidative stress and mitochondrial damage. Cys106 interacts with a neighboring protonated Glu18 residue, stabilizing the Cys106-SO2- (sulfinic acid) form of DJ-1. To study this important post-translational modification, we previously designed several Glu18 mutations (E18N, E18D, E18Q) that alter the oxidative propensity of Cys106. However, recent results suggest these Glu18 mutations cause loss of DJ-1 dimerization, which would severely compromise the protein's function. The purpose of this study was to conclusively determine the oligomerization state of these mutants using X-ray crystallography, NMR spectroscopy, thermal stability analysis, circular dichroism spectroscopy, sedimentation equilibrium ultracentrifugation, and cross-linking. We found that all of the Glu18 DJ-1 mutants were dimeric. Thiol cross-linking indicates that these mutant dimers are more flexible than the wild-type protein and can form multiple cross-linked dimeric species due to the transient exposure of cysteine residues that are inaccessible in the wild-type protein. The enhanced flexibility of Glu18 DJ-1 mutants provides a parsimonious explanation for their lower observed cross-linking efficiency in cells. In addition, thiol cross-linkers may have an underappreciated value as qualitative probes of protein conformational flexibility. C1 [Prahlad, Janani; Milkovic, Nicole M.; Wilson, Mark A.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Prahlad, Janani; Milkovic, Nicole M.; Wilson, Mark A.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Hauser, David N.; Cookson, Mark R.] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Hauser, David N.] Brown Univ, Dept Neurosci, Natl Inst Hlth Grad Partnership Program, Providence, RI 02912 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov; mwilson13@unl.edu RI Hauser, David/I-4933-2012 OI Hauser, David/0000-0002-9500-5255 FU National Institutes of Health [R01 GM092999]; NIH, National Institute on Aging FX We thank Dr Jiri Adamec (University of Nebraska-Lincoln) of the Redox Biology Center Mass Spectrometry Core Facility, Dr Robert Powers (University of Nebraska-Lincoln) and Sara Basiaga with assistance in collection of the NMR data, and Dr Jiusheng Lin (University of Nebraska-Lincoln) for helpful discussions. This work was supported, in part, by National Institutes of Health Grant R01 GM092999 (to M. A. W.). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (D.N.H. and M.R.C.). The authors declare no conflicts of interest. NR 61 TC 4 Z9 4 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2014 VL 130 IS 6 BP 839 EP 853 DI 10.1111/jnc.12763 PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AP1IA UT WOS:000341820800012 PM 24832775 ER PT J AU Meyers, JL Shmulewitz, D Elliott, JC Thompson, RG Aharonovich, E Spivak, B Weizman, A Frisch, A Grant, BE Hasin, DS AF Meyers, Jacquelyn L. Shmulewitz, Dvora Elliott, Jennifer C. Thompson, Ronald G. Aharonovich, Efrat Spivak, Baruch Weizman, Abraham Frisch, Amos Grant, Bridget E. Hasin, Deborah S. TI Parental Alcohol History Differentially Predicts Offspring Disorders in Distinct Subgroups in Israel SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID INTERVIEW SCHEDULE AUDADIS; RECENT RUSSIAN IMMIGRANTS; GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; MENTAL-HEALTH SURVEYS; FAMILY-HISTORY; DSM-IV; ENVIRONMENTAL-INFLUENCES; PSYCHIATRIC HISTORY; DRINKING PATTERNS AB Objective: The association between alcoholism in parents and related disorders in their offspring is well established in cultures with intermediate/high alcohol consumption, but not in those with low consumption, such as Israel. This study investigated differences in parental transmission of alcohol problems and related psychopathology between immigrants from the former Soviet Union (FSU) to Israel and other Israelis two Israeli subgroups with differing alcohol consumption behaviors and social norms. Method: A total of 1,347 adults from a household sample were interviewed. Regression analyses were used to examine associations between parental alcohol problems and participant disorders: alcohol, nicotine, and cannabis use disorders (AUD, NUD, CUD); antisocial personality disorder (ASPD); major depressive disorder (MDD); and posttraumatic stress disorder (PTSD). We also examined the associations of parental alcohol problems with participant disorders characterized with two latent factors: externalizing (EXT: AUD, NUD, CUD, ASPD) and internalizing (INT: MDD, PTSD). Differential parental transmission of alcohol problems in FSU (n = 315) and non-FSU (n = 1,032) Israelis was examined with statistical interaction. Results: Among emigrants from the FSU, parental alcohol problems predicted AUD, NUD, CUD, ASPD, PTSD, EXT, and INT (mean ratios = 1.38-4.83). In non-FSU Israelis, parental alcohol problems predicted only ASPD and PTSD (mean ratios = 1.08-4.09). Significant interactions were observed for AUD, CUD, PTSD, and EXT; each relationship was stronger in FSU Israelis and null (AUD, CUD, EXT) or less robust (PTSD) in other Israelis. Conclusions: Parental alcohol problems were related to substance use and psychiatric disorders differently in FSU and other Israelis, two groups with different alcohol consumption levels and drinking norms. We propose that, in social contexts that vary in the degree to which they constrain alcohol behavior, underlying genetic predispositions may manifest as different disorders. C1 [Meyers, Jacquelyn L.; Elliott, Jennifer C.; Hasin, Deborah S.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Shmulewitz, Dvora; Thompson, Ronald G.; Aharonovich, Efrat; Hasin, Deborah S.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Shmulewitz, Dvora; Thompson, Ronald G.; Aharonovich, Efrat; Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Spivak, Baruch] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Weizman, Abraham; Frisch, Amos] Felsenstein Med Res Ctr, Petah Tiqwa, Israel. [Weizman, Abraham] Geha Mental Hlth Ctr, Res Unit, Petah Tiqwa, Israel. [Grant, Bridget E.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD USA. RP Hasin, DS (reprint author), Columbia Univ Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr 123, New York, NY 10032 USA. EM dsh2@columbia.edu FU National Institutes of Health [U01AA018111, R01AA013654, R01DA018652, K05AA014223, K23DA016743, T32MH13043]; New York State Psychiatric Institute FX This research was funded by National Institutes of Health Grants U01AA018111, R01AA013654, R01DA018652, K05AA014223 (to Deborah Hasin); K23DA016743 (to Efrat Aharonovich); and T32MH13043 (to Jacquelyn L. Meyers) and the New York State Psychiatric Institute (to Deborah Hasin). NR 57 TC 1 Z9 1 U1 7 U2 8 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD SEP PY 2014 VL 75 IS 5 BP 859 EP 869 PG 11 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA AO8PA UT WOS:000341615500015 PM 25208204 ER PT J AU Benveniste, MF Korst, RJ Rajan, A Detterbeck, FC Marom, EM AF Benveniste, Marcelo F. Korst, Robert J. Rajan, Arun Detterbeck, Frank C. Marom, Edith M. TI A Practical Guide from the International Thymic Malignancy Interest Group (ITMIG) Regarding the Radiographic Assessment of Treatment Response of Thymic Epithelial Tumors Using Modified RECIST Criteria SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Thymic neoplasm; International Thymic Malignancy Interest Group; Response measurement ID LUNG-CANCER; INTRAOBSERVER VARIABILITY; SOLID TUMORS; INTEROBSERVER; THYMOMA; FILM AB Measuring tumor response to chemotherapy is important for both clinical decision-making and for multi-institutional studies. Thymoma tends to spread along the pleura: a challenge for accurate tumor measurement. Inaccurate and inconsistent tumor measurements often compromise results from clinical trials that are dependent on identifying response rate and progression-free survival. In this article, we sought to provide a practical guide on how to measure thymoma by the International Thymic Malignancy Interest Group's recommendations for standard outcome measures. The aim of this article is to clarify this measuring technique, lead to consistency between institutions, and minimize intra- and interobserver variability. C1 [Benveniste, Marcelo F.; Marom, Edith M.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Korst, Robert J.] Daniel & Gloria Blumenthal Canc Ctr, Paramus, NJ USA. [Korst, Robert J.] Valley Hosp, Div Thorac Surg, Ridgewood, NJ USA. [Rajan, Arun] NCI, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. [Detterbeck, Frank C.] Yale Univ, Sch Med, Dept Surg, Div Thorac Surg, New Haven, CT 06510 USA. RP Benveniste, MF (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Unit 1478, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM mfbenveniste@mdanderson.org NR 16 TC 13 Z9 14 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2014 VL 9 IS 9 SU 2 BP S119 EP S124 DI 10.1097/JTO.0000000000000296 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AO9PU UT WOS:000341688800009 PM 25396308 ER PT J AU Rajan, A Girard, N Marx, A AF Rajan, Arun Girard, Nicolas Marx, Alexander TI State of the Art of Genetic Alterations in Thymic Epithelial Tumors SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Thymoma; Thymic carcinoma; Methylation; Chromosomal abnormalities; Gene expression; Sequencing; Gene signatures ID GROWTH-FACTOR RECEPTOR; FACTOR-I RECEPTOR; EXPRESSION; THYMOMA; ABERRATIONS; CARCINOMAS; STAGE; RECURRENT; CANCER; KIT AB The rapid advent of technology in recent years has resulted in a substantial increase in our knowledge of the molecular underpinnings of thymic epithelial tumors. In addition to previously described chromosomal aberrations and alterations in DNA methylation, genome sequencing has helped unravel hitherto unknown mutations in these tumors. Attempts are also being made to develop gene signatures to help in the identification of patients likely to benefit from adjuvant therapy. Some of the recently identified genetic alterations have the potential to serve as targets for biological therapy, thus opening newer avenues for treatment of thymic epithelial tumors and increasing the number of effective options for treatment of recurrent or refractory disease. C1 [Rajan, Arun] NCI, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. [Girard, Nicolas] Hosp Civils Lyon, Hop Louis Pradel, Thorac Oncol Serv, Lyon, France. [Marx, Alexander] Heidelberg Univ, Univ Med Ctr Mannheim, Inst Pathol, Mannheim, Germany. RP Rajan, A (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, 10 Ctr Dr,10-CRC,Room 4-5330, Bethesda, MD 20892 USA. EM rajana@mail.nih.gov NR 57 TC 11 Z9 11 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2014 VL 9 IS 9 SU 2 BP S131 EP S136 DI 10.1097/JTO.0000000000000298 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AO9PU UT WOS:000341688800011 PM 25396310 ER PT J AU Farber, A Imrey, P Kaufman, J Huber, T Kraiss, L Vita, J Kusek, J Bercelli, S Fenves, A Young, C Vazquez, M Larive, B Li, L Radeva, M Beck, G Feldman, H AF Farber, Alik Imrey, Peter Kaufman, James Huber, Thomas Kraiss, Larry Vita, Joseph Kusek, John Bercelli, Scott Fenves, Andrew Young, Carlton Vazquez, Miguel Larive, Brett Li, Liang Radeva, Milena Beck, Gerald Feldman, Harold CA HFM Study Grp TI Surgeon's Intraoperative Assessments During Autogenous Arteriovenous Fistula Creation Strongly Correlate With Early Fistula Thrombosis SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT Joint Annual Meeting of the New-England-Society-for-Vascular-Surgery (NESVS) and the Eastern-Vascular-Society (EVS) CY SEP 11-14, 2014 CL Boston, MA SP New England Soc Vasc Surg, Eastern Vasc Soc C1 [Farber, Alik; Vita, Joseph] Boston Med Ctr, Boston, MA USA. [Imrey, Peter; Larive, Brett; Li, Liang; Radeva, Milena; Beck, Gerald] Cleveland Clin Fdn, Cleveland, OH USA. [Kaufman, James] VA Boston Healthcare Syst, Boston, MA USA. [Huber, Thomas; Bercelli, Scott] Univ Florida, Coll Med, Gainesville, FL USA. [Kraiss, Larry] Univ Utah, Salt Lake City, UT USA. [Kusek, John] NIDDK, Bethesda, MD 20892 USA. [Fenves, Andrew] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Young, Carlton] Univ Alabama Birmingham, Birmingham, AL USA. [Vazquez, Miguel] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Feldman, Harold] Univ Penn, Philadelphia, PA 19104 USA. NR 0 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2014 VL 60 IS 3 BP 832 EP 832 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AO8UE UT WOS:000341629700103 ER PT J AU Vimaleswaran, KS Cavadino, A Berry, DJ Jorde, R Dieffenbach, AK Lu, C Alves, AC Heerspink, HJL Tikkanen, E Eriksson, J Wong, A Mangino, M Jablonski, KA Nolte, IM Houston, DK Ahluwalia, TS van der Most, PJ Pasko, D Zgaga, L Thiering, E Vitart, V Fraser, RM Huffman, JE de Boer, RA Schottker, B Saum, KU McCarthy, MI Dupuis, J Herzig, KH Sebert, S Pouta, A Laitinen, J Kleber, ME Navis, G Lorentzon, M Jameson, K Arden, N Cooper, JA Acharya, J Hardy, R Raitakari, O Ripatti, S Billings, LK Lahti, J Osmond, C Penninx, BW Rejnmark, L Lohman, KK Paternoster, L Stolk, RP Hernandez, DG Byberg, L Hagstrom, E Melhus, H Ingelsson, E Mellstrom, D Ljunggren, O Tzoulaki, I McLachlan, S Theodoratou, E Tiesler, CMT Jula, A Navarro, P Wright, AF Polasek, O Hayward, C Wilson, JF Rudan, I Salomaa, V Heinrich, J Campbell, H Price, JF Karlsson, M Lind, L Michaesson, K Bandinelli, S Frayling, TM Hartman, CA Sorensen, TIA Kritchevsky, SB Flo, BLLJGEJC Eriksson, JG Florez, JC Spector, TD Lehtimaki, T Kuh, D Humphries, SE Cooper, C Ohlsson, C Marz, W de Borst, MH Kumari, M Kivimaki, M Wang, TJ Power, C Brenner, H Grimnes, G van der Harst, P Snieder, H Hingorani, AD Pilz, S Whittaker, JC Jarvelin, MR Hypponen, E AF Vimaleswaran, Karani S. Cavadino, Alana Berry, Diane J. Jorde, Rolf Dieffenbach, Aida Karina Lu, Chen Alves, Alexessander Couto Heerspink, Hiddo J. Lambers Tikkanen, Emmi Eriksson, Joel Wong, Andrew Mangino, Massimo Jablonski, Kathleen A. Nolte, Ilja M. Houston, Denise K. Ahluwalia, Tarunveer Singh van der Most, Peter J. Pasko, Dorota Zgaga, Lina Thiering, Elisabeth Vitart, Veronique Fraser, Ross M. Huffman, Jennifer E. de Boer, Rudolf A. Schoettker, Ben Saum, Kai-Uwe McCarthy, Mark I. Dupuis, Josee Herzig, Karl-Heinz Sebert, Sylvain Pouta, Anneli Laitinen, Jaana Kleber, Marcus E. Navis, Gerjan Lorentzon, Mattias Jameson, Karen Arden, Nigel Cooper, Jackie A. Acharya, Jayshree Hardy, Rebecca Raitakari, Olli Ripatti, Samuli Billings, Liana K. Lahti, Jari Osmond, Clive Penninx, Brenda W. Rejnmark, Lars Lohman, Kurt K. Paternoster, Lavinia Stolk, Ronald P. Hernandez, Dena G. Byberg, Liisa Hagstrom, Emil Melhus, Hakan Ingelsson, Erik Mellstroem, Dan Ljunggren, Osten Tzoulaki, Ioanna McLachlan, Stela Theodoratou, Evropi Tiesler, Carla M. T. Jula, Antti Navarro, Pau Wright, Alan F. Polasek, Ozren Hayward, Caroline Wilson, James F. Rudan, Igor Salomaa, Veikko Heinrich, Joachim Campbell, Harry Price, Jacqueline F. Karlsson, Magnus Lind, Lars Michaesson, Karl Bandinelli, Stefania Frayling, Timothy M. Hartman, Catharina A. Sorensen, Thorkild I. A. Kritchevsky, Stephen B. Langdahl, Bente Lomholt Eriksson, Johan G. Florez, Jose C. Spector, Tim D. Lehtimaki, Terho Kuh, Diana Humphries, Steve E. Cooper, Cyrus Ohlsson, Claes Maerz, Winfried de Borst, Martin H. Kumari, Meena Kivimaki, Mika Wang, Thomas J. Power, Chris Brenner, Hermann Grimnes, Guri van der Harst, Pim Snieder, Harold Hingorani, Aroon D. Pilz, Stefan Whittaker, John C. Jarvelin, Marjo-Riitta Hypponen, Elina CA LifeLines Cohort Study Investigato ICBP CHARGE Consortium Global Blood Pressure Genetics Gl TI Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; RENIN-ANGIOTENSIN SYSTEM; D SUPPLEMENTATION; GENETIC-VARIANTS; TRIAL; METAANALYSIS; OUTCOMES; DISEASE; HEALTH; KIDNEY AB Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings In phenotypic analyses (up to n=49 363), increased 25(OH) D concentration was associated with decreased systolic blood pressure (beta per 10% increase, -0.12 mm Hg, 95% CI -0.20.to -0.04; p=0.003) and reduced odds of hypertension (odds ratio [OR] 0.98, 95% CI 0.97-0.99; p=0.0003), but not with decreased diastolic blood pressure (beta per 10% increase, -0.02 mm Hg, -0.08 to 0.03; p=0.37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0.10 mm Hg in systolic blood pressure (-0.21 to -0.0001; p=0.0498) and a change of -0.08 mm Hg in diastolic blood pressure (-0.15 to -0.02; p=0.01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0.98, 0.96-0.99; p=0.001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH) D concentration was associated with a change of -0.29 mm Hg in diastolic blood pressure (-0.52 to -0.07; p=0.01), a change of -0.37 mm Hg in systolic blood pressure (-0.73 to 0.003; p=0.052), and an 8 1% decreased odds of hypertension (OR 0.92, 0.87-0.97; p=0.002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study. C1 [Vimaleswaran, Karani S.; Cavadino, Alana; Berry, Diane J.; Power, Chris; Hypponen, Elina] UCL Inst Child Hlth, London, England. [Vimaleswaran, Karani S.] Univ Reading, Sch Chem Food & Pharm, Dept Food & Nutr Sci, Hugh Sinclair Unit Human Nutr, Reading, Berks, England. [Jorde, Rolf; Grimnes, Guri] Univ Tromso, Dept Clin Med, Tromso Endocrine Res Grp, Tromso, Norway. [Dieffenbach, Aida Karina; Schoettker, Ben; Saum, Kai-Uwe; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Lu, Chen; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Alves, Alexessander Couto; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Tzoulaki, Ioanna] Univ London Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, London, England. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, MRC, PHE Ctr Environm & Hlth, London, England. [Heerspink, Hiddo J. Lambers] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharmacol, Groningen, Netherlands. [Nolte, Ilja M.; van der Most, Peter J.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Hartman, Catharina A.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Navis, Gerjan; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Navis, Gerjan; de Borst, Martin H.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, Groningen, Netherlands. [Tikkanen, Emmi] Inst Mol Med Finland, Tukholmankatu, Finland. [Eriksson, Joel; Lorentzon, Mattias; Mellstroem, Dan; Ohlsson, Claes] Sahlgrens Univ Hosp, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden. [Wong, Andrew; Hardy, Rebecca; Kuh, Diana] UCL, MRC, Unit Lifelong Hlth & Ageing, London, England. [Cooper, Jackie A.; Acharya, Jayshree; Humphries, Steve E.] UCL, Inst Cardiovasc Sci, BHF Labs, London, England. [Hingorani, Aroon D.] UCL, Genet Epidemiol Grp, London, England. [Kumari, Meena; Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, London, England. [Mangino, Massimo; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Jablonski, Kathleen A.] George Washington Univ, Sch Publ Hlth, Biostat Ctr, Dept Epidemiol & Biostat, Rockville, MD USA. [Houston, Denise K.; Kritchevsky, Stephen B.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Lohman, Kurt K.] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Ahluwalia, Tarunveer Singh; Sorensen, Thorkild I. A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Ahluwalia, Tarunveer Singh] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen Prospect Studies Asthma Childhood, Copenhagen, Denmark. [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Copenhagen, Denmark. [Ahluwalia, Tarunveer Singh] Gentofte Univ Hosp, Danish Pediat Asthma Ctr, Copenhagen, Denmark. [Pasko, Dorota; Frayling, Timothy M.] Univ Exeter, Sch Med, Exeter, Devon, England. [Zgaga, Lina; Fraser, Ross M.; McLachlan, Stela; Theodoratou, Evropi; Wilson, James F.; Rudan, Igor; Campbell, Harry; Price, Jacqueline F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Vitart, Veronique; Huffman, Jennifer E.; Navarro, Pau; Wright, Alan F.; Hayward, Caroline] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Zgaga, Lina] Trinity Coll Dublin, Dept Publ Hlth & Primary Care, Dublin, Ireland. [Thiering, Elisabeth; Tiesler, Carla M. T.; Heinrich, Joachim] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Thiering, Elisabeth] Univ Munich, Dr von Hauner Childrens Hosp, Div Metab Dis & Nutr Med, Munich, Germany. [Tiesler, Carla M. T.] Univ Munich, Dr von Hauner Childrens Hosp, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Arden, Nigel; Cooper, Jackie A.] Univ Oxford, NIHR Oxford Musculoskeletal Biomed Res Unit, Oxford, England. [McCarthy, Mark I.] Oxford NIHR Biomed Res Ctr, Oxford, England. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Herzig, Karl-Heinz] Univ Oulu, Inst Biomed, Oulu, Finland. [Herzig, Karl-Heinz; Sebert, Sylvain; Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr, Oulu, Finland. [Alves, Alexessander Couto; Sebert, Sylvain; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Herzig, Karl-Heinz] Oulu Univ Hosp, Med Res Ctr Oulu, Oulu, Finland. [Pouta, Anneli] Oulu Univ Hosp, Dept Clin Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Pouta, Anneli; Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Oulu, Finland. [Laitinen, Jaana] Finnish Inst Occupat Hlth, Helsinki, Finland. [Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Mannheim Med Fac, Med Clin Nephrol Hypertensiol Rheumatol Endocrino, Mannheim, Germany. [Jameson, Karen; Arden, Nigel; Cooper, Jackie A.; Osmond, Clive] Univ Southampton, MRC, Lifecourse Epidemiol Unit, Southampton, Hants, England. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Tikkanen, Emmi; Ripatti, Samuli] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Tikkanen, Emmi; Ripatti, Samuli] Univ Helsinki, Hjelt Inst, Helsinki, Finland. [Lahti, Jari] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Dept Psychiat, Amsterdam, Netherlands. [Billings, Liana K.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Billings, Liana K.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Billings, Liana K.; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Billings, Liana K.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Billings, Liana K.] NorthShore Univ Hlth Syst, Evanston, IL USA. [Rejnmark, Lars; Langdahl, Bente Lomholt] Aarhus Univ Hosp, Dept Endocrinol & Internal Med, DK-8000 Aarhus, Denmark. [Paternoster, Lavinia] Univ Bristol, Sch Social & Community Med, MRC, Integrat Epidemiol Unit, Bristol, Avon, England. [Hernandez, Dena G.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Byberg, Liisa; Michaesson, Karl] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden. [Hagstrom, Emil; Melhus, Hakan; Ingelsson, Erik; Ljunggren, Osten; Lind, Lars] Uppsala Univ, Uppsala Clin Res Ctr, Dept Med Sci, Uppsala, Sweden. [Ingelsson, Erik] Uppsala Univ, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Jula, Antti] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Turku, Finland. [Polasek, Ozren] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia. [Salomaa, Veikko; Eriksson, Johan G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Karlsson, Magnus] Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthopaed Surg, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, Fimlab Labs, Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Sch Med, Tampere, Finland. [Maerz, Winfried] Synlab Acad, Mannheim, Germany. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37235 USA. [Maerz, Winfried; Pilz, Stefan] Med Univ Graz, Dept Internal Med, Div Endocrinol, Graz, Austria. [Maerz, Winfried; Pilz, Stefan] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Whittaker, John C.] GlaxoSmithKline, Quantitat Sci, Stevenage, Herts, England. [Hypponen, Elina] Univ S Australia, Sch Populat Hlth, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia. [Hypponen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. RP Hypponen, E (reprint author), Univ S Australia, Sch Populat Hlth, GPO Box 2471, Adelaide, SA 5001, Australia. EM elina.hypponen@unisa.edu.au RI Lambers Heerspink, Hiddo/K-3358-2014; Hypponen, Elina/B-2596-2014; Theodoratou, Evropi/C-3430-2014; Lu, Chen/D-8514-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Rudan, Igor/I-1467-2012; mangino, massimo/F-5134-2011; Wong, Andrew/M-8899-2016; Brenner, Hermann/B-4627-2017; OI Lahti, Jari/0000-0002-4310-5297; Kleber, Marcus/0000-0003-0663-7275; Schottker, Ben/0000-0002-1217-4521; Thiering, Elisabeth/0000-0002-5429-9584; Fraser, Ross/0000-0003-0488-2592; Paternoster, Lavinia/0000-0003-2514-0889; Zgaga, Lina/0000-0003-4089-9703; Humphries, Stephen E/0000-0002-8221-6547; Kumari, Meena/0000-0001-9716-1035; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Navarro, Pau/0000-0001-5576-8584; Lambers Heerspink, Hiddo/0000-0002-3126-3730; Hypponen, Elina/0000-0003-3670-9399; Theodoratou, Evropi/0000-0001-5887-9132; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rudan, Igor/0000-0001-6993-6884; mangino, massimo/0000-0002-2167-7470; Wong, Andrew/0000-0003-2079-4779; Brenner, Hermann/0000-0002-6129-1572; Alves, Alex/0000-0001-8519-7356; Karani, Vimal/0000-0002-8485-8930 FU British Heart Foundation; UK Medical Research Council; Academy of Finland FX British Heart Foundation, UK Medical Research Council, and Academy of Finland. NR 33 TC 78 Z9 79 U1 3 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD SEP PY 2014 VL 2 IS 9 BP 719 EP 729 DI 10.1016/S2213-8587(14)70113-5 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP1AY UT WOS:000341800000014 PM 24974252 ER PT J AU Landgren, O Tageja, N AF Landgren, O. Tageja, N. TI MYD88 and beyond: novel opportunities for diagnosis, prognosis and treatment in Waldenstrom's Macroglobulinemia SO LEUKEMIA LA English DT Review ID L265P SOMATIC MUTATION; CELL LYMPHOPROLIFERATIVE DISORDERS; BRUTON TYROSINE KINASE; TOLL-LIKE RECEPTOR; IL-1; ACTIVATION; DELETIONS; LYMPHOMA; IMMUNITY; PROTEIN AB Waldenstrom's Macroglobulinemia (WM) is a rare disease of the elderly with a median age of 63-68 years at diagnosis. Despite recent progress in biological insights and therapeutics, WM remains clinically challenging to diagnose and is difficult to manage with significant morbidity and lack of established curative therapies. Recently, the use of whole-genome sequencing has helped to identify a highly recurrent somatic mutation, myeloid differentiation factor 88 [MYD88] L265P in WM. This has fueled major interest in the field and as newer evidence accumulates, it is clear that that discovery of MYD88 L265P mutation may represent an important breakthrough in understanding the pathogenesis of WM and lymphoproliferative disorders. Recent scientific work in this field has also guided the identification of new targets such as CXCR4 and PI3K-delta that may have major implications in the future treatment of WM. This review discusses the role of MYD88 L265P mutations as well as targets beyond MYD88 in the setting of pathogenesis and development of future rational therapeutic trials focusing on patients diagnosed with WM. C1 [Landgren, O.; Tageja, N.] NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, 9000 Rockville Pike,Bldg 10 Room 13N240, Bethesda, MD 20892 USA. EM landgrec@mskcc.org FU Intramural Research Program of the National Cancer Institute of the National Institutes of Health FX The Intramural Research Program of the National Cancer Institute of the National Institutes of Health supported this work. NR 38 TC 4 Z9 5 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD SEP PY 2014 VL 28 IS 9 BP 1799 EP 1803 DI 10.1038/leu.2014.88 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA AP0VG UT WOS:000341783000005 PM 24573383 ER PT J AU Kroelinger, CD Rankin, KM Chambers, DA Roux, AVD Hughes, K Grigorescu, V AF Kroelinger, Charlan D. Rankin, Kristin M. Chambers, David A. Roux, Ana V. Diez Hughes, Karen Grigorescu, Violanda TI Using the Principles of Complex Systems Thinking and Implementation Science to Enhance Maternal and Child Health Program Planning and Delivery SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Implementation science; Complex systems thinking; Quality assurance; Public health; Theory ID EPIDEMIOLOGY AB Traditionally, epidemiologic methodologies have focused on measurement of exposures, outcomes, and program impact through reductionistic, yet complex statistical modeling. Although not new to the field of epidemiology, two frameworks that provide epidemiologists with a foundation for understanding the complex contexts in which programs and policies are implemented were presented to maternal and child health (MCH) professionals at the 2012 co-hosted 18th Annual MCH Epidemiology Conference and 22nd CityMatCH Urban Leadership Conference. The complex systems approach offers researchers in MCH the opportunity to understand the functioning of social, medical, environmental, and behavioral factors within the context of implemented public health programs. Implementation science provides researchers with a framework to translate the evidence-based program interventions into practices and policies that impact health outcomes. Both approaches offer MCH epidemiologists conceptual frameworks with which to re-envision how programs are implemented, monitored, evaluated, and reported to the larger public health audience. By using these approaches, researchers can begin to understand and measure the broader public health context, account for the dynamic interplay of the social environment, and ultimately, develop more effective MCH programs and policies. C1 [Kroelinger, Charlan D.; Grigorescu, Violanda] Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Chamblee, GA 30341 USA. [Rankin, Kristin M.] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL USA. [Chambers, David A.] NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. [Roux, Ana V. Diez] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Hughes, Karen] Ohio Dept Hlth, Div Family & Community Hlth Serv, Columbus, OH 43266 USA. RP Kroelinger, CD (reprint author), Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Hwy NE,MS F-74, Chamblee, GA 30341 USA. EM ckroelinger@cdc.gov FU Intramural CDC HHS [CC999999] NR 10 TC 0 Z9 0 U1 1 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD SEP PY 2014 VL 18 IS 7 BP 1560 EP 1564 DI 10.1007/s10995-014-1586-9 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AO9RM UT WOS:000341693900003 PM 25108501 ER PT J AU Singhal, A Chattopadhyay, A Garcia, AI Adams, AB Cheng, DA AF Singhal, Astha Chattopadhyay, Amit Garcia, A. Isabel Adams, Amy B. Cheng, Diana TI Disparities in Unmet Dental Need and Dental Care Received by Pregnant Women in Maryland SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Pregnancy; Dental visits; Unmet need; Disparities; Oral health; Prenatal care ID LOW-BIRTH-WEIGHT; GRADE ASSOCIATING PERIODONTITIS; ASSESSMENT MONITORING-SYSTEM; CARIES-PREVENTIVE MEASURES; STREPTOCOCCUS-MUTANS; PRETERM BIRTH; ORAL-HEALTH; INITIAL ACQUISITION; HORMONAL VARIATIONS; GINGIVAL CHANGES AB To examine prenatal dental care needs, utilization and oral health counseling among Maryland women who delivered a live infant during 2001-2003 and identify the factors associated with having a dental visit and having an unmet dental need during pregnancy. Pregnancy Risk Assessment Monitoring System is an ongoing population based surveillance system that collects information of women's attitudes and experiences before, during, and shortly after pregnancy. Logistic regression was used to model dental visits and unmet dental need using predictor variables for Maryland 2001-2003 births. Less than half of all women reported having a dental visit and receiving oral health advice during pregnancy. Twenty-five percent of women reported a need for dental care, of which 33 % did not receive dental care despite their perceived need. Multivariate modeling revealed that racial minorities, women who were not married and those with annual income <$40,000 were least likely to have a dental visit. Women who were not married, had low annual income, were older than 40 years of age, had an unintended pregnancy and received prenatal care later than desired were most likely to have an unmet dental need during pregnancy. Despite reported needs and existing recommendations to include oral health as a component of prenatal care, less than half of pregnant women have a dental visit during their pregnancy. One-third of women with a dental problem did not have a dental visit highlighting the unmet need for dental care during pregnancy. C1 [Singhal, Astha] Univ Iowa, Coll Dent, Dept Prevent & Community Dent, Iowa City, IA 52242 USA. [Chattopadhyay, Amit; Adams, Amy B.] NIDCR, Off Sci Policy & Anal, NIH, Bethesda, MD USA. [Garcia, A. Isabel] NIDCR, NIH, Bethesda, MD USA. [Cheng, Diana] Dept Hlth & Mental Hyg, Baltimore, MD USA. RP Singhal, A (reprint author), Univ Iowa, Coll Dent, Dept Prevent & Community Dent, Iowa City, IA 52242 USA. EM asthasinghal@gmail.com RI Chattopadhyay, Amit/L-1919-2013 OI Chattopadhyay, Amit/0000-0003-3278-7525 NR 52 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD SEP PY 2014 VL 18 IS 7 BP 1658 EP 1666 DI 10.1007/s10995-013-1406-7 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AO9RM UT WOS:000341693900015 PM 24337895 ER PT J AU Barzik, M McClain, LM Gupton, SL Gertler, FB AF Barzik, Melanie McClain, Leslie M. Gupton, Stephanie L. Gertler, Frank B. TI Ena/VASP regulates mDia2-initiated filopodial length, dynamics, and function SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FOCAL ADHESION KINASE; VASODILATOR-STIMULATED PHOSPHOPROTEIN; ACTIN-FILAMENT ELONGATION; BARBED-END ASSOCIATION; GROWTH CONE FILOPODIA; ARP2/3 COMPLEX; CELL-MIGRATION; LISTERIA-MONOCYTOGENES; EVH1 DOMAIN; TYROSINE PHOSPHORYLATION AB Filopodia are long plasma membrane extensions involved in the formation of adhesive, contractile, and protrusive actin-based structures in spreading and migrating cells. Whether filopodia formed by different molecular mechanisms equally support these cellular functions is unresolved. We used Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP)-deficient MVD7 fibroblasts, which are also devoid of endogenous mDia2, as a model system to investigate how these different actin regulatory proteins affect filopodia morphology and dynamics independently of one another. Filopodia initiated by either Ena/VASP or mDia2 contained similar molecular inventory but differed significantly in parameters such as number, length, F-actin organization, lifetime, and protrusive persistence. Moreover, in the absence of Ena/VASP, filopodia generated by mDia2 did not support initiation of integrin-dependent signaling cascades required for adhesion and subsequent lamellipodial extension, thereby causing a defect in early cell spreading. Coexpression of VASP with constitutively active mDia2(M/A) rescued these early adhesion defects. We conclude that Ena/VASP and mDia2 support the formation of filopodia with significantly distinct properties and that Ena/VASP regulates mDia2-initiated filopodial morphology, dynamics, and function. C1 [Barzik, Melanie; McClain, Leslie M.; Gertler, Frank B.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Gupton, Stephanie L.] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA. RP Barzik, M (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM melanie.barzik@nih.gov OI Barzik, Melanie/0000-0003-3003-1281 FU National Institutes of Health [GM58801, R01GM108970]; Integrated Cancer Biology Program [1-U54-CA112967]; National Institutes of Health intramural funds from the National Institute on Deafness and Other Communication Disorders (NIDCD) [1 Z01 DC000039-17] FX We thank M. Machner, N. Rusan, and J. Bird for critical reading of the manuscript. We are grateful to K. Remmert for providing wildtype MEFs. F.B.G. was supported by National Institutes of Health Grant GM58801 and Integrated Cancer Biology Program Grant 1-U54-CA112967. S.L.G. was supported by National Institutes of Health Grant R01GM108970. This work was also supported by National Institutes of Health intramural funds from the National Institute on Deafness and Other Communication Disorders (NIDCD) 1 Z01 DC000039-17 to T. Friedman (Laboratory of Molecular Genetics, NIDCD, National Institutes of Health). NR 104 TC 15 Z9 15 U1 1 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 1 PY 2014 VL 25 IS 17 BP 2604 EP 2619 DI 10.1091/mbc.E14-02-0712 PG 16 WC Cell Biology SC Cell Biology GA AO8WW UT WOS:000341637300007 PM 24989797 ER PT J AU King, KE Reddi, DM Ponnamperuma, RM Gerdes, M Weinberg, WC AF King, Kathryn E. Reddi, Deepti Muraleedharan Ponnamperuma, Roshini M. Gerdes, Michael Weinberg, Wendy C. TI Dysregulated Delta Np63 alpha Negatively Regulates the Maspin Promoter in Keratinocytes Via Blocking Endogenous p73 Binding SO MOLECULAR CARCINOGENESIS LA English DT Article DE squamous cell cancer; p53 homologs; protease inhibitory proteins ID PLASMINOGEN-ACTIVATOR INHIBITOR-2; SQUAMOUS-CELL CARCINOMA; HEPATOCYTE GROWTH-FACTOR; SUPPRESSOR GENE MASPIN; INDUCED APOPTOSIS; TUMOR-SUPPRESSOR; TISSUE INHIBITOR; SERINE-PROTEASE; TNF-ALPHA; MATRIX METALLOPROTEINASES AB While overexpression of the p63 isoform, Delta Np63 alpha, has been reported in squamous cell cancers, the contribution of p63 to cancer pathogenesis remains unclear. We previously demonstrated that overexpressed Delta Np63 alpha aberrantly maintains proliferation of primary mouse keratinocytes under conditions that normally induce growth arrest and differentiation. To identify genes downstream of dysregulated Delta Np63 alpha that may contribute to squamous cancer development and progression, we performed microarray analyses using primary mouse keratinocytes. Herein we report that elevated Delta Np63 alpha differentially regulates genes involved in a variety of cellular functions. Of note, multiple protease inhibitor mRNAs were downregulated including: maspin (serpinB5); plasminogen activator inhibitor-2 (PAI-2; serpinB2); and tissue inhibitor of metalloproteinase-3 (TIMP-3). Correspondingly, secreted TIMP-3 and PAI-2 protein declined in the presence of dysregulated Delta Np63 alpha, however secreted maspin remained stable. Intracellular maspin protein expression decreased in response to overexpressed Delta Np63 alpha, as did PAI-2. In contrast, TIMP-3 protein was not detected intracellularly, supporting a solely extracellular function. Electrophoretic mobility shift assays (EMSAs) using a maspin promoter p53/p63 consensus sequence revealed endogenous transcription factor(s) binding to this sequence in keratinocytes that was disrupted by overexpressed Delta Np63 alpha. This was confirmed by ChIP assays. This binding was interrupted by the addition of antibodies recognizing p73, but not p53 or p63, and significantly diminished in EMSA reactions from p73(-/-) keratinocytes, confirming p73 as a constituent. Physical association between p73/Delta Np63 alpha was observed in control beta-gal overexpressing keratinocytes and was enhanced in the presence of overexpressed Delta Np63 alpha These findings underscore the importance of properly balanced p53 homologs for tissue homeostasis. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [King, Kathryn E.; Reddi, Deepti Muraleedharan; Ponnamperuma, Roshini M.; Weinberg, Wendy C.] US FDA, Off Biotechnol Prod, CDER, Bethesda, MD 20892 USA. [Gerdes, Michael] NCI, NIH, Bethesda, MD 20892 USA. RP Weinberg, WC (reprint author), US FDA, Mol Oncol Lab, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 29 Lincoln Dr,HFD 123, Bethesda, MD 20892 USA. NR 121 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD SEP PY 2014 VL 53 IS 9 BP 698 EP 710 DI 10.1002/mc.22022 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AP4QD UT WOS:000342062100003 PM 23475637 ER PT J AU Paltoo, DN Rodriguez, LL Feolo, M Gillanders, E Ramos, EM Rutter, JL Sherry, S Wang, VO Bailey, A Baker, R Caulder, M Harris, EL Langlais, K Leeds, H Luetkemeier, E Paine, T Roomian, T Tryka, K Patterson, A Green, ED AF Paltoo, Dina N. Rodriguez, Laura Lyman Feolo, Michael Gillanders, Elizabeth Ramos, Erin M. Rutter, Joni L. Sherry, Stephen Wang, Vivian Ota Bailey, Alice Baker, Rebecca Caulder, Mark Harris, Emily L. Langlais, Kristofor Leeds, Hilary Luetkemeier, Erin Paine, Taunton Roomian, Tamar Tryka, Kimberly Patterson, Amy Green, Eric D. CA Natl Inst Hlth Genomic Data Sharin TI Data use under the NIH GWAS Data Sharing Policy and future directions SO NATURE GENETICS LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; RISK LOCI; DISORDERS AB In 2007, the US National Institutes of Health (NIH) introduced the Genome-Wide Association Studies (GWAS) Policy and the database of Genotypes and Phenotypes (dbGaP) to facilitate 'controlled' access to GWAS data based on participants' informed consent. dbGaP has provided 2,221 investigators access to 304 studies, resulting in 924 publications and significant scientific advances. Following on this success, the 2014 Genomic Data Sharing Policy will extend the GWAS Policy to additional data types. C1 [Paltoo, Dina N.; Baker, Rebecca; Langlais, Kristofor; Luetkemeier, Erin; Paine, Taunton; Patterson, Amy] US Natl Inst Hlth, Off Sci Policy, Off Director, Bethesda, MD 20892 USA. [Rodriguez, Laura Lyman; Ramos, Erin M.; Wang, Vivian Ota; Bailey, Alice; Roomian, Tamar; Green, Eric D.] NHGRI, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Feolo, Michael; Sherry, Stephen; Tryka, Kimberly] US Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. [Gillanders, Elizabeth] US Natl Inst Hlth, NCI, Bethesda, MD USA. [Rutter, Joni L.; Caulder, Mark] US Natl Inst Hlth, NIDA, Bethesda, MD USA. [Harris, Emily L.] US Natl Inst Hlth, Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Leeds, Hilary] US Natl Inst Hlth, NHLBI, Bethesda, MD USA. RP Paltoo, DN (reprint author), US Natl Inst Hlth, Off Sci Policy, Off Director, Bethesda, MD 20892 USA. EM GDS@mail.nih.gov OI Tryka, Kimberly/0000-0002-5399-4235 FU Intramural NIH HHS [Z99 LM999999] NR 13 TC 23 Z9 23 U1 0 U2 8 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 SEP PY 2014 VL 46 IS 9 BP 934 EP 938 DI 10.1038/ng.3062 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA AO8CE UT WOS:000341579400005 PM 25162809 ER PT J AU Nalls, MA Pankratz, N Lill, CM Do, CB Hernandez, DG Saad, M DeStefano, AL Kara, E Bras, J Sharma, M Schulte, C Keller, MF Arepalli, S Letson, C Edsall, C Stefansson, H Liu, X Pliner, H Lee, JH Cheng, R Ikram, MA Ioannidis, JPA Hadjigeorgiou, GM Bis, JC Martinez, M Perlmutter, JS Goate, A Marder, K Fiske, B Sutherland, M Xiromerisiou, G Myers, RH Clark, LN Stefansson, K Hardy, JA Heutink, P Chen, H Wood, NW Houlden, H Payami, H Brice, A Scott, WK Gasser, T Bertram, L Eriksson, N Foroud, T Singleton, AB AF Nalls, Mike A. Pankratz, Nathan Lill, Christina M. Do, Chuong B. Hernandez, Dena G. Saad, Mohamad DeStefano, Anita L. Kara, Eleanna Bras, Jose Sharma, Manu Schulte, Claudia Keller, Margaux F. Arepalli, Sampath Letson, Christopher Edsall, Connor Stefansson, Hreinn Liu, Xinmin Pliner, Hannah Lee, Joseph H. Cheng, Rong Ikram, M. Arfan Ioannidis, John P. A. Hadjigeorgiou, Georgios M. Bis, Joshua C. Martinez, Maria Perlmutter, Joel S. Goate, Alison Marder, Karen Fiske, Brian Sutherland, Margaret Xiromerisiou, Georgia Myers, Richard H. Clark, Lorraine N. Stefansson, Kari Hardy, John A. Heutink, Peter Chen, Honglei Wood, Nicholas W. Houlden, Henry Payami, Haydeh Brice, Alexis Scott, William K. Gasser, Thomas Bertram, Lars Eriksson, Nicholas Foroud, Tatiana Singleton, Andrew B. CA IPDG GParkinson's Study Grp PSG Parkins 23AndMe GenePD NGRC HIHG Ashkenazi Jewish Dataset Investiga CHARGE NABEC UKBEC Greek Parkinson's Dis Consortium Alzheimer Genetic Analysis Gr TI Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease SO NATURE GENETICS LA English DT Article ID IMPUTATION; VARIANTS; POPULATION; PREDICTION; REGION; GENES; HEART; SIZE AB We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 x 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation. C1 [Nalls, Mike A.; Hernandez, Dena G.; Keller, Margaux F.; Arepalli, Sampath; Letson, Christopher; Edsall, Connor; Pliner, Hannah; Singleton, Andrew B.] Natl Inst Aging, Lab Neurogenet, Bethesda, MD 20892 USA. [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Lill, Christina M.; Bertram, Lars] Max Planck Inst Mol Genet, Dept Vertebrate Gen, D-14195 Berlin, Germany. [Lill, Christina M.] Johannes Gutenberg Univ Mainz, Focus Program Translat Neurosci, Dept Neurol, D-55122 Mainz, Germany. [Do, Chuong B.; Eriksson, Nicholas] 23andMe Inc, Mountain View, CA USA. [Hernandez, Dena G.; Hardy, John A.] UCL, Inst Neurol, Reta Lila Weston Inst, London, England. [Saad, Mohamad] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Saad, Mohamad; Martinez, Maria; Gasser, Thomas] Ctr Physiopathol Toulouse Purpan, INSERM, UMR 1043, Toulouse, France. [Saad, Mohamad; Martinez, Maria; Gasser, Thomas] Univ Toulouse 3, F-31062 Toulouse, France. [DeStefano, Anita L.; Myers, Richard H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [DeStefano, Anita L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [DeStefano, Anita L.] Natl Heart Lung & Blood Inst NHLBI Framingham, Framingham, MA USA. [Kara, Eleanna; Bras, Jose; Wood, Nicholas W.; Houlden, Henry] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Sharma, Manu] Univ Tubingen, Inst Clin Epidemiol & Appl Biometry, Tubingen, Germany. [Sharma, Manu; Schulte, Claudia; Gasser, Thomas] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Stefansson, Hreinn; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Liu, Xinmin; Clark, Lorraine N.] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY USA. [Lee, Joseph H.; Cheng, Rong; Marder, Karen; Clark, Lorraine N.] Columbia Univ, Med Ctr, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA. [Ikram, M. Arfan; Houlden, Henry] Erasmus MC Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Houlden, Henry] Erasmus MC Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Pankratz, Nathan; Ikram, M. Arfan; Houlden, Henry] Erasmus MC Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Ioannidis, John P. A.; Payami, Haydeh] Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Hadjigeorgiou, Georgios M.; Xiromerisiou, Georgia; Brice, Alexis] Univ Thessaly, Fac Med, Dept Neurol, Neurosci Unit, Larisa, Greece. [Bis, Joshua C.; Scott, William K.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Perlmutter, Joel S.; Goate, Alison; Bertram, Lars] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA. [Bertram, Lars] Washington Univ, Sch Med, Dept Radiol, St Louis, MO USA. [Perlmutter, Joel S.; Goate, Alison; Bertram, Lars] Washington Univ, Sch Med, Dept Neurol, St Louis, MO USA. [Goate, Alison] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Goate, Alison] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Marder, Karen] Columbia Univ, Med Ctr, Gertrude H Sergievsky Ctr, New York, NY USA. [Marder, Karen] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA. [Marder, Karen] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY USA. [Fiske, Brian] Michael J Fox Fdn Parkinsons Res, New York, NY USA. [Sutherland, Margaret] Natl Inst Neurol Disorders & Stroke, Neurosci Ctr, Bethesda, MD USA. [Xiromerisiou, Georgia] Papageorgiou Hosp, Dept Neurol, Thessaloniki, Greece. [Heutink, Peter] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Payami, Haydeh] NIEHS, Epidemiol Branch, US Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. [Payami, Haydeh] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Brice, Alexis] Univ Paris 06, Sorbonne Univ, UM 75, INSERM U1127, Paris, France. [Brice, Alexis] CNRS, UMR 7225, Paris, France. [Brice, Alexis] Hop La Pitie Salpetriere, Dept Genet & Cytogenet, Paris, France. [Scott, William K.] Univ Miami, Sch Med, Dept Human Genet, Miami, FL USA. [Bertram, Lars] Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, London, England. [Foroud, Tatiana] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. RP Singleton, AB (reprint author), Natl Inst Aging, Lab Neurogenet, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Wood, Nicholas/C-2505-2009; van de Warrenburg, Bart/D-1935-2010; Bertram, Lars/K-3889-2015; Martinez, Maria/B-3111-2013; Johnson, Andrew/G-6520-2013; Houlden, Henry/C-1532-2008; corvol, jean-christophe/I-6387-2012; Revesz, Tamas/A-8732-2010; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Cooper, J Mark/D-5826-2013; Morris, Huw/B-8527-2008; Lill, Christina/J-9449-2015; Lunnon, Katie/C-4638-2012; Deloukas, Panos/B-2922-2013; Deuschl, Gunther/A-7986-2010; Ramasamy, Adaikalavan/G-2632-2010; Scheffer, Hans/E-4644-2012; Weale, Michael/F-2587-2010; Pliner, Hannah/F-3608-2015; lambert, jean-charles/F-8787-2013 OI Ikram, Mohammad Arfan/0000-0003-0372-8585; Plagnol, Vincent/0000-0002-5597-9215; Chen, Honglei/0000-0003-3446-7779; Goldwurm, Stefano/0000-0002-1651-567X; Lee, Joseph H/0000-0002-2000-4821; Wood, Nicholas/0000-0002-9500-3348; Bertram, Lars/0000-0002-0108-124X; Martinez, Maria/0000-0003-2180-4537; Houlden, Henry/0000-0002-2866-7777; corvol, jean-christophe/0000-0001-7325-0199; Revesz, Tamas/0000-0003-2501-0259; Seshadri, Sudha/0000-0001-6135-2622; Bras, Jose/0000-0001-8186-0333; Verlinden, Vincentius/0000-0002-0560-7691; Stefansson, Hreinn/0000-0002-9331-6666; Cooper, J Mark/0000-0002-3007-3054; Morris, Huw/0000-0002-5473-3774; Lill, Christina/0000-0002-2805-1307; Lunnon, Katie/0000-0001-7570-6065; Deloukas, Panos/0000-0001-9251-070X; Ramasamy, Adaikalavan/0000-0002-7598-2892; Scheffer, Hans/0000-0002-2986-0915; Weale, Michael/0000-0003-4593-1186; Pliner, Hannah/0000-0003-1484-6501; FU Intramural NIH HHS [Z01 AG000932-01, Z01 AG000949-03]; Medical Research Council [G0700943, G0701075, G0802462, G0802760, G0901254, G1001253, G108/638, G1100479, G1100643, MC_G0901330, MC_G1000735, MC_PC_09003, MR/J004758/1, MR/L010305/1, MR/L016400/1, MR/L501554/1]; NCATS NIH HHS [UL1 TR000124, UL1 TR001108, UL1TR000124]; NCI NIH HHS [R01CA141668]; NCRR NIH HHS [1KL2RR024154, 2UL1 RR024156]; NHGRI NIH HHS [R44 HG006981]; NIA NIH HHS [AG023629, AG025259, AG031287, AG033193, AG08122, AG16495, P30AG013846, P30AG024826, U24 AG021886]; NIDDK NIH HHS [DK063491]; NINDS NIH HHS [1K23NS070867, K02 NS073836, NS036630, NS050487, NS060113, NS17950, P50 NS038377, P50 NS071674, P50NS071674, R01 NS075321, R01 NS076843, R01 NS088538, R01-NS-36960, R01NS037167]; Parkinson's UK [F-1202, G-0907, G-0909, J-0804]; Wellcome Trust [076113, 083948/Z/07/Z, 085475, 089698, 090355, WT089698, WT089698/Z/09/Z] NR 36 TC 299 Z9 300 U1 20 U2 88 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 SEP PY 2014 VL 46 IS 9 BP 989 EP + DI 10.1038/ng.3043 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AO8CE UT WOS:000341579400013 PM 25064009 ER PT J AU Wolpin, BM Rizzato, C Kraft, P Kooperberg, C Petersen, GM Wang, ZM Arslan, AA Beane-Freeman, L Bracci, PM Buring, J Canzian, F Duell, EJ Gallinger, S Giles, GG Goodman, GE Goodman, PJ Jacobs, EJ Kamineni, A Klein, AP Kolonel, LN Kulke, MH Li, DH Malats, N Olson, SH Risch, HA Sesso, HD Visvanathan, K White, E Zheng, W Abnet, CC Albanes, D Andreotti, G Austin, MA Barfield, R Basso, D Berndt, SI Boutron-Ruault, MC Brotzman, M Buchler, MW Bueno-de-Mesquita, HB Bugert, P Burdette, L Campa, D Caporaso, NE Capurso, G Chung, C Cotterchio, M Costello, E Elena, J Funel, N Gaziano, JM Giese, NA Giovannucci, EL Gorman, MJ Gross, M Haiman, CA Hassan, M Helzlsouer, KJ Henderson, BE Holly, EA Hu, N Hunter, DJ Innocenti, F Jenab, M Kaaks, R Key, TJ Khaw, KT Klein, EA Kogevinas, M Krogh, V Kupcinskas, J Kurtz, RC LaCroix, A Landi, MT Landi, S Le Marchand, L Mambrini, A Mannisto, S Milne, RL Nakamura, Y Oberg, AL Owzar, K Patel, AV Peeters, PHM Peters, U Pezzilli, R Piepoli, A Porta, M Real, FX Riboli, E Rothman, N Scarpa, A Shu, XO Silverman, DT Soucek, P Sund, M Talar-Wojnarowska, R Taylor, PR Theodoropoulos, GE Thornquist, M Tjonneland, A Tobias, GS Trichopoulos, D Vodicka, P Wactawski-Wende, J Wentzensen, N Wu, C Yu, H Yu, K Zeleniuch-Jacquotte, A Hoover, R Hartge, P Fuchs, C Chanock, SJ Stolzenberg-Solomon, RS Amundadottir, LT AF Wolpin, Brian M. Rizzato, Cosmeri Kraft, Peter Kooperberg, Charles Petersen, Gloria M. Wang, Zhaoming Arslan, Alan A. Beane-Freeman, Laura Bracci, Paige M. Buring, Julie Canzian, Federico Duell, Eric J. Gallinger, Steven Giles, Graham G. Goodman, Gary E. Goodman, Phyllis J. Jacobs, Eric J. Kamineni, Aruna Klein, Alison P. Kolonel, Laurence N. Kulke, Matthew H. Li, Donghui Malats, Nuria Olson, Sara H. Risch, Harvey A. Sesso, Howard D. Visvanathan, Kala White, Emily Zheng, Wei Abnet, Christian C. Albanes, Demetrius Andreotti, Gabriella Austin, Melissa A. Barfield, Richard Basso, Daniela Berndt, Sonja I. Boutron-Ruault, Marie-Christine Brotzman, Michelle Buechler, Markus W. Bueno-de-Mesquita, H. Bas Bugert, Peter Burdette, Laurie Campa, Daniele Caporaso, Neil E. Capurso, Gabriele Chung, Charles Cotterchio, Michelle Costello, Eithne Elena, Joanne Funel, Niccola Gaziano, J. Michael Giese, Nathalia A. Goggins, Michael Gorman, Megan J. Gross, Myron Haiman, Christopher A. Hassan, Manal Helzlsouer, Kathy J. Henderson, Brian E. Holly, Elizabeth A. Hu, Nan Hunter, David J. Innocenti, Federico Jenab, Mazda Kaaks, Rudolf Key, Timothy J. Khaw, Kay-Tee Klein, Eric A. Kogevinas, Manolis Krogh, Vittorio Kupcinskas, Juozas Kurtz, Robert C. LaCroix, Andrea Landi, Maria T. Landi, Stefano Le Marchand, Loic Mambrini, Andrea Mannisto, Satu Milne, Roger L. Nakamura, Yusuke Oberg, Ann L. Owzar, Kouros Patel, Alpa V. Peeters, Petra H. M. Peters, Ulrike Pezzilli, Raffaele Piepoli, Ada Porta, Miquel Real, Francisco X. Riboli, Elio Rothman, Nathaniel Scarpa, Aldo Shu, Xiao-Ou Silverman, Debra T. Soucek, Pavel Sund, Malin Talar-Wojnarowska, Renata Taylor, Philip R. Theodoropoulos, George E. Thornquist, Mark Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Dimitrios Vodicka, Pavel Wactawski-Wende, Jean Wentzensen, Nicolas Wu, Chen Yu, Herbert Yu, Kai Zeleniuch-Jacquotte, Anne Hoover, Robert Hartge, Patricia Fuchs, Charles Chanock, Stephen J. Stolzenberg-Solomon, Rachael S. Amundadottir, Laufey T. TI Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer SO NATURE GENETICS LA English DT Article ID RECOMBINATION HOTSPOTS; BLADDER-CANCER; RISK LOCI; LINKAGE DISEQUILIBRIUM; GENETIC SUSCEPTIBILITY; OVARIAN-CANCER; VARIANTS; METAANALYSIS; IMPUTATION; DISEASE AB We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 x 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 x 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 x 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 x 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 x 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 x 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wolpin, Brian M.; Gorman, Megan J.; Fuchs, Charles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wolpin, Brian M.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Rizzato, Cosmeri; Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Kraft, Peter; Sesso, Howard D.; Trichopoulos, Dimitrios; Wu, Chen] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter; Barfield, Richard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Kooperberg, Charles; Goodman, Gary E.; LaCroix, Andrea; Thornquist, Mark] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Wang, Zhaoming; Beane-Freeman, Laura; Abnet, Christian C.; Albanes, Demetrius; Andreotti, Gabriella; Berndt, Sonja I.; Caporaso, Neil E.; Chung, Charles; Hu, Nan; Landi, Maria T.; Rothman, Nathaniel; Silverman, Debra T.; Taylor, Philip R.; Tobias, Geoffrey S.; Wentzensen, Nicolas; Yu, Kai; Hoover, Robert; Hartge, Patricia; Chanock, Stephen J.; Stolzenberg-Solomon, Rachael S.; Amundadottir, Laufey T.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Burdette, Laurie; Chung, Charles; Chanock, Stephen J.] Leidos Biomed Res Inc, Div Canc Epidemiol & Genet, Frederick Natl Lab Canc Res, Canc Genom Res Lab,Natl Canc Inst, Frederick, MD USA. [Arslan, Alan A.] NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, New York, NY USA. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Buring, Julie; Sesso, Howard D.; Gaziano, J. Michael] Harvard Univ, Sch Med, Boston, MA USA. [Buring, Julie; Sesso, Howard D.; Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Duell, Eric J.] Bellvitge Biomed Res Inst IDIBELL, Catalan Inst Oncol ICO, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona, Spain. [Gallinger, Steven] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, Southwest Oncol Grp Stat Ctr, Seattle, WA 98104 USA. [Jacobs, Eric J.; Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Kamineni, Aruna] Grp Hlth Res Inst, Seattle, WA USA. [Klein, Alison P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Klein, Alison P.] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Kolonel, Laurence N.] Canc Res Ctr Hawaii, Honolulu, HI USA. [Li, Donghui; Hassan, Manal] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Malats, Nuria] CNIO Spanish Natl Canc Res Ctr, Genet & Mol Epidemiol Grp, Madrid, Spain. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [White, Emily] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [White, Emily; Austin, Melissa A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Basso, Daniela] Univ Hosp Padova, Dept Lab Med, Padua, Italy. [Boutron-Ruault, Marie-Christine] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Nutr Hormones & Womens Hlth Team, Villejuif, France. [Boutron-Ruault, Marie-Christine] Univ Paris 11, UMRS 1018, Villejuif, France. [Boutron-Ruault, Marie-Christine] IGR, Villejuif, France. [Brotzman, Michelle] Westat Corp, Rockville, MD USA. [Buechler, Markus W.; Giese, Nathalia A.] Univ Heidelberg Hosp, Dept Gen Surg, Heidelberg, Germany. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas; Peeters, Petra H. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Bugert, Peter] Heidelberg Univ, Med Fac Mannheim, Inst Transfus Med & Immunol, German Red Cross Blood Serv Baden Wurttemberg Hes, Mannheim, Germany. [Campa, Daniele; Kaaks, Rudolf] DKFZ, Div Canc Epidemiol, Heidelberg, Germany. [Capurso, Gabriele] Univ Roma La Sapienza, Digest & Liver Dis Unit, I-00185 Rome, Italy. [Cotterchio, Michelle] Univ Toronto, Canc Care Ontario, Toronto, ON M5S 1A1, Canada. [Cotterchio, Michelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Costello, Eithne] Univ Liverpool, Liverpool Pancreas Biomed Res Unit, Natl Inst Hlth, Liverpool L69 3BX, Merseyside, England. [Elena, Joanne] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Funel, Niccola] Univ Hosp Pisa, Unit Expt Surg Pathol, Dept Surg, Pisa, Italy. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Res & Informat Ctr, Massachusetts Vet Epidemiol, Boston, MA USA. [Fuchs, Charles] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Fuchs, Charles] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, Charles] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Pathol, Baltimore, MD USA. [Goggins, Michael] Johns Hopkins Univ, Baltimore, MD USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Med, Baltimore, MD USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Oncol, Baltimore, MD USA. [Gross, Myron] Univ Minnesota, Lab Med & Pathol, Minneapolis, MN USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Los Angeles, CA USA. [Helzlsouer, Kathy J.] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. [Innocenti, Federico] Univ N Carolina, Eshelman Sch Pharm, Ctr Pharmacogen & Individualized Therapy, Lineberger Comprehens Canc Ctr,Sch Med, Chapel Hill, NC USA. [Jenab, Mazda] Int Agcy Res Canc, Lyon, France. [Key, Timothy J.] Canc Epidemiol Unit, Oxford, England. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Cambridge, England. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Kogevinas, Manolis] CIBER Epidemiol & Salud Publ CIBERESP, Ctr Recerca Epidemiol Ambiental CREAL, Barcelona, Spain. [Kogevinas, Manolis; Porta, Miquel] Hosp del Mar, Inst Med Res IMIM, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Dept Nutr, Athens, Greece. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Kupcinskas, Juozas] Lithuanian Univ Hlth Sci, Dept Gastroenterol, Kaunas, Lithuania. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Landi, Stefano] Univ Pisa, Dept Biol, Pisa, Italy. [Le Marchand, Loic; Yu, Herbert] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Mambrini, Andrea] ASL1 Massa Carrara, Oncol Dept, Massa Carrara, Italy. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Tokyo, Japan. [Oberg, Ann L.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Alliance Stat & Data Ctr, Rochester, MN USA. [Owzar, Kouros] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Alliance Stat & Data Ctr, Durham, NC USA. [Peeters, Petra H. M.; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Dept Epidemiol, Seattle, WA 98104 USA. [Pezzilli, Raffaele] SantOrsola Malpighi Hosp, Dept Digest Dis & Internal Med, Pancreas Unit, Bologna, Italy. [Piepoli, Ada] Opera Padre Pio Pietrelcina, Inst Sci, Dept Gastroenterol, San Giovanni Rotondo, Italy. [Piepoli, Ada] Opera Padre Pio Pietrelcina, Reg Gen Hosp Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy. [Porta, Miquel] Univ Autonoma Barcelona, Sch Med, Dept Epidemiol, E-08193 Barcelona, Spain. [Porta, Miquel] CIBERESP, Madrid, Spain. [Real, Francisco X.] CNIO Spanish Natl Canc Res Ctr, Epithelial Carcinogenesis Grp, Madrid, Spain. [Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies & Salut, Barcelona, Spain. [Scarpa, Aldo] Univ & Hosp Trust Verona, ARC NET Ctr Appl Res Canc, Verona, Italy. [Soucek, Pavel] Natl Inst Publ Hlth, Ctr Toxicol & Safety, Toxicogenom Unit, Prague, Czech Republic. [Sund, Malin] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Talar-Wojnarowska, Renata] Med Univ Lodz, Dept Digest Tract Dis, Lodz, Poland. [Theodoropoulos, George E.] Hippocrat Univ Hosp, Propaideut Surg Dept 1, Athens, Greece. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellenic Hlth Fdn, Athens, Greece. [Vodicka, Pavel] Acad Sci Czech Republic, Inst Expt Med, Dept Mol Biol Canc, Prague, Czech Republic. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Stolzenberg-Solomon, RS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM rachael.solomon@nih.gov; amundadottirl@mail.nih.gov RI Piepoli, Ada/K-9299-2016; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; scarpa, aldo/K-6832-2016; Talar-Wojnarowska, Renata/T-1009-2016; Kogevinas, Manolis/C-3918-2017; Gallinger, Steven/E-4575-2013; Porta, Miquel/B-5787-2008; Albanes, Demetrius/B-9749-2015; Beane Freeman, Laura/C-4468-2015; Real Arribas, Francisco/H-5275-2015; Basso, Daniela/J-7855-2016; Campa, Daniele/K-1617-2016; Krogh, Vittorio/K-2628-2016; Abnet, Christian/C-4111-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Malats, Nuria/H-7041-2015; OI Piepoli, Ada/0000-0001-7487-8754; Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; scarpa, aldo/0000-0003-1678-739X; Duell, Eric J/0000-0001-5256-0163; Soucek, Pavel/0000-0002-4294-6799; Funel, Niccola/0000-0002-5028-2363; Porta, Miquel/0000-0003-1684-7428; Beane Freeman, Laura/0000-0003-1294-4124; Real Arribas, Francisco/0000-0001-9501-498X; Basso, Daniela/0000-0001-8745-6171; Campa, Daniele/0000-0003-3220-9944; Krogh, Vittorio/0000-0003-0122-8624; Abnet, Christian/0000-0002-3008-7843; Malats, Nuria/0000-0003-2538-3784; Giles, Graham/0000-0003-4946-9099; Landi, Stefano/0000-0001-8364-6357; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU National Cancer Institute (NCI), US National Institutes of Health (NIH) [HHSN261200800001E]; NIH/NCI [K07 CA140790]; American Society of Clinical Oncology Conquer Cancer Foundation; Howard Hughes Medical Institute; Lustgarten Foundation FX This project was funded in whole or in part with federal funds from the National Cancer Institute (NCI), US National Institutes of Health (NIH) under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, and mention of trade names, commercial products or organizations does not imply endorsement by the US government. Major support for PanScan III sample identification and processing was provided by the Lustgarten Foundation for Pancreatic Cancer Research. Additional support was received from NIH/NCI K07 CA140790, the American Society of Clinical Oncology Conquer Cancer Foundation, the Howard Hughes Medical Institute, the Lustgarten Foundation, the Robert T. and Judith B. Hale Fund for Pancreatic Cancer Research and Promises for Purple to B.M.W. A full list of acknowledgments for each participating study is provided in the Supplementary Note. NR 75 TC 52 Z9 54 U1 7 U2 35 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 SEP PY 2014 VL 46 IS 9 BP 994 EP + DI 10.1038/ng.3052 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AO8CE UT WOS:000341579400014 PM 25086665 ER PT J AU Wu, C Wang, ZM Song, X Feng, XS Abnet, CC He, J Hu, N Zuo, XB Tan, W Zhan, QM Hu, ZB He, ZH Jia, WH Zhou, YF Yu, K Shu, XO Yuan, JM Zheng, W Zhao, XK Gao, SG Yuan, ZQ Zhou, FY Fan, ZM Cui, JL Lin, HL Han, XN Li, B Chen, X Dawsey, SM Liao, LD Lee, MP Ding, T Qiao, YL Liu, ZH Liu, Y Yu, DK Chang, J Wei, LX Gao, YT Koh, WP Xiang, YB Tang, ZZ Fan, JH Han, JJ Zhou, SL Zhang, P Zhang, DY Yuan, Y Huang, Y Liu, CL Zhai, K Qiao, Y Jin, GF Guo, CH Fu, JH Miao, XP Lu, CD Yang, HJ Wang, CY Wheeler, WA Gail, M Yeager, M Yuenger, J Guo, ET Li, AL Zhang, W Li, XM Sun, LD Ma, BG Li, Y Tang, S Peng, XQ Liu, J Hutchinson, A Jacobs, K Giffen, C Burdette, L Fraumeni, JF Shen, HB Ke, Y Zeng, YX Wu, TC Kraft, P Chung, CC Tucker, MA Hou, ZC Liu, YL Hu, YL Liu, Y Wang, L Yuan, G Chen, LS Liu, X Ma, T Meng, H Sun, L Li, XM Li, XM Ku, JW Zhou, YF Yang, LQ Wang, Z Li, Y Qige, QRW Yang, WJ Lei, GY Chen, LQ Li, EM Yuan, L Yue, WB Wang, R Wang, LW Fan, XP Zhu, FH Zhao, WX Mao, YM Zhang, M Xing, GL Li, JL Han, M Ren, JL Liu, B Ren, SW Kong, QP Kong, QP Sheyhidin, I Wei, W Zhang, YR Feng, CW Wang, J Yang, YH Hao, HZ Bao, QD Liu, BC Wu, AQ Xie, D Yang, WC Wang, L Zhao, XH Chen, SQ Hong, JY Zhang, XJ Freedman, ND Goldstein, AM Lin, DX Taylor, PR Wang, LD Chanock, SJ AF Wu, Chen Wang, Zhaoming Song, Xin Feng, Xiao-Shan Abnet, Christian C. He, Jie Hu, Nan Zuo, Xian-Bo Tan, Wen Zhan, Qimin Hu, Zhibin He, Zhonghu Jia, Weihua Zhou, Yifeng Yu, Kai Shu, Xiao-Ou Yuan, Jian-Min Zheng, Wei Zhao, Xue-Ke Gao, She-Gan Yuan, Zhi-Qing Zhou, Fu-You Fan, Zong-Min Cui, Ji-Li Lin, Hong-Li Han, Xue-Na Li, Bei Chen, Xi Dawsey, Sanford M. Liao, Linda Lee, Maxwell P. Ding, Ti Qiao, You-Lin Liu, Zhihua Liu, Yu Yu, Dianke Chang, Jiang Wei, Lixuan Gao, Yu-Tang Koh, Woon-Puay Xiang, Yong-Bing Tang, Ze-Zhong Fan, Jin-Hu Han, Jing-Jing Zhou, Sheng-Li Zhang, Peng Zhang, Dong-Yun Yuan, Yuan Huang, Ying Liu, Chunling Zhai, Kan Qiao, Yan Jin, Guangfu Guo, Chuanhai Fu, Jianhua Miao, Xiaoping Lu, Changdong Yang, Haijun Wang, Chaoyu Wheeler, William A. Gail, Mitchell Yeager, Meredith Yuenger, Jeff Guo, Er-Tao Li, Ai-Li Zhang, Wei Li, Xue-Min Sun, Liang-Dan Ma, Bao-Gen Li, Yan Tang, Sa Peng, Xiu-Qing Liu, Jing Hutchinson, Amy Jacobs, Kevin Giffen, Carol Burdette, Laurie Fraumeni, Joseph F., Jr. Shen, Hongbing Ke, Yang Zeng, Yixin Wu, Tangchun Kraft, Peter Chung, Charles C. Tucker, Margaret A. Hou, Zhi-Chao Liu, Ya-Li Hu, Yan-Long Liu, Yu Wang, Li Yuan, Guo Chen, Li-Sha Liu, Xiao Ma, Teng Meng, Hui Sun, Li Li, Xin-Min Li, Xiu-Min Ku, Jian-Wei Zhou, Ying-Fa Yang, Liu-Qin Wang, Zhou Li, Yin Qige, Qirenwang Yang, Wen-Jun Lei, Guang-Yan Chen, Long-Qi Li, En-Min Yuan, Ling Yue, Wen-Bin Wang, Ran Wang, Lu-Wen Fan, Xue-Ping Zhu, Fang-Heng Zhao, Wei-Xing Mao, Yi-Min Zhang, Mei Xing, Guo-Lan Li, Ji-Lin Han, Min Ren, Jing-Li Liu, Bin Ren, Shu-Wei Kong, Qing-Peng Li, Feng Sheyhidin, Ilyar Wei, Wu Zhang, Yan-Rui Feng, Chang-Wei Wang, Jin Yang, Yu-Hua Hao, Hong-Zhang Bao, Qi-De Liu, Bao-Chi Wu, Ai-Qun Xie, Dong Yang, Wan-Cai Wang, Liang Zhao, Xiao-Hang Chen, Shu-Qing Hong, Jun-Yan Zhang, Xue-Jun Freedman, Neal D. Goldstein, Alisa M. Lin, Dongxin Taylor, Philip R. Wang, Li-Dong Chanock, Stephen J. TI Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations SO NATURE GENETICS LA English DT Article ID SUSCEPTIBILITY LOCI; RISK; VARIANTS; CANCER; NASOPHARYNGEAL; METAANALYSIS; LEUKEMIA; GLIOMA; COHORT; PLCE1 AB We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS)(1-3) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 x 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 x 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 x 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC. C1 [Wu, Chen; Tan, Wen; Zhan, Qimin; Liu, Zhihua; Liu, Yu; Yu, Dianke; Chang, Jiang; Wei, Lixuan; Huang, Ying; Liu, Chunling; Zhai, Kan; Qiao, Yan; Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing 100730, Peoples R China. [Wu, Chen; Tan, Wen; Zhan, Qimin; Liu, Zhihua; Liu, Yu; Yu, Dianke; Chang, Jiang; Wei, Lixuan; Huang, Ying; Liu, Chunling; Zhai, Kan; Qiao, Yan; Lin, Dongxin] Peking Union Med Coll, Beijing 100021, Peoples R China. [Wang, Zhaoming; Abnet, Christian C.; Hu, Nan; Dawsey, Sanford M.; Liao, Linda; Gail, Mitchell; Yeager, Meredith; Yuenger, Jeff; Hutchinson, Amy; Jacobs, Kevin; Burdette, Laurie; Fraumeni, Joseph F., Jr.; Chung, Charles C.; Tucker, Margaret A.; Freedman, Neal D.; Goldstein, Alisa M.; Taylor, Philip R.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Wang, Zhaoming; Yeager, Meredith; Yuenger, Jeff; Hutchinson, Amy; Jacobs, Kevin; Burdette, Laurie; Chung, Charles C.] SAIC Frederick Inc, NCI Frederick, Adv Technol Program, Div Canc Epidemiol & Genet,Canc Genome Res Lab, Frederick, MD USA. [Song, Xin; Yuan, Zhi-Qing; Cui, Ji-Li; Lin, Hong-Li; Liu, Ya-Li; Hu, Yan-Long; Wang, Li; Yuan, Guo; Chen, Li-Sha; Li, Xiu-Min; Zhao, Wei-Xing; Yang, Wan-Cai; Wang, Liang; Wang, Li-Dong] Xinxiang Med Univ, Basic Med Coll, Canc Res Ctr, Dept Pathol, Xinxiang, Peoples R China. [Song, Xin; Zhao, Xue-Ke; Fan, Zong-Min; Cui, Ji-Li; Lin, Hong-Li; Han, Xue-Na; Li, Bei; Chen, Xi; Han, Jing-Jing; Zhou, Sheng-Li; Zhang, Peng; Zhang, Dong-Yun; Yuan, Yuan; Guo, Er-Tao; Li, Ai-Li; Zhang, Wei; Li, Yan; Tang, Sa; Peng, Xiu-Qing; Liu, Jing; Hou, Zhi-Chao; Liu, Ya-Li; Hu, Yan-Long; Liu, Yu; Yuan, Guo; Chen, Li-Sha; Liu, Xiao; Ma, Teng; Meng, Hui; Sun, Li; Li, Xin-Min; Ku, Jian-Wei; Zhou, Ying-Fa; Yue, Wen-Bin; Wang, Ran; Wang, Lu-Wen; Fan, Xue-Ping; Zhang, Mei; Xing, Guo-Lan; Wang, Jin; Wang, Li-Dong] Zhengzhou Univ, Affiliated Hosp 1, Henan Key Lab Esophageal Canc Res, Zhengzhou, Peoples R China. [Feng, Xiao-Shan; Gao, She-Gan; Peng, Xiu-Qing; Mao, Yi-Min] Henan Univ Sci & Technol, Affiliated Hosp 1, Clin Lab & Resp Med, Dept Oncol, Luoyang, Peoples R China. [He, Jie] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Thorac Surg, Beijing 100730, Peoples R China. [He, Jie] Peking Union Med Coll, Beijing 100021, Peoples R China. 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[Han, Min] First Peoples Hosp Shangqiu, Dept Gastroenterol & Thorac Surg, Shangqiu, Peoples R China. [Liu, Bin] Capital Med Univ, Beijing Tongren Hosp, Dept Gastroenterol, Beijing, Peoples R China. [Ren, Shu-Wei] Xinyang Cent Hosp, Dept Oncol, Xinyang, Peoples R China. [Kong, Qing-Peng] Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resource & Evolut, Kunming, Peoples R China. [Li, Feng] Shihezi Univ, Sch Med, Dept Pathol, Shihezi, Peoples R China. [Sheyhidin, Ilyar] Xinjiang Med Univ, Affiliated Hosp 1, Dept Thorac Surg, Urumqi, Peoples R China. [Sheyhidin, Ilyar] Xinjiang Med Univ, Affiliated Hosp 1, Med Res Ctr, Urumqi, Peoples R China. [Wei, Wu] Changzhi Med Univ, Inst Hematol Dis, Changzhi, Peoples R China. [Wei, Wu] Changzhi Med Univ, Dept Pathol, Changzhi, Peoples R China. [Yang, Yu-Hua] Hebi Dahejian Hosp, Dept Surg, Hebi, Peoples R China. [Hao, Hong-Zhang; Bao, Qi-De] Anyang Dist Hosp, Anyang, Peoples R China. [Liu, Bao-Chi] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Surg Dept, Shanghai 200433, Peoples R China. [Wu, Ai-Qun] Second Mil Med Univ Chinese Peoples Liberat Army, Dept Anat, Shanghai, Peoples R China. [Xie, Dong] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai, Peoples R China. [Wang, Liang] Med Coll Wisconsin, Canc Res Ctr, Milwaukee, WI 53226 USA. [Zhao, Xiao-Hang] Chinese Acad Med Sci, Canc Inst & Hosp, Natl Lab Mol Oncol, Beijing 100730, Peoples R China. [Chen, Shu-Qing; Hong, Jun-Yan] Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310003, Zhejiang, Peoples R China. [Hong, Jun-Yan] Univ Med & Dent New Jersey, Dept Environm & Occupat Hlth, Newark, NJ 07103 USA. RP Taylor, PR (reprint author), NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov; lindx72@cicams.ac.cn RI miao, xiaoping/C-4336-2011; Tucker, Margaret/B-4297-2015; Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Qiao, You-Lin/B-4139-2012; OI Yuan, Jian-Min/0000-0002-4620-3108; miao, xiaoping/0000-0002-6818-9722; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Qiao, You-Lin/0000-0001-6380-0871; Chen, Shuqing/0000-0002-0792-3735; Liao, Linda/0000-0002-1923-5294 FU National High-Tech Research and Development Program of China [2009AA022706]; National Basic Research Program of China [2011CB504303]; National Natural Science Foundation of China [30721001, 81071783]; Invitation Team of the Ministry of Education [2008IRTSTHN010]; 863 High-Tech Key Projects [2012AA02A209, 2012AA02A503, 2012AA02A201]; Innovation Scientists and Technicians Troop Construction Projects of Henan Province [3047]; Key Disciplines Revitalization Plan of Zhengzhou University [20132016]; Collaborative Innovation Center for Esophageal Cancer Research of Henan Province [20132016]; NCI [R01 CA82729, R37 CA70837, NO2-CP-11010, NO2-SC-66211, NO1-SC-91030, HHSN261200477001C]; Vanderbilt University; Shanxi Cancer Hospital and Institute; Cancer Institute and Hospital of the Chinese Academy of Medical Sciences; intramural research program of the US NIH/NCI; Division of Cancer Epidemiology and Genetics; Center for Cancer Research; US NIH/NCI [HHSN261200800001E] FX This work was funded by the National High-Tech Research and Development Program of China (2009AA022706 to D.L.), the National Basic Research Program of China (2011CB504303 to D.L. and W.T.) and the National Natural Science Foundation of China (30721001 to D.L., Q.Z. and Z.L.).; This work was supported by the Invitation Team of the Ministry of Education (2008IRTSTHN010), the National Natural Science Foundation of China (81071783), 863 High-Tech Key Projects (2012AA02A209, 2012AA02A503 and 2012AA02A201), Innovation Scientists and Technicians Troop Construction Projects of Henan Province (3047), the Key Disciplines Revitalization Plan of Zhengzhou University (20132016) and the Collaborative Innovation Center for Esophageal Cancer Research of Henan Province (20132016).; The Shanghai Men's Health Study (SMHS) was supported by NCI extramural research grant R01 CA82729. The Shanghai Women's Health Study (SWHS) was supported by NCI extramural research grant R37 CA70837 and, in part, for biological sample collection, by NCI intramural research program contract NO2-CP-11010 with Vanderbilt University. The studies would not be possible without continuing support and devotion from the study participants and the staff of SMHS and SWHS.; The Shanxi Upper Gastrointestinal Cancer Genetics Project was supported by NCI intramural research program contract NO2-SC-66211 with the Shanxi Cancer Hospital and Institute.; The Nutrition Intervention Trials (NIT) was supported by NCI intramural research program contracts NO1-SC-91030 and HHSN261200477001C with the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences.; This research was supported in part by the intramural research program of the US NIH/NCI, the Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research.; This project was funded in part with federal funds from the US NIH/NCI under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. NR 32 TC 30 Z9 33 U1 17 U2 98 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 SEP PY 2014 VL 46 IS 9 BP 1001 EP + DI 10.1038/ng.3064 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AO8CE UT WOS:000341579400015 PM 25129146 ER PT J AU Boztug, K Jarvinen, PM Salzer, E Racek, T Monch, S Garncarz, W Gertz, EM Schaffer, AA Antonopoulos, A Haslam, SM Schieck, L Puchalka, J Diestelhorst, J Appaswamy, G Lescoeur, B Giambruno, R Bigenzahn, JW Elling, U Pfeifer, D Conde, CD Albert, MH Welte, K Brandes, G Sherkat, R ten Bosch, JV Rezaei, N Etzioni, A Bellanne-Chantelot, C Superti-Furga, G Penninger, JM Bennett, KL von Blume, J Dell, A Donadieu, J Klein, C AF Boztug, Kaan Jaervinen, Paeivi M. Salzer, Elisabeth Racek, Tomas Moench, Sebastian Garncarz, Wojciech Gertz, E. Michael Schaeffer, Alejandro A. Antonopoulos, Aristotelis Haslam, Stuart M. Schieck, Lena Puchalka, Jacek Diestelhorst, Jana Appaswamy, Giridharan Lescoeur, Brigitte Giambruno, Roberto Bigenzahn, Johannes W. Elling, Ulrich Pfeifer, Dietmar Conde, Cecilia Dominguez Albert, Michael H. Welte, Karl Brandes, Gudrun Sherkat, Roya ten Bosch, Jutte van der Werff Rezaei, Nima Etzioni, Amos Bellanne-Chantelot, Christine Superti-Furga, Giulio Penninger, Josef M. Bennett, Keiryn L. von Blume, Julia Dell, Anne Donadieu, Jean Klein, Christoph TI JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia SO NATURE GENETICS LA English DT Article ID STIMULATING FACTOR-RECEPTOR; UNFOLDED PROTEIN RESPONSE; HERMANSKY-PUDLAK-SYNDROME; ENDOPLASMIC-RETICULUM; MASS-SPECTROMETRY; ELANE MUTATIONS; SEQUENCING DATA; COHEN-SYNDROME; GENE; ELASTASE AB The analysis of individuals with severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling the differentiation, maintenance and decay of neutrophils. We identify 9 distinct homozygous mutations in the JAGN1 gene encoding Jagunal homolog 1 in 14 individuals with SCN. JAGN1-mutant granulocytes are characterized by ultrastructural defects, a paucity of granules, aberrant N-glycosylation of multiple proteins and increased incidence of apoptosis. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptor-mediated signaling. JAGN1 emerges as a factor that is necessary in the differentiation and survival of neutrophils. C1 [Boztug, Kaan; Salzer, Elisabeth; Garncarz, Wojciech; Giambruno, Roberto; Bigenzahn, Johannes W.; Conde, Cecilia Dominguez; Superti-Furga, Giulio; Bennett, Keiryn L.] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1010 Vienna, Austria. [Boztug, Kaan] Med Univ Vienna, Dept Pediat & Adolescent Med, Vienna, Austria. [Jaervinen, Paeivi M.; Racek, Tomas; Moench, Sebastian; Puchalka, Jacek; Diestelhorst, Jana; Albert, Michael H.; Klein, Christoph] Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat, Munich, Germany. [Gertz, E. Michael; Schaeffer, Alejandro A.] US Natl Inst Hlth, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD USA. [Antonopoulos, Aristotelis; Haslam, Stuart M.; Dell, Anne] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London, England. [Schieck, Lena; Diestelhorst, Jana; Appaswamy, Giridharan; Welte, Karl] Hannover Med Sch, Dept Pediat Hematol Oncol, Hannover, Germany. [Lescoeur, Brigitte] Hosp R Debre, Dept Hematol, Paris, France. [Elling, Ulrich] Austrian Acad Sci IMBA, Inst Mol Biotechnol, Vienna, Austria. [Pfeifer, Dietmar] Univ Med Ctr Freiburg, Dept Hematol Oncol & Stem Cell Transplantat, Freiburg, Germany. [Brandes, Gudrun] Hannover Med Sch, Dept Cell Biol, Hannover, Germany. [Sherkat, Roya] Isfahan Univ Med Sci, Acquired Immunodeficiency Res Ctr, Esfahan, Iran. [Conde, Cecilia Dominguez] Hosp Free Univ Brussels, Dept Pediat, Brussels, Belgium. [Rezaei, Nima] Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Res Ctr Immunodeficiencies, Tehran, Iran. [Etzioni, Amos] Technion Israel Inst Technol, Rappaport Sch Med, Div Pediat & Immunol, Haifa, Israel. [Bellanne-Chantelot, Christine] Univ Paris 06, Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France. [von Blume, Julia] Max Planck Inst Biochem, D-82152 Martinsried, Germany. [Donadieu, Jean] Armand Trousseau Childrens Hosp, AP HP, Reference Ctr Hereditary Immunodeficiencies, Neutropenia Registry, Paris, France. RP Klein, C (reprint author), Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat, Munich, Germany. EM christoph.klein@med.uni-muenchen.de RI Superti-Furga, Giulio/F-4755-2015; Penninger, Josef/I-6860-2013; Rezaei, Nima/B-4245-2008 OI Superti-Furga, Giulio/0000-0002-0570-1768; Penninger, Josef/0000-0002-8194-3777; Rezaei, Nima/0000-0002-3836-1827 FU CeMM; FWF (Austrian Science Fund) START Programme; European Research Council; European Program on Rare Diseases (E-RARE Neutro-Net); German Research Foundation (Gottfried-Wilhelm-Leibniz Program) [SFB914]; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F0083091, BB/K016164/1]; Amgen; Chugai; Fondation Maladies Rares; Institut de Veille Sanitaire; INSERM; Association Sportive de Saint Quentin Fallavier; CEREDIH (Reference Center for Hereditary Immunodeficiencies); Societe d'Hemato-Immunologie Pediatrique; US National Institutes of Health; National Library of Medicine; DZIF (German Center for Infection Research); Care-for-Rare Foundation FX The authors thank the patients and their families for their participation in this study. The help of all contributing medical, technical and administrative staff is greatly appreciated. The authors thank J. Colinge for bioinformatics analysis of the mass spectrometry data. The authors thank G. Leverger, H. Ducou Lepointe, J. Levin, the association IRIS (Immunodeficience Primitive, Recherche, Information, Soutien) and V. Grosjean for their support. This study was supported by CeMM intramural funds and the FWF (Austrian Science Fund) START Programme (to K.B.) and by grants from the European Research Council (Advanced Grants to C.K. and J.P.; Starting Grant to K.B.), the European Program on Rare Diseases (E-RARE Neutro-Net) and the German Research Foundation (SFB914 and Gottfried-Wilhelm-Leibniz Program). The work at Imperial College was supported by the Biotechnology and Biological Sciences Research Council (BBSRC; grants BB/F0083091 and BB/K016164/1). The French SCN registry is supported by grants from Amgen, Chugai, Fondation Maladies Rares, the Institut de Veille Sanitaire, INSERM, the Association Sportive de Saint Quentin Fallavier, CEREDIH (Reference Center for Hereditary Immunodeficiencies) and the Societe d'Hemato-Immunologie Pediatrique. This research is supported in part by the Intramural Research Program of the US National Institutes of Health, the National Library of Medicine, the DZIF (German Center for Infection Research) and the Care-for-Rare Foundation. NR 51 TC 20 Z9 22 U1 3 U2 11 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 SEP PY 2014 VL 46 IS 9 BP 1021 EP + DI 10.1038/ng.3069 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AO8CE UT WOS:000341579400019 PM 25129144 ER PT J AU Bernard, CE Gibbons, SJ Mann, IS Froschauer, L Parkman, HP Harbison, S Abell, TL Snape, WJ Hasler, WL McCallum, RW Sarosiek, I Nguyen, LAB Koch, KL Tonascia, J Hamilton, FA Kendrick, ML Shen, KR Pasricha, PJ Farrugia, G AF Bernard, C. E. Gibbons, S. J. Mann, I. S. Froschauer, L. Parkman, H. P. Harbison, S. Abell, T. L. Snape, W. J. Hasler, W. L. McCallum, R. W. Sarosiek, I. Nguyen, L. A. B. Koch, K. L. Tonascia, J. Hamilton, F. A. Kendrick, M. L. Shen, K. R. Pasricha, P. J. Farrugia, G. CA NIDDK Gastroparesis Clin Res TI Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE gastroparesis; interstitial cells of Cajal; macrophages ID SEVERE IDIOPATHIC GASTROPARESIS; NITRIC-OXIDE SYNTHASE; INTERSTITIAL-CELLS; MONOCLONAL-ANTIBODIES; OXIDATIVE STRESS; MACROPHAGE; CAJAL; EXPRESSION; ACTIVATION; RECEPTOR AB Background There is increasing evidence for specific cellular changes in the stomach of patients with diabetic (DG) and idiopathic (IG) gastroparesis. The most significant findings are loss of interstitial cells of Cajal (ICC), neuronal abnormalities, and an immune cellular infiltrate. Studies done in diabetic mice have shown a cytoprotective effect of CD206+ M2 macrophages. To quantify overall immune cellular infiltrate, identify macrophage populations, and quantify CD206+ and iNOS+ cells. To investigate associations between cellular phenotypes and ICC. Methods Full thickness gastric body biopsies were obtained from non-diabetic controls (C), diabetic controls (DC), DG, and IG patients. Sections were labeled for CD45, CD206, Kit, iNOS, and putative human macrophage markers (HAM56, CD68, and EMR1). Immunoreactive cells were quantified from the circular muscle layer. Key Results Significantly fewer ICC were detected in DG and IG tissues, but there were no differences in the numbers of cells immunoreactive for other markers between patient groups. There was a significant correlation between the number of CD206+ cells and ICC in DG and DC patients, but not in C and IG and a significant correlation between iNOS+ cells and ICC in the DC group, but not the other groups. CD68 and HAM56 reliably labeled the same cell populations, but EMR1 labeled other cell types. Conclusions & Inferences Depletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes. These findings may lead to novel therapeutic options, targeting alternatively activated macrophages. C1 [Bernard, C. E.; Gibbons, S. J.; Mann, I. S.; Froschauer, L.; Hasler, W. L.; Kendrick, M. L.; Shen, K. R.; Farrugia, G.] Mayo Clin, Enter NeuroSci Program, Rochester, MN 55905 USA. [Parkman, H. P.] Temple Univ Hosp & Med Sch, Dept Med, Div Gastroenterol, Philadelphia, PA 19140 USA. [Harbison, S.] Temple Univ Hosp & Med Sch, Dept Surg, Philadelphia, PA 19140 USA. [Abell, T. L.] Univ Louisville, Div Gastroenterol, Louisville, KY 40292 USA. [Snape, W. J.] Calif Pacific Med Ctr, Div Gastroenterol, San Francisco, CA USA. [Hasler, W. L.] Univ Michigan Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [McCallum, R. W.; Sarosiek, I.] Texas Tech Univ Hlth Sci Ctr, Div Gastroenterol, El Paso, TX USA. [Nguyen, L. A. B.] Stanford Univ, Div Gastroenterol, Stanford, CA 94305 USA. [Koch, K. L.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Tonascia, J.] Johns Hopkins Univ, Baltimore, MD USA. [Hamilton, F. A.] NIDDK, Bethesda, MD USA. [Kendrick, M. L.; Shen, K. R.] Mayo Clin, Dept Surg, Rochester, MN USA. [Pasricha, P. J.] Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. [Farrugia, G.] Mayo Clin, Div Gastroenterol, Rochester, MN USA. RP Farrugia, G (reprint author), Mayo Clin, Enter NeuroSci Program, 200 First St SW, Rochester, MN 55905 USA. EM Farrugia.gianrico@mayo.edu OI Gibbons, Simon/0000-0001-5311-5993 FU NIH [DK68055, DK57061]; Gastroparesis Consortium (GpCRC); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK074035, U01DK074007, U01DK073985, U01DK073974, U01DK074008]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000424, UL1TR000093, UL1TR000433, UL1TR000135] FX This work was supported by NIH DK68055, DK57061 and the Gastroparesis Consortium (GpCRC) supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073983, U01DK073975, U01DK074035, U01DK074007, U01DK073985, U01DK073974, U01DK074008) and the National Center for Advancing Translational Sciences (NCATS) (grants UL1TR000424, UL1TR000093, UL1TR000433, UL1TR000135). NR 48 TC 5 Z9 7 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2014 VL 26 IS 9 BP 1275 EP 1284 DI 10.1111/nmo.12389 PG 10 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA AO8SQ UT WOS:000341625000007 PM 25041465 ER PT J AU Leung, CT Li, A Banerjee, J Gao, ZG Kambayashi, T Jacobson, KA Civan, MM AF Leung, Chi Ting Li, Ang Banerjee, Juni Gao, Zhan-Guo Kambayashi, Taku Jacobson, Kenneth A. Civan, Mortimer M. TI The role of activated adenosine receptors in degranulation of human LAD2 mast cells SO PURINERGIC SIGNALLING LA English DT Article DE Fc epsilon RI; C3a; A(2A); A(2B); A(3); ATP release ID FC-EPSILON-RI; TRABECULAR MESHWORK CELLS; HISTAMINE-RELEASE; INTERNATIONAL UNION; SIGNALING PATHWAYS; A(3) RECEPTORS; HIGH-AFFINITY; ASTHMA; IGE; CLASSIFICATION AB Mast cell degranulation triggers hypersensitivity reactions at the body-environment interface. Adenosine modulates degranulation, but enhancement and inhibition have both been reported. Which of four adenosine receptors (ARs) mediate modulation, and how, remains uncertain. Also uncertain is whether adenosine reaches mast cell ARs by autocrine ATP release and ecto-enzymatic conversion. Uncertainties partly reflect species and cell heterogeneity, circumvented here by focusing on homogeneous human LAD2 cells. Quantitative PCR detected expression of A(2A), A(2B), and A(3), but not A(1), ARs. Nonselective activation of ARs with increasing NECA monotonically enhanced immunologically or C3a-stimulated degranulation. NECA alone stimulated degranulation slightly. Selective AR antagonists did not affect C3a-stimulated degranulation. NECA's enhancement of C3a-triggered degranulation was partially inhibited by separate application of each selective antagonist, and abolished by simultaneous addition of antagonists to the three ARs. Only the A(2A) antagonist separately inhibited NECA's enhancement of immunologically stimulated degranulation, which was abolished by simultaneous addition of the three selective antagonists. Immunological or C3a activation did not stimulate ATP release. NECA also enhanced immunologically triggered degranulation of mouse bone marrow derived mast cells (BMMCs), which was partially reduced only by simultaneous addition of the three antagonists or by the nonselective antagonist CGS15943. BMMCs also expressed A(2A), A(2B), and A(3) ARs. but not A(1)AR detectably. We conclude that (a) A(1)AR is unnecessary for LAD2 degranulation or AR enhancement; (b) A(2A), A(2B), and A(3) ARs all contribute to pharmacologic AR enhancement of LAD2 and BMMC degranulation; and (c) LAD2 cells depend on microenvironmental adenosine to trigger AR modulation. C1 [Leung, Chi Ting; Li, Ang; Banerjee, Juni; Civan, Mortimer M.] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Li, Ang] Univ Hong Kong, Li Ka Shing Fac Med, Dept Anat, Hong Kong, Hong Kong, Peoples R China. [Li, Ang] Univ Hong Kong, Li Ka Shing Fac Med, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Kambayashi, Taku] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Civan, Mortimer M.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. RP Civan, MM (reprint author), Univ Penn, Sch Med, Dept Physiol, A303 Richards Bldg, Philadelphia, PA 19104 USA. EM civan@mail.med.upenn.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH [EY13624, EY01583]; University of Pennsylvania Research Foundation; NIDDK Intramural Research Program, National Institutes of Health FX Supported by NIH Research Grant EY13624 and Core Grant EY01583 (M. M. C.); University of Pennsylvania Research Foundation and NIDDK Intramural Research Program, National Institutes of Health. We thank Drs. Arnold Kirshenbaum and Dean Metcalfe (NIAID, NIH, Bethesda, MD, USA) for providing LAD2 cells, and Dr. Hydar Ali (University of Pennsylvania) for helpful discussions. NR 48 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 EI 1573-9546 J9 PURINERG SIGNAL JI Purinergic Signal. PD SEP PY 2014 VL 10 IS 3 BP 465 EP 475 DI 10.1007/s11302-014-9409-4 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AP0RZ UT WOS:000341772500006 PM 24595664 ER PT J AU Teyhen, DS Aldag, M Edinborough, E Ghannadian, JD Haught, A Kinn, J Kunkler, KJ Levine, B McClain, J Neal, D Stewart, T Thorndike, FP Trabosh, V Wesensten, N Parramore, DJ AF Teyhen, Deydre S. Aldag, Matt Edinborough, Elton Ghannadian, Jason D. Haught, Andrea Kinn, Julie Kunkler, Kevin J. Levine, Betty McClain, James Neal, David Stewart, Tiffany Thorndike, Frances P. Trabosh, Valerie Wesensten, Nancy Parramore, David J. TI Leveraging Technology: Creating and Sustaining Changes for Health SO TELEMEDICINE AND E-HEALTH LA English DT Article DE activity; nutrition; sleep ID WEIGHT-LOSS; PHYSICAL-ACTIVITY; BEHAVIOR-CHANGE; SMOKING CESSATION; EXTRINSIC REWARDS; STEPPED CARE; INTERVENTIONS; SLEEP; HABITS; ACTIGRAPHY AB Objective:The rapid growth and evolution of health-related technology capabilities are driving an established presence in the marketplace and are opening up tremendous potential to minimize and/or mitigate barriers associated with achieving optimal health, performance, and readiness. This article summarizes technology-based strategies that promote healthy habits related to physical activity, nutrition, and sleep.Materials and Methods:The Telemedicine and Advanced Technology Research Center convened a workshop titled Leveraging Technology: Creating & Sustaining Changes for Health (May 29-30, 2013, Fort Detrick, MD). Participants included experts from academia (n=3), government (n=33), and industry (n=16). A modified Delphi method was used to establish expert consensus in six topic areas: (1) physical activity, (2) nutrition, (3) sleep, (4) incentives for behavior change, (5) usability/interoperability, and (6) mobile health/open platform.Results:Overall, 162 technology features, constructs, and best practices were reviewed and prioritized for physical activity monitors (n=29), nutrition monitors (n=35), sleep monitors (n=24), incentives for change (n=36), usability and interoperability (n=25), and open data (n=13).Conclusions:Leading practices, gaps, and research needs for technology-based strategies were identified and prioritized. This information can be used to provide a research and development road map for (1) leveraging technology to minimize barriers to enhancing health and (2) facilitating evidence-based techniques to create and sustain healthy behaviors. C1 [Teyhen, Deydre S.; Edinborough, Elton; Ghannadian, Jason D.; Haught, Andrea; Levine, Betty] US Army Med Res & Mat Command, Telemed & Adv Technol Res Ctr, Ft Detrick, MD 21774 USA. [Aldag, Matt] Booz Allen Hamilton, Rockville, MD USA. [Kinn, Julie] Natl Ctr Telehlth & Technol, Joint Base Lewis McChord, Tacoma, WA USA. [Kunkler, Kevin J.] US Army Med Res & Mat Command, Joint Program Comm, Ft Detrick, MD 21774 USA. [McClain, James] NCI, Bethesda, MD 20892 USA. [Neal, David] Empirica Res, Miami, FL USA. [Stewart, Tiffany] Pennington Biomed Res Ctr, Behav Technol Lab, Baton Rouge, LA 70808 USA. [Thorndike, Frances P.] Univ Virginia Hlth Syst, Dept Psychiat & Neurobehav Sci, Charlottesville, VA USA. [Trabosh, Valerie] US Army Med Res & Mat Command, Mil Operat Med Res Program, Ft Detrick, MD 21774 USA. [Wesensten, Nancy] Walter Reed Army Inst Res, Silver Spring, MD USA. [Parramore, David J.] Army Med, Off Surgeon Gen, Falls Church, VA USA. RP Teyhen, DS (reprint author), US Army Med Res & Mat Command, Telemed & Adv Technol Res Ctr, Ft Detrick, MD 21774 USA. EM deydre.s.teyhen.mil@mail.mil RI Trivedi, Kruti/E-7558-2015 NR 62 TC 0 Z9 0 U1 2 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD SEP PY 2014 VL 20 IS 9 BP 835 EP 849 DI 10.1089/tmj.2013.0328 PG 15 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AP0OU UT WOS:000341762300009 PM 24978152 ER PT J AU Krauzlis, RJ Bollimunta, A Arcizet, F Wang, LP AF Krauzlis, Richard J. Bollimunta, Anil Arcizet, Fabrice Wang, Lupeng TI Attention as an effect not a cause SO TRENDS IN COGNITIVE SCIENCES LA English DT Review DE attention; basal ganglia; decision making; learning; perception; superior colliculus ID VISUAL SELECTIVE ATTENTION; BASAL GANGLIA CIRCUIT; CM-PF COMPLEX; SUPERIOR COLLICULUS; PARKINSONS-DISEASE; SPATIAL ATTENTION; DECISION-MAKING; CORTICOSTRIATAL PROJECTIONS; MULTIPLE REPRESENTATIONS; DOPAMINERGIC-NEURONS AB Attention is commonly thought to be important for managing the limited resources available in sensory areas of the neocortex. Here we present an alternative view that attention arises as a byproduct of circuits centered on the basal ganglia involved in value-based decision making. The central idea is that decision making depends on properly estimating the current state of the animal and its environment and that the weighted inputs to the currently prevailing estimate give rise to the filter-like properties of attention. After outlining this new framework, we describe findings from physiological, anatomical, computational, and clinical work that support this point of view. We conclude that the brain mechanisms responsible for attention employ a conserved circuit motif that predates the emergence of the neocortex. C1 [Krauzlis, Richard J.; Bollimunta, Anil; Arcizet, Fabrice; Wang, Lupeng] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Krauzlis, RJ (reprint author), NEI, Sensorimotor Res Lab, Bldg 10, Bethesda, MD 20892 USA. EM richard.krauzlis@nih.gov FU National Eye Institute Intramural Research Program at the National Institutes of Health FX The authors thank Drs A. Bogadhi, P. Cavanagh, J. Herman, O. Hikosaka and his laboratory, and R. Wurtz for many helpful discussions. This work was supported by the National Eye Institute Intramural Research Program at the National Institutes of Health. NR 102 TC 27 Z9 27 U1 3 U2 50 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD SEP PY 2014 VL 18 IS 9 BP 457 EP 464 DI 10.1016/j.tics.2014.05.008 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AO8OE UT WOS:000341613000007 PM 24953964 ER PT J AU He, BYJ AF He, Biyu J. TI Scale-free brain activity: past, present, and future SO TRENDS IN COGNITIVE SCIENCES LA English DT Review DE scale-free brain activity; power-law distribution; arrhythmic; scale invariance; neural field potentials; brain dynamics; brain oscillations ID RANGE TEMPORAL CORRELATIONS; BALANCED CORTICAL NETWORKS; RESTING-STATE; NEURONAL AVALANCHES; POWER SPECTRUM; THETA-OSCILLATIONS; PERSISTENT ACTIVITY; FIELD POTENTIALS; AUDITORY-CORTEX; DEFAULT-MODE AB Brain activity observed at many spatiotemporal scales exhibits a 1 /f-like power spectrum, including neuronal membrane potentials, neural field potentials, noninvasive electroencephalography (EEG), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) signals. A 1 /f-like power spectrum is indicative of arrhythmic brain activity that does not contain a predominant temporal scale (hence, 'scale-free'). This characteristic of scale-free brain activity distinguishes it from brain oscillations. Although scale-free brain activity and brain oscillations coexist, our understanding of the former remains limited. Recent research has shed light on the spatiotemporal organization, functional significance, and potential generative mechanisms of scale-free brain activity, as well as its developmental and clinical relevance. A deeper understanding of this prevalent brain signal should provide new insights into, and analytical tools for, cognitive neuroscience. C1 NINDS, NIH, Bethesda, MD 20892 USA. RP He, BYJ (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM biyu.he@nih.gov OI He, Biyu/0000-0003-1549-1351 FU NIH/NINDS FX This work was supported by the Intramural Research program of the NIH/NINDS. I thank Xiao-Jing Wang and Rishidev Chaudhuri for discussions; Qi Li and Zachary Hill for collecting resting-state MEG and EEG data for estimating the power-law exponent; and Brian Maniscalco and three anonymous reviewers for helpful feedback on previous drafts. NR 87 TC 44 Z9 45 U1 7 U2 39 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD SEP PY 2014 VL 18 IS 9 BP 480 EP 487 DI 10.1016/j.tics.2014.04.003 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AO8OE UT WOS:000341613000010 PM 24788139 ER PT J AU Mandrup, S MacDougald, OA Moss, J Ntambi, J Pekala, P Tang, QQ Wolfgang, M Bernlohr, DA AF Mandrup, Susanne MacDougald, Ormond A. Moss, Joel Ntambi, James Pekala, Phillip Tang, Qi-Qun Wolfgang, Michael Bernlohr, David A. TI In memoriam: M. Daniel Lane, 1930-2014 SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Biographical-Item C1 [Mandrup, Susanne] Univ Southern Denmark, Dept Biochem & Mol Biol, Odense, Denmark. [MacDougald, Ormond A.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Ntambi, James] Univ Wisconsin Madison, Dept Biochem, Ann Arbor, MI USA. [Ntambi, James] Univ Wisconsin Madison, Dept Nutr Sci, Ann Arbor, MI USA. [Pekala, Phillip] E Carolina Univ, Brody Sch Med, Dept Biochem & Mol Biol, Greenville, NC USA. [Tang, Qi-Qun] Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai 200433, Peoples R China. [Wolfgang, Michael] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Bernlohr, David A.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. RP Bernlohr, DA (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. EM bernl001@umn.edu OI MacDougald, Ormond/0000-0001-6907-7960; Mandrup, Susanne/0000-0002-0961-5787 FU NIDDK NIH HHS [R01 DK053189] NR 1 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD SEP PY 2014 VL 25 IS 9 BP 437 EP 439 DI 10.1016/j.tem.2014.06.013 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AO8OD UT WOS:000341612900001 PM 25084731 ER PT J AU Limou, S Nelson, GW Kopp, JB Winkler, CA AF Limou, Sophie Nelson, George W. Kopp, Jeffrey B. Winkler, Cheryl A. TI APOL1 Kidney Risk Alleles: Population Genetics and Disease Associations SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Glomerular disease; Apolipoprotein L1; African admixture; APOL1 demographics; Chronic kidney disease ID HIV-ASSOCIATED NEPHROPATHY; STAGE RENAL-DISEASE; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; HUMAN AFRICAN TRYPANOSOMIASIS; VARIANTS ASSOCIATE; NONDIABETIC NEPHROPATHY; HUMAN SERUM; AMERICANS; MYH9; PROGRESSION AB APOL1 kidney disease is a unique case in the field of the genetics of common disease: 2 variants (termed G1 and G2) with high population frequency have been repeatedly associated with nondiabetic CKDs, with very strong effect size (odds ratios 3-29) in populations of sub-Saharan African descent. This review provides an update on the spectrum of APOL1 kidney disease and on the worldwide distribution of these kidney risk variants. We also summarize the proper way to run a recessive analysis on joint and independent effects of APOL1 G1 and G2 kidney risk variants. (C) 2014 by the National Kidney Foundation, Inc. All rights reserved. C1 NCI, Basic Sci Program, Ctr Canc Res, NIH,Leidos Biomed Res Inc,Frederick Natl Lab, Ft Detrick, MD 21702 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Winkler, CA (reprint author), NCI, Ctr Cancer Res, NIH, Leidos Biomed Res Inc,Frederick Natl Lab, Bldg 560,Room 21-104,Box B, Ft Detrick, MD 21702 USA. EM winklerc@mail.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU National Cancer Institute, National Institutes of Health [HHSN26120080001 E]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institute of Diabetes and Digestive and Kidney Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN26120080001 E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This Research was supported [in part] by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and National Institute of Diabetes and Digestive and Kidney Diseases. We thank Dr R. Bhimma (University of KwaZulu Natal) and Drs C. W. Wester (Vanderbilt University) and M. Essex (Harvard University) for providing DNA samples from South Africa and Botswana, respectively. We dedicate this article to the late Dr Howard Cann (Foundation Jean Dausset-CEPH) in recognition of his significant contributions to the field of human population genetics and for his leadership of the Human Genome Diversity Project. NR 45 TC 21 Z9 21 U1 2 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 1548-5595 EI 1548-5609 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD SEP PY 2014 VL 21 IS 5 BP 426 EP 433 DI 10.1053/j.ackd.2014.06.005 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AO5RV UT WOS:000341403900007 PM 25168832 ER PT J AU Liu, CY Bluemke, DA Gerstenblith, G Zimmerman, SL Li, J Zhu, H Lai, SH Lai, H AF Liu, Chia-Ying Bluemke, David A. Gerstenblith, Gary Zimmerman, Stefan L. Li, Ji Zhu, Hong Lai, Shenghan Lai, Hong TI Reference Values of Myocardial Structure, Function, and Tissue Composition by Cardiac Magnetic Resonance in Healthy African-Americans at 3T and Their Relations to Serologic and Cardiovascular Risk Factors SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HEART-DISEASE; DILATED CARDIOMYOPATHY; DIFFUSE FIBROSIS; HARP MRI; INFARCTION; QUANTIFICATION; AMYLOIDOSIS AB Cardiac magnetic resonance (CMR) is a standard of reference for cardiac structure and function. Recent advances in T1 mapping and spectroscopy also provide assessment of myocardial tissue composition. However, the reference ranges of left ventricular parameters have rarely been assessed in an African-American (AA) population without known cardiac disease. To estimate the reference values of myocardial structure, function, and tissue composition by CMR and to explore their relationships to serologic factors and cardiovascular risk factors in asymptomatic AAs with low Framingham risk, between November 2010 and June 2012, 92 healthy AAs aged >= 21 years, from Baltimore, MD, were enrolled in an observational study. CMR examination was performed on a 3T scanner. Proton magnetic resonance spectroscopy was performed to noninvasively quantify myocardial triglyceride content. Native T1 values were obtained from modified Look-Locker inversion recovery sequence. The median age was 37 (interquartile range IQR 27 to 44) years (41% men). The median native T1 time of the myocardium was 1,228 ms (IQR 1,200 to 1,263) with no gender difference. The median myocardial fat content was 0.6% (IQR 0.7% to 4.6%). Native T1 time was not influenced by age, sex, and body mass index. Among the factors investigated, myocardial fat and elevated C-reactive protein (>2.0 mg/dL) were independently associated with T1 relaxation time. Native T1 time was also independently associated with left ventricular end-diastolic volume indexed to body surface area. In conclusion, this study of asymptomatic AAs provides reference ranges for cardiovascular structure, function, and tissue composition. Alterations in myocardial fat are associated with native T1 time, a CMR measure of interstitial fibrosis. (C) 2014 Elsevier Inc. All rights reserved. C1 [Liu, Chia-Ying; Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gerstenblith, Gary; Lai, Shenghan] Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA. [Zimmerman, Stefan L.; Lai, Shenghan; Lai, Hong] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD USA. [Li, Ji; Zhu, Hong; Lai, Shenghan] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Zhu, Hong] Tianjin Med Univ, Dept Epidemiol & Biostat, Tianjin, Peoples R China. RP Lai, SH (reprint author), Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA. EM slai@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institute on Drug Abuse, National Institutes of Health [NIH R01-DA 12777, DA25524, DA15020] FX The study was supported by grants from the National Institute on Drug Abuse, National Institutes of Health (NIH R01-DA 12777, DA25524 and DA15020). The authors have no conflicts of interest to disclose. NR 28 TC 4 Z9 4 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 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 1 PY 2014 VL 114 IS 5 BP 789 EP 795 DI 10.1016/j.amjcard.2014.06.007 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4TF UT WOS:000341333600021 PM 25037675 ER PT J AU Canepa, M Malti, O David, M AlGhatrif, M Strait, JB Ameri, P Brunelli, C Lakatta, EG Ferrucci, L Abraham, TP AF Canepa, Marco Malti, Omar David, Melissa AlGhatrif, Majd Strait, James B. Ameri, Pietro Brunelli, Claudio Lakatta, Edward G. Ferrucci, Luigi Abraham, Theodore P. TI Prevalence, Clinical Correlates, and Functional Impact of Subaortic Ventricular Septal Bulge (from the Baltimore Longitudinal Study of Aging) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HYPERTROPHIC CARDIOMYOPATHY; DIASTOLIC FUNCTION; OUTFLOW TRACT; ECHOCARDIOGRAPHY; AGE; RECOMMENDATIONS; HYPERTENSION; OBSTRUCTION; ADIPOSITY; TOLERANCE AB A localized hypertrophy of the subaortic segment of the ventricular septum-ventricular septal bulge (VSB)-has been frequently described in series of elderly population, but its prevalence with age, clinical correlates, and impact on cardiac function and exercise capacity remain uncertain. We explored these associations in a cross-sectional sample without known cardiac disease from the Baltimore Longitudinal Study of Aging. We randomly selected 700 participants (50% men, mean age 64 +/- 15, range 26 to 95 years) and reviewed their echocardiograms. We identified 28 men and 21 women with VSB (7% overall prevalence). The prevalence of VSB significantly increased with age in both genders (p < 0.0001). In multivariate logistic regression including hypertension and other cardiovascular risk factors, only age displayed a significant independent association with VSB (OR 1.06 per year, 95% confidence interval 1.03 to 1.10, p = 0.0001). After multiple adjustments, participants with VSB compared with those without had enhanced global left ventricular contractility (fractional shortening 41 +/- 1.3 vs 38 +/- 0.3%, p = 0.04; ejection fraction 71 +/- 1.6 vs 67 +/- 0.4%, p = 0.06; systolic velocity of the mitral annulus 8.4 +/- 0.1 vs 8.9 +/- 0.3, p = 0.06), and larger aortic root diameters (3.3 +/- 0.06 vs 3.1 +/- 0.02 cm, p = 0.02). In subgroup of participants who completed a maximal treadmill test (177 women and 196 men), those with VSB (19, 5.1%) had significantly lower peak oxygen consumption than their counterparts (19.6 +/- 3.8 vs 22.9 +/- 6.6 ml/kg/min, p = 0.03). However, this association was no longer significant after multiple adjustments. In conclusion, the presence of VSB is independently associated with older age and determines enhanced left ventricular contractility, without any evident impact on exercise capacity. (C) 2014 Elsevier Inc. All rights reserved. C1 [Canepa, Marco; Malti, Omar; David, Melissa; AlGhatrif, Majd; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Canepa, Marco; Malti, Omar; David, Melissa; AlGhatrif, Majd; Strait, James B.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Human Cardiovasc Studies Unit, NIH, Baltimore, MD 21224 USA. [Canepa, Marco; AlGhatrif, Majd; Abraham, Theodore P.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21205 USA. [Canepa, Marco; Ameri, Pietro; Brunelli, Claudio] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [David, Melissa] MedStar Hlth Res Inst, Washington, DC USA. RP Abraham, TP (reprint author), Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21205 USA. EM tabraha3@jhmi.edu FU Intramural Research Program of the NIH, National Institute on Aging; MedStar Health Research Institute FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, and the MedStar Health Research Institute. NR 28 TC 1 Z9 2 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 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 1 PY 2014 VL 114 IS 5 BP 796 EP 802 DI 10.1016/j.amjcard.2014.05.068 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4TF UT WOS:000341333600022 PM 25129067 ER PT J AU Gracia, JN Ruffin, J AF Gracia, J. Nadine Ruffin, John TI Partnership, Research, and Leadership to Advance Health Equity and Eliminate Health Disparities SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Gracia, J. Nadine] US Dept HHS, Off Minor Hlth, Rockville, MD USA. [Ruffin, John] Natl Inst Minor Hlth & Hlth Dispar, NIH, US Dept HHS, Rockville, MD USA. RP Gracia, JN (reprint author), 1101 Wootton Pkwy,Suite 600, Rockville, MD 20852 USA. EM Nadine.Gracia@hhs.gov NR 5 TC 1 Z9 1 U1 0 U2 3 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2014 VL 104 SU 4 BP S520 EP S521 DI 10.2105/AJPH.2014.302201 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AO5DR UT WOS:000341363000005 PM 25100412 ER PT J AU Denholm, R Schuz, J Straif, K Stucker, I JockeI, KH Brenner, DR De Matteis, S Boffetta, P Guida, F Bruske, I Wichmann, HE Landi, MT Caporaso, N Siemiatycki, J Ahrens, W Pohlabeln, H Zaridze, D Field, JK McLaughlin, J Demers, P Szeszenia-Dabrowska, N Lissowska, J Rudnai, P Fabianova, E Dumitru, RS Bencko, V Foretova, L Janout, V Kendzia, B Peters, S Behrens, T Vermeulen, R Bruning, T Kromhout, H Olsson, AC AF Denholm, Rachel Schuez, Joachim Straif, Kurt Stuecker, Isabelle Joecke, Karl-Heinz, I Brenner, Darren R. De Matteis, Sara Boffetta, Paolo Guida, Florence Brueske, Irene Wichmann, Heinz-Erich Landi, Maria Teresa Caporaso, Neil Siemiatycki, Jack Ahrens, Wolfgang Pohlabeln, Hermann Zaridze, David Field, John K. McLaughlin, John Demers, Paul Szeszenia-Dabrowska, Neonila Lissowska, Jolanta Rudnai, Peter Fabianova, Eleonora Dumitru, Rodica Stanescu Bencko, Vladimir Foretova, Lenka Janout, Vladimir Kendzia, Benjamin Peters, Susan Behrens, Thomas Vermeulen, Roel Bruening, Thomas Kromhout, Hans Olsson, Ann C. TI Is Previous Respiratory Disease a Risk Factor for Lung Cancer? SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE epidemiologic study; lung neoplasm; pulmonary disease; data pooling; case-control study ID OBSTRUCTIVE PULMONARY-DISEASE; POOLED ANALYSIS; NEVER-SMOKERS; UNITED-STATES; SELF-REPORT; COPD; MORTALITY; HISTORY; ASTHMA; INFLAMMATION AB Rationale: Previous respiratory diseases have been associated with increased risk of lung cancer. Respiratory conditions often co-occur and few studies have investigated multiple conditions simultaneously. Objectives: Investigate lung cancer risk associated with chronic bronchitis, emphysema, tuberculosis, pneumonia, and asthma. Methods: The SYNERGY project pooled information on previous respiratory diseases from 12,739 case subjects and 14,945 control subjects from 7 case-control studies conducted in Europe and Canada. Multivariate logistic regression models were used to investigate the relationship between individual diseases adjusting for co-occurring conditions, and patterns of respiratory disease diagnoses and lung cancer. Analyses were stratified by sex, and adjusted for age, center, ever-employed in a high-risk occupation, education, smoking status, cigarette pack-years, and time since quitting smoking. Measurements and Main Results: Chronic bronchitis and emphysema were positively associated with lung cancer, after accounting for other respiratory diseases and smoking (e.g., in men: odds ratio [On 1.33; 95% confidence interval [CI], 1.20-1.48 and OR, 1.50; 95% CI, 1.21-1.87, respectively). A positive relationship was observed between. lung cancer and pneumonia diagnosed 2 years or less before lung cancer (OR, 3.31; 95% CI, 2.33-4.70 for men), but not longer. Co-occurrence of chronic bronchitis and emphysema and/or pneumonia had a stronger positive association with lung cancer than chronic bronchitis "only." Asthma had an inverse association with lung cancer, the association being stronger with an asthma diagnosis 5 years or more before lung cancer compared with shorter. Conclusions: Findings from this large international case-control consortium indicate that after accounting for co-occurring respiratory diseases, chronic bronchitis and emphysema continue to have a positive association with lung cancer. Keywords: epidemiologic study; lung neoplasm; pulmonary disease; data pooling; case-control study C1 [Denholm, Rachel; Schuez, Joachim; Straif, Kurt; Brenner, Darren R.; Olsson, Ann C.] Int Agcy Res Canc, F-69372 Lyon 08, France. [Stuecker, Isabelle; Guida, Florence] Ctr Res Epidemiol & Populat Hlth, INSERM, U1018, Environm Epidemiol Canc Team, Villejuif, France. [Stuecker, Isabelle; Guida, Florence] Univ Paris 11, Unite Mixte Rech Sante 1018, Villejuif, France. [Joecke, Karl-Heinz, I] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Brenner, Darren R.] Alberta Health Serv, Canc Control Alberta, Dept Populat Hlth Res, Calgary, AB, Canada. [De Matteis, Sara] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [De Matteis, Sara] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Brueske, Irene; Wichmann, Heinz-Erich] Deutsch Forschungszentrum Gesundheit & Umwelt, Inst Epidemiol, Neuherberg, Germany. [Landi, Maria Teresa; Caporaso, Neil] NCI, Bethesda, MD 20892 USA. [Siemiatycki, Jack] Univ Montreal, Hosp Res Ctr, Montreal, PQ, Canada. [Ahrens, Wolfgang; Pohlabeln, Hermann] Bremen Inst Prevent Res & Social Med, Bremen, Germany. [Zaridze, David] Russian Canc Res Ctr, Moscow, Russia. [Field, John K.] Univ Liverpool, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool L69 3BX, Merseyside, England. [McLaughlin, John] Canc Care Ontario, Samuel Lunenfeld Res Inst, Toronto, ON, Canada. [Demers, Paul] Canc Care Ontario, Occupat Canc Res Ctr, Toronto, ON, Canada. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Lodz, Poland. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Dumitru, Rodica Stanescu] Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, CR-77147 Olomouc, Czech Republic. [Kendzia, Benjamin; Behrens, Thomas; Bruening, Thomas] Ruhr Univ Bochum, Inst Prevent & Occupat Med, German Social Accid Insurance Inst, Bochum, Germany. [Peters, Susan; Vermeulen, Roel; Kromhout, Hans] Inst Risk Assessment Sci, Utrecht, Netherlands. [Peters, Susan] Univ Western Australia, Sch Populat Hlth, Perth, WA 6009, Australia. [Olsson, Ann C.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. RP Olsson, AC (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM olssona@iarc.fr RI Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Bruning, Thomas/G-8120-2015; Vermeulen, Roel/F-8037-2011; OI Bruning, Thomas/0000-0001-9560-5464; Vermeulen, Roel/0000-0003-4082-8163; Field, John/0000-0003-3951-6365; Ahrens, Wolfgang/0000-0003-3777-570X FU Institut National du Cancer in France; German Social Accident Insurance (DGUV); Canadian Institutes for Health Research; Guzzo-SRC Chair in Environment and Cancer; National Cancer Institute of Canada; Canadian Cancer Society; Workplace Safety and Insurance Board; Cancer Care Ontario; French Agency of Health Security (ANSES); Fondation de France; French National Research Agency (ANR); National Institute of Cancer (INCA); Foundation for Medical Research (FRM); French Institute for Public Health Surveillance (InVS); Health Ministry (DGS); Organization for the Research on Cancer (ARC); French Ministry of Work, Solidarity, and Public Function (DGT); Federal Ministry of Education, Science, Research, and Technology [01 HK 173/0]; Federal Ministry of Science [01 HK 546/8]; Ministry of Labor and Social Affairs [IIIb7-27/13]; European Commission [IC15-CT96-0313]; Polish State Committee for Scientific Research [SPUB-M-COPERNICUS/P-05/DZ-30/99/2000]; Roy Castle Lung Cancer Foundation; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Bethesda, MD); Environmental Epidemiology Program of the Lombardy Region, Italy; Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro (Rome, Italy) FX Supported by the Institut National du Cancer in France (Projets Libre Epidemiologie 2009). The SYNERGY project was funded by the German Social Accident Insurance (DGUV). The Montreal study was supported by the Canadian Institutes for Health Research and Guzzo-SRC Chair in Environment and Cancer. The Toronto study was funded by the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society, and the occupational analysis was conducted by the Occupational Cancer Research Centre, which was supported by the Workplace Safety and Insurance Board, the Canadian Cancer Society, and Cancer Care Ontario. The ICARE study was supported by the French Agency of Health Security (ANSES); the Fondation de France; the French National Research Agency (ANR); the National Institute of Cancer (INCA); the Foundation for Medical Research (FRM); the French Institute for Public Health Surveillance (InVS); the Health Ministry (DGS); the Organization for the Research on Cancer (ARC); and the French Ministry of Work, Solidarity, and Public Function (DGT). The AUT study in Germany was funded by the Federal Ministry of Education, Science, Research, and Technology grant no. 01 HK 173/0. The HdA study was funded by the Federal Ministry of Science (grant 01 HK 546/8) and the Ministry of Labor and Social Affairs (grant IIIb7-27/13). The INCO study was supported by a grant from the European Commission's INCO-COPERNICUS program (contract IC15-CT96-0313). In Warsaw, the study was supported by a grant from the Polish State Committee for Scientific Research (grant SPUB-M-COPERNICUS/P-05/DZ-30/99/2000). The Liverpool Lung Project (LLP) was supported by the Roy Castle Lung Cancer Foundation. The EAGLE study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Bethesda, MD); the Environmental Epidemiology Program of the Lombardy Region, Italy; and the Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro (Rome, Italy). NR 36 TC 21 Z9 22 U1 1 U2 18 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2014 VL 190 IS 5 BP 549 EP 559 DI 10.1164/rccm.201402-0338OC PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AO7TB UT WOS:000341554400010 PM 25054566 ER PT J AU Adjemian, J Olivier, KN Prevots, DR AF Adjemian, Jennifer Olivier, Kenneth N. Prevots, D. Rebecca TI Nontuberculous Mycobacteria among Patients with Cystic Fibrosis in the United States Screening Practices and Environmental Risk SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE nontuberculous mycobacteria; pulmonary; epidemiology; cystic fibrosis; spatial ID LUNG-DISEASE; PREVALENCE; INFECTIONS; ATMOSPHERE; PULMONARY; EXPOSURE AB Rationale: Persons with cystic fibrosis (CF) are at greater risk of nontuberculous mycobacterial (NTM) infections than the general population. However, among patients with CF, geographic variation in prevalence is poorly understood. Objectives: To describe the prevalence and screening practices of NTM among U.S. patients with CF. Methods: CF Patient Registry data from 2010-2011 were obtained to estimate the prevalence of NTM among patients with CF 12 years of age or older by state. Climatic data were also obtained and predictors of NTM infection analyzed using regression analysis. Geographic clustering and mycobacterial culture rates by state were also assessed. Measurements and Main Results: Among patients with CF 12 years of age or older, 58% had mycobacterial cultures; 14% were positive for NTM. Most states (n = 31) had a prevalence of 10-20%; seven states predominantly in the West and Southeast had a prevalence of 20% or greater, including Alaska, which cultured patients more frequently than any other state. Nearly 60% of positive cultures were for Mycobacterium avium complex, although this ranged by state, from 29% in Louisiana to 100% for Nebraska/Delaware. Significant (P < 0.002) spatial clustering of NTM was detected, centering in Wisconsin, Arizona, Florida, and Maryland. Higher saturated vapor pressure increased risk for NTM (odds ratio = 1.06; 95% confidence interval = 1.02-1.10). The proportion of patients cultured for mycobacteria varied greatly by state of residence (median = 46%; range = 9-73%). Conclusions: NTM prevalence varies significantly among patients with CF by geographic area, and is largely influenced by environmental factors. However, NTM culture practices vary greatly, with some high-prevalence states screening less than 25% annually. Routine screening for all patients with CF is needed for timely detection. C1 [Adjemian, Jennifer; Prevots, D. Rebecca] NIAID, Epidemiol Unit, NIH, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Adjemian, Jennifer] US PHS, Rockville, MD USA. RP Adjemian, J (reprint author), Quarters 15 B-1,8 West Dr,MSC 2665, Bethesda, MD 20892 USA. EM jennifer.adjemian@nih.gov FU Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases FX Supported in part by the Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 24 TC 25 Z9 25 U1 0 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2014 VL 190 IS 5 BP 581 EP 586 DI 10.1164/rccm.201405-0884OC PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AO7TB UT WOS:000341554400013 PM 25068291 ER PT J AU Dooley, KE Luetkemeyer, AF Park, JG Allen, R Cramer, Y Murray, S Sutherland, D Aweeka, F Koletar, SL Marzan, F Bao, J Savic, R Haas, DW AF Dooley, Kelly E. Luetkemeyer, Anne F. Park, Jeong-Gun Allen, Reena Cramer, Yoninah Murray, Stephen Sutherland, Deborah Aweeka, Francesca Koletar, Susan L. Marzan, Florence Bao, Jing Savic, Rada Haas, David W. CA AIDS Clinical Trials Grp A5306 Stu TI Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID EARLY BACTERICIDAL ACTIVITY; HIV PROTEASE INHIBITORS; ANTIRETROVIRAL THERAPY; SLCO1B1 POLYMORPHISMS; MURINE MODEL; PLASMA-CONCENTRATIONS; TUBERCULOSIS; CYP2B6; PYRAZINAMIDE; MOXIFLOXACIN AB There is an urgent need for new antituberculosis (anti-TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel antituberculosis nitroimidazole in late-phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and antituberculosis drugs, is a minor (similar to 20%) metabolic pathway for PA-824. In a phase I clinical trial, we characterized interactions between PA-824 and efavirenz (arm 1), lopinavir/ritonavir (arm 2), and rifampin (arm 3) in healthy, HIV-uninfected volunteers without TB disease. Participants in arms 1 and 2 were randomized to receive drugs via sequence 1 (PA-824 alone, washout, ARV, and ARV plus PA-824) or sequence 2 (ARV, ARV with PA-824, washout, and PA-824 alone). In arm 3, participants received PA-824 and then rifampin and then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated. Compared to PA-824 alone, plasma PA-824 values (based on geometric mean ratios) for maximum concentration (C-max), area under the concentration- time curve from 0 to 24 h (AUC(0-24)), and trough concentration (C-min) were reduced 28%, 35%, and 46% with efavirenz, 13%, 17%, and 21% with lopinavir-ritonavir (lopinavir/r) and 53%, 66%, and 85% with rifampin, respectively. Medications were well tolerated. In conclusion, lopinavir/r had minimal effect on PA-824 exposures, supporting PA-824 use with lopinavir/r without dose adjustment. PA-824 exposures, though, were reduced more than expected when given with efavirenz or rifampin. The clinical implications of these reductions will depend upon data from current clinical trials defining PA-824 concentration-effect relationships. C1 [Dooley, Kelly E.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Luetkemeyer, Anne F.; Aweeka, Francesca; Marzan, Florence; Savic, Rada] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Park, Jeong-Gun; Cramer, Yoninah] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Allen, Reena] Social & Sci Syst Inc, Silver Spring, MD USA. [Murray, Stephen] Global Alliance TB Drug Dev, New York, NY USA. [Sutherland, Deborah; Haas, David W.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Koletar, Susan L.] Ohio State Univ, Columbus, OH 43210 USA. [Bao, Jing] NIH, Div Aids, Henry M Jackson Foundation, Bethesda, MD 20892 USA. RP Dooley, KE (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. EM kdooley1@jhmi.edu FU ACTG CTU grant [U01-AI069439-01, U01-AI069502-01, 1U01AI069474-01, UL1TR001070, 1U01AI069465-01, UL1 TR001079]; Vanderbilt CTSA grant from NCRR/NIH [UL1RR024975]; UCSF CTSI grant [UL1TR000004]; National Institute of Allergy and Infectious Diseases; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C]; [U01 AI069465]; [TR-000445]; [AI-077505]; [K23AI080842]; [U01 AI068634]; [UM1AI068636]; [UM1AI68634] FX We appreciate the efforts of the investigators and research staff at the following ACTG Clinical Trial Units (CTU) and Clinical Research Sites (CRS): Michael Leonard and Fred Nicotera, Vanderbilt Therapeutics Clinical Research Site (site 3652) (ACTG CTU grant U01-AI069439-01; Vanderbilt CTSA grant UL1RR024975 from NCRR/NIH); John Dwyer, Anna Smith, and Jacqueline Clark, UCSF AIDS CRS (site 801) (ACTG CTU grant U01-AI069502-01 and UCSF CTSI grant UL1TR000004); Heather Harber and Jan Clark, The Ohio State University AIDS CRS (site 2301) (ACTG CTU grant 1U01AI069474-01 and grant UL1TR001070); Ilene Wiggins and Andrea Weiss, Johns Hopkins Adult AIDS CRS (site 201) (ACTG CTU grant 1U01AI069465-01 and grant UL1 TR001079; Johns Hopkins University Institute for Clinical and Translational Research).; This study was supported by the AIDS Clinical Trials Group sponsored by the National Institute of Allergy and Infectious Diseases and was supported by the following grants: UM1AI068636 (NIAID), UM1AI68634 (ACTG Statistical and Data Management Center), U01 AI069465 (K. E. D.), TR-000445, AI-077505 (D. W. H.), K23AI080842 (K. E. D.), and U01 AI068634 (J.-G. P. and Y. C.). This study was also funded in part by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services contract HHSN272200800014C (J. B.). NR 34 TC 6 Z9 6 U1 2 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2014 VL 58 IS 9 BP 5245 EP 5252 DI 10.1128/AAC.03332-14 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AO3UV UT WOS:000341262700028 PM 24957823 ER PT J AU Curreli, F Do Kwon, Y Zhang, HT Yang, YP Scacalossi, D Kwong, PD Debnath, AK AF Curreli, Francesca Do Kwon, Young Zhang, Hongtao Yang, Yongping Scacalossi, Daniel Kwong, Peter D. Debnath, Asim K. TI Binding Mode Characterization of NBD Series CD4-Mimetic HIV-1 Entry Inhibitors by X-Ray Structure and Resistance Study SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 ENVELOPE GLYCOPROTEIN; SMALL-MOLECULE INHIBITORS; STRUCTURE-BASED DESIGN; CD4 MIMICS; RECEPTOR-BINDING; ENV CLONES; NEUTRALIZATION EPITOPES; TYPE-1 VARIANTS; HUMAN-ANTIBODY AB We previously identified two small-molecule CD4 mimetics-NBD-556 and NBD-557-and synthesized a series of NBD compounds that resulted in improved neutralization activity in a single-cycle HIV-1 infectivity assay. For the current investigation, we selected several of the most active compounds and assessed their antiviral activity on a panel of 53 reference HIV-1 Env pseudoviruses representing diverse clades of clinical isolates. The selected compounds inhibited tested clades with low-micromolar potencies. Mechanism studies indicated that they act as CD4 agonists, a potentially unfavorable therapeutic trait, in that they can bind to the gp120 envelope glycoprotein and initiate a similar physiological response as CD4. However, one of the compounds, NBD-09027, exhibited reduced agonist properties, in both functional and biophysical studies. To understand the binding mode of these inhibitors, we first generated HIV-1-resistant mutants, assessed their behavior with NBD compounds, and determined the X-ray structures of two inhibitors, NBD-09027 and NBD-10007, in complex with the HIV-1 gp120 core at similar to 2-angstrom resolution. Both studies confirmed that the NBD compounds bind similarly to NBD-556 and NBD-557 by inserting their hydrophobic groups into the Phe43 cavity of gp120. The basic nitrogen of the piperidine ring is located in close proximity to D368 of gp120 but it does not form any H-bond or salt bridge, a likely explanation for their nonoptimal antagonist properties. The results reveal the structural and biological character of the NBD series of CD4 mimetics and identify ways to reduce their agonist properties and convert them to antagonists. C1 [Curreli, Francesca; Zhang, Hongtao; Scacalossi, Daniel; Debnath, Asim K.] New York Blood Ctr, Lindsey F Kimball Res Inst, Lab Mol Modeling & Drug Design, New York, NY 10021 USA. [Do Kwon, Young; Yang, Yongping; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Debnath, AK (reprint author), New York Blood Ctr, Lindsey F Kimball Res Inst, Lab Mol Modeling & Drug Design, New York, NY 10021 USA. EM adebnath@nybloodcenter.org RI Kwon, Young Do/A-6957-2010 FU NIH [R01 AI104416]; New York Blood Center; Intramural AIDS-Targeted Antiretroviral Program (IATAP) of the NIH; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX This study was supported by funds from NIH grant R01 AI104416 (A. K. D.), the New York Blood Center (A. K. D.), and the Intramural AIDS-Targeted Antiretroviral Program (IATAP) of the NIH.; Use of Sector 22 (Southeast Region Collaborative Access Team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science contract W-31-109-Eng-38. NR 65 TC 10 Z9 10 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2014 VL 58 IS 9 BP 5478 EP 5491 DI 10.1128/AAC.03339-14 PG 14 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AO3UV UT WOS:000341262700056 PM 25001301 ER PT J AU Vanpouille, C Khandazhinskaya, A Karpenko, I Zicari, S Barreto-de-Souza, V Frolova, S Margolis, L Kochetkov, S AF Vanpouille, Christophe Khandazhinskaya, Anastasia Karpenko, Inna Zicari, Sonia Barreto-de-Souza, Victor Frolova, Svetlana Margolis, Leonid Kochetkov, Sergey TI A new antiviral: Chimeric 3TC-AZT phosphonate efficiently inhibits HIV-1 in human tissues ex vivo SO ANTIVIRAL RESEARCH LA English DT Article DE HIV-1; NRTI; Depot form ID REVERSE-TRANSCRIPTASE; DEPOT FORMS; PRODRUGS; ZIDOVUDINE; RESISTANCE; DRUGS; 3'-AZIDO-3'-DEOXYTHYMIDINE; DERIVATIVES; DISCOVERY; DESIGN AB Although more-recently developed antivirals target different molecules in the HIV-1 replication cycle, nucleoside reverse transcriptase inhibitors (NRTIs) remain central for HIV-1 therapy. Here, we test the anti-HIV activity of a phosphonate chimera of two well-known NRTIs, namely AZT and 3TC. We show that this newly synthesized compound suppressed HIV-1 infection in lymphoid tissue ex vivo more efficiently than did other phosphonates of NRTIs. Moreover, the new compound was not toxic for tissue cells, thus making the chimeric phosphonate strategy a valid approach for the development of anti HIV-1 compound heterodimers. Published by Elsevier B.V. C1 [Vanpouille, Christophe; Zicari, Sonia; Barreto-de-Souza, Victor; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Khandazhinskaya, Anastasia; Karpenko, Inna; Frolova, Svetlana; Kochetkov, Sergey] Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow, Russia. RP Margolis, L (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Bldg 10,Room 9D58,10 Ctr Dr,MSC 1855, Bethesda, MD 20892 USA. EM margolis@helix.nih.gov; kochet@eimb.ru RI Karpenko, Inna/F-5879-2015 OI Karpenko, Inna/0000-0001-9849-0447 FU NIH - office of AIDS Research - Intramural-to-Russian (I-to-R) Program; NICHD intramural Program; joint NIH-RFBR grant [RFBR 12-04-91450-NIH]; Brazilian Ministry of Education/CAPES; Brazilian Ministry of Science and Technology/CNPq FX The work of CV, SZ, VS and LM was supported by the NIH - office of AIDS Research - Intramural-to-Russian (I-to-R) Program and the NICHD intramural Program. The work of AK, IK, SF and SK was supported by joint NIH-RFBR grant (RFBR 12-04-91450-NIH). VBS was partially supported by fellowships from the Brazilian Ministry of Education/CAPES and the Brazilian Ministry of Science and Technology/CNPq. We thank the entire staff of the Department of Pathology of Children's National Medical Center for their generous assistance in obtaining human tonsillar tissues. NR 22 TC 1 Z9 1 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD SEP PY 2014 VL 109 BP 125 EP 131 DI 10.1016/j.antiviral.2014.06.019 PG 7 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA AO6OF UT WOS:000341470700015 PM 25010891 ER PT J AU Ward, MM Guthrie, LC Alba, MI AF Ward, Michael M. Guthrie, Lori C. Alba, Maria I. TI Rheumatoid Arthritis Response Criteria and Patient-Reported Improvement in Arthritis Activity: Is an American College of Rheumatology Twenty Percent Response Meaningful to Patients? SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID CLINICAL-TRIALS; CORE SET; VALIDATION AB Objective. To examine the association of the American College of Rheumatology (ACR) response criteria (20% improvement [ACR20], ACR50, and ACR70) and the European League Against Rheumatism (EULAR) response criteria with patient-reported improvement in rheumatoid arthritis (RA) activity. Methods. Two hundred fifty patients with active RA were studied prospectively, before and after escalation of antirheumatic treatment. Patients were asked to report if they subjectively judged that they had experienced important improvement with treatment, and the proportion of patients who reported improvement was compared with the proportion who met the ACR20, ACR50, ACR70, and EULAR response criteria. Results. Improvement in overall arthritis status was reported by 167 patients (66.8%), while 107 patients (42.8%) had an ACR20 response, 52 (20.8%) had an ACR50 response, 24 (9.6%) had an ACR70 response, and 136 (54.4%) had a EULAR moderate/good response. ACR20 response had a sensitivity of 0.57 and a specificity of 0.85 for clinically important improvement as judged by patients. Sensitivities of the ACR50, ACR70, and EULAR moderate/good responses were 0.30, 0.14, and 0.68, respectively, while their specificities were 0.97, 0.99, and 0.73, respectively. The ACR hybrid score with the highest sensitivity and specificity for important improvement was 19.99. Conclusion. Among patients with active RA, ACR20 responses are highly specific measures of improvement as judged by patients, but exclude a substantial proportion of patients who consider themselves improved. Response criteria are associated with, but not equivalent to, patient-perceived improvement. C1 [Ward, Michael M.; Guthrie, Lori C.; Alba, Maria I.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH FX Supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. NR 15 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD SEP PY 2014 VL 66 IS 9 BP 2339 EP 2343 DI 10.1002/art.38705 PG 5 WC Rheumatology SC Rheumatology GA AO3RD UT WOS:000341251100005 PM 24838475 ER PT J AU Smith, CK Vivekanandan-Giri, A Tang, CR Knight, JS Mathew, A Padilla, RL Gillespie, BW Carmona-Rivera, C Liu, XD Subramanian, V Hasni, S Thompson, PR Heinecke, JW Saran, R Pennathur, S Kaplan, MJ AF Smith, Carolyne K. Vivekanandan-Giri, Anuradha Tang, Chongren Knight, Jason S. Mathew, Anna Padilla, Robin L. Gillespie, Brenda W. Carmona-Rivera, Carmelo Liu, Xiaodan Subramanian, Venkataraman Hasni, Sarfaraz Thompson, Paul R. Heinecke, Jay W. Saran, Rajiv Pennathur, Subramaniam Kaplan, Mariana J. TI Neutrophil Extracellular Trap-Derived Enzymes Oxidize High-Density Lipoprotein An Additional Proatherogenic Mechanism in Systemic Lupus Erythematosus SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID APOLIPOPROTEIN-A-I; CHOLESTEROL EFFLUX CAPACITY; CORONARY-ARTERY-DISEASE; RHEUMATOID-ARTHRITIS; CARDIOVASCULAR-SYSTEM; ANTIMALARIAL-DRUGS; NITRIC-OXIDE; ATHEROSCLEROSIS; MYELOPEROXIDASE; PROTEIN AB Objective. Oxidative stress and oxidized high-density lipoprotein (HDL) are implicated as risk factors for cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Yet, how HDL is oxidized and rendered dysfunctional in SLE remains unclear. Neutrophil extracellular traps (NETs), the levels of which are elevated in lupus, possess oxidant-generating enzymes, including myeloperoxidase (MPO), NADPH oxidase (NOX), and nitric oxide synthase (NOS). We hypothesized that NETs mediate HDL oxidation, impairing cholesterol efflux capacity (CEC). Methods. Plasma MPO levels and CEC activity were examined in controls and lupus patients, and 3-chlorotyrosine (MPO specific) and 3-nitrotyrosine (derived from reactive nitrogen species) were quantified in human HDL. Multivariable linear models were used to estimate and test differences between groups. HDL was exposed to NETs from control and lupus neutrophils in the presence or absence of MPO, NOX, NOS inhibitors, and chloroquine (CQ). Murine HDL oxidation was quantified after NET inhibition in vivo. Results. SLE patients displayed higher MPO levels and diminished CEC compared to controls. SLE HDL had higher 3-nitrotyrosine and 3-chlorotyrosine content than control HDL, with site-specific oxidation signatures on apolipoprotein A-I. Experiments with human and murine NETs confirmed that chlorination was mediated by MPO and NOX, and nitration by NOS and NOX. Mice with lupus treated with the NET inhibitor Cl-amidine displayed significantly decreased HDL oxidation. CQ inhibited NET formation in vitro. Conclusion. Active NOS, NOX, and MPO within NETs significantly modify HDL, rendering the lipoprotein proatherogenic. Since NET formation is enhanced in SLE, these findings support a novel role for NET-derived lipoprotein oxidation in SLE-associated CVD and identify additional proatherogenic roles of neutrophils and putative protective roles of antimalarials in autoimmunity. C1 [Smith, Carolyne K.; Carmona-Rivera, Carmelo; Hasni, Sarfaraz; Kaplan, Mariana J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Vivekanandan-Giri, Anuradha; Knight, Jason S.; Mathew, Anna; Padilla, Robin L.; Gillespie, Brenda W.; Liu, Xiaodan; Saran, Rajiv; Pennathur, Subramaniam] Univ Michigan, Ann Arbor, MI 48105 USA. [Subramanian, Venkataraman; Thompson, Paul R.] Scripps Res Inst, Jupiter, FL USA. RP Pennathur, S (reprint author), Univ Michigan, Sch Med, Brehm Ctr 5309, Dept Internal Med, 1000 Wall St, Ann Arbor, MI 48105 USA. EM spennath@umich.edu; mariana.kaplan@nih.gov OI Mathew, Anna/0000-0002-7043-4221 FU Lupus Research Institute; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIH through Public Health Service [GM-079357, DK-089503, DK-097153, HL-088419]; Public Health Service [AI-007413]; Rheumatology Research Foundation FX Supported by the Lupus Research Institute (grant to Dr. Kaplan), the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the NIH through Public Health Service grants GM-079357 (to Dr. Thompson), DK-089503 and DK-097153 (to Dr. Pennathur), and HL-088419 (to Dr. Kaplan). Ms Smith's work was supported by Public Health Service grant AI-007413. Dr. Knight is recipient of a Scientist Development Award from the Rheumatology Research Foundation. Dr. Pennathur is recipient of a Within Our Reach grant from the Rheumatology Research Foundation. NR 50 TC 29 Z9 30 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD SEP PY 2014 VL 66 IS 9 BP 2532 EP 2544 DI 10.1002/art.38703 PG 13 WC Rheumatology SC Rheumatology GA AO3RD UT WOS:000341251100025 PM 24838349 ER PT J AU Roberts, MEP Kaminski, D Jenks, SA Maguire, C Ching, K Burbelo, PD Iadarola, MJ Rosenberg, A Coca, A Anolik, J Sanz, I AF Roberts, Mustimbo E. P. Kaminski, Denise Jenks, Scott A. Maguire, Craig Ching, Kathryn Burbelo, Peter D. Iadarola, Michael J. Rosenberg, Alexander Coca, Andreea Anolik, Jennifer Sanz, Inaki TI Primary Sjogren's Syndrome Is Characterized by Distinct Phenotypic and Transcriptional Profiles of IgD plus Unswitched Memory B Cells SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; SALIVARY-GLANDS; CLASSIFICATION CRITERIA; DEPRESSED PERCENTAGE; EXPRESSION; DIFFERENTIATION; ACTIVATION; DISEASE; POPULATION; SUBSET AB Objective. The significance of distinct B cell abnormalities in primary Sjogren's syndrome (SS) remains to be established. We undertook this study to analyze the phenotype and messenger RNA (mRNA) transcript profiles of B cell subsets in patients with primary SS and to compare them with those in sicca syndrome patients and healthy controls. Methods. CD19+ B cells from 26 patients with primary SS, 27 sicca syndrome patients, and 22 healthy controls were analyzed by flow cytometry. Gene expression profiles of purified B cell subsets (from 3-5 subjects per group per test) were analyzed using Affymetrix gene arrays. Results. Patients with primary SS had lower frequencies of CD27+IgD- switched memory B cells and CD27+IgD- unswitched memory B cells compared with healthy controls. Unswitched memory B cell frequencies were also lower in sicca syndrome patients and correlated inversely with serologic hyperactivity in both disease states. Further, unswitched memory B cells in primary SS had lower expression of CD1c and CD21. Gene expression analysis of CD27+ memory B cells separated patients with primary SS from healthy controls and identified a subgroup of sicca syndrome patients with a primary SS-like transcript profile. Moreover, unswitched memory B cell gene expression analysis identified 187 genes differentially expressed between patients with primary SS and healthy controls. Conclusion. A decrease in unswitched memory B cells with serologic hyperactivity is characteristic of both established primary SS and a subgroup of sicca syndrome, which suggests the value of these B cells both as biomarkers of future disease progression and for understanding disease pathogenesis. Overall, the mRNA transcript analysis of unswitched memory B cells suggests that their activation in primary SS takes place through innate immune pathways in the context of attenuated antigen-mediated adaptive signaling. Thus, our findings provide important insight into the mechanisms and potential consequences of decreased unswitched memory B cells in primary SS. C1 [Roberts, Mustimbo E. P.; Kaminski, Denise; Jenks, Scott A.; Maguire, Craig; Rosenberg, Alexander; Coca, Andreea; Anolik, Jennifer; Sanz, Inaki] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Ching, Kathryn; Burbelo, Peter D.; Iadarola, Michael J.] NIDR, NIH, Bethesda, MD 20892 USA. RP Sanz, I (reprint author), Emory Univ, Sch Med, Div Rheumatol, 615 Michael St, Atlanta, GA 30322 USA. EM ignacio.sanz@emory.edu FU NIH (National Institute of Dental and Craniofacial Research) [R01-DE-017585-0]; NIH (Intramural Research Program funding, National Institute of Allergy and Infectious Diseases) [P01-AI-078907]; NIH (Autoimmunity Centers of Excellence Program) [U19-AI-56390]; MedImmune FX Supported by the NIH (National Institute of Dental and Craniofacial Research grant R01-DE-017585-0 and Intramural Research Program funding, National Institute of Allergy and Infectious Diseases grant P01-AI-078907 to Dr. Sanz, and Autoimmunity Centers of Excellence Program grant U19-AI-56390 to Dr. Sanz).; Dr. Anolik has received consulting fees, speaking fees, and/or honoraria from MedImmune (less than $10,000) and research grants from MedImmune. Dr. Sanz has received honoraria from Pfizer for service on the Visiting Professor Board (more than $10,000). NR 50 TC 9 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD SEP PY 2014 VL 66 IS 9 BP 2558 EP 2569 DI 10.1002/art.38734 PG 12 WC Rheumatology SC Rheumatology GA AO3RD UT WOS:000341251100027 PM 24909310 ER PT J AU Assassi, S Weisman, MH Lee, M Savage, L Diekman, L Graham, TA Rahbar, MH Schall, JI Gensler, LS Deodhar, AA Clegg, DO Colbert, RA Reveille, JD AF Assassi, Shervin Weisman, Michael H. Lee, MinJae Savage, Laurie Diekman, Laura Graham, Tiffany A. Rahbar, Mohammad H. Schall, Joan I. Gensler, Lianne S. Deodhar, Atul A. Clegg, Daniel O. Colbert, Robert A. Reveille, John D. TI New Population-Based Reference Values for Spinal Mobility Measures Based on the 2009-2010 National Health and Nutrition Examination Survey SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID ANKYLOSING-SPONDYLITIS; METROLOGY INDEX; PREVALENCE; CRITERIA; BATH AB Objective. To report population-based percentile reference values for selected spinal mobility measures in a nationally representative sample of 5,001 US adults ages 20-69 years who were examined in the 2009-2010 US National Health and Nutrition Examination Survey (NHANES). Methods. Occiput-to-wall distance (OWD), thoracic expansion (TE), and anterior lumbar flexion (ALF; by modified Schober test) were measured by trained examiners in a standardized manner. TE was measured at the xiphisternal level, while the lower reference point for ALF was a line marked at the level of the superior margin of the lateral iliac crests. We report reference values based on the 95th percentile for the OWD and the 5th percentile for TE and ALF, as well as other summary statistics for these measures, in the study population. Results. An OWD of >0 was present in 3.8% of the participants, while 8.8% of them had out-of-range values for TE based on the commonly used threshold of 2.5 cm. The 95th percentile of the OWD measurement was 0, while the 5th percentile for TE and ALF were 1.9 cm and 2 cm, respectively. The spinal measures were significantly associated with sex, age, ethnicity, height, and body mass index (BMI). Exclusion of individuals with severe obesity (BMI >35 kg/m(2)) changed the proposed reference values for TE and ALF to 2.2 cm and 1.9 cm, respectively. Conclusion. We verified a reference value of 0 for the OWD in the general population. Using the reported population-based percentile values, new reference values for TE and ALF can be derived. C1 [Assassi, Shervin; Lee, MinJae; Diekman, Laura; Graham, Tiffany A.; Rahbar, Mohammad H.; Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Savage, Laurie] Spondylitis Assoc Amer, Sherman, TX USA. [Schall, Joan I.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Gensler, Lianne S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Deodhar, Atul A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Clegg, Daniel O.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Colbert, Robert A.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Assassi, S (reprint author), Univ Texas Hlth Sci Ctr Houston, 6431 Fannin,MSB 5-266, Houston, TX 77030 USA. EM shervin.assassi@uth.tmc.edu FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [K23-AR-061436, Z01-AR-041184, 2 P01-AR-052915-06A1, UL1-TR-000371]; Spondylitis Association of America; Spondyloarthritis Research and Treatment Network (SPARTAN); Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center at the University of California, San Francisco; UCB; Westat; AbbVie; Pfizer; Novartis FX Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K23-AR-061436 to Dr. Assassi, grant Z01-AR-041184 to Dr. Colbert, grant 2 P01-AR-052915-06A1 to Dr. Reveille, and Clinical and Translational Science Award program grant UL1-TR-000371), the Spondylitis Association of America, and the Spondyloarthritis Research and Treatment Network (SPARTAN). Dr. Gensler's work was supported by the Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center at the University of California, San Francisco.; Dr. Weisman has received consulting fees from UCB (less than $10,000). Dr. Schall has received consulting fees from Westat (less than $10,000). Dr. Gensler has received consulting and/or speaking fees from UCB and AbbVie (less than $10,000 each). Dr. Deodhar has received consulting and/or speaking fees from Pfizer and Novartis (less than $10,000 each) and from UCB and AbbVie (more than $10,000 each). NR 23 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD SEP PY 2014 VL 66 IS 9 BP 2628 EP 2637 DI 10.1002/art.38692 PG 10 WC Rheumatology SC Rheumatology GA AO3RD UT WOS:000341251100035 PM 24782356 ER PT J AU Kuzmina, Z Joe, GO Baird, K Cowen, EW Naik, HB Steinberg, SM Curtis, L Comis, LE Pavletic, SZ AF Kuzmina, Zoya Joe, Galen O. Baird, Kristin Cowen, Edward W. Naik, Haley B. Steinberg, Seth M. Curtis, Lauren Comis, Leora E. Pavletic, Steven Z. TI Prevalence of isolated joint involvement in chronic graft-versus-host disease: comment on the article by Inamoto et al SO ARTHRITIS & RHEUMATOLOGY LA English DT Letter C1 [Kuzmina, Zoya; Joe, Galen O.; Baird, Kristin; Cowen, Edward W.; Naik, Haley B.; Steinberg, Seth M.; Curtis, Lauren; Comis, Leora E.; Pavletic, Steven Z.] NIH, Bethesda, MD 20892 USA. RP Kuzmina, Z (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CA999999] NR 5 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD SEP PY 2014 VL 66 IS 9 BP 2646 EP 2648 DI 10.1002/art.38697 PG 4 WC Rheumatology SC Rheumatology GA AO3RD UT WOS:000341251100045 PM 24819543 ER PT J AU Schneider, EH Fowler, SC Lionakis, MS Swamydas, M Holmes, G Diaz, V Munasinghe, J Peiper, SC Gao, JL Murphy, PM AF Schneider, Erich H. Fowler, Stephen C. Lionakis, Michail S. Swamydas, Muthulekha Holmes, Gibran Diaz, Vivian Munasinghe, Jeeva Peiper, Stephen C. Gao, Ji-Liang Murphy, Philip M. TI Regulation of Motor Function and Behavior by Atypical Chemokine Receptor 1 SO BEHAVIOR GENETICS LA English DT Article DE Chemokine; Behavior; Force-plate actometer; Rotarod; Cerebellum ID PURKINJE-CELL DEGENERATION; LURCHER MUTANT MICE; CENTRAL-NERVOUS-SYSTEM; DUFFY NEGATIVE INDIVIDUALS; RAT CEREBELLAR NEURONS; ANXIETY-LIKE BEHAVIOR; SPONTANEOUS-ALTERNATION; ENDOTHELIAL-CELLS; ANTIGEN RECEPTOR; PLASMODIUM-VIVAX AB Atypical Chemokine Receptor 1 (ACKR1), previously known as Duffy Antigen Receptor for Chemokines, stands out among chemokine receptors for high selective expression on cerebellar Purkinje neurons. Although ACKR1 ligands activate Purkinje cells in vitro, evidence for ACKR1 regulation of brain function in vivo is lacking. Here we demonstrate that Ackr1 (-/-) mice have markedly impaired balance and ataxia on a rotating rod and increased tremor when injected with harmaline, which induces whole-body tremor by activating Purkinje cells. Ackr1 (-/-) mice also exhibited impaired exploratory behavior, increased anxiety-like behavior and frequent episodes of marked hypoactivity under low-stress conditions. Surprisingly, Ackr1 (+/-) had similar behavioral abnormalities, indicating pronounced haploinsufficiency. The behavioral phenotype of Ackr1 (-/-) mice was the opposite of mouse models of cerebellar degeneration, and the defects persisted when Ackr1 was deficient only on non-hematopoietic cells. Together, the results suggest that normal motor function and behavior may partly depend on negative regulation of Purkinje cell activity by Ackr1. C1 [Schneider, Erich H.; Lionakis, Michail S.; Swamydas, Muthulekha; Holmes, Gibran; Gao, Ji-Liang; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD USA. [Fowler, Stephen C.] Univ Kansas, Dept Pharmacol & Toxicol, Lawrence, KS 66045 USA. [Diaz, Vivian; Munasinghe, Jeeva] NINDS, Vivo NMR Ctr, NIH, Bethesda, MD 20892 USA. [Peiper, Stephen C.] Thomas Jefferson Univ, Jefferson Med Coll, Inst Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Murphy, Philip M.] NIH, Bethesda, MD 20892 USA. [Lionakis, Michail S.; Swamydas, Muthulekha] Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIAID NIH, Bethesda, MD USA. RP Murphy, PM (reprint author), NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. EM pmm@nih.gov RI Schneider, Erich/B-9051-2016 OI Schneider, Erich/0000-0002-7905-4276 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, USA; German Research Foundation [SCHN1192/1-1]; NIH Grant [HD002528]; Life Span Institute at the University of Kansas FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, USA. Financial support was also provided to E.H.S. through German Research Foundation Grant SCHN1192/1-1. S.C. Fowler received support from NIH Grant HD002528 and from the Life Span Institute at the University of Kansas. Experimental support by Alex Bredenkamp is gratefully acknowledged. NR 65 TC 2 Z9 2 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 EI 1573-3297 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 2014 VL 44 IS 5 BP 498 EP 515 DI 10.1007/s10519-014-9665-7 PG 18 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA AO6XD UT WOS:000341495100007 PM 24997773 ER PT J AU Hu, ZH Follmann, DA Wang, N AF Hu, Zonghui Follmann, Dean A. Wang, Naisyin TI Estimation of mean response via the effective balancing score SO BIOMETRIKA LA English DT Article DE Balancing score; Dimension reduction; Missingness at random; Nonparametric kernel regression; Prognostic score; Propensity score. ID SUFFICIENT DIMENSION REDUCTION; SLICED INVERSE REGRESSION; PROPENSITY SCORE; DISTRIBUTED PREDICTORS; BANDWIDTH SELECTION; EFFICIENCY; MODELS AB We introduce the effective balancing score for estimation of the mean response under a missing-at-random mechanism. Unlike conventional balancing scores, the proposed score is constructed via dimension reduction free. of model specification. Three types of such scores are introduced, distinguished by whether they carry the covariate information about the missingness, the response, or both. The effective balancing score leads to consistent estimation with little or no loss in efficiency. Compared to existing estimators, it reduces the burden of model specification and is more robust. It is a near-automatic procedure which is most appealing when high-dimensional covariates are involved. We investigate its asymptotic and numerical properties, and illustrate its application with an HIV disease study. C1 [Hu, Zonghui; Follmann, Dean A.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Wang, Naisyin] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. RP Hu, ZH (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huzo@niaid.nih.gov; dfollmann@niaid.nih.gov; nwangaa@umich.edu FU U.S. National Cancer Institute FX We thank the editor, associate editor and two referees for their helpful comments. The third author's research was supported by the U.S. National Cancer Institute. NR 41 TC 0 Z9 0 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3444 EI 1464-3510 J9 BIOMETRIKA JI Biometrika PD SEP PY 2014 VL 101 IS 3 BP 613 EP 624 DI 10.1093/biomet/asu022 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA AO6MD UT WOS:000341465300008 PM 25797955 ER PT J AU Hong, N Schartl, M Hong, YH AF Hong, Ni Schartl, Manfred Hong, Yunhan TI Derivation of stable zebrafish ES-like cells in feeder-free culture SO CELL AND TISSUE RESEARCH LA English DT Article DE Blastula; Chimera; Differentiation; ES cell; Zebrafish; Z428 ID EMBRYONIC STEM-CELLS; GERM-LINE CHIMERAS; MEDAKAFISH ORYZIAS-LATIPES; TARGETED GENE DISRUPTION; HOMOLOGOUS RECOMBINATION; DRUG SELECTION; MOUSE EMBRYOS; IN-VITRO; ESTABLISHMENT; PLURIPOTENT AB Zebrafish offers an excellent opportunity to combine embryological, genetic and molecular analyses of vertebrate development in vivo. Embryonic stem (ES) cells have enormous potential to study developmental potency and differentiation in vitro and thus to complement in vivo approaches. Zebrafish ES-like cells have been produced on a feeder cell layer. Here, we report the derivation of Z428, a zebrafish ES-like cell line, from blastula embryos in feeder-free culture. Fetal bovine serum, fish serum, fish embryo extract, basic fibroblast growth factor, non-essential amino acids and 2-mercaptoethanol were found to be important for Z428 growth. After more than 120 passages and many freezing/thawing cycles over a period of 20 years, Z428 exhibits stable growth and manifests many ES cell features including an ES cell phenotype, high alkaline phosphatase activity and spontaneous differentiation in culture. Most importantly, Z428 was transplantable to blastula hosts and capable of contributing to embryonic tissues and organ systems of the three germ layers. Therefore, Z428 is a stable cell line and contains ES-like cells with pluripotency in vitro and in vivo, and a feeder layer is dispensable for ES-like cell derivation in zebrafish. The derivation and easy maintenance of zebrafish ES-like cells under feeder-free conditions provide a useful extension of the present toolbox for studying development and differentiation in the zebrafish model. C1 [Hong, Ni; Hong, Yunhan] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore. [Schartl, Manfred] Univ Wurzburg, Bioctr, D-97070 Wurzburg, Germany. [Schartl, Manfred] Univ Clin Wurzburg, Ctr Comprehens Canc, Wurzburg, Germany. [Hong, Ni] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Hong, YH (reprint author), Natl Univ Singapore, Dept Biol Sci, 14 Sci Dr 4, Singapore 117543, Singapore. EM dbshyh@nus.edu.sg RI Hong , Yunhan/D-4197-2009; OI Schartl, Manfred/0000-0001-9882-5948 FU National Research Foundation Singapore [NRF-CRP7-2010-03]; Deutsche Forschungsgemeinschaft FX We thank J. Deng for fish breeding and CM. Foong for laboratory management. We are grateful to Dr. M. Westerfield (Oregon) for the zebrafish stock. This work was supported by grants from the National Research Foundation Singapore to Y.H. (NRF-CRP7-2010-03) and from the Deutsche Forschungsgemeinschaft to M.S. NR 57 TC 7 Z9 7 U1 3 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0302-766X EI 1432-0878 J9 CELL TISSUE RES JI Cell Tissue Res. PD SEP PY 2014 VL 357 IS 3 BP 623 EP 632 DI 10.1007/s00441-014-1882-0 PG 10 WC Cell Biology SC Cell Biology GA AO6XF UT WOS:000341495400010 PM 24850275 ER PT J AU Yan, L Chen, HX AF Yan, Li Chen, Helen X. TI Cancer immunotherapy SO CHINESE JOURNAL OF CANCER LA English DT Editorial Material C1 [Chen, Helen X.] NCI, Therapy Evaluat Program CTEP, Bethesda, MD 20892 USA. EM ynyinternational@yahoo.com; helen.chen@nih.gov NR 10 TC 0 Z9 1 U1 2 U2 9 PU SUN YAT SEN UNIV MED SCI WHO PI GUANGZHOU PA 651 DONGFENG RD E, GUANGZHOU, GUANGDONG 510060, PEOPLES R CHINA SN 1000-467X EI 1944-446X J9 CHIN J CANCER JI Chin. J. Cancer PD SEP PY 2014 VL 33 IS 9 BP 413 EP 415 DI 10.5732/cjc.014.10153 PG 3 WC Oncology SC Oncology GA AO5SR UT WOS:000341406100001 PM 25478631 ER PT J AU Sharon, E Streicher, H Goncalves, P Chen, HX AF Sharon, Elad Streicher, Howard Goncalves, Priscila Chen, Helen X. TI Immune checkpoints in cancer clinical trials SO CHINESE JOURNAL OF CANCER LA English DT Review DE Immune checkpoints; PD-1; PD-L1; CTLA4; immunotherapy; immune modulators ID PHASE-II TRIAL; ADVANCED MELANOMA; LIGAND 1; T-CELLS; PROTEIN EXPRESSION; ANTITUMOR IMMUNITY; ADJUVANT THERAPY; POOR-PROGNOSIS; REGULATORY T; BLOCKADE AB Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints." These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibody-based therapies targeting cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development. C1 [Sharon, Elad; Streicher, Howard; Chen, Helen X.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Goncalves, Priscila] NCI, Med Oncol Serv, Ctr Canc Res, Bethesda, MD 20892 USA. RP Sharon, E (reprint author), 9609 Med Ctr Dr,5W502, Bethesda, MD 20892 USA. EM sharone@mail.nih.gov NR 76 TC 14 Z9 18 U1 4 U2 38 PU SUN YAT SEN UNIV MED SCI WHO PI GUANGZHOU PA 651 DONGFENG RD E, GUANGZHOU, GUANGDONG 510060, PEOPLES R CHINA SN 1000-467X EI 1944-446X J9 CHIN J CANCER JI Chin. J. Cancer PD SEP PY 2014 VL 33 IS 9 BP 434 EP 444 DI 10.5732/cjc.014.10122 PG 11 WC Oncology SC Oncology GA AO5SR UT WOS:000341406100004 PM 25189716 ER PT J AU Jonklaas, J Sathasivam, A Wang, H Gu, JH Burman, KD Soldin, SJ AF Jonklaas, Jacqueline Sathasivam, Anpalakan Wang, Hong Gu, Jianghong Burman, Kenneth D. Soldin, Steven J. TI Total and free thyroxine and triiodothyronine: Measurement discrepancies, particularly in inpatients SO CLINICAL BIOCHEMISTRY LA English DT Article DE Free thyroxine; Thyroxine; Free triiodothyronine; Triiodothyronine; Immunoassays; Tandem mass spectrometry ID TANDEM MASS-SPECTROMETRY; THYROID-STIMULATING HORMONE; REFERENCE INTERVALS; SERUM; TSH; IMMUNOASSAY; POPULATIONS; ACCURACY; COMPLEX; BINDING AB Objective: We compared the performance of tandem mass spectrometry versus immunoassay for measuring thyroid hormones in a diverse group of inpatients and outpatients. Methods: Thyroxine (T4), triiodothyronine (T3), free thyroxine (FT4), and free triiodothyronine (FT3) were measured by liquid chromatography tandem mass spectrometry and immunoassay in 100 patients and the two assays were compared. Results: T4 and T3 values measured by the two different assays correlated well with each other (r=0.91-0.95). However, the correlation was less good at the extremes (r=0.51-0.75). FT4 and FT3 concentrations measured by the two assays correlated less well with each other (r=0.75 and 0.50 respectively). The studied analytes had poor inverse correlation with the log-transformed TSH values (r=-0.22-0.51) in the population as a whole. The strongest correlations were seen in the groups of outpatients (r=-0.25-0.61). The weakest degree of correlation was noted in the inpatient group, with many correlations actually being positive. Conclusion: The worst between-assay correlation was demonstrated at low and high hormone concentrations, in the very concentration ranges where accurate assay performance is typically most clinically important. Based on the lesser susceptibility of mass spectrometry to interferences from conditions such as binding protein abnormalities, we speculate that mass spectrometry better reflects the clinical situation. In this mixed population of inpatients and outpatients, we also note failure of assays to conform to the anticipated inverse linear relationship between thyroid hormones and log-transformed TSH. (C) 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Jonklaas, Jacqueline; Sathasivam, Anpalakan] Georgetown Univ, Div Endocrinol, Washington, DC 20007 USA. [Sathasivam, Anpalakan; Burman, Kenneth D.] Medstar Washington Hosp Ctr, Endocrinol Sect, Washington, DC USA. [Wang, Hong] Medstar Hlth Res Inst, Hyattsville, MD USA. [Gu, Jianghong; Soldin, Steven J.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Jonklaas, J (reprint author), Georgetown Univ, Div Endocrinol, Suite 230,Bldg D,4000 Reservoir Rd NW, Washington, DC 20007 USA. EM jonklaaj@georgetown.edu FU National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA) a trademark of DHHS part of the [UL1TR000101] FX This project has been funded in part with Federal funds (UL1TR000101 previously UL1RR031975) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, "Re-Engineering the Clinical Research Enterprise". NR 25 TC 5 Z9 5 U1 4 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD SEP PY 2014 VL 47 IS 13-14 BP 1272 EP 1278 DI 10.1016/j.clinbiochem.2014.06.007 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AO4RN UT WOS:000341329000019 PM 24936679 ER PT J AU Dal Monte, O Schintu, S Pardini, M Berti, A Wassermann, EM Grafman, J Krueger, F AF Dal Monte, Olga Schintu, Selene Pardini, Matteo Berti, Anna Wassermann, Eric M. Grafman, Jordan Krueger, Frank TI The left inferior frontal gyrus is crucial for reading the mind in the eyes: Brain lesion evidence SO CORTEX LA English DT Article DE RMET; Mental states; Voxel-based lesion symptom mapping; Traumatic brain injury; Semantic working memory ID PREFRONTAL CORTEX; ARCUATE FASCICULUS; EMOTION RECOGNITION; COGNITIVE IMPAIRMENT; ASPERGER-SYNDROME; SOCIAL COGNITION; LOBE DAMAGE; INJURY; FMRI; LANGUAGE AB Deficit in the ability to understand and predict the mental states of others is one of the central features of traumatic brain injury (TBI), leading to problems in social-daily life such as social withdrawal and the inability to maintain work or family relationships. Although several functional neuroimaging studies have identified a widely distributed brain network involved in the Reading the Mind in the Eyes Test (RMET), the necessary brain regions engaged in this capacity are still heavily debated. In this study, we combined the RMET with a whole-brain voxel-based lesion symptom mapping (VLSM) approach to identify brain regions necessary for adequate RMET performance in a large sample of patients with penetrating TBI (pTBI). Our results revealed that pTBI patients performed worse on the RMET compared to non-head injured controls, and impaired RMET performance was associated with lesions in the left inferior frontal gyms (IFG). Our findings suggest that the left IFG is a key region in reading the mind in the eyes, probably involved in a more general impairment of a semantic working memory system that facilitates reasoning about what others are feeling and thinking as expressed by the eyes. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Dal Monte, Olga; Berti, Anna] Univ Turin, Dept Neuropsychol, Turin, Italy. [Schintu, Selene] Lyon Neurosci Res Ctr, CNRS, INSERM, ImpAct Team,UMR5292,U1028, Lyon, France. [Schintu, Selene] Univ UCBL Lyon 1, Lyon, France. [Pardini, Matteo] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet & Mat & Ch, Genoa, Italy. [Wassermann, Eric M.] Natl Inst Neurol Disorders & Stroke, Behav Neurol Unit, NIH, Bethesda, MD USA. [Grafman, Jordan] Rehabil Inst Chicago, Cognit Neurosci Lab, Chicago, IL 60611 USA. [Krueger, Frank] George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA USA. RP Krueger, F (reprint author), George Mason Univ, Dept Psychol, Mol Neurosci Dept, 4400 Univ Dr,Mail Stop 2A1, Fairfax, VA 22030 USA. EM fkrueger@gmu.edu OI Berti, Anna/0000-0001-9972-5543; dal monte, olga/0000-0002-7823-4769 FU U.S. National Institute of Neurological Disorders and Stroke Intramural Research Program FX This study was conducted and supported by the U.S. National Institute of Neurological Disorders and Stroke Intramural Research Program and took place at the National Institutes of Health Clinical Research Center. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the U.S. Government. For further information about the Vietnam Head Injury Study, contact J.G. at jgrafman@northwestern.edu. We thank the NIH Clinical Center for the provision of their facilities and for their supportive services. We thank Sandra Bonifant, Michael Tiemey, Leila Glass, Lyanne Yozawitz, Carolee Noury, Vivien YJ Tsen, and Anne Leopold who worked tirelessly to test subjects and organize the study. As always, the authors are grateful to all of the Vietnam veterans and caregivers who participated in this study. Their unending commitment to improving the health care of veterans is the reason this study could be completed. NR 64 TC 21 Z9 21 U1 4 U2 24 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD SEP PY 2014 VL 58 BP 9 EP 17 DI 10.1016/j.cortex.2014.05.002 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AO6OA UT WOS:000341470200002 PM 24946302 ER PT J AU Shah, S Wu, E Rao, VK Tarrant, TK AF Shah, Shaili Wu, Eveline Rao, V. Koneti Tarrant, Teresa K. TI Autoimmune Lymphoproliferative Syndrome: an Update and Review of the Literature SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Review; Autoimmune lymphoproliferative syndrome (ALPS); Apoptosis; Autoimmunity; Primary immunodeficiency ID BONE-MARROW-TRANSPLANTATION; FAS GENE-MUTATIONS; SYNDROME ALPS; THROMBOCYTOPENIC PURPURA; DEFECTIVE LYMPHOCYTE; APOPTOSIS; PATIENT; ADULT; CYTOPENIAS; DEFICIENCY AB Autoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis. C1 [Shah, Shaili] Univ N Carolina, Sch Med, Dept Med, Div Rheumatol Allergy & Immunol, Chapel Hill, NC 27599 USA. [Wu, Eveline] Univ N Carolina, Sch Med, Dept Pediat, Div Rheumatol Allergy & Immunol, Chapel Hill, NC 27599 USA. [Rao, V. Koneti] NIAID, ALPS Unit, Mol Dev Sect, Lab Immunol,DIR,NIH,DHHS, Bethesda, MD 20892 USA. [Tarrant, Teresa K.] Thurston Arthrit Res Ctr, Dept Med, Div Rheumatol Allergy & Immunol, Chapel Hill, NC 27599 USA. RP Tarrant, TK (reprint author), Thurston Arthrit Res Ctr, Dept Med, Div Rheumatol Allergy & Immunol, CB 7280,3300 Manning Dr, Chapel Hill, NC 27599 USA. EM snshah@unch.unc.edu; eywu@email.unc.edu; korao@niaid.nih.gov; teresa_tarrant@med.unc.edu FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; [1R03AR059286] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and 1R03AR059286. NR 33 TC 10 Z9 13 U1 0 U2 7 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 EI 1534-6315 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD SEP PY 2014 VL 14 IS 9 AR 462 DI 10.1007/s11882-014-0462-4 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA AO6AC UT WOS:000341428400006 PM 25086580 ER PT J AU Lucas, GM Young, A Donnell, D Richardson, P Aramrattana, A Shao, YM Ruan, YH Liu, W Fug, LP Ma, J Celentano, DD Metzger, D Jackson, JB Burns, D AF Lucas, Gregory M. Young, Alicia Donnell, Deborah Richardson, Paul Aramrattana, Apinun Shao, Yiming Ruan, Yuhua Liu, Wei Fug, Liping Ma, Jun Celentano, David D. Metzger, David Jackson, J. Brooks Burns, David TI Hepatotoxicity in a 52-week randomized trial of short-term versus long-term treatment with buprenorphine/naloxone in HIV-negative injection opioid users in China and Thailand SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Buprenorphine/naloxone; Injection drug use; Opioid dependence; HIV prevention; Safety; Hepatotoxicity; Alanine aminotransferase; Hepatitis C virus ID DEPENDENT PATIENTS; HEPATITIS; LIVER AB Background: Buprenorphine/naloxone (BUP/NX), an effective treatment for opioid dependence, has been implicated in hepatic toxicity. However, as persons taking BUP/NX have multiple hepatic risk factors, comparative data are needed to quantify the risk of hepatoxicity with BUP/NX. Methods: We compared rates of alanine aminotransferase (ALT) elevation >= grade 3 (ALT >= 5.1 times the upper limit of normal) and graded bilirubin elevations in HIV-negative opioid injectors randomized to long-term (52 weeks) or short-term (18 days) medication assisted treatment (LT-MAT and ST-MAT, respectively) with BUP/NX in a multisite trial conducted in China and Thailand. ALT and bilirubin were measured at baseline, 12, 26, 40 and 52 weeks, times temporally remote from BUP/NX exposure in the ST-MAT participants. Results: Among1036 subjects with at least one laboratory follow-up measurement, 76 (7%) participants experienced ALT elevation >= grade 3. In an intent-to-treat analysis, the risk of ALT events was similar in participants randomized to LT-MAT compared with ST-MAT (adjusted hazard ratio 1.25,95% confidence interval 0.79 to 1.98). This finding was supported by an as-treated analysis, in which actual exposure to BUP/NX was considered. Hepatitis C seroconversion during follow-up was strongly associated with ALT events. Bilirubin elevations >= grade 2 occurred in 2% of subjects, with no significant difference between arms. Conclusions: Over 52-week follow-up, the risk of hepatotoxicity was similar in opioid injectors receiving brief and prolonged treatment with BUP/NX. These data suggest that most hepatotoxic events observed during treatment with BUP/NX are due to other factors. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Lucas, Gregory M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Young, Alicia; Donnell, Deborah] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Richardson, Paul; Jackson, J. Brooks] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Aramrattana, Apinun] Chiang Mai Univ, Fac Med, Dept Family Med, Chiang Mai 50000, Thailand. [Shao, Yiming; Ruan, Yuhua] Natl Ctr AIDS STD Control & Prevent, Chinese Ctr Dis Control & Prevent, Ctr Diag & Treatment Infect Dis, State Key Lab Infect Dis Prevent & Control, Beijing, Peoples R China. [Liu, Wei] Guangxi Ctr HIV AIDS Prevent & Control, Guangxi Ctr Dis Control & Prevent, Nanning 530028, Guangxi, Peoples R China. [Fug, Liping; Ma, Jun] Xinjiang Autonomous Reg Ctr Dis Control & Prev, Urumqi 830002, Xinjiang, Peoples R China. [Celentano, David D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Metzger, David] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Burns, David] NIAID, Div Aids, Prevent Sci Branch, Bethesda, MD 20892 USA. RP Lucas, GM (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 1830 E Monument St,Room 435A, Baltimore, MD 21287 USA. EM glucas@jhmi.edu RI Metzger, David/D-9499-2012; OI Donnell, Deborah/0000-0002-0587-7480 FU HIV Prevention Trials Network (HPTN); National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse [K24 DA035684]; National Institute of Mental Health; Office of AIDS Research, of the National Institutes of Health, U.S. Department of Health and Human Services [UM1 AI068619, UO1 AI068613, UM1 AI068613]; Johns Hopkins Center for AIDS Research [P30 AI094189] FX This study was funded by the HIV Prevention Trials Network (HPTN) and sponsored by the National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the National Institutes of Health, U.S. Department of Health and Human Services under award numbers UM1 AI068619, UO1 AI068613, and UM1 AI068613. GML was supported by the National Institute on Drug Abuse (K24 DA035684) and by the Johns Hopkins Center for AIDS Research (P30 AI094189). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The buprenorphine/naloxone (Suboxone) used in the trial was provided by Reckitt Benckiser Pharmaceuticals, Inc. The National Institutes of Health and participating manufacturer had no further role in the study design; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. NR 18 TC 2 Z9 2 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 1 PY 2014 VL 142 BP 139 EP 145 DI 10.1016/j.drugalcdep.2014.06.013 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AO4YQ UT WOS:000341347700019 PM 24999060 ER PT J AU Compton, WM Gfroerer, J Conway, KP Finger, MS AF Compton, Wilson M. Gfroerer, Joe Conway, Kevin P. Finger, Matthew S. TI Unemployment and substance outcomes in the United States 2002-2010 SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Unemployment; Economic cycle; Substance abuse; Social epidemiology; Policy ID ILLEGAL DRUG-USE; ECONOMIC-CONDITIONS; GENERAL-POPULATION; ALCOHOL-PROBLEMS; DRINKING; EMPLOYMENT; PREVALENCE; DISORDERS; ABUSE AB Background: The economic shock of 2008-2009 provided an opportunity to study the robustness of observed statistical associations between unemployment and problematic substance use. Methods: Data from 405,000 non-institutionalized adult participants in the 2002 to 2010 U.S. National Survey on Drug Use and Health were used to compare substance outcomes among unemployed and employed persons. Association of unemployment with substance outcomes was examined for the years 2002-2004, 2005-2007, 2008, and 2009-2010, corresponding to periods prior to and after the economic downturn of 2008. Multivariate logistic regression models adjusted forage, sex, race/ethnicity, education, urban/rural residence, current DSM-IV Major Depression, and local county unemployment rates. Results: Higher rates of past month tobacco and illicit drug use, heavy alcohol use, and past-year drug or alcohol abuse/dependence were found among the unemployed. Markedly increased unemployment in 2009-2010 did not moderate the association between substance outcomes and employment. This association was not confounded by sex, age group, or race/ethnicity for tobacco and illicit drugs, although it varied for alcohol outcomes among 18-25 year-olds. Results based on retrospective data regarding marijuana use in the period prior to unemployment suggest its use was associated with future job loss. Conclusions: Employment status was strongly and robustly associated with problematic use of substances. Prevention and treatment interventions are warranted for a group whose employment and resulting insurance status may impair access to much needed health care. Published by Elsevier Ireland Ltd. C1 [Compton, Wilson M.; Conway, Kevin P.; Finger, Matthew S.] NIDA, NIH, Bethesda, MD 20892 USA. [Gfroerer, Joe] Substance Abuse & Mental Hlth Serv Adm, Ctr Behav Hlth Stat & Qual, Rockville, MD 20857 USA. RP Compton, WM (reprint author), NIDA, NIH, 6001 Execut Blvd,MSC 9581, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov OI Conway, Kevin/0000-0002-7638-339X FU Center for Behavioral Health Statistics and Quality (CBHSQ) [HHSS283201000003C]; Substance Abuse and Mental Health Services Administration (SAMHSA); U.S. Department of Health and Human Services (HHS); RTI International, Research Triangle Park, North Carolina FX Support for this work was through Contract Number HHSS283201000003C by the Center for Behavioral Health Statistics and Quality (CBHSQ), Substance Abuse and Mental Health Services Administration (SAMHSA), U.S. Department of Health and Human Services (HHS), with RTI International, Research Triangle Park, North Carolina. The co-authors planned and supervised all data analysis and drafted the manuscript as part of their official work at SAMHSA (JG) and the National Institute on Drug Abuse (WC, KC, MF). NR 34 TC 22 Z9 22 U1 4 U2 45 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 1 PY 2014 VL 142 BP 350 EP 353 DI 10.1016/j.drugalcdep.2014.06.012 PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AO4YQ UT WOS:000341347700049 PM 25042761 ER PT J AU Booth, M Donaldson, L Cui, XZ Sun, JF Cole, S Dailsey, S Hart, A Johns, N McConnell, P McLennan, T Parcell, B Robb, H Shippey, B Sim, M Wallis, C Eichacker, PQ AF Booth, Malcolm Donaldson, Lindsay Cui, Xizhong Sun, Junfeng Cole, Stephen Dailsey, Susan Hart, Andrew Johns, Neil McConnell, Paul McLennan, Tina Parcell, Benjamin Robb, Henry Shippey, Benjamin Sim, Malcolm Wallis, Charles Eichacker, Peter Q. TI Confirmed Bacillus anthracis Infection among Persons Who Inject Drugs, Scotland, 2009-2010 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID SOFT-TISSUE INFECTIONS; NECROTIZING FASCIITIS; INHALATIONAL ANTHRAX; HEROIN USERS; LETHAL TOXIN; EDEMA TOXINS; PATHOGENESIS; PATHOLOGY; OUTBREAK; SCORE AB In Scotland, the 2009 outbreak of Bacillus anthracis infection among persons who inject drugs resulted in a 28% death rate. To compare nonsurvivors and survivors, we obtained data on 11 nonsurvivors and 16 survivors. Time from B. anthracis exposure to symptoms or hospitalization and skin and limb findings at presentation did not differ between nonsurvivors and survivors. Proportionately more nonsurvivors had histories of excessive alcohol use (p = 0.05) and required vasopressors and/or mechanical ventilation (p <= 0.01 for each individually). Nonsurvivors also had higher sequential organ failure assessment scores (mean +/- SEM) (7.3 +/- 0.9 vs. 1.2 +/- 0.4, p<0.0001). Antibacterial drug administration, surgery, and anthrax polyclonal immune globulin treatments did not differ between nonsurvivors and survivors. Of the 14 patients who required vasopressors during hospitalization, 11 died. Sequential organ failure assessment score or vasopressor requirement during hospitalization might identify patients with injectional anthrax for whom limited adjunctive therapies might be beneficial. C1 [Booth, Malcolm; Donaldson, Lindsay; Hart, Andrew] Glasgow Royal Infirm, Glasgow G4 0SF, Lanark, Scotland. [Cui, Xizhong; Sun, Junfeng; Eichacker, Peter Q.] NIH, Bethesda, MD 20892 USA. [Cole, Stephen; Parcell, Benjamin] Ninewells Hosp, Dundee DD1 9SY, Scotland. [Dailsey, Susan] Victoria Infirm, Glasgow G42 9TY, Lanark, Scotland. [Johns, Neil; Shippey, Benjamin] Queen Margaret Hosp, Dumfermline, Scotland. [Johns, Neil; Shippey, Benjamin] Victoria Hosp, Dumfermline, Scotland. [McConnell, Paul] Crosshouse Hosp, Kilmarnock, Scotland. [McLennan, Tina] Hairmyres Hosp, E Kilbride, Lanark, Scotland. [Robb, Henry] Forth Valley Royal Hosp, Larbert, Scotland. [Sim, Malcolm] Univ Glasgow, Western Infirm, Glasgow G11 6NT, Lanark, Scotland. [Wallis, Charles] Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM peichacker@mail.nih.gov FU National Institutes of Health; National Institutes of Health Clinical Center FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institutes of Health Clinical Center. NR 34 TC 9 Z9 9 U1 1 U2 6 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD SEP PY 2014 VL 20 IS 9 BP 1452 EP 1463 DI 10.3201/eid2009.131481 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AO3JY UT WOS:000341226700003 PM 25148307 ER PT J AU Weller, D Campbell, C Taplin, S Klabunde, C AF Weller, David Campbell, Christine Taplin, Stephen Klabunde, Carrie TI The role of primary care in cancer screening international comparison study by Ca-PRI and the International Cancer Screening Network SO EUROPEAN JOURNAL OF CANCER CARE LA English DT Meeting Abstract C1 [Weller, David; Campbell, Christine] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9YL, Midlothian, Scotland. [Taplin, Stephen; Klabunde, Carrie] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM David.Weller@ed.ac.uk NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-5423 EI 1365-2354 J9 EUR J CANCER CARE JI Eur. J. Cancer Care PD SEP PY 2014 VL 23 SU 1 SI SI MA P-01 BP 1 EP 1 PG 1 WC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation SC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation GA AO9YA UT WOS:000341715300002 ER PT J AU Gorin, SS Breslau, E AF Gorin, Sherri Sheinfeld Breslau, Erica TI Place, patients, populations and primary care: the impact of place on health-related quality of life among US cancer survivors SO EUROPEAN JOURNAL OF CANCER CARE LA English DT Meeting Abstract C1 [Gorin, Sherri Sheinfeld] Columbia Univ, Natl Canc Inst, Div Canc Control & Populat Sci, New York, NY USA. EM sherri.gorin@gmail.com NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-5423 EI 1365-2354 J9 EUR J CANCER CARE JI Eur. J. Cancer Care PD SEP PY 2014 VL 23 SU 1 SI SI MA P-38 BP 14 EP 15 PG 2 WC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation SC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation GA AO9YA UT WOS:000341715300037 ER PT J AU Neal, RD Campbell, C Hamilton, W Stapley, S Weller, D Lyratzopoulos, G Emery, J Torring, ML Vedsted, P Rubin, G Charlton, P AF Neal, Richard D. Campbell, Christine Hamilton, Willie Stapley, Sal Weller, David Lyratzopoulos, Georgios Emery, Jon Torring, Marie Louise Vedsted, Peter Rubin, Greg Charlton, Paul TI Building the evidence base for the early symptomatic diagnosis of cancer (the ABC-DEEP consortium) - what are the policy and research implications for the international community? SO EUROPEAN JOURNAL OF CANCER CARE LA English DT Meeting Abstract C1 [Neal, Richard D.] Bangor Univ, North Wales Ctr Primary Care Res, Bangor, Gwynedd, Wales. [Campbell, Christine; Weller, David] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Hamilton, Willie; Stapley, Sal] Univ Exeter, Exeter EX4 4QJ, Devon, England. [Lyratzopoulos, Georgios] Univ Cambridge, Cambridge CB2 1TN, England. [Emery, Jon] Univ Melbourne, Melbourne, Vic 3010, Australia. [Torring, Marie Louise; Vedsted, Peter] Aarhus Univ, DK-8000 Aarhus C, Denmark. [Rubin, Greg] Univ Durham, Durham DH1 3HP, England. [Charlton, Paul] Natl Inst Canc Res, Bethesda, MD USA. EM r.neal@bangor.ac.uk RI Vedsted, Peter/C-2583-2008 OI Vedsted, Peter/0000-0003-2113-5599 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-5423 EI 1365-2354 J9 EUR J CANCER CARE JI Eur. J. Cancer Care PD SEP PY 2014 VL 23 SU 1 SI SI MA W-02 BP 34 EP 34 PG 1 WC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation SC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation GA AO9YA UT WOS:000341715300086 ER PT J AU Cohen, AA Milot, E Li, Q Legault, V Fried, LP Ferrucci, L AF Cohen, Alan A. Milot, Emmanuel Li, Qing Legault, Veronique Fried, Linda P. Ferrucci, Luigi TI Cross-population validation of statistical distance as a measure of physiological dysregulation during aging SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Physiological dysregulation; Aging; WHAS; InCHIANTI; Biomarker; Mahalanobis distance ID ALLOSTATIC LOAD; ELDERLY-PEOPLE; OLDER-ADULTS; FRAILTY; DECLINE; STRESS AB Measuring physiological dysregulation during aging could be a key tool both to understand underlying aging mechanisms and to predict clinical outcomes in patients. However, most existing indices are either circular or hard to interpret biologically. Recently, we showed that statistical distance of 14 common blood biomarkers (a measure of how strange an individual's biomarker profile is) was associated with age and mortality in the WHAS II data set, validating its use as a measure of physiological dysregulation. Here, we extend the analyses to other data sets (WHAS I and InCHIANTI) to assess the stability of the measure across populations. We found that the statistical criteria used to determine the original 14 biomarkers produced diverging results across populations; in other words, had we started with a different data set, we would have chosen a different set of markers. Nonetheless, the same 14 markers (or the subset of 12 available for InCHIANTI) produced highly similar predictions of age and mortality. We include analyses of all combinatorial subsets of the markers and show that results do not depend much on biomarker choice or data set, but that more markers produce a stronger signal. We conclude that statistical distance as a measure of physiological dysregulation is stable across populations in Europe and North America. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cohen, Alan A.; Milot, Emmanuel; Li, Qing; Legault, Veronique] Univ Sherbrooke, CHUS Fleurimont, Dept Family Med, Grp Rech PRIMUS, Sherbrooke, PQ J1H 5N4, Canada. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, Longitudinal Studies Sect, NIH,MedStar Harbor Hosp, Baltimore, MD 21225 USA. RP Cohen, AA (reprint author), Univ Sherbrooke, CHUS Fleurimont, Dept Family Med, Grp Rech PRIMUS, 3001 12e Ave N, Sherbrooke, PQ J1H 5N4, Canada. EM Alan.Cohen@USherbrooke.ca FU Centre de recherche sur le vieillissement; Centre de recherche Etienne Le-Bel; FRQ-S; CIHR [s 110789, 120305, 119485]; NSERC [402079-2011]; NIH [P30 AG021334]; Intramural Research Program of the National Institute on Aging FX AAC is a member of the FRQ-S-supported Centre de recherche sur le vieillissement and Centre de recherche Etienne Le-Bel, and is a funded Research Scholar of the FRQ-S. This research was supported by CIHR grant #s 110789, 120305, 119485, by NSERC Discovery Grant # 402079-2011, and by NIH grant # P30 AG021334. Two anonymous reviewers provided comments that greatly improved the manuscript. This research was supported by the Intramural Research Program of the National Institute on Aging. NR 24 TC 9 Z9 9 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD SEP PY 2014 VL 57 BP 203 EP 210 DI 10.1016/j.exger.2014.04.016 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AO5HI UT WOS:000341374300027 PM 24802990 ER PT J AU Patel, A Malik, M Britten, J Cox, J Catherino, WH AF Patel, Amrita Malik, Minnie Britten, Joy Cox, Jeris Catherino, William H. TI Alternative therapies in management of leiomyomas SO FERTILITY AND STERILITY LA English DT Article DE Leiomyomas; MRgFUS; cryomyolyisis; occlusion of uterine arteries ID FOCUSED ULTRASOUND SURGERY; SYMPTOMATIC UTERINE MYOMAS; RADIOFREQUENCY THERMAL ABLATION; LAPAROSCOPIC CRYOMYOLYSIS; CONSERVATIVE TREATMENT; ARTERY-OCCLUSION; FIBROID TUMORS; FEASIBILITY; TEMPORARY; MRGFUS AB Leiomyomas are benign soft-tissue neoplasms that arise from smooth muscle. Relief of symptoms (abnormal uterine bleeding, pain, pressure) is the major goal in management of women with significant symptoms. For symptomatic myomas, hysterectomy is a definitive solution; however, there are emerging less-invasive options. Magnetic resonance imaging-guided focused ultrasound surgery, cryomyolysis, and temporary occlusion of the uterine arteries are treatment options that are minimally invasive interventions with the benefit of preserving the uterus. This review summarizes procedure techniques, eligibility, complications, and outcomes of these alternate therapies. (C) 2014 by American Society for Reproductive Medicine. C1 [Patel, Amrita; Malik, Minnie; Britten, Joy; Cox, Jeris; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Cox, Jeris; Catherino, William H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM william.catherino@usuhs.edu OI Malik, Minnie/0000-0003-1129-6575 NR 35 TC 6 Z9 8 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2014 VL 102 IS 3 BP 649 EP 655 DI 10.1016/j.fertnstert.2014.07.008 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AO5DU UT WOS:000341363300006 PM 25106764 ER PT J AU Zarek, SM Hill, MJ Richter, KS Wu, M DeCherney, AH Osheroff, JE Levens, ED AF Zarek, Shvetha M. Hill, Micah J. Richter, Kevin S. Wu, Mae DeCherney, Alan H. Osheroff, Joseph E. Levens, Eric D. TI Single-donor and double-donor sperm intrauterine insemination cycles: does double intrauterine insemination increase clinical pregnancy rates? SO FERTILITY AND STERILITY LA English DT Article DE Donor sperm; double intrauterine insemination; ovulation induction ID MALE FACTOR INFERTILITY; UNEXPLAINED INFERTILITY; COST-EFFECTIVENESS; METAANALYSIS; TRIAL AB Objective: To compare the pregnancy outcomes in the setting of a single-vs. double-donor sperm intrauterine insemination (IUI) treatment cycle. Design: Retrospective cohort study. Setting: Large, private assisted reproductive technology practice. Patient(s): Donor sperm IUI recipients. Intervention(s): None. Main Outcome Measure(s): Clinical pregnancy. Result(s): There were 2,486 double and 673 single-donor sperm IUI cycles. The two groups were similar for age, body mass index, and the number of prior cycles. The clinical pregnancy rates were similar between the two groups (single: 16.4% vs. double: 13.6%). In univariate regression analysis, age, total motile sperm, and diminished ovarian reserve (DOR) were associated with pregnancy. Generalized estimating equation models accounting for repeated measures, age, DOR and total motile sperm and the interactions of these factors demonstrated that single and double IUI had similar odds of pregnancy (odds ratio 1.12; 95% confidence interval, 0.96-1.44). Pregnancy rates remained similar between the two groups in matched comparison and other subgroup analyses. Conclusion(s): Single and double-donor IUI cycles had similar clinical pregnancy rates. This large data set did not demonstrate a benefit to routine double IUI in donor sperm cycles. (C) 2014 by American Society for Reproductive Medicine.) C1 [Zarek, Shvetha M.; Hill, Micah J.; Richter, Kevin S.; Osheroff, Joseph E.; Levens, Eric D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD 20850 USA. [Zarek, Shvetha M.; Hill, Micah J.; Wu, Mae; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Levens, ED (reprint author), Shady Grove Fertil Reprod Sci Ctr, 15001 Shady Grove Rd, Rockville, MD 20850 USA. EM eric.levens@integramed.com OI Hill, Micah/0000-0002-3104-7763 FU Intramural Research Program of the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported, in part, by the Intramural Research Program of the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U. S. Government. NR 14 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2014 VL 102 IS 3 BP 739 EP 743 DI 10.1016/j.fertnstert.2014.05.018 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AO5DU UT WOS:000341363300023 PM 24934490 ER PT J AU Jaremka, LM Andridge, RR Fagundes, CP Alfano, CM Povoski, SP Lipari, AM Agnese, DM Arnold, MW Farrar, WB Yee, LD Carson, WE Bekaii-Saab, T Martin, EW Schmidt, CR Kiecolt-Glaser, JK AF Jaremka, Lisa M. Andridge, Rebecca R. Fagundes, Christopher P. Alfano, Catherine M. Povoski, Stephen P. Lipari, Adele M. Agnese, Doreen M. Arnold, Mark W. Farrar, William B. Yee, Lisa D. Carson, William E., III Bekaii-Saab, Tanios Martin, Edward W., Jr. Schmidt, Carl R. Kiecolt-Glaser, Janice K. TI Pain, Depression, and Fatigue: Loneliness as a Longitudinal Risk Factor SO HEALTH PSYCHOLOGY LA English DT Article DE pain; depression; fatigue; loneliness; aging ID QUALITY-OF-LIFE; GENERAL-POPULATION; SYMPTOM CLUSTER; OLDER-ADULTS; MULTIPLE-SCLEROSIS; NEUROENDOCRINE RESPONSES; HEALTH-PROBLEMS; CHRONIC STRESS; SLEEP QUALITY; IMMUNE-SYSTEM AB Objective: Pain, depression, and fatigue function as a symptom cluster and thus may share common risk factors. Interpersonal relationships clearly influence health, suggesting that loneliness may promote the development of the pain, depression, and fatigue symptom cluster. We hypothesized that loneliness would be related to concurrent symptom cluster levels and increases in symptom cluster levels over time. Method: We utilized two observational studies with distinct longitudinal samples. Study 1 was a sample of cancer survivors and benign controls (N = 115) assessed annually for 2 years. Study 2 was a sample of older adults caring for a spouse with dementia (caregivers) and noncaregiver controls (N = 229) assessed annually for 4 years. Participants completed annual measures assessing loneliness, pain, depression, and fatigue. Results: Across both samples, lonelier participants experienced more concurrent pain, depression, and fatigue and larger increases in symptom cluster levels from one year to the next than less lonely participants. Sleep quality did not mediate the results in either study. All analyses were adjusted for relevant demographic and health variables. Conclusions: Two longitudinal studies with different populations demonstrated that loneliness was a risk factor for the development of the pain, depression, and fatigue symptom cluster over time. The current research helps identify people most at risk for pain, depression, and fatigue, and lays the groundwork for research about their diagnosis and treatment. These data also highlight the health risks of loneliness; pain, depression, and fatigue often accompany serious illness and place people at risk for poor health and mortality. C1 [Jaremka, Lisa M.; Fagundes, Christopher P.] Ohio State Univ, Coll Med, Inst Behav Med Res, Columbus, OH 43210 USA. [Andridge, Rebecca R.] Ohio State Univ, Coll Publ Hlth, Coll Med, Columbus, OH 43210 USA. [Alfano, Catherine M.] NCI, Bethesda, MD 20892 USA. [Povoski, Stephen P.; Lipari, Adele M.; Agnese, Doreen M.; Arnold, Mark W.; Farrar, William B.; Yee, Lisa D.; Carson, William E., III; Bekaii-Saab, Tanios; Martin, Edward W., Jr.; Schmidt, Carl R.] Ohio State Univ, Coll Med, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Povoski, Stephen P.; Lipari, Adele M.; Agnese, Doreen M.; Arnold, Mark W.; Farrar, William B.; Yee, Lisa D.; Carson, William E., III; Martin, Edward W., Jr.; Schmidt, Carl R.] Ohio State Univ, Coll Med, Dept Surg, Columbus, OH 43210 USA. [Bekaii-Saab, Tanios] Ohio State Univ, Coll Med, Dept Internal Med, Columbus, OH 43210 USA. [Kiecolt-Glaser, Janice K.] Ohio State Univ, Coll Med, Inst Behav Med Res, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Kiecolt-Glaser, Janice K.] Ohio State Univ, Coll Med, Dept Psychiat, Columbus, OH 43210 USA. RP Jaremka, LM (reprint author), Ohio State Univ, Coll Med, Inst Behav Med Res, 460 Med Ctr Dr, Columbus, OH 43210 USA. EM lisa.jaremka@osumc.edu RI Kiecolt-Glaser, Janice/A-3236-2009; Andridge, Rebecca/C-8457-2012; Carson, William/E-2846-2011; Povoski, Stephen/E-3887-2011; Agnese, Doreen/I-1351-2012; Bekaii-Saab, Tanios/E-2733-2011 OI Kiecolt-Glaser, Janice/0000-0003-4900-9578; Andridge, Rebecca/0000-0001-9991-9647; FU NIH [AG011585, CA131029, M01RR0034, UL1RR025755]; American Cancer Society Postdoctoral Fellowship [121911-PF-12-040-01-CPPB, PF-11-007-01-CPPB]; Ohio State University Comprehensive Cancer Center FX Work on this project was supported in part by NIH grants AG011585, CA131029, M01RR0034, and UL1RR025755 as well as American Cancer Society Postdoctoral Fellowship Grants 121911-PF-12-040-01-CPPB and PF-11-007-01-CPPB and a Pelotonia Postdoctoral Fellowship from the Ohio State University Comprehensive Cancer Center. All authors declare that there are no financial conflicts of interest. NR 62 TC 21 Z9 21 U1 17 U2 68 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD SEP PY 2014 VL 33 IS 9 BP 948 EP 957 DI 10.1037/a0034012 PG 10 WC Psychology, Clinical; Psychology SC Psychology GA AO6VC UT WOS:000341488900003 PM 23957903 ER PT J AU Persoskie, A Ferrer, RA Nelson, WL Klein, WMP AF Persoskie, Alexander Ferrer, Rebecca A. Nelson, Wendy L. Klein, William M. P. TI Precancer Risk Perceptions Predict Postcancer Subjective Well-Being SO HEALTH PSYCHOLOGY LA English DT Article DE risk perception; cancer; subjective well-being; resilience; optimism ID QUALITY-OF-LIFE; CANCER SURVIVORS; UNREALISTIC OPTIMISM; BREAST-CANCER; MENTAL-HEALTH; SELF; ADJUSTMENT; PREVENTION; KNOWLEDGE; BEHAVIOR AB Objective: The present study used longitudinal data to explore whether subjective well-being in cancer survivors was related to predisease judgments of their likelihood of getting cancer. Method: Subjective well-being was assessed in terms of affective well-being (frequency of positive and negative affective states) and satisfaction with one's life overall. The sample consisted of 158 participants in the National Survey of Midlife Development in the U. S. (MIDUS) who developed cancer during the 8-10 years between the first and second waves of the survey (average time since diagnosis = 3.37 years; SD = 2.48), and 3,243 control participants who reported no history of cancer at either wave. Results: Controlling for demographic variables and well-being at Wave 1, the effect of cancer on well-being depended on whether, prior to being diagnosed, people judged themselves to be at low or high risk of cancer. For those perceiving a high risk, a cancer diagnosis had a modest but significant negative impact on affect and life satisfaction, whereas no negative impact emerged for those perceiving a low risk. Similar effects were not observed for heart attack risk perceptions, or for measures of trait optimism or depression, suggesting that the effect was domain-specific. Conclusions: Low precancer risk perceptions were associated with long-term benefits for subjective well-being in people who developed cancer. C1 [Persoskie, Alexander; Ferrer, Rebecca A.; Nelson, Wendy L.; Klein, William M. P.] NCI, Behav Res Program, Bethesda, MD 20892 USA. RP Persoskie, A (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM persoskieai@mail.nih.gov FU NIA NIH HHS [P01 AG020166] NR 49 TC 1 Z9 1 U1 1 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD SEP PY 2014 VL 33 IS 9 BP 1023 EP 1032 DI 10.1037/hea0000074 PG 10 WC Psychology, Clinical; Psychology SC Psychology GA AO6VC UT WOS:000341488900011 PM 24588629 ER PT J AU Parpart, S Roessler, S Dong, F Rao, V Takai, A Ji, JF Qin, LX Ye, QH Jia, HL Tang, ZY Wang, XW AF Parpart, Sonya Roessler, Stephanie Dong, Fei Rao, Vinay Takai, Atsushi Ji, Junfang Qin, Lun-Xiu Ye, Qing-Hai Jia, Hu-Liang Tang, Zhao-You Wang, Xin Wei TI Modulation of miR-29 Expression by Alpha-Fetoprotein Is Linked to the Hepatocellular Carcinoma Epigenome SO HEPATOLOGY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; DNA METHYLATION; TRANSGENIC MICE; X-PROTEIN; C-MYC; CANCER; MICRORNAS; IDENTIFICATION; SURVIVAL; GENES AB Globally, hepatocellular carcinoma (HCC) accounts for 70%-85% of primary liver cancers and ranks as the second leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP(+) and AFP(-) tumors differ biologically. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage (P < 0.043). Using microarray-based global microRNA (miRNA) profiling, we found that miRNA-29 (miR-29) family members were the most significantly (P < 0.001) down-regulated miRNAs in AFP(+) tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (P < 0.001) between miR-29 and DNMT3A gene expression, suggesting that they might be functionally antagonistic. Moreover, global DNA methylation profiling reveals that AFP(+) and AFP(-) HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP(+) HCC. Experimentally, we found that AFP expression in AFP(-) HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP(+) cells, inhibits miR-29a expression and induces DNMT3A expression in AFP(-) HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus, and this effect is mediated through c-MYC binding to the transcript of miR-29a/b-1. Furthermore, AFP expression promotes tumor growth of AFP(-) HCC cells in nude mice. Conclusion: Tumor biology differs considerably between AFP(+) HCC and AFP(-) HCC; AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC. C1 [Parpart, Sonya; Roessler, Stephanie; Dong, Fei; Rao, Vinay; Takai, Atsushi; Ji, Junfang; Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Parpart, Sonya] Georgetown Univ, Dept Tumor Biol, Washington, DC USA. [Qin, Lun-Xiu; Ye, Qing-Hai; Jia, Hu-Liang; Tang, Zhao-You] Fudan Univ, Liver Canc Inst, Shanghai 200032, Peoples R China. [Qin, Lun-Xiu; Ye, Qing-Hai; Jia, Hu-Liang; Tang, Zhao-You] Fudan Univ, Zhongshan Hosp, Shanghai 200032, Peoples R China. RP Wang, XW (reprint author), NCI, 37 Convent Dr, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 FU Center for Cancer Research, National Cancer Institute (Bethesda, MD) [Z01 BC 010313] FX This work was supported by a grant (Z01 BC 010313) from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (Bethesda, MD). NR 39 TC 24 Z9 25 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD SEP PY 2014 VL 60 IS 3 BP 872 EP 883 DI 10.1002/hep.27200 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO3NV UT WOS:000341239200015 PM 24798303 ER PT J AU Yi, HS Lee, YS Byun, JS Seo, W Jeong, JM Park, O Duester, G Haseba, T Kim, SC Park, KG Gao, B Jeong, WI AF Yi, Hyon-Seung Lee, Young-Sun Byun, Jin-Seok Seo, Wonhyo Jeong, Jong-Min Park, Ogyi Duester, Gregg Haseba, Takeshi Kim, Sun Chang Park, Keun-Gyu Gao, Bin Jeong, Won-Il TI Alcohol Dehydrogenase III Exacerbates Liver Fibrosis by Enhancing Stellate Cell Activation and Suppressing Natural Killer Cells in Mice SO HEPATOLOGY LA English DT Article ID RETINOIC ACID; HEPATIC-FIBROSIS; VITAMIN-A; ALL-TRANS; TGF-BETA; METABOLISM; PROLIFERATION; PHENOTYPE; GROWTH; ORGAN AB The important roles of retinols and their metabolites have recently been emphasized in the interactions between hepatic stellate cells (HSCs) and natural killer (NK) cells. Nevertheless, the expression and role of retinol metabolizing enzyme in both cell types have yet to be clarified. Thus, we investigated the expression of retinol metabolizing enzyme and its role in liver fibrosis. Among several retinol metabolizing enzymes, only alcohol dehydrogenase (ADH) 3 expression was detected in isolated HSCs and NK cells, whereas hepatocytes express all of them. In vitro treatment with 4-methylpyrazole (4-MP), a broad ADH inhibitor, or depletion of the ADH3 gene down-regulated collagen and transforming growth factor-beta 1 (TGF-beta 1) gene expression, but did not affect alpha-smooth muscle actin gene expression in cultured HSCs. Additionally, in vitro, treatments with retinol suppressed NK cell activities, whereas inhibition of ADH3 enhanced interferon-gamma (IFN-gamma) production and cytotoxicity of NK cells against HSCs. In vivo, genetic depletion of the ADH3 gene ameliorated bile duct ligation- and carbon tetrachloride-induced liver fibrosis, in which a higher number of apoptotic HSCs and an enhanced activation of NK cells were detected. Freshly isolated HSCs from ADH3-deficient mice showed reduced expression of collagen and TGF-beta 1, but enhanced expression of IFN-gamma was detected in NK cells from these mice compared with those of control mice. Using reciprocal bone marrow transplantation of wild-type and ADH3-deficient mice, we demonstrated that ADH3 deficiency in both HSCs and NK cells contributed to the suppressed liver fibrosis. Conclusion: ADH3 plays important roles in promoting liver fibrosis by enhancing HSC activation and inhibiting NK cell activity, and could be used as a potential therapeutic target for the treatment of liver fibrosis. C1 [Yi, Hyon-Seung; Lee, Young-Sun; Seo, Wonhyo; Jeong, Jong-Min; Jeong, Won-Il] Korea Adv Inst Sci & Technol, GSMSE, Lab Liver Res, Taejon 305701, South Korea. [Byun, Jin-Seok] Kyungpook Natl Univ, Sch Dent, Dept Oral Med, Taegu, South Korea. [Park, Ogyi; Gao, Bin] NIAAA, Lab Liver Study, NIH, Bethesda, MD USA. [Duester, Gregg] Sanford Burnham Med Res Inst, La Jolla, CA USA. [Haseba, Takeshi] Nippon Med Sch, Dept Lab Med, Tokyo 113, Japan. [Kim, Sun Chang] Intelligent Synthet Biol Ctr, Taejon, South Korea. [Kim, Sun Chang] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. [Park, Keun-Gyu] Kyungpook Natl Univ, Sch Med, Dept Internal Med, Taegu, South Korea. RP Jeong, WI (reprint author), Korea Adv Inst Sci & Technol, GSMSE, Lab Liver Res, Bldg E7 Rm8107,373-1 Guseong Dong, Taejon 305701, South Korea. EM wijeong@kaist.ac.kr RI Kim, Sun Chang/C-2026-2011; JEONG, WON IL/B-6615-2011 FU National Research Foundation - Korean government [2012M3A9C7050093]; Intelligent Synthetic Biology Center of Global Frontier Project - Ministry of Science, ICT & Future Planning [2011-0031955]; Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A111345, A111498]; Rural Development Administration, Republic of Korea [PJ009957] FX Supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (2012M3A9C7050093), the Intelligent Synthetic Biology Center of Global Frontier Project funded by the Ministry of Science, ICT & Future Planning (2011-0031955), grants of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111345 and A111498) and a grant from the Next-Generation BioGreen 21 Program (No. PJ009957), Rural Development Administration, Republic of Korea NR 39 TC 13 Z9 14 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD SEP PY 2014 VL 60 IS 3 BP 1044 EP 1053 DI 10.1002/hep.27137 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO3NV UT WOS:000341239200030 PM 24668648 ER PT J AU Simone, BA Ly, D Savage, JE Hewitt, SM Dan, TD Ylaya, K Shankavaram, U Lim, M Jin, LJ Camphausen, K Mitchell, JB Simone, NL AF Simone, Brittany A. Ly, David Savage, Jason E. Hewitt, Stephen M. Dan, Tu D. Ylaya, Kris Shankavaram, Uma Lim, Meng Jin, Lianjin Camphausen, Kevin Mitchell, James B. Simone, Nicole L. TI microRNA Alterations Driving Acute and Late Stages of Radiation-Induced Fibrosis in a Murine Skin Model SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; INDUCED LUNG INJURY; C-MET; DOWN-REGULATION; RADIOTHERAPY; PENTOXIFYLLINE; MANAGEMENT; CANCER; CELLS; EXPRESSION AB Purpose: Although ionizing radiation is critical in treating cancer, radiation-induced fibrosis (RIF) can have a devastating impact on patients' quality of life. The molecular changes leading to radiation-induced fibrosis must be elucidated so that novel treatments can be designed. Methods and Materials: To determine whether microRNAs (miRs) could be responsible for RIF, the fibrotic process was induced in the right hind legs of 9-week old CH3 mice by a single-fraction dose of irradiation to 35 Gy, and the left leg served as an unirradiated control. Fibrosis was quantified by measurements of leg length compared with control leg length. By 120 days after irradiation, the irradiated legs were 20% (P = .013) shorter on average than were the control legs. Results: Tissue analysis was done on muscle, skin, and subcutaneous tissue from irradiated and control legs. Fibrosis was noted on both gross and histologic examination by use of a pentachrome stain. Microarrays were performed at various times after irradiation, including 7 days, 14 days, 50 days, 90 days, and 120 days after irradiation. miR-15a, miR-21, miR-30a, and miR-34a were the miRs with the most significant alteration by array with miR-34a, proving most significant on confirmation by reverse transcriptase polymerase chain reaction, c-Met, a known effector of fibrosis and downstream molecule of miR-34a, was evaluated by use of 2 cell lines: HCT116 and 1522. The cell lines were exposed to various stressors to induce miR changes, specifically ionizing radiation. Additionally, in vitro transfections with pre-miRs and anti-miRs confirmed the relationship of miR-34a and c-Met. Conclusions: Our data demonstrate an inverse relationship with miR-34a and c-Met; the upregulation of miR-34a in RIF causes inhibition of c-Met production. miRs may play a role in RIF; in particular, miR-34a should be investigated as a potential target to prevent or treat this devastating side effect of irradiation. Published by Elsevier Inc. C1 [Simone, Brittany A.; Dan, Tu D.; Lim, Meng; Jin, Lianjin; Simone, Nicole L.] Thomas Jefferson Univ Hosp, Jefferson Med Coll, Kimmel Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Ly, David; Savage, Jason E.; Shankavaram, Uma; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Hewitt, Stephen M.; Ylaya, Kris] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. [Mitchell, James B.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Simone, NL (reprint author), Thomas Jefferson Univ, Bodine Ctr Canc Treatment, Kimmel Canc Ctr, Dept Radiat Oncol, 111 S 11th St,G-301G, Philadelphia, PA 19107 USA. EM nicole.simone@jeffersonhospital.org OI Hewitt, Stephen/0000-0001-8283-1788 FU NCI NIH HHS [P30 CA056036] NR 40 TC 8 Z9 8 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD SEP 1 PY 2014 VL 90 IS 1 BP 44 EP 52 DI 10.1016/j.ijrobp.2014.05.003 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AO6JJ UT WOS:000341456500007 PM 24986745 ER PT J AU Lynch, SV Wood, RA Boushey, H Bacharier, LB Bloomberg, GR Kattan, M O'Connor, GT Sandel, MT Calatroni, A Matsui, E Johnson, CC Lynn, H Visness, CM Jaffee, KF Gergen, PJ Gold, DR Wright, RJ Fujimura, K Rauch, M Busse, WW Gern, JE AF Lynch, Susan V. Wood, Robert A. Boushey, Homer Bacharier, Leonard B. Bloomberg, Gordon R. Kattan, Meyer O'Connor, George T. Sandel, Megan T. Calatroni, Agustin Matsui, Elizabeth Johnson, Christine C. Lynn, Henry Visness, Cynthia M. Jaffee, Katy F. Gergen, Peter J. Gold, Diane R. Wright, Rosalind J. Fujimura, Kei Rauch, Marcus Busse, William W. Gern, James E. TI Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; atopy; allergen exposure; microbial exposure; inner city ID HOUSE-DUST MITE; CHILDHOOD ASTHMA; INNER-CITY; IMMUNE DEVELOPMENT; VIRUS-INFECTION; DOG OWNERSHIP; UNITED-STATES; LUNG-FUNCTION; BIRTH-COHORT; CAT ALLERGEN AB Background: Wheezing illnesses cause major morbidity in infants and are frequent precursors to asthma. Objective: We sought to examine environmental factors associated with recurrent wheezing in inner-city environments. Methods: The Urban Environment and Childhood Asthma study examined a birth cohort at high risk for asthma (n = 560) in Baltimore, Boston, New York, and St Louis. Environmental assessments included allergen exposure and, in a nested case-control study of 104 children, the bacterial content of house dust collected in the first year of life. Associations were determined among environmental factors, aeroallergen sensitization, and recurrent wheezing at age 3 years. Results: Cumulative allergen exposure over the first 3 years was associated with allergic sensitization, and sensitization at age 3 years was related to recurrent wheeze. In contrast, first-year exposure to cockroach, mouse, and cat allergens was negatively associated with recurrent wheeze (odds ratio, 0.60, 0.65, and 0.75, respectively; P <= .01). Differences in house dust bacterial content in the first year, especially reduced exposure to specific Firmicutes and Bacteriodetes, was associated with atopy and atopic wheeze. Exposure to high levels of both allergens and this subset of bacteria in the first year of life was most common among children without atopy or wheeze. Conclusions: In inner-city environments children with the highest exposure to specific allergens and bacteria during their first year were least likely to have recurrent wheeze and allergic sensitization. These findings suggest that concomitant exposure to high levels of certain allergens and bacteria in early life might be beneficial and suggest new preventive strategies for wheezing and allergic diseases. C1 [Lynch, Susan V.; Boushey, Homer; Fujimura, Kei; Rauch, Marcus] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Wood, Robert A.; Matsui, Elizabeth] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Bacharier, Leonard B.; Bloomberg, Gordon R.] Washington Univ, St Louis Childrens Hosp, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Kattan, Meyer] Columbia Univ, Med Ctr, Div Pediat Allergy & Immunol, New York, NY USA. [O'Connor, George T.; Sandel, Megan T.] Boston Univ, Sch Med, Ctr Pulm, Chapel Hill, NC USA. [Calatroni, Agustin; Lynn, Henry; Visness, Cynthia M.; Jaffee, Katy F.] Rho Inc, Chapel Hill, NC USA. [Johnson, Christine C.] Div Allergy & Immunol Henry Ford Hlth Syst, Detroit, MI USA. [Gergen, Peter J.] Natl Inst Allergy & Infect Dis, Bethesda, MD USA. [Gold, Diane R.; Wright, Rosalind J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. [Busse, William W.; Gern, James E.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI USA. RP Wood, RA (reprint author), Johns Hopkins Univ, Sch Med, 600 North Wolfe St,CMSC 1102, Baltimore, MD 21287 USA. EM rwood@jhmi.edu FU National Institute of Allergy and Infectious Diseases; National Institutes of Health [NO1-AI-25496, NO1-AI-25482, HHSN272200900052C, HHSN272201000052I]; National Center for Advancing Translational Sciences, National Institutes of Health [RR00052, M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, 5UL1RR024992 02] FX This project has been supported in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract numbers NO1-AI-25496, NO1-AI-25482, HHSN272200900052C, and HHSN272201000052I. Additional support was provided by the National Center for Advancing Translational Sciences, National Institutes of Health, under grants RR00052, M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, and 5UL1RR024992 02. NR 60 TC 76 Z9 77 U1 6 U2 30 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD SEP PY 2014 VL 134 IS 3 BP 593 EP + DI 10.1016/j.jaci.2014.04.018 PG 21 WC Allergy; Immunology SC Allergy; Immunology GA AO5GR UT WOS:000341372400011 PM 24908147 ER PT J AU Goncalves, PH AF Goncalves, Priscila H. TI Not Answering Is Also an Answer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material C1 NCI, NIH, Bethesda, MD 20892 USA. RP Goncalves, PH (reprint author), NCI, NIH, Bldg 10,Room 6N110,9000 Rockville Pike, Bethesda, MD 20892 USA. EM priscila.goncalves@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2014 VL 32 IS 25 BP 2809 EP 2810 DI 10.1200/JCO.2014.55.3495 PG 2 WC Oncology SC Oncology GA AO7WF UT WOS:000341562600022 PM 25092773 ER PT J AU Nella, AA Kaplowitz, PB Ramnitz, MS Nandagopal, R AF Nella, Aikaterini A. Kaplowitz, Paul B. Ramnitz, Mary Scott Nandagopal, Radha TI Benign vaginal bleeding in 24 prepubertal patients: clinical, biochemical and imaging features SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE isolated menses; precocious puberty; premature menarche ID PRECOCIOUS PUBERTY; PREMATURE MENARCHE; GIRLS AB Objective: Premature menarche is an uncommon, benign condition characterized by isolated or recurrent menstrual bleeding in the absence of secondary sexual characteristics. Methods: We performed an observational retrospective study to further characterize the clinical, biochemical and imaging features of benign prepubertal vaginal bleeding (BPVB). Out of 1037 girls evaluated for precocious puberty over a 5-year period, 24 girls with BPVB were identified based on >= 1 episodes of vaginal bleeding, Tanner I or non-progressive Tanner II breast development, and lack of physical findings suggesting genital infection, trauma or foreign body. Results: Age at presentation ranged from 3 years 2 months to 9 years 11 months. Ten patients (42%) had one episode of vaginal bleeding, six (25%) had two episodes and eight patients (33%) had three or more. First bleeding episode lasted 3 days (range; 1-30 days). Six girls had intermittent spotting for up to 1 year. No breast development was noted in 19 (79%) patients. Minimal breast was present in five girls; early pubic hair was present in 2. LH and FSH were prepubertal; estradiol was >20 pg/mL in two girls. Pelvic ultrasound, performed in 11 patients, showed pre-pubertal uterus and ovaries without adnexal masses. Conclusion: Isolated prepubertal vaginal bleeding is typically benign and self-limited, in the absence of sexual precocity signs or other vaginal pathology. Laboratory and imaging studies are generally unrevealing. C1 [Nella, Aikaterini A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Kaplowitz, Paul B.; Ramnitz, Mary Scott; Nandagopal, Radha] Childrens Natl Med Ctr, Div Endocrinol, Washington, DC 20010 USA. [Ramnitz, Mary Scott] NICHHD, Bethesda, MD 20892 USA. RP Nella, AA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg 10-CRC,Room 1-3330,10 Ctr Dr MSC 1103, Bethesda, MD 20892 USA. EM nellaa@mail.nih.gov NR 11 TC 6 Z9 6 U1 0 U2 4 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X EI 2191-0251 J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD SEP PY 2014 VL 27 IS 9-10 BP 821 EP 825 DI 10.1515/jpem-2013-0415 PG 5 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA AO6AG UT WOS:000341429100004 PM 24756050 ER PT J AU Raygada, M King, KS Adams, KT Stratakis, CA Pacak, K AF Raygada, Margarita King, Kathryn S. Adams, Karen T. Stratakis, Constantine A. Pacak, Karel TI Counseling patients with succinate dehydrogenase subunit defects: genetics, preventive guidelines, and dealing with uncertainty SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE counseling; paragangliomas; pheochromocytoma; subunits; succinate dehydrogenase ID FAMILIAL NONCHROMAFFIN PARAGANGLIOMAS; RENAL-CELL CARCINOMA; HEREDITARY PARAGANGLIOMAS; NECK PARAGANGLIOMAS; GERMLINE MUTATIONS; CHROMOSOME 11Q23; IMPRINTED GENE; SDHB MUTATIONS; GLOMUS TUMORS; PHEOCHROMOCYTOMA AB The discovery that mutations in the succinate dehydrogenase (SDH) complex subunit (SDHA, B/C/D/AF2) genes predispose patients to the development of tumors has led to the identification of a large population of patients and relatives at risk for developing malignancies. The most frequent conditions associated with these mutations are the familial paraganglioma syndromes. Other tumors that are frequently associated with SDH mutations (SDHx) are gastrointestinal stromal tumors and renal cell carcinomas. A number of other rare associations have also been described. SDHx mutations are often clinically silent and metastatic, but they may also be aggressive in their presentation. The penetrance of these mutations is beginning to be understood, and the characteristics of the phenotype are being elucidated. However, the inability to accurately predict the appearance, nature, and location of tumors as well as their tendency to recur or metastasize pose challenges to those who counsel and manage patients with SDHx mutations. In this work, we present our approach for counseling these families in the context of the current uncertainties, while striving to maintain patient autonomy. C1 [Raygada, Margarita] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, Bethesda, MD 20892 USA. [King, Kathryn S.; Adams, Karen T.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, CRC, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Clin Res Ctr, East Labs, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. RP Raygada, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, 10 Ctr Dr MSC 1831,Room 10D36A, Bethesda, MD 20892 USA. EM Raygadam@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was funded by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 43 TC 2 Z9 2 U1 0 U2 1 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X EI 2191-0251 J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD SEP PY 2014 VL 27 IS 9-10 BP 837 EP 844 DI 10.1515/jpem-2013-0369 PG 8 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA AO6AG UT WOS:000341429100006 PM 24854530 ER PT J AU Goldberg, CS Lu, MM Sleeper, LA Mahle, WT Gaynor, JW Williams, IA Mussatto, KA Ohye, RG Graham, EM Frank, DU Jacobs, JP Krawczeski, C Lambert, L Lewis, A Pemberton, VL Sananes, R Sood, E Wechsler, SB Bellinger, DC Newburger, JW AF Goldberg, Caren S. Lu, Minmin Sleeper, Lynn A. Mahle, William T. Gaynor, J. William Williams, Ismee A. Mussatto, Kathleen A. Ohye, Richard G. Graham, Eric M. Frank, Deborah U. Jacobs, Jeffrey P. Krawczeski, Catherine Lambert, Linda Lewis, Alan Pemberton, Victoria L. Sananes, Renee Sood, Erica Wechsler, Stephanie B. Bellinger, David C. Newburger, Jane W. CA Pediat Heart Network Investigators TI Factors Associated with Neurodevelopment for Children with Single Ventricle Lesions SO JOURNAL OF PEDIATRICS LA English DT Article ID LEFT-HEART SYNDROME; HYPOTHERMIC CIRCULATORY ARREST; REGIONAL CEREBRAL PERFUSION; NORWOOD PROCEDURE; CARDIAC-SURGERY; RECONSTRUCTION TRIAL; INFANT DEVELOPMENT; BLALOCK-TAUSSIG; BAYLEY SCALES; SCHOOL-AGE AB Objective To measure neurodevelopment at 3 years of age in children with single right-ventricle anomalies and to assess its relationship to Norwood shunt type, neurodevelopment at 14months of age, and patient and medical factors. Study design All subjects in the Single Ventricle Reconstruction Trial who were alive without cardiac transplant were eligible for inclusion. The Ages and Stages Questionnaire (ASQ, n = 203) and other measures of behavior and quality of life were completed at age 3 years. Medical history, including measures of growth, feeding, and complications, was assessed through annual review of the records and phone interviews. The Bayley Scales of Infant Development, Second Edition (BSID-II) scores from age 14 months were also evaluated as predictors. Results Scores on each ASQ domain were significantly lower than normal (P<.001). ASQ domain scores at 3 years of age varied nonlinearly with 14-month BSID-II. More complications, abnormal growth, and evidence of feeding, vision, or hearing problems were independently associated with lower ASQ scores, although models explained <30% of variation. Type of shunt was not associated with any ASQ domain score or with behavior or quality-of-life measures. Conclusion Children with single right-ventricle anomalies have impaired neurodevelopment at 3 years of age. Lower ASQ scores are associated with medical morbidity, and lower BSID-II scores but not with shunt type. Because only a modest percentage of variation in 3-year neurodevelopmental outcome could be predicted from early measures, however, all children with single right-ventricle anomalies should be followed longitudinally to improve recognition of delays. C1 [Goldberg, Caren S.; Ohye, Richard G.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Goldberg, Caren S.; Ohye, Richard G.] Univ Michigan, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. [Lu, Minmin; Sleeper, Lynn A.] New England Res Inst, Watertown, MA 02172 USA. [Mahle, William T.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Mahle, William T.] Emory Univ, Sch Med, Atlanta, GA USA. [Gaynor, J. William] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Williams, Ismee A.] Columbia Univ, New York, NY USA. [Williams, Ismee A.] Morgan Stanley Childrens Hosp, New York, NY USA. [Mussatto, Kathleen A.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Mussatto, Kathleen A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Graham, Eric M.] Med Univ S Carolina, Charleston, SC 29425 USA. [Frank, Deborah U.; Lambert, Linda] Univ Utah, Primary Childrens Med Ctr, Salt Lake City, UT USA. [Jacobs, Jeffrey P.] Johns Hopkins Med, All Childrens Hosp, St Petersburg, FL USA. [Krawczeski, Catherine] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Lewis, Alan] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Pemberton, Victoria L.] NHLBI, Bethesda, MD 20892 USA. [Sananes, Renee] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Sood, Erica] Alfred I duPont Hosp Children, Wilmington, DE USA. [Wechsler, Stephanie B.] Duke Univ, Med Ctr, Durham, NC USA. [Bellinger, David C.; Newburger, Jane W.] Boston Childrens Hosp, Boston, MA USA. RP Goldberg, CS (reprint author), Univ Michigan, Dept Pediat, CS Mott Childrens Hosp, 1540 E Hosp Dr, Ann Arbor, MI 48109 USA. EM cgoldber@umich.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057, HL109781, HL109737] FX Supported by the National Heart, Lung, and Blood Institute (NHLBI; HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057, HL109781, HL109737). The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of NHLBI or the National Institutes of Health. The authors declare no conflicts of interest. NR 30 TC 11 Z9 11 U1 2 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD SEP PY 2014 VL 165 IS 3 BP 490 EP + DI 10.1016/j.jpeds.2014.05.019 PG 15 WC Pediatrics SC Pediatrics GA AO6CT UT WOS:000341437100017 PM 24952712 ER PT J AU Ng, VL Haber, BH Magee, JC Miethke, A Murray, KF Michail, S Karpen, SJ Kerkar, N Molleston, JP Romero, R Rosenthal, P Schwarz, KB Shneider, BL Turmelle, YP Alonso, EM Sherker, AH Sokol, RJ AF Ng, Vicky Lee Haber, Barbara H. Magee, John C. Miethke, Alexander Murray, Karen F. Michail, Sonia Karpen, Saul J. Kerkar, Nanda Molleston, Jean P. Romero, Rene Rosenthal, Philip Schwarz, Kathleen B. Shneider, Benjamin L. Turmelle, Yumirle P. Alonso, Estella M. Sherker, Averell H. Sokol, Ronald J. CA Childhood Liver Dis Res Educ Netwo TI Medical Status of 219 Children with Biliary Atresia Surviving Long-Term with Their Native Livers: Results from a North American Multicenter Consortium SO JOURNAL OF PEDIATRICS LA English DT Article ID QUALITY-OF-LIFE; KASAI PORTOENTEROSTOMY; HEPATIC OSTEODYSTROPHY; RECURRENT CHOLANGITIS; BACTERIAL CHOLANGITIS; UNITED-STATES; SINGLE-CENTER; RISK-FACTORS; FOLLOW-UP; TRANSPLANTATION AB Objectives To examine the medical status of children with biliary atresia (BA) with their native livers after hepatoportoenterostomy (HPE) surgery. Study design The Childhood Liver Disease Research and Education Network database was utilized to examine subjects with BA living with their native livers 5 or more years after HPE and to describe the prevalence of subjects with BA with an "ideal" outcome, defined as no clinical evidence of chronic liver disease, normal liver biochemical indices (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, platelet count, total bilirubin, international normalized ratio, and albumin), and normal health-related quality of life 5 or more years after HPE. Results Children with BA (n = 219; 43% male) with median age 9.7 years were studied. Median age at HPE was 56 (range 7-125) days. Median age- and sex-adjusted height and weight z-scores at 5-year follow-up were 0.487 (IQR -0.27 to 1.02) and 0.00 (IQR -0.74 to 0.70), respectively. During the 12 preceding months, cholangitis and bone fractures occurred in 17% and 5.5%, respectively. Health-related quality of life was reported normal by 53% of patients. However, only 1.8% met the study definition of "ideal" outcome. Individual tests of liver synthetic function (total bilirubin, albumin, and international normalized ratio) were normal in 75%, 85%, and 73% of the study cohort. Conclusion Cholangitis and fractures in long-term survivors underscore the importance of ongoing medical surveillance. Over 98% of this North American cohort of subjects with BA living with native livers 5 or more years after HPE have clinical or biochemical evidence of chronic liver disease. C1 [Ng, Vicky Lee] Univ Toronto, Hosp Sick Children, Div Pediat Gastroenterol Hepatol & Nutr, Toronto, ON M5G 1X5, Canada. [Haber, Barbara H.] Childrens Hosp Philadelphia, Div Gastroenterol & Nutr, Philadelphia, PA 19104 USA. [Magee, John C.] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI USA. [Miethke, Alexander] Cincinnati Childrens Hosp Med Ctr, Div Pediat Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA. [Murray, Karen F.] Seattle Childrens Hosp, Hepatobiliary Program, Seattle, WA USA. [Murray, Karen F.] Univ Washington, Seattle, WA USA. [Michail, Sonia; Kerkar, Nanda] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Gastroenterol & Nutr, Los Angeles, CA 90033 USA. [Karpen, Saul J.] Texas Childrens Hosp, Houston, TX 77030 USA. [Karpen, Saul J.; Romero, Rene] Emory Univ, Childrens Healthcare Atlanta, Div Pediat Gastroenterol Hepatol & Nutr, Atlanta, GA 30322 USA. [Kerkar, Nanda] Mt Sinai Sch Med, Div Pediat Hepatol, New York, NY USA. [Molleston, Jean P.] Indiana Univ, Riley Hosp Children, Indianapolis, IN 46204 USA. [Rosenthal, Philip] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Schwarz, Kathleen B.] Johns Hopkins Med Inst, Div Pediat Gastroenterol & Nutr, Baltimore, MD 21205 USA. [Shneider, Benjamin L.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Dept Pediat Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA. [Turmelle, Yumirle P.] Washington Univ, Div Gastroenterol & Nutr, St Louis, MO USA. [Alonso, Estella M.] Ann & Robert H Lurie Childrens Hosp, Div Pediat Gastroenterol Hepatol & Nutr, Chicago, IL USA. [Alonso, Estella M.] Northwestern Univ, Chicago, IL 60611 USA. [Sherker, Averell H.] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD USA. [Sokol, Ronald J.] Univ Colorado, Sch Med, Childrens Hosp Colorado, Dept Gastroenterol Hepatol & Nutr, Aurora, CO USA. RP Ng, VL (reprint author), Univ Toronto, Hosp Sick Children, Div Pediat Gastroenterol Hepatol & Nutr, 555 Univ Ave, Toronto, ON M5G 1X5, Canada. EM vicky.ng@sickkids.ca RI Sawyers, Charles/G-5327-2016; OI Rider, Jennifer/0000-0002-2637-6036 FU National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) [U01 DK061693, U54 DK078377] FX Supported by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK; U01 DK061693 and U54 DK078377; individual grants available in the Appendix). The authors declare no conflicts of interest. NR 49 TC 9 Z9 12 U1 2 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD SEP PY 2014 VL 165 IS 3 BP 539 EP + DI 10.1016/j.jpeds.2014.05.038 PG 10 WC Pediatrics SC Pediatrics GA AO6CT UT WOS:000341437100027 PM 25015575 ER PT J AU Winer, KK Fulton, KA Albert, PS Cutler, GB AF Winer, Karen K. Fulton, Kara A. Albert, Paul S. Cutler, Gordon B., Jr. TI Effects of Pump versus Twice-Daily Injection Delivery of Synthetic Parathyroid Hormone 1-34 in Children with Severe Congenital Hypoparathyroidism SO JOURNAL OF PEDIATRICS LA English DT Article ID RANDOMIZED CROSSOVER TRIAL; LONG-TERM TREATMENT; REPLACEMENT THERAPY; CALCITRIOL; CALCIUM; PARATHYROID-HORMONE-1-34; REABSORPTION; PHOSPHATE; INFUSION AB Objective To compare the response with synthetic human parathyroid hormone (PTH) 1-34 delivered by twice-daily injection vs insulin pump in children with severe congenital hypoparathyroidism due to calcium receptor mutation or autoimmune polyglandular syndrome type 1. Study design Children and young adults aged 7-20 years with congenital hypoparathyroidism (N = 12) were randomized to receive PTH 1-34, delivered either by twice-daily subcutaneous injection or insulin pump for 13 weeks, followed by crossover to the opposite delivery method. The principal outcome measures were serum and urine calcium levels. Secondary outcomes included serum and urine magnesium and phosphate levels and bone turnover markers. Results PTH 1-34 delivered via pump produced near normalization of mean serum calcium (2.02 +/- 0.05 [pump] vs 1.88 +/- 0.03 [injection] mmol/L, P < .05, normal 2.05-2.5 mmol/L), normalized mean urine calcium excretion (5.17 +/- 1.10 [pump] vs 6.67 +/- 0.76 mmol/24h/1.73 m(2), P = .3), and significantly reduced markers of bone turnover (P < .02). Serum and urine calcium and magnesium showed a biphasic pattern during twice-daily injection vs minimal fluctuation during pump delivery. The PTH 1-34 dosage was markedly reduced during pump delivery (0.32 +/- 0.04 vs 0.85 +/- 0.11 mu g/kg/d, P < .001), and magnesium supplements were also reduced (P < .001). Conclusion Compared with twice-daily delivery, pump delivery of PTH 1-34 provides more physiologic calcium homeostasis and bone turnover in children with severe congenital hypoparathyroidism. C1 [Winer, Karen K.; Fulton, Kara A.; Albert, Paul S.; Cutler, Gordon B., Jr.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Winer, KK (reprint author), NICHD, NIH, PGNB, Bldg 6100,Room 4B11, Bethesda, MD 20892 USA. EM karenwiner@gmail.com FU Division of Intramural Research, Clinical Center, National Institutes of Health FX Supported, in part, by the Division of Intramural Research, Clinical Center, the National Institutes of Health. G.C. is a retired employee of Eli Lilly (in 2008), where rhPTH (Forteo) is produced. Insulet supplied the OmniPod (R) pumps. The other authors declare no conflicts of interest. NR 25 TC 13 Z9 15 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD SEP PY 2014 VL 165 IS 3 BP 556 EP + DI 10.1016/j.jpeds.2014.04.060 PG 9 WC Pediatrics SC Pediatrics GA AO6CT UT WOS:000341437100029 PM 24948345 ER PT J AU Guay-Woodford, LM Bissler, JJ Braun, MC Bockenhauer, D Cadnapaphornchai, MA Dell, KM Kerecuk, L Liebau, MC Alonso-Peclet, MH Shneider, B Emre, S Heller, T Kamath, BM Murray, KF Moise, K Eichenwald, EE Evans, J Keller, RL Wilkins-Haug, L Bergmann, C Gunay-Aygun, M Hooper, SR Hardy, KK Hartung, EA Streisand, R Perrone, R Moxey-Mims, M AF Guay-Woodford, Lisa M. Bissler, John J. Braun, Michael C. Bockenhauer, Detlef Cadnapaphornchai, Melissa A. Dell, Katherine M. Kerecuk, Larissa Liebau, Max C. Alonso-Peclet, Maria H. Shneider, Benjamin Emre, Sukru Heller, Theo Kamath, Binita M. Murray, Karen F. Moise, Kenneth Eichenwald, Eric E. Evans, Jacquelyn Keller, Roberta L. Wilkins-Haug, Louise Bergmann, Carsten Gunay-Aygun, Meral Hooper, Stephen R. Hardy, Kristina K. Hartung, Erum A. Streisand, Randi Perrone, Ronald Moxey-Mims, Marva TI Consensus Expert Recommendations for the Diagnosis and Management of Autosomal Recessive Polycystic Kidney Disease: Report of an International Conference SO JOURNAL OF PEDIATRICS LA English DT Article ID CONGENITAL HEPATIC-FIBROSIS; PKHD1 MUTATIONS; UNILATERAL NEPHRECTOMY; HYPERECHOGENIC KIDNEYS; PRENATAL-DIAGNOSIS; ARPKD; CHILDREN; INFANTS; HYPERTENSION; ANOMALIES C1 [Streisand, Randi] Childrens Natl Hlth Syst, Ctr Translat Sci, Washington, DC 20010 USA. [Bissler, John J.] LeBonheur Childrens Hosp, Div Pediat Nephrol, Memphis, TN USA. [Bissler, John J.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Braun, Michael C.] Texas Childrens Hosp, Renal Sect, Houston, TX 77030 USA. [Bockenhauer, Detlef] UCL, Inst Child Hlth, London, England. [Bockenhauer, Detlef] Great Ormond St Hosp Sick Children, Dept Nephrol, London, England. [Cadnapaphornchai, Melissa A.] Childrens Hosp Colorado, Div Pediat Nephrol, Aurora, CO USA. [Dell, Katherine M.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Dell, Katherine M.] Cleveland Clin, Childrens Hosp, Cleveland, OH 44106 USA. [Kerecuk, Larissa] Natl Hlth Serv Fdn Trust, Birmingham Childrens Hosp, Dept Pediat Nephrol, Birmingham, W Midlands, England. [Liebau, Max C.] Cologne Univ Hosp, Dept Pediat, Cologne, Germany. [Liebau, Max C.] Cologne Univ Hosp, Ctr Mol Med, Cologne, Germany. [Alonso-Peclet, Maria H.] Cincinnati Childrens Hosp Med Ctr, Dept Surg, Cincinnati, OH 45229 USA. [Shneider, Benjamin] Childrens Hosp Pittsburgh, Div Pediat Hepatol, Pittsburgh, PA 15213 USA. [Emre, Sukru] Yale Univ, Sch Med, Dept Surg, Sect Transplantat & Immunol, New Haven, CT 06510 USA. [Heller, Theo] Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD USA. [Kamath, Binita M.] Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON M5G 1X8, Canada. [Murray, Karen F.] Seattle Childrens Hosp, Div Pediat Gastroenterol & Hepatol, Seattle, WA USA. [Moise, Kenneth] Univ Texas Hlth Sci Ctr Houston, Dept Obstet Gynecol & Reprod Sci, Houston, TX 77030 USA. [Eichenwald, Eric E.] Univ Texas Hlth Sci Ctr Houston, Dept Pediat, Houston, TX 77030 USA. [Evans, Jacquelyn] Childrens Hosp Philadelphia, Div Neonatol, Philadelphia, PA 19104 USA. [Keller, Roberta L.] Univ Calif San Francisco, Childrens Hosp, Div Neonatol, San Francisco, CA 94143 USA. [Wilkins-Haug, Louise] Brigham & Womens Hosp, Div Maternal Fetal Med & Reprod Genet, Boston, MA 02115 USA. [Bergmann, Carsten] Bioscientia, Ctr Human Genet, Ingelheim, Germany. [Bergmann, Carsten] Univ Hosp Freiburg, Dept Nephrol, Freiburg, Germany. [Bergmann, Carsten] Univ Hosp Freiburg, Clin Res Ctr, Freiburg, Germany. [Gunay-Aygun, Meral] Johns Hopkins Univ, Sch Med, Dept Pediat, Inst Med Genet, Baltimore, MD 21205 USA. [Gunay-Aygun, Meral] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Gunay-Aygun, Meral] Univ N Carolina, Sch Med, Dept Allied Hlth Sci, Chapel Hill, NC USA. [Hooper, Stephen R.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Hardy, Kristina K.] Childrens Natl Hlth Syst, Dept Neuropsychol, Washington, DC 20010 USA. [Hartung, Erum A.] Childrens Hosp Philadelphia, Div Nephrol, Philadelphia, PA 19104 USA. [Perrone, Ronald] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Moxey-Mims, Marva] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. RP Guay-Woodford, LM (reprint author), Childrens Natl Hlth Syst, Ctr Translat Sci, 6th Floor Main Hosp,Ctr 6,111 Michigan Ave NW, Washington, DC 20010 USA. EM LGuaywoo@childrensnational.org RI Hartung, Erum/M-3143-2015; OI Hartung, Erum/0000-0001-5617-6505; Bockenhauer, Detlef/0000-0001-5878-941X; Hardy, Kristina/0000-0002-5479-5043; Liebau, Max Christoph/0000-0003-0494-9080 FU University of Alabama at Birmingham Hepato-Renal Fibrocystic Disease Core Center [P30 DK074038]; Polycystic Kidney Disease Foundation FX Meeting organization and postmeeting development were supported by the University of Alabama at Birmingham Hepato-Renal Fibrocystic Disease Core Center (P30 DK074038) and the Polycystic Kidney Disease Foundation. The authors declare no conflicts of interest. NR 39 TC 11 Z9 13 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD SEP PY 2014 VL 165 IS 3 BP 611 EP 617 DI 10.1016/j.jpeds.2014.06.015 PG 7 WC Pediatrics SC Pediatrics GA AO6CT UT WOS:000341437100037 PM 25015577 ER PT J AU Banegas, MP Harlan, LC Mann, B Yabroff, KR AF Banegas, Matthew P. Harlan, Linda C. Mann, Bhupinder Yabroff, K. Robin TI Renal Cell Cancer: A Shift in Approaches for Treatment of Advanced Disease in the United States SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID PHASE-III TRIAL; INTERFERON-ALPHA; CYTOREDUCTIVE NEPHRECTOMY; INHIBITOR THERAPIES; TARGETED THERAPY; CARCINOMA; SURVIVAL; SUNITINIB; EVEROLIMUS; PATTERNS AB Several new agents have become available to treat renal cell cancer (RCC) in recent years, although evidence on their dissemination is limited. This study examined recent trends in RCC treatment in US community practices. Data from the population-based National Cancer Institute's Patterns of Care studies were used to evaluate treatment of patients with RCC newly diagnosed in 2004 and 2009 (N=2357). Descriptive statistics and logistic and Cox proportional hazards regression analyses were used to assess treatment patterns and the associations among demographic, clinical, and hospital characteristics, with receipt of systemic therapy and time-to-systemic treatment. Between 2004 and 2009, systemic therapy use increased among patients with stage Ill and IV RCC, from 3.8% to 15.7% and 35.2% to 57.4%, respectively. Among patients with stage IV disease, the most commonly used therapies changed from interleukin-2 (16.3%) and interferon-alfa (16.6%) in 2004 to sunitinib (39.2%) and temsirolimus (15.2%) in 2009. Further, notable decreases were seen in the use of surgery and time-to-systemic treatment for patients with stage IV disease. Patients who were older, living in areas with lower educational attainment, and diagnosed in 2004 were significantly less likely to receive systemic therapy and had longer time-to-systemic treatment (P<.05). The findings indicate that over the past decade, treatment for RCC in the United States has evolved toward increased use of systemic therapy. As the diffusion of new therapies continues, it will be imperative to understand how variation in care for RCC will impact health outcomes and costs of care. C1 [Banegas, Matthew P.; Harlan, Linda C.; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Mann, Bhupinder] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Banegas, MP (reprint author), NCI, 9609 Med Ctr Dr,MSC 9762, Bethesda, MD 20892 USA. EM banegasmp@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU National Cancer Institute [HHSN261201000024C, HHSN261201000025C, HHSN261201000032C, HHSN261201000027C, HHSN261201000026C, HHSN261201000140C, HHSN261201000037C, HHSN261201000033C, HHSN261201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, HHSN261201000030C] FX This work was supported by National Cancer Institute contracts: HHSN261201000024C; HHSN261201000025C, HHSN261201000032C, HHSN261201000027C, HHSN261201000026C, HHSN261201000140C, HHSN261201000037C, HHSN261201000033C, HHSN261201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, and HHSN261201000030C. The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. This article is a US Government work and, as such, is in the public domain in the United States. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or NIH. NR 32 TC 2 Z9 3 U1 1 U2 4 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 SEP PY 2014 VL 12 IS 9 BP 1271 EP 1279 PG 9 WC Oncology SC Oncology GA AO4ZM UT WOS:000341349900008 PM 25190695 ER PT J AU Bloch, M Parascandola, M AF Bloch, Michele Parascandola, Mark TI Tobacco use in pregnancy: a window of opportunity for prevention SO LANCET GLOBAL HEALTH LA English DT Editorial Material ID COUNTRIES; EXPOSURE; SMOKE C1 [Bloch, Michele; Parascandola, Mark] NCI, Tobacco Control Res Branch, Bethesda, MD 20892 USA. RP Bloch, M (reprint author), NCI, Tobacco Control Res Branch, Bethesda, MD 20892 USA. EM blochm@mail.nih.gov NR 10 TC 4 Z9 4 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD SEP PY 2014 VL 2 IS 9 BP E489 EP E490 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AO5EB UT WOS:000341364400002 PM 25304402 ER PT J AU Shah, SK Persaud, D Wendler, DS Taylor, HA Gay, H Kruger, M Grady, C AF Shah, Seema K. Persaud, Deborah Wendler, David S. Taylor, Holly A. Gay, Hannah Kruger, Mariana Grady, Christine TI Research on very early ART in neonates at risk of HIV infection SO LANCET INFECTIOUS DISEASES LA English DT Letter C1 [Shah, Seema K.; Persaud, Deborah; Wendler, David S.; Taylor, Holly A.; Gay, Hannah; Kruger, Mariana; Grady, Christine] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Shah, SK (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,10-1C118, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov FU NIAID NIH HHS [P30 AI094189, 1P30AI094189] NR 5 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD SEP PY 2014 VL 14 IS 9 BP 797 EP 797 PG 1 WC Infectious Diseases SC Infectious Diseases GA AO4WS UT WOS:000341342700017 PM 25164194 ER PT J AU Grant, RM Anderson, PL McMahan, V Liu, A Amico, KR Mehrotra, M Hosek, S Mosquera, C Casapia, M Montoya, O Buchbinder, S Veloso, VG Mayer, K Chariyalertsak, S Bekker, LG Kallas, EG Schechter, M Guanira, J Bushman, L Burns, DN Rooney, JF Glidden, DV AF Grant, Robert M. Anderson, Peter L. McMahan, Vanessa Liu, Albert Amico, K. Rivet Mehrotra, Megha Hosek, Sybil Mosquera, Carlos Casapia, Martin Montoya, Orlando Buchbinder, Susan Veloso, Valdilea G. Mayer, Kenneth Chariyalertsak, Suwat Bekker, Linda-Gail Kallas, Esper G. Schechter, Mauro Guanira, Juan Bushman, Lane Burns, David N. Rooney, James F. Glidden, David V. CA iPrEx Study Team TI Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study SO LANCET INFECTIOUS DISEASES LA English DT Article ID RISK COMPENSATION; HETEROSEXUAL MEN; PREVENTION; BEHAVIOR; INFECTION; TENOFOVIR; TRIAL; PREP AB Background The effect of HIV pre-exposure prophylaxis (PrEP) depends on uptake, adherence, and sexual practices. We aimed to assess these factors in a cohort of HIV-negative people at risk of infection. Methods In our cohort study, men and transgender women who have sex with men previously enrolled in PrEP trials (ATN 082, iPrEx, and US Safety Study) were enrolled in a 72 week open-label extension. We measured drug concentrations in plasma and dried blood spots in seroconverters and a random sample of seronegative participants. We assessed PrEP uptake, adherence, sexual practices, and HIV incidence. Statistical methods induded Poisson models, comparison of proportions, and generalised estimating equations. Findings We enrolled 1603 HIV-negative people, of whom 1225 (76%) received PrEP. Uptake was higher among those reporting condomless receptive anal intercourse (416/519 [81%] vs 809/1084 [75%], p=0.003) and having serological evidence of herpes (612/791 [77%] vs 613/812 [75%] p=0.03). Of those receiving PrEP, HIV incidence was 1.8 infections per 100 person-years, compared with 2-6 infections per 100 person-years in those who concurrently did not choose PrEP (HR 0.51,95% CI 0.26-1.01, adjusted for sexual behaviours), and 3.9 infections per 100 person-years in the placebo group of the previous randomised phase (HR 0.49,95% CI 0.31-0.77). Among those receiving PrEP, HIV incidence was 4.7 infections per 100 person-years if drug was not detected in dried blood spots, 2.3 infections per 100 person-years if drug concentrations suggested use of fewer than two tablets per week, 0.6 per 100 person-years for use of two to three tablets per week, and 0.0 per 100 person-years for use of four or more tablets per week (p<0.0001). PrEP drug concentrations were higher among people of older age, with more schooling, who reported non-condom receptive anal intercourse, who had more sexual partners, and who had a history of syphilis or herpes. Interpretation PrEP uptake was high when made available free of charge by experienced providers. The effect of PrEP is increased by greater uptake and adherence during periods of higher risk. Drug concentrations in dried blood spots are strongly correlated with protective benefit. C1 [Grant, Robert M.; McMahan, Vanessa; Mehrotra, Megha] Gladstone Inst, San Francisco, CA USA. [Grant, Robert M.; Liu, Albert; Buchbinder, Susan; Glidden, David V.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Grant, Robert M.] San Francisco AIDS Fdn, San Francisco, CA USA. [Anderson, Peter L.; Bushman, Lane] Univ Colorado, Aurora, CO USA. [Liu, Albert; Buchbinder, Susan] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Amico, K. Rivet] Univ Connecticut, Storrs, CT USA. [Hosek, Sybil] John H Stroger Jr Hosp Cook Cty, Chicago, IL USA. [Mosquera, Carlos; Guanira, Juan] INMENSA, Lima, Peru. [Casapia, Martin] ACSA, Iquitos, Peru. [Montoya, Orlando] Equidad, Guayaquil, Ecuador. [Veloso, Valdilea G.] Fiocruz MS, BR-21045900 Rio De Janeiro, Brazil. [Mayer, Kenneth] Fenway Hlth, Boston, MA USA. [Chariyalertsak, Suwat] Chiang Mai Univ, Chiang Mai 50000, Thailand. [Bekker, Linda-Gail] Desmond Tutu Hlth Fdn, Cape Town, South Africa. [Kallas, Esper G.] Univ Sao Paulo, Sao Paulo, Brazil. [Schechter, Mauro] Univ Fed Rio de Janeiro, Hosp Escola Sao Francisco Assis, Projeto Praca Onze, Rio De Janeiro, Brazil. [Burns, David N.] NIH, Bethesda, MD 20892 USA. [Rooney, James F.] Gilead Sci Inc, Foster City, CA 94404 USA. RP Grant, RM (reprint author), 1650 Owens St, San Francisco, CA 94158 USA. EM rgrant@gladstone.ucsf.edu OI Guanira, Juan/0000-0002-2746-3086 FU US National Institutes of Health FX US National Institutes of Health. NR 32 TC 169 Z9 171 U1 5 U2 46 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD SEP PY 2014 VL 14 IS 9 BP 820 EP 829 DI 10.1016/S1473-3099(14)70847-3 PG 10 WC Infectious Diseases SC Infectious Diseases GA AO4WS UT WOS:000341342700025 PM 25065857 ER PT J AU Leshem, E Lopman, B Glass, R Gentsch, J Banyai, K Parashar, U Patel, M AF Leshem, Eyal Lopman, Ben Glass, Roger Gentsch, Jon Banyai, Krisztian Parashar, Umesh Patel, Manish TI Distribution of rotavirus strains and strain-specific effectiveness of the rotavirus vaccine after its introduction: a systematic review and meta-analysis SO LANCET INFECTIOUS DISEASES LA English DT Article ID GROUP-A ROTAVIRUS; 1ST 2 YEARS; MOLECULAR EPIDEMIOLOGY; PROVIDES PROTECTION; POTENTIAL IMPACT; AFRICAN INFANTS; SEVERE DIARRHEA; DOUBLE-BLIND; US CHILDREN; PENTAVALENT AB Background Concerns exist about whether monovalent (RV1) and pentavalent (RV5) rotavirus vaccines provide adequate protection against diverse strains and whether vaccine introduction will lead to selective pressure. We aimed to investigate the distribution of rotavirus strains and strain-specific rotavirus vaccine effectiveness after vaccine introduction. Methods We did a systematic review of published work to assess the strain-specific effectiveness of RV1 and RV5 rotavirus vaccines. We classified strains as homotypic, partly heterotypic, and fully heterotypic based on the amount of antigen-matching between strain and vaccine. When studies reported vaccine effectiveness against single antigens (G-type or P-type), we categorised them as either single-antigen vaccine type or single-antigen non-vaccine type. Our primary outcome was strain-specific vaccine effectiveness, comparing effectiveness of homotypic strains with fully or partly heterotypic strains. A secondary outcome was the prevalence of rotavirus strains after vaccine introduction. We estimated pooled odds ratios using random-effect regression models, stratified by country income level and vaccine type, and tested for differences in strain-specific vaccine effectiveness. We assessed strain distribution trends from surveillance reports. Findings In high-income countries, RV1 pooled vaccine effectiveness was 94% (95% CI 80-98) against homotypic strains, 71% (39-86) against partly heterotypic strains, and 87% (76-93) against fully heterotypic strains. In middle-income settings, respective pooled data were 59% (36-73), 72% (58-81), and 47% (28-61). In high-income countries, RV5 vaccine effectiveness was 83% (78-87) against homotypic strains, 82% (70-89) against single-antigen vaccine type strains, 82% (70-89) against partly heterotypic strains, and 75% (47-88) against single-antigen non-vaccine type strains. In middle-income settings, RV5 vaccine effectiveness was 70% (58-78) against single-antigen vaccine type strains, 37% (10-56) against partly heterotypic strains, and 87% (38-97) against single-antigen non-vaccine type strains. No difference was noted in vaccine effectiveness for either RV1 or RV5 in any setting (all p>0-05). Prevalent strains in countries using RV1 were G2P[4] (2198 of 4428,50%) and G1P[8] (953,22%), and those in countries using RV5 were G1P[8] (1280 of 3875, 33%) and G2P[4] (1169,30%). Sustained predominance of a single strain was not recorded. Interpretation RV1 and RV5 exert similar effectiveness against homotypic and heterotypic rotavirus strains. Persistence of specific strains was not recorded, suggesting vaccine-induced selective pressure did not occur. Expansion of rotavirus surveillance efforts to low-income countries and ongoing surveillance are crucial to identify emergence of new strains and to assess strain-specific vaccine effectiveness in various settings. C1 [Leshem, Eyal; Lopman, Ben; Gentsch, Jon; Parashar, Umesh; Patel, Manish] Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Leshem, Eyal] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Div Sci Educ & Profess Dev, Atlanta, GA 30333 USA. [Glass, Roger] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Banyai, Krisztian] Hungarian Acad Sci, Vet Med Res Inst, Agr Res Ctr, H-1581 Budapest, Hungary. RP Leshem, E (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. EM eleshem@cdc.gov OI Leshem, Eyal/0000-0003-1267-6131; Banyai, Krisztian/0000-0002-6270-1772 NR 52 TC 33 Z9 35 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD SEP PY 2014 VL 14 IS 9 BP 847 EP 856 DI 10.1016/S1473-3099(14)70832-1 PG 10 WC Infectious Diseases SC Infectious Diseases GA AO4WS UT WOS:000341342700028 PM 25082561 ER PT J AU Fugate, JE Lyons, JL Thakur, KT Smith, BR Hedley-Whyte, ET Mateen, FJ AF Fugate, Jennifer E. Lyons, Jennifer L. Thakur, Kiran T. Smith, Bryan R. Hedley-Whyte, E. Tessa Mateen, Farrah J. TI Infectious causes of stroke SO LANCET INFECTIOUS DISEASES LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; ISCHEMIC CEREBROVASCULAR EVENTS; VARICELLA-ZOSTER-VIRUS; HIV-POSITIVE PATIENTS; HERPES-SIMPLEX-VIRUS; CHAGAS HEART-DISEASE; OF-THE-LITERATURE; TUBERCULOUS MENINGITIS; RISK-FACTOR; BACTERIAL-MENINGITIS AB Most infectious pathogens have anecdotal evidence to support a link with stroke, but certain pathogens have more robust associations, in which causation is probable. Few dedicated prospective studies of stroke in the setting of infection have been done. The use of head imaging, a clinical standard of diagnostic care, to confirm stroke and stroke type is not universal. Data for stroke are scarce in locations where infections are probably most common, making it difficult to reach condusions on how populations differ in terms of risk of infectious stroke. The treatment of infections and stroke, when concomitant, is based on almost no evidence and requires dedicated efforts to understand variations that might exist. We highlight the present knowledge and emphasise the need for stronger evidence to assist in the diagnosis, treatment, and secondary prevention of stroke in patients in whom an infectious cause for stroke is probable. C1 [Fugate, Jennifer E.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Lyons, Jennifer L.] Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Sch Med, Boston, MA 02115 USA. [Thakur, Kiran T.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Smith, Bryan R.] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Hedley-Whyte, E. Tessa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Mateen, Farrah J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Mateen, FJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, ACC 720,55 Fruit St, Boston, MA 02114 USA. EM fmateen@mgh.harvard.edu NR 142 TC 18 Z9 19 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD SEP PY 2014 VL 14 IS 9 BP 869 EP 880 DI 10.1016/S1473-3099(14)70755-8 PG 12 WC Infectious Diseases SC Infectious Diseases GA AO4WS UT WOS:000341342700030 PM 24881525 ER PT J AU Shah, SK Persaud, D Wendler, DS Taylor, HA Gay, H Kruger, M Grady, C AF Shah, Seema K. Persaud, Deborah Wendler, David S. Taylor, Holly A. Gay, Hannah Kruger, Mariana Grady, Christine TI Research into a functional cure for HIV in neonates: the need for ethical foresight SO LANCET INFECTIOUS DISEASES LA English DT Article ID TO-CHILD TRANSMISSION; INFORMED-CONSENT; ANTIRETROVIRAL THERAPY; RISKS; TRIAL; COUNTRIES; STANDARD; INFANTS; UGANDA; STEPS AB In 2013, researchers announced that a newborn child from Mississippi, USA might have been functionally cured of HIV by being given combination antiretroviral therapy within hours of birth. Public and media attention has since been captured by the possibility of finding a cure for HIV transmitted from mother to child. Research into the strategy used for the Mississippi patient is crucially important to establish whether it can be replicated and shown to work in diverse populations. At the same time, any ethical issues likely to arise in such studies should be addressed and not ignored in the pursuit of a functional cure. In this Personal View we identify ethical issues that could arise in research towards achievment of a functional cure for HIV in neonates, including difficult trade-offs associated with choosing the study population and questions about the broader social implications of the research, and propose ways to resolve them. C1 [Shah, Seema K.; Wendler, David S.; Grady, Christine] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Persaud, Deborah] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Persaud, Deborah] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Taylor, Holly A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Taylor, Holly A.] Johns Hopkins Berman Inst Bioeth, Baltimore, MD USA. [Gay, Hannah] Univ Mississippi, Med Ctr, Dept Pediat, Jackson, MS 39216 USA. [Kruger, Mariana] Univ Stellenbosch, Dept Paediat & Child Hlth, Cape Town, South Africa. RP Shah, SK (reprint author), NIH, Ctr Clin, Dept Bioeth, Div Aids, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov FU IMPAACT HIV CURE Scientific Committee; IMPAACT network; Division of AIDS at the NIH; NIH in the Warren G Magnuson Clinical Center; John Hopkins Center for AIDS Research - NIH [1P30AI094189] FX This research was supported and sponsored by the IMPAACT HIV CURE Scientific Committee, the IMPAACT network, the Division of AIDS at the NIH, and the Intramural Research Program of the NIH in the Warren G Magnuson Clinical Center. Work on this manuscript by DP and HT was supported in part by the John Hopkins Center for AIDS Research, funded by the NIH (grant number 1P30AI094189). We thank Patrick Jean-Phillipe, Sarah Read, Mahesh Somashekhar, Sheryl Zwerski, Emily Erbelding, and Alan Wertheimer. The opinions expressed are the view of the authors. They do not represent any position or policy of the US National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. NR 41 TC 14 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD SEP PY 2014 VL 14 IS 9 BP 893 EP 898 DI 10.1016/S1473-3099(14)70766-2 PG 6 WC Infectious Diseases SC Infectious Diseases GA AO4WS UT WOS:000341342700032 PM 24906850 ER PT J AU Song, SB Cohen, L AF Song, Sunbin Cohen, Leonardo TI Impact of conscious intent on chunking during motor learning SO LEARNING & MEMORY LA English DT Article ID REACTION-TIME TASKS; SLEEP; CONSOLIDATION; SEQUENCES; PATTERNS; EXPLICIT; SKILL; AWARENESS AB Humans and other mammals learn sequences of movements by splitting them into smaller "chunks." Such chunks are defined by the faster speed of performance of groups of movements. The purpose of this report is to determine how conscious intent to learn impacts chunking, an issue that remains unknown. Here, we studied 80 subjects who either with or without conscious intent learned a motor sequence. Performance was tested before and up to 1-wk post-training. Chunk formation, carryover of chunks, and concatenation of chunks into longer chunks, all measures of motor chunking success, were determined at each time-point. We found that formation, carryover, and concatenation of chunks were comparable across groups and did not improve over the training session and subsequent testing times. Thus, motor learning progressed in the absence of improvements in chunking irrespective of conscious intent. These data suggest that mechanisms other than chunking contribute to successful motor learning with and without conscious intent. C1 [Song, Sunbin; Cohen, Leonardo] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Song, SB (reprint author), NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. EM songss@mail.nih.gov; cohenl@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://biowulf.nih.gov). NR 26 TC 5 Z9 5 U1 1 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 EI 1549-5485 J9 LEARN MEMORY JI Learn. Mem. PD SEP PY 2014 VL 21 IS 9 BP 449 EP 451 DI 10.1101/lm.035824.114 PG 3 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AO4IR UT WOS:000341301200003 PM 25128535 ER PT J AU Pichard, DC Cowen, EW AF Pichard, Dominique C. Cowen, Edward W. TI Trigeminal Trophic Syndrome After Stroke SO MAYO CLINIC PROCEEDINGS LA English DT Editorial Material C1 [Pichard, Dominique C.] Georgetown Univ Hosp, Washington Hosp Ctr, Dept Dermatol, Washington, DC 20007 USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Pichard, DC (reprint author), Georgetown Univ Hosp, Washington Hosp Ctr, Dept Dermatol, Washington, DC 20007 USA. FU Intramural NIH HHS [Z99 CA999999] NR 5 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD SEP PY 2014 VL 89 IS 9 BP E87 EP E88 DI 10.1016/j.mayocp.2013.10.038 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AO5UR UT WOS:000341411300002 PM 25192622 ER PT J AU Guerrieri, GM Martinez, PE Klug, SP Haq, NA Vanderhoof, VH Koziol, DE Popat, VB Kalantaridou, SN Calis, KA Rubinow, DR Schmidt, PJ Nelson, LM AF Guerrieri, Gioia M. Martinez, Pedro E. Klug, Summer P. Haq, Nazli A. Vanderhoof, Vien H. Koziol, Deloris E. Popat, Vaishali B. Kalantaridou, Sophia N. Calis, Karim A. Rubinow, David R. Schmidt, Peter J. Nelson, Lawrence M. TI Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Testosterone; Primary ovarian insufficiency; Mood; Quality of life; Self-esteem ID PLACEBO-CONTROLLED TRIAL; SURGICALLY MENOPAUSAL WOMEN; SEXUAL DESIRE DISORDER; POSTMENOPAUSAL WOMEN; OOPHORECTOMIZED WOMEN; ESTROGEN REPLACEMENT; DOUBLE-BLIND; YOUNG-WOMEN; DEPRESSION; FAILURE AB Objective: Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI. Methods: One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests. Results: No differences in baseline characteristics, including serum hormone levels (P > 0.05), were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively (P = 0.35). After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo (P < 0.001). Baseline testosterone levels were not associated with either adverse or beneficial clinical effects. Conclusions: A 150-mu g testosterone patch achieves physiologic hormone levels in women with POI. Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder. C1 [Guerrieri, Gioia M.; Martinez, Pedro E.; Klug, Summer P.; Haq, Nazli A.; Schmidt, Peter J.] NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. [Vanderhoof, Vien H.; Popat, Vaishali B.; Kalantaridou, Sophia N.; Calis, Karim A.; Nelson, Lawrence M.] NICHHD, Integrat Reprod Med Grp, Intramural Res Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Koziol, Deloris E.] NIH, Biostat & Clin Epidemiol Serv, Off Deputy Director Clin Care, Clin Ctr,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Guerrieri, GM (reprint author), Room 25330,MSC 1274,10 Ctr Dr, Bethesda, MD 20892 USA. EM gioia.guerrieri@nih.gov FU Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health; Procter Gamble [CRADA 00983] FX Funding/support: This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health, and Procter & Gamble under Cooperative Research and Development Agreement (CRADA 00983). NR 52 TC 4 Z9 5 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD SEP PY 2014 VL 21 IS 9 BP 952 EP 961 DI 10.1097/gme.0000000000000195 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AO7JN UT WOS:000341529400009 PM 24473536 ER PT J AU Corrigan-Curay, J Kiem, HP Baltimore, D O'Reilly, M Brentjens, RJ Cooper, L Forman, S Gottschalk, S Greenberg, P Junghans, R Heslop, H Jensen, M Mackall, C June, C Press, O Powell, D Ribas, A Rosenberg, S Sadelain, M Till, B Patterson, AP Jambou, RC Rosenthal, E Gargiulo, L Montgomery, M Kohn, DB AF Corrigan-Curay, Jacqueline Kiem, Hans-Peter Baltimore, David O'Reilly, Marina Brentjens, Renier J. Cooper, Laurence Forman, Stephen Gottschalk, Stephen Greenberg, Philip Junghans, Richard Heslop, Helen Jensen, Michael Mackall, Crystal June, Carl Press, Oliver Powell, Daniel Ribas, Antoni Rosenberg, Steven Sadelain, Michel Till, Brian Patterson, Amy P. Jambou, Robert C. Rosenthal, Eugene Gargiulo, Linda Montgomery, Maureen Kohn, Donald B. TI T-Cell Immunotherapy: Looking Forward SO MOLECULAR THERAPY LA English DT News Item ID CHIMERIC-ANTIGEN-RECEPTOR; ACUTE LYMPHOBLASTIC-LEUKEMIA; CYTOKINE RELEASE SYNDROME; CANCER REGRESSION; SUICIDE-GENE; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; MACROPHAGE ACTIVATION; METASTATIC MELANOMA; ANTITUMOR-ACTIVITY; DONOR LYMPHOCYTES C1 [Corrigan-Curay, Jacqueline; O'Reilly, Marina; Patterson, Amy P.; Jambou, Robert C.; Rosenthal, Eugene; Gargiulo, Linda; Montgomery, Maureen] NIH, Off Sci Policy, Off Director, Bethesda, MD 20892 USA. [Kiem, Hans-Peter; Greenberg, Philip; Press, Oliver; Till, Brian] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Baltimore, David] CALTECH, Pasadena, CA 91125 USA. [Brentjens, Renier J.; Sadelain, Michel] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Cooper, Laurence] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Forman, Stephen] City Hope Natl Med Ctr, Duarte, CA USA. [Gottschalk, Stephen; Heslop, Helen] Baylor Coll Med, Houston, TX 77030 USA. [Junghans, Richard] Roger Williams Med Ctr, Providence, RI USA. [Jensen, Michael] Univ Washington, Seattle, WA 98195 USA. [Mackall, Crystal; Rosenberg, Steven] NCI, NIH, Bethesda, MD 20892 USA. [June, Carl; Powell, Daniel] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Ribas, Antoni; Kohn, Donald B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Corrigan-Curay, J (reprint author), NIH, Off Biotechnol Activ, 6705 Rockledge Dr,Suite 750, Bethesda, MD 20892 USA. EM corrigaja@od.nih.gov NR 67 TC 18 Z9 19 U1 3 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD SEP PY 2014 VL 22 IS 9 BP 1564 EP 1574 DI 10.1038/mt.2014.148 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AO4TQ UT WOS:000341334700003 PM 25186558 ER PT J AU Kutys, ML Yamada, KM AF Kutys, Matthew L. Yamada, Kenneth M. TI An extracellular-matrix-specific GEE GAP interaction regulates Rho GTPase crosstalk for 3D collagen migration SO NATURE CELL BIOLOGY LA English DT Article ID PERSISTENT CELL-MIGRATION; BETA-PIX; SIGNAL-TRANSDUCTION; DEPENDENT PATHWAY; FAMILY GTPASES; LEADING-EDGE; ADHESION; ACTIVATION; CDC42; COORDINATION AB Rho-family GTPases govern distinct types of cell migration on different extracellular matrix proteins in tissue culture or three-dimensional (3D) matrices1-3. We searched for mechanisms selectively regulating 3D cell migration in different matrix environments4'5 and discovered a form of Cdc42-RhoA crosstalk governing cell migration through a specific pair of GTPase activator and inhibitor molecules. We first identified pPix, a guanine nucleotide exchange factor (GEF), as a specific regulator of migration in 3D collagen using an affinity-precipitation-based GEF screen. Knockdown of PPix specifically blocks cell migration in fibrillar collagen microenvironments, leading to hyperactive cellular protrusion accompanied by increased collagen matrix contraction. Live FRET imaging and RNAi knockdown linked this I3Pix knockdown phenotype to loss of polarized Cdc42 but not Racl activity, accompanied by enhanced, de-localized RhoA activity. Mechanistically, collagen phospho-regulates pPix, leading to its association with srGAP1, a GTPase-activating protein (GAP), needed to suppress RhoA activity. Our results reveal a matrix-specific pathway controlling migration involving a GEF-GAP interaction of f3Pix with srGAP1 that is critical for maintaining suppressive crosstalk between Cdc42 and RhoA during 3D collagen migration. C1 [Kutys, Matthew L.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Kutys, ML (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM kutysml@mail.nih.gov; kyamada@mail.nih.gov OI Kutys, Matthew /0000-0002-0752-649X FU National Institute of Dental and Craniofacial Research, NIH FX The authors would like to thank W Daley, R. Petrie and D. Tran for critical reading of the manuscript. This study was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH. NR 38 TC 22 Z9 23 U1 0 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD SEP PY 2014 VL 16 IS 9 BP 909 EP 917 DI 10.1038/ncb3026 PG 9 WC Cell Biology SC Cell Biology GA AO5SA UT WOS:000341404400011 PM 25150978 ER PT J AU He, XL Zhang, LG Chen, Y Remke, M Shih, D Lu, FH Wang, HB Deng, YQ Yu, Y Xia, Y Wo, XC Ramaswamy, V Hu, T Wang, F Zhou, WH Burns, DK Kim, SH Kool, M Pfister, SM Weinstein, LS Pomeroy, SL Gilbertson, RJ Rubin, JB Hou, YP Wechsler-Reya, R Taylor, MD Lu, QR AF He, Xuelian Zhang, Liguo Chen, Ying Remke, Marc Shih, David Lu, Fanghui Wang, Haibo Deng, Yaqi Yu, Yang Xia, Yong Wo, Xiaochong Ramaswamy, Vijay Hu, Tom Wang, Fan Zhou, Wenhao Burns, Dennis K. Kim, Se Hoon Kool, Marcel Pfister, Stefan M. Weinstein, Lee S. Pomeroy, Scott L. Gilbertson, Richard J. Rubin, Joshua B. Hou, Yiping Wechsler-Reya, Robert Taylor, Michael D. Lu, Q. Richard TI The G protein alpha subunit G alpha(s) is a tumor suppressor in Sonic hedgehog-driven medulloblastoma SO NATURE MEDICINE LA English DT Article ID PRIMARY CILIUM; SHH MEDULLOBLASTOMA; COUPLED RECEPTORS; KINASE-A; PATHWAY; CANCER; INHIBITOR; BRAIN; MICE; ACTIVATION AB Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein G alpha(s), as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. G alpha(s) is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a G alpha(s) effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for G alpha(s) that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue. C1 [He, Xuelian; Wang, Fan; Hou, Yiping] Sichuan Univ, Sch Preclin & Forens Med, Collaborat Innovat Ctr Biotherapy, Dept Forens Med,State Key Lab Biotherapy,West Ch, Chengdu 610064, Peoples R China. [He, Xuelian; Zhang, Liguo; Lu, Fanghui; Wang, Haibo; Deng, Yaqi; Lu, Q. Richard] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Brain Tumor Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA. [He, Xuelian; Zhang, Liguo; Lu, Fanghui; Wang, Haibo; Deng, Yaqi; Lu, Q. Richard] Cincinnati Childrens Hosp Med Ctr, Canc Biol Canc & Blood Dis Inst, Cincinnati, OH 45229 USA. [Chen, Ying] Xiamen Univ, Sch Life Sci, Xiamen, Fujian, Peoples R China. [Remke, Marc; Shih, David; Wo, Xiaochong; Ramaswamy, Vijay; Taylor, Michael D.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Yu, Yang; Lu, Q. Richard] Sichuan Univ, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy, Dept Pediat,West China Hosp 2, Chengdu 610064, Peoples R China. [Xia, Yong] Sichuan Univ, Dept Neurosurg, West China Hosp, Chengdu 610064, Peoples R China. [Hu, Tom; Burns, Dennis K.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Zhou, Wenhao; Lu, Q. Richard] Fudan Univ, Key Lab Birth Defects, Childrens Hosp, Shanghai 200433, Peoples R China. [Kim, Se Hoon] Yonsei Univ, Coll Med, Dept Pathol, Seoul, South Korea. [Kool, Marcel; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany. [Weinstein, Lee S.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD USA. [Pomeroy, Scott L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Neurol,Childrens Hosp, Boston, MA 02115 USA. [Gilbertson, Richard J.] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Rubin, Joshua B.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Wechsler-Reya, Robert] Sanford Burnham Med Res Inst, Tumor Dev Program, La Jolla, CA USA. RP Lu, QR (reprint author), Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Brain Tumor Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA. EM richard.lu@cchmc.org RI Shih, David/H-3186-2011; Pfister, Stefan/F-6860-2013; OI Shih, David/0000-0002-9802-4937; Pfister, Stefan/0000-0002-5447-5322; Remke, Marc/0000-0002-9404-9993 FU US National Institutes of Health [R01 NS078092, R01 NS075243]; Ministry of Education of China [IRT0935]; Canadian Institutes of Health Research; Mildred-Scheel Foundation/German Cancer Aid FX We would like to thank A. Gilman, L. Lum, E. Hurlock, K. Campbell, J. Chan, H. Li, A. Hassan, D. He, E. Lu, L. He and W Ding for comments and technical support. We thank B. Fritzsch (University of Iowa) and J. Johnson (UT Southwestern) for Atoh1-Cre and Atoh1-GFP lines, respectively, C. Stiles (Harvard Medical School) for anti-Olig2, R. Rohatgi (Stanford University) for Ptch1-specific antibody and S. Scales (Genentech) for Gli2-, Gli3- and GPR161-specific antibodies. This study was funded in part by grants from the US National Institutes of Health (R01 NS078092 and R01 NS075243) to Q.R.L., the Ministry of Education of China (IRT0935) and from the Canadian Institutes of Health Research to M.D.T. and a postdoctoral fellowship by the Mildred-Scheel Foundation/German Cancer Aid (M.R.). NR 55 TC 28 Z9 28 U1 3 U2 23 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 SEP PY 2014 VL 20 IS 9 BP 1035 EP 1042 DI 10.1038/nm.3666 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AO5RW UT WOS:000341404000016 PM 25150496 ER PT J AU Lyozin, GT Bressloff, PC Kumar, A Kosaka, Y Demarest, BL Yost, HJ Kuehn, MR Brunelli, L AF Lyozin, George T. Bressloff, Paul C. Kumar, Amit Kosaka, Yasuhiro Demarest, Bradley L. Yost, H. Joseph Kuehn, Michael R. Brunelli, Luca TI Isolation of rare recombinants without using selectable markers for one-step seamless BAC mutagenesis SO NATURE METHODS LA English DT Article ID ESCHERICHIA-COLI; EXPRESSION; MUTANTS; YEAST; OLIGONUCLEOTIDES; PIPELINE; PROTEIN; ORIGIN; SYSTEM; NODE AB Current methods to isolate rare (1:10,000-1:100,000) bacterial artificial chromosome (BAC) recombinants require selectable markers. For seamless BAC mutagenesis, selectable markers need to be removed after isolation of recombinants through counterselection. Here we illustrate founder principle driven enrichment (FPE), a simple method to rapidly isolate rare recombinants without using selectable markers, allowing one-step seamless BAC mutagenesis. As proof of principle, we isolated 1:100,000 seamless fluorescent protein modified Nodal BACs and confirmed BAC functionality by generating fluorescent reporter mice. We also isolated small indel P1 phage-derived artificial chromosome (PAC) and BAC recombinants. Statistical analysis revealed that 1:100,000 recombinants can be isolated with <40 PCRs, and we developed a web-based calculator to optimize FPE. C1 [Lyozin, George T.; Kosaka, Yasuhiro; Yost, H. Joseph; Brunelli, Luca] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT 84132 USA. [Bressloff, Paul C.] Univ Utah, Dept Math, Salt Lake City, UT USA. [Kumar, Amit; Kuehn, Michael R.] NCI, Lab Prot Dynam & Signaling, Frederick, MD 21701 USA. [Demarest, Bradley L.; Yost, H. Joseph] Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT USA. RP Brunelli, L (reprint author), Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT 84132 USA. EM luca.brunelli@genetics.utah.edu RI Kuehn, Michael/A-4573-2014 OI Kuehn, Michael/0000-0002-7703-9160 FU University of Utah School of Medicine's Department of Pediatrics (Neonatology); American Heart Association [09BGIA2251076]; US National Heart, Lung, and Blood Institute Bench-to-Bassinet Consortium [U01HL0981]; US National Institutes of Health; National Cancer Institute FX We acknowledge S.K. Sharan (US National:Cancer Institute) for providing mini-lambda and for helpful discussions; M.L. Condic, F.S. Gizatullin, J.T. Hill and R.A. McKnight for comments on the manuscript; V. Lyozin and B. Stephan for technical help in figure preparation; and V. Boyko (US National Cancer Institute) for providing plasmids containing the coding sequences of fluorescent proteins. This work was supported by funds from the University of Utah School of Medicine's Department of Pediatrics (Neonatology) and an American Heart Association grant to L.B. (09BGIA2251076); the US National Heart, Lung, and Blood Institute Bench-to-Bassinet Consortium grant to H.J.Y. (U01HL0981); and the Intramural Research Program of the US National Institutes of Health and National Cancer Institute to M.R.K. 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 endorsernent by the US government. NR 34 TC 2 Z9 2 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD SEP PY 2014 VL 11 IS 9 BP 966 EP 970 DI 10.1038/NMETH.3030 PG 5 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AO5UB UT WOS:000341409700027 PM 25028895 ER PT J AU Chaiworapongsa, T Chaemsaithong, P Korzeniewski, SJ Yeo, L Romero, R AF Chaiworapongsa, Tinnakom Chaemsaithong, Piya Korzeniewski, Steven J. Yeo, Lami Romero, Roberto TI Pre-eclampsia part 2: prediction, prevention and management SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID UTERINE ARTERY DOPPLER; ENDOTHELIAL GROWTH-FACTOR; CHRONIC KIDNEY-DISEASE; CELL-FREE FETAL; CIRCULATING ANGIOGENIC FACTORS; MATERNAL PLASMA-CONCENTRATIONS; TYROSINE KINASE-1 SFLT1; HIGH-RISK WOMEN; CALCIUM SUPPLEMENTATION; EARLY-PREGNANCY AB An antiangiogenic state might constitute a terminal pathway for the multiple aetiologies of pre-eclampsia, especially those resulting from placental abnormalities. The levels of angiogenic and antiangiogenic proteins in maternal blood change prior to a diagnosis of pre-eclampsia, correlate with disease severity and have prognostic value in identifying women who will develop maternal and/or perinatal complications. Potential interventions exist to ameliorate the imbalance of angiogenesis and, hence, might provide opportunities to improve maternal and/or perinatal outcomes in pre-eclampsia. Current strategies for managing pre-eclampsia consist of controlling hypertension, preventing seizures and timely delivery of the fetus. Prediction of pre-eclampsia in the first trimester is of great interest, as early administration of aspirin might reduce the risk of pre-eclampsia, albeit modestly. Combinations of biomarkers typically predict pre-eclampsia better than single biomarkers; however, the encouraging initial results of biomarker studies require external validation in other populations before they can be used to facilitate intervention in patients identified as at increased risk. Angiogenic and antiangiogenic factors might also be useful in triage of symptomatic patients with suspected pre-eclampsia, differentiating pre-eclampsia from exacerbations of pre-existing medical conditions and performing risk assessment in asymptomatic women. This Review article discusses the performance of predictive and prognostic biomarkers for pre-eclampsia, current strategies for preventing and managing the condition and its long-term consequences. C1 [Chaiworapongsa, Tinnakom; Chaemsaithong, Piya; Korzeniewski, Steven J.; Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Chaiworapongsa, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM tchaiwor@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Department of Health and Human Services (NICHD/NIH/DHHS); NICHD; NIH [HHSN275201300006C] FX The authors' research is supported partly by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Department of Health and Human Services (NICHD/NIH/DHHS) and partly with Federal funding from the NICHD and NIH under contract no. HHSN275201300006C. NR 134 TC 23 Z9 25 U1 0 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD SEP PY 2014 VL 10 IS 9 BP 531 EP 540 DI 10.1038/nrneph.2014.103 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AO4TH UT WOS:000341333800008 PM 25003612 ER PT J AU Swarts, DC Makarova, K Wang, YL Nakanishi, K Ketting, RF Koonin, EV Patel, DJ van der Oost, J AF Swarts, Daan C. Makarova, Kira Wang, Yanli Nakanishi, Kotaro Ketting, Rene F. Koonin, Eugene V. Patel, Dinshaw J. van der Oost, John TI The evolutionary journey of Argonaute proteins SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Review ID EUKARYOTE TRYPANOSOMA-BRUCEI; GERMLINE GENE-EXPRESSION; SEED-TARGET RECOGNITION; PIWI-INTERACTING RNAS; DICER-LIKE PROTEINS; CRYSTAL-STRUCTURE; PAZ DOMAIN; STRUCTURAL BASIS; SLICER ACTIVITY; GUIDE RNA AB Argonaute proteins are conserved throughout all domains of life. Recently characterized prokaryotic Argonaute proteins (pAgos) participate in host defense by DNA interference, whereas eukaryotic Argonaute proteins (eAgos) control a wide range of processes by RNA interference. Here we review molecular mechanisms of guide and target binding by Argonaute proteins, and describe how the conformational changes induced by target binding lead to target cleavage. On the basis of structural comparisons and phylogenetic analyses of pAgos and eAgos, we reconstruct the evolutionary journey of the Argonaute proteins through the three domains of life and discuss how different structural features of pAgos and eAgos relate to their distinct physiological roles. C1 [Swarts, Daan C.; van der Oost, John] Wageningen Univ, Dept Agrotechnol & Food Sci, Microbiol Lab, NL-6700 AP Wageningen, Netherlands. [Makarova, Kira; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Wang, Yanli] Chinese Acad Sci, Inst Biophys, Beijing 100080, Peoples R China. [Nakanishi, Kotaro] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. [Ketting, Rene F.] Inst Mol Biol, Mainz, Germany. [Patel, Dinshaw J.] Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10021 USA. RP van der Oost, J (reprint author), Wageningen Univ, Dept Agrotechnol & Food Sci, Microbiol Lab, NL-6700 AP Wageningen, Netherlands. EM pateld@mskcc.org; john.vanderoost@wur.nl OI Swarts, Daan/0000-0003-4412-9191 FU Netherlands Organization of Scientific Research (NWO) (NWO-TOP) [845.10.003]; US National Institutes of Health [TR01 GM104962]; US Department of Health and Human Services; Japan Science and Technology (JST) Agency FX This work was financially supported by grants from the Netherlands Organization of Scientific Research (NWO) to J.v.d.O. (NWO-TOP, 845.10.003) and the US National Institutes of Health to D.J.P. (TR01 GM104962). K.M. and E.V.K. are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). K.N. is supported by Precursory Research for Embryonic Science and Technology (PRESTO) from the Japan Science and Technology (JST) Agency. NR 108 TC 43 Z9 44 U1 7 U2 65 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD SEP PY 2014 VL 21 IS 9 BP 743 EP 753 DI 10.1038/nsmb.2879 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AO5RY UT WOS:000341404200003 PM 25192263 ER PT J AU Brady, I Hall, KD AF Brady, Ignatius Hall, Kevin D. TI Dispatch from the Field: Is Mathematical Modeling Applicable to Obesity Treatment in the Real World? SO OBESITY LA English DT Article ID ENERGY C1 [Brady, Ignatius] MercyCare Community Phys, Cedar Rapids, IA USA. [Hall, Kevin D.] NIDDK, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov FU Intramural Research Program of the NIH; National Institute of Diabetes & Digestive & Kidney Diseases; Mercy Medical Center FX This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes & Digestive & Kidney Diseases (to K.D.H.), and Mercy Medical Center (to I.B.). NR 10 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD SEP PY 2014 VL 22 IS 9 BP 1939 EP 1941 DI 10.1002/oby.20804 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AO8BR UT WOS:000341578000002 PM 24895253 ER PT J AU Agarwal, N Apolo, AB Tsao, CK Lee, KM Godbold, JH Soto, R Poole, A Gimpel-Tetra, K Lowe, N Oh, WK Galsky, MD AF Agarwal, Neeraj Apolo, Andrea B. Tsao, Che-Kai Lee, Karen M. Godbold, James H. Soto, Rothschild Poole, Austin Gimpel-Tetra, Kiev Lowe, Nancy Oh, William K. Galsky, Matthew D TI Phase Ib/II Trial of Gemcitabine, Cisplatin, and Lenalidomide as First-Line Therapy in Patients With Metastatic Urothelial Carcinoma SO ONCOLOGIST LA English DT Editorial Material AB Background. Outcomes with current chemotherapy in metastatic urothelial carcinoma (MUC) remain poor. Lenalidomide, an antiangiogenic and immunomodulatory agent, enhances the effects of chemotherapy in preclinical studies. In this phase Ib/II study, we sought to determine a tolerable dose of lenalidomide in combination with gemcitabine and cisplatin (GCL) in patients with MUC and to explore the safety and activity of this regimen. Methods. Patients with chemotherapy-naive MUC received gemcitabine 1,000mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 1 every 21 days. In phase Ib, there were four planned escalating dose levels of lenalidomide (10, 15, 20, and 25 mg) daily on days 1-14. Results. Seven patients received GCL in phase Ib. The dose of lenalidomide was not escalated beyond 10 mg because of cytopenias requiring repeated dose delays and reductions. Two additional patients were enrolled in phase II, but the study was ultimately terminated due to poor tolerability and slow accrual. The most frequent grade >= 3 adverse events were cytopenias and diarrhea. Three of the nine patients experienced an objective response (one complete response, two partial responses). Conclusion. Chronic administration of the GCL regimen was poorly tolerated because of additive and cumulative myelo-suppression. C1 [Agarwal, Neeraj; Poole, Austin] Univ Utah, Dept Med, Div Med Oncol, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Apolo, Andrea B.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tsao, Che-Kai; Lee, Karen M.; Godbold, James H.; Soto, Rothschild; Gimpel-Tetra, Kiev; Lowe, Nancy; Oh, William K.; Galsky, Matthew D] Icahn Sch Med Mt Sinai, Dept Med, Div Hematol Oncol, Tisch Canc Inst, New York, NY 10029 USA. RP Galsky, MD (reprint author), Mt Sinai Sch Med, Tisch Canc Inst, 1 Gustave L Levy Pl,Box 1079, New York, NY 10029 USA. EM matthew.galsky@mssm.edu FU NCATS NIH HHS [UL1 TR000457] NR 0 TC 1 Z9 1 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD SEP PY 2014 VL 19 IS 9 BP 915 EP 916 DI 10.1634/theoncologist.2014-0153 PG 2 WC Oncology SC Oncology GA AO5VB UT WOS:000341412300003 PM 25052451 ER PT J AU Keane, PA Karampelas, M Sim, DA Sadda, SR Tufail, A Sen, HN Nussenblatt, RB Dick, AD Lee, RW Murray, PI Pavesio, CE Denniston, AK AF Keane, Pearse A. Karampelas, Michael Sim, Dawn A. Sadda, Srinivas R. Tufail, Adnan Sen, H. Nida Nussenblatt, Robert B. Dick, Andrew D. Lee, Richard W. Murray, Philip I. Pavesio, Carlos E. Denniston, Alastair K. TI Objective Measurement of Vitreous Inflammation Using Optical Coherence Tomography SO OPHTHALMOLOGY LA English DT Article ID DIABETIC MACULAR EDEMA; QUANTITATIVE SUBANALYSIS; SUBRETINAL FLUID; UVEITIS; DISEASE; EYES; DEGENERATION; DENSITY; SPACES; OCT AB Purpose: To obtain measurements of vitreous signal intensity from optical coherence tomography (OCT) image sets in patients with uveitis, with the aim of developing an objective, quantitative marker of inflammatory activity in patients with this disease. Design: Retrospective, observational case-control series. Participants: Thirty patients (30 eyes) with vitreous haze secondary to intermediate, posterior, or panuveitis; 12 patients (12 eyes) with uveitis but without evidence of vitreous haze; and 18 patients (18 eyes) without intraocular inflammation or vitreoretinal disease. Methods: Clinical and demographic characteristics were recorded, including visual acuity (VA), diagnosis, and anatomic type of uveitis. In each eye, the anterior chamber (AC) was graded for cellular activity and flare according to standardized protocols. The presence and severity of vitreous haze were classified according to the National Eye Institute system. Spectral-domain OCT images were analyzed using custom software. This software provided an "absolute" measurement of vitreous signal intensity, which was then compared with that of the retinal pigment epithelium (RPE), generating an optical density ratio with arbitrary units ("VIT/RPE-Relative Intensity"). Main Outcome Measures: Correlation between clinical vitreous haze scores and OCT-derived measurements of vitreous signal intensity. Results: The VIT/RPE-Relative Intensity was significantly higher in uveitic eyes with known vitreous haze (0.150) than in uveitic eyes without haze or in healthy controls (0.0767, P = 0.0001). The VIT/RPE-Relative Intensity showed a significant, positive correlation with clinical vitreous haze scores (r = 0.566, P = 0.0001). Other ocular characteristics significantly associated with VIT/RPE-Relative Intensity included VA (r = 0.573, P = 0.0001), AC cells (r = 0.613, P = 0.0001), and AC flare (r = 0.385, P = 0.003). Measurement of VIT/RPE-Relative Intensity showed a good degree of intergrader reproducibility (95% limits of agreement, -0.019 to 0.016). Conclusions: These results provide preliminary evidence that OCT-derived measurements of vitreous signal intensity may be useful as an outcome measure in patients with uveitis. If validated in future studies, such measures may serve as an objective, quantitative disease activity end point, with the potential to improve the "signal:noise" ratio of clinical trials in this area, thus enabling smaller studies for the same power. The incorporation of automated vitreous analysis in commercial OCT systems may, in turn, facilitate monitoring and re-treatment of patients with uveitis in clinical practice. (C) 2014 American Academy of Ophthalmology. C1 [Keane, Pearse A.; Karampelas, Michael; Sim, Dawn A.; Tufail, Adnan; Pavesio, Carlos E.] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr Ophthalmol, London, England. [Keane, Pearse A.; Karampelas, Michael; Sim, Dawn A.; Tufail, Adnan; Pavesio, Carlos E.] UCL Inst Ophthalmol, London, England. [Karampelas, Michael] Hinchingbrooke Hlth Care NHS Trust, Hinchingbrooke Hosp, Huntingdon, England. [Sadda, Srinivas R.] Univ So Calif, Keck Sch Med, Doheny Eye Inst, Los Angeles, CA 90033 USA. [Sadda, Srinivas R.] Univ So Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA 90033 USA. [Sen, H. Nida; Nussenblatt, Robert B.] NEI, NIH, Bethesda, MD 20892 USA. [Dick, Andrew D.; Lee, Richard W.] Univ Hosp Bristol NHS Fdn Trust, Bristol Eye Hosp, Bristol, Avon, England. [Murray, Philip I.] Univ Birmingham, Acad Unit Ophthalmol, Birmingham, W Midlands, England. [Murray, Philip I.; Denniston, Alastair K.] Sandwell & West Birmingham NHS Trust, Birmingham & Midland Eye Ctr, Birmingham, W Midlands, England. [Denniston, Alastair K.] Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp Birmingham, Birmingham, W Midlands, England. RP Denniston, AK (reprint author), Univ Hosp Birmingham NHS Trust, Queen Elizabeth Hosp Birmingham, Birmingham, W Midlands, England. EM a.denniston@bham.ac.uk RI Lee, Richard/A-3116-2017; OI Lee, Richard/0000-0002-9480-6843; Denniston, Alastair/0000-0001-7849-0087; Murray, Philip/0000-0001-8491-3795 FU Department of Health's NIHR Biomedical Research Centre; UCL Institute of Ophthalmology; Allergan European Retina Panel; Carl Zeiss Meditec; Optos; Optovue, Inc; NEI's Intramural Research Program; Fight for Sight UK/Olivia's Vision Uveitis Small Grant Award; Fight for Sight UK [1987] FX The author(s) have made the following disclosure(s): P.A.K., D.A.S., A.T., and C.E.P. have received a proportion of their funding from the Department of Health's NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology. The views expressed in the publication are those of the author and not necessarily those of the Department of Health.; P.A.K. and D.A.S.: travel grants from the Allergan European Retina Panel.; A.T.: advisory boards for Heidelberg Engineering, Novartis, Pfizer, GSK, Thrombogenics, Bayer, and Allergan.; S.R.S.: co-inventor of Doheny intellectual property related to OCT that has been licensed by Topcon Medical Systems; current member of the scientific advisory board for Heidelberg Engineering; receives research support from Carl Zeiss Meditec, Optos, and Optovue, Inc; and has served as a consultant for Genentech, Inc, Regeneron, and Allergan, Inc.; H.N.S. and R.B.N.: sponsored by the NEI's Intramural Research Program.; This research was funded by a Fight for Sight UK/Olivia's Vision Uveitis Small Grant Award (principal investigator: A.K.D.). D.A.S. also receives funding from Fight for Sight UK, Grant Number 1987. NR 43 TC 15 Z9 15 U1 0 U2 2 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 SEP PY 2014 VL 121 IS 9 BP 1706 EP 1714 DI 10.1016/j.ophtha.2014.03.006 PG 9 WC Ophthalmology SC Ophthalmology GA AO2KY UT WOS:000341151800019 PM 24835759 ER PT J AU Jonasson, F Fisher, DE Eiriksdottir, G Sigurdsson, S Klein, R Launer, LJ Harris, T Gudnason, V Cotch, MF AF Jonasson, Fridbert Fisher, Diana E. Eiriksdottir, Gudny Sigurdsson, Sigurdur Klein, Ronald Launer, Lenore J. Harris, Tamara Gudnason, Vilmundur Cotch, Mary Frances TI Five-Year Incidence, Progression, and Risk Factors for Age-Related Macular Degeneration The Age, Gene/Environment Susceptibility Study SO OPHTHALMOLOGY LA English DT Article ID BLUE MOUNTAINS EYE; BEAVER-DAM-EYE; ANGELES LATINO EYE; VISUAL IMPAIRMENT; REYKJAVIK EYE; 4-YEAR INCIDENCE; MACULOPATHY; PREVALENCE; OLDER; ASSOCIATION AB Objective: To investigate the incidence and progression of age-related macular degeneration (AMD) and associated risk factors. Design: Population-based, prospective, cohort study. Participants: We included 2868 participants from the Age Gene/Environment Susceptibility-Reykjavik Study with retinal data at baseline and 5-year follow-up. Methods: Digital macular photographs were graded for presence of AMD. Participants completed a questionnaire and extensive clinical battery. Biomarkers were assessed. Risk factors for AMD were analyzed using multivariate regression analysis with odds ratios (ORs) and 95% CIs. Main Outcome Measures: We assessed AMD, defined as early or late. Results: Among 2196 participants free of AMD at baseline, 14.9% developed incident AMD. In multivariate models, incident AMD was significantly associated with age (OR per year, 1.14; 95% CI, 1.11-1.17), current smoking (OR, 2.07; 95% CI, 1.38-3.11), former smoking (OR, 1.36; 95% CI, 1.04-1.79), plasma high-density lipoprotein (HDL) cholesterol level (OR, 1.62 per mmol/L; 95% CI, 1.19-2.22), and body mass index (BMI; OR, 1.04 per kg/m(2); 95% CI, 1.01-1.07). Among 563 participants with early AMD at baseline, 22.7% progressed to late AMD (11.0% pure geographic atrophy [GA] and 11.7% exudative AMD). On multivariate analyses, age was significantly associated with progression to GA (OR 1.14; 95% CI, 1.07-1.21) and exudative AMD (OR, 1.08; 95% CI, 1.01-1.14). Adjusting for age, female sex was associated with exudative AMD (OR, 2.10; 95% CI, 1.10-3.98) and plasma HDL cholesterol with GA (OR, 2.03 per mmol/L; 95% CI, 1.02-4.05). Conclusions: By age 85, 57.4% of participants had signs of AMD. Age, smoking, plasma HDL cholesterol, BMI, and female sex are associated with AMD. Elevated HDL cholesterol is associated with GA development. (C) 2014 American Academy of Ophthalmology. C1 [Jonasson, Fridbert] Landspitali Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland. [Jonasson, Fridbert; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Fisher, Diana E.; Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Eiriksdottir, Gudny; Sigurdsson, Sigurdur; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Klein, Ronald] Univ Wisconsin, Madison, WI USA. [Launer, Lenore J.; Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Jonasson, F (reprint author), Univ Iceland, IS-101 Reykjavik, Iceland. EM fridbert@landspitali.is RI Gudnason, Vilmundur/K-6885-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Cotch, Mary Frances/0000-0002-2046-4350 FU National Institute of Health (Intramural Research Program of the National Institute of Aging and the National Eye Institute) [ZIAEY00401]; National Institute of Health [N01-AG-1-2100]; Icelandic Heart Association; Icelandic Parliament; University of Iceland Research Fund; Helga Jonsdottir and Sigurlidi Kristjansson Research Fund FX Supported by the National Institute of Health (Intramural Research Program of the National Institute of Aging and the National Eye Institute, ZIAEY00401), National Institute of Health contract number N01-AG-1-2100, the Icelandic Heart Association, the Icelandic Parliament, the University of Iceland Research Fund, and the Helga Jonsdottir and Sigurlidi Kristjansson Research Fund. The funders had no role in data collection, management, analysis and interpretation of the data, preparation, writing and approval of the manuscript, and decision to submit the manuscript for publication. NR 44 TC 19 Z9 19 U1 2 U2 9 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 SEP PY 2014 VL 121 IS 9 BP 1766 EP 1772 DI 10.1016/j.ophtha.2014.03.013 PG 7 WC Ophthalmology SC Ophthalmology GA AO2KY UT WOS:000341151800027 PM 24768241 ER PT J AU Raju, TNK AF Raju, Tonse N. K. TI Reasonable Break Time for Nursing Mothers: A Provision Enacted Through the Affordable Care Act SO PEDIATRICS LA English DT Article DE breastfeeding; human milk; Affordable Care Act; infant nutrition; maternal employment C1 [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Raju, TNK (reprint author), NICHD, NIH, 6100 Execut Blvd,Room 4B03, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov NR 6 TC 3 Z9 3 U1 1 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD SEP PY 2014 VL 134 IS 3 BP 423 EP 424 DI 10.1542/peds.2014-0762 PG 2 WC Pediatrics SC Pediatrics GA AO5DN UT WOS:000341362600039 PM 25092946 ER PT J AU Rana, S Houston, PE Wang, WC Iyer, RV Goldsmith, J Casella, JF Reed, CK Rogers, ZR Waclawiw, MA Thompson, B AF Rana, Sohail Houston, Patricia E. Wang, Winfred C. Iyer, Rathi V. Goldsmith, Jonathan Casella, James F. Reed, Caroline K. Rogers, Zora R. Waclawiw, Myron A. Thompson, Bruce CA BABY HUG Investigators TI Hydroxyurea and Growth in Young Children With Sickle Cell Disease SO PEDIATRICS LA English DT Article DE sickle cell disease; growth; hydroxyurea; children; height; weight; head circumference; BMI ID RESTING ENERGY-EXPENDITURE; TRIAL BABY HUG; NUTRITIONAL-STATUS; ENCOUNTER FREQUENCY; DIABETES-MELLITUS; BLOOD-PRESSURE; ANEMIA; MANIFESTATIONS; PATTERNS; ADOLESCENTS AB BACKGROUND: Growth impairment is a known complication of sickle cell disease. Effects of hydroxyurea (HU) on growth in very young children are not known. METHODS: Height, weight, BMI, and head circumference (HC) were compared with World Health Organization (WHO) standards in BABY HUG, a multicenter, randomized, double-blinded, placebo-controlled 2-year clinical trial of HU in 193 children 9 to 18 months of age. Anthropometric data were closely monitored and converted to z scores by using WHO standardized algorithms for descriptive analyses. The treatment and placebo groups were compared longitudinally by using a mixed model analysis. RESULTS: At entry, the z scores of BABY HUG children were higher than WHO norms. After 2 years of HU or placebo treatment, there were no significant differences between the groups, except for the mean HC z scores at study exit (HU: + 0.8 versus placebo: + 1.0, P = .05). Baseline z scores were the best predictors of z scores at study exit. The absolute neutrophil count, absolute reticulocyte count, and total white blood cell count had significant negative correlations with growth measures. CONCLUSIONS: Both groups had normal or near normal anthropometric measures during the study. The HC z scores at study entry and exit were slightly greater than WHO norms. Higher baseline white blood cell count, absolute reticulocyte count, and absolute neutrophil count were associated with poorer growth. The significance of the slightly lower HC in the treatment group at study exit is not clear. Trends toward normalization of weight and height and effects on HC will be monitored in ongoing BABY HUG follow-up studies. C1 [Rana, Sohail; Houston, Patricia E.; Reed, Caroline K.] Howard Univ, Dept Pediat & Child Hlth, Washington, DC 20060 USA. [Wang, Winfred C.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Iyer, Rathi V.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Goldsmith, Jonathan; Waclawiw, Myron A.] NHLBI, Bethesda, MD 20892 USA. [Casella, James F.] Johns Hopkins Univ, Dept Pediat, Div Hematol, Baltimore, MD 21218 USA. [Rogers, Zora R.] UT Southwestern Med Ctr, Dallas, TX USA. [Thompson, Bruce] Clin Trials & Surveys Corp, Owings Mills, MD USA. RP Rana, S (reprint author), Howard Univ, Dept Pediat & Child Hlth, 2041 Georgia Ave NW, Washington, DC 20060 USA. EM srana@howard.edu FU National Heart, Lung, and Blood Institute/National Institutes of Health [N01-HB-07150, N01-HB-07160]; Best Pharmaceuticals for Children Act; National Institute of Child Health and Human Development; National Institutes of Health (NIH) FX Supported by the National Heart, Lung, and Blood Institute/National Institutes of Health contracts N01-HB-07150 to N01-HB-07160, with partial support of the Best Pharmaceuticals for Children Act and the National Institute of Child Health and Human Development. Funded by the National Institutes of Health (NIH). NR 45 TC 9 Z9 9 U1 3 U2 12 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD SEP PY 2014 VL 134 IS 3 BP 465 EP 472 DI 10.1542/peds.2014-0917 PG 8 WC Pediatrics SC Pediatrics GA AO5DN UT WOS:000341362600045 PM 25157002 ER PT J AU LaBresh, KA Ariza, AJ Lazorick, S Furberg, RD Whetstone, L Hobbs, C de Jesus, J Salinas, IG Bender, RH Binns, HJ AF LaBresh, Kenneth A. Ariza, Adolfo J. Lazorick, Suzanne Furberg, Robert D. Whetstone, Lauren Hobbs, Connie de Jesus, Janet Salinas, Ilse G. Bender, Randall H. Binns, Helen J. TI Adoption of Cardiovascular Risk Reduction Guidelines: A Cluster-Randomized Trial SO PEDIATRICS LA English DT Article DE cardiovascular disorders; children; cluster randomized trial; guideline implementation; prevention; quality improvement ID CONTINUING MEDICAL-EDUCATION; BODY-MASS INDEX; BLOOD-PRESSURE; FAMILY-PRACTICE; CHILDREN; CHILDHOOD; OBESITY; HEALTH; ASSOCIATION; ADOLESCENTS AB BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) and underlying atherosclerosis begin in childhood and are related to CVD risk factors. This study evaluates tools and strategies to enhance adoption of new CVD risk reduction guidelines for children. METHODS: Thirty-two practices, recruited and supported by 2 primary care research networks, were cluster randomized to a multifaceted controlled intervention. Practices were compared with guideline-based individual and composite measures for BMI, blood pressure (BP), and tobacco. Composite measures were constructed by summing the numerators and denominators of individual measures. Preintervention and postintervention measures were assessed by medical record review of children ages 3 to 11 years. Changes in measures (pre-post and intervention versus control) were compared. RESULTS: The intervention group BP composite improved by 29.5%, increasing from 49.7% to 79.2%, compared with the control group (49.5% to 49.6%; P < .001). Intervention group BP interpretation improved by 61.1% (from 0.2% to 61.3%), compared with the control group (0.4% to 0.6%; P < .001). The assessment of tobacco exposure or use for 5-to 11-year-olds in the intervention group improved by 30.3% (from 3.4% to 49.1%) versus the control group (0.6% to 21.4%) (P = .042). No significant change was seen in the BMI or tobacco composites measures. The overall composite of 9 measures improved by 13.4% (from 48.2% to 69.8%) for the intervention group versus the control group (47.4% to 55.2%) (P = .01). CONCLUSIONS: Significant improvement was demonstrated in the overall composite measure, the composite measure of BP, and tobacco assessment and advice for children aged 5 to 11 years. C1 [LaBresh, Kenneth A.; Furberg, Robert D.; Hobbs, Connie; Bender, Randall H.] RTI Int, Waltham, MA 02451 USA. [Ariza, Adolfo J.; Binns, Helen J.] Stanley Manne Childrens Res Inst, Pediat Practice Res Grp, Mary Ann & J Milburn Smith Child Hlth Res Program, Chicago, IL USA. [Ariza, Adolfo J.; Whetstone, Lauren] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Lazorick, Suzanne; Whetstone, Lauren] E Carolina Univ, Brody Sch Med, Dept Pediat, Greenville, NC USA. [Lazorick, Suzanne; Whetstone, Lauren] E Carolina Univ, Dept Publ Hlth, Greenville, NC USA. [Salinas, Ilse G.] Publ Hlth Inst, Res & Evaluat Sect Nutr Educ, Sacramento, CA USA. [Salinas, Ilse G.] Calif Dept Publ Hlth, Obes Prevent Branch, Sacramento, CA USA. [de Jesus, Janet] NHLBI, Bethesda, MD 20892 USA. RP LaBresh, KA (reprint author), RTI Int, 1440 Main St, Waltham, MA 02451 USA. EM klabresh@rti.org RI LaBresh, Kenneth/A-6995-2017; OI LaBresh, Kenneth/0000-0001-9040-1956; Furberg, Robert/0000-0002-3803-1879 FU National Heart, Lung, and Blood Institute [NHLBI-PB-[HL]-2009195D, HHSN268200900120U]; National Institutes of Health (NIH) FX This study was funded by the National Heart, Lung, and Blood Institute (NHLBI-PB-[HL]-2009195D HHSN268200900120U). Funded by the National Institutes of Health (NIH). NR 34 TC 2 Z9 2 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD SEP PY 2014 VL 134 IS 3 BP E732 EP E738 DI 10.1542/peds.2014-0876 PG 7 WC Pediatrics SC Pediatrics GA AO5DN UT WOS:000341362600013 PM 25157013 ER PT J AU Elahi, D Angeli, FS Vakilipour, A Carlson, OD Tomas, E Egan, JM Habener, JF Shannon, RP AF Elahi, Dariush Angeli, Franca S. Vakilipour, Amin Carlson, Olga D. Tomas, Eva Egan, Josephine M. Habener, Joel F. Shannon, Richard P. TI GLP-1(32-36) amide, a novel pentapeptide cleavage product of GLP-1, modulates whole body glucose metabolism in dogs SO PEPTIDES LA English DT Article DE Glucagon-like peptide-1; Diabetes; Obesity; Insulin resistance; Glucose utilization ID GLUCAGON-LIKE PEPTIDE-1; INSULIN-SECRETION; RECEPTOR; HUMANS; MICE AB We have previously demonstrated in human subjects who under euglycemic clamp conditions GLP-1(9-36) amide infusions inhibit endogenous glucose production without substantial insulinotropic effects. An earlier report indicates that GLP-1(9-36) amide is cleaved to a nonapeptide, GLP-1(28-36) amide and a pentapeptide GLP-1(32-36) amide (LVKGR amide). Here we study the effects of the pentapeptide on whole body glucose disposal during hyperglycemic clamp studies. Five dogs underwent indwelling catheterizations. Following recovery, the dogs underwent a 180 min hyperglycemic clamp(basal glucose +98 mg/dl) in a cross-over design. Saline or pentapeptide (30 pmol kg(-1) min(-1)) was infused during the last 120 min after commencement of the hyperglycemic clamp in a primed continuous manner. During the last 30 min of the pentapeptide infusion, glucose utilization (M) significantly increased to 21.4 +/- 2.9 mg kg(-1) min(-1)c ompared to M of 14.3 +/- 1.1 mg kg(-1) min(-1) during the saline infusion (P = 0.026, paired t-test; P = 0.062, Mann-Whitney U test). During this interval, no significant differences in insulin(26.6 +/- 3.2 vs. 23.7 +/- 2.5 mu U/ml, P = NS) or glucagon secretion (34.0 +/- 2.1 vs. 31.7 +/- 1.8 pg/ml, P = NS) were observed. These findings demonstrate that under hyperglycemic clamp studies the pentapeptide modulates glucose metabolism by a stimulation of whole-body glucose disposal. Further, the findings suggest that the metabolic benefits previously observed during GLP-1(9-36) amide infusions in humans might be due, at least in part, to the metabolic effects of the pentapeptide that is cleaved from the pro-peptide, GLP-1(9-36) amide in the circulation. (C) 2014 Elsevier Inc. All rights reserved. C1 [Elahi, Dariush; Angeli, Franca S.; Vakilipour, Amin; Shannon, Richard P.] Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. [Carlson, Olga D.; Egan, Josephine M.] NIA, Diabet Sect, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Tomas, Eva; Habener, Joel F.] Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. [Tomas, Eva; Habener, Joel F.] Harvard Univ, Sch Med, Boston, MA USA. RP Elahi, D (reprint author), ICON Dev Solut, 8307 Gault Lane, San Antonio, TX 78209 USA. EM dariush.elahi@iconplc.com FU Department of Medicine at the Perelman School of Medicine; Intramural Research Program of the National Institutes on Aging; Laboratory of Molecular Endocrinology at the Massachusetts General Hospital [P30DK05751] FX We thank Drs. You-Tang Shen and Li Chen for performing the surgery in the dogs. This study was funded in part from the Department of Medicine at the Perelman School of Medicine, from the Intramural Research Program of the National Institutes on Aging, and from the Laboratory of Molecular Endocrinology at the Massachusetts General Hospital (Grant No. P30DK05751). NR 32 TC 3 Z9 4 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 EI 1873-5169 J9 PEPTIDES JI Peptides PD SEP PY 2014 VL 59 BP 20 EP 24 DI 10.1016/j.peptides.2014.06.004 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA AO5ZT UT WOS:000341427300004 PM 24937653 ER PT J AU White, DK Neogi, T King, WC LaValley, MP Kritchevsky, SB Nevitt, MC Harris, TB Ferrucci, L Simonsick, EM Satterfield, S Strotmeyer, ES Zhang, YQ AF White, Daniel K. Neogi, Tuhina King, Wendy C. LaValley, Michael P. Kritchevsky, Stephen B. Nevitt, Michael C. Harris, Tamara B. Ferrucci, Luigi Simonsick, Eleanor M. Satterfield, Suzanne Strotmeyer, Elsa S. Zhang, Yuqing CA Hlth ABC Study TI Can Change in Prolonged Walking Be Inferred From a Short Test of Gait Speed Among Older Adults Who Are Initially Well-Functioning? SO PHYSICAL THERAPY LA English DT Article ID BODY-COMPOSITION; PERFORMANCE; DISTANCE; TRAJECTORIES; MORTALITY; PEOPLE; STROKE; HEALTH AB Background. The ability to walk for short and prolonged periods of time is often measured with separate walking tests. It is unclear whether decline in the 2-minute walk coincides with decline in a shorter 20-m walk among older adults. Objective. The aim of this study was to describe patterns of change in the 20-m walk and 2-minute walk over 8 years among a large cohort of older adults. Should change be similar between tests of walking ability, separate retesting of prolonged walking may need to be reconsidered. Design. A longitudinal, observational cohort study was conducted. Methods. Data were from 1,893 older adults who were well-functioning (>= 70 years of age). The 20-m walk and 2-minute walk were repeatedly measured over 8 years to measure change during short and prolonged periods of walking, respectively. Change was examined using a dual group-based trajectory model (dual model), and agreement between walking trajectories was quantified with a weighted kappa statistic. Results. Three trajectory groups for the 20-m walk and 2-minute walk were identified. More than 86% of the participants were in similar trajectory groups for both tests from the dual model. There was high chance-corrected agreement (kappa=.84; 95% confidence interval=.82, .86) between the 20-m walk and 2-minute walk trajectory groups. Limitations. One-third of the original Health, Aging and Body Composition (Health ABC) study cohort was excluded from analysis due to missing clinic visits, followed by being excluded for health reasons for performing the 2-minute walk, limiting generalizability to healthy older adults. Conclusions. Patterns of change in the 2-minute walk are similar to those in the 20-m walk. Thus, separate retesting of the 2-minute walk may need to be reconsidered to gauge change in prolonged walking. C1 [White, Daniel K.] Boston Univ, Dept Phys Therapy & Athlet Training, Boston, MA 02215 USA. [Neogi, Tuhina] Boston Univ, Sch Med, Clin Epidemiol Res & Training Unit, Boston, MA 02215 USA. [King, Wendy C.; Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [LaValley, Michael P.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Nevitt, Michael C.] Univ Calif San Francisco, Dept Biostat & Epidemiol, San Francisco, CA 94143 USA. [Harris, Tamara B.] NIH, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIH, Longitudinal Studies Sect, Baltimore, MD USA. [Simonsick, Eleanor M.] NIA, NIH, Baltimore, MD 21224 USA. [Satterfield, Suzanne] Univ Tennessee, Memphis, TN USA. [Zhang, Yuqing] Boston Univ, Clin Epidemiol Res & Training Unit, Boston, MA 02215 USA. RP White, DK (reprint author), Boston Univ, Dept Phys Therapy & Athlet Training, 635 Commonwealth Ave,5th Floor, Boston, MA 02215 USA. EM white.daniel@gmail.com OI King, Wendy/0000-0002-0740-0029; Strotmeyer, Elsa/0000-0002-4093-6036; Neogi, Tuhina/0000-0002-9515-1711 FU National Institutes of Health (NIH); National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR0124590]; National Institute of Child Health and Human Development as part of the Medical Rehabilitation Research Infrastructure Network [R24HD0065688]; Boston Claude D. Pepper Older Americans Independence Center from the NIA [P30-AG031679]; Foundation for Physical Therapy Geriatrics Research Grant; American College of Rheumatology Research Foundation's Rheumatology Investigator Award; National Institute of Arthritis and Musculoskeletal and Skin at NIH [AR47785, R01-AR062506] FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH); the National Institute on Aging (NIA) (grants N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, and R01-AG028050); the National Institute of Nursing Research (grant R01-NR0124590); the National Institute of Child Health and Human Development as part of the Medical Rehabilitation Research Infrastructure Network R24HD0065688; the Boston Claude D. Pepper Older Americans Independence Center from the NIA (grant P30-AG031679); the Foundation for Physical Therapy Geriatrics Research Grant; the American College of Rheumatology Research Foundation's Rheumatology Investigator Award; and the National Institute of Arthritis and Musculoskeletal and Skin at NIH (grants AR47785 and R01-AR062506). NR 16 TC 2 Z9 2 U1 2 U2 10 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 EI 1538-6724 J9 PHYS THER JI Phys. Ther. PD SEP PY 2014 VL 94 IS 9 BP 1285 EP 1293 DI 10.2522/ptj.20130628 PG 9 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA AO3JX UT WOS:000341226600009 PM 24786943 ER PT J AU Chung, EJ Hudak, K Horton, JA White, A Scroggins, BT Vaswani, S Citrin, D AF Chung, Eun Joo Hudak, Kathryn Horton, Jason A. White, Ayla Scroggins, Bradley T. Vaswani, Shiva Citrin, Deborah TI Transforming Growth Factor Alpha is a Critical Mediator of Radiation Lung Injury SO RADIATION RESEARCH LA English DT Article ID FIBROBLAST LYSYL OXIDASE; SMOOTH-MUSCLE CELLS; FACTOR RECEPTOR; PULMONARY-FIBROSIS; SIGNALING PATHWAYS; TRANSGENIC MICE; TGF-BETA; II CELLS; EXPRESSION; COLLAGEN AB Radiation fibrosis of the lung is a late toxicity of thoracic irradiation. Epidermal growth factor (EGF) signaling has previously been implicated in radiation lung injury. We hypothesized that TGF-alpha, an EGF receptor ligand, plays a key role in radiation-induced fibrosis in lung. Mice deficient in transforming growth factor (TGF-alpha(-/-)) and control C57Bl/6J (C57-WT) mice were exposed to thoracic irradiation in 5 daily fractions of 6 Gy. Cohorts of mice were followed for survival (n >= 5 per group) and tissue collection (n = 3 per strain and time point). Collagen accumulation in irradiated lungs was assessed by Masson's trichrome staining and analysis of hydroxyproline content. Cytokine levels in lung tissue were assessed with ELISA. The effects of TGF-alpha on pneumocyte and fibroblast proliferation and collagen production were analyzed in vitro. Lysyl oxidase (LOX) expression and activity were measured in vitro and in vivo. Irradiated C57-WT mice had a median survival of 24.4 weeks compared to 48.2 weeks for irradiated TGF-alpha(-/-) mice (P = 0.001). At 20 weeks after irradiation, hydroxyproline content was markedly increased in C57-WT mice exposed to radiation compared to TGF-alpha(-/-) mice exposed to radiation or unirradiated C57-WT mice (63.0, 30.5 and 37.6 mu g/lung, respectively, P = 0.01). C57-WT mice exposed to radiation had dense foci of subpleural fibrosis at 20 weeks after exposure, whereas the lungs of irradiated TGF-alpha(-/-) mice were largely devoid of fibrotic foci. Lung tissue concentrations of IL-1 beta, IL-4, TNF-alpha, TGF-beta and EGF at multiple time points after irradiation were similar in C57-WT and TGF-alpha(-/-) mice. TGF-alpha in lung tissue of C57-WT mice rose rapidly after irradiation and remained elevated through 20 weeks. TGF-alpha(-/-) mice had lower basal LOX expression than C57-WT mice. Both LOX expression and LOX activity were increased after irradiation in all mice but to a lesser degree in TGF-alpha(-/-) mice. Treatment of NIH-3T3 fibroblasts with TGF-alpha resulted in increases in proliferation, collagen production and LOX activity. These studies identify TGF-alpha as a critical mediator of radiation-induced lung injury and a novel therapeutic target in this setting. Further, these data implicate TGF-alpha as a mediator of collagen maturation through a TGF-beta independent activation of lysyl oxidase. (C) 2014 by Radiation Research Society C1 [Chung, Eun Joo; Hudak, Kathryn; Horton, Jason A.; White, Ayla; Scroggins, Bradley T.; Vaswani, Shiva; Citrin, Deborah] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Citrin, D (reprint author), NCI, Radiat Oncol Branch, Bldg 10 CRC,B2-3500, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 48 TC 8 Z9 10 U1 1 U2 6 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD SEP PY 2014 VL 182 IS 3 BP 350 EP 362 DI 10.1667/RR13625.1 PG 13 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AO4LH UT WOS:000341309000013 PM 25117621 ER PT J AU Woods, SW Walsh, BC Addington, J Cadenhead, KS Cannon, TD Cornblatt, BA Heinssen, R Perkins, DO Seidman, LJ Tarbox, SI Tsuang, MT Walker, EF McGlashan, TH AF Woods, Scott W. Walsh, Barbara C. Addington, Jean Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. Heinssen, Robert Perkins, Diana O. Seidman, Larry J. Tarbox, Sarah I. Tsuang, Ming T. Walker, Elaine F. McGlashan, Thomas H. TI Current status specifiers for patients at clinical high risk for psychosis SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Psychosis; Clinical high risk; Risk syndrome; Current status; Course of illness ID ULTRA-HIGH RISK; FOLLOW-UP; COMPREHENSIVE ASSESSMENT; PRODROMAL PHASE; REMISSION RATES; MENTAL STATES; YOUNG-PEOPLE; SCHIZOPHRENIA; TRANSITION; INDIVIDUALS AB Background: Longitudinal studies of the clinical high risk (CHR) syndrome for psychosis have emphasized the conversion vs non-conversion distinction and thus far have not focused intensively on classification among non-converters. The present study proposes a system for classifying CHR outcomes over time when using the Structured Interview for Psychosis-risk Syndromes and evaluates its validity. Method: The system for classifying CHR outcomes is referred to as "current status specifiers," with "current" meaning over the month prior to the present evaluation and "specifiers" indicating a set of labels and descriptions of the statuses. Specifiers for four current statuses are described: progression, persistence, partial remission, and full remission. Data from the North American Prodromal Longitudinal Study were employed to test convergent, discriminant, and predictive validity of the current status distinctions. Results: Validity analyses partly supported current status distinctions. Social and role functioning were more impaired in progressive and persistent than in remitted patients, suggesting a degree of convergent validity. Agreement between CHR current statuses and current statuses for a different diagnostic construct (DSM-IV Major Depression) was poor, suggesting discriminant validity. The proportion converting to psychosis within a year was significantly higher in cases meeting progression criteria than in those meeting persistence criteria and tended to be higher than in those meeting full remission criteria, consistent with a degree of predictive validity. Discussion: CHR syndrome current status specifiers could offer a potentially valid and useful description of current clinical status among non-converters. Study in additional samples is needed. (C) 2014 Published by Elsevier B.V. C1 [Woods, Scott W.; Walsh, Barbara C.; Tarbox, Sarah I.; McGlashan, Thomas H.] Yale Univ, Dept Psychiat, New Haven, CT 06519 USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT 06519 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Heinssen, Robert] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.; Tsuang, Ming T.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. RP Woods, SW (reprint author), Yale Univ, Sch Med, Dept Psychiat, PRIME Res Clin Psychosis Risk Syndrome, 34 Pk St, New Haven, CT 06519 USA. EM scott.woods@yale.edu FU National Institute of Mental Health [U01 MH066160, U01 MH082022, U01 MH066134, U01 MH081984, U01 MH060720, R01 MH60720, U01 MH081944, K24 MH76191, U01 MH065079]; The National Institute of Mental Health [MH081902, U01 MH061523, U01 MH081857, U01 MH066069, U01 MH082004, U01 MH065562, U01 MH081928, P50 MH080272, SCDMH82101008006, U01 MH062066, U01 MH081988] FX This study was supported by the National Institute of Mental Health (grants U01 MH066160 and U01 MH082022 to Dr Woods; grants U01 MH066134 and U01 MH081984 to Dr Addington; grants U01 MH060720, R01 MH60720, U01 MH081944 and K24 MH76191 to Dr Cadenhead; grants U01 MH065079 and MH081902 to Dr Cannon; grants U01 MH061523 and U01 MH081857 to Dr Cornblatt; grants U01 MH066069 and U01 MH082004 to Dr Perkins; grants U01 MH065562, U01 MH081928, and P50 MH080272 and Commonwealth of Massachusetts SCDMH82101008006 to Dr Seidman; and grants U01 MH062066 and U01 MH081988 to Dr Walker). The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 37 TC 4 Z9 4 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2014 VL 158 IS 1-3 BP 69 EP 75 DI 10.1016/j.schres.2014.06.022 PG 7 WC Psychiatry SC Psychiatry GA AO4MW UT WOS:000341314800012 PM 25012147 ER PT J AU Petrov, ME Kim, Y Lauderdale, DS Lewis, CE Reis, JP Carnethon, MR Knutson, KL Glasser, SP AF Petrov, Megan E. Kim, Yongin Lauderdale, Diane S. Lewis, Cora E. Reis, Jared P. Carnethon, Mercedes R. Knutson, Kristen L. Glasser, Stephen P. TI Objective sleep, a novel risk factor for alterations in kidney function: the CARDIA study SO SLEEP MEDICINE LA English DT Article DE Objective sleep; Kidney function; Sleep quality; Sex; Race; Glomerular filtration rate; Sleep duration ID GLOMERULAR-FILTRATION-RATE; DISEASE; HYPERFILTRATION; POPULATION; ALBUMINURIA; PROGRESSION; PREDICTION; MORTALITY; EQUATION; DURATION AB Objective: To determine the association between objectively measured sleep and 10-year changes in estimated glomerular filtration rate (eGFR). Methods: From 2003 to 2005, an ancillary sleep study was conducted at the Chicago site of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Community-based black and white adults (aged 32-51 years) wore a wrist actigraph for up to six nights to record sleep duration and fragmentation. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Participants without history of cardiovascular or chronic kidney diseases, proteinuria, or hypertension at the 2000-2001 CARDIA examination were followed over 10 years (n = 463). eGFR was estimated from serum creatinine (eGFR(Cr)) at the 2000-2001, 2005-2006, and 2010-2011 CARDIA examinations, whereas cystatin-C-estimated eGFR (eGFR(Cys)) was measured at the 2000-2001 and 2005-2006 examinations. Generalized estimating equation regression and linear models estimated the associations of each sleep parameter with changes in eGFR(Cr) and eGFR(Cys), controlling for cardiovascular and renal risk. Results: Sleep parameters were not related to 5-year change in eGFR(Cys). However, each 1 h decrease in sleep duration was significantly associated with a 1.5 mL/min/1.73 m(2) higher eGFR(Cr) [95% confidence interval (CI), 0.2-2.7], and each one-point increase in PSQI was significantly associated with a 0.5 mL/min/1.73 m2 higher eGFR(Cr) (95% CI, 0.04-0.9) over 10 years. Conclusion: In this community-based sample, shorter sleep and poorer sleep quality were related to higher kidney filtration rates over 10 years. (C) 2014 Elsevier B.V. All rights reserved. C1 [Petrov, Megan E.] Arizona State Univ, Coll Nursing & Hlth Innovat, Phoenix, AZ 85004 USA. [Kim, Yongin; Lewis, Cora E.; Glasser, Stephen P.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Lauderdale, Diane S.; Knutson, Kristen L.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. RP Petrov, ME (reprint author), Arizona State Univ, Coll Nursing & Hlth Innovat, 500 N 3rd St,MC 3020, Phoenix, AZ 85004 USA. EM megan.petrov@asu.edu OI Knutson, Kristen/0000-0002-2751-6168; Glasser, Stephen/0000-0001-9620-6406 FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005]; AHRQ [5 T32 HS013852-09]; NCMHD [3 P60 MD000502-08S1] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). Dr Petrov received training support from AHRQ (5 T32 HS013852-09) and NCMHD (3 P60 MD000502-08S1). NR 31 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD SEP PY 2014 VL 15 IS 9 BP 1140 EP 1146 DI 10.1016/j.sleep.2014.05.021 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AO6TA UT WOS:000341483200021 PM 25037841 ER PT J AU Kloverpris, HN McGregor, R McLaren, JE Ladell, K Stryhn, A Koofhethile, C Brener, J Chen, FB Riddell, L Graziano, L Klenerman, P Leslie, A Buus, S Price, DA Goulder, P AF Kloverpris, Henrik N. McGregor, Reuben McLaren, James E. Ladell, Kristin Stryhn, Anette Koofhethile, Catherine Brener, Jacqui Chen, Fabian Riddell, Lynn Graziano, Luzzi Klenerman, Paul Leslie, Alasdair Buus, Soren Price, David A. Goulder, Philip TI Programmed death-1 expression on HIV-1-specific CD8(+) T cells is shaped by epitope specificity, T-cell receptor clonotype usage and antigen load SO AIDS LA English DT Article DE HIV; human leukocyte antigen class I tetramers; immune exhaustion; programmed death-1 expression ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHRONIC VIRAL-INFECTION; HLA CLASS-I; HIV-1 INFECTION; PD-1 EXPRESSION; UP-REGULATION; HEPATITIS-B; EXHAUSTION; RESPONSES; ESCAPE AB Objectives: Although CD8(+) T cells play a critical role in the control of HIV-1 infection, their antiviral efficacy can be limited by antigenic variation and immune exhaustion. The latter phenomenon is characterized by the upregulation of multiple inhibitory receptors, such as programmed death-1 (PD-1), CD244 and lymphocyte activation gene-3 (LAG-3), which modulate the functional capabilities of CD8(+) T cells. Design and methods: Here, we used an array of different human leukocyte antigen (HLA)-B*15 : 03 and HLA-B*42 : 01 tetramers to characterize inhibitory receptor expression as a function of differentiation on HIV-1-specific CD8(+) T-cell populations (n = 128) spanning 11 different epitope targets. Results: Expression levels of PD-1, but not CD244 or LAG-3, varied substantially across epitope specificities both within and between individuals. Differential expression of PD-1 on T-cell receptor (TCR) clonotypes within individual HIV-1-specific CD8(+) T-cell populations was also apparent, independent of clonal dominance hierarchies. Positive correlations were detected between PD-1 expression and plasma viral load, which were reinforced by stratification for epitope sequence stability and dictated by effector memory CD8(+) T cells. Conclusion: Collectively, these data suggest that PD-1 expression on HIV-1-specific CD8(+) T cells tracks antigen load at the level of epitope specificity and TCR clonotype usage. These findings are important because they provide evidence that PD-1 expression levels are influenced by peptide/HLA class I antigen exposure. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Kloverpris, Henrik N.; McGregor, Reuben; Koofhethile, Catherine; Brener, Jacqui; Goulder, Philip] Univ Oxford, Dept Paediat, Oxford, England. [McLaren, James E.; Ladell, Kristin; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. [Kloverpris, Henrik N.; Stryhn, Anette; Buus, Soren] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Copenhagen N, Denmark. [Chen, Fabian] Royal Berkshire Hosp, Dept Sexual Hlth, Reading RG1 5AN, Berks, England. [Riddell, Lynn] Northampton Gen Hosp, Northamptonshire Healthcare Natl Hlth Serv Trust, Dept Genitourinary Med, Northampton, England. [Graziano, Luzzi] Wycombe Gen Hosp, Dept Sexual Hlth, High Wycombe, Bucks, England. [Klenerman, Paul] Univ Oxford, Pathogen Res & NIHR Biomed Res Ctr, Oxford, England. [Kloverpris, Henrik N.; Leslie, Alasdair] Univ KwaZulu Natal, Nelson R Mandela Sch Med, KwaZulu Natal Res Inst TB & HIV, K RITH, ZA-4001 Durban, South Africa. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kloverpris, HN (reprint author), Univ KwaZulu Natal, Nelson R Mandela Sch Med, KwaZulu Natal Res Inst TB & HIV, K RITH, ZA-4001 Durban, South Africa. EM henrik.kloverpris@k-rith.org RI Price, David/C-7876-2013; Buus, Soren/F-5446-2010; Ladell, Kristin/C-8301-2013; OI Price, David/0000-0001-9416-2737; Ladell, Kristin/0000-0002-9856-2938; Buus, Soren/0000-0001-8363-1999 FU Wellcome Trust; National Institutes of Health [R01 AI46995]; Danish Agency for Science, Technology and Innovation [12-132295] FX This work was supported by the Wellcome Trust (D. P. and P. G.) and the National Institutes of Health (grant #R01 AI46995). H. K. is funded by the Danish Agency for Science, Technology and Innovation (grant #12-132295). D. P. is a Wellcome Trust Senior Investigator. NR 59 TC 7 Z9 7 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD SEP PY 2014 VL 28 IS 14 BP 2007 EP 2021 DI 10.1097/QAD.0000000000000362 PG 15 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AO1NM UT WOS:000341079800002 PM 24906112 ER PT J AU Barrett, L Stapleton, SN Fudge, NJ Grant, MD AF Barrett, Lisa Stapleton, Staci N. Fudge, Neva J. Grant, Michael D. TI Immune resilience in HIV-infected individuals seronegative for cytomegalovirus SO AIDS LA English DT Article DE CD4(+)/CD8(+) T-cell ratio; cytomegalovirus; HAART; HIV; immune senescence ID COMBINATION ANTIRETROVIRAL THERAPY; T-LYMPHOCYTE SUBPOPULATIONS; LONGITUDINAL OCTO-IMMUNE; REPLICATIVE SENESCENCE; NATURAL-HISTORY; DISEASE; CELLS; COHORT; CD8; OLD AB Objective: Low CD4(+)/CD8(+) T-cell ratios occur in conditions associated with reduced immune resilience, including older age and HIV infection. Effective antiretroviral therapy increases CD4(+)/CD8(+) T-cell ratios, but often not to preinfection levels. The reasons for this deficit remain unclear. As cytomegalovirus (CMV) infection exacerbates falling CD4(+)/CD8(+) T-cell ratios and immune senescence in the old elderly population, we investigated whether CMV infection is associated with refractory inversion of CD4(+)/CD8(+) T-cell ratios and increased phenotypic evidence of immune senescence in HIV infection. Design: An observational cohort study of HIV-infected individuals attending the Newfoundland and Labrador Provincial HIV Clinic in St. John's. Methods: CMV infection status was determined by ELISA with infected cell lysate. Expression of CD28 and CD57 on CD8(+) T cells and cellular immune responses against CMV were measured by flow cytometry. We compared CD4(+)/CD8(+) T-cell ratios, percentage of CD8(+) T cells expressing CD28 and percentage of CD8(+) T cells expressing CD57 between groups of HIV-infected persons discordant for CMV infection. Results: The CMV-seronegative group had significantly higher CD4(+)/CD8(+) T-cell ratios, more frequent normalization of the ratio to at least 1, and lesser phenotypic evidence of immune senescence. Conclusion: CMV infection is associated with reduced immune reconstitution in HIV infection, even with suppression of HIV replication below detectable levels. This suggests that CMV infection, or some related factor, influences immune resilience in the setting of HIV infection. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Barrett, Lisa] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Barrett, Lisa] Dalhousie Univ, Dept Med, Div Infect Dis, Halifax, NS, Canada. [Stapleton, Staci N.; Fudge, Neva J.; Grant, Michael D.] Mem Univ Newfoundland, Fac Med, Div Biomed Sci, St John, NF A1B 3V6, Canada. RP Grant, MD (reprint author), Mem Univ Newfoundland, Fac Med, Div Biomed Sci, St John, NF A1B 3V6, Canada. EM mgrant@mun.ca OI Fudge, Neva/0000-0001-9018-0698 FU Canadian Institutes of Health Research (CIHR); CIHR catalyst grant [HC1 112568] FX The authors thank all the individuals who consented to provide blood samples and access to their medical records and thank Dr Ken Hirasawa for the MRC-5 cell line. L. B. was supported by a Canadian Institutes of Health Research (CIHR) phase 1 clinician scientist investigator award. This research was supported by a CIHR catalyst grant (HC1 112568) awarded to M.G. NR 38 TC 13 Z9 13 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD SEP PY 2014 VL 28 IS 14 BP 2045 EP 2049 DI 10.1097/QAD.0000000000000405 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AO1NM UT WOS:000341079800005 PM 25265072 ER PT J AU Petersen, ML Tran, L Geng, EH Reynolds, SJ Kambugu, A Wood, R Bangsberg, DR Yiannoutsos, CT Deeks, SG Martin, JN AF Petersen, Maya L. Linh Tran Geng, Elvin H. Reynolds, Steven J. Kambugu, Andrew Wood, Robin Bangsberg, David R. Yiannoutsos, Constantin T. Deeks, Steven G. Martin, Jeffrey N. TI Delayed switch of antiretroviral therapy after virologic failure associated with elevated mortality among HIV-infected adults in Africa SO AIDS LA English DT Article DE antiretroviral; cohort studies; HIV; HIV RNA level; inverse probability weight; marginal structural model; time-dependent confounding; treatment failure; viral load ID RESOURCE-LIMITED SETTINGS; CD4 CELL COUNT; MARGINAL STRUCTURAL MODELS; VIRAL LOAD; IMMUNOLOGICAL CRITERIA; COST-EFFECTIVENESS; EARLY OUTCOMES; 2ND-LINE ART; SOUTH-AFRICA; PREDICTORS AB Objective: Routine monitoring of plasma HIV RNA among HIV-infected patients on antiretroviral therapy (ART) is unavailable in many resource-limited settings. Alternative monitoring approaches correlate poorly with virologic failure and can substantially delay switch to second-line therapy. We evaluated the impact of delayed switch on mortality among patients with virologic failure in Africa. Design: A cohort. Methods: We examined patients with confirmed virologic failure on first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from four cohorts with serial HIV RNA monitoring in Uganda and South Africa. Marginal structural models aimed to estimate the effect of delayed switch on mortality in a hypothetical trial in which switch time was randomly assigned. Inverse probability weights adjusted for measured confounders including time-updated CD4(+) T-cell count and HIV RNA. Results: Among 823 patients with confirmed virologic failure, the cumulative incidence of switch 180 days after failure was 30% [95% confidence interval (CI) 27-33]. The majority of patients (74%) had not failed immunologically as defined by WHO criteria by the time of virologic failure. Adjusted mortality was higher for individuals who remained on first-line therapy than for those who had switched [odds ratio (OR) 2.1, 95% CI 1.1-4.2]. Among those without immunologic failure, the relative harm of failure to switch was similar (OR 2.4; 95% CI 0.99-5.8) to that of the entire cohort, although of borderline statistical significance. Conclusion: Among HIV-infected patients with confirmed virologic failure on first-line ART, remaining on first-line therapy led to an increase in mortality relative to switching. Our results suggest that detection and response to confirmed virologic failure could decrease mortality. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Petersen, Maya L.; Linh Tran] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Geng, Elvin H.; Deeks, Steven G.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Reynolds, Steven J.] Rakai Hlth Sci Program, Entebbe, Uganda. [Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Kambugu, Andrew] Infect Dis Inst, Kampala, Uganda. [Wood, Robin] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Yiannoutsos, Constantin T.] Indiana Univ RM Fairbanks, Sch Publ Hlth, Indianapolis, IN USA. RP Petersen, ML (reprint author), Univ Calif Berkeley, 101 Haviland Hall, Berkeley, CA 94720 USA. EM mayaliv@berkeley.edu FU National Institutes of Health [P30 AI027763, R01 MH054907, U01 AI069911, U01 CA066529]; Doris Duke Clinical Scientist Development Award; Division of Intramural Research, NIAID, NIH; [K24 AI069994]; [K24 MH87227]; [K23 AI084544] FX This research was supported by grants from the National Institutes of Health, P30 AI027763, R01 MH054907 and U01 AI069911, and U01 CA066529. Maya Petersen was supported by a Doris Duke Clinical Scientist Development Award. Steven Deeks was supported by K24 AI069994. David Bangsberg was supported by K24 MH87227 Elvin Geng was supported by K23 AI084544. S.J.R. was supported in part by the Division of Intramural Research, NIAID, NIH. NR 49 TC 13 Z9 13 U1 0 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD SEP PY 2014 VL 28 IS 14 BP 2097 EP 2107 DI 10.1097/QAD.0000000000000349 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AO1NM UT WOS:000341079800011 PM 24977440 ER PT J AU Redd, AD Ssemwanga, D Vandepitte, J Wendel, SK Ndembi, N Bukenya, J Nakubulwa, S Grosskurth, H Parry, CM Martens, C Bruno, D Porcella, SF Quinn, TC Kaleebu, P AF Redd, Andrew D. Ssemwanga, Deogratius Vandepitte, Judith Wendel, Sarah K. Ndembi, Nicaise Bukenya, Justine Nakubulwa, Susan Grosskurth, Heiner Parry, Chris M. Martens, Craig Bruno, Daniel Porcella, Stephen F. Quinn, Thomas C. Kaleebu, Pontiano TI Rates of HIV-1 superinfection and primary HIV-1 infection are similar in female sex workers in Uganda SO AIDS LA English DT Article DE Africa; female sex workers; HIV; superinfection; Uganda ID IMMUNODEFICIENCY-VIRUS TYPE-1; RISK; RAKAI AB Objective: To determine and compare the rates of HIV superinfection and primary HIV infection in high-risk female sex workers (FSWs) in Kampala, Uganda. Design: A retrospective analysis of individuals who participated in a clinical cohort study among high-risk FSWs in Kampala, Uganda. Methods: Plasma samples from HIV-infected FSWs in Kampala, Uganda were examined with next-generation sequencing of the p24 and gp41HIV genomic regions for the occurrence of superinfection. Primary HIV incidence was determined from initially HIV-uninfected FSWs from the same cohort, and incidence rate ratios were compared. Results: The rate of superinfection in these women (7/85; 3.4/100 person-years) was not significantly different from the rate of primary infection in the same population (3.7/100 person-years; incidence rate ratio = 0.91, P = 0.42). Seven women also entered the study dual-infected (16.5% either dual or superinfected). The women with any presence of dual infection were more likely to report sex work as their only source of income (P = 0.05), and trended to be older and more likely to be widowed (P = 0.07). Conclusions: In this cohort of FSWs, HIV superinfection occurred at a high rate and was similar to that of primary HIV infection. These results differ from a similar study of high-risk female bar workers in Kenya that found the rate of superinfection to be significantly lower than the rate of primary HIV infection. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Redd, Andrew D.; Wendel, Sarah K.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Redd, Andrew D.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Ssemwanga, Deogratius; Vandepitte, Judith; Ndembi, Nicaise; Bukenya, Justine; Nakubulwa, Susan; Grosskurth, Heiner; Parry, Chris M.; Kaleebu, Pontiano] MRC, Uganda Virus Res Inst, AIDS Res Unit, Entebbe, Uganda. [Grosskurth, Heiner] London Sch Hyg & Trop Med, London WC1, England. [Martens, Craig; Bruno, Daniel; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Redd, AD (reprint author), Johns Hopkins Med Inst, 855 N Wolfe St,Rangos Bldg,Room 527, Baltimore, MD 21205 USA. EM aredd2@jhmi.edu OI Grosskurth, Heiner/0000-0001-9960-7280 FU Division of Intramural Research; Bench to Bedside Program; Office of AIDS Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Medical Research Council, of the United Kingdom; European and Developing Countries Clinical Trials Partnership (EDCTP) [CG_ct_05_33070, TA.2007.40200.011, CG-2007-40200-001]; Wellcome Trust [084344] FX The authors would like to thank all the women who participated in the study, and the staff of the Good Health for Women Project. This study was supported by the Division of Intramural Research, the Bench to Bedside Program, and the Office of AIDS Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Cohort recruitment and follow-up were funded by The Medical Research Council, of the United Kingdom, the European and Developing Countries Clinical Trials Partnership (EDCTP) grant numbers CG_ct_05_33070, TA.2007.40200.011 and CG-2007-40200-001 and Wellcome Trust Strategic Award, grant number 084344. NR 18 TC 5 Z9 5 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD SEP PY 2014 VL 28 IS 14 BP 2147 EP 2152 DI 10.1097/QAD.0000000000000365 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AO1NM UT WOS:000341079800015 PM 25265078 ER PT J AU Laeyendecker, O Brookmeyer, R AF Laeyendecker, Oliver Brookmeyer, Ron TI Response to using incidence assays within the context of the recent infections testing algorithm SO AIDS LA English DT Letter C1 [Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIH, Baltimore, MD 21205 USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Brookmeyer, Ron] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. RP Laeyendecker, O (reprint author), NIAID, Immunoregulat Lab, NIH, 855 North Wolfe St,Room 538A, Baltimore, MD 21205 USA. EM olaeyen1@jhmi.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 NR 7 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD SEP PY 2014 VL 28 IS 14 BP 2168 EP 2168 DI 10.1097/QAD.0000000000000368 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AO1NM UT WOS:000341079800021 PM 25265083 ER PT J AU Hall, KD AF Hall, Kevin D. TI Estimating human energy intake using mathematical models SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID WEIGHT-LOSS; BODY-WEIGHT C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, NIH, 12A South Dr,Room 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov FU Intramural NIH HHS NR 19 TC 3 Z9 3 U1 1 U2 7 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 SEP PY 2014 VL 100 IS 3 BP 744 EP 745 DI 10.3945/ajcn.114.094441 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AN6WJ UT WOS:000340738800003 PM 25080459 ER PT J AU Kant, AK Graubard, BI AF Kant, Ashima K. Graubard, Barry I. TI Association of self-reported sleep duration with eating behaviors of American adults: NHANES 2005-2010 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID NUTRITION EXAMINATION SURVEY; CALORIC-INTAKE; ENERGY-EXPENDITURE; WEIGHT-GAIN; GENDER-DIFFERENCES; NATIONAL-HEALTH; DIETARY-INTAKE; UNITED-STATES; FOOD-INTAKE; WOMEN AB Background: Published evidence suggests an inverse association between sleep duration and body weight status. Objective: We examined the association of sleep duration with eating behaviors reported by adult Americans to understand the relation between sleep duration and body weight status. Design: This cross-sectional study used sleep duration and dietary data from the continuous NHANES conducted from 2005 to 2010 (n = 15,199, age >= 20 y). Eating behaviors examined included the following: reporting of and energy from main meals (breakfast, lunch, and dinner) and snacks (before breakfast, after dinner, and after 2000 h), intermeal intervals, time of day of main meal reporting, and intakes of macronutrients and beverages. Multiple regression methods were used to examine the independent association of hours of sleep duration grouped as short (<= 6 h), average (7-8 h), and long (>= 9 h) with eating behavior outcomes. Results: Relative to average-duration sleepers, a smaller percentage of short-duration sleepers mentioned breakfast, lunch (women only), and dinner in the recall (P <= 0.04). They also reported a lower mean percentage of energy from main meals but higher energy from all snacks (P <= 0.0004) and after 2000 h (P = 0.03). Short-duration sleepers reported the earliest eating time of the first episode and the latest time of the last eating episode. Absolute amounts of sugar and caffeine and percentage of energy from beverages (women only) were higher in short-duration sleepers. However, the total number of eating episodes and energy intake were not related with sleep duration. Conclusions: Short-duration sleepers began eating earlier and ended their eating later in the day, but despite the longer eating period, they did not report more eating events. Profiles of the relative contribution of main meals and snacks, at or after 2000 h eating, and beverages in short-duration sleepers were suggestive of eating behaviors that may increase energy intake, but 24-h energy intake did not differ among categories of sleep duration. C1 [Kant, Ashima K.] CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Remsen Hall,Room 306E,65-30 Kissena Blvd, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu FU Professional Staff Congress of the City of University of New York; Intramural Research Program of the Department of Health and Human Services, National Cancer Institute, NIH FX Supported in part by a research award from the Professional Staff Congress of the City of University of New York (AKK) and by the Intramural Research Program of the Department of Health and Human Services, National Cancer Institute, NIH (BIG). NR 53 TC 16 Z9 16 U1 0 U2 14 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 SEP PY 2014 VL 100 IS 3 BP 938 EP 947 DI 10.3945/ajcn.114.085191 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AN6WJ UT WOS:000340738800026 PM 25057157 ER PT J AU Murphy, SP Taylor, CL AF Murphy, Suzanne P. Taylor, Christine L. TI Vitamin D supplementation in African Americans: dose-response Reply SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter ID 25-HYDROXYVITAMIN D C1 [Murphy, Suzanne P.] Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Taylor, Christine L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Murphy, SP (reprint author), Canc Res Ctr Hawaii, 1236 Lauhala St, Honolulu, HI 96813 USA. EM taylorc13@od.nih.gov NR 5 TC 0 Z9 0 U1 3 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 SEP PY 2014 VL 100 IS 3 BP 984 EP 986 DI 10.3945/ajcn.114.090746 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AN6WJ UT WOS:000340738800035 ER PT J AU Flatley, E Chen, AI Zhao, XR Jaffe, ES Dunlap, JB Pittaluga, S Abdullah, S Olson, SB Spurgeon, SE Fan, G AF Flatley, Ellen Chen, Andy I. Zhao, Xiangrong Jaffe, Elaine S. Dunlap, Jennifer B. Pittaluga, Stefania Abdullah, Shahed Olson, Susan B. Spurgeon, Stephen E. Fan, Guang TI Aberrations of MYC Are a Common Event in B-Cell Prolymphocytic Leukemia SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Leukemia; MYC; Prolymphocytic leukemia; Cytogenetics; FISH ID CHRONIC LYMPHOCYTIC-LEUKEMIA; C-MYC; COMPLEX KARYOTYPE; BURKITT-LYMPHOMA; POOR-PROGNOSIS; GENE; ABNORMALITIES; TRANSLOCATION; EXPRESSION; PLL AB Objectives: B-cell prolymphocytic leukemia (B-PLL) remains a controversial entity, and its molecular pathogenesis is largely unknown. Patients are older; typically having marked lymphocytosis and splenomegaly in the absence of lymphadenopathy. It is defined as a mature B-cell leukemia with more than 55% circulating prolymphocytes. Leukemic mantle cell lymphoma and chronic lymphocytic leukemia in prolymphocytic transformation must be excluded. Methods: Case archives were retrospectively reviewed for B-PLL in patients without a previous diagnosis of chronic lymphocytic leukemia or other B-cell neoplasm. Results: We identified six cases of B-PLL with available cytogenetic data, five of which showed evidence of aberrations in MYC. Three cases showed additional signals for the MYC gene by fluorescence in situ hybridization (FISH), and two cases demonstrated t(8; 14)MYC/IGH by karyotyping or FISH. High levels of MYC protein expression were detected in all cases tested with MYC aberrations. Conclusions: These results suggest that deregulation of MYC plays an important role in the pathogenesis of B-PLL and expands the spectrum of B-cell neoplasms associated with aberrations of MYC. C1 [Flatley, Ellen; Dunlap, Jennifer B.; Fan, Guang] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Chen, Andy I.; Spurgeon, Stephen E.] Oregon Hlth & Sci Univ, Knight Canc Inst, Dept Hematol Oncol, Portland, OR 97201 USA. [Zhao, Xiangrong; Jaffe, Elaine S.; Pittaluga, Stefania; Abdullah, Shahed] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Olson, Susan B.] Oregon Hlth & Sci Univ, Knight Canc Inst, Knight Diagnost Lab, Portland, OR 97201 USA. RP Fan, G (reprint author), Oregon Hlth & Sci Univ, Dept Pathol, 3181 SW Sam Jackson Pk Rd,Mail Code L471, Portland, OR 97201 USA. EM fang@ohsu.edu FU Department of Pathology, Oregon Health and Science University, Portland, Oregon; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland FX This work was supported by the intramural research program, Department of Pathology, Oregon Health and Science University, Portland, Oregon, and the intramural research program of the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. NR 21 TC 4 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2014 VL 142 IS 3 BP 347 EP 354 DI 10.1309/AJCPUBHM8U7ZFLOB PG 8 WC Pathology SC Pathology GA AN7YC UT WOS:000340815900011 PM 25125625 ER PT J AU Gardner, LA Klawitter, J Gregory, MA Zaberezhnyy, V Baturin, D Pollyea, DA Takebe, N Christians, U Gore, L DeGregori, J Porter, CC AF Gardner, Lori A. Klawitter, Jelena Gregory, Mark A. Zaberezhnyy, Vadym Baturin, Dmitry Pollyea, Daniel A. Takebe, Naoko Christians, Uwe Gore, Lia DeGregori, James Porter, Christopher C. TI Inhibition of calcineurin combined with dasatinib has direct and indirect anti-leukemia effects against BCR-ABL1(+) leukemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; PHILADELPHIA-CHROMOSOME; BCR-ABL; IN-VITRO; KINASE INHIBITOR; P-GLYCOPROTEIN; STEM-CELLS; PHASE-II AB Treatment of BCR-ABL1(+) leukemia has been revolutionized with the development of tyrosine kinase inhibitors. However, patients with BCR-ABL1(+) acute lymphoblastic leukemia and subsets of patients with chronic myeloid leukemia are at high risk of relapse despite kinase inhibition therapy, necessitating novel treatment strategies. We previously reported synthetic lethality in BCR-ABL1(+) leukemia cells by blocking both calcineurin/NFAT signaling and BCR-ABL1, independent of drug efflux inhibition by cyclosporine. Here, using RNA-interference we confirm that calcineurin inhibition sensitizes BCR-ABL1(+) cells to tyrosine kinase inhibition in vitro. However, when we performed pharmacokinetic and pharmacodynamic studies of dasatinib and cyclosporine in mice, we found that co-administration of cyclosporine increases peak concentrations and the area under the curve of dasatinib, which contributes to the enhanced disease control. We also report the clinical experience of two subjects in whom we observed more hematopoietic toxicity than expected while enrolled in a Phase Ib trial designed to assess the safety and tolerability of adding cyclosporine to dasatinib in humans. Thus, the anti-leukemia benefit of co-administration of cyclosporine and dasatinib is mechanistically pleiotropic, but may not be tolerable, at least as administered in this trial. These data highlight some of the challenges associated with combining targeted agents to treat leukemia. (C) 2014 Wiley Periodicals, Inc. C1 [Gardner, Lori A.; Baturin, Dmitry; Gore, Lia; DeGregori, James; Porter, Christopher C.] Univ Colorado, Dept Pediat, Sch Med, Aurora, CO USA. [Klawitter, Jelena; Christians, Uwe] Univ Colorado, Dept Anesthesiol, Sch Med, Aurora, CO USA. [Gregory, Mark A.; Zaberezhnyy, Vadym; DeGregori, James] Univ Colorado, Dept Biochem & Mol Genet, Sch Med, Aurora, CO USA. [Pollyea, Daniel A.; Takebe, Naoko] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Rockville, MD USA. [Gore, Lia] Univ Colorado, Dept Med, Sch Med, Aurora, CO USA. [DeGregori, James] Univ Colorado, Dept Immunol, Sch Med, Aurora, CO USA. RP Porter, CC (reprint author), 12800 East 19th Ave,RC1N 4101,Mail Stop 8302, Aurora, CO 80045 USA. EM chris.porter@ucdenver.edu OI Klawitter, Jost/0000-0002-6413-4820 FU Leukemia and Lymphoma Society's Translational Research and Therapy Acceleration Programs [6076-09]; National Cancer Institute [K01CA133182, P30CA046934] FX Contract grant sponsor: The Leukemia and Lymphoma Society's Translational Research and Therapy Acceleration Programs; Contract grant number: 6076-09.; Contract grant sponsor: National Cancer Institute; Contract grant numbers: K01CA133182, P30CA046934. NR 34 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD SEP PY 2014 VL 89 IS 9 BP 896 EP 903 DI 10.1002/ajh.23776 PG 8 WC Hematology SC Hematology GA AN6BT UT WOS:000340679400011 PM 24891015 ER PT J AU Meier, ER Wright, EC Miller, JL AF Meier, Emily Riehm Wright, Elizabeth C. Miller, Jeffery L. TI Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the Cooperative Study of Sickle Cell Disease SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID ADVERSE OUTCOMES; CHILDREN; PREDICTION; SEVERITY; INFANTS AB Prior analyses of the Cooperative Study of Sickle Cell Disease (CSSCD) newborn cohort identified elevated white blood cell (WBC) count, low baseline hemoglobin and dactylitis between the ages of 1 and 2 years as markers of severe disease. Reticulocytosis was also associated with severe disease. Here, we further analyzed data collected on enrolled CSSCD infants for the predictive value of those markers for stroke and death later in life. Three hundred fifty-four CSSCD subjects were identified who had absolute reticulocyte counts (ARC) measured during infancy (2 to 6 months of age). Infants with higher ARC had significantly increased risk of stroke or death during childhood; lower hemoglobin levels also increased the risk but to a lesser degree than ARC. WBC levels and dactylitis were not predictive of death or stroke. These data suggest that reticulocytosis among asymptomatic infants with sickle cell anemia is associated with an increased risk of death or stroke during childhood. (C) 2014 Wiley Periodicals, Inc. C1 [Meier, Emily Riehm; Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Meier, Emily Riehm] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Meier, Emily Riehm] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20037 USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9N311, Bethesda, MD 20892 USA. EM jeffm@bdg10.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; NIH National Center for Advancing Translational Sciences [UL1TR000075, KL2TR000076] FX Contract grant sponsor: The Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.; Contract grant sponsor: NIH National Center for Advancing Translational Sciences; Contract grant numbers: UL1TR000075 and KL2TR000076 (to E.R.M). NR 16 TC 11 Z9 11 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD SEP PY 2014 VL 89 IS 9 BP 904 EP 906 DI 10.1002/ajh.23777 PG 3 WC Hematology SC Hematology GA AN6BT UT WOS:000340679400012 PM 24891147 ER PT J AU Shepshelovich, D Diker-Cohen, T Lahav, M AF Shepshelovich, Daniel Diker-Cohen, Talia Lahav, Meir TI Searching for the leak SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID C1 INHIBITOR DEFICIENCY; ACQUIRED ANGIOEDEMA; C1-INHIBITOR DEFICIENCY; HEREDITARY; RITUXIMAB; PATIENT C1 [Shepshelovich, Daniel; Diker-Cohen, Talia; Lahav, Meir] Rabin Med Ctr, IL-49100 Petah Tiqwa, Israel. [Shepshelovich, Daniel; Diker-Cohen, Talia; Lahav, Meir] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Diker-Cohen, Talia] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Lahav, Meir] Rabin Med Ctr, Inst Hematol, Davidoff Ctr, IL-49100 Petah Tiqwa, Israel. RP Shepshelovich, D (reprint author), Rabin Med Ctr, Dept Med A, Beilinson Campus, IL-49100 Petah Tiqwa, Israel. EM Shepshelovich@yahoo.com NR 14 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD SEP PY 2014 VL 89 IS 9 BP 928 EP 930 DI 10.1002/ajh.23763 PG 3 WC Hematology SC Hematology GA AN6BT UT WOS:000340679400016 PM 24850307 ER PT J AU Sadovsky, Y Esplin, MS Garite, TJ Nelson, DM Parry, SI Saade, GR Socol, ML Spong, CY Varner, MW D'Alton, ME AF Sadovsky, Yoel Esplin, M. Sean Garite, Thomas J. Nelson, D. Michael Parry, Samuel I. Saade, George R. Socol, Michael L. Spong, Catherine Y. Varner, Michael W. D'Alton, Mary E. TI Advancing research transdisciplinarity within our discipline SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE maternal-fetal medicine; scholars; reproductive sciences; transdisciplinarity AB Advancing biomedical knowledge is crucial to the understanding of disease pathophysiology, diagnosis, treatment, and the maintenance of health. Whereas collaborative pursuits among basic and translational scientists, clinical researchers, and clinicians should advance biomedical progress and its translation to better medicine. The field of obstetrics and gynecology and its subspecialties has not escaped this problem. Obstetrics and gynecology specialists and subspecialists have limited opportunities to interact with translational or basic investigators, and cross-fertilization and collaborations are further challenged by the current healthcare and funding climate. This opinion manuscript focuses on the field of maternal-fetal medicine, serving as an example that illustrates the risks and opportunities that might exist within our obstetrics and gynecology academic community. A Pregnancy Task Force recently sought to identify ways to overcome hurdles related to research training, and ensure a sufficient pool of physician-scientists pursuing pertinent questions in the field. The group discussed strategies to promote a culture of intellectual curiosity and research excellence, securing additional resources for trainees, and attracting current and next generation basic, translational, and clinical scholars to our field. Recommendations encompassed activities within annual academic meetings, training initiatives, and additional funding opportunities. Inferences from these discussions can be made to all obstetrics and gynecology subspecialty areas. C1 [Sadovsky, Yoel] Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15260 USA. [Esplin, M. Sean] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Garite, Thomas J.] Obstetrix Med Grp, Littleton, CO USA. [Nelson, D. Michael] Washington Univ, Dept Obstet & Gynecol, St Louis, MO USA. [Parry, Samuel I.] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Socol, Michael L.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Spong, Catherine Y.] Univ Utah, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Extramural Res, Salt Lake City, UT USA. [Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [D'Alton, Mary E.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. RP Sadovsky, Y (reprint author), Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15260 USA. RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 NR 0 TC 0 Z9 0 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2014 VL 211 IS 3 BP 205 EP 207 DI 10.1016/j.ajog.2014.02.006 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AO4HO UT WOS:000341297900006 PM 24530819 ER PT J AU Parikh, LI Reddy, UM Mannisto, T Mendola, P Sjaarda, L Hinkle, S Chen, Z Lu, ZH Laughon, SK AF Parikh, Laura I. Reddy, Uma M. Maennistoe, Tuija Mendola, Pauline Sjaarda, Lindsey Hinkle, Stefanie Chen, Zhen Lu, Zhaohui Laughon, S. Katherine TI Neonatal outcomes in early term birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE early term birth; neonatal morbidity; precursors for delivery ID INDICATED LATE-PRETERM; RESPIRATORY MORBIDITY; MORTALITY; PREGNANCY; SINGLETON; DELIVERY; RISK AB OBJECTIVE: To determine neonatal morbidity rates for early term birth compared with full term birth by precursor leading to delivery. STUDY DESIGN: This was a retrospective study of 188,809 deliveries from 37 0/7 to 41 6/7 weeks of gestation with electronic medical record data from 2002 to 2008. Precursors for delivery were categorized as spontaneous labor, premature rupture of membranes indicated, and no recorded indication. After excluding anomalies, rates of neonatal morbidities by precursor were compared at each week of delivery. RESULTS: Early term births (37 0/7-38 6/7 weeks) accounted for 34.1% of term births. Overall, 53.6% of early term births were due to spontaneous labor, followed by 27.6% indicated, 15.5% with no recorded indication, and 3.3% with premature rupture of membranes. Neonatal intensive care unit admission and respiratory morbidity were lowest at or beyond 39 weeks compared with the early term period for most precursors, although indicated deliveries had the highest morbidity compared with other precursors. The greatest difference in morbidity was between 37 and 39 weeks for most precursors, although most differences in morbidities between 38 and 39 weeks were not significant. Respiratory morbidity was higher at 37 than 39 weeks regardless of route of delivery. CONCLUSION: Given the higher neonatal morbidity at 37 compared with 39 weeks regardless of delivery precursor, our data support recent recommendations for designating early term to include 37 weeks. Prospective data is urgently needed to determine the optimal timing of delivery for common pregnancy complications. C1 [Parikh, Laura I.] MedStar Washington Hosp Ctr, Dept Obstet & Gynecol, Washington, DC USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Pregnancy & Perinatal Branch, Bethesda, MD USA. [Parikh, Laura I.; Maennistoe, Tuija; Mendola, Pauline; Sjaarda, Lindsey; Hinkle, Stefanie; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Epidemiol Branch, Bethesda, MD USA. [Chen, Zhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, Bethesda, MD USA. [Lu, Zhaohui] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Glotech Inc, Bethesda, MD USA. RP Laughon, SK (reprint author), NICHD, NIH, Epidemiol Branch, DESPR, 6100 Executive Blvd,Room 7B03, Rockville, MD 20852 USA. EM laughonsk@mail.nih.gov OI Hinkle, Stefanie/0000-0003-4312-708X; Sjaarda, Lindsey/0000-0003-0539-8110; Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN26720060 3425C] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract number HHSN26720060 3425C). Institutions involved in the Consortium include, in alphabetical order: Baystate Medical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA; Christiana Care Health System, Newark, DE; Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, IN; Inter-mountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, NY; MetroHealth Medical Center, Cleveland, OH.; Summa Health System, Akron City Hospital, Akron, OH; The EMMES Corporation, Rockville MD (Data Coordinating Center); University of Illinois at Chicago, Chicago, IL; University of Miami, Miami, FL; and University of Texas Health Science Center at Houston, Houston, Texas. The named authors alone are responsible for the views expressed in this manuscript, which does not necessarily represent the decisions or the stated policy of the NICHD. NR 23 TC 8 Z9 8 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2014 VL 211 IS 3 AR 265.e1 DI 10.1016/j.ajog.2014.03.021 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AO4HO UT WOS:000341297900029 PM 24631438 ER PT J AU Wang, R Ferraris, JD Izumi, Y Dmitrieva, N Ramkissoon, K Wang, GH Gucek, M Burg, MB AF Wang, Rong Ferraris, Joan D. Izumi, Yuichiro Dmitrieva, Natalia Ramkissoon, Kevin Wang, Guanghui Gucek, Marjan Burg, Maurice B. TI Global discovery of high-NaCl-induced changes of protein phosphorylation SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE renal medulla; organic osmolytes; stable isotopic labeling of amino acids in cell culture; phosphorylation ID ELEMENT-BINDING PROTEIN; INNER MEDULLARY CELLS; DNA-DAMAGE RESPONSE; C-JUN; HYPERTONIC STRESS; TRANSCRIPTION FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; DEPENDENT PHOSPHORYLATION; RETINOBLASTOMA PROTEIN; MITOCHONDRIAL FISSION AB High extracellular NaCl, such as in the renal medulla, can perturb and even kill cells, but cells mount protective responses that enable them to survive and function. Many high-NaCl-induced perturbations and protective responses are known, but the signaling pathways involved are less clear. Change in protein phosphorylation is a common mode of cell signaling, but there was no unbiased survey of protein phosphorylation in response to high NaCl. We used stable isotopic labeling of amino acids in cell culture coupled to mass spectrometry to identify changes in protein phosphorylation in human embryonic kidney (HEK 293) cells exposed to high NaCl. We reproducibly identify >8,000 unique phosphopeptides in 4 biological replicate samples with a 1% false discovery rate. High NaCl significantly changed phosphorylation of 253 proteins. Western analysis and targeted ion selection mass spectrometry confirm a representative sample of the phosphorylation events. We analyze the affected proteins by functional category to infer how altered protein phosphorylation might signal cellular responses to high NaCl, including alteration of cell cycle, cyto/nucleoskeletal organization, DNA double-strand breaks, transcription, proteostasis, metabolism of mRNA, and cell death. C1 [Wang, Rong; Ferraris, Joan D.; Izumi, Yuichiro; Dmitrieva, Natalia; Ramkissoon, Kevin; Wang, Guanghui; Gucek, Marjan; Burg, Maurice B.] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Burg, MB (reprint author), NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. EM maurice_burg@nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute FX This work was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute. NR 76 TC 0 Z9 0 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD SEP 1 PY 2014 VL 307 IS 5 BP C442 EP C454 DI 10.1152/ajpcell.00379.2013 PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA AO1RJ UT WOS:000341091000004 PM 24965592 ER PT J AU Qi, YP Jiang, CT Tanaka, N Krausz, KW Brocker, CN Fang, ZZ Bredell, BX Shah, YM Gonzalez, FJ AF Qi, Yunpeng Jiang, Changtao Tanaka, Naoki Krausz, Kristopher W. Brocker, Chad N. Fang, Zhong-Ze Bredell, Bryce X. Shah, Yatrik M. Gonzalez, Frank J. TI PPAR alpha-dependent exacerbation of experimental colitis by the hypolipidemic drug fenofibrate SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE PPAR alpha; lipidomics; fenofibrate; colitis; sphingomyelin ID INFLAMMATORY-BOWEL-DISEASE; EXPERIMENTAL MURINE COLITIS; NECROSIS-FACTOR-ALPHA; PREGNANE-X-RECEPTOR; ULCERATIVE-COLITIS; ALKALINE SPHINGOMYELINASE; NEUTRAL SPHINGOMYELINASE; HEPATOCELLULAR-CARCINOMA; METABOLOMICS REVEALS; EXPRESSION AB Fibrates, such as fenofibrate, are peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonists and have been used for several decades as hypolipidemic agents in the clinic. However, contradictory observations exist on the role of fibrates in host response to acute inflammation, with unclear mechanisms. The role of PPAR alpha in colitis was assessed using fenofibrate and Ppara-null mice. Wild-type or Ppara-null mice were subjected to acute colitis under three distinct protocols, dextran sulfate sodium, trinitrobenzenesulfonic acid, and Salmonella Typhi. Serum and colon lipidomics were analyzed to characterize the metabolic profiles by ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Messenger RNAs of PPAR alpha target genes and genes involved in inflammation were determined by qunatitative PCR analysis. Fenofibrate treatment exacerbated inflammation and tissue injury in acute colitis, and this was dependent on PPAR alpha activation. Lipidomics analysis revealed that bioactive sphingolipids, including sphingomyelins (SM) and ceramides, were significantly increased in the colitis group compared with the control group; this was further potentiated following fenofibrate treatment. In the colon, fenofibrate did not reduce the markedly increased expression of mRNA encoding TNF alpha found in the acute colitis model, while it decreased hydrolysis and increased synthesis of SM, upregulated RIPK3-dependent necrosis, and elevated mitochondrial fatty acid beta-oxidation, which were possibly related to the exacerbated colitis. C1 [Qi, Yunpeng] Second Mil Med Univ, Sch Pharm, Dept Pharmaceut Anal, Shanghai, Peoples R China. [Qi, Yunpeng; Jiang, Changtao; Tanaka, Naoki; Krausz, Kristopher W.; Brocker, Chad N.; Fang, Zhong-Ze; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bredell, Bryce X.; Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Internal Med, Dept Mol & Integrat Physiol,Div Gastroenterol, Ann Arbor, MI USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov FU National Cancer Institute Intramural Research Program, National Institutes of Health [CA-148828, DK-095201]; University of Michigan Gastrointestinal Peptide Center; Crohn's Colitis Foundation of America; National Science and Technology Major Project of the Ministry of Science and Technology of China [2013ZX09103-001]; Li-Shi-Zhen Young Scientist Project of School of Pharmacy at the Second Military Medical University, Shanghai, China FX This study was supported by National Cancer Institute Intramural Research Program, National Institutes of Health Grants CA-148828 and DK-095201, University of Michigan Gastrointestinal Peptide Center, Crohn's Colitis Foundation of America, National Science and Technology Major Project of the Ministry of Science and Technology of China (2013ZX09103-001), and Li-Shi-Zhen Young Scientist Project of School of Pharmacy at the Second Military Medical University, Shanghai, China. NR 54 TC 10 Z9 10 U1 1 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD SEP 1 PY 2014 VL 307 IS 5 BP G564 EP G573 DI 10.1152/ajpgi.00153.2014 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA AO1SP UT WOS:000341094700007 PM 25035112 ER PT J AU Claassen, CA Pearson, JL Khodyakov, D Satow, PM Gebbia, R Berman, AL Reidenberg, DJ Feldman, S Molock, S Carras, MC Lento, RM Sherrill, J Pringle, B Dalai, S Insel, TR AF Claassen, Cynthia A. Pearson, Jane L. Khodyakov, Dmitry Satow, Phillip M. Gebbia, Robert Berman, Alan L. Reidenberg, Daniel J. Feldman, Saul Molock, Sherry Carras, Michelle C. Lento, Rene M. Sherrill, Joel Pringle, Beverly Dalai, Siddhartha Insel, Thomas R. TI Reducing the Burden of Suicide in the US The Aspirational Research Goals of the National Action Alliance for Suicide Prevention Research Prioritization Task Force SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article AB Background: The National Action Alliance for Suicide Prevention Research Prioritization Task Force (RPTF) has created a prioritized national, research agenda with the potential to rapidly and substantially reduce the suicide burden in the U.S. if fully funded and implemented. Purpose: Viable, sustainable scientific research agendas addressing challenging public health issues such as suicide often need to incorporate perspectives from multiple stakeholder groups (e.g., researchers, policymakers, and other end-users of new knowledge) during an agenda-setting process. The Stakeholder Survey was a web-based survey conducted and analyzed in 2011-2012 to inform the goal-setting step in the RPTF agenda development process. The survey process, and the final list of "aspirational" research goals it produced, are presented here. Methods: Using a modified Delphi process, diverse constituent groups generated and evaluated candidate research goals addressing pressing suicide prevention research needs. Results: A total of 716 respondents representing 49 U.S. states and 18 foreign countries provided input that ultimately produced 12 overarching, research-informed aspirational goals aimed at reducing the U.S. suicide burden. Highest-rated goals addressed prevention of subsequent suicidal behavior after an initial attempt, strategies to retain patients in care, improved healthcare provider training, and generating care models that would ensure accessible treatment. Conclusions: The Stakeholder Survey yielded widely valued research targets. Findings were diverse in focus, type, and current phase of research development but tended to prioritize practical solutions over theoretical advancement. Other complex public health problems requiring input from a broad-based constituency might benefit from web-based tools that facilitate such community input. (C) 2014 American Journal of Preventive Medicine. All rights reserved. C1 [Claassen, Cynthia A.] Univ N Texas, Hlth Sci Ctr, Ft Worth, TX 76107 USA. [Pearson, Jane L.; Sherrill, Joel; Pringle, Beverly] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Insel, Thomas R.] Off Director, Bethesda, MD 20892 USA. [Carras, Michelle C.] Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD USA. [Khodyakov, Dmitry; Dalai, Siddhartha] RAND Corp, Santa Monica, CA USA. [Reidenberg, Daniel J.] Suicide Awareness Voices Educ, Bloomington, MN USA. [Feldman, Saul] United Behav Hlth, Golden Valley, MN USA. [Satow, Phillip M.] Jed Fdn, New York, NY USA. [Gebbia, Robert] Amer Fdn Suicide Prevent, New York, NY USA. [Satow, Phillip M.] Natl Action Alliance Suicide Prevent, Washington, DC USA. [Berman, Alan L.] Amer Assoc Suicidol, Washington, DC USA. [Berman, Alan L.] Amer Assoc Suicide Prevent, Washington, DC USA. [Molock, Sherry] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Lento, Rene M.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. RP Claassen, CA (reprint author), Univ N Texas, Hlth Sci Ctr, Dept Psychiat, 3500 Bowie Blvd, Ft Worth, TX 76107 USA. EM cindy.claassen@unthsc.edu FU American Foundation for Suicide Prevention; Jed David Satow Foundation; American Association of Suicidology; Suicide Awareness Voices of Education; Saul Feldman FX The National Action Alliance for Suicide Prevention Research Prioritization Task Force is composed of members from both private organizations and the Federal government and was founded to support progress in suicide prevention research in the U.S. Funding for the Stakeholder Survey was provided by organizations represented on the Task Force, including the American Foundation for Suicide Prevention, Jed David Satow Foundation, American Association of Suicidology, Suicide Awareness Voices of Education, and Saul Feldman (private donor). In addition, the RAND Corporation underwrote part of the Survey. Individuals affiliated with these organizations helped to design and conduct the Survey and analyze results. Beyond these individuals, the authors wish to extend their thanks to Sarah Brown, DrPH, Assistant Professor in the Department of Psychiatry, University of North Texas Health Sciences Center, Fort Worth TX; T. Michael Kashner, PhD, JD, Director of the VA Center of Excellence for Graduate Medical Education and Advanced Biostatistics, Loma Linda CA; and Terrance Savitsky of the RAND Corporation, Santa Monica CA for their generous donation of time and expertise in the development and reporting of the analytic approach used in this paper. In addition, the authors are deeply grateful to those individuals who were willing to serve as moderators during the Discussion Round of this project: Belinda Sims, Mercedes Rubio, Amy Goldstein, Jovier Evans, Peggy West, Benedetto Vitiello, Katrina Bledsoe, Gayle Jaffe, Ann Haas, and Keisha Shropshire. Finally, the authors wish to thank Jacob Solomon of RAND and Trevor Summerfield of the American Foundation for Suicide Prevention for technical assistance with the online survey process. The views presented are those of the authors and do not necessarily represent the views of the NIH or USDHHS. NR 19 TC 10 Z9 10 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2014 VL 47 IS 3 BP 309 EP 314 DI 10.1016/j.amepre.2014.01.004 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AN6WH UT WOS:000340738600009 PM 24750971 ER PT J AU Paterson, C Wang, YH Kleinman, JE Law, AJ AF Paterson, Clare Wang, Yanhong Kleinman, Joel E. Law, Amanda J. TI Effects of Schizophrenia Risk Variation in the NRG1 Gene on NRG1-IV Splicing During Fetal and Early Postnatal Human Neocortical Development SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID NEUREGULIN 1; BIPOLAR DISORDER; SCOTTISH POPULATION; SYNAPTIC PLASTICITY; PREFRONTAL CORTEX; BRAIN-DEVELOPMENT; ASSOCIATION; EXPRESSION; ISOFORM; SUSCEPTIBILITY AB Objective: Neuregulin 1 (NRG1) is a multifunctional neurotrophin that mediates neurodevelopment and schizophrenia risk. The NRG1 gene undergoes extensive alternative splicing, and association of brain NRG1 type IV isoform expression with the schizophrenia-risk polymorphism rs6994992 is a potential mechanism of risk. Novel splice variants of NRG1-IV (NRG1-IVNV), with predicted unique signaling capabilities, have been cloned in fetal brain tissue. The authors investigated the temporal dynamics of transcription of NRG1-IVNV, compared with the major NRG1 isoforms, across human prenatal and postnatal prefrontal cortical development, and they examined the association of rs6994992 with NRG1-IVNV expression. Method: NRG1 type 1-IV and NRG1-IVNV isoforms were evaluated with quantitative real-time polymerase chain reaction in human postmortem prefrontal cortex tissue samples at 14 to 39 weeks gestation and postnatal ages 0-83 years. The association of rs6994992 genotype with NRG1-IVNV expression and the subcellular distribution and proteolytic processing of NRG1-IVNV isoforms were also determined. Results: Expression of NRG1 types I, II, and III was temporally regulated during prenatal and postnatal neocortical development. NRG1-IVNV was expressed from 16 weeks gestation until age 3. Homozygosity for the schizophrenia risk allele (T) of rs6994992 conferred lower cortical NRG1-IVNV levels. Assays showed that NRG1-IVNV is a novel nuclear-enriched, truncated NRG1 protein resistant to proteolytic processing. Conclusions: To the authors' knowledge, this study provides the first quantitative map of NRG1 isoform expression during human neocortical development and aging. It identifies a potential mechanism of early developmental risk for schizophrenia at the NRG1 locus, involving a novel class of NRG1 proteins. C1 [Law, Amanda J.] Univ Colorado, Sch Med, Dept Psychiat, Aurora, CO 80204 USA. NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program, Bethesda, MD 20892 USA. Lieber Inst Brain Dev, Baltimore, MD USA. RP Law, AJ (reprint author), Univ Colorado, Sch Med, Dept Psychiat, Aurora, CO 80204 USA. EM amanda.law@ucdenver.edu OI Law, Amanda/0000-0002-2574-1564 FU NARSAD; NIMH; NIMH Conte Center [P50 MH-086383] FX Funded by a NARSAD Young Investigator Award to Dr. Law, funds from the NIMH Intramural Research Program, and NIMH Conte Center grant P50 MH-086383. NR 51 TC 10 Z9 10 U1 0 U2 7 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2014 VL 171 IS 9 BP 979 EP 989 DI 10.1176/appi.ajp.2014.13111518 PG 11 WC Psychiatry SC Psychiatry GA AO1MU UT WOS:000341077000015 PM 24935406 ER PT J AU Driver, DI Rapoport, JL Gogtay, N AF Driver, David I. Rapoport, Judith L. Gogtay, Nitin TI Consider ECT for Treatment-Resistant Childhood Schizophrenia Response SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Letter ID CLOZAPINE; ADOLESCENTS; CHILDREN C1 [Driver, David I.; Rapoport, Judith L.; Gogtay, Nitin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Driver, DI (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 6 TC 0 Z9 0 U1 7 U2 7 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2014 VL 171 IS 9 BP 1000 EP 1000 DI 10.1176/appi.ajp.2014.14050628r PG 1 WC Psychiatry SC Psychiatry GA AO1MU UT WOS:000341077000018 PM 25178754 ER PT J AU Lasota, J Kowalik, A Wasag, B Wang, ZF Felisiak-Golabek, A Coates, T Kopczynski, J Gozdz, S Miettinen, M AF Lasota, Jerzy Kowalik, Artur Wasag, Bartosz Wang, Zeng-Feng Felisiak-Golabek, Anna Coates, Tiffany Kopczynski, Janusz Gozdz, Stanislaw Miettinen, Markku TI Detection of the BRAF V600E Mutation in Colon Carcinoma Critical Evaluation of the Imunohistochemical Approach SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE BRAF V600E; colon cancer; immunohistochemistry; Sanger sequencing; the Cobas 4800 BRAF V600 mutation test; BRAF V600 allele-specific PCR; BRAF V600 qPCR ID METASTATIC COLORECTAL-CANCER; LYNCH SYNDROME; PITUITARY-ADENOMAS; TUMOR-TISSUE; IMMUNOHISTOCHEMISTRY; KRAS; VE1; EXPRESSION; MELANOMA; THERAPY AB Recently BRAF V600E mutant-specific antibody (clone VE1) became available to immunohistochemically pinpoint the occurrence of these BRAF-mutant proteins in different tumors, such as colon carcinoma. Detection of BRAF mutations is important for the accurate application of targeted therapy against BRAF serine-threonine kinase activation. In this study, we evaluated 113 colon carcinomas including 95 primary and 27 metastatic tumors with the VE1 antibody using Leica Bond-Max automated immunohistochemistry. To ensure comprehensive BRAF V600E mutation detection, all cases were evaluated using 4 molecular methods (Sanger sequencing, the Cobas 4800 BRAF V600 Mutation Test, BRAF V600 allele-specific polymerase chain reaction, and BRAF V600 quantitative polymerase chain reaction) with nearly 100% concordance. Molecular and immunohistochemical studies were blinded. Furthermore, all cases were evaluated for KRAS and NRAS mutations as parameters mutually exclusive with BRAF mutations offering parallel evidence for BRAF mutation status. Strong to moderate VE1 positivity was seen in 34 tumors. Twelve colon carcinomas showed weak VE1 immunohistochemical staining, and 67 were entirely negative. An identical c.1799T>A single nucleotide substitution leading to the BRAF V600E mutation was identified in 27 of 113 (24%) colon carcinomas. A majority of BRAF-mutant tumors were located in the right side of the colon and had mismatch-repair deficiency. V600E mutation-negative carcinomas were more often sigmoid tumors and usually showed intact mismatch-repair proteins and KRAS or NRAS mutations. The sensitivity and specificity of positive results (strong to moderate staining) of VE1 immunohistochemistry were 85% and 68%, respectively. If any positivity would be considered, then the specificity declined to 51% with no significant improvement of sensitivity. Therefore, only strong positivity should be considered when using the VE1 antibody and Leica Bond-Max automated immunohistochemistry with these parameters. Although VE1 antibody can be useful in the screening of colon carcinomas for BRAF V600E-mutant proteins, molecular genetic confirmation is always necessary for mutation diagnosis. C1 [Lasota, Jerzy; Wang, Zeng-Feng; Felisiak-Golabek, Anna; Coates, Tiffany; Miettinen, Markku] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Kowalik, Artur] Jan Kochanowski Univ Humanities & Sci, Dept Mol Diagnost, Kielce, Poland. [Kopczynski, Janusz] Jan Kochanowski Univ Humanities & Sci, Dept Surg Pathol, Kielce, Poland. [Gozdz, Stanislaw] Jan Kochanowski Univ Humanities & Sci, Holycross Canc Ctr, Dept Clin Oncol, Kielce, Poland. [Gozdz, Stanislaw] Jan Kochanowski Univ Humanities & Sci, Fac Hlth Sci, Kielce, Poland. [Wasag, Bartosz] Med Univ Gdansk, Dept Biol & Genet, Gdansk, Poland. RP Lasota, J (reprint author), NCI, Pathol Lab, 9000 Rockville Pike,Bldg 10,Room B1B47, Bethesda, MD 20892 USA. EM jerzy.lasota@nih.gov RI Kielce, SCO/O-6702-2016; Gozdz, Stanislaw/D-3300-2013 FU Intramural NIH HHS [ZIA BC011427-02] NR 28 TC 25 Z9 27 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD SEP PY 2014 VL 38 IS 9 BP 1235 EP 1241 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA AO1TE UT WOS:000341096800009 PM 24832158 ER PT J AU Kennedy, DA Dukic, V Dwyer, G AF Kennedy, David A. Dukic, Vanja Dwyer, Greg TI Pathogen Growth in Insect Hosts: Inferring the Importance of Different Mechanisms Using Stochastic Models and Response-Time Data SO AMERICAN NATURALIST LA English DT Article DE within-host model; speed-of-kill; demographic stochasticity; baculovirus ID AUTOGRAPHA-CALIFORNICA NUCLEOPOLYHEDROVIRUS; NUCLEAR POLYHEDROSIS-VIRUS; GYPSY-MOTH LEPIDOPTERA; SURVIVAL-TIME; POPULATION-DYNAMICS; BIRTH-DEATH; BACULOVIRUS ENHANCIN; MICROBIAL INFECTION; FOREST DEFOLIATORS; INDEPENDENT-ACTION AB Pathogen population dynamics within individual hosts can alter disease epidemics and pathogen evolution, but our understanding of the mechanisms driving within-host dynamics is weak. Mathematical models have provided useful insights, but existing models have only rarely been subjected to rigorous tests, and their reliability is therefore open to question. Most models assume that initial pathogen population sizes are so large that stochastic effects due to small population sizes, so-called demographic stochasticity, are negligible, but whether this assumption is reasonable is unknown. Most models also assume that the dynamic effects of a host's immune system strongly affect pathogen incubation times or "response times," but whether such effects are important in real host-pathogen interactions is likewise unknown. Here we use data for a baculovirus of the gypsy moth to test models of within-host pathogen growth. By using Bayesian statistical techniques and formal model-selection procedures, we are able to show that the response time of the gypsy moth virus is strongly affected by both demographic stochasticity and a dynamic response of the host immune system. Our results imply that not all response-time variability can be explained by host and pathogen variability, and that immune system responses to infection may have important effects on population-level disease dynamics. C1 [Kennedy, David A.; Dwyer, Greg] Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. [Kennedy, David A.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Kennedy, David A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Dukic, Vanja] Univ Colorado, Dept Appl Math, Boulder, CO 80305 USA. RP Dwyer, G (reprint author), Univ Chicago, Dept Ecol & Evolut, 940 E 57Th St, Chicago, IL 60637 USA. EM gdwyer@uchicago.edu RI Dwyer, Greg/L-1134-2015 OI Dwyer, Greg/0000-0002-7387-2075 FU National Institutes of Health (NIH) [R01GM096655]; National Science Foundation [DEB-1316334, GEO-1211668]; Achievement Rewards for College Scientists fellowship while at the University of Chicago; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, NIH FX D.A.K. thanks the members of his dissertation committee, S. Allesina, J. Bergelson, M. Kreitman, and C. Pfister, for helpful comments on earlier drafts of the manuscript. G.D., V.D., and the experimental work were supported by National Institutes of Health (NIH) grant R01GM096655. V.D. was also supported by National Science Foundation grants DEB-1316334 and GEO-1211668. D.A.K. was supported by an Achievement Rewards for College Scientists fellowship while at the University of Chicago and by the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, NIH. We thank L. Hemerik, O. Restif, and one anonymous reviewer for comments that substantially improved the manuscript. NR 94 TC 3 Z9 3 U1 0 U2 27 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0003-0147 EI 1537-5323 J9 AM NAT JI Am. Nat. PD SEP PY 2014 VL 184 IS 3 BP 407 EP 423 DI 10.1086/677308 PG 17 WC Ecology; Evolutionary Biology SC Environmental Sciences & Ecology; Evolutionary Biology GA AN8HG UT WOS:000340844300013 PM 25141148 ER PT J AU Skuladottir, H Wilcox, A McConnaughey, R Vindenes, H Lie, RT AF Skuladottir, Hildur Wilcox, Allen McConnaughey, Robert Vindenes, Hallvard Lie, Rolv T. TI First-trimester nonsystemic corticosteroid use and the risk of oral clefts in Norway SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Corticosteroids; Cleft lip; Cleft palate; Maternal exposure; Pregnancy; Moba ID OROFACIAL CLEFTS; PALATE; PREGNANCY; EXPOSURE; CORTISOL; DRUGS; IRF6; LIP AB Purpose: Exposure of pregnant mice to corticosteroids can produce oral clefts in offspring. Although data in humans are more mixed, recent reports have suggested that dermatologic steroids are associated with oral clefts. Methods: We investigated maternal first-trimester exposure to corticosteroids (focusing on dermatologic uses) and oral clefts in offspring using two population-based studies. The Norway Cleft Study (1996-2001) is a national case-control study including 377 infants with cleft Iip +/- palate (CLP), 196 infants with cleft palate only (CPO), and 763 controls. The Norwegian Mother and Child Cohort Study (MoBa, 1998-2008) is a national birth cohort including 123 infants with CLP, 61 infants with CPO, and 551 controls. Results: In the case-control study, there was the suggestion of an association of dermatologic corticosteroids with both CLP (adjusted OR [aOR], 23; 95% confidence interval [CI], 0.71-7.7) and CPO (aOR, 3.4; CI, 0.87-13). There was no evidence of this association in the cohort data (odds ratio for CLP, 1.2; CI, 0.50-2.8 and odds ratio for CPO, 1.0; Cl, 030-3.4), although exposure to dermatologic steroids was less specifically ascertained. There were no associations with other types of corticosteroids. Conclusions: Our data add to the suggestive but inconsistent findings for this association. (C) 2014 Elsevier Inc. All rights reserved. C1 [Skuladottir, Hildur; Vindenes, Hallvard] Haukeland Hosp, Dept Plast Surg, N-5021 Bergen, Norway. [Skuladottir, Hildur; Lie, Rolv T.] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Wilcox, Allen] NIEHS, Epidemiol Branch, NIH, Durham, NC USA. [McConnaughey, Robert] Westat Corp, Epidemiol Branch, Durham, NC USA. RP Skuladottir, H (reprint author), Haukeland Hosp, Dept Plast Surg, Jonas Lies Vei 67, N-5021 Bergen, Norway. EM hildur.skuladottir@gmail.com OI Wilcox, Allen/0000-0002-3376-1311 FU Western Norwegian Health Authorities; Norwegian Ministry of Health; Ministry of Education and Research; National Institutes of Health/National Institute of Environmental Health Sciences [N01-ES-75558]; US National Institute of Environmental Health Sciences [Z01 ES049027-11, Z01 ES040007]; Research Council of Norway [166026/V50] FX This work was funded by the Western Norwegian Health Authorities. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, National Institutes of Health/National Institute of Environmental Health Sciences (contract no N01-ES-75558), US National Institute of Environmental Health Sciences (grants Z01 ES049027-11 and Z01 ES040007), and the Research Council of Norway (grant 166026/V50). Special thanks to Quaker Harmon and Donna Baird for useful comments. NR 39 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD SEP PY 2014 VL 24 IS 9 BP 635 EP 640 DI 10.1016/j.annepidem.2014.06.005 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AN8OX UT WOS:000340864600002 PM 25127739 ER PT J AU Chawla, N Yabroff, KR Mariotto, A McNeel, TS Schrag, D Warren, JL AF Chawla, Neetu Yabroff, K. Robin Mariotto, Angela McNeel, Timothy S. Schrag, Deborah Warren, Joan L. TI Limited validity of diagnosis codes in Medicare claims for identifying cancer metastases and inferring stage SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Cancer; Metastasis; SEER; Registry; Medicare claims; Stage at diagnosis ID BREAST-CANCER; LUNG-CANCER; SURVIVAL; IDENTIFICATION; CHEMOTHERAPY; RECURRENCE; ALGORITHM; GEORGIA; DISEASE; UTILITY AB Purpose: Researchers are using diagnosis codes from health claims to identify metastatic disease in cancer patients. The validity of this approach has not been established. Methods: We used the linked 2005-2007 Surveillance, Epidemiology and End Results (SEER)-Medicare data to assess the validity of metastasis codes at diagnosis from claims compared with stage reported by SEER cancer registries. The cohort included 80,052 incident breast, lung, and colorectal cancer patients aged 65 years and older. Using gold-standard SEER data, we evaluated sensitivity, specificity, positive predictive value, and negative predictive value of claims-based stage, survival by stage classification, and patient factors associated with stage misclassification using multivariable regression. Results: For patients with a registry report of distant metastatic cancer, the sensitivity, specificity, and positive predictive value of claims never simultaneously exceeded 80% for any cancer: lung (42.7%, 94.8%, and 88.1%), breast (51.0%, 98.3%, and 65.8%), and Colorectal (72.8%, 93.8%, and 68.5%). Misclassification of stage from Medicare claims was significantly associated with inaccurate estimates of stage-specific survival (P < .001). In adjusted analysis, patients who were older, black, or living in low-income areas were more likely to have their stage misclassified in claims. Conclusions: Diagnosis codes in Medicare claims have limited validity for inferring cancer stage and metastatic disease. Published by Elsevier Inc. C1 [Chawla, Neetu] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Chawla, Neetu; Yabroff, K. Robin; Warren, Joan L.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Mariotto, Angela] NCI, Data Modeling Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Calverton, MD USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Chawla, N (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM neetu.chawla@nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU Intramural NIH HHS [Z99 CA999999] NR 27 TC 7 Z9 7 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD SEP PY 2014 VL 24 IS 9 BP 666 EP 672 DI 10.1016/j.annepidem.2014.06.099 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AN8OX UT WOS:000340864600007 PM 25066409 ER PT J AU Shi, M Umbach, DM Weinberg, CR AF Shi, Min Umbach, David M. Weinberg, Clarice R. TI Disentangling Pooled Triad Genotypes for Association Studies SO ANNALS OF HUMAN GENETICS LA English DT Article DE Case-parents; pooled DNA; log-linear; expectation-maximization; maternal effect ID GENOME-WIDE ASSOCIATION; FAMILY-BASED ASSOCIATION; MARKERS MEDIATING SUSCEPTIBILITY; CASE-PARENT TRIADS; CANDIDATE MARKERS; LINKAGE DISEQUILIBRIUM; DNA; DISEASE; GENE; RISK AB Association studies that genotype affected offspring and their parents (triads) offer robustness to genetic population structure while enabling assessments of maternal effects, parent-of-origin effects, and gene-by-environment interaction. We propose case-parents designs that use pooled DNA specimens to make economical use of limited available specimens. One can markedly reduce the number of genotyping assays required by randomly partitioning the case-parent triads into pooling sets of h triads each and creating three pools from every pooling set, one pool each for mothers, fathers, and offspring. Maximum-likelihood estimation of relative risk parameters proceeds via log-linear modeling using the expectation-maximization algorithm. The approach can assess offspring and maternal genetic effects and accommodate genotyping errors and missing genotypes. We compare the power of our proposed analysis for testing offspring and maternal genetic effects to that based on a difference approach and that of the gold standard based on individual genotypes, under a range of allele frequencies, missing parent proportions, and genotyping error rates. Power calculations show that the pooling strategies cause only modest reductions in power if genotyping errors are low, while reducing genotyping costs and conserving limited specimens. C1 [Shi, Min; Umbach, David M.; Weinberg, Clarice R.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Shi, M (reprint author), NIEHS, Biostat Branch, NIH, DHHS, 111 TW Alexander Dr,MD A3-03, Res Triangle Pk, NC 27709 USA. EM shi2@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01 ES040007, Z01 ES045002] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, under project numbers Z01 ES040007 and Z01 ES045002. We thank Drs Chia-Ling Kuo and Richard Morris for their careful review and valuable comments, as well as the Computational Biology Core at NIEHS for facilitating our computationally intensive study. NR 36 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0003-4800 EI 1469-1809 J9 ANN HUM GENET JI Ann. Hum. Genet. PD SEP PY 2014 VL 78 IS 5 BP 345 EP 356 DI 10.1111/ahg.12073 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AN2OC UT WOS:000340424200004 PM 24962618 ER PT J AU Jani, M Massey, J Wedderburn, LR Vencovsky, J Danko, K Lundberg, IE Padyukov, L Selva-O'Callaghan, A Radstake, T Platt, H Warren, RB Griffiths, CE Lee, A Gregersen, PK Miller, FW Ollier, WE Cooper, RG Chinoy, H Lamb, JA AF Jani, M. Massey, J. Wedderburn, L. R. Vencovsky, J. Danko, K. Lundberg, I. E. Padyukov, L. Selva-O'Callaghan, A. Radstake, T. Platt, H. Warren, R. B. Griffiths, C. E. Lee, A. Gregersen, P. K. Miller, F. W. Ollier, W. E. Cooper, R. G. Chinoy, H. Lamb, J. A. CA EUMYONET TI Genotyping of immune-related genetic variants identifies TYK2 as a novel associated locus for idiopathic inflammatory myopathies SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Letter ID SUSCEPTIBILITY LOCI; DERMATOMYOSITIS; POLYMYOSITIS; ARTHRITIS C1 [Jani, M.; Massey, J.; Chinoy, H.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Ctr Epidemiol, Ctr Musculoskeletal Res, Manchester M13 9PT, Lancs, England. [Massey, J.; Warren, R. B.; Griffiths, C. E.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Salford Royal NHS Fdn Trust, Dermatol Ctr, Manchester M13 9PT, Lancs, England. [Wedderburn, L. R.] UCL, Inst Child Hlth, Rheumatol Unit, London, England. [Vencovsky, J.] Charles Univ Prague, Inst Rheumatol, Prague, Czech Republic. [Danko, K.] Univ Debrecen, H-4012 Debrecen, Hungary. [Lundberg, I. E.; Padyukov, L.] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden. [Selva-O'Callaghan, A.] Vall dHebron Gen Hosp, Barcelona, Spain. [Radstake, T.] Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands. [Platt, H.; Ollier, W. E.; Chinoy, H.; Lamb, J. A.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Integrated Genom Med Res, Manchester M13 9PT, Lancs, England. [Lee, A.; Gregersen, P. K.] Feinstein Inst Med Res, Manhasset, NY USA. [Miller, F. W.] NIEHS, NIH, Bethesda, MD USA. [Cooper, R. G.] Univ Liverpool, Dept Musculoskeletal Biol, Liverpool L69 3BX, Merseyside, England. RP Jani, M (reprint author), Univ Manchester, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Ctr Epidemiol, Ctr Musculoskeletal Res,Inst Inflammat & Repair, Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM Meghna.jani@manchester.ac.uk RI Griffiths, Christopher/P-5448-2014; Warren, Richard/G-4929-2015; Jani, Meghna/D-5152-2016; OI Padyukov, Leonid/0000-0003-2950-5670; Griffiths, Christopher/0000-0001-5371-4427; Warren, Richard/0000-0002-2918-6481; Jani, Meghna/0000-0002-1487-277X; Massey, Jonathan/0000-0002-4576-1124; Lundberg, Ingrid/0000-0002-6068-9212; Miller, Frederick/0000-0003-2831-9593; Chinoy, Hector/0000-0001-6492-1288 FU Arthritis Research UK [14518, 18474, ]; Medical Research Council [G1000417]; Wellcome Trust [, 085860] NR 10 TC 9 Z9 10 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD SEP PY 2014 VL 73 IS 9 BP 1750 EP 1752 DI 10.1136/annrheumdis-2014-205440 PG 3 WC Rheumatology SC Rheumatology GA AN6RK UT WOS:000340723700032 PM 24812289 ER PT J AU Lv, QW Zhang, W Shi, Q Zheng, WJ Lipsky, PE Zhang, X AF Lv, Qian-wen Zhang, Wen Shi, Qun Zheng, Wen-jie Lipsky, Peter E. Zhang, Xuan TI Response to DM Marcus's comment on the TRIFRA study (comparison of Tripterygium wilfordii Hook F vs methotrexate in the treatment of active rheumatoid arthritis) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Letter ID EXTRACT C1 [Lv, Qian-wen; Zhang, Wen; Shi, Qun; Zheng, Wen-jie; Zhang, Xuan] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing 100730, Peoples R China. [Lv, Qian-wen; Zhang, Wen; Shi, Qun; Zheng, Wen-jie; Zhang, Xuan] Peking Union Med Coll, Beijing 100730, Peoples R China. [Lipsky, Peter E.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Zhang, X (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing 100730, Peoples R China. EM peterlipsky@comcast.net; zxpumch2003@sina.com OI zhang, xuan/0000-0001-8775-1699 NR 9 TC 1 Z9 1 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD SEP PY 2014 VL 73 IS 9 BP E57 EP E57 DI 10.1136/annrheumdis-2014-205973 PG 1 WC Rheumatology SC Rheumatology GA AN6RK UT WOS:000340723700004 PM 25085980 ER PT J AU LeVan, JM Brion, LP Wrage, LA Gantz, MG Wyckoff, MH Sanchez, PJ Heyne, R Jaleel, M Finer, NN Carlo, WA Das, A Stoll, BJ Higgins, RD AF LeVan, Jaclyn M. Brion, Luc P. Wrage, Lisa A. Gantz, Marie G. Wyckoff, Myra H. Sanchez, Pablo J. Heyne, Roy Jaleel, Mambarambath Finer, Neil N. Carlo, Waldemar A. Das, Abhik Stoll, Barbara J. Higgins, Rosemary D. CA Eunice Kennedy Shriver NICHD TI Change in practice after the Surfactant, Positive Pressure and Oxygenation Randomised Trial SO ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION LA English DT Article ID BIRTH-WEIGHT INFANTS; EXTREMELY PRETERM INFANTS; BRONCHOPULMONARY DYSPLASIA; LUNG-DISEASE; RISK-FACTORS; PREMATURITY; DEATH; CARE AB Objective To test the hypothesis that the proportion of endotracheal intubation (ETI) in the delivery room (DR) decreased in Neonatal Research Network (NRN) centres after the National Institute of Child Health and Human Development NRN Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT). Design Retrospective cohort study using the prospective NRN generic database. Setting Eleven centres that participated in the SUPPORT trial and remained part of the NRN. Preterm neonates 24(0/7)-27(6/7) weeks' gestational age enrolled in the SUPPORT trial were randomised to: (1) DR continuous positive airway pressure or DR ETI with early surfactant administration; and (2) oxygen saturation targets of 85-89% or 91-95%. The prior NRN feasibility trial had assessed the feasibility of randomisation to continuous positive airway pressure versus ETI. Patients Infants 24(0/7)-27(6/7) weeks' gestational age, excluding infants with syndromes or major malformations and those on comfort care only. Main outcome measure Proportion of DR ETI. Results The proportion of DR ETI decreased significantly in the group of infants from centres that had not participated in the feasibility trial (91% before vs 75% after SUPPORT, adjusted relative risk 0.86, 95% CI 0.83-0.89, p<0.0001) but not in the group of infants from the other centres, where the proportion of ETI was already lower prior to initiation of the SUPPORT trial (61% before vs 58% after SUPPORT, adjusted relative risk 0.96, 95% CI 0.89 to 1.05, p=0.40). Conclusion This study shows that DR ETI changed after SUPPORT only in NRN centres that had not participated in a similar trial. C1 [LeVan, Jaclyn M.; Brion, Luc P.; Wyckoff, Myra H.; Sanchez, Pablo J.; Heyne, Roy; Jaleel, Mambarambath] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [LeVan, Jaclyn M.] Pediatrix Med Grp, San Antonio, TX USA. [Wrage, Lisa A.; Gantz, Marie G.; Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Sanchez, Pablo J.] Ohio State Univ, Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Finer, Neil N.] Univ Calif San Diego, Div Neonatol, San Diego, CA 92103 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Childrens Healthcare Atlanta, Atlanta, GA USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Brion, LP (reprint author), Univ Texas SW Med Ctr Dallas, 5323 Harry Hines Blvd,STOP 9063, Dallas, TX 75390 USA. EM luc.brion@utsouthwestern.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10 HD21364, U10 HD21373, U10 HD21385, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27880, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40689]; National Center for Research Resources [M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR8084]; National Center for Advancing Translational Sciences [UL1 TR6, UL1 TR77, UL1 TR93, UL1 TR371, UL1 TR454, UL1 TR1117] FX The Study Sponsor, the National Institute of Child Health and Human Development (NICHD), did not have any role in the study design; in the collection, analysis and interpretation data; in the writing of the report; and in the decision to submit the paper for publication. Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD21364, U10 HD21373, U10 HD21385, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27880, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40689), the National Center for Research Resources (M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR8084), and the National Center for Advancing Translational Sciences (UL1 TR6, UL1 TR77, UL1 TR93, UL1 TR371, UL1 TR454, UL1 TR1117). NR 16 TC 3 Z9 3 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1359-2998 EI 1468-2052 J9 ARCH DIS CHILD-FETAL JI Arch. Dis. Child.-Fetal Neonatal Ed. PD SEP PY 2014 VL 99 IS 5 BP F386 EP F390 DI 10.1136/archdischild-2014-306057 PG 5 WC Pediatrics SC Pediatrics GA AN7LH UT WOS:000340781200008 PM 24876196 ER PT J AU Subramanian, S Liu, CY Aviv, A Ho, JE Courchesne, P Muntendam, P Larson, MG Cheng, S Wang, TJ Mehta, NN Levy, D AF Subramanian, Subha Liu, Chunyu Aviv, Abraham Ho, Jennifer E. Courchesne, Paul Muntendam, Pieter Larson, Martin G. Cheng, Susan Wang, Thomas J. Mehta, Nehal N. Levy, Daniel TI Stromal Cell-Derived Factor 1 as a Biomarker of Heart Failure and Mortality Risk SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE cardiovascular diseases; chemokine CXCL12; epidemiology; heart failure; mortality; myocardial infarction; stem cells ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; ENDOTHELIAL PROGENITOR CELLS; TELOMERE LENGTH; FACTOR-I; ATHEROSCLEROSIS; NUMBER; BLOOD; POPULATION; EXPRESSION AB Objective-CXCL12 encodes stromal cell-derived factor 1 alpha (SDF-1), which binds to the receptor encoded by CXCR4. Variation at the CXCL12 locus is associated with coronary artery disease and endothelial progenitor cell numbers, whereas variation at the CXCR4 locus is associated with leukocyte telomere length, which has been shown to be associated with coronary artery disease. Therefore, we examined the relationships of plasma SDF-1 levels to cardiovascular disease (CVD)-related outcomes, risk factors, leukocyte telomere length, and endothelial progenitor cells. Approach and Results-SDF-1 was measured in 3359 Framingham Heart Study participants. We used Cox regression to examine relationships of SDF-1 to new-onset CVD, myocardial infarction, heart failure, and all-cause mortality; we used linear regression to evaluate associations of SDF-1 with risk factors, leukocyte telomere length, and CD34+ cell phenotypes. In multivariable models, higher SDF-1 levels were associated with older age, lower levels of high-density lipoprotein-cholesterol and cigarette smoking. Higher SDF-1 levels were associated with lower CD34+ cell frequency (P=0.02) but not with leukocyte telomere length. During follow-up (median, 9.3 years), there were 263 new-onset CVD events, 160 myocardial infarctions, 200 heart failure events, and 385 deaths. After adjusting for clinical risk factors, SDF-1 levels were associated with heart failure (P=0.04) and all-cause mortality (P=0.003) but not with CVD (P=0.39) or myocardial infarction (P=0.10). The association of SDF-1 levels with myocardial infarction was attenuated after adjustment for high-density lipoprotein-cholesterol. Conclusions-After adjusting for traditional CVD risk factors, SDF-1 is associated with heart failure and all-cause mortality risk. Additional studies are needed to determine whether measurement of SDF-1 levels has clinical use. C1 [Subramanian, Subha; Liu, Chunyu; Ho, Jennifer E.; Courchesne, Paul; Larson, Martin G.; Cheng, Susan; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Subramanian, Subha; Liu, Chunyu; Courchesne, Paul; Levy, Daniel] NHLBI, Populat Sci Branch, Bethesda, MD 20892 USA. [Subramanian, Subha; Liu, Chunyu; Courchesne, Paul; Mehta, Nehal N.; Levy, Daniel] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Aviv, Abraham] Rutgers State Univ, New Jersey Med Sch, Ctr Human Dev & Aging, Newark, NJ 07102 USA. [Ho, Jennifer E.; Levy, Daniel] Boston Univ, Med Ctr, Cardiovasc Med Sect, Dept Med, Boston, MA 02215 USA. [Muntendam, Pieter] BG Med Inc, Waltham, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Cheng, Susan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Dept Med, Div Cardiovasc Med, Nashville, TN USA. RP Levy, D (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM levyd@nih.gov OI Ho, Jennifer/0000-0002-7987-4768 FU National Institutes of Health (NIH) [N01-HC-25195]; Division of Intramural Research of the National Heart, Lung, and Blood Institute; NIH [R01AG030678, R01HD071180] FX The Framingham Heart Study of the National Heart, Lung, and Blood Institute is funded by National Institutes of Health (NIH) contract N01-HC-25195; the Division of Intramural Research of the National Heart, Lung, and Blood Institute also supported this research. The research of Dr Aviv was supported by NIH grants R01AG030678 and R01HD071180. NR 23 TC 17 Z9 17 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP PY 2014 VL 34 IS 9 BP 2100 EP 2105 DI 10.1161/ATVBAHA.114.303579 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AN8UX UT WOS:000340881600043 PM 25060794 ER PT J AU Hernaez, A Fernandez-Castillejo, S Farras, M Catalan, U Subirana, I Montes, R Sola, R Munoz-Aguayo, D Gelabert-Gorgues, A Diaz-Gil, O Nyyssonen, K Zunft, HJF de la Torre, R Martin-Pelaez, S Pedret, A Remaley, AT Covas, MI Fito, M AF Hernaez, Alvaro Fernandez-Castillejo, Sara Farras, Marta Catalan, Ursula Subirana, Isaac Montes, Rosa Sola, Rosa Munoz-Aguayo, Daniel Gelabert-Gorgues, Anna Diaz-Gil, Oscar Nyyssoenen, Kristiina Zunft, Hans-Joachim F. de la Torre, Rafael Martin-Pelaez, Sandra Pedret, Anna Remaley, Alan T. Covas, Maria-Isabel Fito, Montserrat TI Olive Oil Polyphenols Enhance High-Density Lipoprotein Function in Humans A Randomized Controlled Trial SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE diet; high-density lipoproteins; olive oil ID CORONARY-ARTERY-DISEASE; APOLIPOPROTEIN-A-I; CHOLESTEROL EFFLUX; INTERVENTION TRIAL; MEDITERRANEAN DIET; HEART-DISEASE; HDL; SUBFRACTIONS; CAPACITY; ATHEROSCLEROSIS AB Objective-Olive oil polyphenols have shown beneficial properties against cardiovascular risk factors. Their consumption has been associated with higher cholesterol content in high-density lipoproteins (HDL). However, data on polyphenol effects on HDL quality are scarce. We, therefore, assessed whether polyphenol-rich olive oil consumption could enhance the HDL main function, its cholesterol efflux capacity, and some of its quality-related properties, such HDL polyphenol content, size, and composition. Approach and Results-A randomized, crossover, controlled trial with 47 healthy European male volunteers was performed. Participants ingested 25 mL/d of polyphenol-poor (2.7 mg/kg) or polyphenol-rich (366 mg/kg) raw olive oil in 3-week intervention periods, preceded by 2-week washout periods. HDL cholesterol efflux capacity significantly improved after polyphenol-rich intervention versus the polyphenol-poor one (+3.05% and -2.34%, respectively; P=0.042). Incorporation of olive oil polyphenol biological metabolites to HDL, as well as large HDL (HDL 2) levels, was higher after the polyphenol-rich olive oil intervention, compared with the polyphenol-poor one. Small HDL (HDL 3) levels decreased, the HDL core became triglyceride-poor, and HDL fluidity increased after the polyphenol-rich intervention. Conclusions-Olive oil polyphenols promote the main HDL antiatherogenic function, its cholesterol efflux capacity. These polyphenols increased HDL size, promoted a greater HDL stability reflected as a triglyceride-poor core, and enhanced the HDL oxidative status, through an increase in the olive oil polyphenol metabolites content in the lipoprotein. Our results provide for the first time a first-level evidence of an enhancement in HDL function by polyphenol-rich olive oil. C1 [Hernaez, Alvaro; Farras, Marta; Munoz-Aguayo, Daniel; Gelabert-Gorgues, Anna; Diaz-Gil, Oscar; Martin-Pelaez, Sandra; Covas, Maria-Isabel; Fito, Montserrat] IMIM Res Inst Hosp del Mar, CIBER Fisiopatol Nutr & Obesidad CIBEROBN, Cardiovasc Risk & Nutr Res Grp, REGICOR Study Grp, Barcelona 08003, Spain. [Subirana, Isaac] IMIM Res Inst Hosp del Mar, CIBER Epidemiol & Salud Publ CIBERESP, REGICOR Study Grp, Cardiovasc Epidemiol & Genet Res Grp, Barcelona 08003, Spain. [de la Torre, Rafael] IMIM Res Inst Hosp del Mar, Human Pharmacol & Clin Neurosci Res Grp, Barcelona 08003, Spain. [Hernaez, Alvaro] Univ Barcelona, PhD Program Food Sci & Nutr, Barcelona, Spain. [Montes, Rosa] Univ Barcelona, Fac Pharm, Dept Nutr & Bromatol, Barcelona, Spain. [Fernandez-Castillejo, Sara; Catalan, Ursula; Sola, Rosa; Pedret, Anna] Univ Rovira & Virgili, Res Unit Lipids & Atherosclerosis, Hosp Univ St Joan, IISPV, E-43201 Reus, Spain. [Fernandez-Castillejo, Sara; Catalan, Ursula; Sola, Rosa; Pedret, Anna] CIBER Diabet & Enfermedades Metab Asociadas CIBER, Reus, Spain. [Farras, Marta] Univ Autonoma Barcelona, Dept Biochem & Mol Biol, PhD Program Biochem Mol Biol & Biomed, E-08193 Barcelona, Spain. [Nyyssoenen, Kristiina] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Zunft, Hans-Joachim F.] German Inst Human Nutr Potsdam Rehbrucke, Potsdam, Germany. [Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, NIH, Bethesda, MD 20892 USA. RP Fito, M (reprint author), IMIM Res Inst Hosp del Mar, CIBER Fisiopatol Nutr & Obesidad CIBEROBN, Cardiovasc Risk & Nutr Res Grp, Parc Recerca Biomed Barcelona, Barcelona 08003, Spain. EM mfito@imim.es RI Catalan, Ursula/N-5712-2014; SOLA, Rosa/N-5919-2014; MARTIN-PELAEZ, SANDRA/G-4945-2015; Fito, Montserrat/C-1822-2012; OI Farras Mane, Marta/0000-0001-9776-3773; Catalan, Ursula/0000-0001-8884-9823; Fito, Montserrat/0000-0002-1817-483X; Pedret, Anna/0000-0002-5327-932X; SOLA, Rosa/0000-0002-8359-235X; Hernaez, Alvaro/0000-0001-8593-1477; Montes, Rosa/0000-0002-4154-3541 FU AGAUR [2014-SGR-240]; CICYT-FEDER [AGL2009-13517-C03-01]; European Commission [QLRT-2001-00287]; FIS [PI070759, PI11/01647]; FPI [BES-2010-040766]; FPU [FPU12/01318]; Miguel Servet's contract [CP06/00100]; Sara Borrell contract [CD10/00224] FX The work of these authors was supported by the AGAUR (2014-SGR-240), the CICYT-FEDER (AGL2009-13517-C03-01), the European Commission (QLRT-2001-00287), FIS programs (PI070759 and PI11/01647), FPI contract (BES-2010-040766), FPU fellowship program (FPU12/01318), Miguel Servet's contract (CP06/00100), and Sara Borrell contract (CD10/00224). The CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN) is an initiative of the Instituto de Salud Carlos III, Madrid, Spain. NR 25 TC 16 Z9 16 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP PY 2014 VL 34 IS 9 BP 2115 EP 2119 DI 10.1161/ATVBAHA.114.303374 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AN8UX UT WOS:000340881600045 PM 25060792 ER PT J AU Casey, BJ Oliveri, ME Insel, T AF Casey, B. J. Oliveri, Mary Ellen Insel, Thomas TI A Neurodevelopmental Perspective on the Research Domain Criteria (RDoC) Framework SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID DISORDERS; FEAR C1 [Casey, B. J.] Weill Cornell Med Coll, Sackler Inst Dev Psychobiol, New York, NY USA. [Oliveri, Mary Ellen; Insel, Thomas] NIMH, Rockville, MD 20857 USA. RP Casey, BJ (reprint author), Cornell Univ, Weill Cornell Med Coll, Dept Psychiat, Sackler Inst Dev Psychobiol, 1300 York Ave,Box 140, New York, NY 10021 USA. EM bjc2002@med.cornell.edu NR 10 TC 71 Z9 72 U1 4 U2 45 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2014 VL 76 IS 5 BP 350 EP 353 DI 10.1016/j.biopsych.2014.01.006 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AN8WQ UT WOS:000340886800002 PM 25103538 ER PT J AU Hourigan, CS AF Hourigan, Christopher S. TI Next Generation MRD SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material ID MINIMAL RESIDUAL DISEASE; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; QUANTITATIVE PCR; EVOLUTION C1 NHLBI, Myeloid Malignancies Sect, Hematol Branch, Bethesda, MD 20892 USA. RP Hourigan, CS (reprint author), NHLBI, Myeloid Malignancies Sect, Hematol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM hourigan@nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU Intramural NIH HHS [ZIA HL006163-01] NR 16 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2014 VL 20 IS 9 BP 1259 EP 1260 DI 10.1016/j.bbmt.2014.07.002 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AO0GD UT WOS:000340986200001 PM 25016196 ER PT J AU El-Jawahri, A Pidala, J Inamoto, Y Chai, XY Khera, N Wood, WA Cutler, C Arora, M Carpenter, PA Palmer, J Flowers, M Weisdorf, D Pavletic, S Jaglowski, S Jagasia, M Lee, SJ Chen, YB AF El-Jawahri, Areej Pidala, Joseph Inamoto, Yoshi Chai, Xiaoyu Khera, Nandita Wood, William A. Cutler, Corey Arora, Mukta Carpenter, Paul A. Palmer, Jeanne Flowers, Mary Weisdorf, Daniel Pavletic, Steven Jaglowski, Samantha Jagasia, Madan Lee, Stephanie J. Chen, Yi-Bin TI Impact of Age on Quality of Life, Functional Status, and Survival in Patients with Chronic Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Quality-of-life; Functional status; Chronic graft-versus-host disease; Age ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; HEMATOPOIETIC-CELL TRANSPLANTATION; HEALTH SURVEY SF-36; HEMATOLOGIC MALIGNANCIES; RISK-ASSESSMENT; PATIENTS OLDER; SCALE; CYTOGENETICS; VALIDATION AB Although older patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) may experience higher morbidity, the impact of chronic graft-versus-host disease (GVHD) on quality of life (QOL) and survival outcomes for older compared with younger patients is currently unknown. We utilized data of patients with moderate or severe chronic GVHD (N = 522, 1661 follow-up visits, a total of 2183 visits) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. We examined the relationship between age group (adolescent and young adult, "AYA," 18 to 40 years; "middle-aged," 41 to 59 years; and "older," >= 60 years) and QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation [FACT-BMT]), physical functioning (Human Activity Profile [HAP]), functional status (2-minute walk test [2MWT]), nonrelapse mortality, and overall survival. Because of multiple testing, P values < .01 were considered significant. This study included 115 (22%) AYA, 279 (53%) middle-aged, and 128 (25%) older patients with moderate (58%) or severe (42%) chronic GVHD. Despite more physical limitations in older patients as measured by worse functional status (shorter 2MWT [P < .001] and lower HAP scores [P < .001]) relative to AYA and middle-aged patients, older patients reported better QOL (FACT-BMT, P = .004) compared with middle-aged patients and similar to AYA patients (P = .99). Nonrelapse mortality and overall survival were similar between the age groups. Therefore, despite higher physical and functional limitations, older patients who are selected to undergo HSCT and survive long enough to develop moderate or severe chronic GVHD have preserved QOL and similar overall survival and nonrelapse mortality when compared with younger patients. Therefore, we did not find evidence that older age is associated with worse outcomes in patients with moderate or severe chronic GVHD. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [El-Jawahri, Areej; Chen, Yi-Bin] Massachusetts Gen Hosp, Ctr Canc, Div Bone Marrow Transplantat, Boston, MA 02114 USA. [El-Jawahri, Areej; Chen, Yi-Bin] Harvard Univ, Sch Med, Boston, MA USA. [Pidala, Joseph] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Inamoto, Yoshi; Chai, Xiaoyu; Carpenter, Paul A.; Flowers, Mary; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Khera, Nandita] Mayo Clin, Div Hematol Oncol, Phoenix, AZ USA. [Wood, William A.] Univ North Carolina Hosp, Linenberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Arora, Mukta; Weisdorf, Daniel] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Palmer, Jeanne] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Pavletic, Steven] NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Jaglowski, Samantha] Ohio State Univ, Med Ctr, Div Hematol Oncol, Columbus, OH 43210 USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Hematol & Stem Cell Transplant Program, Nashville, TN USA. RP El-Jawahri, A (reprint author), Massachusetts Gen Hosp, Dept Hematol Oncol, 12 N Grove St,Lawrence House,Second Floor, Boston, MA 02114 USA. EM ael-jawahri@partners.org OI Wood, William/0000-0001-7439-2543 FU National Institutes of Health [CA118953, CA163438]; NIH Office of Rare Diseases Research at the National Center for Advancing Translational Sciences; National Cancer Institute; Fred Hutchinson Cancer Research Center FX This work was supported by grants CA118953 and CA163438 from the National Institutes of Health. The Chronic GVHD Consortium (U54 CA163438) is a part of the NIH Rare Diseases Clinical Research Network, supported through collaboration between the NIH Office of Rare Diseases Research at the National Center for Advancing Translational Sciences, the National Cancer Institute, and the Fred Hutchinson Cancer Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 37 TC 8 Z9 8 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2014 VL 20 IS 9 BP 1341 EP 1348 DI 10.1016/j.bbmt.2014.05.001 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AO0GD UT WOS:000340986200013 PM 24813171 ER PT J AU Sobecks, RM Leis, JF Gale, RP Ahn, KW Zhu, XC Sabloff, M de Lima, M Brown, JR Inamoto, Y Hale, GA Aljurf, MD Kamble, RT Hsu, JW Pavletic, SZ Wirk, B Seftel, MD Lewis, ID Alyea, EP Cortes, J Kalaycio, ME Maziarz, RT Saber, W AF Sobecks, Ronald M. Leis, Jose F. Gale, Robert Peter Ahn, Kwang Woo Zhu, Xiaochun Sabloff, Mitchell de Lima, Marcos Brown, Jennifer R. Inamoto, Yoshihiro Hale, Gregory A. Aljurf, Mahmoud D. Kamble, Rammurti T. Hsu, Jack W. Pavletic, Steven Z. Wirk, Baldeep Seftel, Matthew D. Lewis, Ian D. Alyea, Edwin P. Cortes, Jorge Kalaycio, Matt E. Maziarz, Richard T. Saber, Wael TI Outcomes of Human Leukocyte Antigen-Matched Sibling Donor Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia: Myeloablative Versus Reduced-Intensity Conditioning Regimens SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic lymphocytic leukemia; Reduced-intensity conditioning; Myeloablative allogeneic hematopoietic cell transplantation; Outcomes ID VERSUS-HOST-DISEASE; MARROW TRANSPLANTATION; FOLLOW-UP; INTERNATIONAL-BLOOD; CLL3X TRIAL; GRAFT; FLUDARABINE; RITUXIMAB AB Allogeneic hematopoietic cell transplantation (HCT) can cure some chronic lymphocytic leukemia (CLL) subjects. This study compared outcomes of myeloablative (MA) and reduced-intensity conditioning (RIC) transplants from HLA-matched sibling donors (MSD) for CLL. From 1995 to 2007, information regarding 297 CLL subjects was reported to the Center of International Blood and Marrow Transplant Research; of these, 163 underwent MA and 134 underwent RIC MSD HCT. The MA subjects underwent transplantation less often after 2000 and less commonly received antithymocyte globulin (4% versus 13%, P = .004) or prior antibody therapy (14% versus 53%; P < .001). RIC was associated with a greater likelihood of platelet recovery and less grade 2 to 4 acute graft-versus-host disease compared with MA conditioning. One- and 5-year treatment-related mortality (TRM) were 24% (95% confidence intervals [CI], 16% to 33%) versus 37% (95% Cl, 30% to 45%; P = .023), and 40% (95% Cl, 29% to 51%) versus 54% (95% Cl, 46% to 62%; P = .036), respectively, and the relapse/progression rates at 1 and 5 years were 21% (95% Cl, 14% to 29%) versus 10% (95% Cl, 6% to 15%; P = .020), and 35% (95% Cl, 26% to 46%) versus 17% (95% CI, 12% to 24%; P = .003), respectively. MA conditioning was associated with better progression-free (PFS) (relative risk, .60; 95% CI, .37 to .97; P = .038) and 3-year survival in transplantations before 2001, but for subsequent years, RIC was associated with better PFS and survival (relative risk, 1.49 [95% CI, .92 to 2.421; P = .10; and relative risk, 1.86 [95% Cl, 1.11 to 3.13]; P = .019). Pretransplantation disease status was the most important predictor of relapse (P = .003) and PFS (P = .0007) for both forms of transplantation conditioning. MA and RIC MSD transplantations are effective for CLL. Future strategies to decrease TRM and reduce relapses are warranted. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Sobecks, Ronald M.; Kalaycio, Matt E.] Cleveland Clin, Taussig Canc Inst, Dept Hematol & Med Oncol, Cleveland, OH 44195 USA. [Leis, Jose F.] Mayo Clin Arizona, Dept Hematol Oncol, Phoenix, AZ USA. [Leis, Jose F.] Phoenix Childrens Hosp, Phoenix, AZ USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Hematol Res Ctr, Dept Med, Div Expt Med, London, England. [Ahn, Kwang Woo; Zhu, Xiaochun; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Sabloff, Mitchell] Univ Ottawa, Dept Med, Div Hematol, Ottawa, ON, Canada. [Sabloff, Mitchell] Ottawa Hosp Res Inst, Ottawa, ON, Canada. [de Lima, Marcos] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Brown, Jennifer R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Inamoto, Yoshihiro] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, Dept Hematol Oncol, St Petersburg, FL 33701 USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Kamble, Rammurti T.] Baylor Coll Med, Dept Hematol Oncol, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Hsu, Jack W.] Shands HealthCare, Dept Med, Div Hematol & Oncol, Gainesville, FL USA. [Hsu, Jack W.] Univ Florida, Gainesville, FL USA. [Pavletic, Steven Z.] NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Wirk, Baldeep] SUNY Stony Brook, Med Ctr, Stony Brook, NY 11794 USA. [Seftel, Matthew D.] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Lewis, Ian D.] Royal Adelaide Hosp, Adelaide, SA 5000, Australia. [Alyea, Edwin P.; Cortes, Jorge] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Leukemia, Houston, TX 77030 USA. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Ctr Hematol Malignancies, Portland, OR 97201 USA. RP Sobecks, RM (reprint author), Cleveland Clin, Taussig Canc Inst, Dept Hematol & Med Oncol, 9500 Euclid Ave,R35, Cleveland, OH 44195 USA. EM sobeckr@ccf.org FU National Cancer Institute (NCI) [U24-CA076518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U10HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen, Inc.; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; Leukemia & Lymphoma Society; Medac GmbH; Medical College of Wisconsin; Merck Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; TerumoBCT; Teva Neuroscience, Inc.; THERAKOS, Inc.; University of Minnesota; University of Utah; Wellpoint, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government. NR 35 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2014 VL 20 IS 9 BP 1390 EP 1398 DI 10.1016/j.bbmt.2014.05.020 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AO0GD UT WOS:000340986200020 PM 24880021 ER PT J AU Torlen, J Ringden, O Le Rademacher, J Batiwalla, M Chen, JF Erkers, T Ho, V Kebriaei, P Keever-Taylor, C Kindwall-Keller, T Lazarus, HM Laughlin, MJ Lill, M O'Brien, T Perales, MA Rocha, V Savani, BN Szwajcer, D Valcarcel, D Eapen, M AF Torlen, Johan Ringden, Olle Le Rademacher, Jennifer Batiwalla, Minoo Chen, Junfang Erkers, Tom Ho, Vincent Kebriaei, Partow Keever-Taylor, Carolyn Kindwall-Keller, Tamila Lazarus, Hillard M. Laughlin, Mary J. Lill, Michael O'Brien, Tracey Perales, Miguel-Angel Rocha, Vanderson Savani, Bipin N. Szwajcer, David Valcarcel, David Eapen, Mary TI Low CD34 Dose Is Associated with Poor Survival after Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia and Myelodygplastic Syndrome SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Cellular content; Peripheral blood graft; Hematological malignancy ID STEM-CELL TRANSPLANTATION; VERSUS-HOST-DISEASE; PERIPHERAL-BLOOD; BONE-MARROW; RISK-FACTORS; UNRELATED DONORS; CHRONIC GRAFT; OUTCOMES; ENGRAFTMENT; RELAPSE AB Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34(+) dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34(+) dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 x 10(6) CD34(+)/kg was associated with higher nonrelapse mortality (hazard ratio [HR], 2.03; P = .001), overall mortality (HR, 1.48; P = .008), and lower neutrophil (odds ratio [OR], .76; P = .03) and platelet (OR, .76; P = .03) recovery. PBPC from unrelated donors with CD34(+) dose <6 x 10(6) CD34(+)/kg was also associated with higher nonrelapse (HR, 1.38; P = .02) and overall mortality (HR, 1.20; P = .05). In contrast to reports after myeloablative HCT, CD34(+) dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34(+) doses >4 x 10(6) CD34(+)/kg and >6 x 10(6) CD34(+)/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Torlen, Johan; Ringden, Olle] Karolinska Univ Hosp Huddinge, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Ringden, Olle; Erkers, Tom] Karolinska Inst, Div Therapeut Immunol, Stockholm, Sweden. [Le Rademacher, Jennifer] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Le Rademacher, Jennifer; Chen, Junfang; Eapen, Mary] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Batiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Ho, Vincent] Dana Farber Canc Inst, Dept Hematol Oncol, Boston, MA 02115 USA. [Kebriaei, Partow] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Keever-Taylor, Carolyn; Eapen, Mary] Med Coll Wisconsin, Dept Med, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Kindwall-Keller, Tamila] Univ Virginia Hlth Syst, Div Hematol Oncol, Charlottesville, VA USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Laughlin, Mary J.] Novartis Pharmaceut Inc, Stem Cell Therapeut Program, E Hanover, NJ USA. [Lill, Michael] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [O'Brien, Tracey] Sydney Childrens Hosp, Ctr Childrens Canc & Blood Disorders, Sydney, NSW, Australia. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Dept Med, Bone Marrow Transplant Serv, New York, NY 10021 USA. [Rocha, Vanderson] Oxford Univ Hosp, Churchill Hosp, Dept Clin Haematol, Oxford, England. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Szwajcer, David] Univ Manitoba, Dept Hematol, Winnipeg, MB, Canada. [Valcarcel, David] Hosp Valle De Hebron, Dept Hematol, Barcelona, Spain. RP Eapen, M (reprint author), Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. EM meapen@mcw.edu FU National Cancer Institute (NCI) [U24-CA076518]; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID) [U24-CA076518]; NHLBI [5U10HL069294]; National Cancer Institute; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen, Inc.; Ariad Pharmaceuticals; Be The Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; Medac GmbH; Medical College of Wisconsin; Merck Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Terumo BCT; Teva Neuroscience, Inc.; Texas Instruments Inc.; WellPoint, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID) U24-CA076518; a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and National Cancer Institute; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); 2 Grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad Pharmaceuticals; Be The Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *Terumo BCT; *Teva Neuroscience, Inc.; *Texas Instruments Inc.; and *WellPoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration, or any other agency of the US Government. NR 29 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2014 VL 20 IS 9 BP 1418 EP 1425 DI 10.1016/j.bbmt.2014.05.021 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AO0GD UT WOS:000340986200023 PM 24892261 ER PT J AU Pantin, J Tian, X Geller, N Ramos, C Cook, L Cho, E Scheinberg, P Vasu, S Khuu, H Stroncek, D Barrett, J Young, NS Donohue, T Childs, RW AF Pantin, Jeremy Tian, Xin Geller, Nancy Ramos, Catalina Cook, Lisa Cho, Elena Scheinberg, Phillip Vasu, Sumithira Khuu, Hahn Stroncek, David Barrett, John Young, Neal S. Donohue, Theresa Childs, Richard W. TI Long-Term Outcome of Fludarabirie-Based Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Debilitating Paroxysmal Nocturnal Hemoglobinuria SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Paroxysmal nocturnal hemoglobinuria; Reduced-intensity; Hematopoietic cell transplantation; Survival; Fludarabine ID BONE-MARROW-TRANSPLANTATION; PERIPHERAL-BLOOD; APLASTIC-ANEMIA; ENGRAFTMENT; CLONE; PNH; ECULIZUMAB; HEMOLYSIS; FAILURE AB Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, venous thrombosis, and bone marrow failure. Seventeen patients with debilitating PNH, including 8 who were HLA-alloimmunized, underwent a reduced-intensity allogeneic hematopoietic cell transplantation (HCT). All received cyclophosphamide/fludarabine +/- antithymocyte globulin followed by a granulocyte colony-stimulating factor mobilized HCT from an HLA-matched relative. Glycosylphosphatidylinositol-negative neutrophils were detectable after engraftment but disappeared completely at a median 100 days after transplantation. With a median follow-up of nearly 6 years, 15 patients (87.8%) survived, all without any evidence of PNH, transfusion independent, and off anticoagulation. Allogeneic reduced-intensity HCT remains a curative therapeutic option for PNH patients who are not candidates for eculizumab treatment. (C) 2014 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Pantin, Jeremy; Ramos, Catalina; Cook, Lisa; Cho, Elena; Scheinberg, Phillip; Vasu, Sumithira; Barrett, John; Young, Neal S.; Donohue, Theresa; Childs, Richard W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Pantin, Jeremy] Georgia Regents Univ, Dept Med, Div Hematol & Oncol, Augusta, GA USA. [Tian, Xin; Geller, Nancy] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Scheinberg, Phillip] Hosp Beneficencia Portuguesa Sao Paulo, Hosp Sao Jose, Sao Paulo, Brazil. [Vasu, Sumithira] Ohio State Univ, Wexner Med Ctr, Dept Med, Div Hematol, Columbus, OH 43210 USA. [Khuu, Hahn; Stroncek, David] NIH, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NHLBI, Sect Transplantat Immunotherapy, Hematol Branch, NIH, Bldg 10,CRC Rm 3E-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM childsr@nih.gov OI Pantin, Jeremy/0000-0001-7536-0623 FU National Heart Lung Blood Institute at the National Institutes of Health, United States FX This work was supported by the Intramural Research Program of the National Heart Lung Blood Institute at the National Institutes of Health, United States. NR 25 TC 4 Z9 5 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 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2014 VL 20 IS 9 BP 1435 EP 1439 DI 10.1016/j.bbmt.2014.05.012 PG 5 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AO0GD UT WOS:000340986200025 PM 24844857 ER PT J AU Teras, LR Kitahara, CM Birmann, BM Hartge, PA Wang, SS Robien, K Patel, AV Adami, HO Weiderpass, E Giles, GG Singh, PN Alavanja, M Freeman, LEB Bernstein, L Buring, JE Colditz, GA Fraser, GE Gapstur, SM Gaziano, JM Giovannucci, E Hofmann, JN Linet, MS Neta, G Park, Y Peters, U Rosenberg, PS Schairer, C Sesso, HD Stampfer, MJ Visvanathan, K White, E Wolk, A Zeleniuch-Jacquotte, A de Gonzalez, AB Purdue, MP AF Teras, Lauren R. Kitahara, Cari M. Birmann, Brenda M. Hartge, Patricia A. Wang, Sophia S. Robien, Kim Patel, Alpa V. Adami, Hans-Olov Weiderpass, Elisabete Giles, Graham G. Singh, Pramil N. Alavanja, Michael Freeman, Laura E. Beane Bernstein, Leslie Buring, Julie E. Colditz, Graham A. Fraser, Gary E. Gapstur, Susan M. Gaziano, J. Michael Giovannucci, Edward Hofmann, Jonathan N. Linet, Martha S. Neta, Gila Park, Yikyung Peters, Ulrike Rosenberg, Philip S. Schairer, Catherine Sesso, Howard D. Stampfer, Meir J. Visvanathan, Kala White, Emily Wolk, Alicja Zeleniuch-Jacquotte, Anne de Gonzalez, Amy Berrington Purdue, Mark P. TI Body size and multiple myeloma mortality: a pooled analysis of 20 prospective studies SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE multiple myeloma; prospective cohort study; pooled analysis; body mass index; and anthropometry ID GROWTH-FACTOR-I; MASS INDEX; ANTHROPOMETRIC CHARACTERISTICS; HEMATOLOGICAL MALIGNANCY; PHYSICAL-ACTIVITY; UNITED-STATES; RISK; CANCER; OBESITY; LYMPHOMA AB Multiple myeloma (MM) is a rare but highly fatal malignancy. High body weight is associated with this cancer, but several questions remain regarding the aetiological relevance of timing and location of body weight. To address these questions, we conducted a pooled analysis of MM mortality using 1.5 million participants (including 1388 MM deaths) from 20 prospective cohorts in the National Cancer Institute Cohort Consortium. Proportional hazards regression was used to calculate pooled multivariate hazard ratios (HRs) and 95% confidence intervals (CIs). Associations with elevated MM mortality were observed for higher early-adult body mass index (BMI; HR = 1.22, 95% CI: 1.09-1.35 per 5 kg/m(2)) and for higher cohort-entry BMI (HR 1.09, 95% CI: 1.03-1.16 per 5 kg/m(2)) and waist circumference (HR = 1.06, 95% CI: 1.02-1.10 per 5 cm). In analyses of the joint effect of young adult and baseline BMI, women who were the heaviest, both in early adulthood (BMI 25+) and at cohort entry (BMI 30+) were at greater risk compared to those with BMI 18.5 = 25 at both time points (HR = 1.95, 95% CI: 1.33-2.86) but there was no significant association in men. Waist-to-hip ratio and height were not associated with MM mortality. These observations suggest that overall, and possibly also central, obesity influence myeloma mortality, and women have the highest risk of death from this cancer if they remain heavy throughout adulthood. C1 [Teras, Lauren R.; Patel, Alpa V.; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Kitahara, Cari M.; Hartge, Patricia A.; Alavanja, Michael; Freeman, Laura E. Beane; Hofmann, Jonathan N.; Linet, Martha S.; Neta, Gila; Park, Yikyung; Rosenberg, Philip S.; Schairer, Catherine; de Gonzalez, Amy Berrington; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Birmann, Brenda M.; Giovannucci, Edward; Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Birmann, Brenda M.; Giovannucci, Edward; Stampfer, Meir J.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Sophia S.; Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Robien, Kim] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC USA. [Adami, Hans-Olov; Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Adami, Hans-Olov; Buring, Julie E.; Giovannucci, Edward; Sesso, Howard D.; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Weiderpass, Elisabete] Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Singh, Pramil N.; Fraser, Gary E.] Loma Linda Univ, Sch Publ Hlth, Ctr Hlth Res, Loma Linda, CA 92350 USA. [Buring, Julie E.; Gaziano, J. Michael; Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Gaziano, J. Michael; Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Gaziano, J. Michael] Boston VA Med Ctr, Boston, MA USA. [Giovannucci, Edward; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [White, Emily] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Visvanathan, Kala] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [White, Emily] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Wolk, Alicja] Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, S-10401 Stockholm, Sweden. [Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, Sch Med, Div Epidemiol, New York, NY 10016 USA. RP Teras, LR (reprint author), Amer Canc Soc, Epidemiol Res Program, 250 Williams St NW, Atlanta, GA 30329 USA. EM lauren.teras@cancer.org RI Beane Freeman, Laura/C-4468-2015; Purdue, Mark/C-9228-2016; Weiderpass, Elisabete/M-4029-2016; Kitahara, Cari/R-8267-2016; Colditz, Graham/A-3963-2009; OI Beane Freeman, Laura/0000-0003-1294-4124; Purdue, Mark/0000-0003-1177-3108; Weiderpass, Elisabete/0000-0003-2237-0128; Colditz, Graham/0000-0002-7307-0291; Giles, Graham/0000-0003-4946-9099; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Institutes of Health (NIH); Division of Cancer Control and Population Sciences, National Cancer Institute (NCI), NIH FX We would like to thank all of the study participants and staff of the 20 included cohorts for their invaluable contribution to this work. In addition we thank Michelle Brotzman (Westat, Rockville, MD) and Franklin Demuth (Information Management Services, Rockville, MD) for project management and data analysis. This project was supported by the Intramural Research Program of the National Institutes of Health (NIH) and the Division of Cancer Control and Population Sciences, National Cancer Institute (NCI), NIH. Details regarding funding for the individual studies are listed in the Appendix S1. NR 30 TC 12 Z9 12 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2014 VL 166 IS 5 BP 667 EP 676 DI 10.1111/bjh.12935 PG 10 WC Hematology SC Hematology GA AN5ZE UT WOS:000340671000007 PM 24861847 ER PT J AU Arons, E Adams, S Venzon, DJ Pastan, I Kreitman, RJ AF Arons, Evgeny Adams, Sharon Venzon, David J. Pastan, Ira Kreitman, Robert J. TI Class II human leucocyte antigen DRB1*11 in hairy cell leukaemia patients with and without haemolytic uraemic syndrome SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE recombinant immunotoxin; moxetumomab pasudotox; HLA-DQB1*03; thrombotic microangiopathy; ADAMTS13 ID THROMBOTIC THROMBOCYTOPENIC PURPURA; CHRONIC LYMPHOCYTIC-LEUKEMIA; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; SEVERE ADAMTS13 DEFICIENCY; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN HEAVY; HLA; ASSOCIATION; LYMPHOMA; ALLELES AB Frequencies of human leucocyte antigens (HLA) were determined in 287 classic hairy cell leukaemia (HCL) patients. With respect to both population (n = 287) and allele (2n = 574) frequency respectively, the most common HLA class I and II antigens expressed were HLA-A*02 (49.1% and 28.6%), HLA-B*07 (21.3% and 11.1%), HLA-C*07 (46.7 and 28.2%), HLA-DQB1*03 (62.7% and 37.3%), HLA-DRB1*11 (30.0% and 16.0%) and HLA-DRB4*01 (45.3% and 29.6%). In comparing 6-14 databases of control Caucasians to 267 Caucasian HCL patients, only HLA-DRB1*11 was consistently over-represented in HCL, 31.1% of patients vs. 17-19.9% of controls (P = 0.0055 to < 0.0001) and 16.5% of alleles vs. 6.5-12.3% of control alleles (P = 0.022 to < 0.0001). HLA-DRB1*11 is a known risk factor for acquired thrombotic microangiopathy. Anti-CD22 recombinant immunotoxin BL22 in HCL was associated with a 12% incidence of completely reversible grade 3-4 haemolytic uraemic syndrome (HUS), mainly during the second or third retreatment cycle. Of 49 HCL patients receiving >= 2 cycles of BL22, 7 (14%) had HUS and HLA-DRB1*11 was expressed in 71% of 7 with HUS compared with only 21% of 42 without (P = 0.015). These data suggest that DBR1*11 may be a marker for increased susceptibility to HCL and, among HCL patients, could be a risk factor for BL22-induced HUS. C1 [Arons, Evgeny; Pastan, Ira; Kreitman, Robert J.] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Adams, Sharon] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, Bldg 37,Room 5124b,9000 Rockville Pike,MSC 4255, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU NCI, NIH; Hairy Cell Leukemia Research Foundation; MedImmune; NCI FX The authors recognize our clinical staff for help in obtaining samples, including Elizabeth Maestri, Natasha Kormanik, Amanda Wiggins, and Barbara Debrah. Assistance in confirming the diagnosis of HCL was provided by Maryalice Stetler- Stevenson, Constance Yuan, Mark Raffeld and Liqiang Xi in the NCI Laboratory of Pathology, and Katherine Calvo, Irina Maric, Roger Kurlander and Raul Braylan in the NIH Clinical Center Department of Laboratory Medicine. We recognize Hong Zhou for technical assistance, and thank the attendings and fellows who helped care for the patients. We recognize David FitzGerald for his work in the construction of BL22. This work was supported by the intramural research program, NCI, NIH, and also in part by the Hairy Cell Leukemia Research Foundation. The HCL trials were sponsored in part by MedImmune and the NCI. NR 51 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2014 VL 166 IS 5 BP 729 EP 738 DI 10.1111/bjh.12956 PG 10 WC Hematology SC Hematology GA AN5ZE UT WOS:000340671000013 PM 24931452 ER PT J AU Isaac, J Erthal, J Gordon, J Duverger, O Sun, HW Lichtler, AC Stein, GS Lian, JB Morasso, MI AF Isaac, J. Erthal, J. Gordon, J. Duverger, O. Sun, H-W Lichtler, A. C. Stein, G. S. Lian, J. B. Morasso, M. I. p TI DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID HOMEODOMAIN PROTEINS; RESPONSE ELEMENT; EXPRESSION; PROMOTER; BINDING; RUNX2; IDENTIFICATION; INVOLVEMENT; PATTERN; FAMILY AB Human mutations and in vitro studies indicate that DLX3 has a crucial function in bone development, however, the in vivo role of DLX3 in endochondral ossification has not been established. Here, we identify DLX3 as a central attenuator of adult bone mass in the appendicular skeleton. Dynamic bone formation, histologic and micro-computed tomography analyses demonstrate that in vivo DLX3 conditional loss of function in mesenchymal cells (Prx1-Cre) and osteoblasts (OCN-Cre) results in increased bone mass accrual observed as early as 2 weeks that remains elevated throughout the lifespan owing to increased osteoblast activity and increased expression of bone matrix genes. Dlx3OCN-conditional knockout mice have more trabeculae that extend deeper in the medullary cavity and thicker cortical bone with an increased mineral apposition rate, decreased bone mineral density and increased cortical porosity. Trabecular TRAP staining and site-specific Q-PCR demonstrated that osteoclastic resorption remained normal on trabecular bone, whereas cortical bone exhibited altered osteoclast patterning on the periosteal surface associated with high Opg/Rankl ratios. Using RNA sequencing and chromatin immunoprecipitation-Seq analyses, we demonstrate that DLX3 regulates transcription factors crucial for bone formation such as Dlx5, Dlx6, Runx2 and Sp7 as well as genes important to mineral deposition (Ibsp, Enpp1, Mepe) and bone turnover (Opg). Furthermore, with the removal of DLX3, we observe increased occupancy of DLX5, as well as increased and earlier occupancy of RUNX2 on the bone-specific osteocalcin promoter. Together, these findings provide novel insight into mechanisms by which DLX3 attenuates bone mass accrual to support bone homeostasis by osteogenic gene pathway regulation. C1 [Isaac, J.; Erthal, J.; Duverger, O.; Morasso, M. I. p] NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. [Gordon, J.; Stein, G. S.; Lian, J. B.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Sun, H-W] NIAMS, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Lichtler, A. C.] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT USA. RP Morasso, MI (reprint author), NIAMS, Skin Biol Lab, NIH, Bldg 50,Room 1523, Bethesda, MD 20892 USA. EM morasso@nih.gov RI Gordon, Jonathan/B-3904-2016 OI Gordon, Jonathan/0000-0003-2644-696X FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH; NIH [R37 DE012528] FX We thank Dr. T Clemens for the OCN-cre mice; S Russell, of the University of Massachusetts MusculoSkeletal Imaging Facility for performing mu CT analyses; Dr. K Zaal of the NIAMS Light Imaging Core Facility; G Gutierrez-Cruz of the Genome Analyzer Core Facility; Drs. A Maeda and M Young of the NIDCR, NIH; Dr. B Foster of NIAMS, NIH for assistance with ALPL staining, Audrey Asselin of the INSERM UMRS 1138 (Team Berdal), for assistance with cell culture, and Christophe Klein of the INSERM UMRS 1138 (CICC) and Laura Solomon (UVM graduate student) for osteoclast quantification. The Morasso and Lian laboratories and their funding contributed equally to this project. This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH. JBL is supported by NIH grant R37 DE012528. NR 48 TC 11 Z9 11 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD SEP PY 2014 VL 21 IS 9 BP 1365 EP 1376 DI 10.1038/cdd.2014.82 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN5WO UT WOS:000340662900004 PM 24948010 ER PT J AU Wei, Y Lilly, MA AF Wei, Y. Lilly, M. A. TI The TORC1 inhibitors Nprl2 and Nprl3 mediate an adaptive response to amino-acid starvation in Drosophila SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID TUMOR-SUPPRESSOR PROTEINS; CELL-GROWTH; RAG GTPASES; STEM-CELLS; EARLY OOGENESIS; DIRECT TARGET; GAP ACTIVITY; COMPLEX; MTOR; TSC2 AB Target of rapamycin complex 1 (TORC1) is a master regulator of metabolism in eukaryotes that integrates information from multiple upstream signaling pathways. In yeast, the Nitrogen permease regulators 2 and 3 (Npr2 and Npr3) mediate an essential response to amino-acid limitation upstream of TORC1. In mammals, the Npr2 ortholog, Nprl2, is a putative tumor suppressor gene that inhibits cell growth and enhances sensitivity to numerous anticancer drugs including cisplatin. However, the precise role of Nprl2 and Nprl3 in the regulation of metabolism in metazoans remains poorly defined. Here we demonstrate that the central importance of Nprl2 and Nprl3 in the response to amino-acid starvation has been conserved from single celled to multicellular animals. We find that in Drosophila Nprl2 and Nprl3 physically interact and are targeted to lysosomes and autolysosomes. Using oogenesis as a model system, we show that Nprl2 and Nprl3 inhibit TORC1 signaling in the female germline in response to amino-acid starvation. Moreover, the inhibition TORC1 by Nprl2/3 is critical to the preservation of female fertility during times of protein scarcity. In young egg chambers the failure to downregulate TORC1 in response to amino-acid limitation triggers apoptosis. Thus, our data suggest the presence of a metabolic checkpoint that initiates a cell death program when TORC1 activity remains inappropriately high during periods of amino-acid and/or nutrient scarcity in oogenesis. Finally, we demonstrate that Nprl2/3 work in concert with the TORC1 inhibitors Tsc1/2 to fine tune TORC1 activity during oogenesis and that Tsc1 is a critical downstream effector of Akt1 in the female germline. C1 [Wei, Y.; Lilly, M. A.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Lilly, MA (reprint author), NICHHD, Cell Biol & Metab Program, NIH, Bldg 18T Room 101, Bethesda, MD 20892 USA. EM mlilly@helix.nih.gov OI Lilly, Mary/0000-0003-1564-619X FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX We thank members of the Lilly laboratory for comments on the manuscript. We thank the TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947) for providing transgenic RNAi plasmid vectors used in this study. We thank Aurelio Teleman, Sharon Bickel and Helmut Kramer for providing reagents. This work was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 59 TC 12 Z9 15 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD SEP PY 2014 VL 21 IS 9 BP 1460 EP 1468 DI 10.1038/cdd.2014.63 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN5WO UT WOS:000340662900013 PM 24786828 ER PT J AU Jiang, ZP Redfern, RE Isler, Y Ross, AH Gericke, A AF Jiang, Zhiping Redfern, Roberta E. Isler, Yasmin Ross, Alonzo H. Gericke, Arne TI Cholesterol stabilizes fluid phosphoinositide domains SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Article DE Phosphoinositide; Domain formation; Lipid phase behavior; Phosphatidylinositol; Cholesterol; Phosphatidylinositol-4,5-bisphosphate; PTEN ID PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; PTEN PHOSPHATASE; PLASMA-MEMBRANE; LIPID RAFTS; 3-KINASE ACTIVATION; MIXED VESICLES; ORGANIZATION; MICRODOMAINS; PHOSPHATIDYLCHOLINE; PROTEIN AB Local accumulation of phosphoinositides (PIPs) is an important factor for a broad range of cellular events including membrane trafficking and cell signaling. The negatively charged phosphoinositide headgroups can interact with cations or cationic proteins and this electrostatic interaction has been identified as the main phosphoinositide clustering mechanism. However, an increasing number of reports show that phosphoinositide-mediated signaling events are at least in some cases cholesterol dependent, suggesting other possible contributors to the segregation of phosphoinositides. Using fluorescence microscopy on giant unilamellar vesicles and monolayers at the air/water interface, we present data showing that cholesterol stabilizes fluid phosphoinositide-enriched phases. The interaction with cholesterol is observed for all investigated phosphoinositides (PI(4)P, PI(3,4)P-2, PI(3,5)P-2, PI(4,5)P-2 and PI(3,4,5)P-3) as well as phosphatidylinositol. We find that cholesterol is present in the phosphoinositide-enriched phase and that the resulting phase is fluid. Cholesterol derivatives modified at the hydroxyl group (cholestenone, cholesteryl ethyl ether) do not promote formation of phosphoinositide domains, suggesting an instrumental role of the cholesterol hydroxyl group in the observed cholesterol/phosphoinositide interaction. This leads to the hypothesis that cholesterol participates in an intermolecular hydrogen bond network formed among the phosphoinositide lipids. We had previously reported that the intra- and intermolecular hydrogen bond network between the phosphoinositide lipids leads to a reduction of the charge density at the phosphoinositide phosphomonoester groups (Kooijman et al., 2009). We believe that cholesterol acts as a spacer between the phosphoinositide lipids, thereby reducing the electrostatic repulsion, while participating in the hydrogen bond network, leading to its further stabilization. To illustrate the effect of phosphoinositide segregation on protein binding, we show that binding of the tumor suppressor protein PTEN to PI(5)P and PI(4,5)P-2 is enhanced in the presence of cholesterol. These results provide new insights into how phosphoinositides mediate important cellular events. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Gericke, Arne] Worcester Polytech Inst, Dept Chem & Biochem, Worcester, MA 01609 USA. [Jiang, Zhiping] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Redfern, Roberta E.] ProMed Hlth Syst, ProMed Res Dept, Toledo, OH 43606 USA. [Isler, Yasmin] ProMed Hlth Syst, Acad Hlth Ctr BioRepository, Toledo, OH 43606 USA. [Ross, Alonzo H.] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. RP Gericke, A (reprint author), Worcester Polytech Inst, Dept Chem & Biochem, 100 Inst Rd, Worcester, MA 01609 USA. EM agericke@wpi.edu OI Redfern, Roberta/0000-0001-9883-2910 FU NSF [CHE 1216827, CHE 0724082] FX This work was supported by NSF CHE 1216827 and CHE 0724082. We thank Prof. Robert Bittman (City University of New York) for providing us with BODIPY-cholesterol and Prof. Robert J. Twieg (Kent State University) for providing us with Di-4-ANEPPDHQ. We also thank Dr. Mike A. Model (Kent State University) assisting us in performing confocal microscopy experiments. NR 47 TC 14 Z9 14 U1 1 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 EI 1873-2941 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD SEP PY 2014 VL 182 SI SI BP 52 EP 61 DI 10.1016/j.chemphyslip.2014.02.003 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AO0IE UT WOS:000340991500006 PM 24556334 ER PT J AU Koshiol, J Pawlish, K Goodman, MT McGlynn, KA Engels, EA AF Koshiol, Jill Pawlish, Karen Goodman, Marc T. McGlynn, Katherine A. Engels, Eric A. TI Risk of Hepatobiliary Cancer After Solid Organ Transplant in the United States SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Liver Disease; Transplantation; Epidemiology; HBV; HCV ID POLYCYSTIC KIDNEY-DISEASE; BILIARY-TRACT CANCER; HEPATOCELLULAR-CARCINOMA; INTRAHEPATIC CHOLANGIOCARCINOMA; RECIPIENTS; LIVER; POPULATION; TRENDS AB BACKGROUND & AIMS: Studies of liver cancer risk in recipients of solid organ transplants generally have been small, yielding mixed results, and little is known about biliary tract cancers among transplant recipients. METHODS: We identified incident hepatobiliary cancers among 201,549 US recipients of solid organs, from 1987 through 2008, by linking data from the US transplant registry with 15 cancer registries. We calculated standardized incidence ratios (SIRs), comparing risk relative to the general population. We also calculated incidence rate ratios (RRs), comparing risk for hepatocellular carcinoma (HCC) and total (intrahepatic and extrahepatic) cholangiocarcinoma among subgroups of recipients. RESULTS: Of transplant recipients, 165 developed hepatobiliary cancers (SIR, 1.2; 95% confidence interval [CI], 1.0-1.4). HCC risk was increased among liver recipients (SIR, 1.5; 95% CI, 1.0-2.2), especially 5 or more years after transplant (SIR, 1.8; 95% CI, 1.0-3.0). Cholangiocarcinoma was increased among liver (SIR, 2.9; 95% CI, 1.6-4.8) and kidney recipients (SIR, 2.1; 95% CI, 1.3-3.1). HCC was associated with hepatitis B virus (RR, 3.2; 95% CI, 1.3-6.9), hepatitis C virus (RR, 10; 95% CI, 5.9-16.9), and non-insulin-dependent diabetes (RR, 2.5; 95% CI, 1.2-4.8). Cholangiocarcinoma was associated with azathioprine maintenance therapy (RR, 2.0; 95% CI, 1.1-3.7). Among liver recipients, primary sclerosing cholangitis was associated with an increased risk of cholangiocarcinoma, compared with the general population (SIR, 21; 95% CI, 8.2-42) and compared with liver recipients without primary sclerosing cholangitis (RR, 12.3; 95% CI, 4.1-36.4). CONCLUSIONS: Risks for liver and biliary tract cancer are increased among organ transplant recipients. Risk factors for these cancers include medical conditions and potentiallymedications taken by recipients. C1 [Koshiol, Jill; Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Pawlish, Karen] New Jersey Dept Hlth, New Jersey State Canc Registry, Trenton, NJ USA. [Goodman, Marc T.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. RP Koshiol, J (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6-E212,MSC 9767, Rockville, MD 20892 USA. EM koshiolj@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX This research was supported by general funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 24 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD SEP PY 2014 VL 12 IS 9 BP 1541 EP U335 DI 10.1016/j.cgh.2013.12.018 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO2EI UT WOS:000341127900025 PM 24362053 ER PT J AU Vuppalanchi, R Gotur, R Reddy, KR Fontana, RJ Ghabril, M Kosinski, AS Gu, JZ Serrano, J Chalasani, N AF Vuppalanchi, Raj Gotur, Raghavender Reddy, K. Rajender Fontana, Robert J. Ghabril, Marwan Kosinski, Andrzej S. Gu, Jiezhun Serrano, Jose Chalasani, Naga TI Relationship Between Characteristics of Medications and Drug-Induced Liver Disease Phenotype and Outcome SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE DILIN; Liver Toxicity; Overdose; Side Effect; ALT ID DISPOSITION CLASSIFICATION-SYSTEM; ORAL MEDICATIONS; INJURY; BDDCS; RISK; FLUCLOXACILLIN; PERMEABILITY; METABOLISM; BCS AB BACKGROUND & AIMS: It is not known whether specific characteristics of medication are associated with type of druginduced liver injury (DILI) or outcome. We examined the relationships among select characteristics of medications and DILI phenotype and outcome. METHODS: We analyzed 383 cases of DILI caused by a single orally administered prescription agent from the DILI Network Prospective Study with causalities of definite, highly likely, or probable. Relationship of daily dosage (>= 50 mg vs <= 49 mg), preponderance of hepatic metabolism (>= 50% vs <50%), or Biopharmaceutics Drug Disposition Classification System (BDDCS) class (1-4, based on solubility and metabolism of the drug) were compared with clinical characteristics and outcomes. RESULTS: Compared with cases of DILI in the <= 49 mg/day group, those associated with daily dosages >= 50 mg had shorter latency (median, 38 days vs 56 days; P = .03) and a different biochemical pattern of liver injury (P = .04); no differences in recovery, severity, or outcome were observed. Patients with DILI caused by medications with or without preponderant hepatic metabolism did not differ in clinical characteristics or outcomes. Compared with other classes of BDDCS, DILI caused by BDDCS class 1 medications had significantly longer latency (P < .001) and greater proportion of hepatocellular injury (P = .001). However, peak liver biochemical values and patients' time to recovery, disease severity, and outcomes did not differ among the 4 BDDCS classes. CONCLUSIONS: Characteristics of medications (dosage, hepatic metabolism, and solubility) are associated with features of DILI such as latency and pattern of liver injury, but not with recovery, severity, or outcome. C1 [Vuppalanchi, Raj; Gotur, Raghavender; Ghabril, Marwan; Chalasani, Naga] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Reddy, K. Rajender] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Fontana, Robert J.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Kosinski, Andrzej S.; Gu, Jiezhun] Duke Clin Res Inst, Durham, NC USA. [Serrano, Jose] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD USA. RP Chalasani, N (reprint author), Indiana Univ Sch Med, Div Gastroenterol & Hepatol, 1050 Wishard Blvd,RG 4100, Indianapolis, IN 46202 USA. EM nchalasa@iu.edu OI Vuppalanchi, Raj/0000-0003-0637-1577; Ghabril, Marwan/0000-0002-4784-3246 FU National Institute of Diabetes and Digestive and Kidney Diseases [1U01DK065021, U01DK065193, 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, 1U01DK065176] FX The U.S. Drug-Induced Liver Injury Network (DILIN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases under the following cooperative agreements: 1U01DK065021, U01DK065193, 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, and 1U01DK065176. NR 25 TC 8 Z9 8 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD SEP PY 2014 VL 12 IS 9 BP 1550 EP 1555 DI 10.1016/j.cgh.2013.12.016 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO2EI UT WOS:000341127900026 PM 24362054 ER PT J AU Danis, M Pollack, JM AF Danis, Marion Pollack, John M. TI The Valuable Contribution of Spiritual Care to End-of-Life Care in the ICU SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE end-of-life care; family satisfaction; medical decision making; palliative care; religious and spiritual care C1 [Danis, Marion] NIH, Dept Bioeth, Bethesda, MD 20892 USA. NIH, Dept Spiritual Care, Bethesda, MD 20892 USA. RP Danis, M (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2014 VL 42 IS 9 BP 2131 EP 2132 DI 10.1097/CCM.0000000000000470 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA AN7LF UT WOS:000340780800040 PM 25126799 ER PT J AU Kuchroo, VK Anderson, AC Petrovas, C AF Kuchroo, Vijay K. Anderson, Ana C. Petrovas, Constantinos TI Coinhibitory receptors and CD8 T cell exhaustion in chronic infections SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE CD160; CD8; exhaustion; HIV; PD-1; Tim-3 ID CHRONIC VIRAL-INFECTION; ANTIGEN-PRESENTING CELL; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; REGULATES PD-1 EXPRESSION; CHRONIC HEPATITIS-B; HIV-1 INFECTION; ANTIRETROVIRAL THERAPY; PROGRAMMED DEATH-1; IMMUNE EXHAUSTION; IN-VIVO AB Purpose of review To describe the recent data on the role of coinhibitory receptors, such as PD-1, Tim-3, CD160, as mediators of the 'exhaustion' of virus-specific CD8 T cells in chronic infections and particularly in HIV. Recent findings Exhaustion of chronic virus-specific CD8 T cells is a dynamic process characterized by altered differentiation, impaired function, and compromised proliferation/survival profile of these cells. This process is mediated by coinhibitory receptors expressed on the surface of virus-specific CD8 T cells and an orchestrated function of centrally connected pathways. Coexpression of several coinhibitory receptors characterizes severely exhausted virus-specific CD8 T cells. Several studies suggest a synergistic action, instead of a redundant role, of the different receptors. In-vivo manipulation of the coinhibitory network can rejuvenate exhausted virus-specific CD8 T cell responses and constrain replication of chronic viruses, including HIV. Summary Revealing the molecular basis of virus-specific CD8 T cell exhaustion in chronic infections is critical for the understanding of the disease pathogenesis and the designing of novel vaccines aiming to enhance the cytolytic arm of the immune system. This is of particular interest for the development of immunotherapies in the context C1 [Kuchroo, Vijay K.; Anderson, Ana C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Petrovas, Constantinos] NIAID, Immuimmunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Petrovas, C (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM petrovasc@mail.nih.gov FU Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health; CAVD from the Bill and Melinda Gates Foundation [OPP1032325] FX Work in the author's laboratories is supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health, and CAVD grant #OPP1032325 from the Bill and Melinda Gates Foundation. NR 109 TC 15 Z9 15 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD SEP PY 2014 VL 9 IS 5 BP 439 EP 445 DI 10.1097/COH.0000000000000088 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AN4NU UT WOS:000340565600002 PM 25010894 ER PT J AU Moir, S Fauci, AS AF Moir, Susan Fauci, Anthony S. TI B-cell exhaustion in HIV infection: the role of immune activation SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE exhaustion; HIV; immunopathogenesis; memory B cells; persistent viremia ID POPULATION; INDIVIDUALS; DISEASE; EXPRESSION; RESPONSES; PATHWAYS; INSIGHTS; SUBSETS; CONTAIN; INNATE AB Purpose of review To discuss a component of the pathogenic mechanisms of HIV infection in the context of phenotypic and functional alterations in B cells that are due to persistent viral replication leading to aberrant immune activation and cellular exhaustion. We explore how B-cell exhaustion arises during persistent viremia and how it compares with T-cell exhaustion and similar B-cell alterations in other diseases. Recent findings HIV-associated B-cell exhaustion was first described in 2008, soon after the demonstration of persistent virus-induced T-cell exhaustion, as well as the identification of a subset B cells in tonsil tissues with immunoregulatory features similar to those observed in T-cell exhaustion. Our understanding of B-cell exhaustion has since expanded in two important areas: the role of inhibitory receptors in the unresponsiveness of exhausted B cells and the increasing evidence that similar B cells are found in other diseases that are associated with aberrant immune activation and inflammation. Summary The phenomenon of B-cell exhaustion is now well established in HIV infection and other diseases characterized by immune activation. Over the coming years, it will be important to understand how cellular exhaustion affects the capacity of the immune system to respond to persisting primary pathogens, as well as to other microbial antigens, whether encountered as secondary infections or following immunization. C1 [Moir, Susan; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A02,9000 Rockville Pike, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU Intramural Research Program of NIAID, NIH FX This work was supported by the Intramural Research Program of NIAID, NIH. NR 33 TC 13 Z9 13 U1 1 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD SEP PY 2014 VL 9 IS 5 BP 472 EP 477 DI 10.1097/COH.0000000000000092 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AN4NU UT WOS:000340565600007 PM 25023621 ER PT J AU Chaffee, BR Shang, F Chang, ML Clement, TM Eddy, EM Wagner, BD Nakahara, M Nagata, S Robinson, ML Taylor, A AF Chaffee, Blake R. Shang, Fu Chang, Min-Lee Clement, Tracy M. Eddy, Edward M. Wagner, Brad D. Nakahara, Masaki Nagata, Shigekazu Robinson, Michael L. Taylor, Allen TI Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis-related nuclear disassembly SO DEVELOPMENT LA English DT Article DE CDK1; Lens fiber differentiation; Organelle-free zone; Mouse ID MOUSE EYE LENS; DNASE-II; NUMA PHOSPHORYLATION; INHIBITORS P27(KIP1); TEMPORAL EXPRESSION; PROLIFERATION; P57(KIP2); DENUCLEATION; DEGRADATION; GROWTH AB Lens epithelial cells and early lens fiber cells contain the typical complement of intracellular organelles. However, as lens fiber cells mature they must destroy their organelles, including nuclei, in a process that has remained enigmatic for over a century, but which is crucial for the formation of the organelle-free zone in the center of the lens that assures clarity and function to transmit light. Nuclear degradation in lens fiber cells requires the nuclease DNase II beta (DLAD) but the mechanism by which DLAD gains access to nuclear DNA remains unknown. In eukaryotic cells, cyclin-dependent kinase 1 (CDK1), in combination with either activator cyclins A or B, stimulates mitotic entry, in part, by phosphorylating the nuclear lamin proteins leading to the disassembly of the nuclear lamina and subsequent nuclear envelope breakdown. Although most post-mitotic cells lack CDK1 and cyclins, lens fiber cells maintain these proteins. Here, we show that loss of CDK1 from the lens inhibited the phosphorylation of nuclear lamins A and C, prevented the entry of DLAD into the nucleus, and resulted in abnormal retention of nuclei. In the presence of CDK1, a single focus of the phosphonuclear mitotic apparatus is observed, but it is not focused in CDK1-deficient lenses. CDK1 deficiency inhibited mitosis, but did not prevent DNA replication, resulting in an overall reduction of lens epithelial cells, with the remaining cells possessing an abnormally large nucleus. These observations suggest that CDK1-dependent phosphorylations required for the initiation of nuclear membrane disassembly during mitosis are adapted for removal of nuclei during fiber cell differentiation. C1 [Chaffee, Blake R.; Wagner, Brad D.; Robinson, Michael L.] Miami Univ, Dept Biol, Oxford, OH 45056 USA. [Shang, Fu; Chang, Min-Lee; Taylor, Allen] Tufts Univ, Nutr & Vis Res USDA HNRCA, Human Nutr Res Ctr Aging, Lab Nutr & Vis Res, Boston, MA 02111 USA. [Clement, Tracy M.; Eddy, Edward M.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Nakahara, Masaki] Kyoto Univ, Grad Sch Med, Dept Mol & Cellular Physiol, Kyoto, Japan. [Nagata, Shigekazu] Kyoto Univ, Grad Sch Med, Dept Med Chem, Kyoto, Japan. [Taylor, Allen] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. RP Robinson, ML (reprint author), Miami Univ, Dept Biol, Oxford, OH 45056 USA. EM robinsm5@miamioh.edu; allen.taylor@tufts.edu FU National Eye Institute [EY012995, EY013250, EY021212]; USDA [1950-510000-060-01A]; Alcon; Johnson and Johnson Focused Giving; Intramural Research Program of the National Institutes of Health (NIH); National Institute of Environmental Health Sciences FX This work was supported, in part, by grants from The National Eye Institute [EY012995 (M.L.R.), EY013250, EY021212 (A.T.)]; The USDA contract 1950-510000-060-01A (A.T.); Alcon (A.T.); Johnson and Johnson Focused Giving (A.T.); and by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (E.M.E.). A.T. is currently the Morris Belkin Weizmann Visiting Professor. Deposited in PMC for release after 12 months. NR 50 TC 8 Z9 8 U1 2 U2 8 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD SEP PY 2014 VL 141 IS 17 BP 3388 EP 3398 DI 10.1242/dev.106005 PG 11 WC Developmental Biology SC Developmental Biology GA AO4KH UT WOS:000341305900013 PM 25139855 ER PT J AU Walford, GA Porneala, BC Dauriz, M Vassy, JL Cheng, S Rhee, EP Wang, TJ Meigs, JB Gerszten, RE Florez, JC AF Walford, Geoffrey A. Porneala, Bianca C. Dauriz, Marco Vassy, Jason L. Cheng, Susan Rhee, Eugene P. Wang, Thomas J. Meigs, James B. Gerszten, Robert E. Florez, Jose C. TI Metabolite Traits and Genetic Risk Provide Complementary Information for the Prediction of Future Type 2 Diabetes SO DIABETES CARE LA English DT Article ID GENOME-WIDE ASSOCIATION; INSULIN-RESISTANCE; SUSCEPTIBILITY LOCI; COMMON VARIANT; BRANCHED-CHAIN; AMINO-ACIDS; RECLASSIFICATION; MELLITUS; GLUCOSE; SCORE AB OBJECTIVE A genetic risk score (GRS) comprised of single nucleotide polymorphisms (SNPs) and metabolite biomarkers have each been shown, separately, to predict incident type 2 diabetes. We tested whether genetic and metabolite markers provide complementary information for type 2 diabetes prediction and, together, improve the accuracy of prediction models containing clinical traits. RESEARCH DESIGN AND METHODS Diabetes risk was modeled with a 62-SNP GRS, nine metabolites, and clinical traits. We fit age- and sex-adjusted logistic regression models to test the association of these sources of information, separately and jointly, with incident type 2 diabetes among 1,622 initially nondiabetic participants from the Framingham Offspring Study. The predictive capacity of each model was assessed by area under the curve (AUC). RESULTS Two hundred and six new diabetes cases were observed during 13.5 years of follow-up. The AUC was greater for the model containing the GRS and metabolite measurements together versus GRS or metabolites alone (0.820 vs. 0.641, P < 0.0001, or 0.820 vs. 0.803, P = 0.01, respectively). Odds ratios for association of GRS or metabolites with type 2 diabetes were not attenuated in the combined model. The AUC was greater for the model containing the GRS, metabolites, and clinical traits versus clinical traits only (0.880 vs. 0.856, P = 0.002). CONCLUSIONS Metabolite and genetic traits provide complementary information to each other for the prediction of future type 2 diabetes. These novel markers of diabetes risk modestly improve the predictive accuracy of incident type 2 diabetes based only on traditional clinical risk factors. C1 [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet, Boston, MA 02114 USA. [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Walford, Geoffrey A.; Dauriz, Marco; Vassy, Jason L.; Cheng, Susan; Rhee, Eugene P.; Meigs, James B.; Gerszten, Robert E.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Porneala, Bianca C.; Dauriz, Marco; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Dauriz, Marco] Univ Verona, Sch Med, Dept Med, Div Endocrinol & Metab Dis, I-37100 Verona, Italy. [Dauriz, Marco] Hosp Trust Verona, I-37100 Verona, Italy. [Vassy, Jason L.] VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA USA. [Vassy, Jason L.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02115 USA. [Cheng, Susan] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Rhee, Eugene P.] Massachusetts Gen Hosp, Div Renal, Boston, MA 02114 USA. [Wang, Thomas J.] Vanderbilt Univ, Med Ctr, Div Cardiol, Nashville, TN USA. [Meigs, James B.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Walford, GA (reprint author), Massachusetts Gen Hosp, Ctr Human Genet, Boston, MA 02114 USA. EM gwalford@partners.org; jcflorez@partners.org RI Dauriz, Marco/S-5843-2016 OI Dauriz, Marco/0000-0002-5542-5941 FU National Institutes of Health [NO1-HC-25195, R01-DK-HL081572, R01-DK-078616, K24-DK-080140]; American Heart Association; University of Verona; Ellison Foundation; [NIH-U01-HG006500]; [L30-DK-089597]; [K99-HL-107642] FX This work was supported by National Institutes of Health contracts NO1-HC-25195, R01-DK-HL081572, R01-DK-078616, and K24-DK-080140 and by the American Heart Association. M. D. is supported by research grants of the University of Verona. J.L.V. is supported by NIH-U01-HG006500 and L30-DK-089597. S.C. is supported in part by K99-HL-107642 and a grant from the Ellison Foundation. NR 35 TC 23 Z9 24 U1 0 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2014 VL 37 IS 9 BP 2508 EP 2514 DI 10.2337/dc14-0560 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN8HX UT WOS:000340846300024 PM 24947790 ER PT J AU Espeland, MA Glick, HA Bertoni, A Brancati, FL Bray, GA Clark, JM Curtis, JM Egan, C Evans, M Foreyt, JP Ghazarian, S Gregg, EW Hazuda, HP Hill, JO Hire, D Horton, ES Hubbard, V Jakicic, JM Jeffery, RW Johnson, KC Kahn, SE Killean, T Kitabchi, AE Knowler, WC Kriska, A Lewis, CE Miller, M Montez, MG Murillo, A Nathan, DM Nyenwe, E Patricio, J Peters, AL Pi-Sunyer, X Pownall, H Redmon, B Rushing, J Ryan, DH Safford, M Tsai, AG Wadden, TA Wing, RR Yanovski, SZ Zhang, P AF Espeland, Mark A. Glick, Henry A. Bertoni, Alain Brancati, Frederick L. Bray, George A. Clark, Jeanne M. Curtis, Jeffrey M. Egan, Caitlin Evans, Mary Foreyt, John P. Ghazarian, Siran Gregg, Edward W. Hazuda, Helen P. Hill, James O. Hire, Don Horton, Edward S. Hubbard, Van S. Jakicic, John M. Jeffery, Robert W. Johnson, Karen C. Kahn, Steven E. Killean, Tina Kitabchi, Abbas E. Knowler, William C. Kriska, Andrea Lewis, Cora E. Miller, Marsha Montez, Maria G. Murillo, Anne Nathan, David M. Nyenwe, Ebenezer Patricio, Jennifer Peters, Anne L. Pi-Sunyer, Xavier Pownall, Henry Redmon, Bruce Rushing, Julia Ryan, Donna H. Safford, Monika Tsai, Adam G. Wadden, Thomas A. Wing, Rena R. Yanovski, Susan Z. Zhang, Ping CA Look AHEAD Res Grp TI Impact of an Intensive Lifestyle Intervention on Use and Cost of Medical Services Among Overweight and Obese Adults With Type 2 Diabetes: The Action for Health in Diabetes SO DIABETES CARE LA English DT Article ID DISEASE RISK-FACTORS; LOOK-AHEAD ACTION; WEIGHT-LOSS; CARDIOVASCULAR-DISEASE; CLINICAL-TRIAL; MELLITUS; INDIVIDUALS; PREVENTION; METFORMIN; SAVINGS AB OBJECTIVE To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial. RESEARCH DESIGN AND METHODS A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years. RESULTS ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385-7,175); however, these were not evident among individuals with a history of cardiovascular disease. CONCLUSIONS Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs. C1 [Espeland, Mark A.; Hire, Don; Rushing, Julia] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Glick, Henry A.; Wadden, Thomas A.] Univ Penn, Weight & Eating Disorder Program, Philadelphia, PA 19104 USA. [Bertoni, Alain] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Brancati, Frederick L.; Clark, Jeanne M.] Johns Hopkins Sch Med, Baltimore, MD USA. [Bray, George A.; Ryan, Donna H.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Curtis, Jeffrey M.; Killean, Tina; Knowler, William C.] NIDDK, Southwest Amer Indian Ctr, Phoenix, AZ USA. [Egan, Caitlin; Wing, Rena R.] Miriam Hosp, Brown Med Sch, Weight Control & Diabet Res Ctr, Providence, RI 02906 USA. [Evans, Mary; Hubbard, Van S.; Yanovski, Susan Z.] NIDDK, NIH, Bethesda, MD USA. [Foreyt, John P.; Pownall, Henry] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Ghazarian, Siran; Peters, Anne L.] Roybal Comprehens Hlth Ctr, Los Angeles, CA USA. [Gregg, Edward W.; Zhang, Ping] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hazuda, Helen P.; Montez, Maria G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Hill, James O.; Miller, Marsha] Univ Colorado, Hlth Sci Ctr, Anschutz Hlth & Wellness Ctr, Aurora, CO USA. [Horton, Edward S.] Joslin Diabet Ctr, Dept Clin Epidemiol, Boston, MA 02215 USA. [Jakicic, John M.; Kriska, Andrea] Univ Pittsburgh, Diabet Unit, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Jeffery, Robert W.; Redmon, Bruce] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Johnson, Karen C.; Kitabchi, Abbas E.; Nyenwe, Ebenezer] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Kahn, Steven E.; Murillo, Anne] Univ Washington, Dept Med, Seattle, WA USA. [Lewis, Cora E.; Safford, Monika] Univ Alabama Birmingham, Birmingham, AL USA. [Nathan, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Patricio, Jennifer; Pi-Sunyer, Xavier] St Lukes Roosevelt Hosp, Div Dept Med, New York, NY 10025 USA. [Tsai, Adam G.] Univ Colorado, Hlth Sci Ctr, Div Internal Med, Aurora, CO USA. RP Espeland, MA (reprint author), Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. EM mespelan@wakehealth.edu OI Redmon, J. Bruce/0000-0002-1883-9467; Kriska, Andrea/0000-0002-3522-0869; Kahn, Steven/0000-0001-7307-9002 FU Merck; Amgen; Amylin Pharmaceuticals, LLC; Bristol-Myers Squibb/AstraZeneca; GI Dynamic, Inc.; Gilead Sciences, Inc.; International Medical Press Global Partnership for Effective Diabetes Management; Janssen Pharmaceuticals, Inc.; Merck Research Laboratories, Inc.; Sanofi, Inc.; Vivus, Inc.; Theracos Pharmaceuticals, Inc.; Takeda Pharmaceuticals, Inc.; Eli Lilly and Company; GlaxoSmithKline; Medtronic MiniMed; Medscape; Novo Nordisk; Janssen; Takeda; Vivus; Eisai; diaDexus FX M.A.E. serves on monitoring boards for Terumo Medical Corporation and the Kowa Research Institute. He serves on a steering committee for Boehringer Ingelheim and has recently served on an advisory committee for Takeda Global Research. H. A. G. has twice been a sponsored lecturer by Merck. J.O.H. serves on advisory boards for Takeda and Novo Nordisk. E. S. H. has received consulting, advisory board, monitoring board, and speakers' board support from Amgen; Amylin Pharmaceuticals, LLC; Bristol-Myers Squibb/AstraZeneca; GI Dynamic, Inc.; Gilead Sciences, Inc.; International Medical Press Global Partnership for Effective Diabetes Management; Janssen Pharmaceuticals, Inc.; Merck Research Laboratories, Inc.; Sanofi, Inc.; Vivus, Inc.; Theracos Pharmaceuticals, Inc.; and Takeda Pharmaceuticals, Inc. E.N. has received research support from Eli Lilly and Company and GlaxoSmithKline. A. L. P. has consulted for Abbott Diabetes Care, Becton Dickinson, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Lilly, Medtronic MiniMed, and Sanofi; has been on the speakers' bureau for Bristol-Myers Squibb/AstraZeneca and Novo Nordisk; has received research grant funding from Medtronic MiniMed; and has received editorial fees from Medscape. D. H. R. was a paid consultant/advisor to Novo Nordisk, Janssen, Takeda, Vivus, and Eisai and has an equity position in Scientific Intake. M. S. has received salary support from Amgen and diaDexus and has served as a consultant for diaDexus. T. A. W. serves on advisory boards for Novo Nordisk and Orexigen and is a consultant to Boehringer Ingelheim. No other potential conflicts of interest relevant to this article were reported. NR 32 TC 39 Z9 39 U1 5 U2 13 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2014 VL 37 IS 9 BP 2548 EP 2556 DI 10.2337/dc14-0093 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN8HX UT WOS:000340846300029 PM 25147253 ER PT J AU Gill, AA Enewold, L Zahm, SH Shriver, CD Stojadinovic, A McGlynn, KA Zhu, KM AF Gill, Abegail A. Enewold, Lindsey Zahm, Shelia H. Shriver, Craig D. Stojadinovic, Alexander McGlynn, Katherine A. Zhu, Kangmin TI Colon Cancer Treatment: Are There Racial Disparities in an Equal-Access Healthcare System? SO DISEASES OF THE COLON & RECTUM LA English DT Article DE Chemotherapy; Colon cancer; Equal access; Race; Surgery; Treatment ID COLORECTAL-CANCER; ETHNIC DISPARITIES; AFRICAN-AMERICANS; RACE; MORTALITY; INSURANCE; OUTCOMES; RECEIPT; RACE/ETHNICITY; COMMUNICATION AB BACKGROUND: In the general US population, blacks and whites have been shown to undergo colon cancer treatment at disproportionate rates. Accessibility to medical care may be the most important factor influencing differences in colon cancer treatment rates among whites and blacks. OBJECTIVE: We assessed whether racial disparities in colon cancer surgery and chemotherapy existed in an equal-access health care system. In addition, we sought to examine whether racial differences varied according to demographic and tumor characteristics. DESIGN AND SETTING: Database research using the Department of Defense Military Health System. PATIENTS: Patients included 2560 non-Hispanic whites (NHW) and non-Hispanic blacks (NHB) with colon cancer diagnosed from 1998 to 2007. MAIN OUTCOME MEASURES: Logistic regression was used to assess the associations between race and the receipt of colon cancer surgery or chemotherapy while controlling for available potential confounders, both overall and stratified by age at diagnosis, sex, and tumor stage. RESULTS: After multivariate adjustment, the odds of receiving colon cancer surgery or chemotherapy for NHBs versus NHWs were similar (OR, 0.75 [95% CI, 0.37-1.53]; OR, 0.79 [95% CI, 0.59-1.04]). In addition, no effect modifications by age at diagnosis, sex, and tumor stage were observed. LIMITATIONS: Treatment data might not be complete for beneficiaries who also had non-Department of Defense health insurance. CONCLUSIONS: When access to medical care is equal, racial disparities in the provision of colon cancer surgery and chemotherapy were not apparent. Thus, it is possible that the inequalities in access to care play a major role in the racial disparities seen in colon cancer treatment in the general population. C1 [Gill, Abegail A.; Enewold, Lindsey; Zhu, Kangmin] Walter Reed Bethesda, Div Mil Epidemiol & Populat Sci, John P Murtha Canc Ctr, Bethesda, MD USA. [Zahm, Shelia H.] NCI, Div Canc Epidemiol & Genet, Off Director, NIH, Bethesda, MD 20892 USA. [Shriver, Craig D.] Walter Reed Bethesda, John P Murtha Canc Ctr, Bethesda, MD USA. [Shriver, Craig D.] Walter Reed Bethesda, Gen Surg Serv, Bethesda, MD USA. [Shriver, Craig D.; Stojadinovic, Alexander] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Stojadinovic, Alexander] Walter Reed Bethesda, Combat Wound Initiat Program, Bethesda, MD USA. [McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. RP Zhu, KM (reprint author), Walter Reed Bethesda, Div Mil Epidemiol & Populat Sci, John P Murtha Canc Ctr, 11300 Rockville Pike,Suite 1215, Rockville, MD 20852 USA. EM kangmin.zhu@usuhs.edu RI Zahm, Shelia/B-5025-2015 FU John P. Murtha Cancer Center, Walter Reed National Military Medical Center, via the Uniformed Services University of the Health Sciences under Henry M. Jackson Foundation for the Advancement of Military Medicine; National Cancer Institute FX Funding/Support: This work was supported by the John P. Murtha Cancer Center, Walter Reed National Military Medical Center, via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine and by the intramural research program of the National Cancer Institute. The original data linkage was supported by the United States Military Cancer Institute and Division of Cancer Epidemiology and Genetics, National Cancer Institute. NR 39 TC 6 Z9 6 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0012-3706 EI 1530-0358 J9 DIS COLON RECTUM JI Dis. Colon Rectum PD SEP PY 2014 VL 57 IS 9 BP 1059 EP 1065 DI 10.1097/DCR.0000000000000177 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AO2RG UT WOS:000341172300003 PM 25101601 ER PT J AU Murai, J Marchand, C Shahane, SA Sun, HM Huang, RL Zhang, YP Chergui, A Ji, JP Doroshow, JH Jadhav, A Takeda, S Xia, MH Pommier, Y AF Murai, Junko Marchand, Christophe Shahane, Sampada A. Sun, Hongmao Huang, Ruili Zhang, Yiping Chergui, Adel Ji, Jiuping Doroshow, James H. Jadhav, Ajit Takeda, Shunichi Xia, Menghang Pommier, Yves TI Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform SO DNA REPAIR LA English DT Article DE TDP1; PARP; Topoisomerases; Drug discovery; Combination therapy ID TYROSYL-DNA PHOSPHODIESTERASE; STRAND BREAK REPAIR; TOPOISOMERASE-I; POLY(ADP-RIBOSE) POLYMERASE; BIOLOGICAL EVALUATION; CLEAVAGE COMPLEXES; REPLICATION FORKS; DAMAGE; ATAXIA; ANTICANCER AB Anti-cancer topoisomerase I (Top1) inhibitors (camptothecin and its derivatives irinotecan and topotecan, and indenoisoquinolines) induce lethal DNA lesions by stabilizing Top1 -DNA cleavage complex (Top1 cc). These lesions are repaired by parallel repair pathways including the tyrosyl-DNA phosphodiesterase 1 (TDP1)-related pathway and homologous recombination. As TDP1-deficient cells in vertebrates are hypersensitive to Top1 inhibitors, small molecules inhibiting TDP1 should augment the cytotoxicity of Top1 inhibitors. We developed a cell-based high-throughput screening assay for the discovery of inhibitors for human TDP1 using a TDP1-deficient chicken DT40 cell line (TDP1-/-) complemented with human TDP1 (hTDP1). Any compounds showing a synergistic effect with the Top1 inhibitor camptothecin (CPT) in hTDP1 cells should either be a TDP1-related pathway inhibitor or an inhibitor of alternate repair pathways for Top1 cc. We screened the 400,000-compound Small Molecule Library Repository (SMLR, NIH Molecular Libraries) against hTDP1 cells in the absence or presence of CPT. After confirmation in a secondary screen using both hTDP1 and TDP1-/- cells in the absence or presence of CPT, five compounds were confirmed as potential TDP1 pathway inhibitors. All five compounds showed synergistic effect with CPT in hTDP1 cells, but not in TDP1-1 cells, indicating that the compounds inhibited a TDP1-related repair pathway. Yet, in vitro gel-based assay revealed that the five compounds did not inhibit TDP1 catalytic activity directly. We tested the compounds for their ability to inhibit poly(ADP-ribose)polymerase (PARP) because PARP inhibitors are known to potentiate the cytotoxicity of CPT by inhibiting the recruitment of TDP1 to Top1 cc. Accordingly, we found that the five compounds inhibit catalytic activity of PARP by ELISA and Western blotting. We identified the most potent compound (Cpd1) that offers characteristic close to veliparib, a leading clinical PARP inhibitor. Cpd1 may represent a new scaffold for the development of PARP inhibitors. Published by Elsevier B.V. C1 [Murai, Junko; Marchand, Christophe; Chergui, Adel; Doroshow, James H.; Pommier, Yves] NCI, Dev Therapeut Branch, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Shahane, Sampada A.; Sun, Hongmao; Huang, Ruili; Jadhav, Ajit; Xia, Menghang] NIH, NCATS, Bethesda, MD 20892 USA. [Zhang, Yiping; Ji, Jiuping; Doroshow, James H.] NCI, Natl Clin Target Validat Lab, NIH, Bethesda, MD 20892 USA. [Takeda, Shunichi] Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Marchand, Christophe/D-8559-2016 FU Center for Cancer Research, National Cancer Institute, NIH [Z01 BC 006150]; NIH R03 Grant [MH095538-01A1] FX This study was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH (Z01 BC 006150) and by the NIH R03 Grant MH095538-01A1 (YP). NR 45 TC 4 Z9 5 U1 2 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD SEP PY 2014 VL 21 BP 177 EP 182 DI 10.1016/j.dnarep.2014.03.006 PG 6 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AO0EQ UT WOS:000340982300020 PM 24794403 ER PT J AU Archer, TK AF Archer, T. K. TI Diverse Epigenetic Enzymes Empower Regulated Gene Expression. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Archer, T. K.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA S36 BP S27 EP S27 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900045 ER PT J AU Auerbach, S AF Auerbach, S. TI A Large-Scale Toxicogenomic Benchmark Dose Analysis and Resource. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Auerbach, S.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA S40 BP S28 EP S28 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900049 ER PT J AU Bushel, PR Wang, C Gong, B Thierry-Mieg, J Thierry-Mieg, D Xu, J Fang, H Kreil, DP Megherbi, D Li, J Paules, RS Shi, L Auerbach, SS Tong, W AF Bushel, P. R. Wang, C. Gong, B. Thierry-Mieg, J. Thierry-Mieg, D. Xu, J. Fang, H. Kreil, D. P. Megherbi, D. Li, J. Paules, R. S. Shi, L. Auerbach, S. S. Tong, W. TI Bioinformatics Applications Reveal Gene Regulation Complexities in Response to Toxicant Exposures. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Bushel, P. R.; Paules, R. S.; Auerbach, S. S.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Gong, B.; Xu, J.; Fang, H.; Shi, L.; Tong, W.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wang, C.] Loma Linda Univ, Loma Linda, CA 92350 USA. [Thierry-Mieg, J.; Thierry-Mieg, D.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Kreil, D. P.] Boku Univ, Vienna, Austria. [Kreil, D. P.] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Megherbi, D.] Univ Massachusetts, Lowell, MA USA. [Li, J.] Kelly Govt Solut, Durham, NC USA. RI Gong, Binsheng/E-2306-2015 OI Gong, Binsheng/0000-0002-8724-5435 NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA S51 BP S31 EP S31 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900060 ER PT J AU Crespo-Mejias, Y Rivera, AV Sanchez, VC Poirier, MC Olivero, OA AF Crespo-Mejias, Y. Rivera, A., V Sanchez, V. C. Poirier, M. C. Olivero, O. A. TI Zidovudine (AZT) Induced Downregulation of hsa-mir-770-5p and Upregulation of STMN-1: A Novel Pathway to Aneuploidy. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Crespo-Mejias, Y.; Rivera, A., V; Poirier, M. C.; Olivero, O. A.] NCI, Carcinogen DNA Interact Sect, LCBG, CCR,NIH, Bethesda, MD 20892 USA. [Sanchez, V. C.] NCI, In Vitro Pathogenesis Sect, LCBG, CCR,NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA P55 BP S53 EP S53 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900147 ER PT J AU Divi, RL Lindeman, TE Shockley, ME Keshava, C Weston, A Poirier, MC AF Divi, R. L. Lindeman, T. E. Shockley, M. E. Keshava, C. Weston, A. Poirier, M. C. TI Correlation between CYP1A1 RNA Transcript, Protein Level, Enzyme Activity, and DNA Adducts in Primary Normal Human Mammary Epithelial Cells Exposed to Benzo[a]pyrene SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Divi, R. L.; Lindeman, T. E.; Shockley, M. E.; Poirier, M. C.] NCI, Bethesda, MD 20892 USA. [Keshava, C.] US EPA, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. [Weston, A.] NIOSH, Div Resp Dis Studies, CDC, Morgantown, WV 26505 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA P68 BP S56 EP S56 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900159 ER PT J AU Gassman, NR Stefanick, DF Horton, JK Wilson, SH AF Gassman, N. R. Stefanick, D. F. Horton, J. K. Wilson, S. H. TI BPA Modulates Repair of Oxidative DNA Damage by Base Excision Repair Pathway SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Gassman, N. R.; Stefanick, D. F.; Horton, J. K.; Wilson, S. H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA P71 BP S56 EP S56 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900162 ER PT J AU Manchester, DK Olivero, OA Rivera, A Dauber, A Hwa, V Poirier, MC Spivak, G AF Manchester, D. K. Olivero, O. A. Rivera, A. Dauber, A. Hwa, V Poirier, M. C. Spivak, G. TI DNA Repair Defects and Centrosomal Deregulation Associated with Seckel Syndrome Microcephaly. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Manchester, D. K.] Univ Colorado Denver, Sch Med, Aurora, CO USA. [Olivero, O. A.; Rivera, A.; Poirier, M. C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Dauber, A.] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Hwa, V] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Spivak, G.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA P57 BP S53 EP S53 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900149 ER PT J AU Samson, LD Wilson, TE Smith-Roe, SL AF Samson, L. D. Wilson, T. E. Smith-Roe, S. L. TI A Perspective on the Role of EMGS in Understanding the Contributions of DNA Damage and Repair to Environmental Mutagenesis SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Samson, L. D.] MIT, Cambridge, MA 02139 USA. [Wilson, T. E.] Univ Michigan, Ann Arbor, MI 48109 USA. [Smith-Roe, S. L.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA S2 BP S20 EP S20 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900012 ER PT J AU Smeaton, MB Bell, EH Austin, CA Deterding, LJ Tomer, KB Hanawalt, PC Miller, PS AF Smeaton, M. B. Bell, E. H. Austin, C. A. Deterding, L. J. Tomer, K. B. Hanawalt, P. C. Miller, P. S. TI TopoisomeraseII beta Is Involved in Initiation of Interstrand Cross-Link Repair in Mammals. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Smeaton, M. B.; Bell, E. H.; Miller, P. S.] Johns Hopkins Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD USA. [Smeaton, M. B.; Hanawalt, P. C.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. [Austin, C. A.] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Deterding, L. J.; Tomer, K. B.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RI Bell, Erica/J-2950-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA S56 BP S32 EP S32 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900064 ER PT J AU Wang, T Feng, J Fargo, D Santos, J Nestler, E Woychik, R AF Wang, T. Feng, J. Fargo, D. Santos, J. Nestler, E. Woychik, R. TI Impact of Repetitive Element Transcriptional Activation in Cocaine Addiction. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Wang, T.; Fargo, D.; Santos, J.; Woychik, R.] NIEHS, Durham, NC USA. [Feng, J.; Nestler, E.] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2014 VL 55 SU 1 MA 22 BP S38 EP S38 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900087 ER PT J AU Debrabant, B Soerensen, M Flachsbart, F Dato, S Mengel-From, J Stevnsner, T Bohr, VA Kruse, TA Schreiber, S Nebe, A Christensen, K Tan, QH Christiansen, L AF Debrabant, Birgit Soerensen, Mette Flachsbart, Friederike Dato, Serena Mengel-From, Jonas Stevnsner, Tinna Bohr, Vilhelm A. Kruse, Torben A. Schreiber, Stefan Nebe, Almut Christensen, Kaare Tan, Qihua Christiansen, Lene TI Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE competitive gene-set analysis; human longevity; SNPs; case-control data; DNA-damage response and DNA repair ID GENOME-WIDE ASSOCIATION; LIFE-SPAN; METHODOLOGICAL ISSUES; TELOMERE LENGTH; AGE; SURVIVAL; MUTATIONS; CANCER; RISK; APOE AB DNA-damage response and repair are crucial to maintain genetic stability, and are consequently considered central to aging and longevity. Here, we investigate whether this pathway overall associates to longevity, and whether specific sub-processes are more strongly associated with longevity than others. Data were applied on 592 SNPs from 77 genes involved in nine sub-processes: DNA-damage response, base excision repair (BER), nucleotide excision repair, mismatch repair, non-homologous end-joining, homologous recombinational repair (HRR), RecQ helicase activities (RECQ), telomere functioning and mitochondria! DNA processes. The study population was 1089 long-lived and 736 middle-aged Danes. A self-contained set-based test of all SNPs displayed association with longevity (P-value = 9.9 x 10(-5)), supporting that the overall pathway could affect longevity. Investigation of the nine sub-processes using the competitive gene-set analysis by Wang et al indicated that BER, HRR and RECQ associated stronger with longevity than the respective remaining genes of the pathway (P-values = 0.004-0.048). For HRR and RECQ, only one gene contributed to the significance, whereas for BER several genes contributed. These associations did, however, generally not pass correction for multiple testing. Still, these findings indicate that, of the entire pathway, variation in BER might influence longevity the most. These modest sized P-values were not replicated in a German sample. This might, though, be due to differences in genotyping procedures and investigated SNPs, potentially inducing differences in the coverage of gene regions. Specifically, five genes were not covered at all in the German data. Therefore, investigations in additional study populations are needed before final conclusion can be drawn. C1 [Debrabant, Birgit; Soerensen, Mette; Mengel-From, Jonas; Christensen, Kaare; Tan, Qihua; Christiansen, Lene] Univ Southern Denmark, Inst Publ Hlth, Danish Aging Res Ctr, DK-5000 Odense C, Denmark. [Soerensen, Mette; Mengel-From, Jonas; Kruse, Torben A.; Christensen, Kaare; Tan, Qihua; Christiansen, Lene] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Flachsbart, Friederike; Schreiber, Stefan; Nebe, Almut] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Dato, Serena] Univ Calabria, Dept Biol Ecol & Earth Sci, I-87036 Arcavacata Di Rende, Italy. [Stevnsner, Tinna; Bohr, Vilhelm A.] Aarhus Univ, Danish Aging Res Ctr, Dept Mol Biol & Genet, Aarhus, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Christensen, Kaare] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, DK-5000 Odense, Denmark. RP Debrabant, B (reprint author), Univ Southern Denmark, Inst Publ Hlth, Danish Aging Res Ctr, JB Winsloews Vej 9B, DK-5000 Odense C, Denmark. EM bdebrabant@health.sdu.dk; msoerensen@health.sdu.dk RI Christensen, Kaare/C-2360-2009; Nebel, Almut/E-4196-2010; Soerensen, Mette/O-1817-2015; OI Christensen, Kaare/0000-0002-5429-5292; Soerensen, Mette/0000-0001-5268-3366; dato, serena/0000-0003-2589-7929 FU Max-Planck Institute for Demographic Research, (Rostock, Germany); European Regional Development Fund; European Union's Seventh Framework Programme (FP7) [259679]; National Institute on Aging [P01 AG08761]; RESOLVE project [FP7-HEALTH-F4-2008-202047]; Novo Nordisk; Aase and Ejnar Danielsen; Broglrene Hartmann; King Christian the 10th Foundation; Ether Willumsens Mindelegat Foundation; VELUX Foundation; Danish Council for Independent Research - Medical Sciences FX This study was supported by the Max-Planck Institute for Demographic Research, (Rostock, Germany), the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N (by EU funds from the European Regional Development Fund), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the National Institute on Aging (P01 AG08761), the RESOLVE project (FP7-HEALTH-F4-2008-202047) and the Novo Nordisk, the Aase and Ejnar Danielsen, the Broglrene Hartmann, the King Christian the 10th and the Ether Willumsens Mindelegat Foundations. The Danish Aging Research Center is supported by a grant from the VELUX Foundation, while Mette Soerensen is supported by an individual postdoctoral grant from The Danish Council for Independent Research - Medical Sciences. NR 53 TC 6 Z9 6 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD SEP PY 2014 VL 22 IS 9 BP 1131 EP 1136 DI 10.1038/ejhg.2013.299 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AN4SA UT WOS:000340577600013 PM 24518833 ER PT J AU Hu, ZL Leppla, SH Li, BG Elkins, CA AF Hu, Zonglin Leppla, Stephen H. Li, Baoguang Elkins, Christopher A. TI Antibodies specific for nucleic acids and applications in genomic detection and clinical diagnostics SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE anti-nucleic acids antibodies; apoptotic cells detection; biosensor; cancer detection; hybrid capture; metakaryotic stem cells; microarray; miRNA; R-loop detection; sRNA ID DNA-RNA HYBRIDS; DOUBLE-STRANDED-RNA; POLYMERASE CHAIN-REACTION; PHOTONIC MICRORING RESONATORS; SYSTEMIC LUPUS-ERYTHEMATOSUS; SOLUTION HYBRIDIZATION ASSAY; HUMAN IMMUNODEFICIENCY VIRUS; SURFACE-PLASMON RESONANCE; CERVICAL LAVAGE SPECIMENS; HUMAN-PAPILLOMAVIRUS DNA AB Detection of nucleic acids using antibodies is uncommon. This is in part because nucleic acids are poor immunogens and it is difficult to elicit antibodies having high affinity to each type of nucleic acid while lacking cross-reactivity to others. We describe the origins and applications of a variety of anti-nucleic acid antibodies, including ones reacting with modified nucleosides and nucleotides, single-stranded DNA, double-stranded DNA, RNA, DNA: RNA hybrids, locked-nucleic acids or peptide nucleic acid: nucleic acid hybrids. Carefully selected antibodies can be excellent reagents for detecting bacteria, viruses, small RNAs, microRNAs, R-loops, cancer cells, stem cells, apoptotic cells and so on. The detection may be sensitive, simple, rapid, specific, reproducible, quantitative and cost-effective. Current microarray and diagnostic methods that depend on cDNA or cRNA can be replaced by using antibody detection of nucleic acids. Therefore, development should be encouraged to explore new utilities and create a robust arsenal of new anti-nucleic acid antibodies. C1 [Hu, Zonglin] US FDA, Winchester Engn & Analyt Ctr, Off Regulatory Affairs, Winchester, MA 01890 USA. [Hu, Zonglin; Li, Baoguang; Elkins, Christopher A.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Leppla, Stephen H.] NIAID, Parasit Dis Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Hu, ZL (reprint author), US FDA, Winchester Engn & Analyt Ctr, Off Regulatory Affairs, 109 Holton St, Winchester, MA 01890 USA. EM Zonglin.hu@fda.hhs.gov FU Oak Ridge Institute for Science and Education, USA; Intramural Research Program of the NIH FX Research described here was supported in part by Oak Ridge Institute for Science and Education, USA, and by the Intramural Research Program of the NIH. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. NR 173 TC 0 Z9 0 U1 5 U2 29 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD SEP PY 2014 VL 14 IS 7 BP 895 EP 916 DI 10.1586/14737159.2014.931810 PG 22 WC Pathology SC Pathology GA AN8CJ UT WOS:000340829200011 PM 25014728 ER PT J AU Cook, KL Clarke, PAG Parmar, J Hu, R Schwartz-Roberts, JL Abu-Asab, M Warri, A Baumann, WT Clarke, R AF Cook, Katherine L. Clarke, Pamela A. G. Parmar, Jignesh Hu, Rong Schwartz-Roberts, Jessica L. Abu-Asab, Mones Waerri, Anni Baumann, William T. Clarke, Robert TI Knockdown of estrogen receptor-alpha induces autophagy and inhibits antiestrogen-mediated unfolded protein response activation, promoting ROS-induced breast cancer cell death SO FASEB JOURNAL LA English DT Article DE fulvestrant; ICI 182780; apoptosis; reactive oxygen species ID ENDOPLASMIC-RETICULUM STRESS; BOX BINDING PROTEIN-1; ACQUIRED-RESISTANCE; FACTOR-I; APOPTOSIS; MACROAUTOPHAGY; MITOCHONDRIA; EXPRESSION; INDUCTION; TAMOXIFEN AB Approximately 70% of all newly diagnosed breast cancers express estrogen receptor (ER)-alpha. Although inhibiting ER action using targeted therapies such as fulvestrant (ICI) is often effective, later emergence of antiestrogen resistance limits clinical use. We used antiestrogen-sensitive and -resistant cells to determine the effect of antiestrogens/ER alpha on regulating autophagy and unfolded protein response (UPR) signaling. Knockdown of ER alpha significantly increased the sensitivity of LCC1 cells (sensitive) and also resensitized LCC9 cells (resistant) to antiestrogen drugs. Interestingly, ER alpha knockdown, but not ICI, reduced nuclear factor (erythroid-derived 2)-like (NRF)-2 (UPR-induced antioxidant protein) and increased cytosolic kelch-like ECH-associated protein (KEAP)-1 (NRF2 inhibitor), consistent with the observed increase in ROS production. Furthermore, autophagy induction by antiestrogens was prosurvival but did not prevent ER alpha knockdown-mediated death. We built a novel mathematical model to elucidate the interactions among UPR, autophagy, ER signaling, and ROS regulation of breast cancer cell survival. The experimentally validated mathematical model explains the counterintuitive result that knocking down the main target of ICI (ER alpha) increased the effectiveness of ICI. Specifically, the model indicated that ER alpha is no longer present in excess and that the effect on proliferation from further reductions in its level by ICI cannot be compensated for by increased autophagy. The stimulation of signaling that can confer resistance suggests that combining autophagy or UPR inhibitors with antiestrogens would reduce the development of resistance in some breast cancers. C1 [Cook, Katherine L.; Clarke, Pamela A. G.; Hu, Rong; Schwartz-Roberts, Jessica L.; Waerri, Anni; Clarke, Robert] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20057 USA. [Cook, Katherine L.; Clarke, Pamela A. G.; Hu, Rong; Schwartz-Roberts, Jessica L.; Waerri, Anni; Clarke, Robert] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Parmar, Jignesh] Virginia Polytech Inst & State Univ, Dept Biol Sci, Blacksburg, VA 24061 USA. [Baumann, William T.] Virginia Polytech Inst & State Univ, Bradley Dept Elect & Comp Engn, Blacksburg, VA 24061 USA. [Abu-Asab, Mones] NEI, US NIH, Immunopathol Sect, Bethesda, MD 20892 USA. [Abu-Asab, Mones] NEI, US NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Clarke, R (reprint author), Georgetown Univ, Med Ctr, W405A Res Bldg,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM clarker@georgetown.edu RI Clarke, Robert/A-6485-2008; OI Clarke, Robert/0000-0002-9278-0854; Cook, Katherine/0000-0001-6241-0214 FU U.S. Department of Defense Breast Cancer Research Program Postdoctoral Fellowship [BC112023]; U.S. Department of Health and Human Services [U54-CA149147, R01-CA131465] FX This study was supported by a U.S. Department of Defense Breast Cancer Research Program Postdoctoral Fellowship (BC112023; to K. C.) and in part by awards from the U.S. Department of Health and Human Services (U54-CA149147 and R01-CA131465) (to R. C.). The authors declare no conflicts of interest. NR 43 TC 13 Z9 14 U1 4 U2 18 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD SEP PY 2014 VL 28 IS 9 BP 3891 EP 3905 DI 10.1096/fj.13-247353 PG 15 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AN8HU UT WOS:000340845900008 PM 24858277 ER PT J AU Chhabra, S Chang, SC Nguyen, HM Huq, R Tanner, MR Londono, LM Estrada, R Dhawan, V Chauhan, S Upadhyay, SK Gindin, M Hotez, PJ Valenzuela, JG Mohanty, B Swarbrick, JD Wulff, H Iadonato, SP Gutman, GA Beeton, C Pennington, MW Norton, RS Chandy, KG AF Chhabra, Sandeep Chang, Shih Chieh Nguyen, Hai M. Huq, Redwan Tanner, Mark R. Londono, Luz M. Estrada, Rosendo Dhawan, Vikas Chauhan, Satendra Upadhyay, Sanjeev K. Gindin, Mariel Hotez, Peter J. Valenzuela, Jesus G. Mohanty, Biswaranjan Swarbrick, James D. Wulff, Heike Iadonato, Shawn P. Gutman, George A. Beeton, Christine Pennington, Michael W. Norton, Raymond S. Chandy, K. George TI Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases SO FASEB JOURNAL LA English DT Article DE ShK; probiotic worm therapy; T lymphocytes; ion channel modulator; hookworm ID MEMORY T-CELLS; REMITTING MULTIPLE-SCLEROSIS; NEUTROPHIL INHIBITORY FACTOR; RANDOMIZED CONTROLLED-TRIAL; TRICHURIS-SUIS THERAPY; SEA-ANEMONE TOXIN; POTASSIUM-CHANNEL; NECATOR-AMERICANUS; SELECTIVE BLOCKADE; PROTEIN STRUCTURES AB The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7-effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFN gamma production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases. C1 [Chhabra, Sandeep; Chang, Shih Chieh; Mohanty, Biswaranjan; Swarbrick, James D.; Norton, Raymond S.] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia. [Nguyen, Hai M.; Upadhyay, Sanjeev K.; Gutman, George A.; Chandy, K. George] Univ Calif Irvine, Sch Med, Dept Physiol & Biophys, Irvine, CA 92717 USA. [Nguyen, Hai M.; Wulff, Heike] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Huq, Redwan; Tanner, Mark R.; Beeton, Christine] Baylor Coll Med, Natl Sch Trop Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA. [Huq, Redwan] Baylor Coll Med, Natl Sch Trop Med, Grad Program Mol Physiol & Biophys, Houston, TX 77030 USA. [Tanner, Mark R.] Baylor Coll Med, Natl Sch Trop Med, Interdepartmental Grad Program Translat Biol & Mo, Houston, TX 77030 USA. [Hotez, Peter J.] Baylor Coll Med, Natl Sch Trop Med, Sabin Vaccine Inst, Houston, TX 77030 USA. [Hotez, Peter J.] Texas Childrens Hosp, Baylor Coll Med, Ctr Vaccine Dev, Natl Sch Trop Med, Houston, TX 77030 USA. [Londono, Luz M.; Iadonato, Shawn P.] Kineta Inc, Seattle, WA USA. [Estrada, Rosendo; Dhawan, Vikas; Chauhan, Satendra; Pennington, Michael W.] Peptides Int, Louisville, KY USA. [Gindin, Mariel] George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC USA. [Gindin, Mariel; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Norton, RS (reprint author), Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia. EM ray.norton@monash.edu; gchandy@uci.edu OI Beeton, Christine/0000-0002-2500-5874; Hotez, Peter/0000-0001-8770-1042 FU U.S. National Institutes of Health (NIH) [R01 NS48252, NS073712, GM076063]; Howard Hughes Medical Institutes Med into Grad Initiative; NIH T32 award [GM088129]; Human Hookworm Initiative of the Gates Foundation; National Institute of Allergy and Infectious Diseases (NIAID) at NIH; University of California, Irvine; National Health and Medical Research Council of Australia FX Support for this work was provided by U.S. National Institutes of Health (NIH) grants R01 NS48252 (to K.G.C.), NS073712 (to C.B., M.W.P., and R.S.N.); GM076063 (to H.W.); Howard Hughes Medical Institutes Med into Grad Initiative and NIH T32 award GM088129 (to M.R.T.); the Human Hookworm Initiative of the Gates Foundation (to P.J.H.); the intramural program of the National Institute of Allergy and Infectious Diseases (NIAID) at NIH (to J.G.V.); a bridge fund from the University of California, Irvine (to K.G.C); and fellowship support by the National Health and Medical Research Council of Australia (to R.S.N.). NR 77 TC 14 Z9 14 U1 0 U2 20 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD SEP PY 2014 VL 28 IS 9 BP 3952 EP 3964 DI 10.1096/fj.14-251967 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AN8HU UT WOS:000340845900013 PM 24891519 ER PT J AU Eggert, T McGlynn, K Greten, TF Altekruse, S AF Eggert, Tobias McGlynn, Katherine Greten, Tim F. Altekruse, Sean TI Response to fibrolamellar hepatocellular carcinoma versus conventional hepatocellular carcinoma: better 5-year survival or artefactual result of research methodology? SO GUT LA English DT Letter C1 [Eggert, Tobias; McGlynn, Katherine] NIH, MOB, Bethesda, MD 20892 USA. [Greten, Tim F.; Altekruse, Sean] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 3 TC 0 Z9 0 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD SEP PY 2014 VL 63 IS 9 BP 1524 EP 1524 DI 10.1136/gutjnl-2013-306407 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO0QC UT WOS:000341014600025 PM 24287277 ER PT J AU Yang, TM Bavley, RL Fomalont, K Blomstrom, KJ Mitz, AR Turchi, J Rudebeck, PH Murray, EA AF Yang, Tianming Bavley, Rachel L. Fomalont, Kevin Blomstrom, Kevin J. Mitz, Andrew R. Turchi, Janita Rudebeck, Peter H. Murray, Elisabeth A. TI Contributions of the Hippocampus and Entorhinal Cortex to Rapid Visuomotor Learning in Rhesus Monkeys SO HIPPOCAMPUS LA English DT Article DE associative learning; fornix transection; temporary inactivation; medial temporal lobe ID MEDIAL TEMPORAL-LOBE; IN-PLACE MEMORY; PERIRHINAL CORTEX; VISUAL-DISCRIMINATION; RELATIONAL MEMORY; MACAQUE MONKEYS; LESIONS; FMRI; RECOGNITION; IMPAIRMENTS AB The hippocampus and adjacent structures in the medial temporal lobe are essential for establishing new associative memories. Despite this knowledge, it is not known whether the hippocampus proper is essential for establishing such memories, nor is it known whether adjacent regions like the entorhinal cortex might contribute. To test the contributions of these regions to the formation of new associative memories, we trained rhesus monkeys to rapidly acquire arbitrary visuomotor associations, i.e., associations between visual stimuli and spatially directed actions. We then assessed the effects of reversible inactivations of either the hippocampus (Experiment 1) or entorhinal cortex (Experiment 2) on the within-session rate of learning. For comparison, we also evaluated the effects of the inactivations on performance of problems of the same type that had been well learned prior to any inactivations. We found that inactivation of the entorhinal cortex but not hippocampus produced impairments in acquiring novel arbitrary associations. The impairment did not extend to the familiar, previously established associations. These data indicate that the entorhinal cortex is causally involved in establishing new associations, as opposed to retrieving previously learned associations. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Yang, Tianming; Bavley, Rachel L.; Fomalont, Kevin; Blomstrom, Kevin J.; Mitz, Andrew R.; Turchi, Janita; Rudebeck, Peter H.; Murray, Elisabeth A.] NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Murray, EA (reprint author), NIMH, Neuropsychol Lab, Bldg 49,Suite 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM murraye@mail.nih.gov RI Yang, Tianming/D-3582-2014; OI Yang, Tianming/0000-0001-6976-9246; Rudebeck, Peter/0000-0002-1411-7555; Murray, Elisabeth/0000-0003-1450-1642 FU Intramural Research Program of the National Institute of Mental Health FX Grant sponsor: Intramural Research Program of the National Institute of Mental Health. NR 51 TC 2 Z9 2 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD SEP PY 2014 VL 24 IS 9 BP 1102 EP 1111 DI 10.1002/hipo.22294 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AO3OW UT WOS:000341243000006 PM 24753214 ER PT J AU Monte, AA Brocker, C Nebert, DW Gonzalez, FJ Thompson, DC Vasiliou, V AF Monte, Andrew A. Brocker, Chad Nebert, Daniel W. Gonzalez, Frank J. Thompson, David C. Vasiliou, Vasilis TI Improved drug therapy: triangulating phenomics with genomics and metabolomics SO HUMAN GENOMICS LA English DT Review DE Individualized medicine; Genomics; Metabolomics; Omics; Personalized medicine; Phenomics; Systems biology; Transcriptomics ID COLORECTAL-CANCER PATIENTS; RANDOMIZED-TRIAL; BIOMARKER DISCOVERY; METABOLITE PROFILES; MASS-SPECTROMETRY; GENE-EXPRESSION; UNITED-STATES; ORAL GLUCOSE; WARFARIN; PHARMACOGENETICS AB Embracing the complexity of biological systems has a greater likelihood to improve prediction of clinical drug response. Here we discuss limitations of a singular focus on genomics, epigenomics, proteomics, transcriptomics, metabolomics, or phenomics-highlighting the strengths and weaknesses of each individual technique. In contrast, 'systems biology' is proposed to allow clinicians and scientists to extract benefits from each technique, while limiting associated weaknesses by supplementing with other techniques when appropriate. Perfect predictive modeling is not possible, whereas modeling of intertwined phenomic responses using genomic stratification with metabolomic modifications may greatly improve predictive values for drug therapy. We thus propose a novel-integrated approach to personalized medicine that begins with phenomic data, is stratified by genomics, and ultimately refined by metabolomic pathway data. Whereas perfect prediction of efficacy and safety of drug therapy is not possible, improvements can be achieved by embracing the complexity of the biological system. Starting with phenomics, the combination of linking metabolomics to identify common biologic pathways and then stratifying by genomic architecture, might increase predictive values. This systems biology approach has the potential, in specific subsets of patients, to avoid drug therapy that will be either ineffective or unsafe. C1 [Monte, Andrew A.] Univ Colorado, Dept Emergency Med, Aurora, CO 80045 USA. [Monte, Andrew A.; Thompson, David C.; Vasiliou, Vasilis] Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO 80045 USA. [Monte, Andrew A.] Rocky Mt Poison & Drug Ctr, Denver, CO 80204 USA. [Brocker, Chad; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Nebert, Daniel W.] Univ Cincinnati, Med Ctr, Dept Pediat & Mol Dev Biol, Div Human Genet, Cincinnati, OH 45220 USA. [Nebert, Daniel W.] Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45220 USA. [Nebert, Daniel W.] Univ Cincinnati, Med Ctr, Ctr Environm Genet, Cincinnati, OH 45220 USA. RP Monte, AA (reprint author), Univ Colorado, Dept Emergency Med, Leprino Bldg,7th Floor Campus Box B-215, Aurora, CO 80045 USA. EM andrew.monte@ucdenver.edu FU National Institutes of Health [K23 GM110516, P30 ES06096, R24 AA022057, R01 EY14390]; Emergency Medicine Foundation Research Training Grant FX This work was supported in part by the National Institutes of Health Grants K23 GM110516 (A.A.M), P30 ES06096 (D.W.N.), R24 AA022057 and R01 EY14390 (V.V). Dr. Monte is supported by the Emergency Medicine Foundation Research Training Grant. NR 80 TC 6 Z9 6 U1 6 U2 39 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD SEP 1 PY 2014 VL 8 AR 16 DI 10.1186/s40246-014-0016-9 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AN9YE UT WOS:000340964600001 PM 25181945 ER PT J AU Venkatesh, BA Volpe, GJ Donekal, S Mewton, N Liu, CY Shea, S Liu, K Burke, G Wu, CL Bluemke, DA Lima, JAC AF Venkatesh, Bharath Ambale Volpe, Gustavo J. Donekal, Sirisha Mewton, Nathan Liu, Chia-Ying Shea, Steven Liu, Kiang Burke, Gregory Wu, Colin Bluemke, David A. Lima, Joao A. C. TI Association of Longitudinal Changes in Left Ventricular Structure and Function With Myocardial Fibrosis The Multi-Ethnic Study of Atherosclerosis Study SO HYPERTENSION LA English DT Article DE fibrosis; hypertension; hypertrophy; magnetic resonance imaging; ventricular function, left; ventricular remodeling ID CARDIAC MAGNETIC-RESONANCE; MICROVASCULAR OBSTRUCTION; HEART-FAILURE; AGE; CARDIOMYOPATHY; GENDER; ENHANCEMENT; HYPERTROPHY; PRECESSION; INFARCTION AB The association of longitudinal changes in left ventricular (LV) structure and function with myocardial fibrosis is unclear. We relate temporal changes in body size-indexed LV mass (LVMi) and end-diastolic volume indexed to body surface area, LV mass-to-volume ratio, and LV ejection fraction (LVEF) from cine cardiac magnetic resonance for 10 years, with replacement scar assessed from late gadolinium enhancement, and lower postcontrast T1 times reflecting greater diffuse myocardial fibrosis measured at the end of the follow-up period. All participants (n=1813) who underwent cardiac magnetic resonance twice as part of the Multi-Ethnic Study of Atherosclerosis 10 years apart were included. Multivariable logistic and linear regression models adjusted for cardiovascular risk factors measured the association of 10-year changes in LV structure and function, with fibrosis measured at follow-up. The presence of LV scar at year 10 was cross-sectionally associated with higher LVMi (approximate to 10 g/m(2)), higher mass-to-volume ratio (0.1-0.2 g/mL), but lower LVEF (approximate to 4%) and longitudinally with 3% decrease in LVEF and 0.7% greater end-diastolic volume indexed to body surface area in men for 10 years. Lower postcontrast T1 times at year 10 were associated cross-sectionally with lower LVMi (r=0.33), end-diastolic volume indexed to body surface area (r=0.25), and LVEF (in men only: r=0.14) and longitudinally with a decrease in LVMi (r=0.20) and reduction in LVEF (in men only: r=0.15). Sustained hypertension for 10 years was associated with increased LVMi and higher diffuse and replacement fibrosis at follow-up. During a 10-year period, increased concentric hypertrophy in women and LV dilatation in men were associated with replacement fibrosis, whereas decreasing LVMi was associated with diffuse fibrosis. Hypertension-induced remodeling was related to enhanced replacement and diffuse fibrosis, as well as hypertrophy. C1 [Venkatesh, Bharath Ambale] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Volpe, Gustavo J.; Donekal, Sirisha; Mewton, Nathan; Lima, Joao A. C.] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Shea, Steven] Columbia Univ, Dept Med, New York, NY USA. [Liu, Kiang] Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. [Burke, Gregory] Wake Forest Univ Hlth Sci, Dept Publ Hlth Sci, Winston Salem, NC USA. [Liu, Chia-Ying; Bluemke, David A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Wu, Colin] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ Hosp, 600 N Wolfe St,Blalock 524D1, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95168] FX This research was supported by contracts N01-HC-95159 through N01-HC-95168 from the National Heart, Lung, and Blood Institute. NR 26 TC 14 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD SEP PY 2014 VL 64 IS 3 BP 508 EP + DI 10.1161/HYPERTENSIONAHA.114.03697 PG 29 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AN9MB UT WOS:000340929900014 ER PT J AU Ye, LB Hua, AY Dai, B Lu, TT Zhang, ZL Ye, ML Weintraub, M Li, QDQT AF Ye, Libin Hua, Aiyuan Dai, Bo Lu, Tingting Zhang, Zhaolin Ye, Meilin Weintraub, Michael Li, Qingdi Quentin TI Perfusion of a Cerebral Protective Solution Enhances Neuroprotection in a Rabbit Model of Occlusion-Reperfusion: Prolonged Cerebral Dormancy Time SO IN VIVO LA English DT Article DE Cerebral dormancy; waking up; cerebral protective solution; rabbit animal model ID BRAIN-DEATH; ISCHEMIA; DIAGNOSIS AB In the present study, we investigated the effect of a cerebral protective solution on prolongation of cerebral dormancy time in a rabbit model of occlusion-reperfusion. In a control group, rabbits were anesthetized and the four cerebral arteries (the left and right common carotid arteries and vertebral arteries) were occluded for 7.5 min followed by reperfusion. All six rabbits in the control group died. In contrast, a second group underwent perfusion of a cerebral protective solution for 15 min between artery occlusion and reperfusion. All six rabbits in this group survived. However, when the perfusion solution was changed to 5% glucose solution or rabbit plasma in two other groups, the rabbits in both the latter two groups also died. Neuroprotection was also observed when the protective solution was administered for 30-60 min after the onset of artery occlusion and before the return of blood flow (reperfusion). To understand the high rate of thrombotic stroke in the clinic, we assessed the influence of different organ tissue infusions on blood coagulation in vitro and found that blood clotting occurred faster in the presence of brain tissue infusion compared to liver, kidney, and heart tissue infusions. These results indicate a higher rate of thrombosis in brain tissue compared to any of the other tissues tested. The current study shows that perfusion of a cerebral protective solution produced a significant neuroprotective benefit in our rabbit model of occlusion-reperfusion, suggesting that administration of a cerebral protective solution may be an effective approach for the treatment of ischemic stroke. C1 [Ye, Libin; Hua, Aiyuan; Lu, Tingting; Zhang, Zhaolin; Ye, Meilin] Guangxi Univ Chinese Med, Rui Kang Hosp, Dept Med, Nanning, Peoples R China. [Dai, Bo] Guangxi Univ Chinese Med, Affiliated Hosp 1, Nanning, Peoples R China. [Weintraub, Michael; Li, Qingdi Quentin] NCI, NIH, Bethesda, MD 20892 USA. RP Li, QDQT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM gxyelibin@sina.com; liquenti@mail.nih.gov FU Guangxi University of Chinese Medicine [P2010092] FX This study was supported by a grant from the Guangxi University of Chinese Medicine (No. P2010092). NR 18 TC 0 Z9 1 U1 5 U2 9 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0258-851X EI 1791-7549 J9 IN VIVO JI In Vivo PD SEP-OCT PY 2014 VL 28 IS 5 BP 727 EP 732 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AO4BT UT WOS:000341281900007 PM 25189883 ER PT J AU Marschall, J Mermel, LA Fakih, M Hadaway, L Kallen, A O'Grady, NP Pettis, AM Rupp, ME Sandora, T Maragakis, LL Yokoe, DS AF Marschall, Jonas Mermel, Leonard A. Fakih, Mohamad Hadaway, Lynn Kallen, Alexander O'Grady, Naomi P. Pettis, Ann Marie Rupp, Mark E. Sandora, Thomas Maragakis, Lisa L. Yokoe, Deborah S. TI Strategies to Prevent Central Line-Associated Bloodstream Infections in Acute Care Hospitals: 2014 Update SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID CENTRAL VENOUS CATHETERS; RANDOMIZED-CONTROLLED-TRIAL; CRITICALLY-ILL PATIENTS; NEONATAL INTENSIVE-CARE; OF-THE-LITERATURE; STERILE BARRIER PRECAUTIONS; DOUBLE-BLIND TRIAL; NEEDLELESS INTRAVASCULAR CONNECTOR; ANTIMICROBIAL-COATED CATHETERS; PULMONARY-ARTERY CATHETERS C1 [Marschall, Jonas] Washington Univ, Sch Med, St Louis, MO USA. [Marschall, Jonas] Univ Hosp Bern, CH-3010 Bern, Switzerland. [Marschall, Jonas] Univ Bern, Bern, Switzerland. [Mermel, Leonard A.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Mermel, Leonard A.] Rhode Isl Hosp, Providence, RI 02903 USA. [Fakih, Mohamad] St John Hosp & Med Ctr, Detroit, MI USA. [Fakih, Mohamad] Wayne State Univ, Sch Med, Detroit, MI USA. [Hadaway, Lynn] Lynn Hadaway Associates Inc, Milner, GA USA. [Kallen, Alexander] Ctr Dis Control & Prevent, Atlanta, GA USA. [O'Grady, Naomi P.] NIH, Bethesda, MD 20892 USA. [Pettis, Ann Marie] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Rupp, Mark E.] Univ Nebraska Med Ctr, Omaha, NE USA. [Sandora, Thomas] Boston Childrens Hosp, Boston, MA USA. [Sandora, Thomas] Harvard Univ, Sch Med, Boston, MA USA. RP Mermel, LA (reprint author), Rhode Isl Hosp, Div Infect Dis, 593 Eddy St, Providence, RI 02903 USA. EM lmermel@lifespan.org FU Bard FX J.M. reports receiving a speaker honorarium from Gilead Sciences Switzerland. L.A.M. reports serving as an advisor/consultant for ICU Medical, Fresenius Medical Care, Bard Access Systems, Marvao Medical Devices, CareFusion, 3M Healthcare, Catheter Connections, Semprus Biosciences, and Sharklet Technologies. L.H. reports serving as an advisor/consultant for B Braun Medical, BD Medical, Excelsior Medical, Ivera Medical, Access Scientific, 3M, and Baxter Healthcare. A.M.P. reports receiving speaking fees from Bard and serving as a speaker and author for Covidien. M.E.R reports serving as an advisor/consultant for 3M, Ariste, Semprus, and Sharklet Technologies and receiving honoraria from Baxter and CareFusion. All other authors report no relevant conflicts of interest. NR 250 TC 0 Z9 0 U1 6 U2 13 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD SEP PY 2014 VL 35 SU 2 BP 753 EP 771 DI 10.1086/676533 PG 19 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AO0QB UT WOS:000341014500010 ER PT J AU Wu, RQ Zhang, DF Tu, E Chen, QM Chen, WJ AF Wu, Rui-Qing Zhang, Dun-Fang Tu, Eric Chen, Qian-Ming Chen, WanJun TI The mucosal immune system in the oral cavity-an orchestra of T cell diversity SO INTERNATIONAL JOURNAL OF ORAL SCIENCE LA English DT Review DE mucosal immune system; oral-pharyngeal mucosa; T cell ID INTESTINAL INTRAEPITHELIAL LYMPHOCYTES; GROWTH-FACTOR-BETA; INFLAMMATORY-BOWEL-DISEASE; ETHNIC CHINESE POPULATION; TGF-BETA; LICHEN-PLANUS; GAMMA-DELTA; DENDRITIC CELLS; HOST-DEFENSE; SUBLINGUAL IMMUNOTHERAPY AB The mucosal immune system defends against a vast array of pathogens, yet it exhibits limited responses to commensal microorganisms under healthy conditions. The oral-pharyngeal cavity, the gateway for both the gastrointestinal and respiratory tracts, is composed of complex anatomical structures and is constantly challenged by antigens from air and food. The mucosal immune system of the oral-pharyngeal cavity must prevent pathogen entry while maintaining immune homeostasis, which is achieved via a range of mechanisms that are similar or different to those utilized by the gastrointestinal immune system. In this review, we summarize the features of the mucosal immune system, focusing on T cell subsets and their functions. We also discuss our current understanding of the oral-pharyngeal mucosal immune system. C1 [Wu, Rui-Qing; Zhang, Dun-Fang; Tu, Eric; Chen, WanJun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, NIH, Bethesda, MD 20892 USA. [Wu, Rui-Qing; Zhang, Dun-Fang; Chen, Qian-Ming] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610064, Peoples R China. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, NIH, Bethesda, MD 20892 USA. EM qmchen@scu.edu.cn; wchen@mail.nih.gov FU National Institutes of Health, National Institute of Dental and Craniofacial Research, USA; International S&T Cooperation Program of China [2012DFA31370]; National Nature Science Foundation of China [81321002] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research, USA. This work was also supported by grant 2012DFA31370 from the International S&T Cooperation Program of China and the National Nature Science Foundation of China (81321002). The authors would like to express their apology for omitting many important primary articles due to the space limitations. We also thank Dr Cheryl Chia for critical reading and suggestions for the manuscript. NR 98 TC 8 Z9 8 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1674-2818 EI 2049-3169 J9 INT J ORAL SCI JI Int. J. Oral Sci. PD SEP PY 2014 VL 6 IS 3 BP 125 EP 132 DI 10.1038/ijos.2014.48 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AO3ZI UT WOS:000341275600001 PM 25105816 ER PT J AU Aumeboonsuke, V Dryver, AL AF Aumeboonsuke, Vesarach Dryver, Arthur L. TI The importance of using a test of weak-form market efficiency that does not require investigating the data first SO INTERNATIONAL REVIEW OF ECONOMICS & FINANCE LA English DT Article DE Autocorrelation test; Data snooping; Market efficiency; Runs test; Variance ratio test ID STOCK MARKETS; TIME-SERIES; HYPOTHESIS; PRICES; MODELS AB Are financial markets efficient? There are multiple tests for answering this question. Forming a hypothesis and testing should be done before looking at the data, i.e. without data snooping. However, the parameters used in the tests of the efficient market hypothesis are often not decided independent of the data. This paper investigates the consequences of not only this form of data snooping but also the issue of looking at multiple tests. The specific tests compared in this paper are the runs test, the autocorrelation test, and the variance ratio test. (C) 2014 Elsevier Inc. All rights reserved. C1 [Aumeboonsuke, Vesarach] Int Coll Natl Inst Dev Adm ICO NIDA, Bangkok 10240, Thailand. [Dryver, Arthur L.] NIDA, Grad Sch Business Adm, Bangkok 10240, Thailand. RP Aumeboonsuke, V (reprint author), Int Coll Natl Inst Dev Adm ICO NIDA, 118 Moo 3,Serithai Rd, Bangkok 10240, Thailand. EM vesarach@gmail.com; dryver@gmail.com OI aumeboonsuke, vesarach/0000-0002-1088-3017 NR 35 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1059-0560 EI 1873-8036 J9 INT REV ECON FINANC JI Int. Rev. Econ. Financ. PD SEP PY 2014 VL 33 BP 350 EP 357 DI 10.1016/j.iref.2014.02.009 PG 8 WC Business, Finance; Economics SC Business & Economics GA AN8OE UT WOS:000340862700027 ER PT J AU Brubaker, L Nager, CW Richter, HE Visco, A Nygaard, I Barber, MD Schaffer, J Meikle, S Wallace, D Shibata, N Wolfe, AJ AF Brubaker, Linda Nager, Charles W. Richter, Holly E. Visco, Anthony Nygaard, Ingrid Barber, Matthew D. Schaffer, Joseph Meikle, Susan Wallace, Dennis Shibata, Noriko Wolfe, Alan J. TI Urinary bacteria in adult women with urgency urinary incontinence SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Article DE Microbiome; Urinary bacteria; Urinary urgency incontinence; Urinary tract infection ID STRESS-INCONTINENCE; 16S RDNA; GENOME; BLADDER AB This study's aims were to detect and quantify bacterial DNA in the urine of randomized trial participants about to undergo treatment for urinary urgency incontinence (UUI) without clinical evidence of urinary tract infection (UTI) and to determine if the presence of bacterial DNA in baseline urine relates to either baseline urinary symptoms or UTI risk after urinary tract instrumentation. Women without clinical evidence of baseline UTI were randomized to cystoscopic onabotulinum toxin A injection and oral placebo medication versus cystoscopic placebo injection and active oral medication. Bacterial DNA in participants' catheterized urine was measured by quantitative polymerase chain reaction (qPCR). Bacterial DNA was detected in the urine of 38.7 % of participants (60 out of 155). In these 60 qPCR-positive participants, baseline daily UUI episodes were greater than in the 95 qPCR-negative participants (5.71 [+/- 2.60] vs 4.72 [+/- 2.86], p = 0.004). Neither symptom severity by questionnaire nor treatment outcome was associated with qPCR status or with qPCR level in qPCR-positive subjects. In contrast, the presence of urinary bacterial DNA was associated with UTI risk: only 10 % of the qPCR-positive women developed a UTI post-treatment, while 24 % of the qPCR-negative women did so. The median qPCR level for qPCR-positive samples did not differ significantly by UTI status (UTI 2.58 x 10(5) vs no UTI 1.35 x 10(5) copies/mL, p = 0.6). These results may indicate a urinary bacterial contribution to both baseline UUI and the risk of post-treatment UTI. C1 [Brubaker, Linda] Loyola Univ Chicago, Stritch Sch Med, Dept Obstet & Gynecol, Maywood, IL 60153 USA. [Brubaker, Linda] Loyola Univ Chicago, Stritch Sch Med, Dept Urol, Maywood, IL 60153 USA. [Nager, Charles W.] UC San Diego Hlth Syst, Dept Reprod Med, San Diego, CA USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Visco, Anthony] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Nygaard, Ingrid] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Barber, Matthew D.] Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, Cleveland, OH 44106 USA. [Schaffer, Joseph] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Meikle, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Hlth & Dis Branch, NIH, Bethesda, MD USA. [Wallace, Dennis] Res Triangle Inst, Div Hlth Sci, Res Triangle Pk, NC 27709 USA. [Shibata, Noriko; Wolfe, Alan J.] Loyola Univ Chicago, Stritch Sch Med, Dept Microbiol & Immunol, Maywood, IL 60153 USA. RP Brubaker, L (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Obstet & Gynecol, 2160 S First Ave,Blvd 120,Room 420, Maywood, IL 60153 USA. EM Lbrubaker@lumc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH Office of Research on Women's Health [2U01 HD41249, 2U10 HD41250, 2U10 HD41261, 2U10 HD41267, 1U10 HD54136, 1U10 HD54214, 1U10 HD54215, 1U10 HD54241] FX Supported by grants from The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the NIH Office of Research on Women's Health (2U01 HD41249, 2U10 HD41250, 2U10 HD41261, 2U10 HD41267, 1U10 HD54136, 1U10 HD54214, 1U10 HD54215, 1U10 HD54241) NR 20 TC 16 Z9 16 U1 1 U2 8 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD SEP PY 2014 VL 25 IS 9 BP 1179 EP 1184 DI 10.1007/s00192-013-2325-2 PG 6 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA AN8QK UT WOS:000340868600006 PM 24515544 ER PT J AU Walsh, A O'Rourke, C Tuzova, A Hayes, B Hansen, J Emmert-Buck, M Finn, S Lynch, T Perry, A AF Walsh, A. O'Rourke, C. Tuzova, A. Hayes, B. Hansen, J. Emmert-Buck, M. Finn, S. Lynch, T. Perry, A. TI MiRNA Expression Profiling Across Progressive Grades of Prostate Cancer SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [Walsh, A.; Lynch, T.] St James Hosp, Dept Urol, Dublin 8, Ireland. [O'Rourke, C.; Tuzova, A.; Perry, A.] St James Hosp, Trinity Coll Dublin, Dept Prostate Mol Oncol, Dublin 8, Ireland. [Hayes, B.; Finn, S.] St James Hosp, Dept Pathol, Dublin 8, Ireland. [Hansen, J.; Emmert-Buck, M.] NCI, Dept Pathol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 EI 1863-4362 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD SEP PY 2014 VL 183 SU 5 MA 51 BP S239 EP S239 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AO1PX UT WOS:000341086600052 ER PT J AU Garner, SA Anude, CJ Adams, E Dawson, L AF Garner, Samual A. Anude, Chuka J. Adams, Elizabeth Dawson, Liza TI Ethical Considerations in HIV Prevention and Vaccine Research in Resource-Limited Settings SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV vaccine trials; ethics of vaccine trials; ethics of HIV prevention; trials in resource-limited settings AB HIV prevention research has been facing increasing ethical and operational challenges. Factors influencing the design and conduct of HIV prevention trials include a rapidly changing evidence base, new biomedical prevention methods and modalities being tested, a large diversity of countries, sites and populations affected by HIV and participating in trials, and challenges of developing and making available products that will be feasible and affordable for at-risk populations. To discuss these challenges, a meeting, Ethical considerations around novel combination prevention modalities in HIV prevention and vaccine trials in resource-limited settings, was convened by NIH/NIAID/Division of AIDS on April 22-23, 2013. Several themes emerged from the meeting: (1) because of both trial design and ethical complexities, choosing prevention packages and designing combination prevention research trials will need to be evaluated on a case by case basis in different clinical trials, countries, and health systems; (2) multi-level stakeholder engagement from the beginning is vital to a fair and transparent process and also to designing ethical and relevant trials; (3) research should generally be responsive to a host country's needs, and sponsors and stakeholders should work together to address potential barriers to future access; and finally, (4) another meeting including a broader group of stakeholders is needed to address many of the outstanding ethical issues raised by this meeting. We offer an overview of the meeting and the key discussion points and recommendations to help guide the design and conduct of future HIV prevention and vaccine research in resource-limited settings. C1 [Garner, Samual A.; Anude, Chuka J.] HJF DAIDS, Bethesda, MD USA. [Adams, Elizabeth; Dawson, Liza] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Garner, SA (reprint author), 5601 Fishers Lane,Room 9G47, Bethesda, MD 20892 USA. EM sam.garner@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract No. HHSN272200800014C. NR 1 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2014 VL 67 IS 1 BP 77 EP 83 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AN6SP UT WOS:000340727600012 PM 25117930 ER PT J AU Adebamowo, CA Casper, C Bhatia, K Mbulaiteye, SM Sasco, AJ Phipps, W Vermund, SH Krown, SE AF Adebamowo, Clement A. Casper, Corey Bhatia, Kishor Mbulaiteye, Sam M. Sasco, Annie J. Phipps, Warren Vermund, Sten H. Krown, Susan E. TI Challenges in the Detection, Prevention, and Treatment of HIV-Associated Malignancies in Low- and Middle-Income Countries in Africa SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV/AIDS; low- and middle-income countries; developing countries; Africa; cancer screening; cancer therapy; infrastructure; health workforce; cancer prevention; cancer diagnosis; training; research ID SUB-SAHARAN AFRICA; SURFACE SQUAMOUS NEOPLASIA; SOUTH-AFRICA; CANCER CONTROL; ANTIRETROVIRAL THERAPY; INDIGENOUS AFRICANS; ACADEMIC MEDICINE; BURKITT-LYMPHOMA; HEALTH-SCIENCES; KAPOSIS-SARCOMA AB Cancers associated with immunosuppression and infections have long been recognized as a major complication of HIV/AIDS. More recently, persons living with HIV are increasingly diagnosed with a wider spectrum of HIV-associated malignancies (HIVAM) as they live longer on combination antiretroviral therapy. This has spurred research to characterize the epidemiology and determine the optimal management of HIVAM with a focus on low- and middle-income countries (LMICs). Given background coinfections, environmental exposures, host genetic profiles, antiretroviral therapy usage, and varying capacities for early diagnosis and treatment, one can expect the biology of cancers in HIV-infected persons in LMICs to have a significant impact on chronic HIV care, as is now the case in high-income countries. Thus, new strategies must be developed to effectively prevent, diagnose, and treat HIVAM in LMICs; provide physical/clinical infrastructures; train the cancer and HIV workforce; and expand research capacity-particularly given the challenges posed by the limitations on available transportation and financial resources and the population's general rural concentration. Opportunities exist to extend resources supported by the President's Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis, and Malaria to improve the health-care infrastructure and train the personnel required to prevent and manage cancers in persons living with HIV. These HIV chronic care infrastructures could also serve cancer patients regardless of their HIV status, facilitating long-term care and treatment for persons who do not live near cancer centers, so that they receive the same degree of care as those receiving chronic HIV care today. C1 [Adebamowo, Clement A.] Inst Human Virol Nigeria, Off Res & Training, Abuja, Nigeria. [Adebamowo, Clement A.] Univ Maryland, Inst Human Virol, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Adebamowo, Clement A.] Univ Maryland, Greenebaum Canc Ctr, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Casper, Corey; Phipps, Warren] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Bhatia, Kishor] NCI, AIDS Malignancy Program, Off HIV & AIDS Malignancy, NIH, Bethesda, MD 20892 USA. [Mbulaiteye, Sam M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Sasco, Annie J.] Univ Bordeaux, Ctr INSERM 897, Bordeaux, France. [Sasco, Annie J.] Univ Bordeaux, Ctr INSERM 897, Inst Sant Publ, Bordeaux, France. [Vermund, Sten H.] Vanderbilt Univ, Sch Med, Inst Global Hlth, Nashville, TN 37212 USA. [Vermund, Sten H.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Krown, Susan E.] AIDS Malignancy Consortium, New York, NY USA. [Krown, Susan E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Adebamowo, CA (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 725 West,Lombard St,Suite 460, Baltimore, MD 21201 USA. EM cadebamowo@som.umaryland.edu FU National Institutes of Health [D43 CA153792, 1U54HG006947, D43 CA153720, R24 TW007988, U01 CA121947] FX Supported in part by the National Institutes of Health grants: D43 CA153792 (IHV-UM Capacity Development for Research into AIDS-Associated Malignancies) and 1U54HG006947 (African Collaborative Center for Microbiome and Genomics Research) (C. A. A.); D43 CA153720 (C. C. and W. P.), R24 TW007988 [Fogarty International Clinical Research Scholars Support Center at Vanderbilt (S. H. V.)], and U01 CA121947 [AIDS Malignancy Consortium (S. E. K. and C.C.)]. NR 93 TC 10 Z9 10 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2014 VL 67 SU 1 BP S17 EP S26 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AO1PT UT WOS:000341086200004 PM 25117957 ER PT J AU Bloomfield, GS Khazanie, P Morris, A Rabadan-Diehl, C Benjamin, LA Murdoch, D Radcliff, VS Velazquez, EJ Hicks, C AF Bloomfield, Gerald S. Khazanie, Prateeti Morris, Alison Rabadan-Diehl, Cristina Benjamin, Laura A. Murdoch, David Radcliff, Virginia S. Velazquez, Eric J. Hicks, Charles TI HIV and Noncommunicable Cardiovascular and Pulmonary Diseases in Low- and Middle-Income Countries in the ART Era: What We Know and Best Directions for Future Research SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; cardiovascular disease; pulmonary disease; global health; developing countries; sub-Saharan Africa ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; ACUTE MYOCARDIAL-INFARCTION; ACUTE CORONARY SYNDROMES; OBSTRUCTIVE LUNG-DISEASE; BLACK SOUTH-AFRICANS; ARTERIAL-HYPERTENSION; INFECTED PATIENTS; HEART-DISEASE; RISK-FACTORS AB With the advent of effective antiretroviral therapy (ART), HIV is becoming a chronic disease. HIV-seropositive (+) patients on ART can expect to live longer and, as a result, they are at risk of developing chronic noncommunicable diseases related to factors, such as aging, lifestyle, long-term HIV infection, and the potential adverse effects of ART. Although data are incomplete, evidence suggests that even in low-and middle-income countries (LMICs), chronic cardiovascular and pulmonary diseases are increasing in HIV-positive patients. This review summarizes evidence-linking HIV infection to the most commonly cited chronic cardiovascular and pulmonary conditions in LMICs: heart failure, hypertension, coronary artery disease/myocardial infarction, stroke, obstructive lung diseases, and pulmonary arterial hypertension. We describe the observed epidemiology of these conditions, factors affecting expression in LMICs, and key populations that may be at higher risk (ie, illicit drug users and children), and finally, we suggest that strategic areas of research and training intended to counter these conditions effectively. As access to ART in LMICs increases, long-term outcomes among HIV-positive persons will increasingly be determined by a range of associated chronic cardiovascular and pulmonary complications. Actions taken now to identify those conditions that contribute to long-term morbidity and mortality optimize early recognition and diagnosis and implement effective prevention strategies and/or disease interventions are likely to have the greatest impact on limiting cardiovascular and pulmonary disease comorbidity and improving population health among HIV-positive patients in LMICs. C1 [Bloomfield, Gerald S.; Khazanie, Prateeti; Velazquez, Eric J.] Duke Univ, Div Cardiol, Dept Med, Durham, NC USA. [Bloomfield, Gerald S.; Khazanie, Prateeti] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Bloomfield, Gerald S.; Velazquez, Eric J.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Morris, Alison] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Morris, Alison] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA 15213 USA. [Rabadan-Diehl, Cristina] NHLBI, NIH, Bethesda, MD 20892 USA. [Benjamin, Laura A.] Univ Liverpool, Inst Infect & Global Hlth, Liverpool L69 3BX, Merseyside, England. [Benjamin, Laura A.] Univ Malawi, Coll Med, Malawi Liverpool Wellcome Major Overseas Clin Res, Blantyre, Malawi. [Murdoch, David; Radcliff, Virginia S.] Duke Univ, Div Pulm, Durham, NC USA. [Murdoch, David; Radcliff, Virginia S.] Duke Univ, Div Crit Care Med, Durham, NC USA. [Hicks, Charles] Duke Univ, Dept Med, Durham, NC USA. RP Bloomfield, GS (reprint author), 2400 Pratt St,DUMC Box 3850, Durham, NC 27705 USA. EM gerald.bloomfield@duke.edu FU Figure Office of AIDS Research, NIH; Fogarty International Center of the National Institutes of Health [K01TW008407]; National Heart, Lung and Blood Institute of the National Institutes of Health [R01HL090339, P01HL103455]; Wellcome Trust Foundation [089672/Z/09/A] FX Supported by Figure Office of AIDS Research, NIH.; G.S.B. is supported by the Fogarty International Center of the National Institutes of Health under Award number K01TW008407. A. M. is supported by the National Heart, Lung and Blood Institute of the National Institutes of Health under Award numbers R01HL090339 and P01HL103455. L. A. B. is supported by the Wellcome Trust Foundation under Grant 089672/Z/09/A. The other authors have no conflicts of interest to disclose. NR 112 TC 26 Z9 27 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2014 VL 67 SU 1 BP S40 EP S53 PG 14 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AO1PT UT WOS:000341086200006 PM 25117960 ER PT J AU Glass, RI AF Glass, Roger I. TI HIV/AIDS and Noncommunicable Disease Comorbidities: Emerging Research Priorities SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Glass, RI (reprint author), NIH, Fogarty Int Ctr, 31 Ctr Dr,Room B2C02, Bethesda, MD 20892 USA. EM roger.glass@nih.gov NR 0 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2014 VL 67 SU 1 BP S1 EP S1 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AO1PT UT WOS:000341086200001 PM 25117956 ER PT J AU Narayan, KMV Miotti, PG Anand, NP Kline, LM Harmston, C Gulakowski, R Vermund, SH AF Narayan, K. M. Venkat Miotti, Paolo G. Anand, Nalini P. Kline, Lydia Mann Harmston, Christine Gulakowski, Roman, III Vermund, Sten H. TI HIV and Noncommunicable Disease Comorbidities in the Era of Antiretroviral Therapy: A Vital Agenda for Research in Low- and Middle-Income Country Settings SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material DE noncommunicable diseases; HIV; AIDS; developing country; low- and middle-income countries; sub-Saharan Africa; antiretroviral therapy; disease complications; comorbidities ID RESOURCE-LIMITED SETTINGS; SUB-SAHARAN AFRICA; FUND-SUPPORTED PROGRAMS; PRIMARY-HEALTH-CARE; SOUTH-AFRICA; INFECTIOUS-DISEASES; HIV/AIDS PREVENTION; SURVIVAL BENEFITS; SERVICE DELIVERY; POOR SETTINGS AB In this special 2014 issue of JAIDS, international investigator teams review a host of noncommunicable diseases (NCDs) that are often reported among people living and aging with HIV in sub-Saharan Africa. With the longer lifespans that antiretroviral therapy programs have made possible, NCDs are occurring due to a mix of chronic immune activation, medication side effects, coinfections, and the aging process itself. Cancer; cardiovascular and pulmonary diseases; metabolic, body, and bone disorders; gastrointestinal, hepatic, and nutritional aspects; mental, neurological, and substance use disorders; and renal and genitourinary diseases are discussed. Cost-effectiveness, key research methods, and issues of special importance in Asia, Latin America, and the Caribbean are also addressed. In this introduction, we present some of the challenges and opportunities for addressing HIV and NCD comorbidities in low- and middle-income countries, and preview the research agenda that emerges from the articles that follow. C1 [Narayan, K. M. Venkat] Emory Univ, Dept Global Hlth, Atlanta, GA 30322 USA. [Narayan, K. M. Venkat] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Miotti, Paolo G.; Gulakowski, Roman, III] Hubert Dept Global Hlth, Off AIDS Res, Bethesda, MD USA. [Anand, Nalini P.; Kline, Lydia Mann; Harmston, Christine] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Vermund, Sten H.] Vanderbilt Univ, Sch Med, Vanderbilt Inst Global Hlth, Dept Pediat, Nashville, TN 37212 USA. RP Miotti, PG (reprint author), NIH, Off AIDS Res, Mail Stop 9310, Bethesda, MD 20892 USA. EM paolo.miotti@nih.gov NR 91 TC 23 Z9 23 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2014 VL 67 SU 1 BP S2 EP S7 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AO1PT UT WOS:000341086200002 PM 25117958 ER PT J AU Bush, CA Yang, JH Yu, BW Cisar, JO AF Bush, C. Allen Yang, Jinghua Yu, Bingwu Cisar, John O. TI Chemical Structures of Streptococcus pneumoniae Capsular Polysaccharide Type 39 (CPS39), CPS47F, and CPS34 Characterized by Nuclear Magnetic Resonance Spectroscopy and Their Relation to CPS10A SO JOURNAL OF BACTERIOLOGY LA English DT Article ID COAGGREGATION RECEPTOR POLYSACCHARIDES; O-ACETYL GROUPS; US TYPE 41; MOLECULAR CHARACTERIZATION; BIOSYNTHETIC LOCI; FULL ASSIGNMENT; SEROTYPE; SUBSTANCE; ORALIS; ELUCIDATION AB Structural characterization of Streptococcus pneumoniae capsular polysaccharides (CPS) is a prerequisite for unraveling both antigenic and genetic relationships that exist between different serotypes. In the current study, comparative structural studies of S. pneumoniae CPS serogroup 10 (CPS10) were extended to include genetically related S. pneumoniae CPS34, CPS39, and CPS47F. High-resolution heteronuclear nuclear magnetic resonance (NMR) spectroscopy confirmed the published structure of CPS34 and, in conjunction with glycosyl composition analyses, revealed the following repeat unit structures of the other serotypes, which have not been previously characterized: [GRAPHICS] Common and unique structural features of these polysaccharides, including different positions of O-acetylation, were unambiguously associated with specific genes in each corresponding cps locus. The only exception involved the gene designated wcrC, which is associated with the alpha 1-2 transfer of Gal pyranoside (Galp) to ribitol-5-phosphate in the synthesis of CPS10A, CPS47F, and CPS34 but with alpha 1-1 transfer of Gal to ribitol-5-phosphate in the synthesis of CPS39. The corresponding gene in the cps39 locus, although related to wcrC, more closely resembled a previously identified gene (i.e., wefM) of Streptococcus oralis that is associated with alpha 1-1 transfer of Galp to ribitol-5-phosphate. These and other recent findings identify linkages from alpha-Galp to ribitol-5-phosphate and from this residue to adjacent Gal furanoside (Galf) as important sites of CPS structural and genetic diversity. C1 [Bush, C. Allen] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21228 USA. [Yang, Jinghua; Cisar, John O.] Natl Inst Dent & Craniofacial Res, Microbial Receptors Sect, NIH, Bethesda, MD USA. [Yu, Bingwu] CBER FDA, Lab Bacterial Polysaccharides, Bethesda, MD USA. RP Bush, CA (reprint author), Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21228 USA. EM bush@umbc.edu FU Intramural Research Program of the NIDCR; NIH [P01-HL-107153] FX This work was supported in part by the Intramural Research Program of the NIDCR, NIH, and by NIH P01-HL-107153. NR 24 TC 2 Z9 2 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2014 VL 196 IS 18 BP 3271 EP 3278 DI 10.1128/JB.01731-14 PG 8 WC Microbiology SC Microbiology GA AO3MG UT WOS:000341233500007 PM 25002537 ER PT J AU Roda, RH Rinaldi, C Singh, R Schindler, AB Blackstone, C AF Roda, Ricardo H. Rinaldi, Carlo Singh, Rajat Schindler, Alice B. Blackstone, Craig TI Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE AOA2; Autosomal recessive cerebellar ataxia; DNA repair; Helicase; Senataxin ID PERIPHERAL NEUROPATHY; SPINOCEREBELLAR ATAXIA; TELANGIECTASIA GENE; CEREBELLAR-ATAXIA; ALPHA-FETOPROTEIN; INDIVIDUAL CELLS; MUTATIONS; SENATAXIN; HELICASE; MANAGEMENT AB Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia associated with mutations in SETX, which encodes the senataxin protein, a DNA/RNA helicase. We describe the clinical phenotype and molecular characterization of a Colombian AOA2 patient who is compound heterozygous for a c.994 C>T (p.R332W) missense mutation in exon 7 and a c.6848_6851deICAGA (p.T2283KfsX32) frameshift deletion in SETX exon 21. Immunocytochemistry of patient-derived fibroblasts revealed a normal cellular distribution of the senataxin protein, suggesting that these mutations do not lead to loss or mis-localization of the protein, but rather that aberrant function of senataxin underlies the disease pathogenesis. Furthermore, we used the alkaline comet assay to demonstrate that patient-derived fibroblast cells exhibit an increased susceptibility to oxidative DNA damage. This assay provides a novel and additional means to establish pathogenicity of SETX mutations. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Roda, Ricardo H.; Singh, Rajat; Blackstone, Craig] NINCDS, Cell Biol Sect, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Rinaldi, Carlo; Schindler, Alice B.] NINCDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Singh, Rajat] Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY USA. RP Roda, RH (reprint author), NINCDS, Cell Biol Sect, Neurogenet Branch, NIH, Bldg 35,Room 2C-911,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ricardo.roda@nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. NR 29 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD SEP PY 2014 VL 21 IS 9 BP 1627 EP 1631 DI 10.1016/j.jocn.2013.11.048 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN7XZ UT WOS:000340815600032 PM 24814856 ER PT J AU Ochiai, S Roediger, B Abtin, A Shklovskaya, E de St Groth, BF Yamane, H Weninger, W Le Gros, G Ronchese, F AF Ochiai, Sotaro Roediger, Ben Abtin, Arby Shklovskaya, Elena de St. Groth, Barbara Fazekas Yamane, Hidehiro Weninger, Wolfgang Le Gros, Graham Ronchese, Franca TI CD326(lo)CD103(lo)CD11b(lo) Dermal Dendritic Cells Are Activated by Thymic Stromal Lymphopoietin during Contact Sensitization in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EPIDERMAL LANGERHANS CELLS; T-CELLS; IN-VIVO; ATOPIC-DERMATITIS; TSLP; RESPONSES; SKIN; HYPERSENSITIVITY; DIFFERENTIATION; INFLAMMATION AB The cytokine thymic stromal lymphopoietin (TSLP) is produced by epithelia exposed to the contact sensitizer dibutyl phthalate (DBP), and it is critical for the induction of Th2 immune responses by DBP-FITC. TSLP is thought to act on dendritic cells (DC), but the precise DC subsets involved in the response to TSLP remain to be fully characterized. In this study we show that a subset of CD326(lo)CD103(lo)CD11b(lo) dermal DC, which we termed "triple-negative (TN) DC," is highly responsive to TSLP. In DBP-FITC treated mice, TN DC upregulated expression of CD86 and rapidly migrated to the draining lymph node to become the most abundant skin-derived DC subset at 24 and 48 h after sensitization. None of these responses was observed in TSLPR-deficient mice. In contrast, TN DC numbers were not increased after treatment with the allergen house dust mite or the bacteria Escherichia coli and bacillus Calmette Guerin, which increased other DC subsets. In vivo, treatment with rTSLP preferentially increased the numbers of TN DC in lymph nodes. In vitro, TN DC responded to rTSLP treatment with a higher level of STAT5 phosphorylation compared with other skin-derived DC subsets. The TN DC subset shared the morphology, phenotype, and developmental requirements of conventional DC, depending on FLT3 expression for their optimal development from bone marrow precursors, and CCR7 for migration to the draining lymph node. Thus, TN DC represent a dermal DC subset that should be considered in future studies of TSLP-dependent contact sensitization and skin immune responses. C1 [Ochiai, Sotaro; Le Gros, Graham; Ronchese, Franca] Malaghan Inst Med Res, Wellington 6012, New Zealand. [Ochiai, Sotaro] Univ Otago, Wellington 6021, New Zealand. [Roediger, Ben; Abtin, Arby; Shklovskaya, Elena; de St. Groth, Barbara Fazekas; Weninger, Wolfgang] Centenary Inst, Sydney, NSW 2042, Australia. [Yamane, Hidehiro] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Weninger, Wolfgang] Sydney Med Sch, Sydney, NSW 2006, Australia. RP Ronchese, F (reprint author), Malaghan Inst Med Res, POB 7060, Wellington 6242, New Zealand. EM fronchese@malaghan.org.nz RI Le Gros, Graham/C-6725-2011 FU Health Research Council of New Zealand; National Health and Medical Research Council; New South Wales government; University of Otago FX This work was supported by a research grant from the Health Research Council of New Zealand (to F.R.), as well as by National Health and Medical Research Council grants and a grant from the New South Wales government. S.O. was supported by a Ph.D. scholarship from the University of Otago. NR 34 TC 8 Z9 8 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2014 VL 193 IS 5 BP 2504 EP 2511 DI 10.4049/jimmunol.1400536 PG 8 WC Immunology SC Immunology GA AO2HT UT WOS:000341140600050 PM 25057004 ER PT J AU Feng, DC Wang, Y Wang, H Weng, HL Kong, XN Martin-Murphy, BV Li, YM Park, O Dooley, S Ju, C Gao, B AF Feng, Dechun Wang, Yan Wang, Hua Weng, Honglei Kong, Xiaoni Martin-Murphy, Brittany V. Li, Yongmei Park, Ogyi Dooley, Steven Ju, Cynthia Gao, Bin TI Acute and Chronic Effects of IL-22 on Acetaminophen-Induced Liver Injury SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; POLYINOSINIC-POLYCYTIDYLIC ACID; CHRONIC ETHANOL-CONSUMPTION; HEPATITIS-B-VIRUS; INDUCED HEPATOTOXICITY; UNITED-STATES; SIGNAL TRANSDUCER; DOWN-REGULATION; TRANSCRIPTION 3; MICE AB Acetaminophen (APAP)-induced liver injury (AILI) accounts for half of the acute liver failure cases in the United States. A better understanding of the underlying mechanisms of AILI is necessary for the development of novel antidotes. We found that pretreatment with IL-22 protected mice from APAP-mediated hepatotoxicity. The protection was dependent on STAT3, as IL-22 failed to reduce APAP hepatotoxicity in liver-specific STAT3 knockout mice. In contrast to the acute exposure to IL-22, the endogenous chronic overexpression of IL-22 in IL-22 transgenic (TG) mice or IL-22 adenovirus treatment for 6 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (Cyp2E1) and Cyp1A2 were much higher in IL-22TG mice. Ablation of Cyp2E1 but not hepatic STAT3 abolished AILI and protein-adduct formation in IL-22TG mice. Finally, hepatic expression of HNF-1 alpha, a transcriptional factor that is known to control Cyp2E1 expression, was elevated in IL-22TG mice compared with wild-type mice. Upregulation of hepatic Cyp2E1 was only observed in mice with constitutive overexpression of IL-22 but not with short-term treatment with one dose of IL-22 or multiple doses of IL-22 for 2 wk. In conclusion, short-term acute IL-22 exposure protects mice against AILI through STAT3 activation; however, chronic constitutive overexpression of IL-22 exacerbates AILI by increasing Cyp2E1 and toxic reactive APAP metabolite production. These findings may not only enhance our understanding of the effects of chronic inflammation on AILI in patients with liver disease, but are also helpful to identify novel therapeutic targets for the treatment of AILI. C1 [Feng, Dechun; Wang, Yan; Wang, Hua; Li, Yongmei; Park, Ogyi; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Weng, Honglei; Dooley, Steven] Heidelberg Univ, Fac Med Mannheim, Med Clin, D-68167 Mannheim, Germany. [Kong, Xiaoni] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai 200030, Peoples R China. [Kong, Xiaoni] Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai 200030, Peoples R China. [Martin-Murphy, Brittany V.; Ju, Cynthia] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO 80045 USA. RP Gao, B (reprint author), NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov RI Feng, Dechun/Q-5962-2016 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX This work was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 57 TC 11 Z9 12 U1 4 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2014 VL 193 IS 5 BP 2512 EP 2518 DI 10.4049/jimmunol.1400588 PG 7 WC Immunology SC Immunology GA AO2HT UT WOS:000341140600051 PM 25063867 ER PT J AU Malecek, K Grigoryan, A Zhong, S Gu, WJ Johnson, LA Rosenberg, SA Cardozo, T Krogsgaard, M AF Malecek, Karolina Grigoryan, Arsen Zhong, Shi Gu, Wei Jun Johnson, Laura A. Rosenberg, Steven A. Cardozo, Timothy Krogsgaard, Michelle TI Specific Increase in Potency via Structure-Based Design of a TCR SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; TUMOR-INFILTRATING LYMPHOCYTES; PEPTIDE-MHC; CROSS-REACTIVITY; HUMAN-MELANOMA; GENE-THERAPY; CANCER REGRESSION; HIGH-AFFINITY; ADOPTIVE IMMUNOTHERAPY; COMPUTATIONAL DESIGN AB Adoptive immunotherapy with Ag-specific T lymphocytes is a powerful strategy for cancer treatment. However, most tumor Ags are nonreactive self proteins, which presents an immunotherapy design challenge. Recent studies have shown that tumor-specific TCRs can be transduced into normal PBLs, which persist after transfer in similar to 30% of patients and effectively destroy tumor cells in vivo. Although encouraging, the limited clinical responses underscore the need for enrichment of T cells with desirable antitumor capabilities prior to patient transfer. In this study, we used structure-based design to predict point mutations of a TCR (DMF5) that enhance its binding affinity for an agonist tumor Ag-MHC (peptide-MHC [pMHC]), Mart-1 (27L)-HLA-A2, which elicits full T cell activation to trigger immune responses. We analyzed the effects of selected TCR point mutations on T cell activation potency and analyzed cross-reactivity with related Ags. Our results showed that the mutated TCRs had improved T cell activation potency while retaining a high degree of specificity. Such affinity-optimized TCRs have demonstrated to be very specific for Mart-1 (27L), the epitope for which they were structurally designed. Although of somewhat limited clinical relevance, these studies open the possibility for future structural-based studies that could potentially be used in adoptive immunotherapy to treat melanoma while avoiding adverse autoimmunity-derived effects. C1 [Malecek, Karolina; Zhong, Shi; Cardozo, Timothy; Krogsgaard, Michelle] NYU, Sch Med, Perlmutter Canc Ctr, New York, NY 10016 USA. [Malecek, Karolina; Krogsgaard, Michelle] NYU, Sch Med, Program Struct Biol, New York, NY 10016 USA. [Grigoryan, Arsen; Cardozo, Timothy] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. [Gu, Wei Jun] NYU, Sch Med, Dept Chem, New York, NY 10012 USA. [Johnson, Laura A.; Rosenberg, Steven A.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Krogsgaard, Michelle] NYU, Sch Med, Interdisciplinary Melanoma Cooperat Grp, New York, NY 10016 USA. RP Krogsgaard, M (reprint author), NYU, Sch Med, 522 1st Ave,13th Floor,Room 1311, New York, NY 10016 USA. EM Michelle.Krogsgaard@nyumc.org FU National Institutes of Health [1U01CA137070, OD004631]; American Cancer Society Research Scholar [RSG-09-070-01-LIB]; Cancer Research Institute Investigator grant; Pew Scholar in Biomedical Sciences - Pew Trust; National Institute of General Medical Sciences [5R01GM085586-04]; American Heart Association predoctoral fellowship; National Institutes of Health molecular biophysics training grant; Molecular Oncology and Tumor Immunology National Institutes of Health/National Cancer Institute [5T32CA009161-39]; New York University Caregiver Intervention Center support grant; National Institutes of Health/National Cancer Institute [5 P30CA16087-31] FX This work was supported by National Institutes of Health Grant 1U01CA137070 (to M.K.), American Cancer Society Research Scholar Grant RSG-09-070-01-LIB (to M.K.), a Cancer Research Institute Investigator grant (to M.K.), the Pew Scholar in Biomedical Sciences supported by the Pew Trust (to M.K.), National Institute of General Medical Sciences Grant 5R01GM085586-04 (to M.K.), an American Heart Association predoctoral fellowship (to K.M.), a National Institutes of Health molecular biophysics training grant and Molecular Oncology and Tumor Immunology National Institutes of Health/National Cancer Institute Grant 5T32CA009161-39 (to K.M.), and by National Institutes of Health Grant OD004631 (to T.C.). Use of flow cytometry was sponsored by a New York University Caregiver Intervention Center support grant with funding from National Institutes of Health/National Cancer Institute Grant 5 P30CA16087-31. NR 100 TC 7 Z9 7 U1 1 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2014 VL 193 IS 5 BP 2587 EP 2599 DI 10.4049/jimmunol.1302344 PG 13 WC Immunology SC Immunology GA AO2HT UT WOS:000341140600059 PM 25070852 ER PT J AU Kumar, RK Foster, PS Rosenberg, HF AF Kumar, Rakesh K. Foster, Paul S. Rosenberg, Helene F. TI Respiratory viral infection, epithelial cytokines, and innate lymphoid cells in asthma exacerbations SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE Th2; interleukin-33; allergy; animal models ID THYMIC STROMAL LYMPHOPOIETIN; ALLERGIC AIRWAY INFLAMMATION; SYNCYTIAL VIRUS-INFECTION; MICE PVM MODEL; PNEUMONIA VIRUS; IMMUNE-RESPONSES; LUNG INFLAMMATION; ADAPTIVE IMMUNITY; DENDRITIC CELLS; INFLUENZA-VIRUS AB Exacerbations of asthma are most commonly triggered by viral infections, which amplify allergic inflammation. Cytokines released by virus-infected AECs may be important in driving this response. This review focuses on accumulating evidence in support of a role for epithelial cytokines, including IL-33, IL-25, and TSLP, as well as their targets, type 2 innate lymphoid cells (ILC2s), in the pathogenesis of virus-induced asthma exacerbations. Production and release of these cytokines lead to recruitment and activation of ILC2s, which secrete mediators, including IL-5 and IL-13, which augment allergic inflammation. However, little information is currently available about the induction of these responses by the respiratory viruses that are strongly associated with exacerbations of asthma, such as rhinoviruses. Further human studies, as well as improved animal experimental models, are needed to investigate appropriately the pathogenetic mechanisms in virus-induced exacerbations of asthma, including the role of ILCs. C1 [Kumar, Rakesh K.] Univ New S Wales, Dept Pathol, Sydney, NSW, Australia. [Foster, Paul S.] Univ Newcastle, Ctr Asthma & Resp Dis, Callaghan, NSW 2308, Australia. [Foster, Paul S.] Hunter Med Res Inst, Callaghan, NSW, Australia. [Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Kumar, RK (reprint author), UNSW Australia, Sch Med Sci, Dept Pathol, Sydney, NSW 2052, Australia. EM r.kumar@unsw.edu.au FU National Health and Medical Research Council Australia; National Institute of Allergy and Infectious Diseases Division of Intramural Research FX Work in the authors' laboratories is supported by grants from National Health and Medical Research Council Australia and the National Institute of Allergy and Infectious Diseases Division of Intramural Research. NR 90 TC 12 Z9 13 U1 2 U2 17 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD SEP PY 2014 VL 96 IS 3 BP 391 EP 396 DI 10.1189/jlb.3RI0314-129R PG 6 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AN8CL UT WOS:000340829400005 PM 24904000 ER PT J AU Nakajima, T Turkbey, B Sano, K Sato, K Bernardo, M Hoyt, RF Choyke, PL Kobayashi, H AF Nakajima, Takahito Turkbey, Baris Sano, Kohei Sato, Kazuhide Bernardo, Marcelino Hoyt, Robert F. Choyke, Peter L. Kobayashi, Hisataka TI MR Lymphangiography With Intradermal Gadofosveset and Human Serum Albumin in Mice and Primates SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE Gadofosveset; MR lymphangiography; sentinel lymph node; contrast agents; lymphatic drainage ID MAGNETIC-RESONANCE LYMPHANGIOGRAPHY; SENTINEL LYMPH-NODE; CONTRAST AGENTS; BREAST-CANCER; CT LYMPHOGRAPHY; FDG-PET; DENDRIMER; MS-325; ANGIOGRAPHY; VISUALIZATION AB Purpose: To investigate MR lymphangiography in mice and primates with intradermal Gadofosveset and human serum albumin. Gadofosveset is a US FDA approved small molecule Gadolinium (Gd) chelate (957 Da) which reversibly binds serum albumin and temporally behaves as a macromolecule. As the structure of albumin varies among species, the affinity of Gadofosveset is optimized for human albumin. In this study, Gadofosveset premixed with 10% human serum albumin (HSA) was injected intradermally in mice and monkeys, and then MR lymphangiography was performed on a 3.0 Tesla clinical scanner. Materials and Methods: Twenty microliters of each agent was injected intradermally at both sides of the front and back paws using a 30-gauge needle into female athymic nude mice (6-8 weeks old, n=3 mice in each group). The performance of Gadofosveset-HSA was compared with Gd-labeled dendrimers (G4: 6 nm, G6: 10 nm) or GdDTPA. The target-to-muscle ratio (TMR target signal intensity (SI)/muscle SI) was calculated at each time point. The TMRs were compared with a one-way analysis of variance followed by a Bonferroni multiple comparison test. Results: Images taken as early as 2.5 min after intradermal (id) injection depicted enhanced lymph nodes using Gadofosveset-HSA (2.41 +/- 0.20). Up to 7.5 min after injection, TMRs of Gadofosveset-HSA were greater than those of dendrimers (G4 or G6-Gd-DTPA: 2.24 +/- 0.10, 2.12 +/- 0.11, respectively). By 15 min postinjection, TMRs of Gadofosveset-HSA (2.18 +/- 0.19) were comparable to Gd-labeled dendrimers (G4-Gd-DTPA: 2.37 +/- 0.15, G6Gd-DTPA: 2.25 +/- 0.18). Gadofosveset-HSA and Gd labeled dendrimers resulted in satisfactory MR lymphography in mice and monkeys. Conclusion: Because both Gadofosveset and HSA are approved for human use and Gadofosveset clears rapidly through the kidneys, this method has advantages over Gd-dendrimers and could be used for visualizing lymphatic drainage and detecting lymph nodes. C1 [Nakajima, Takahito; Turkbey, Baris; Sano, Kohei; Sato, Kazuhide; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino] SAIC Frederick Inc, Res Technol Program, Frederick, MD USA. [Hoyt, Robert F.] NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,RoomB3B69,MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute, Center for Cancer Research FX Contract grant sponsor: Intramural Research Program of the National Institutes of Health; National Cancer Institute, Center for Cancer Research. NR 30 TC 3 Z9 3 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD SEP PY 2014 VL 40 IS 3 BP 691 EP 697 DI 10.1002/jmri.24395 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AN4DQ UT WOS:000340538200024 PM 24123370 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI REPORT OF THE NATIONAL INSTITUTES OF HEALTH TASK FORCE ON RESEARCH STANDARDS FOR CHRONIC LOW BACK PAIN SO JOURNAL OF MANIPULATIVE AND PHYSIOLOGICAL THERAPEUTICS LA English DT Article DE Low Back Pain; Chronic Pain; Patient Outcome Assessment; Research Design ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES; INTERVENTIONAL THERAPIES AB Objectives: Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed nonspecific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. The purpose of this article is to disseminate the report of the National Institutes of Health (NIH) task force on research standards for cLBP. Methods: The NIH Pain Consortium charged a research task force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting. Results: The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research subjects (drawing heavily on the Patient Reported Outcomes Measurement Information System methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved these recommendations, which investigators should incorporate into NIH grant proposals. Conclusions: The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of cLBP. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect the RTF recommendations will become a dynamic document and undergo continual improvement. C1 [Deyo, Richard A.] OHSU, Dept Family Med, Portland, OR 97239 USA. [Deyo, Richard A.; Chou, Roger] OHSU, Dept Med, Portland, OR 97239 USA. [Deyo, Richard A.] OHSU, Dept Publ Hlth & Community Med, Portland, OR 97239 USA. [Dworkin, Samuel F.] Univ Washington, Dept Psychiat & Behav Sci, Dept Oral Med, Seattle, WA 98195 USA. [Amtmann, Dagmar] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Andersson, Gunnar] Rush Univ, Dept Orthopaed Surg, Med Ctr, Chicago, IL 60612 USA. [Borenstein, David] George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. [Carragee, Eugene] Stanford Univ, Dept Orthopaed Surg, Sch Med, Stanford, CA 94305 USA. [Carrino, John] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Chou, Roger] OHSU, Dept Med Informat & Clin Epidemiol, Portland, OR 97239 USA. [Cook, Karon] Northwestern Univ, Dept Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [DeLitto, Anthony] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Palmer Ctr Chiropract Res, Davenport, IA USA. [Khalsa, Partap] NIH, Div Extramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Loeser, John] Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA. [Loeser, John; Turk, Dennis] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Mackey, Sean] Stanford Univ, Dept Anesthesia & Pain Management, Stanford, CA 94305 USA. [Panagis, James] NIAMSD, NIH, Orthopaed Res Program, Bethesda, MD 20892 USA. [Rainville, James] New England Baptist Hosp, Dept Phys Med & Rehabil, Roxbury Crossing, MA USA. [Tosteson, Tor] Geisel Sch Med Dartmouth, Dept Community & Family Med, Hanover, NH USA. [Tosteson, Tor] Geisel Sch Med Dartmouth, Dartmouth Inst, Hanover, NH USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA USA. [Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Deyo, RA (reprint author), OHSU, Mail Code FM,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM deyor@ohsu.edu FU NCCAM; National Institute for Arthritis, Musculoskeletal, and Skin Diseases, NIH FX This study was supported by the NCCAM and the National Institute for Arthritis, Musculoskeletal, and Skin Diseases, NIH. No conflicts of interest were reported for this study. NR 125 TC 3 Z9 3 U1 8 U2 15 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-4754 J9 J MANIP PHYSIOL THER JI J. Manip. Physiol. Ther. PD SEP PY 2014 VL 37 IS 7 BP 449 EP 467 DI 10.1016/j.jmpt.2014.07.006 PG 19 WC Health Care Sciences & Services; Integrative & Complementary Medicine; Rehabilitation SC Health Care Sciences & Services; Integrative & Complementary Medicine; Rehabilitation GA AO2XD UT WOS:000341189600001 PM 25127996 ER PT J AU Romero, R Tarca, AL Chaemsaithong, P Miranda, J Chaiworapongsa, T Jia, H Hassan, SS Kalita, CA Cai, J Yeo, L Lipovich, L AF Romero, Roberto Tarca, Adi L. Chaemsaithong, Piya Miranda, Jezid Chaiworapongsa, Tinnakorn Jia, Hui Hassan, Sonia S. Kalita, Cynthia A. Cai, Juan Yeo, Lami Lipovich, Leonard TI Transcriptome interrogation of human myometrium identifies differentially expressed sense-antisense pairs of protein-coding and long non-coding RNA genes in spontaneous labor at term SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Genomics; lncRNA; parturition; pregnancy; preterm birth ID HUMAN GESTATIONAL TISSUES; PRIMARY CESAREAN DELIVERY; HIGH-DIMENSIONAL BIOLOGY; PROSTATE-CANCER CELLS; HUMAN FETAL MEMBRANES; AMNIOTIC-FLUID; PRETERM PARTURITION; BREAST-CANCER; HUMAN GENOME; FUNCTIONAL GENOMICS AB Objective: To identify differentially expressed long non-coding RNA (lncRNA) genes in human myometrium in women with spontaneous labor at term. Materials and methods: Myometrium was obtained from women undergoing cesarean deliveries who were not in labor (n = 19) and women in spontaneous labor at term (n = 20). RNA was extracted and profiled using an Illumina (R) microarray platform. We have used computational approaches to bound the extent of long non-coding RNA representation on this platform, and to identify co-differentially expressed and correlated pairs of long non-coding RNA genes and protein-coding genes sharing the same genomic loci. Results: We identified co-differential expression and correlation at two genomic loci that contain coding-lncRNA gene pairs: SOCS2-AK054607 and LMCD1-NR_024065 in women in spontaneous labor at term. This co-differential expression and correlation was validated by qRT-PCR, an experimental method completely independent of the microarray analysis. Intriguingly, one of the two lncRNA genes differentially expressed in term labor had a key genomic structure element, a splice site, that lacked evolutionary conservation beyond primates. Conclusions: We provide, for the first time, evidence for coordinated differential expression and correlation of cis-encoded antisense lncRNAs and protein-coding genes with known as well as novel roles in pregnancy in the myometrium of women in spontaneous labor at term. C1 [Romero, Roberto; Tarca, Adi L.; Chaemsaithong, Piya; Miranda, Jezid; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto; Tarca, Adi L.; Chaemsaithong, Piya; Miranda, Jezid; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Tarca, Adi L.] Wayne State Univ, Sch Med, Dept Comp Sci, Detroit, MI 48201 USA. [Tarca, Adi L.; Jia, Hui; Kalita, Cynthia A.; Cai, Juan; Lipovich, Leonard] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Yeo, Lami] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, NICHD, Perinatol Res Branch, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD; NIH [HHSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HHSN275201300006C. L. L. is a member of the ENCODE Consortium; however, no funds or material resources from ENCODE were used in this study. NR 183 TC 6 Z9 6 U1 1 U2 20 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD SEP PY 2014 VL 27 IS 14 BP 1397 EP 1408 DI 10.3109/14767058.2013.860963 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AN8BH UT WOS:000340825300001 PM 24168098 ER PT J AU Feng, J Hong, LC Wu, YG Li, CZ Wan, H Li, GL Sun, YL Yu, SY Chittiboina, P Montgomery, B Zhuang, ZP Zhang, YZ AF Feng, Jie Hong, Lichuan Wu, Yonggang Li, Chuzhong Wan, Hong Li, Guilin Sun, Yilin Yu, Shenyuan Chittiboina, Prashant Montgomery, Blake Zhuang, Zhengping Zhang, Yazhuo TI Identification of a subtype-specific ENC1 gene related to invasiveness in human pituitary null cell adenoma and oncocytomas SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Invasiveness; ENC1; NFPAs; Null cell adenomas; Oncocytomas ID NUCLEAR-MATRIX PROTEIN; HUMAN BRAIN-TUMORS; EXPRESSION; NRP/B; PROGRESSION; BIOMARKERS; INDEX; KI-67 AB Non-functioning pituitary adenomas (NFPAs) may be locally invasive. Surgery is a treatment option, but unlike the case for functional pituitary adenomas, there are almost no drug treatments available for NFPAs. Markers of invasiveness are needed to guide therapeutic decision-making and identify potential adjuvant drugs. Owing to the highly heterogeneous nature of NFPAs, little is known regarding the subtype-specific gene expression profiles associated with invasiveness. To identify important biomarkers of invasiveness, we selected 23 null cell adenomas and 20 oncocytomas. These tumors were classified as invasive or non-invasive adenomas based on magnetic resonance imaging, pathology slides and surgical findings. Firstly, we observed that there were significant differences in expression between invasive (n = 3) and non-invasive (n = 4) adenomas by gene expression microarray. A total of 1,188 genes were differentially expressed in the invasive and non-invasive adenomas. Among these 1,188 genes, 578 were upregulated and 610 were downregulated in invasive adenomas. Secondly, the expression of ENC1, which displayed the significant alterations, was further confirmed by qRT-PCR and Western blot analysis in all 43 tumor samples and three normal pituitary glands. Low levels of ENC1 were found in tumor samples, while high levels were detected in normal pituitary glands. Interestingly, the ENC1 expression level was low in invasive null cell adenomas compared with non-invasive adenomas, but this relationship was not observed in invasive oncocytomas. Immunohistochemistry also demonstrated that the staining of ENC1 was different between invasive and non-invasive null cell adenomas. In addition, bioinformatics studies, including gene ontology and protein interaction analyses, were also performed to better understand the critical role of ENC1 in the development and progression of null cell adenomas and oncocytomas. Consequently, ENC1 may be an important biomarker for null cell adenomas and oncocytomas, and it is specific to invasive null cell adenomas. C1 [Feng, Jie; Hong, Lichuan; Wu, Yonggang; Li, Chuzhong; Wan, Hong; Li, Guilin; Sun, Yilin; Yu, Shenyuan; Zhang, Yazhuo] Capital Med Univ, Beijing Neurosurg Inst, Beijing 100050, Peoples R China. [Hong, Lichuan] Tsinghua Univ, Med Ctr, Beijing 100084, Peoples R China. [Wu, Yonggang] Peoples Hosp Xinjiang Uygur Autonomous Reg, Dept Neurosurg, Urumqi 830001, Peoples R China. [Chittiboina, Prashant; Montgomery, Blake; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, YZ (reprint author), Capital Med Univ, Beijing Neurosurg Inst, Beijing 100050, Peoples R China. EM fj79330@163.com; homerhong1017@163.com; wyg931543@163.com; lichuzhong@163.com; wanhong96@163.com; liguilin40@hotmail.com; sunyilin@hotmail.com; daodaoysy@foxmail.com; prashant.chittiboina@nih.hhs.gov; blake.montgomery@nih.hhs.gov; Zhengping.Zhuang@nih.hhs.gov; zyz2004520@yeah.net FU National Scientific Foundation of China [31000498, 81072075] FX The authors thank the subjects for donating DNA samples. The study is supported by National Scientific Foundation of China (31000498, 81072075) grants to Chuzhong, Li and Yazhuo, Zhang. NR 29 TC 4 Z9 4 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD SEP PY 2014 VL 119 IS 2 BP 307 EP 315 DI 10.1007/s11060-014-1479-1 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AO2VN UT WOS:000341184500009 PM 24916845 ER PT J AU Uchoa, ET Aguilera, G Herman, JP Fiedler, JL Deak, T de Sousa, MBC AF Uchoa, E. T. Aguilera, G. Herman, J. P. Fiedler, J. L. Deak, T. de Sousa, M. B. C. TI Novel Aspects of Glucocorticoid Actions SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Review DE glucocorticoids; feedback; HPA axis; neuroplasticity; immune system; food intake ID CORTICOTROPIN-RELEASING HORMONE; PITUITARY-ADRENAL-AXIS; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; MESSENGER-RNA STABILITY; GLUCAGON-LIKE PEPTIDE-1; RECEPTOR ANTAGONIST BLOCKS; STRESS-INDUCED INCREASES; CENTRAL-NERVOUS-SYSTEM; RAT HIPPOCAMPUS; FOOD-INTAKE AB Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to the rhythmic and episodic release of adrenal glucocorticoids (GCs) is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, GCs regulate behaviour, as well as metabolic, cardiovascular, immune and neuroendocrine activities. By contrast to chronic elevated levels, circadian and acute stress-induced increases in GCs are necessary for hippocampal neuronal survival and memory acquisition and consolidation, as a result of the inhibition of apoptosis, the facilitation of glutamatergic neurotransmission and the formation of excitatory synapses, and the induction of immediate early genes and dendritic spine formation. In addition to metabolic actions leading to increased energy availability, GCs have profound effects on feeding behaviour, mainly via the modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that, in addition to the recognised immune suppressive actions of GCs by counteracting adrenergic pro-inflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative-feedback by GCs involves multiple mechanisms leading to limited HPA axis activation and prevention of the deleterious effects of excessive GC production. Adequate GC secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin-releasing hormone (CRH) and vasopressin secretion, which are the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving nongenomic actions of GCs, mediate the immediate inhibition of hypothalamic CRH and ACTH secretion, whereas intermediate and delayed mechanisms mediated by genomic actions involve the modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily conserved, being present in the earliest vertebrates. An understanding of these basic mechanisms may lead to novel approaches for the development of diagnostic and therapeutic tools for disorders related to stress and alterations of GC secretion. C1 [Uchoa, E. T.] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Physiol, Ribeirao Preto, SP, Brazil. [Aguilera, G.] NICHHD, Sect Endocrine Physiol, Bethesda, MD 20892 USA. [Herman, J. P.] Univ Cincinnati, Dept Psychiat & Behav Neurosci, Metab Dis Inst, Cincinnati, OH USA. [Fiedler, J. L.] Univ Chile, Dept Biochem & Mol Biol, Fac Chem & Pharmaceut Sci, Santiago, Chile. [Deak, T.] SUNY Binghamton, Dept Psychol, Binghamton, NY USA. [de Sousa, M. B. C.] Univ Fed Rio Grande do Norte, Inst Brain, BR-59072970 Natal, RN, Brazil. RP Uchoa, ET (reprint author), Ave Bandeirantes 3900, BR-14049900 Sao Paulo, Brazil. EM ernane_uchoa@yahoo.com.br RI Fiedler, Jenny/I-5617-2016; Herman, James/D-4960-2015 OI Herman, James/0000-0003-3571-2406 FU FAPESP; CNPq; Intramural Research Program, National Institute of Child Health and Human Development; NIH [MH049698, MH069860]; FONDECYT [1120528]; National Science Foundation (NSF) [0822129]; CNPq [302592/2009-1] FX This study was supported by FAPESP and CNPq to E. T. U.; Intramural Research Program, National Institute of Child Health and Human Development to G. A.; NIH grants MH049698 and MH069860 to J.P.H.; FONDECYT 1120528 to J.L.F.; National Science Foundation (NSF) grant 0822129 to T. D.; and CNPq (Proc. No. 302592/2009-1) to M.B.C.S. NR 181 TC 28 Z9 28 U1 1 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-8194 EI 1365-2826 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD SEP PY 2014 VL 26 IS 9 SI SI BP 557 EP 572 DI 10.1111/jne.12157 PG 16 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA AO2FM UT WOS:000341131800002 PM 24724595 ER PT J AU Mehta, GU Bakhtian, KD Oldfield, EH AF Mehta, Gautam U. Bakhtian, Kamran D. Oldfield, Edward H. TI Effect of primary empty sella syndrome on pituitary surgery for Cushing's disease SO JOURNAL OF NEUROSURGERY LA English DT Article DE Cushing's disease; empty sella syndrome; pituitary adenoma; transsphenoidal surgery; pituitary surgery ID TRANSSPHENOIDAL SURGERY; CONSENSUS STATEMENT; ADENOMAS; MICROADENOMA; RADIOSURGERY; REMISSION; DIAGNOSIS; HORMONE AB Object. Primary empty sella syndrome (ESS) results from herniation of arachnoid mater into the pituitary fossa. It has been suggested to have a negative effect on pituitary surgery; however, outcomes in this cohort have not been defined. This study was performed to determine the effect of ESS on immediate and long-term biochemical outcome after pituitary surgery for Cushing's disease (CD). Methods. Using a matched cohort study design, the authors followed patients treated with pituitary surgery for CD with and without ESS. Complete ESS was defined as pituitary gland height <= 2 mm, whereas partial ESS was defined as pituitary gland height > 2 mm but less than three-quarters of the total sellar depth. The primary end points were immediate and long-term biochemical outcome. Cerebrospinal fluid leaks were recorded as a secondary end point. Results. Seventy-eight patients with CD and primary ESS were identified and matched with 78 patients with CD without ESS. After surgical management, immediate biochemical remission was achieved in 69 patients (88%) with ESS and 75 controls (96%, p = 0.10). Long-term remission was achieved in most patients in both groups (5-year cure: 85% vs 92%, p = 0.10). Among patients with ESS, the presence of complete ESS predicted a worse long-term outcome (p = 0.04). Intraoperative CSF leaks were significantly more frequent with ESS (54% vs 24%, p <0.001), and despite sellar floor repair, the rate of postoperative CSF leaks was also increased (6% vs 3%, p = 0.27). Conclusions. Biochemical outcome after pituitary surgery for CD was worse in patients with complete ESS, and the risk of a CSF leak was increased with both partial and complete ESS. However, as outcome remains superior to those following alternative therapies and the biology of these tumors is unchanged in the setting of ESS, pituitary surgery should remain the initial treatment of choice. C1 [Mehta, Gautam U.; Bakhtian, Kamran D.; Oldfield, Edward H.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD USA. [Mehta, Gautam U.; Oldfield, Edward H.] Univ Virginia Hlth Sci Ctr, Dept Neurosurg, Charlottesville, VA USA. RP Oldfield, EH (reprint author), Univ Virginia, Univ Virginia Hlth Sci Ctr, Dept Neurosurg, Box 800212, Charlottesville, VA 22903 USA. EM eho4u@hscmail.mcc.virginia.edu OI Mehta, Gautam/0000-0002-8009-6430 FU Intramural Research Program of the National Institute of Neurological Disorders and Strokeat the National Institutes of Health FX The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 37 TC 2 Z9 2 U1 0 U2 5 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2014 VL 121 IS 3 BP 518 EP 526 DI 10.3171/2014.3.JNS132012 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AN6EW UT WOS:000340688700003 PM 24857241 ER PT J AU Forman, MR Zhu, YY Hernandez, LM Himes, JH Dong, YQ Danish, RK James, KE Caulfield, LE Kerver, JM Arab, L Voss, P Hale, DE Kanafani, N Hirschfeld, S AF Forman, Michele R. Zhu, Yeyi Hernandez, Ladia M. Himes, John H. Dong, Yongquan Danish, Robert K. James, Kyla E. Caulfield, Laura E. Kerver, Jean M. Arab, Lenore Voss, Paula Hale, Daniel E. Kanafani, Nadim Hirschfeld, Steven TI Arm Span and Ulnar Length Are Reliable and Accurate Estimates of Recumbent Length and Height in a Multiethnic Population of Infants and Children under 6 Years of Age SO JOURNAL OF NUTRITION LA English DT Article ID BODY-MASS INDEX; CEREBRAL-PALSY; NUTRITIONAL-STATUS; TIBIA LENGTH; PULMONARY-FUNCTION; LINEAR GROWTH; UNITED-STATES; ETHNIC-GROUPS; SURFACE AREA; STATURE AB Surrogate measures are needed when recumbent length or height is unobtainable or unreliable. Arm span has been used as a surrogate but is not feasible in children with shoulder or arm contractures. Ulnar length is not usually impaired by joint deformities, yet its utility as a surrogate has not been adequately studied. In this cross-sectional study, we aimed to examine the accuracy and reliability of ulnar length measured by different tools as a surrogate measure of recumbent length and height. Anthropometrics [recumbent length, height, arm span, and ulnar length by caliper (ULC), ruler (ULR), and grid (ULG)) were measured in 1479 healthy infants and children aged <6 y across 8 study centers in the United States. Multivariate mixed-effects linear regression models for recumbent length and height were developed by using ulnar length and arm span as surrogate measures. The agreement between the measured length or height and the predicted values by ULC, ULR, ULG, and arm span were examined by Bland-Altman plots. All 3 measures of ulnar length and arm span were highly correlated with length and height. The degree of precision of prediction equations for length by U LC, ULR, and ULG (R-2 = 0.95, 0.95, and 0.92, respectively) was comparable with that by arm span (R-2 = 0.97) using age, sex, and ethnicity as covariates; however, height prediction by ULC (R-2 = 0.87), ULR (R-2 = 0.85), and ULG (R-2 = 0.88) was less comparable with arm span (R-2 = 0.94). Our study demonstrates that arm span and ULC, ULR, or ULG can serve as accurate and reliable surrogate measures of recumbent length and height in healthy children; however, ULC, ULR, and ULG tend to slightly overestimate length and height in young infants and children. Further teting of ulnar length as a surrogate is warranted in physically impaired or nonambulatory children. C1 [Forman, Michele R.; Zhu, Yeyi; Hernandez, Ladia M.; Dong, Yongquan; James, Kyla E.] Univ Texas Austin, Dept Nutr Sci, Sch Human Ecol, Austin, TX 78712 USA. [Himes, John H.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Danish, Robert K.; Hale, Daniel E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA. [Caulfield, Laura E.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Baltimore, MD USA. [Kerver, Jean M.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Arab, Lenore] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Voss, Paula] Univ Calif Irvine, Irvine, CA USA. [Kanafani, Nadim] St Louis Univ, Sch Med, Dept Pediat, St Louis, MO 63104 USA. [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Forman, MR (reprint author), Univ Texas Austin, Dept Nutr Sci, Sch Human Ecol, Austin, TX 78712 USA. EM mforman@austin.utexas.edu RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275200800020C] FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development contract award (No. HHSN275200800020C). NR 51 TC 2 Z9 2 U1 1 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 SEP PY 2014 VL 144 IS 9 BP 1480 EP 1487 DI 10.3945/jn.114.194340 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AN6VK UT WOS:000340736300019 PM 25031329 ER PT J AU Berger, A AF Berger, Ann TI Spirituality in the Context of Life-Threatening Illness and Life-Transforming Change SO JOURNAL OF PALLIATIVE CARE LA English DT Meeting Abstract C1 [Berger, Ann] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU CENTRE RECHERCHE INSTITUT UNIV GERIATRIE MONTREAL PI MONTREAL PA 4565 CHEMIN QUEEN MARY, MONTREAL, QUEBEC H3W 1W5, CANADA SN 0825-8597 J9 J PALLIAT CARE JI J. Palliative Care PD FAL PY 2014 VL 30 IS 3 MA P246 BP 243 EP 244 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AO3IQ UT WOS:000341223300179 ER PT J AU Berger, A AF Berger, Ann TI Current Status of Spirituality in Cardiac Rehabilitation Programs SO JOURNAL OF PALLIATIVE CARE LA English DT Meeting Abstract C1 [Berger, Ann] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CENTRE RECHERCHE INSTITUT UNIV GERIATRIE MONTREAL PI MONTREAL PA 4565 CHEMIN QUEEN MARY, MONTREAL, QUEBEC H3W 1W5, CANADA SN 0825-8597 J9 J PALLIAT CARE JI J. Palliative Care PD FAL PY 2014 VL 30 IS 3 MA P248 BP 244 EP 244 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AO3IQ UT WOS:000341223300181 ER PT J AU Berger, A AF Berger, Ann TI The Nature of Life-Transforming Changes Among Cancer Survivors SO JOURNAL OF PALLIATIVE CARE LA English DT Meeting Abstract C1 [Berger, Ann] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CENTRE RECHERCHE INSTITUT UNIV GERIATRIE MONTREAL PI MONTREAL PA 4565 CHEMIN QUEEN MARY, MONTREAL, QUEBEC H3W 1W5, CANADA SN 0825-8597 J9 J PALLIAT CARE JI J. Palliative Care PD FAL PY 2014 VL 30 IS 3 MA P247 BP 244 EP 244 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AO3IQ UT WOS:000341223300180 ER PT J AU Ahn, M Park, JE Lee, KS Shin, SY Bang, JK AF Ahn, M. Park, J. -E. Lee, K. S. Shin, S. Y. Bang, J. K. TI SYNTHESIS OF SMALL PEPTIDE INHIBITORS TO THE POLO-BOX DOMAIN OF POLO-LIKE KINASE 1 SO JOURNAL OF PEPTIDE SCIENCE LA English DT Meeting Abstract DE polo-like kinase 1 (Plk1); polo-box domain (PBD); peptide inhibitor; solid phase peptide synthesis; anticancer therapeutic agent C1 [Ahn, M.; Bang, J. K.] Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chung Buk, South Korea. [Park, J. -E.; Lee, K. S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shin, S. Y.] Chosun Univ, Grad Sch, Dept Biomat, Kwangju 501759, South Korea. [Shin, S. Y.] Chosun Univ, Sch Med, Dept Cellular & Mol Med, Kwangju 501759, South Korea. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1075-2617 EI 1099-1387 J9 J PEPT SCI JI J. Pept. Sci. PD SEP PY 2014 VL 20 SU 1 MA P070 BP S155 EP S155 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AN8TD UT WOS:000340876400215 ER PT J AU Bang, JK Srinivasrao, G Park, JE Lee, KS Shin, SY AF Bang, J. K. Srinivasrao, G. Park, J-E. Lee, K. S. Shin, S. Y. TI DESIGN AND SYNTHESIS OF DRUG-LIKE SMALL MOLECULE INHIBITOR TARGETING THE POLO-BOX-DOMAIN OF POLO-LIKE KINASE KINASE 1 SO JOURNAL OF PEPTIDE SCIENCE LA English DT Meeting Abstract DE Polo-like kinase 1; Polo-box domain (PBD); Cell permeable; Apoptosis C1 [Bang, J. K.; Srinivasrao, G.] Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chung Buk, South Korea. [Park, J-E.; Lee, K. S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shin, S. Y.] Chosun Univ, Grad Sch, Dept Biomat, Kwangju 501759, South Korea. [Shin, S. Y.] Chosun Univ, Sch Med, Dept Cellular & Mol Med, Kwangju 501759, South Korea. NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1075-2617 EI 1099-1387 J9 J PEPT SCI JI J. Pept. Sci. PD SEP PY 2014 VL 20 SU 1 MA P283 BP S286 EP S287 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AN8TD UT WOS:000340876400428 ER PT J AU Bang, JK Srinivasrao, G Park, JE Lee, KS Shin, SY AF Bang, J. K. Srinivasrao, G. Park, J-E. Lee, K. S. Shin, S. Y. TI DESIGN AND SYNTHESIS OF DRUG-LIKE SMALL MOLECULE INHIBITOR TARGETING THE POLO-BOX-DOMAIN OF POLO-LIKE KINASE KINASE 1 SO JOURNAL OF PEPTIDE SCIENCE LA English DT Meeting Abstract DE Polo-like kinase 1; Polo-box domain (PBD); Cell permeable; Apoptosis C1 [Bang, J. K.; Srinivasrao, G.] Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chung Buk, South Korea. [Park, J-E.; Lee, K. S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shin, S. Y.] Chosun Univ, Dept Biomat, Grad Sch, Kwangju 501759, South Korea. [Shin, S. Y.] Chosun Univ, Dept Cellular & Mol Med, Sch Med, Kwangju 501759, South Korea. NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1075-2617 EI 1099-1387 J9 J PEPT SCI JI J. Pept. Sci. PD SEP PY 2014 VL 20 SU 1 MA P43 BP S111 EP S111 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AN8TD UT WOS:000340876400136 ER PT J AU Muszynski, MA Zerbe, CS Holland, SM Kong, HH AF Muszynski, Melissa A. Zerbe, Christa S. Holland, Steven M. Kong, Heidi H. TI A woman with warts, leg swelling, and deafness SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material ID ACUTE MYELOID-LEUKEMIA; MONOMAC SYNDROME; GATA2 MUTATIONS; LYMPHEDEMA; MYELODYSPLASIA; DEFICIENCY C1 [Muszynski, Melissa A.] Medstar Washington Hosp Ctr, Dept Dermatol, Washington, DC USA. [Muszynski, Melissa A.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kong, HH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 10,Rm 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU Intramural NIH HHS [Z99 CA999999] NR 10 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD SEP PY 2014 VL 71 IS 3 BP 577 EP 580 DI 10.1016/j.jaad.2014.04.027 PG 4 WC Dermatology SC Dermatology GA AO2JH UT WOS:000341146700051 PM 25128101 ER PT J AU Abhyankar, S Demner-Fushman, D Callaghan, FM McDonald, CJ AF Abhyankar, Swapna Demner-Fushman, Dina Callaghan, Fiona M. McDonald, Clement J. TI Combining structured and unstructured data to identify a cohort of ICU patients who received dialysis SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID IDENTIFICATION; ACCURACY; RECORDS; CODES; TEXT AB Objective To develop a generalizable method for identifying patient cohorts from electronic health record (EHR) data in this case, patients having dialysis that uses simple information retrieval (IR) tools. Methods We used the coded data and clinical notes from the 24 506 adult patients in the Multiparameter Intelligent Monitoring in Intensive Care database to identify patients who had dialysis. We used SQL queries to search the procedure, diagnosis, and coded nursing observations tables based on ICD-9 and local codes. We used a domain-specific search engine to find clinical notes containing terms related to dialysis. We manually validated the available records for a 10% random sample of patients who potentially had dialysis and a random sample of 200 patients who were not identified as having dialysis based on any of the sources. Results We identified 1844 patients that potentially had dialysis: 1481 from the three coded sources and 1624 from the clinical notes. Precision for identifying dialysis patients based on available data was estimated to be 78.4% (95% Cl 71.9% to 84.2%) and recall was 100% (95% Cl 86% to 100%). Conclusions Combining structured EHR data with information from clinical notes using simple queries increases the utility of both types of data for cohort identification. Patients identified by more than one source are more likely to meet the inclusion criteria; however, including patients found in any of the sources increases recall. This method is attractive because it is available to researchers with access to EHR data and off-the-shelf IR tools. C1 [Abhyankar, Swapna; Demner-Fushman, Dina; Callaghan, Fiona M.; McDonald, Clement J.] NIH, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20892 USA. RP Abhyankar, S (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike,Bldg 38A-9N917, Bethesda, MD 20894 USA. EM swapna.abhyankar@nih.gov FU National Library of Medicine, National Institutes of Health, under NIH IRB exemption FX This research was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, under NIH IRB exemption. NR 28 TC 4 Z9 4 U1 0 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2014 VL 21 IS 5 BP 801 EP 807 DI 10.1136/amiajnl-2013-001915 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AN4TM UT WOS:000340581400007 PM 24384230 ER PT J AU Burke, HB Hoang, A Becher, D Fontelo, P Liu, F Stephens, M Pangaro, LN Sessums, LL O'Malley, P Baxi, NS Bunt, CW Capaldi, VF Chen, JM Cooper, BA Djuric, DA Hodge, JA Kane, S Magee, C Makary, ZR Mallory, RM Miller, T Saperstein, A Servey, J Gimbel, RW AF Burke, Harry B. Hoang, Albert Becher, Dorothy Fontelo, Paul Liu, Fang Stephens, Mark Pangaro, Louis N. Sessums, Laura L. O'Malley, Patrick Baxi, Nancy S. Bunt, Christopher W. Capaldi, Vincent F. Chen, Julie M. Cooper, Barbara A. Djuric, David A. Hodge, Joshua A. Kane, Shawn Magee, Charles Makary, Zizette R. Mallory, Renee M. Miller, Thomas Saperstein, Adam Servey, Jessica Gimbel, Ronald W. TI QNOTE: an instrument for measuring the quality of EHR clinical notes SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID PHYSICIAN DOCUMENTATION; MEDICAL RECORDS; MILITARY; CARE; DIAGNOSES; SYSTEMS; TEACH; GUIDE AB Background and objective The outpatient clinical note documents the clinician's information collection, problem assessment, and patient management, yet there is currently no validated instrument to measure the quality of the electronic clinical note. This study evaluated the validity of the QNOTE instrument, which assesses 12 elements in the clinical note, for measuring the quality of clinical notes. It also compared its performance with a global instrument that assesses the clinical note as a whole. Materials and methods Retrospective multicenter blinded study of the clinical notes of 100 outpatients with type 2 diabetes mellitus who had been seen in clinic on at least three occasions. The 300 notes were rated by eight general internal medicine and eight family medicine practicing physicians. The QNOTE instrument scored the quality of the note as the sum of a set of 12 note element scores, and its inter-rater agreement was measured by the intraclass correlation coefficient. The Global instrument scored the note in its entirety, and its inter-rater agreement was measured by the Fleiss kappa. Results The overall QNOTE inter-rater agreement was 0.82 (Cl 0.80 to 0.84), and its note quality score was 65 (Cl 64 to 66). The Global inter-rater agreement was 0.24 (Cl 0.19 to 0.29), and its note quality score was 52 (Cl 49 to 55). The QNOTE quality scores were consistent, and the overall QNOTE score was significantly higher than the overall Global score (p=0.04). Conclusions We found the QNOTE to be a valid instrument for evaluating the quality of electronic clinical notes, and its performance was superior to that of the Global instrument. C1 [Burke, Harry B.; Hoang, Albert; Becher, Dorothy; O'Malley, Patrick; Gimbel, Ronald W.] Uniformed Serv Univ Hlth Sci, Biomed Informat Dept, Bethesda, MD 20814 USA. [Burke, Harry B.; Pangaro, Louis N.; Sessums, Laura L.; O'Malley, Patrick; Magee, Charles] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Fontelo, Paul; Liu, Fang] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Stephens, Mark; Bunt, Christopher W.; Miller, Thomas; Saperstein, Adam; Servey, Jessica] Uniformed Serv Univ Hlth Sci, Dept Family Med, Bethesda, MD 20814 USA. [Baxi, Nancy S.; Capaldi, Vincent F.; Chen, Julie M.; Cooper, Barbara A.; Kane, Shawn; Makary, Zizette R.; Mallory, Renee M.] Walter Reed Natl Mil Med Ctr, Internal Med Serv, Bethesda, MD USA. [Djuric, David A.; Hodge, Joshua A.] Ft Belvoir Community Hosp, Ft Belvoir, VA USA. RP Burke, HB (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM harry.burke@usuhs.edu RI Stephens, Mark/A-2679-2015; OI Magee, Charles/0000-0001-5655-617X; Bunt, Christopher/0000-0002-5130-6902 FU US Army Medical Research and Materials Command [W81XWH-08-2-0056] FX Extramural funding was provided by the US Army Medical Research and Materials Command, cooperative agreement W81XWH-08-2-0056. All of the authors are employed by the Uniformed Services University of the Health Sciences or another entity of the US Federal Government. NR 21 TC 5 Z9 5 U1 0 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2014 VL 21 IS 5 BP 910 EP 916 DI 10.1136/amiajnl-2013-002321 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AN4TM UT WOS:000340581400021 PM 24384231 ER PT J AU Hanauer, DA Saeed, M Zheng, K Mei, QZ Shedden, K Aronson, AR Ramakrishnan, N AF Hanauer, David A. Saeed, Mohammed Zheng, Kai Mei, Qiaozhu Shedden, Kerby Aronson, Alan R. Ramakrishnan, Naren TI Applying MetaMap to Medline for identifying novel associations in a large clinical dataset: a feasibility analysis SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID LITERATURE-BASED DISCOVERY; ELECTRONIC HEALTH RECORDS; DRUG-DRUG INTERACTIONS; ADVERSE-EVENT REPORTS; CLASSIFICATION; DIAGNOSES; DISEASE; CARE; TEXT; IDENTIFICATION AB Objective We describe experiments designed to determine the feasibility of distinguishing known from novel associations based on a clinical dataset comprised of International Classification of Disease, V.9 (ICD-9) codes from 1.6 million patients by comparing them to associations of ICD-9 codes derived from 20.5 million Medline citations processed using MetaMap. Associations appearing only in the clinical dataset, but not in Medline citations, are potentially novel. Methods Pairwise associations of ICD-9 codes were independently identified in both the clinical and Medline datasets, which were then compared to quantify their degree of overlap. We also performed a manual review of a subset of the associations to validate how well MetaMap performed in identifying diagnoses mentioned in Medline citations that formed the basis of the Medline associations. Results The overlap of associations based on ICD-9 codes in the clinical and Medline datasets was low: only 6.6% of the 3.1 million associations found in the clinical dataset were also present in the Medline dataset. Further, a manual review of a subset of the associations that appeared in both datasets revealed that co-occurring diagnoses from Medline citations do not always represent clinically meaningful associations. Discussion Identifying novel associations derived from large clinical datasets remains challenging. Medline as a sole data source for existing knowledge may not be adequate to filter out widely known associations. Conclusions In this study, novel associations were not readily identified. Further improvements in accuracy and relevance for tools such as MetaMap are needed to realize their expected utility. C1 [Hanauer, David A.] Univ Michigan, Sch Med, Dept Pediat, Ann Arbor, MI 48109 USA. [Saeed, Mohammed] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Zheng, Kai] Univ Michigan, Sch Publ Hlth, Dept Hlth Management & Policy, Ann Arbor, MI 48109 USA. [Zheng, Kai; Mei, Qiaozhu] Univ Michigan, Sch Informat, Ann Arbor, MI 48109 USA. [Mei, Qiaozhu] Univ Michigan, Dept Elect Engn & Comp Sci, Ann Arbor, MI 48109 USA. [Shedden, Kerby] Univ Michigan, Ctr Stat Consultat & Res, Ann Arbor, MI 48109 USA. [Aronson, Alan R.] Natl Lib Med, Lister Hill Ctr, Bethesda, MD USA. [Ramakrishnan, Naren] Virginia Tech, Discovery Analyt Ctr, Dept Comp Sci, Arlington, VA USA. RP Hanauer, DA (reprint author), Univ Michigan, Sch Med, Dept Pediat, 5312 CC,SPC 5940,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM hanauer@umich.edu FU National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000433]; University of Michigan Cancer Center's (UMCC) Biomedical Informatics Core; National Institutes of Health through the UMCC Support Grant [CA46592]; National Science Foundation [IIS-0905313, CCF-0937133, IIS-1054199, CCF-1048168]; Intramural Research Program of the NIH, National Library of Medicine FX The research reported in this publication was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000433. Additional support was provided by the University of Michigan Cancer Center's (UMCC) Biomedical Informatics Core with partial support from the National Institutes of Health through the UMCC Support Grant (CA46592), and from National Science Foundation grants IIS-0905313, CCF-0937133, IIS-1054199, and CCF-1048168. This work was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the supporting agencies. NR 80 TC 3 Z9 3 U1 2 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2014 VL 21 IS 5 BP 925 EP 937 DI 10.1136/amiajnl-2014-002767 PG 13 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AN4TM UT WOS:000340581400023 PM 24928177 ER PT J AU Gbadegesin, RA Hall, G Adeyemo, A Hanke, N Tossidou, I Burchette, J Wu, GH Homstad, A Sparks, MA Gomez, J Jiang, RJ Alonso, A Lavin, P Conlon, P Korstanje, R Stander, MC Shamsan, G Barua, M Spurney, R Singhal, PC Kopp, JB Haller, H Howell, D Pollak, MR Shaw, AS Schiffer, M Winn, MP AF Gbadegesin, Rasheed A. Hall, Gentzon Adeyemo, Adebowale Hanke, Nils Tossidou, Irini Burchette, James Wu, Guanghong Homstad, Alison Sparks, Matthew A. Gomez, Jose Jiang, Ruiji Alonso, Andrea Lavin, Peter Conlon, Peter Korstanje, Ron Stander, M. Christine Shamsan, Ghaidan Barua, Moumita Spurney, Robert Singhal, Pravin C. Kopp, Jeffrey B. Haller, Hermann Howell, David Pollak, Martin R. Shaw, Andrey S. Schiffer, Mario Winn, Michelle P. TI Mutations in the Gene That Encodes the F-Actin Binding Protein Anillin Cause FSGS SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; NEPHROTIC SYNDROME; CD2-ASSOCIATED PROTEIN; CYTOKINESIS; INVOLVEMENT; ZEBRAFISH; PODOCYTES; MODEL; RAC1; RHOA AB FSGS is characterized by segmental scarring of the glomerulus and is a leading cause of kidney failure. Identification of genes causing FSGS has improved our understanding of disease mechanisms and points to defects in the glomerular epithelial cell, the podocyte, as a major factor in disease pathogenesis. Using a combination of genome-wide linkage studies and whole-exonne sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS. We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS. We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1 associated nephropathy. Overexpression of R431C mutant ANLN in immortalized human podocytes results in enhanced podocyte motility. The mutant anillin displays reduced binding to the slit diaphragm associated scaffold protein CD2AP. Knockdown of the ANLN gene in zebrafish morphants caused a loss of glomerular filtration barrier integrity, podocyte foot process effacement, and an edematous phenotype. Collectively, these findings suggest that anillin is important in maintaining the integrity of the podocyte actin cytoskeleton. C1 [Gbadegesin, Rasheed A.; Homstad, Alison; Jiang, Ruiji; Alonso, Andrea] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Hall, Gentzon; Wu, Guanghong; Sparks, Matthew A.; Gomez, Jose; Lavin, Peter; Spurney, Robert; Winn, Michelle P.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Burchette, James; Howell, David] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Gbadegesin, Rasheed A.; Hall, Gentzon; Wu, Guanghong; Homstad, Alison; Jiang, Ruiji; Alonso, Andrea; Lavin, Peter; Winn, Michelle P.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. [Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Hanke, Nils; Tossidou, Irini; Haller, Hermann; Schiffer, Mario] Hannover Med Sch, Dept Nephrol, Hannover, Germany. [Hanke, Nils; Korstanje, Ron; Haller, Hermann; Schiffer, Mario] Mt Desert Isl Biol Lab, Salsbury Cove, ME 04672 USA. [Lavin, Peter] Univ Dublin Trinity Coll, Tallaght Hosp, Trinity Hlth Kidney Ctr, Dublin 2, Ireland. [Conlon, Peter] Beaumont Hosp, Dept Nephrol, Dublin 9, Ireland. [Korstanje, Ron] Jackson Lab, Bar Harbor, ME 04609 USA. [Stander, M. Christine; Shamsan, Ghaidan; Shaw, Andrey S.] Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Barua, Moumita; Pollak, Martin R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Singhal, Pravin C.] North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Gbadegesin, RA (reprint author), Duke Univ, Med Ctr, Dept Pediat, T Level RM0909 CHC,Box 3959, Durham, NC 27710 USA. EM rasheed.gbadegesin@duke.edu OI Adeyemo, Adebowale/0000-0002-3105-3231; Sparks, Matthew/0000-0003-2075-2691; Schiffer, Mario/0000-0002-8414-1470 FU NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K08-DK082495, 1R56-DK098135-01, 5R01-DK074748-06]; NIH Division of Intramural Research; National Institute of Allergy and Infectious Diseases (NIAID); American Recovery and Reinvestment Act [1RC2-NS070342-01]; Joseph and Kathleen Bryan Alzheimer's Disease Research Center; National Institute on Aging [P30-AG028377]; National Institute of Mental Health [RC2-MH089915]; NIAID [1R56-AI098588-01A1]; NephCure Foundation; Doris Duke Clinical Scientist Development Award; Doris Duke Charitable Foundation [2009033]; DukeMed Scholars program; German Research Foundation [SCHI587/4, SCHI587/6]; MDIBL; Howard Hughes Medical Institute; NIDDK FX We thank Lynne Staggs and Patricia Schroder (MDIBL) for technical assistance with the zebrafish experiments, Sophie Paschke for zebrafish artwork, and Dr. Donald Houghton for his help in interpretation of renal histology and constructive review of the manuscript. We also thank Dr. Elizabeth T. Cirulli, Dr. David B. Goldstein, Dr. Kevin V. Shianna, and the personnel of the Center for Human Genome Variation for assistance with sequencing. In addition, we acknowledge the following individuals for the contributions of control samples: Dr. James Burke, Dr. Christine Hulette, Dr. Kathleen Welsh-Bohmer, Dr. Francis J. McMahon, Nirmala Akula, Dr. Julie Hoover-Fong, Dr. Nara L. Sobreira, Dr. David Valle, Dr. M. Chiara Manzini, Dr. Annapurna Poduri, Dr. Nicole Calakos, Mr. David H. Murdock and The MURDOCK Study Community Registry and Biorepository, Dr. Joseph McEvoy, Dr. Anna Need, Mr. Jordan Silver, Ms. Marlyne Silver, Dr. Eli J. Holtzman, Dr. Gianpiero Cavalleri, Dr. Norman Delanty, Dr. Chantal Depondt, Dr. Sanjay Sisodiya, Dr. William B. Gallentine, Dr. Erin L. Heinzen, Dr. Aatif M. Husain, Ms. Kristen N. Linney, Dr. Mohamad A. Mikati, Dr. Rodney A. Radtke, Dr. Saurabh R. Sinha, Ms. Nicole M. Walley, Dr. Deborah Koltai Attix, Ms. Vicki Dixon, Ms. Jill McEvoy, Dr. Vandana Shashi, Dr. Patricia Lugar, Dr. William L. Lowe, Dr. Scott M. Palmer, Dr. Doug Marchuk, Dr. Deborah Levy, Dr. Zvi Farfel, Dr. Doron Lancet, Dr. Elon Pras, Dr. Yong-Hui Jiang, Dr. Qian Zhao, Dr. Joshua Milner, Dr. Demetre Daskalakis, Mr. Arthur Holden, Dr. Elijah Behr, Dr. Robert H. Brown Jr., Dr. Sarah Kerns, and Dr. Harriet Oster. Finally, we thank the personnel of the Center for Human Genetics core facilities and most importantly the family members of the Duke FSGS project. This study was funded by grants from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (K08-DK082495 and 1R56-DK098135-01 to R.G.; 5R01-DK074748-06 to M.P.W.). This research was supported in part by funding from the NIH Division of Intramural Research and the National Institute of Allergy and Infectious Diseases (NIAID). The sequenced controls used for this study were funded in part by the American Recovery and Reinvestment Act (1RC2-NS070342-01), the Joseph and Kathleen Bryan Alzheimer's Disease Research Center and the National Institute on Aging (P30-AG028377), the National Institute of Mental Health (RC2-MH089915), and the NIAID (1R56-AI098588-01A1). R.G. is supported by grants from the NephCure Foundation as well as the Doris Duke Clinical Scientist Development Award, and acknowledges that this work was supported by a grant from the Doris Duke Charitable Foundation (2009033). M.P.W. is a recipient of the DukeMed Scholars program. M.S. is supported by the German Research Foundation (SCHI587/4,6). N.H. is supported by an MDIBL New Investigator Award. A.S.S. is supported by the Howard Hughes Medical Institute and the NIDDK. NR 37 TC 29 Z9 31 U1 0 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2014 VL 25 IS 9 BP 1991 EP 2002 DI 10.1681/ASN.2013090976 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA AO1FY UT WOS:000341059200015 PM 24676636 ER PT J AU Shaikh, QN Memon, AA Kamal, AK AF Shaikh, Quratulain Nauman Memon, Adeel Ali Kamal, Ayeesha Kamran TI The impact of green tea and coffee consumption on risk of stroke in Japanese population SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CANCER C1 [Shaikh, Quratulain Nauman; Memon, Adeel Ali; Kamal, Ayeesha Kamran] Aga Khan Univ, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Res Team, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Res Team, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660] NR 4 TC 1 Z9 1 U1 0 U2 2 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD SEP PY 2014 VL 64 IS 9 BP 1094 EP 1094 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AO1MQ UT WOS:000341076600025 PM 25823197 ER PT J AU Mohiuddin, MM Singh, AK Corcoran, PC Hoyt, RF Thomas, ML Ayares, D Horvath, KA AF Mohiuddin, Muhammad M. Singh, Avneesh K. Corcoran, Philip C. Hoyt, Robert F. Thomas, Marvin L., III Ayares, David Horvath, Keith A. TI Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID ANTI-CD154 MONOCLONAL-ANTIBODY; HEART-TRANSPLANTATION; XENOGRAFT SURVIVAL; BABOON MODEL; BLOCKADE; PROGRESS; GAL AB Objectives: Cardiac transplantation and available mechanical alternatives are the only possible solutions for end-stage cardiac disease. Unfortunately, because of the limited supply of human organs, xenotransplantation may be the ideal method to overcome this shortage. We have recently seen significant prolongation of heterotopic cardiac xenograft survival from 3 to 12 months and beyond. Methods: Hearts from genetically engineered piglets that were alpha 1-3 galactosidase transferase knockout and expressed the human complement regulatory gene, CD46 (groups A-C), and the human thrombomodulin gene (group D) were heterotropically transplanted in baboons treated with antithymocyte globulin, cobra venom factor, anti-CD20 antibody, and costimulation blockade (anti-CD154 antibody [clone 5C8]) in group A, anti-CD40 antibody (clone 3A8; 20 mg/kg) in group B, clone 2C10R4 (25 mg/kg) in group C, or clone 2C10R4 (50 mg/kg) in group D, along with conventional nonspecific immunosuppressive agents. Results: Group A grafts (n = 8) survived for an average of 70 days, with the longest survival of 236 days. Some animals in this group (n = 3) developed microvascular thrombosis due to platelet activation and consumption, which resulted in spontaneous hemorrhage. The median survival time was 21 days in group B (n = 3), 80 days in group C (n = 6), and more than 200 days in group D (n = 5). Three grafts in group D are still contracting well, with the longest ongoing graft survival surpassing the 1-year mark. Conclusions: Genetically engineered pig hearts (GTKOhTg.hCD46.hTBM) with modified targeted immunosuppression (anti-CD40 monoclonal antibody) achieved long-term cardiac xenograft survival. This potentially paves the way for clinical xenotransplantation if similar survival can be reproduced in an orthotopic transplantation model. C1 [Mohiuddin, Muhammad M.; Singh, Avneesh K.; Corcoran, Philip C.; Horvath, Keith A.] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Hoyt, Robert F.] Leidos Biomed Res Inc, Frederick Natl Labs, Frederick, MD USA. [Thomas, Marvin L., III] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RP Mohiuddin, MM (reprint author), NHLBI, CSRP, NIH, Bldg 10,Rm B1D47G,10 Ctr Dr,MSC 1550, Bethesda, MD 20892 USA. EM mohiuddinm@mail.nih.gov RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X FU NHLBI NIH HHS [HHSN268201300001C] NR 23 TC 38 Z9 39 U1 5 U2 41 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2014 VL 148 IS 3 BP 1106 EP 1113 DI 10.1016/j.jtcvs.2014.06.002 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA AN9PF UT WOS:000340938700079 PM 24998698 ER PT J AU Zhou, YF Singh, AK Hoyt, RF Wang, SN Yu, ZX Hunt, T Kindzelski, B Corcoran, PC Mohiuddin, MM Horvath, KA AF Zhou, Yifu Singh, Avneesh K. Hoyt, Robert F., Jr. Wang, Suna Yu, Zuxi Hunt, Timothy Kindzelski, Bogdan Corcoran, Philip C. Mohiuddin, Muhammad M. Horvath, Keith A. TI Regulatory T cells enhance mesenchymal stem cell survival and proliferation following autologous cotransplantation in ischemic myocardium SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID COLONY-STIMULATING FACTOR; CORONARY-ARTERY-DISEASE; TOPCARE-AMI; REGENERATION ENHANCEMENT; VENTRICULAR-FUNCTION; PENETRATING PEPTIDE; PROGENITOR CELLS; HEART-FAILURE; TRANSPLANTATION; INFARCTION AB Objectives: We sought to investigate if autologous freshly isolated regulatory T cells (Tregs) provide a protective and supportive role when cotransplanted with mesenchymal stem cells (MSCs). Methods: In a porcine model of chronic ischemia, autologous MSCs were isolated and expanded ex vivo for 4 weeks. Autologous Treg cells were freshly isolated from 100 mL peripheral blood and purified by fluorescence-activated cell sorting. MSCs and Treg cells were then cotransplanted into the chronic ischemic myocardium of Yorkshire pigs by direct intramyocardial injection (1.2 x 10(8) MSCs plus an average of 1.5 million Treg cells in 25 injection sites). Animals were killed 6 weeks postinjection to study the fate of the cells and compare the effect of combined MSCs + Treg cells transplantation versus MSCs alone. Results: The coinjection of MSCs along with Tregs was safe and no deleterious side effects were observed. Six weeks after injection of the cell combination, spherical MSCs clusters with thin layer capsules were found in the injected areas. In animals treated with MSCs only, the MSC clusters were less organized and not encapsulated. Immunofluorescent staining showed CD25+ cells among the CD90+ (MSC marker) cells, suggesting that the injected Treg cells remained present locally, and survived. Factor VIII+ cells were also prevalent suggesting new angiogenesis. We found no evidence that coinjections were associated with the generation of cardiac myocytes. Conclusions: The cotransplantation of Treg cells with MSCs dramatically increased the MSC survival rate, proliferation, and augmented their role in angiogenesis, which suggests a new way for future clinical application of cell-based therapy. C1 [Zhou, Yifu; Singh, Avneesh K.; Hoyt, Robert F., Jr.; Wang, Suna; Yu, Zuxi; Hunt, Timothy; Kindzelski, Bogdan; Corcoran, Philip C.; Mohiuddin, Muhammad M.; Horvath, Keith A.] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. RP Zhou, YF (reprint author), CSRP NHLBI, Cellular Biol Sect, NIH, 10 Ctr Dr,MSC 1550,Bldg 10,Rm B1-D47, Bethesda, MD 20892 USA. EM zhouyifu@mail.nih.gov RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X FU Intramural NIH HHS [Z99 HL999999] NR 29 TC 9 Z9 10 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2014 VL 148 IS 3 BP 1131 EP 1137 DI 10.1016/j.jtcvs.2014.06.029 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA AN9PF UT WOS:000340938700085 PM 25052825 ER PT J AU Kwa, S Lai, LL Gangadhara, S Siddiqui, M Pillai, VB Labranche, C Yu, TW Moss, B Montefiori, DC Robinson, HL Kozlowski, PA Amara, RR AF Kwa, Suefen Lai, Lilin Gangadhara, Sailaja Siddiqui, Mariam Pillai, Vinod B. Labranche, Celia Yu, Tianwei Moss, Bernard Montefiori, David C. Robinson, Harriet L. Kozlowski, Pamela A. Amara, Rama Rao TI CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus SIV239 Vaccine Enhances SIV-Specific Humoral and Cellular Immunity and Improves Protection against a Heterologous SIVE660 Mucosal Challenge SO JOURNAL OF VIROLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; EXPRESSING CD40 LIGAND; IN-VIVO; DNA VACCINATION; RHESUS MACAQUES; DNA/MVA VACCINE; T-LYMPHOCYTES; CUTTING EDGE; CD154; ACQUISITION AB It remains a challenge to develop a successful human immunodeficiency virus (HIV) vaccine that is capable of preventing infection. Here, we utilized the benefits of CD40L, a costimulatory molecule that can stimulate both dendritic cells (DCs) and B cells, as an adjuvant for our simian immunodeficiency virus (SIV) DNA vaccine in rhesus macaques. We coexpressed the CD40L with our DNA/SIV vaccine such that the CD40L is anchored on the membrane of SIV virus-like particle (VLP). These CD40L containing SIV VLPs showed enhanced activation of DCs in vitro. We then tested the potential of DNA/SIV-CD40L vaccine to adjuvant the DNA prime of a DNA/modified vaccinia virus Ankara (MVA) vaccine in rhesus macaques. Our results demonstrated that the CD40L adjuvant enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV CD8 and CD4 T cell responses, significantly delayed the acquisition of heterologous mucosal SIV infection, and improved viral control. Notably, the CD40L adjuvant enhanced the control of viral replication in the gut at the site of challenge that was associated with lower mucosal CD8 immune activation, one of the strong predictors of disease progression. Collectively, our results highlight the benefits of CD40L adjuvant for enhancing antiviral humoral and cellular immunity, leading to enhanced protection against a pathogenic SIV. A single adjuvant that enhances both humoral and cellular immunity is rare and thus underlines the importance and practicality of CD40L as an adjuvant for vaccines against infectious diseases, including HIV-1. IMPORTANCE Despite many advances in the field of AIDS research, an effective AIDS vaccine that can prevent infection remains elusive. CD40L is a key stimulator of dendritic cells and B cells and can therefore enhance T cell and antibody responses, but its overly potent nature can lead to adverse effects unless used in small doses. In order to modulate local expression of CD40L at relatively lower levels, we expressed CD40L in a membrane-bound form, along with SIV antigens, in a nucleic acid (DNA) vector. We tested the immunogenicity and efficacy of the CD40L-adjuvanted vaccine in macaques using a heterologous mucosal SIV infection. The CD40L-adjuvanted vaccine enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV T cell responses and improved protection. These results demonstrate that VLP-membrane-bound CD40L serves as a novel adjuvant for an HIV vaccine. C1 [Kwa, Suefen; Lai, Lilin; Gangadhara, Sailaja; Siddiqui, Mariam; Pillai, Vinod B.; Amara, Rama Rao] Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Labranche, Celia; Montefiori, David C.] Duke Univ, Dept Surg, Durham, NC USA. [Yu, Tianwei] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Robinson, Harriet L.] GeoVax Inc, Smyrna, GA USA. [Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA USA. RP Amara, RR (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. EM ramara@emory.edu FU NIH/National Institute of Allergy and Infectious Disease (NIAID) [R01 AI057029, R01 AI071852, R01 AI074417, P01 AI088575]; Office of Research Infrastructure Programs [P51OD011132]; NIH [P30 AI050409]; Division of Intramural Research, NIAID/NIH; [HHSN27201100016C] FX This study was supported by NIH/National Institute of Allergy and Infectious Disease (NIAID) grants R01 AI057029, R01 AI071852, R01 AI074417, and P01 AI088575 to R.R.A., NCRR (currently supported by the Office of Research Infrastructure Programs) grant P51OD011132 to Yerkes National Primate Research Center, NIH grant P30 AI050409 to Emory CFAR, an HHSN27201100016C grant to D.C.M., and Division of Intramural Research, NIAID/NIH, support to B.M. NR 45 TC 19 Z9 20 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 17 BP 9579 EP 9589 DI 10.1128/JVI.00975-14 PG 11 WC Virology SC Virology GA AO3LW UT WOS:000341232300009 PM 24920805 ER PT J AU Kim, SH Chen, S Jiang, X Green, KY Samal, SK AF Kim, Shin-Hee Chen, Shun Jiang, Xi Green, Kim Y. Samal, Siba K. TI Newcastle Disease Virus Vector Producing Human Norovirus-Like Particles Induces Serum, Cellular, and Mucosal Immune Responses in Mice SO JOURNAL OF VIROLOGY LA English DT Article ID AVIAN INFLUENZA-VIRUS; VACCINE VECTOR; CAPSID PROTEIN; FOREIGN GENE; IMMUNIZATION; ANTIBODIES; EXPRESSION; CHALLENGE; PRIMATES; GASTROENTERITIS AB Human norovirus infection is the most common cause of viral gastroenteritis worldwide. Development of an effective vaccine is required for reducing norovirus outbreaks. The inability to grow human norovirus in cell culture has hindered the development of live-attenuated vaccines. To overcome this obstacle, we generated a recombinant Newcastle disease virus (rNDV)-vectored experimental norovirus vaccine by expressing the capsid protein (VP1) of norovirus strain VA387. We compared two different NDV vectors, a conventional rNDV vector and a modified rNDV vector, for their efficiencies in expressing VP1 protein. Our results showed that the modified vector replicated to higher titers and expressed higher levels of VP1 protein in DF1 cells and in allantoic fluid of embryonated chicken eggs than did the conventional vector. We further demonstrated that the VP1 protein produced by rNDVs was able to self-assemble into virus-like particles (VLPs) that are morphologically similar to baculovirus-expressed VLPs. Evaluation of their immunogenicity in mice showed that the modified rNDV vector induced a higher level of IgG response than those induced by the conventional vector and by the baculovirus-expressed VLPs. The rNDV vectors predominantly induced IgG2a subclass antibody for the Th1 response, and specifically, high levels of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-2 (IL-2) were detected in splenocytes. In addition, the modified rNDV vector induced a higher level of fecal IgA response in mice than did baculovirus-expressed VLPs. Our findings suggest that the rNDV vector is an efficient system to produce cost-effective VLPs in embryonated chicken eggs and has the potential to be used as a live-attenuated vaccine in humans. IMPORTANCE Noroviruses are the major cause of viral gastroenteritis worldwide. Currently, effective vaccines against norovirus infection are not available. In this study, we have evaluated Newcastle disease virus (NDV) as a vaccine vector for norovirus. Our results suggest that NDV can be used not only as a cost-effective method for large-scale production of norovirus-like particle vaccines but also as a live-attenuated vectored vaccine. C1 [Kim, Shin-Hee; Chen, Shun; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Jiang, Xi] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Coll Med, Div Infect Dis, Cincinnati, OH USA. [Green, Kim Y.] NIAID, Infect Dis Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU NIAID [1R21AI100195] FX This research was supported by the NIAID (1R21AI100195). NR 41 TC 9 Z9 11 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 17 BP 9718 EP 9727 DI 10.1128/JVI.01570-14 PG 10 WC Virology SC Virology GA AO3LW UT WOS:000341232300021 PM 24920815 ER PT J AU Laliberte, JP Moss, B AF Laliberte, Jason P. Moss, Bernard TI A Novel Mode of Poxvirus Superinfection Exclusion That Prevents Fusion of the Lipid Bilayers of Viral and Cellular Membranes SO JOURNAL OF VIROLOGY LA English DT Article ID VACCINIA VIRUS ENTRY; SERINE-PROTEASE INHIBITOR; INFECTED-CELLS; F11L-MEDIATED INHIBITION; PROTEINS SPI-3; EARLY GENES; IN-VITRO; EXPRESSION; VIRION; INTERFERENCE AB Superinfection exclusion is a widespread phenomenon that prevents secondary infections by closely related viruses. The vaccinia virus A56 and K2 proteins in the cell membrane can prevent superinfection by interacting with the entry-fusion complex of subsequent viruses. Here, we described another form of exclusion that is established earlier in infection and does not require the A56 or K2 protein. Cells infected with one or more infectious virions excluded hundreds of superinfecting vaccinia virus particles. A related orthopoxvirus, but neither a flavivirus nor a rhabdovirus, was also excluded, indicating selectivity. Although superinfecting vaccinia virus bound to cells, infection was inhibited at the membrane fusion step, thereby preventing core entry into the cytoplasm and early gene expression. In contrast, A56/K2 protein-mediated exclusion occurred subsequent to membrane fusion. Induction of resistance to superinfection depended on viral RNA and protein synthesis by the primary virus but did not require DNA replication. Although superinfection resistance correlated with virus-induced changes in the cytoskeleton, studies with mutant vaccinia viruses indicated that the cytoskeletal changes were not necessary for resistance to superinfection. Interferon-inducible transmembrane proteins, which can inhibit membrane fusion in other viral systems, did not prevent vaccinia virus membrane fusion, suggesting that these interferon-inducible proteins are not involved in superinfection exclusion. While the mechanism remains to be determined, the early establishment of superinfection exclusion may provide a "winner-take-all" reward to the first poxvirus particles that successfully initiate infection and prevent the entry and genome reproduction of defective or less fit particles. IMPORTANCE The replication of a virus usually follows a defined sequence of events: attachment, entry into the cytoplasm or nucleus, gene expression, genome replication, assembly of infectious particles, and spread to other cells. Although multiple virus particles may enter a cell at the same time, mechanisms exist to prevent infection by subsequent viruses. The latter phenomenon, known as superinfection exclusion, can occur by a variety of mechanisms that are not well understood. We showed that superinfection by vaccinia virus was prevented at the membrane fusion step, which closely followed virion attachment. Thus, neither gene expression nor genome replication of the superinfecting virus occurred. Expression of early proteins by the primary virus was necessary and sufficient to induce the superinfection-resistant state. Superinfection exclusion may be beneficial to vaccinia virus by selecting particles that can infect cells rapidly, excluding defective particles and synchronizing the replication cycle. C1 [Laliberte, Jason P.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@mail.nih.gov NR 69 TC 10 Z9 10 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 17 BP 9751 EP 9768 DI 10.1128/JVI.00816-14 PG 18 WC Virology SC Virology GA AO3LW UT WOS:000341232300024 PM 24920806 ER PT J AU Zhang, S McDonald, PW Thompson, TA Dennis, AF Akopov, A Kirkness, EF Patton, JT McDonald, SM AF Zhang, Shu McDonald, Paul W. Thompson, Travis A. Dennis, Allison F. Akopov, Asmik Kirkness, Ewen F. Patton, John T. McDonald, Sarah M. TI Analysis of Human Rotaviruses from a Single Location Over an 18-Year Time Span Suggests that Protein Coadaption Influences Gene Constellations SO JOURNAL OF VIROLOGY LA English DT Article ID GROUP-A ROTAVIRUSES; DOUBLE-REASSORTANT ROTAVIRUS; LINKED-IMMUNOSORBENT-ASSAY; RNA VIRUS EVOLUTION; ACUTE GASTROENTERITIS; GENOMIC CHARACTERIZATION; GENOTYPE CONSTELLATION; NETWORK RELATIONSHIP; MAXIMUM-LIKELIHOOD; ANIMAL ROTAVIRUSES AB Rotaviruses (RVs) are 11-segmented, double-stranded RNA viruses that cause severe gastroenteritis in children. In addition to an error-prone genome replication mechanism, RVs can increase their genetic diversity by reassorting genes during host coinfection. Such exchanges allow RVs to acquire advantageous genes and adapt in the face of selective pressures. However, reassortment may also impose fitness costs if it unlinks genes/proteins that have accumulated compensatory, coadaptive mutations and that operate best when kept together. To better understand human RV evolutionary dynamics, we analyzed the genome sequences of 135 strains (genotype G1/G3/G4-P[8]-I1-C1-R1-A1-N1-T1-E1-H1) that were collected at a single location in Washington, DC, during the years 1974 to 1991. Intragenotypic phylogenetic trees were constructed for each viral gene using the nucleotide sequences, thereby defining novel allele level gene constellations (GCs) and illuminating putative reassortment events. The results showed that RVs with distinct GCs cocirculated during the vast majority of the collection years and that some of these GCs persisted in the community unchanged by reassortment. To investigate the influence of protein coadaptation on GC maintenance, we performed a mutual information-based analysis of the concatenated amino acid sequences and identified an extensive covariance network. Unexpectedly, amino acid covariation was highest between VP4 and VP2, which are structural components of the RV virion that are not thought to directly interact. These results suggest that GCs may be influenced by the selective constraints placed on functionally coadapted, albeit noninteracting, viral proteins. This work raises important questions about mutation-reassortment interplay and its impact on human RV evolution. IMPORTANCE Rotaviruses are devastating human pathogens that cause severe diarrhea and kill > 450,000 children each year. The virus can evolve by accumulating mutations and by acquiring new genes from other strains via a process called reassortment. However, little is known about the relationship between mutation accumulation and gene reassortment for rotaviruses and how it impacts viral evolution. In this study, we analyzed the genome sequences of human strains found in clinical fecal specimens that were collected at a single hospital over an 18-year time span. We found that many rotaviruses did not reassort their genes but instead maintained them as specific sets (i.e., constellations). By analyzing the encoded proteins, we discovered concurrent amino acid changes among them, which suggests that they are functionally coadapted to operate best when kept together. This study increases our understanding of how rotaviruses evolve over time in the human population. C1 [Zhang, Shu; McDonald, Paul W.; Thompson, Travis A.; McDonald, Sarah M.] Virginia Tech Caril Sch Med, Roanoke, VA 24016 USA. [Zhang, Shu; McDonald, Paul W.; Thompson, Travis A.; McDonald, Sarah M.] Res Inst, Roanoke, VA USA. [Dennis, Allison F.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Akopov, Asmik; Kirkness, Ewen F.] J Craig Venter Inst, Rockville, MD USA. [McDonald, Sarah M.] Virginia Polytech Inst & State Univ, Virginia Maryland Reg Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA 24061 USA. RP McDonald, SM (reprint author), Virginia Tech Caril Sch Med, Roanoke, VA 24016 USA. EM mcdonaldsa@vtc.vt.edu RI Patton, John/P-1390-2014 FU Virginia Tech Carilion Research Institute; Virginia Tech Carilion School of Medicine; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900007C] FX S.Z., T.A.T., P.W.M., and S.M.M. were supported by laboratory start-up funds from the Virginia Tech Carilion Research Institute. T.A.T. was also supported by funds from the Virginia Tech Carilion School of Medicine. J.T.P. and A.F.D. were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. This project was also supported in part by federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (contract no. HHSN272200900007C). NR 80 TC 9 Z9 9 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 17 BP 9842 EP 9863 DI 10.1128/JVI.01562-14 PG 22 WC Virology SC Virology GA AO3LW UT WOS:000341232300032 PM 24942570 ER PT J AU Kindrachuk, J Wahl-Jensen, V Safronetz, D Trost, B Hoenen, T Arsenault, R Feldmann, F Traynor, D Postnikova, E Kusalik, A Napper, S Blaney, JE Feldmann, H Jahrling, PB AF Kindrachuk, Jason Wahl-Jensen, Victoria Safronetz, David Trost, Brett Hoenen, Thomas Arsenault, Ryan Feldmann, Friederike Traynor, Dawn Postnikova, Elena Kusalik, Anthony Napper, Scott Blaney, Joseph E. Feldmann, Heinz Jahrling, Peter B. TI Ebola Virus Modulates Transforming Growth Factor beta Signaling and Cellular Markers of Mesenchyme-Like Transition in Hepatocytes SO JOURNAL OF VIROLOGY LA English DT Article ID MARBURG HEMORRHAGIC-FEVER; INNATE IMMUNE-RESPONSE; GENE-EXPRESSION; IN-VITRO; FILOVIRUS INFECTION; ENDOTHELIAL-CELLS; HUMAN MACROPHAGES; PRIMATE MODELS; IFN-ALPHA; PATHOGENESIS AB Ebola virus (EBOV) causes a severe hemorrhagic disease in humans and nonhuman primates, with a median case fatality rate of 78.4%. Although EBOV is considered a public health concern, there is a relative paucity of information regarding the modulation of the functional host response during infection. We employed temporal kinome analysis to investigate the relative early, intermediate, and late host kinome responses to EBOV infection in human hepatocytes. Pathway overrepresentation analysis and functional network analysis of kinome data revealed that transforming growth factor (TGF-beta)-mediated signaling responses were temporally modulated in response to EBOV infection. Upregulation of TGF-beta signaling in the kinome data sets correlated with the upregulation of TGF-beta secretion from EBOV-infected cells. Kinase inhibitors targeting TGF-beta signaling, or additional cell receptors and downstream signaling pathway intermediates identified from our kinome analysis, also inhibited EBOV replication. Further, the inhibition of select cell signaling intermediates identified from our kinome analysis provided partial protection in a lethal model of EBOV infection. To gain perspective on the cellular consequence of TGF-beta signaling modulation during EBOV infection, we assessed cellular markers associated with upregulation of TGF-beta signaling. We observed upregulation of matrix metalloproteinase 9, N-cadherin, and fibronectin expression with concomitant reductions in the expression of E-cadherin and claudin-1, responses that are standard characteristics of an epithelium-to-mesenchyme-like transition. Additionally, we identified phosphorylation events downstream of TGF-beta that may contribute to this process. From these observations, we propose a model for a broader role of TGF-beta -mediated signaling responses in the pathogenesis of Ebola virus disease. IMPORTANCE Ebola virus (EBOV), formerly Zaire ebolavirus, causes a severe hemorrhagic disease in humans and nonhuman primates and is the most lethal Ebola virus species, with case fatality rates of up to 90%. Although EBOV is considered a worldwide concern, many questions remain regarding EBOV molecular pathogenesis. As it is appreciated that many cellular processes are regulated through kinase-mediated phosphorylation events, we employed temporal kinome analysis to investigate the functional responses of human hepatocytes to EBOV infection. Administration of kinase inhibitors targeting signaling pathway intermediates identified in our kinome analysis inhibited viral replication in vitro and reduced EBOV pathogenesis in vivo. Further analysis of our data also demonstrated that EBOV infection modulated TGF-beta -mediated signaling responses and promoted "mesenchyme-like" phenotypic changes. Taken together, these results demonstrated that EBOV infection specifically modulates TGF-beta -mediated signaling responses in epithelial cells and may have broader implications in EBOV pathogenesis. C1 [Kindrachuk, Jason; Blaney, Joseph E.; Jahrling, Peter B.] Natl Inst Allergy & Infect Dis, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. [Kindrachuk, Jason; Wahl-Jensen, Victoria; Traynor, Dawn; Postnikova, Elena; Jahrling, Peter B.] Natl Inst Allergy & Infect Dis, Div Clin Res, Integrated Res Facil, NIH, Frederick, MD USA. [Safronetz, David; Hoenen, Thomas; Feldmann, Heinz] Natl Inst Allergy & Infect Dis, Div Intramural Res, Virol Lab, NIH, Hamilton, MT USA. [Trost, Brett; Kusalik, Anthony] Univ Saskatchewan, Dept Comp Sci, Saskatoon, SK S7N 0W0, Canada. [Arsenault, Ryan; Napper, Scott] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 0W0, Canada. [Arsenault, Ryan; Napper, Scott] Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK, Canada. [Feldmann, Friederike] Natl Inst Allergy & Infect Dis, Div Intramural Res, Rocky Mt Vet Branch, NIH, Hamilton, MT USA. [Wahl-Jensen, Victoria] Natl Biodef Anal & Countermeasures Ctr, Frederick, MD USA. RP Kindrachuk, J (reprint author), Natl Inst Allergy & Infect Dis, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. EM kindrachuk.kenneth@nih.gov RI Trost, Brett/K-4127-2016; OI Trost, Brett/0000-0003-4863-7273; Kindrachuk, Jason/0000-0002-3305-7084 FU NIAID Division of Intramural Research; NIAID [HHSN272200700016I] FX This study was supported in part by the NIAID Division of Intramural Research. We also thank Lydia Kibiuk (NIH Medical Arts & Design) for her illustrations and Catherine Jett for her contributions to the Bioplex analysis. We thank Jens Kuhn for critical review of the manuscript.; J.K. performed this work partially as an employee of Battelle Memorial Institute, and V.W.-J. performed this work partially as an employee of Tunnell Government Services, Inc., both under Battelle Memorial Institute's prime contract with NIAID, contract no. HHSN272200700016I. NR 68 TC 10 Z9 11 U1 0 U2 81 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 17 BP 9877 EP 9892 DI 10.1128/JVI.01410-14 PG 16 WC Virology SC Virology GA AO3LW UT WOS:000341232300034 PM 24942569 ER PT J AU Smith, JL Izumi, T Borbet, TC Hagedorn, AN Pathak, VK AF Smith, Jessica L. Izumi, Taisuke Borbet, Timothy C. Hagedorn, Ariel N. Pathak, Vinay K. TI HIV-1 and HIV-2 Vif Interact with Human APOBEC3 Proteins Using Completely Different Determinants SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SINGLE AMINO-ACID; VIRION INFECTIVITY FACTOR; FUSION INHIBITOR T-20; CD4(+) T-CELLS; ANTIVIRAL ACTIVITY; CYTIDINE DEAMINASE; ENZYME APOBEC3G; CBF-BETA; DNA AB Human APOBEC3 (A3) restriction factors provide intrinsic immunity against zoonotic transmission of pathogenic viruses. A3D, A3F, A3G, and A3H haplotype II (A3H-hapII) can be packaged into virion infectivity factor (Vif)-deficient HIVs to inhibit viral replication. To overcome these restriction factors, Vif binds to the A3 proteins in viral producer cells to target them for ubiquitination and proteasomal degradation, thus preventing their packaging into assembling virions. Therefore, the Vif-A3 interactions are attractive targets for novel drug development. HIV-1 and HIV-2 arose via distinct zoonotic transmission events of simian immunodeficiency viruses from chimpanzees and sooty mangabeys, respectively, and Vifs from these viruses have limited homology. To gain insights into the evolution of virus-host interactions that led to successful cross-species transmission of lentiviruses, we characterized the determinants of the interaction between HIV-2 Vif (Vif2) with human A3 proteins and compared them to the previously identified HIV-1 Vif (Vif1) interactions with the A3 proteins. We found that A3G, A3F, and A3H-hapII, but not A3D, were susceptible to Vif2-induced degradation. Alanine-scanning mutational analysis of the first 62 amino acids of Vif2 indicated that Vif2 determinants important for degradation of A3G and A3F are completely distinct from these regions in Vif1, as are the determinants in A3G and A3F that are critical for Vif2-induced degradation. These observations suggest that distinct Vif-A3 interactions evolved independently in different SIVs and their nonhuman primate hosts and conservation of the A3 determinants targeted by the SIV Vif proteins resulted in successful zoonotic transmission into humans. IMPORTANCE Primate APOBEC3 proteins provide innate immunity against invading pathogens, and Vif proteins of primate lentiviruses have evolved to overcome these host defenses by interacting with them and inducing their proteasomal degradation. HIV-1 and HIV-2 are two human pathogens that induce AIDS, and elucidating interactions between their Vif proteins and human A3 proteins could facilitate the development of novel antiviral drugs. Furthermore, understanding Vif-A3 interactions can provide novel insights into the cross-species transmission events that led to the HIV-1 and HIV-2 pandemics and evolution of host-virus interactions. We carried out mutational analysis of the N-terminal 62 amino acids of HIV-2 Vif (Vif2) and analyzed A3G/A3F chimeras that retained antiviral activity to identify the determinants of the Vif2 and A3 interaction. Our results show that the Vif2-A3 interactions are completely different from the Vif1-A3 interactions, suggesting that these interactions evolved independently and that conservation of the A3 determinants resulted in successful zoonotic transmission into humans. C1 [Smith, Jessica L.; Izumi, Taisuke; Borbet, Timothy C.; Hagedorn, Ariel N.; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Pathak, VK (reprint author), NCI, Viral Mutat Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21701 USA. EM vinay.pathak@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 72 TC 7 Z9 7 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 17 BP 9893 EP 9908 DI 10.1128/JVI.01318-14 PG 16 WC Virology SC Virology GA AO3LW UT WOS:000341232300035 PM 24942576 ER PT J AU Nelson, MI Wentworth, DE Culhane, MR Vincent, AL Viboud, C LaPointe, MP Lin, XD Holmes, EC Detmer, SE AF Nelson, Martha I. Wentworth, David E. Culhane, Marie R. Vincent, Amy L. Viboud, Cecile LaPointe, Matthew P. Lin, Xudong Holmes, Edward C. Detmer, Susan E. TI Introductions and Evolution of Human-Origin Seasonal Influenza A Viruses in Multinational Swine Populations SO JOURNAL OF VIROLOGY LA English DT Article ID PANDEMIC H1N1 2009; UNITED-STATES; HUMAN INFECTIONS; AMERICAN PIGS; TRANSMISSION; REASSORTMENT; OUTBREAK; EPIDEMIOLOGY; ARGENTINA; EMERGENCE AB The capacity of influenza A viruses to cross species barriers presents a continual threat to human and animal health. Knowledge of the human-swine interface is particularly important for understanding how viruses with pandemic potential evolve in swine hosts. We sequenced the genomes of 141 influenza viruses collected from North American swine during 2002 to 2011 and identified a swine virus that possessed all eight genome segments of human seasonal A/H3N2 virus origin. A molecular clock analysis indicates that this virus-A/sw/Saskatchewan/02903/2009(H3N2)-has likely circulated undetected in swine for at least 7 years. For historical context, we performed a comprehensive phylogenetic analysis of an additional 1,404 whole-genome sequences from swine influenza A viruses collected globally during 1931 to 2013. Human-to-swine transmission occurred frequently over this time period, with 20 discrete introductions of human seasonal influenza A viruses showing sustained onward transmission in swine for at least 1 year since 1965. Notably, human-origin hemagglutinin (H1 and H3) and neuraminidase (particularly N2) segments were detected in swine at a much higher rate than the six internal gene segments, suggesting an association between the acquisition of swine-origin internal genes via reassortment and the adaptation of human influenza viruses to new swine hosts. Further understanding of the fitness constraints on the adaptation of human viruses to swine, and vice versa, at a genomic level is central to understanding the complex multihost ecology of influenza and the disease threats that swine and humans pose to each other. IMPORTANCE The swine origin of the 2009 A/H1N1 pandemic virus underscored the importance of understanding how influenza A virus evolves in these animals hosts. While the importance of reassortment in generating genetically diverse influenza viruses in swine is well documented, the role of human-to-swine transmission has not been as intensively studied. Through a large-scale sequencing effort, we identified a novel influenza virus of wholly human origin that has been circulating undetected in swine for at least 7 years. In addition, we demonstrate that human-to-swine transmission has occurred frequently on a global scale over the past decades but that there is little persistence of human virus internal gene segments in swine. C1 [Nelson, Martha I.; Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Wentworth, David E.; LaPointe, Matthew P.; Lin, Xudong] J Craig Venter Inst, Rockville, MD USA. [Culhane, Marie R.] Univ Minnesota, Vet Diagnost Lab, St Paul, MN 55108 USA. [Vincent, Amy L.] USDA ARS, Natl Anim Dis Ctr, Virus & Prion Res Unit, Ames, IA 50010 USA. [Holmes, Edward C.] Univ Sydney, Charles Perkins Ctr, Sch Biol Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Detmer, Susan E.] Univ Saskatchewan, Western Coll Vet Med, Saskatoon, SK S7N 0W0, Canada. RP Nelson, MI (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM nelsonma@mail.nih.gov OI Wentworth, David/0000-0002-5190-980X; Holmes, Edward/0000-0001-9596-3552 FU Saskatchewan Ministry of Agriculture [C70077]; Multinational Influenza Seasonal Mortality Study (MISMS); Fogarty International Center; National Institutes of Health; Office of Global Affairs at the Department of Health and Human Services; National Institute of Allergy and Infectious Diseases; National Institutes of Health, Department of Health and Human Services [HHSN272200900007C]; NHMRC Australia Fellowship FX Partial support for this work was provided by a grant from the Saskatchewan Ministry of Agriculture, contract number C70077. This work was supported in part by the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiology and evolution, led by the Fogarty International Center, National Institutes of Health, with funding from the Office of Global Affairs at the Department of Health and Human Services [MIN, CV]. This project has also been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract number HHSN272200900007C. E.C.H. is supported by an NHMRC Australia Fellowship. NR 45 TC 21 Z9 21 U1 1 U2 22 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 17 BP 10110 EP 10119 DI 10.1128/JVI.01080-14 PG 10 WC Virology SC Virology GA AO3LW UT WOS:000341232300051 PM 24965467 ER PT J AU Williams, LD Amatya, N Bansal, A Sabbaj, S Heath, SL Sereti, I Goepfert, PA AF Williams, LaTonya D. Amatya, Nilesh Bansal, Anju Sabbaj, Steffanie Heath, Sonya L. Sereti, Irini Goepfert, Paul A. TI Immune Activation Is Associated with CD8 T Cell Interleukin-21 Production in HIV-1-Infected Individuals SO JOURNAL OF VIROLOGY LA English DT Article ID CHRONIC VIRAL-INFECTION; CD4-DEFICIENT MICE; IL-21; LYMPHOCYTES; RESPONSES; AUTOIMMUNITY; EOMESODERMIN; SIVAGM; CANCER AB Interleukin-21 (IL-21) can be produced by CD8 T cells from HIV-1-infected individuals and those with autoimmune disease, but the mechanism remains poorly understood. Here we demonstrate that IL-21-producing CD8 T cells are not associated with CD4 depletion and are absent in patients with idiopathic CD4 lymphocytopenia. Instead, IL-21 production by CD8 T cells was associated with high levels of activation, suggesting that these cells emerge as a consequence of excessive chronic immune activation rather than CD4 lymphopenia. C1 [Williams, LaTonya D.; Goepfert, Paul A.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Amatya, Nilesh; Bansal, Anju; Sabbaj, Steffanie; Heath, Sonya L.; Goepfert, Paul A.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Goepfert, PA (reprint author), Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. EM paulg@uab.edu OI Sabbaj, Steffanie/0000-0003-4052-6819; Amatya, Nilesh/0000-0002-7942-1742 FU National Institutes of Health [R01 AI082966, AI084772, T32 AI007051, F31 AI085970, T32 AI007392, P30 AI027767, P30 AI64510]; Bill & Melinda Gates Foundation [37874]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This work was supported by National Institutes of Health grants R01 AI082966 and AI084772 and Bill & Melinda Gates Foundation grant 37874 to P.A.G. and NIH grants T32 AI007051, F31 AI085970, and T32 AI007392 to L.D.W. I.S. was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. Flow cytometry was performed, in part, at the UAB Center for AIDS Research Flow Cytometry Core (funded by NIH grant P30 AI027767) and the Duke University Center for AIDS Research Flow Cytometry Facility (funded by NIH grant P30 AI64510). NR 30 TC 4 Z9 4 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 17 BP 10259 EP 10263 DI 10.1128/JVI.00764-14 PG 5 WC Virology SC Virology GA AO3LW UT WOS:000341232300064 PM 24942568 ER PT J AU Do, T Murphy, G Earl, LA Del Prete, GQ Grandinetti, G Li, GH Estes, JD Rao, P Trubey, CM Thomas, J Spector, J Bliss, D Nath, A Lifson, JD Subramaniam, S AF Thao Do Murphy, Gavin Earl, Lesley A. Del Prete, Gregory Q. Grandinetti, Giovanna Li, Guan-Han Estes, Jacob D. Rao, Prashant Trubey, Charles M. Thomas, James Spector, Jeffrey Bliss, Donald Nath, Avindra Lifson, Jeffrey D. Subramaniam, Sriram TI Three-Dimensional Imaging of HIV-1 Virological Synapses Reveals Membrane Architectures Involved in Virus Transmission SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TO-CELL TRANSMISSION; REVERSE TRANSCRIPTION; ELECTRON-MICROSCOPY; TYPE-1; ASTROCYTES; INFECTION; SPREAD; ENTRY; AIDS AB HIV transmission efficiency is greatly increased when viruses are transmitted at virological synapses formed between infected and uninfected cells. We have previously shown that virological synapses formed between HIV-pulsed mature dendritic cells (DCs) and uninfected T cells contain interdigitated membrane surfaces, with T cell filopodia extending toward virions sequestered deep inside invaginations formed on the DC membrane. To explore membrane structural changes relevant to HIV transmission across other types of intercellular conjugates, we used a combination of light and focused ion beam scanning electron microscopy (FIB-SEM) to determine the three-dimensional (3D) architectures of contact regions between HIV-1-infected CD4(+) T cells and either uninfected human CD4(+) T cells or human fetal astrocytes. We present evidence that in each case, membrane extensions that originate from the uninfected cells, either as membrane sheets or filopodial bridges, are present and may be involved in HIV transmission from infected to uninfected cells. We show that individual virions are distributed along the length of astrocyte filopodia, suggesting that virus transfer to the astrocytes is mediated, at least in part, by processes originating from the astrocyte itself. Mechanisms that selectively disrupt the polarization and formation of such membrane extensions could thus represent a possible target for reducing viral spread. IMPORTANCE Our findings lead to new insights into unique aspects of HIV transmission in the brain and at T cell-T cell synapses, which are thought to be a predominant mode of rapid HIV transmission early in the infection process. C1 [Thao Do; Murphy, Gavin; Earl, Lesley A.; Grandinetti, Giovanna; Rao, Prashant; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Del Prete, Gregory Q.; Estes, Jacob D.; Trubey, Charles M.; Thomas, James; Lifson, Jeffrey D.] Leidos Biomed Res Inc, Frederick Natl Lab, AIDS & Canc Virus Program, Frederick, MD USA. [Li, Guan-Han; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Spector, Jeffrey] NIST, Gaithersburg, MD 20899 USA. [Bliss, Donald] Natl Lib Med, NIH, Bethesda, MD USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov RI sourisseau, marion/M-7542-2014 FU NIH IATAP program and Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD; intramural program of the NIH, Bethesda, MD; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Science Foundation Graduate Research Fellowship Program FX This work was supported by funds from the NIH IATAP program and Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD (to S.S.), from the intramural program of the NIH, Bethesda, MD (to A.N.), from the National Cancer Institute, National Institutes of Health contract HHSN261200800001E (to J.D.L.), and from the National Science Foundation Graduate Research Fellowship Program (to T.D.). NR 60 TC 16 Z9 16 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 18 BP 10327 EP 10339 DI 10.1128/JVI.00788-14 PG 13 WC Virology SC Virology GA AO3MQ UT WOS:000341234900007 PM 24965444 ER PT J AU Watt, A Moukambi, F Banadyga, L Groseth, A Callison, J Herwig, A Ebihara, H Feldmann, H Hoenen, T AF Watt, Ari Moukambi, Felicien Banadyga, Logan Groseth, Allison Callison, Julie Herwig, Astrid Ebihara, Hideki Feldmann, Heinz Hoenen, Thomas TI A Novel Life Cycle Modeling System for Ebola Virus Shows a Genome Length-Dependent Role of VP24 in Virus Infectivity SO JOURNAL OF VIROLOGY LA English DT Article ID NIEMANN-PICK C1; KARYOPHERIN ALPHA-1; REVERSE GENETICS; ENTRY REQUIRES; MARBURG-VIRUS; REPLICATION; TRANSCRIPTION; PROTEIN; PARTICLES; VP40 AB Work with infectious Ebola viruses is restricted to biosafety level 4 (BSL4) laboratories, presenting a significant barrier for studying these viruses. Life cycle modeling systems, including minigenome systems and transcription-and replication-competent virus-like particle (trVLP) systems, allow modeling of the virus life cycle under BSL2 conditions; however, all current systems model only certain aspects of the virus life cycle, rely on plasmid-based viral protein expression, and have been used to model only single infectious cycles. We have developed a novel life cycle modeling system allowing continuous passaging of infectious trVLPs containing a tetracistronic minigenome that encodes a reporter and the viral proteins VP40, VP24, and GP(1,2). This system is ideally suited for studying morphogenesis, budding, and entry, in addition to genome replication and transcription. Importantly, the specific infectivity of trVLPs in this system was similar to 500-fold higher than that in previous systems. Using this system for functional studies of VP24, we showed that, contrary to previous reports, VP24 only very modestly inhibits genome replication and transcription when expressed in a regulated fashion, which we confirmed using infectious Ebola viruses. Interestingly, we also discovered a genome length-dependent effect of VP24 on particle infectivity, which was previously undetected due to the short length of monocistronic minigenomes and which is due at least partially to a previously unknown function of VP24 in RNA packaging. Based on our findings, we propose a model for the function of VP24 that reconciles all currently available data regarding the role of VP24 in nucleocapsid assembly as well as genome replication and transcription. IMPORTANCE Ebola viruses cause severe hemorrhagic fevers in humans, with no countermeasures currently being available, and must be studied in maximum-containment laboratories. Only a few of these laboratories exist worldwide, limiting our ability to study Ebola viruses and develop countermeasures. Here we report the development of a novel reverse genetics-based system that allows the study of Ebola viruses without maximum-containment laboratories. We used this system to investigate the Ebola virus protein VP24, showing that, contrary to previous reports, it only modestly inhibits virus genome replication and transcription but is important for packaging of genomes into virus particles, which constitutes a previously unknown function of VP24 and a potential antiviral target. We further propose a comprehensive model for the function of VP24 in nucleocapsid assembly. Importantly, on the basis of this approach, it should easily be possible to develop similar experimental systems for other viruses that are currently restricted to maximum-containment laboratories. C1 [Watt, Ari; Banadyga, Logan; Groseth, Allison; Callison, Julie; Ebihara, Hideki; Feldmann, Heinz; Hoenen, Thomas] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Moukambi, Felicien; Groseth, Allison; Herwig, Astrid; Hoenen, Thomas] Univ Marburg, Inst Virol, D-35032 Marburg, Germany. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov; thomas.hoenen@nih.gov OI Hoenen, Thomas/0000-0002-5829-6305 FU NIH; NIAID; Schering Foundation FX This research was supported in part by the Intramural Research Program of the NIH, NIAID, and in part through a postdoctoral scholarship from the Schering Foundation (to T.H.). NR 43 TC 22 Z9 25 U1 1 U2 75 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 18 BP 10511 EP 10524 DI 10.1128/JVI.01272-14 PG 14 WC Virology SC Virology GA AO3MQ UT WOS:000341234900023 PM 24965473 ER PT J AU Perkins, MR Briant, JA Calantone, N Whitted, S Vinton, CL Klatt, NR Ourmanov, I Ortiz, AM Hirsch, VM Brenchley, JM AF Perkins, Molly R. Briant, Judith A. Calantone, Nina Whitted, Sonya Vinton, Carol L. Klatt, Nichole R. Ourmanov, Ilnour Ortiz, Alexandra M. Hirsch, Vanessa M. Brenchley, Jason M. TI Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8 alpha alpha T Cells SO JOURNAL OF VIROLOGY LA English DT Article ID SIV INFECTION; NATURAL HOST; LYMPHOCYTES; RESPONSES; PATHOGENICITY; TRANSMISSION; REPLICATION; MACAQUES; VERVET; AIDS AB African green monkeys (AGMs; genus Chlorocebus) are a natural host of simian immunodeficiency virus (SIVAGM). As they do not develop simian AIDS, there is great interest in understanding how this species has evolved to avoid immunodeficiency. Adult African green monkeys naturally have low numbers of CD4 T cells and a large population of major histocompatibility complex class II-restricted CD8 alpha(dim) T cells that are generated through CD4 downregulation in CD4(+) T cells. Mechanisms that drive this process of CD4 downregulation are unknown. Here, we show that juvenile AGMs accelerate CD4-to-CD8 alpha alpha conversion upon SIV infection and avoid progression to AIDS. The CD4 downregulation induced by SIV infection is not limited to SIV-specific T cells, and vaccination of an adult AGM who had a negligible number of CD4 T cells demonstrated that CD4 downregulation can occur without antigenic exposure. Finally, we show that the T cell homeostatic cytokines interleukin-2 (IL-2), IL-7, and IL-15 can induce CD4 downregulation in vitro. These data identify a mechanism that allows AGMs to generate a large, diverse population of T cells that perform CD4 T cell functions but are resistant to SIV infection. A better understanding of this mechanism may allow the development of treatments to induce protective CD4 downregulation in humans. IMPORTANCE Many African primate species are naturally infected with SIV. African green monkeys, one natural host species, avoid simian AIDS by creating a population of T cells that lack CD4, the human immunodeficiency virus/SIV receptor; therefore, they are resistant to infection. However, these T cells maintain properties of CD4(+) T cells even after receptor downregulation and preserve immune function. Here, we show that juvenile AGMs, who have not undergone extensive CD4 downregulation, accelerate this process upon SIV infection. Furthermore, we show that in vivo, CD4 downregulation does not occur exclusively in antigen-experienced T cells. Finally, we show that the cytokines IL-2, IL-7, and IL-15, which induce homeostatic T cell proliferation, lead to CD4 downregulation in vitro; therefore, they can provide signals that lead to antigen-independent CD4 downregulation. These results suggest that if a similar process of CD4 downregulation could be induced in humans, it could provide a cure for AIDS. C1 [Perkins, Molly R.; Briant, Judith A.; Calantone, Nina; Whitted, Sonya; Vinton, Carol L.; Klatt, Nichole R.; Ourmanov, Ilnour; Ortiz, Alexandra M.; Hirsch, Vanessa M.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@niaid.nih.gov FU Division of Intramural Research/NIAID/NIH FX Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH. NR 29 TC 1 Z9 1 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 18 BP 10714 EP 10724 DI 10.1128/JVI.01331-14 PG 11 WC Virology SC Virology GA AO3MQ UT WOS:000341234900039 PM 24991011 ER PT J AU Thomas, JM Pos, Z Reinboth, J Wang, RY Wang, E Frank, GM Lusso, P Trinchieri, G Alter, HJ Marincola, FM Thomas, E AF Thomas, Jaime M. Pos, Zoltan Reinboth, Jennifer Wang, Richard Y. Wang, Ena Frank, Gregory M. Lusso, Paolo Trinchieri, Giorgio Alter, Harvey J. Marincola, Francesco M. Thomas, Emmanuel TI Differential Responses of Plasmacytoid Dendritic Cells to Influenza Virus and Distinct Viral Pathogens SO JOURNAL OF VIROLOGY LA English DT Article ID INNATE IMMUNE-RESPONSE; INFECTION; INTERFERONS; TRAFFICKING; RECOGNITION; IMPACT AB Plasmacytoid dendritic cells (pDCs) are key components of the innate immune response that are capable of synthesizing and rapidly releasing vast amounts of type I interferons (IFNs), particularly IFN-alpha. Here we investigated whether pDCs, often regarded as a mere source of IFN, discriminate between various functionally discrete stimuli and to what extent this reflects differences in pDC responses other than IFN-alpha release. To examine the ability of pDCs to differentially respond to various doses of intact and infectious HIV, hepatitis C virus, and H1N1 influenza virus, whole-genome gene expression analysis, enzyme-linked immunosorbent assays, and flow cytometry were used to investigate pDC responses at the transcriptional, protein, and cellular levels. Our data demonstrate that pDCs respond differentially to various viral stimuli with significant changes in gene expression, including those involved in pDC activation, migration, viral endocytosis, survival, or apoptosis. In some cases, the expression of these genes was induced even at levels comparable to that of IFN-alpha. Interestingly, we also found that depending on the viral entity and the viral titer used for stimulation, induction of IFN-alpha gene expression and the actual release of IFN-alpha are not necessarily temporally coordinated. In addition, our data suggest that high-titer influenza A (H1N1) virus infection can stimulate rapid pDC apoptosis. IMPORTANCE Plasmacytoid dendritic cells (pDCs) are key players in the viral immune response. With the host response to viral infection being dependent on specific virus characteristics, a thorough examination and comparison of pDC responses to various viruses at various titers is beneficial for the field of virology. Our study illustrates that pDC infection with influenza virus, HIV, or hepatitis C virus results in a unique and differential response to each virus. These results have implications for future virology research, vaccine development, and virology as a whole. C1 [Thomas, Jaime M.; Pos, Zoltan; Reinboth, Jennifer; Wang, Richard Y.; Wang, Ena; Alter, Harvey J.; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, CC, Bethesda, MD 20892 USA. [Thomas, Jaime M.; Pos, Zoltan; Reinboth, Jennifer; Wang, Richard Y.; Wang, Ena; Alter, Harvey J.; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Pos, Zoltan] MTA Semmelweis Univ, Lendulet Expt & Translat Immun Res Grp, Budapest, Hungary. [Frank, Gregory M.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Lusso, Paolo] NIAID, Immunoregulat Lab, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. [Trinchieri, Giorgio] Frederick Natl Lab, Canc Immunobiol Sect, Expt Immunol Lab, Frederick, MD USA. [Wang, Ena; Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Thomas, Emmanuel] Univ Miami, Miller Sch Med, Schiff Ctr Liver Dis, Sylvester Comprehens Canc Ctr,Dept Cell Biol, Miami, FL 33136 USA. RP Marincola, FM (reprint author), Sidra Med & Res Ctr, Doha, Qatar. EM fmarincola@sidra.org; ethomas1@med.miami.edu OI Pos, Zoltan/0000-0002-2574-7616 FU NIH intramural research program; Miami Center for AIDS Research (CFAR) at the University of Miami Miller School of Medicine - an NIH grant [P30AI073961] FX This work was completed through funds from the NIH intramural research program. E.T. acknowledges support from the Miami Center for AIDS Research (CFAR) at the University of Miami Miller School of Medicine funded by an NIH grant (P30AI073961). NR 30 TC 4 Z9 5 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 18 BP 10758 EP 10766 DI 10.1128/JVI.01501-14 PG 9 WC Virology SC Virology GA AO3MQ UT WOS:000341234900043 PM 25008918 ER PT J AU Tran, EEH Simmons, JA Bartesaghi, A Shoemaker, CJ Nelson, E White, JM Subramaniam, S AF Tran, Erin E. H. Simmons, James A. Bartesaghi, Alberto Shoemaker, Charles J. Nelson, Elizabeth White, Judith M. Subramaniam, Sriram TI Spatial Localization of the Ebola Virus Glycoprotein Mucin-Like Domain Determined by Cryo-Electron Tomography SO JOURNAL OF VIROLOGY LA English DT Article ID ANTIBODY; ENTRY; PROTECTION; PROTEINS; EPITOPES; BINDING AB The Ebola virus glycoprotein mucin-like domain (MLD) is implicated in Ebola virus cell entry and immune evasion. Using cryo-electron tomography of Ebola virus-like particles, we determined a three-dimensional structure for the full-length glycoprotein in a near-native state and compared it to that of a glycoprotein lacking the MLD. Our results, which show that the MLD is located at the apex and the sides of each glycoprotein monomer, provide a structural template for analysis of MLD function. C1 [Tran, Erin E. H.; Bartesaghi, Alberto; Subramaniam, Sriram] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Simmons, James A.; Shoemaker, Charles J.; Nelson, Elizabeth; White, Judith M.] Univ Virginia, Sch Med, Dept Cell Biol, Charlottesville, VA 22908 USA. RP Subramaniam, S (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU NIH [AI103601] FX This work was supported in part by NIH grant AI103601 to J.M.W. NR 25 TC 15 Z9 15 U1 0 U2 34 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2014 VL 88 IS 18 BP 10958 EP 10962 DI 10.1128/JVI.00870-14 PG 5 WC Virology SC Virology GA AO3MQ UT WOS:000341234900060 PM 25008940 ER PT J AU Ilatovskaya, DV Palygin, O Chubinskiy-Nadezhdin, V Negulyaev, YA Ma, R Birnbaumer, L Staruschenko, A AF Ilatovskaya, Dana V. Palygin, Oieg Chubinskiy-Nadezhdin, Vladislav Negulyaev, Yuri A. Ma, Rang Birnbaumer, Lutz Staruschenko, Alexander TI Angiotensin II has acute effects on TRPC6 channels in podocytes of freshly isolated glomeruli SO KIDNEY INTERNATIONAL LA English DT Article DE angiotensin; calcium; focal segmental glomerulosclerosis; ion channel; nephrotic syndrome; podocyte ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; ISOLATED RAT GLOMERULI; INTRACELLULAR CALCIUM; FILTRATION BARRIER; NEPHROTIC SYNDROME; INTACT GLOMERULUS; ACTIVATION; RECEPTORS; EXPRESSION; KIDNEY AB A key role for podocytes in the pathogenesis of proteinuric renal diseases has been established. Angiotensin II causes depolarization and increased intracellular calcium concentration in podocytes; members of the cation TRPC channels family, particularly TRPC6, are proposed as proteins responsible for calcium flux. Angiotensin II evokes calcium transient through TRPC channels and mutations in the gene encoding the TRPC6 channel result in the development of focal segmental glomerulosclerosis. Here we examined the effects of angiotensin II on intracellular calcium ion levels and endogenous channels in intact podocytes of freshly isolated decapsulated mouse glomeruli. An ion channel with distinct TRPC6 properties was identified in wild-type, but was absent in TRPC6 knockout mice. Single-channel electrophysiological analysis found that angiotensin II acutely activated native TRPC-like channels in both podocytes of freshly isolated glomeruli and TRPC6 channels transiently overexpressed in CHO cells; the effect was mediated by changes in the channel open probability. Angiotensin II evoked intracellular calcium transients in the wild-type podocytes, which was blunted in TRPC6 knockout glomeruli. Pan-TRPC inhibitors gadolinium and SKF 96365 reduced the response in wild-type glomerular epithelial cells, whereas the transient in TRPC6 knockout animals was not affected. Thus, angiotensin II-dependent activation of TRPC6 channels in podocytes may have a significant role in the development of kidney diseases. C1 [Ilatovskaya, Dana V.; Palygin, Oieg; Staruschenko, Alexander] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA. [Ilatovskaya, Dana V.; Chubinskiy-Nadezhdin, Vladislav; Negulyaev, Yuri A.] Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. [Negulyaev, Yuri A.] St Petersburg State Polytech Univ, Dept Med Phys, St Petersburg, Russia. [Ma, Rang] Univ N Texas, Hlth Sci Ctr, Dept Integrat Physiol, Ft Worth, TX USA. [Ma, Rang] Univ N Texas, Hlth Sci Ctr, Cardiovasc Res Inst, Ft Worth, TX USA. [Birnbaumer, Lutz] NIH, Transmembrane Signaling Grp, Res Triangle Pk, NC USA. RP Staruschenko, A (reprint author), Med Coll Wisconsin, Dept Physiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM staruschenko@mcw.edu RI Negulyaev, Yuri/N-6531-2015; Chubinskiy-Nadezhdin, Vladislav/E-4214-2017; OI Staruschenko, Alexander/0000-0002-5190-8356; Palygin, Oleg/0000-0002-3680-5527 FU National Institutes of Health [HL108880, DK079968]; Intramural Research Program [Z01-ES-101684]; American Diabetes Association [1-10-BS-168]; Russian Foundation for Basic Research [RFBR-13-04-00700]; Molecular and Cell Biology Program of the Russian Academy of Sciences; Ben J Lipps Research Fellowship from the American Society of Nephrology FX This research was supported by the National Institutes of Health grants HL108880 (to AS) and DK079968 (to RM) and the Intramural Research Program Z01-ES-101684 (to LB), the American Diabetes Association grant 1-10-BS-168 (to AS), the Russian Foundation for Basic Research grant RFBR-13-04-00700, the Molecular and Cell Biology Program of the Russian Academy of Sciences (to YAN, VC-N, and DVI), and the Ben J Lipps Research Fellowship from the American Society of Nephrology (to DVI). NR 40 TC 25 Z9 25 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2014 VL 86 IS 3 BP 506 EP 514 DI 10.1038/ki.2014.71 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AO2QC UT WOS:000341169300012 PM 24646854 ER PT J AU Okada, Y Shirai, K Reinach, PS Kitano-Izutani, A Miyajima, M Flanders, KC Jester, JV Tominaga, M Saika, S AF Okada, Yuka Shirai, Kumi Reinach, Peter S. Kitano-Izutani, Ai Miyajima, Masayasu Flanders, Kathleen C. Jester, James V. Tominaga, Makoto Saika, Shizuya TI TRPA1 is required for TGF-beta signaling and its loss blocks inflammatory fibrosis in mouse corneal stroma SO LABORATORY INVESTIGATION LA English DT Article ID EPITHELIAL BASEMENT-MEMBRANE; ION-CHANNEL TRPA1; ALKALI BURNS; MICE; PAIN; ACTIVATION; TISSUE; EXPRESSION; PATHWAYS; TRPV1 AB We examined whether loss of transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing ion channel, or TRPA1 antagonist treatment affects the severity inflammation and scarring during tissue wound healing in a mouse cornea injury model. In addition, the effects of the absence of TRPA1 on transforming growth factor beta 1 (TGF-beta 1)-signaling activation were studied in cell culture. The lack of TRPA1 in cultured ocular fibroblasts attenuated expression of TGF-beta 1, interleukin-6, and alpha-smooth muscle actin, a myofibroblast the marker, but suppressed the activation of Smad3, p38 MAPK, ERK, and JNK. Stroma of the healing corneas of TRPA1(-/-) knockout (KO) mice appeared more transparent compared with those of wild-type mice post-alkali burn. Eye globe diameters were measured from photographs. An examination of the corneal surface and eye globes suggested the loss of TRPA1 suppressed post-alkali burn inflammation and fibrosis/scarring, which was confirmed by histology, immunohistochemistry, and gene expression analysis. Reciprocal bone marrow transplantation between mice showed that KO corneal tissue resident cells, but not KO bone marrow-derived cells, are responsible for KO mouse wound healing with reduced inflammation and fibrosis. Systemic TRPA1 antagonists reproduced the KO phenotype of healing. In conclusion, a loss or blocking of TRPA1 in mice reduces inflammation and fibrosis/scarring in the corneal stroma during wound healing following an alkali burn. The responsible mechanism may include the inhibition of TGF-beta 1-signaling cascades in fibroblasts by attenuated TRPA1 signaling. Inflammatory cells are considered to have a minimum involvement in the exhibition of the KO phenotype after injury. C1 [Okada, Yuka; Shirai, Kumi; Kitano-Izutani, Ai; Saika, Shizuya] Wakayama Med Univ, Dept Ophthalmol, Wakayama 6410012, Japan. [Reinach, Peter S.] Wenzhou Med Univ, Sch Ophthalmol & Optometry, Wenzhou, Peoples R China. [Miyajima, Masayasu] Wakayama Med Univ, Lab Anim Ctr, Wakayama 6410012, Japan. [Flanders, Kathleen C.] NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. [Jester, James V.] Univ Calif Irvine, Irvine, CA USA. [Tominaga, Makoto] Natl Inst Nat Sci, Okazaki Inst Integrat Biosci, Div Cell Signaling, Okazaki, Aichi 4448787, Japan. RP Okada, Y (reprint author), Wakayama Med Univ, Dept Ophthalmol, 811-1 Kimiidera, Wakayama 6410012, Japan. EM yokada@wakayama-med.ac.jp FU Ministry of Education, Science, Sports and Culture of Japan [C21592241, C19592036]; Mitsui Life Social Welfare Foundation; Mochida Memorial Foundation; Takeda Science Foundation; Uehara Foundation [EY04795] FX This study was supported by the grants from the Ministry of Education, Science, Sports and Culture of Japan (C21592241 to YO, C19592036 to SS), Mitsui Life Social Welfare Foundation, Mochida Memorial Foundation, Takeda Science Foundation and Uehara Foundation (SS) and EY04795 (to PSR). NR 39 TC 11 Z9 11 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD SEP PY 2014 VL 94 IS 9 BP 1030 EP 1041 DI 10.1038/labinvest.2014.85 PG 12 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AO2RC UT WOS:000341171900008 PM 25068659 ER PT J AU Bhattacharyya, S Patel, NL Wei, L Riffle, LA Kalen, JD Hill, GC Jacobs, PM Zinn, KR Rosenthal, E AF Bhattacharyya, Sibaprasad Patel, Nimit L. Wei, Ling Riffle, Lisa A. Kalen, Joseph D. Hill, G. Craig Jacobs, Paula M. Zinn, Kurt R. Rosenthal, Eben TI Synthesis and biological evaluation of panitumumab-IRDye800 conjugate as a fluorescence imaging probe for EGFR-expressing cancers SO MEDCHEMCOMM LA English DT Article ID MONOCLONAL-ANTIBODY; GUIDED SURGERY; BREAST-CANCER; TOMOGRAPHY; CARCINOMA; HEAD; PET AB To investigate panitumumab-IRDye800 as an intraoperative optical imaging agent for epidermal growth factor receptor (EGFR)-expressing cancers, we developed clinical-quality panitumumab-IRDye800 and evaluated its specificity and sensitivity to visualize tumors by fluorescence imaging in a variety of mouse xenograft models with different levels of EGFR-expression. Panitumumab was chemically conjugated to NIR-dye (Li-COR 800CW) at well-defined and limited substitution ratio (1 : 1-2) for the characterization of fluorescence signals. The yield and purity of the conjugate was 80 +/- 5% and 95 +/- 2%, respectively (n = 6). Quality control (QC) tests showed that the product was suitable for clinical development. Female athymic nude xenograft tumor bearing mice (n = 5 per tumor model) with very low (BT-474), moderate (MDA-MB-231), and high (MDA-MB-468) EGFR-expression levels were administered panitumumab-IRDye800 formulations (100 mu g of mAb in 100 mu L of 0.9% saline) via tail-vein injection. Animal imaging and biodistribution experiments were conducted on an FMT 2500 (Perkin Elmer) fluorescence scanner at 24, 48, 72, 96, and 144 hours post-injection. Immuno-fluorescence images of a panitumumab-IRDye conjugate recorded in mouse xenograft models showed a good correlation (R-2 = 0.91) between EGFR-expression level and tumor uptake. Uptake of panitumumab labeled with IR-Dye or [Zr-89] in different tumor xenografts with high, medium, and low EGFR expression, as measured by fluorescence or radioactive counts, is highly correlated (r(2) = 0.99). This preclinical in vivo study proved that panitumumab-IRDye800 is specific and optical imaging in conjunction with this probe is sensitive enough to detect EGFR-expressing tumors. C1 [Bhattacharyya, Sibaprasad; Wei, Ling] Leidos Biomed Res, FNLCR, ADRD, Frederick, MD 21702 USA. [Patel, Nimit L.; Riffle, Lisa A.; Kalen, Joseph D.] Leidos Biomed Res, FNLCR, SAIP, Frederick, MD 21702 USA. [Hill, G. Craig] Leidos Biomed Res, FNLCR, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD 21702 USA. [Jacobs, Paula M.] NCI, CIP, DCTD, Bethesda, MD 20892 USA. [Zinn, Kurt R.; Rosenthal, Eben] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. RP Bhattacharyya, S (reprint author), Leidos Biomed Res, FNLCR, ADRD, Frederick, MD 21702 USA. EM bhattacharyyas2@mail.nih.gov OI Zinn, Kurt/0000-0001-7463-4741 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Authors are thankful to Refika Turnier for collecting flow-cytometry data. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 15 TC 2 Z9 2 U1 4 U2 23 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-2503 EI 2040-2511 J9 MEDCHEMCOMM JI MedChemComm PD SEP PY 2014 VL 5 IS 9 BP 1337 EP 1346 DI 10.1039/c4md00116h PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AO0RA UT WOS:000341017700009 PM 25431648 ER PT J AU Malhotra, SV Kumar, V Velez, C Zayas, B AF Malhotra, Sanjay V. Kumar, Vineet Velez, Christian Zayas, Beatriz TI Imidazolium-derived ionic salts induce inhibition of cancerous cell growth through apoptosis SO MEDCHEMCOMM LA English DT Article ID THALIDOMIDE; DEATH; FRAGMENTATION; LIQUIDS; DNA AB A study of the effects of imidazolium-based ionic liquids on 60 human cancer cell lines representing diverse histologies has identified four compounds which show potency at a nanomolar dose. Their effects on annexin V, DNA fragmentation, and the cell cycle, together with mitochondrial membrane permeabilization tests, provide insights into their mechanism of action. Also, experiments with A431 human epidermoid carcinoma cells suggest the activation of an apoptotic pathway, due to activity of the initiator caspase 8 and effector caspase 3. C1 [Malhotra, Sanjay V.; Kumar, Vineet] Leidos Biomed Res Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Velez, Christian; Zayas, Beatriz] Univ Metropolitana, Sch Environm Affairs, San Juan, PR 00928 USA. RP Malhotra, SV (reprint author), Leidos Biomed Res Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors would like to thank the NCI Developmental Therapeutics Program for 60 cell line screening. Also, SVM and VK would like to acknowledge the support from National Cancer Institute, National Institutes of Health under contract no. HHSN261200800001E. NR 33 TC 1 Z9 1 U1 1 U2 10 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-2503 EI 2040-2511 J9 MEDCHEMCOMM JI MedChemComm PD SEP PY 2014 VL 5 IS 9 BP 1404 EP 1409 DI 10.1039/c4md00161c PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AO0RA UT WOS:000341017700018 ER PT J AU He, B Bai, JW Zipunnikov, VV Koster, A Caserotti, P Lange-Maia, B Glynn, NW Harris, TB Crainiceanu, CM AF He, Bing Bai, Jiawei Zipunnikov, Vadim V. Koster, Annemarie Caserotti, Paolo Lange-Maia, Brittney Glynn, Nancy W. Harris, Tamara B. Crainiceanu, Ciprian M. TI Predicting Human Movement with Multiple Accelerometers Using Movelets SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ACCELEROMETER; PHYSICAL ACTIVITY; SIGNAL PROCESSING; PATTERN RECOGNITION; TIME SERIES ID PHYSICAL-ACTIVITY; ACTIVITY RECOGNITION; ENERGY-EXPENDITURE; CLASSIFICATION; BEHAVIOR; WRIST AB Purpose: The study aims were 1) to develop transparent algorithms that use short segments of training data for predicting activity types and 2) to compare the prediction performance of the proposed algorithms using single accelerometers and multiple accelerometers. Methods: Sixteen participants (age, 80.6 yr (4.8 yr); body mass index, 26.1 kg.m(-2) (2.5 kg.m(-2))) performed 15 lifestyle activities in the laboratory, each wearing three accelerometers at the right hip and left and right wrists. Triaxial accelerometry data were collected at 80 Hz using ActiGraph GT3X+. Prediction algorithms were developed, which, instead of extracting features, build activity-specific dictionaries composed of short signal segments called movelets. Three alternative approaches were proposed to integrate the information from the multiple accelerometers. Results: With at most several seconds of training data per activity, the prediction accuracy at the second-level temporal resolution was very high for lying, standing, normal/fast walking, and standing up from a chair (the median prediction accuracy ranged from 88.2% to 99.9% on the basis of the single-accelerometer movelet approach). For these activities, wrist-worn accelerometers performed almost as well as hip-worn accelerometers (the median difference in accuracy between wrist and hip ranged from -2.7% to 5.8%). Modest improvements in prediction accuracy were achieved by integrating information from multiple accelerometers. Discussion and Conclusions: It is possible to achieve high prediction accuracy at the second-level temporal resolution with very limited training data. To increase prediction accuracy from the simultaneous use of multiple accelerometers, a careful selection of integrative approaches is required. C1 [He, Bing; Bai, Jiawei; Zipunnikov, Vadim V.; Crainiceanu, Ciprian M.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Koster, Annemarie] Univ Maastricht, Dept Social Med, Maastricht, Netherlands. [Caserotti, Paolo] Univ Southern Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Lange-Maia, Brittney; Glynn, Nancy W.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP He, B (reprint author), Johns Hopkins Univ, E3148,615 N Wolfe St, Baltimore, MD 21205 USA. EM bihe@jhsph.edu RI Koster, Annemarie/E-7438-2010; He, Bing/H-8271-2016; OI Glynn, Nancy/0000-0003-2265-0162 FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL123407]; NIA NIH HHS [K23 AG024826, P30 AG024824, P30 AG024826, P30 AG024827, RC2 AG036594, RC2AG036594, T32 AG000181, T32AG000181]; NIMH NIH HHS [R01 MH095836, R01MH095836]; NINDS NIH HHS [R01 NS060910, R01 NS085211, R01NS060910, R01NS085211]; PHS HHS [HHSN271201100605P] NR 29 TC 11 Z9 11 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD SEP PY 2014 VL 46 IS 9 BP 1859 EP 1866 DI 10.1249/MSS.0000000000000285 PG 8 WC Sport Sciences SC Sport Sciences GA AO0JQ UT WOS:000340995300022 PM 25134005 ER PT J AU Cronise, RJ Sinclair, DA Bremer, AA AF Cronise, Raymond J. Sinclair, David A. Bremer, Andrew A. TI The "Metabolic Winter'' Hypothesis: A Cause of the Current Epidemics of Obesity and Cardiometabolic Disease SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID BROWN ADIPOSE-TISSUE; DE-NOVO LIPOGENESIS; CALORIE RESTRICTION; ENERGY-EXPENDITURE; BODY-TEMPERATURE; SLEEP DURATION; ADAPTIVE THERMOGENESIS; MAMMALIAN SIRTUINS; CIRCADIAN CLOCK; MODERATE COLD AB The concept of the "Calorie'' originated in the 1800s in an environment with limited food availability, primarily as a means to define economic equivalencies in the energy density of food substrates. Soon thereafter, the energy densities of the major macronutrients-fat, protein, and carbohydrates-were defined. However, within a few decades of its inception, the "Calorie'' became a commercial tool for industries to promote specific food products, regardless of health benefit. Modern technology has altered our living conditions and has changed our relationship with food from one of survival to palatability. Advances in agriculture, food manufacturing, and processing have ensured that calorie scarcity is less prevalent than calorie excess in the modern world. Yet, many still approach dietary macronutrients in a reductionist manner and assume that isocalorie foodstuffs are isometabolic. Herein, we discuss a novel way to view the major food macronutrients and human diet in this era of excessive caloric consumption, along with a novel relationship among calorie scarcity, mild cold stress, and sleep that may explain the increasing prevalence of nutritionally related diseases. C1 [Cronise, Raymond J.] Thermogenex, Huntsville, AL USA. [Sinclair, David A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Sinclair, David A.] Univ New S Wales, Dept Pharmacol, Sch Med Sci, Sydney, NSW, Australia. [Bremer, Andrew A.] Vanderbilt Univ, Dept Pediat, Nashville, TN USA. [Bremer, Andrew A.] Vanderbilt Univ, Dept Med, Nashville, TN USA. RP Bremer, AA (reprint author), NIDDKD, 6707 Democracy Blvd Bldg 2DEM,Room 6107, Bethesda, MD 20892 USA. EM andrew.bremer@nih.gov OI Sinclair, David/0000-0002-9936-436X FU National Institutes of Health (NIH) [R01 AG028730] FX This work received funding support from National Institutes of Health (NIH) grant R01 AG028730 to DAS. NR 102 TC 6 Z9 6 U1 1 U2 19 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 EI 1557-8518 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD SEP PY 2014 VL 12 IS 7 BP 355 EP 361 DI 10.1089/met.2014.0027 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AO2UK UT WOS:000341181300001 PM 24918620 ER PT J AU Rutter, MK Sullivan, LM Fox, CS Wilson, PWF Nathan, DM Vasan, RS D'Agostino, RB Meigs, JB AF Rutter, Martin K. Sullivan, Lisa M. Fox, Caroline S. Wilson, Peter W. F. Nathan, David M. Vasan, Ramachandran S. D'Agostino, Ralph B. Meigs, James B. TI Baseline Levels, and Changes Over Time in Body Mass Index and Fasting Insulin, and Their Relationship to Change in Metabolic Trait Clustering SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID HOMEOSTASIS MODEL ASSESSMENT; CORONARY-HEART-DISEASE; SYNDROME SYNDROME-X; RESISTANCE SYNDROME; CARDIOVASCULAR-DISEASE; WAIST CIRCUMFERENCE; OBESITY; RISK; ADULTS; HYPERINSULINEMIA AB Background: Multiple abnormal metabolic traits are found together or "cluster'' within individuals more often than is predicted by chance. The individual and combined role of adiposity and insulin resistance (IR) on metabolic trait clustering is uncertain. We tested the hypothesis that change in trait clustering is a function of both baseline level and change in these measures. Methods: In 2616 nondiabetic Framingham Offspring Study participants, body mass index (BMI) and fasting insulin were related to a within-person 7-year change in a trait score of 0-4 Adult Treatment Panel III metabolic syndrome traits (hypertension, high triglycerides, low high-density lipoprotein cholesterol, hyperglycemia). Results: At baseline assessment, mean trait score was 1.4 traits, and 7-year mean (SEM) change in trait score was +0.25 (0.02) traits, P < 0.0001. In models with BMI predictors only, for every quintile difference in baseline BMI, the 7-year trait score increase was 0.14 traits, and for every quintile increase in BMI during 7-year follow-up, the trait score increased by 0.3 traits. Baseline level and change in fasting insulin were similarly related to trait score change. In models adjusted for age-sex-baseline cluster score, 7-year change in trait score was significantly related to both a 1-quintile difference in baseline BMI (0.07 traits) and fasting insulin (0.18 traits), and to both a 1-quintile 7-year increase in BMI (0.21 traits) and fasting insulin (0.18 traits). Conclusions: Change in metabolic trait clustering was significantly associated with baseline levels and changes in both BMI and fasting insulin, highlighting the importance of both obesity and IR in the clustering of metabolic traits. C1 [Rutter, Martin K.] Univ Manchester, Fac Med & Human Sci, Inst Human Dev, Endocrinol & Diabet Res Grp, Manchester M13 9PT, Lancs, England. [Rutter, Martin K.] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Diabet Ctr, Manchester, Lancs, England. [Sullivan, Lisa M.] Boston Univ, Dept Biostat, Boston, MA USA. [D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Consulting Unit, Boston, MA USA. [Fox, Caroline S.; Nathan, David M.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.; Vasan, Ramachandran S.] NHLBI, Framingham, MA USA. [Fox, Caroline S.; Vasan, Ramachandran S.] Framingham Mass Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol & Metab, Boston, MA 02115 USA. [Wilson, Peter W. F.] Emory Univ, Sch Med, Atlanta, GA USA. [Nathan, David M.; Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. RP Rutter, MK (reprint author), Univ Manchester, Fac Med & Human Sci, Inst Human Dev, Endocrinol & Diabet Res Grp, Manchester M13 9PT, Lancs, England. EM martin.rutter@manchester.ac.uk OI Rutter, Martin/0000-0001-6380-539X; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute (NHLBI); Boston University [N01-HC-25195]; National Institute for Diabetes and Digestive and Kidney Diseases [K24 DK080140]; Higher Education Funding Council for England FX This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract no. N01-HC-25195), and the National Institute for Diabetes and Digestive and Kidney Diseases (K24 DK080140) (J.B.M.). M. K. R. is supported by the Higher Education Funding Council for England (Clinical Senior Lecturer Award). The research was facilitated by the Manchester Biomedical Research Centre and the NIHR Greater Manchester Clinical Research Network. NR 48 TC 5 Z9 5 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 EI 1557-8518 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD SEP PY 2014 VL 12 IS 7 BP 372 EP 380 DI 10.1089/met.2013.0148 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AO2UK UT WOS:000341181300004 PM 25007010 ER PT J AU Tian, YF Tian, XY Gawlak, G O'Donnell, JJ Sacks, DB Birukova, AA AF Tian, Yufeng Tian, Xinyong Gawlak, Grzegorz O'Donnell, James J., III Sacks, David B. Birukova, Anna A. TI IQGAP1 Regulates Endothelial Barrier Function via EB1-Cortactin Cross Talk SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID OXIDIZED PHOSPHOLIPIDS; ACTIN CYTOSKELETON; RHO-PATHWAY; LUNG INJURY; GROWTH; PERMEABILITY; MICROTUBULES; DYSFUNCTION; CDC42; PHOSPHORYLATION AB Cross talk between the actin cytoskeleton and microtubules (MT) has been implicated in the amplification of agonist-induced Rho signaling, leading to increased vascular endothelial permeability. This study tested the involvement of actin-MT cross talk in the mechanisms of barrier enhancement induced by hepatocyte growth factor (HGF) and evaluated the role of the adaptor protein IQGAP1 in integrating the MT- and actin-dependent pathways of barrier enhancement. IQGAP1 knockdown by small interfering RNA attenuated the HGF-induced increase in endothelial barrier properties and abolished HGF-activated cortical actin dynamics. IQGAP1 reduction abolished HGF-induced peripheral accumulation of Rac cytoskeletal effector cortactin and cortical actin remodeling. In addition, HGF stimulated peripheral MT growth in an IQGAP1-dependent fashion. HGF also induced Rac1-dependent IQGAP1 association with the MT fraction and the formation of a protein complex containing end-binding protein 1 (EB1), IQGAP1, and cortactin. Decreasing endogenous IQGAP1 abolished HGF-induced EB1-cortactin colocalization at the cell periphery. In turn, expression of IQGAP1 Delta C (IQGAP1 lacking the C-terminal domain) attenuated the cortactin association with EB1 and suppressed HGF-induced endothelial cell peripheral actin cytoskeleton enhancement. These results demonstrate for the first time the MT-actin cross talk mechanism of HGF-induced endothelial barrier enhancement and suggest that IQGAP1 functions as a hub linking HGF-induced signaling to MT and actin remodeling via EB1-IQGAP1-cortactin interactions. C1 [Tian, Yufeng; Tian, Xinyong; Gawlak, Grzegorz; O'Donnell, James J., III; Birukova, Anna A.] Univ Chicago, Dept Med, Sect Pulm & Crit Care Med, Chicago, IL 60637 USA. [Sacks, David B.] Natl Inst Hlth, Dept Lab Med, Bethesda, MD USA. RP Birukova, AA (reprint author), Univ Chicago, Dept Med, Sect Pulm & Crit Care Med, Chicago, IL 60637 USA. EM abirukov@medicine.bsd.uchicago.edu OI Sacks, David/0000-0003-3100-0735 FU National Heart, Lung, and Blood Institute [HL89257, HL107920]; Intramural Program of the National Institutes of Health FX This work was supported by the grants from the National Heart, Lung, and Blood Institute (HL89257 and HL107920 to A.A.B.) and by the Intramural Program of the National Institutes of Health (to D.B.S.). NR 36 TC 10 Z9 10 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2014 VL 34 IS 18 BP 3546 EP 3558 DI 10.1128/MCB.00248-14 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AO0TK UT WOS:000341024900016 PM 25022754 ER PT J AU Proulx, CD Hikosaka, O Malinow, R AF Proulx, Christophe D. Hikosaka, Okihide Malinow, Roberto TI Reward processing by the lateral habenula in normal and depressive behaviors SO NATURE NEUROSCIENCE LA English DT Review ID VENTRAL TEGMENTAL AREA; DORSAL RAPHE NUCLEUS; MIDBRAIN DOPAMINE NEURONS; MEDIAL HABENULA; BASAL GANGLIA; INTERPEDUNCULAR NUCLEUS; DECISION-MAKING; CRE-RECOMBINASE; GABA NEURONS; RAT AB The brain reward circuit has a central role in reinforcing behaviors that are rewarding and preventing behaviors that lead to punishment. Recent work has shown that the lateral habenula is an important part of the reward circuit by providing 'negative value' signals to the dopaminergic and serotonergic systems. Studies have also suggested that dysfunction of the lateral habenula is associated with psychiatric disorders, including major depression. Here, we discuss insights gained from neuronal recordings in monkeys regarding how the lateral habenula processes reward-related information. We then highlight recent optogenetic experiments in rodents addressing normal and abnormal functions of the habenula. Finally, we discuss how deregulation of the lateral habenula may be involved in depressive behaviors. C1 [Proulx, Christophe D.; Malinow, Roberto] Univ Calif San Diego, Dept Neurosci, Neurobiol Sect, Ctr Neural Circuits & Behav, San Diego, CA 92103 USA. [Hikosaka, Okihide] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Proulx, CD (reprint author), Univ Calif San Diego, Dept Neurosci, Neurobiol Sect, Ctr Neural Circuits & Behav, San Diego, CA 92103 USA. EM cproulx@ucsd.edu FU Institutions de Recherche en Sante du Canada; NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation [21367]; Intramural Research Program at the US National Institutes of Health, National Eye Institute [EY000415-09]; US National Institutes of Health [R01MH091119] FX C.D.P. received support from the Institutions de Recherche en Sante du Canada and a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (21367). O.H. received support by the Intramural Research Program at the US National Institutes of Health, National Eye Institute (EY000415-09), and R.M. received support from the US National Institutes of Health (R01MH091119). NR 96 TC 45 Z9 46 U1 2 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2014 VL 17 IS 9 BP 1146 EP 1152 DI 10.1038/nn.3779 PG 7 WC Neurosciences SC Neurosciences & Neurology GA AO2DJ UT WOS:000341125400006 PM 25157511 ER PT J AU Samuel, MA Voinescu, PE Lilley, BN de Cabo, R Foretz, M Viollet, B Pawlyk, B Sandberg, MA Vavvas, DG Sanes, JR AF Samuel, Melanie A. Voinescu, P. Emanuela Lilley, Brendan N. de Cabo, Rafa Foretz, Marc Viollet, Benoit Pawlyk, Basil Sandberg, Michael A. Vavvas, Demetrios G. Sanes, Joshua R. TI LKB1 and AMPK regulate synaptic remodeling in old age SO NATURE NEUROSCIENCE LA English DT Article ID PROTEIN-KINASE AMPK; NEURONAL POLARIZATION; MOUSE RETINA; SAD KINASES; CALORIC RESTRICTION; MAMMALIAN RETINA; BIPOLAR CELLS; LIFE-SPAN; ROD; PHOSPHORYLATION AB Age-related decreases in neural function result in part from alterations in synapses. To identify molecular defects that lead to such changes, we focused on the outer retina, in which synapses are markedly altered in old rodents and humans. We found that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate this process. In old mice, synaptic remodeling was accompanied by specific decreases in the levels of total LKB1 and active (phosphorylated) AMPK. In the absence of either kinase, young adult mice developed retinal defects similar to those that occurred in old wild-type animals. LKB1 and AMPK function in rod photoreceptors where their loss leads to aberrant axonal retraction, the extension of postsynaptic dendrites and the formation of ectopic synapses. Conversely, increasing AMPK activity genetically or pharmacologically attenuates and may reverse age-related synaptic alterations. Together, these results identify molecular determinants of age-related synaptic remodeling and suggest strategies for attenuating these changes. C1 [Samuel, Melanie A.; Voinescu, P. Emanuela; Lilley, Brendan N.; Sanes, Joshua R.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Samuel, Melanie A.; Voinescu, P. Emanuela; Lilley, Brendan N.; Sanes, Joshua R.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [de Cabo, Rafa] NIA, Lab Expt Gerontol, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Foretz, Marc; Viollet, Benoit] INSERM, Inst Cochin, U1016, Paris, France. [Foretz, Marc; Viollet, Benoit] CNRS, UMR8104, Paris, France. [Foretz, Marc; Viollet, Benoit] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Pawlyk, Basil; Sandberg, Michael A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat,Dept Opht, Boston, MA USA. [Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA USA. RP Sanes, JR (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. EM sanesj@mcb.harvard.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693; Vavvas, Demetrios/0000-0002-8622-6478 FU US National Institutes of Health [AG32322, 5K99AG044444]; Damon Runyon Cancer Research Foundation; Research to Prevent Blindness; Foundation Fighting Blindness; Intramural Research Program of the National Institute on Aging FX We thank members of our laboratory for scientific discussions and advice, and A. Thanos for help with the AMPK animals. This work was funded by the US National Institutes of Health (AG32322 to J.R.S. and 5K99AG044444 to M.A. Samuel), the Damon Runyon Cancer Research Foundation (M.A. Samuel), Research to Prevent Blindness (J.R.S. and D.G.V.), the Foundation Fighting Blindness (B.P.), and the Intramural Research Program of the National Institute on Aging (R.d.C.). NR 48 TC 17 Z9 17 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2014 VL 17 IS 9 BP 1190 EP 1197 DI 10.1038/nn.3772 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AO2DJ UT WOS:000341125400012 PM 25086610 ER PT J AU Benvenuti, F Stuart, M Cappena, V Gabella, S Corsi, S Taviani, A Albino, A Marchese, SS Weinrich, M AF Benvenuti, Francesco Stuart, Mary Cappena, Veruska Gabella, Sara Corsi, Sara Taviani, Antonio Albino, Antonio Marchese, Sandro Scattareggia Weinrich, Michael TI Community-Based Exercise for Upper Limb Paresis: A Controlled Trial With Telerehabilitation SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE telerehabilitation; stroke; upper limb; paresis ID UPPER EXTREMITY FUNCTION; RANDOMIZED CONTROLLED-TRIAL; MINIMAL DETECTABLE CHANGE; INDUCED MOVEMENT THERAPY; MOTOR FUNCTION-TEST; STROKE PATIENTS; VIRTUAL-REALITY; CLINICAL-TRIAL; REHABILITATION; RECOVERY AB Background. Arm paresis remains a major impairment after stroke despite the best conventional rehabilitation. Randomized, controlled trials of intensive exercise programs have demonstrated improvements in arm function for patients with chronic stroke. However, the gains achieved have been relatively modest for the large investments in patient and therapist time. Objective. To evaluate the safety, acceptance, adherence, and effectiveness of a community-based exercise program for upper limb paresis in patients with chronic stroke and the effects of telerehabilitation monitoring in kiosks distributed through the community. Methods. Longitudinal cohort with geographic control group. The experimental group received devices needed for a home exercise program based on the Carr and Shepherd "Motor Learning Program" and were instructed to practice the exercises at least twice a week at the kiosk and at least 3 more days a week at home. The control group received usual care. Results. Compared with the control group, patients in the experimental group demonstrated significant gains in arm function as measured by the Wolf Motor Function Test, 9-Hole Peg Test, Motricity Index, and Nottingham Extended Activities of Daily Living Questionnaire. The intervention received high satisfaction ratings and produced no adverse events. Only 30% of the subjects attended kiosks regularly. Outcomes for this group did not differ significantly from those who only practiced at home. Conclusions. Home-and community-based exercise for arm paresis is safe and effective. Telerehabilitation interventions will need additional enhancements to improve effectiveness. The optimal upper extremity exercise prescription poststroke remains to be established. C1 [Benvenuti, Francesco; Cappena, Veruska; Gabella, Sara; Corsi, Sara; Taviani, Antonio] UOC Cura & Riabilitaz Fragilita, Azienda Unita Sanit Locale 11, Empoli, Italy. [Stuart, Mary] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Albino, Antonio] Azienda Unita Sanit Locale 7, Dipartimento Tecn Funz, Siena, Italy. [Marchese, Sandro Scattareggia] Signo Motus Srl, Messina, Italy. [Weinrich, Michael] NIH, Natl Ctr Med Rehabil Res, Bethesda, MD 20852 USA. RP Weinrich, M (reprint author), NIH, Natl Ctr Med Rehabil Res, 6100 Execut Blvd,Room 2A-03, Bethesda, MD 20852 USA. EM weinricm@mail.nih.gov FU European Union [ICT-PSP-224985] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by grant ICT-PSP-224985 from the European Union. NR 50 TC 6 Z9 6 U1 4 U2 23 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 EI 1552-6844 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD SEP PY 2014 VL 28 IS 7 BP 611 EP 620 DI 10.1177/1545968314521003 PG 10 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA AN6ST UT WOS:000340728100001 PM 24515928 ER PT J AU Mercer, BM Raju, TNK Burchfield, DJ Joseph, GF AF Mercer, Brian M. Raju, Tonse N. K. Burchfield, David J. Joseph, Gerald F., Jr. TI Periviable Birth: Executive Summary of a Joint Workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Mercer, Brian M.] Soc Maternal Fetal Med, Cleveland, OH 44109 USA. [Mercer, Brian M.] Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Burchfield, David J.] Amer Acad Pediat, Gainesville, FL USA. [Burchfield, David J.] Univ Florida, Gainesville, FL USA. [Joseph, Gerald F., Jr.] Amer Coll Obstetricians & Gynecologists, Washington, DC 20024 USA. RP Mercer, BM (reprint author), Soc Maternal Fetal Med, Cleveland, OH 44109 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2014 VL 124 IS 3 BP 635 EP 636 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AO4OV UT WOS:000341320800027 PM 25162272 ER PT J AU Colegate, SM Gardner, DR Betz, JM Panter, KE AF Colegate, Steven M. Gardner, Dale R. Betz, Joseph M. Panter, Kip E. TI Semi-automated Separation of the Epimeric Dehydropyrrolizidine Alkaloids Lycopsamine and Intermedine: Preparation of their N-oxides and NMR Comparison with Diastereoisomeric Rinderine and Echinatine SO PHYTOCHEMICAL ANALYSIS LA English DT Article DE Boronated soda glass chromatography; HPLC-ESI/MS; NMR; optical rotation; echinatine; dehydropyrrolizidine alkaloids; intermedine; lycopsamine; rinderine; comfrey; Symphytum officinale ID PYRROLIZIDINE ALKALOIDS; COUNTERCURRENT CHROMATOGRAPHY; SENECIO-RIDDELLII; AMSINCKIA; MS; EXTRACTION; TOXICITY; INDICINE; ANALOGS AB Introduction - The diversity of structure and, particularly, stereochemical variation of the dehydropyrrolizidine alkaloids can present challenges for analysis and the isolation of pure compounds for the preparation of analytical standards and for toxicology studies. Objective - To investigate methods for the separation of gram-scale quantities of the epimeric dehydropyrrolizidine alkaloids lycopsamine and intermedine and to compare their NMR spectroscopic data with those of their heliotridine-based analogues echinatine and rinderine. Methods - Lycopsamine and intermedine were extracted, predominantly as their N-oxides and along with their acetylated derivatives, from commercial samples of comfrey (Symphytum officinale) root. Alkaloid enrichment involved liquid-liquid partitioning of the crude methanol extract between dilute aqueous acid and n-butanol, reduction of N-oxides and subsequent continuous liquid-liquid extraction of free base alkaloids into CHCl3. The alkaloid-rich fraction was further subjected to semi-automated flash chromatography using boronated soda glass beads or boronated quartz sand. Results - Boronated soda glass beads (or quartz sand) chromatography adapted to a Biotage Isolera Flash Chromatography System enabled large-scale separation (at least up to 1-2 g quantities) of lycopsamine and intermedine. The structures were confirmed using one- and two-dimensional H-1- and C-13-NMR spectroscopy. Examination of the NMR data for lycopsamine, intermedine and their heliotridine-based analogues echinatine and rinderine allowed for some amendments of literature data and provided useful comparisons for determining relative configurations in monoester dehydropyrrolizidine alkaloids. A similar NMR comparison of lycopsamine and intermedine with their N-oxides showed the effects of N-oxidation on some key chemical shifts. A levorotatory shift in specific rotation from +3.29 degrees to -1.5 degrees was observed for lycopsamine when dissolved in ethanol or methanol respectively. Conclusion - A semi-automated flash chromatographic process using boronated soda glass beads was standardised and confirmed as a useful, larger scale preparative approach for separating the epimers lycopsamine and intermedine. The useful NMR correlations to stereochemical arrangements within this specific class of dehydropyrrolizidine alkaloid cannot be confidently extrapolated to other similar dehydropyrrolizidine alkaloids. Published 2014. This article is a U. S. Government work and is in the public domain in the USA. C1 [Colegate, Steven M.; Gardner, Dale R.; Panter, Kip E.] ARS, Poisonous Plant Res Lab, USDA, Logan, UT 84341 USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Colegate, SM (reprint author), ARS, Poisonous Plant Res Lab, USDA, 1150 E 1400 N, Logan, UT 84341 USA. EM steven.colegate@ars.usda.gov NR 31 TC 7 Z9 7 U1 1 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0958-0344 EI 1099-1565 J9 PHYTOCHEM ANALYSIS JI Phytochem. Anal. PD SEP-OCT PY 2014 VL 25 IS 5 BP 429 EP 438 DI 10.1002/pca.2511 PG 10 WC Biochemical Research Methods; Plant Sciences; Chemistry, Analytical SC Biochemistry & Molecular Biology; Plant Sciences; Chemistry GA AO2KD UT WOS:000341149500006 PM 24816769 ER PT J AU Schiller, CE Schmidt, PJ Rubinow, DR AF Schiller, Crystal Edler Schmidt, Peter J. Rubinow, David R. TI Allopregnanolone as a mediator of affective switching in reproductive mood disorders SO PSYCHOPHARMACOLOGY LA English DT Review DE Reproductive mood disorders; Premenstrual dysphoria; Postpartum depression; Neurosteroids; Gonadal steroids; Estradiol; Progesterone; Allopregnanolone; Animal models ID PREMENSTRUAL DYSPHORIC DISORDER; 3-ALPHA-REDUCED NEUROACTIVE STEROIDS; POLYCYSTIC-OVARY-SYNDROME; RECEPTOR ALPHA-4 SUBUNIT; TRAUMATIC BRAIN-INJURY; MENSTRUAL-CYCLE PHASE; MAJOR DEPRESSION; POSTPARTUM DEPRESSION; GABA(A) RECEPTOR; GONADAL-STEROIDS AB Reproductive mood disorders, including premenstrual dysphoria (PMD) and postpartum depression (PPD), are characterized by affective dysregulation that occurs during specific reproductive states. The occurrence of illness onset during changes in reproductive endocrine function has generated interest in the role of gonadal steroids in the pathophysiology of reproductive mood disorders, yet the mechanisms by which the changing hormone milieu triggers depression in susceptible women remain poorly understood. This review focuses on one of the neurosteroid metabolites of progesterone - allopregnanolone (ALLO) - that acutely regulates neuronal function and may mediate affective dysregulation that occurs concomitant with changes in reproductive endocrine function. We describe the role of the "neuroactive" steroids estradiol and progesterone in reproductive endocrine-related mood disorders to highlight the potential mechanisms by which ALLO might contribute to their pathophysiology. Finally, using existing data, we test the hypothesis that changes in ALLO levels may trigger affective dysregulation in susceptible women. Although there is no reliable evidence that basal ALLO levels distinguish those with PMD or PPD from those without, existing animal models suggest potential mechanisms by which specific reproductive states may unmask susceptibility to affective dysregulation. Consistent with these models, initially euthymic women with PMD and those with a history of PPD show a negative association between depressive symptoms and circulating ALLO levels following progesterone administration. Existing animal models and our own preliminary data suggest that ALLO may play an important role in the pathophysiology of reproductive mood disorders by triggering affective dysregulation in susceptible women. C1 [Schiller, Crystal Edler; Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Schmidt, Peter J.] NIMH, Dept Hlth & Human Serv, Sect Behav Endocrinol, Bethesda, MD 20892 USA. RP Schiller, CE (reprint author), Univ N Carolina, Dept Psychiat, 250 Med Sch Wing D,Campus Box 7175, Chapel Hill, NC 27599 USA. EM crystal_schiller@med.unc.edu RI Schiller, Crystal/K-8403-2015 OI Schiller, Crystal/0000-0001-6186-701X FU Intramural NIH HHS [ZIA MH002537-20, ZIA MH002865-08]; NICHD NIH HHS [K12 HD001441] NR 108 TC 17 Z9 17 U1 2 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2014 VL 231 IS 17 BP 3557 EP 3567 DI 10.1007/s00213-014-3599-x PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AN6DN UT WOS:000340684300028 PM 24846476 ER PT J AU Roujol, S Weingartner, S Foppa, M Chow, K Kawaji, K Ngo, LH Kellman, P Manning, WJ Thompson, RB Nezafat, R AF Roujol, Sebastien Weingaertner, Sebastian Foppa, Murilo Chow, Kelvin Kawaji, Keigo Ngo, Long H. Kellman, Peter Manning, Warren J. Thompson, Richard B. Nezafat, Reza TI Accuracy, Precision, and Reproducibility of Four T1 Mapping Sequences: A Head-to-Head Comparison of MOLLI, ShMOLLI, SASHA, and SAPPHIRE SO RADIOLOGY LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; GADOPENTETATE DIMEGLUMINE; MYOCARDIAL-INFARCTION; RECOVERY; VOLUME; QUANTIFICATION; ACQUISITION; FIBROSIS; CMR AB Purpose: To compare accuracy, precision, and reproducibility of four commonly used myocardial T1 mapping sequences: modified Look-Locker inversion recovery (MOLLI), shortened MOLLI (ShMOLLI), saturation recovery single-shot acquisition (SASHA), and saturation pulse prepared heart rate independent inversion recovery (SAPPHIRE). Materials and Methods: This HIPAA-compliant study was approved by the institutional review board. All subjects provided written informed consent. Accuracy, precision, and reproducibility of the four T1 mapping sequences were first compared in phantom experiments. In vivo analysis was performed in seven healthy subjects (mean age 6 standard deviation, 38 years +/- 19; four men, three women) who were imaged twice on two separate days. In vivo reproducibility of native T1 mapping and extracellular volume (ECV) were measured. Differences between the sequences were assessed by using Kruskal-Wallis and Wilcoxon rank sum tests (phantom data) and mixed-effect models (in vivo data). Results: T1 mapping accuracy in phantoms was lower with ShMOLLI (62 msec) and MOLLI (44 msec) than with SASHA (13 msec; P < .05) and SAPPHIRE (12 msec; P,.05). MOLLI had similar precision to ShMOLLI (4.0 msec vs 5.6 msec; P = .07) but higher precision than SAPPHIRE (6.8 msec; P = .002) and SASHA (8.7 msec; P < .001). All sequences had similar reproducibility in phantoms (P = .1). The four sequences had similar in vivo reproducibility for native T1 mapping (similar to 25-50 msec; P > .05) and ECV quantification (similar to 0.01-0.02; P > .05). Conclusion: SASHA and SAPPHIRE yield higher accuracy, lower precision, and similar reproducibility compared with MOLLI and ShMOLLI for T1 measurement. Different sequences yield different ECV values; however, all sequences have similar reproducibility for ECV quantification. (C),RSNA, 2014. C1 [Roujol, Sebastien; Weingaertner, Sebastian; Foppa, Murilo; Kawaji, Keigo; Ngo, Long H.; Manning, Warren J.; Nezafat, Reza] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Manning, Warren J.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Chow, Kelvin; Thompson, Richard B.] Univ Alberta, Fac Med & Dent, Dept Biomed Engn, Edmonton, AB, Canada. [Kellman, Peter] NHLBI, NIH, Bethesda, MD 20892 USA. RP Nezafat, R (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, 300 Brookline Ave, Boston, MA 02215 USA. EM rnezafat@bidmc.harvard.edu FU National Institutes of Health [R01EB008743-01A2] FX This research was supported by the National Institutes of Health (grant R01EB008743-01A2). P. K. is an employee of the National Institutes of Health. NR 28 TC 45 Z9 47 U1 0 U2 14 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 SEP PY 2014 VL 272 IS 3 BP 683 EP 689 DI 10.1148/radiol.14140296 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AO2WX UT WOS:000341188900008 PM 24702727 ER PT J AU Kwan, AC May, HT Cater, G Sibley, CT Rosen, BD Lima, JAC Rodriguez, K Lappe, DL Muhlestein, JB Anderson, JL Bluemke, DA AF Kwan, Alan C. May, Heidi T. Cater, George Sibley, Christopher T. Rosen, Boaz D. Lima, Joao A. C. Rodriguez, Karen Lappe, Donald L. Muhlestein, Joseph B. Anderson, Jeffrey L. Bluemke, David A. TI Coronary Artery Plaque Volume and Obesity in Patients with Diabetes: The Factor-64 Study SO RADIOLOGY LA English DT Article ID HISTOLOGY INTRAVASCULAR ULTRASOUND; MYOCARDIAL-PERFUSION SCINTIGRAPHY; BODY-MASS INDEX; ASYMPTOMATIC PATIENTS; COMPUTED-TOMOGRAPHY; VIRTUAL HISTOLOGY; CALCIUM SCORE; ATHEROSCLEROTIC PLAQUES; RISK STRATIFICATION; DISEASE AB Purpose: To determine the relationship between coronary plaque detected with coronary computed tomographic (CT) angiography and clinical parameters and cardiovascular risk factors in asymptomatic patients with diabetes. Materials and Methods: All patients signed institutional review board-approved informed consent forms before enrollment. Two hundred twenty-four asymptomatic diabetic patients (121 men; mean patient age, 61.8 years; mean duration of diabetes, 10.4 years) underwent coronary CT angiography. Total coronary artery wall volume in all three vessels was measured by using semiautomated software. The coronary plaque volume index (PVI) was determined by dividing the wall volume by the coronary length. The relationship between the PVI and cardiovascular risk factors was determined with multivariable analysis. Results: The mean PVI (+/- standard deviation) was 11.2 mm(2) +/- 2.7. The mean coronary artery calcium (CAC) score (determined with the Agatston method) was 382; 67% of total plaque was noncalcified. The PVI was related to age (standardized beta = 0.32, P < .001), male sex (standardized b = 0.36, P < .001), body mass index (BMI) (standardized beta = 0.26, P < .001), and duration of diabetes (standardized beta = 0.14, P = .03). A greater percentage of soft plaque was present in younger individuals with a shorter disease duration (P = .02). The soft plaque percentage was directly related to BMI (P = .002). Patients with discrepancies between CAC score and PVI rank quartiles had a higher percentage of soft and fibrous plaque (18.7% +/- 3.3 vs 17.4% +/- 3.5 [P = .008] and 52.2% +/- 7.2 vs 47.2% +/- 8.8 [P < .0001], respectively). Conclusion: In asymptomatic diabetic patients, BMI was the primary modifiable risk factor that was associated with total and soft coronary plaque as assessed with coronary CT angiography. (C)RSNA, 2014. C1 [Kwan, Alan C.; Cater, George; Sibley, Christopher T.; Rodriguez, Karen; Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [May, Heidi T.; Lappe, Donald L.; Muhlestein, Joseph B.; Anderson, Jeffrey L.] Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA. [Rosen, Boaz D.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Lappe, Donald L.; Muhlestein, Joseph B.; Anderson, Jeffrey L.] Univ Utah, Div Cardiol, Salt Lake City, UT 84112 USA. RP Bluemke, DA (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10-1C355, Bethesda, MD 20892 USA. EM David.Bluemke@nih.gov FU National Institutes of Health FX Funded in part by the National Institutes of Health intramural research program. D. A. B. and C. T. S. are employees of the National Institutes of Health. NR 33 TC 7 Z9 7 U1 0 U2 3 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 SEP PY 2014 VL 272 IS 3 BP 690 EP 699 DI 10.1148/radiol.14140611 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AO2WX UT WOS:000341188900009 PM 24754493 ER PT J AU Choi, DS Blanco, E Kim, YS Rodriguez, AA Zhao, H Huang, THM Chen, CL Jin, GX Landis, MD Burey, LA Qian, W Granados, SM Dave, B Wong, HH Ferrari, M Wong, STC Chang, JC AF Choi, Dong Soon Blanco, Elvin Kim, Yoo-Shin Rodriguez, Angel A. Zhao, Hong Huang, Tim Hui-Ming Chen, Chun-Liang Jin, Guangxu Landis, Melissa D. Burey, Lacey A. Qian, Wei Granados, Sergio M. Dave, Bhuvanesh Wong, Helen H. Ferrari, Mauro Wong, Stephen T. C. Chang, Jenny C. TI Chloroquine Eliminates Cancer Stem Cells Through Deregulation of Jak2 and DNMT1 SO STEM CELLS LA English DT Article DE Breast cancer stem cells; Autophagy; Chloroquine; DNMT1; Jak2 ID NEGATIVE BREAST-CANCER; TUMOR-SUPPRESSOR GENE; ENRICHMENT ANALYSIS; AUTOPHAGY; PATHWAY; METHYLATION; ACTIVATION; THERAPY; GROWTH; RESISTANCE AB Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44(+)/CD24(-/low) cancer stem cells (CSCs), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an antimalarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44(+)/CD24(-/low) CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus, the objectives of this study were to examine the potential enhanced efficacy arising from addition of CQ to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44(+)/CD24(-/low) CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2)-signal transducer and activator of transcription 3 signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1. C1 [Choi, Dong Soon; Rodriguez, Angel A.; Landis, Melissa D.; Burey, Lacey A.; Qian, Wei; Granados, Sergio M.; Dave, Bhuvanesh; Wong, Helen H.; Chang, Jenny C.] Houston Methodist Hosp, Methodist Canc Ctr, Houston, TX USA. [Blanco, Elvin; Ferrari, Mauro] Weill Cornell Med Coll, Dept Nanomed, Houston, TX USA. [Kim, Yoo-Shin] Weill Cornell Med Coll, Dept Translat Imaging, Houston, TX USA. [Zhao, Hong; Jin, Guangxu; Wong, Stephen T. C.] Weill Cornell Med Coll, Dept Syst Med & Bioengn, Houston, TX USA. [Zhao, Hong; Wong, Stephen T. C.] Houston Methodist Res Inst, NCI Ctr Modeling Canc Dev, Houston, TX USA. [Huang, Tim Hui-Ming; Chen, Chun-Liang] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, Dept Mol Med, San Antonio, TX 78229 USA. [Ferrari, Mauro; Chang, Jenny C.] Weill Cornell Med Sch, New York, NY USA. RP Chang, JC (reprint author), 6445 Main St,P21-34, Houston, TX 77030 USA. EM jcchang@tmhs.org RI Granados, Sergio/B-4987-2014; chang, jenny/G-7614-2015 OI chang, jenny/0000-0002-0890-9302 FU NIH/NCI [R01 CA138197, U54 CA149196]; Golfers against Cancer; Breast Cancer Research Foundation; Causes for a Cure; Team Tiara; Emily W. Herrman Cancer Research Laboratory; Komen for Cure [KG 081694] FX This work was supported by NIH/NCI Grants R01 CA138197, U54 CA149196, Golfers against Cancer, Breast Cancer Research Foundation, Causes for a Cure, Team Tiara, Emily W. Herrman Cancer Research Laboratory, and Komen for Cure KG 081694. We declare that none of the authors have any financial interest related to this work. NR 45 TC 21 Z9 22 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD SEP PY 2014 VL 32 IS 9 BP 2309 EP 2323 DI 10.1002/stem.1746 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA AO4GM UT WOS:000341294500003 PM 24809620 ER PT J AU Zou, XN Lin, DM Chao, A Wan, X Feng, QF Li, JL Yang, J Yang, GH Lv, N AF Zou, Xiao Nong Lin, Dongmei Chao, Ann Wan, Xia Feng, Qinfu Li, Junling Yang, Jie Yang, Gong Huan Lv, Ning TI Histological subtypes of lung cancer in Chinese women from 2000 to 2012 SO THORACIC CANCER LA English DT Article DE Chinese; epidemiology; female; histology; lung cancer ID CIGARETTE-SMOKING; SECONDHAND SMOKE; TOBACCO CONTROL; ADENOCARCINOMA; MORTALITY; EXPOSURE; INDUSTRY; COHORT; TRENDS; MALES AB Background: The aim of the study was to characterize the histological and epidemiological features of lung cancer in Chinese women. Methods: Demographic and histological information on female lung cancer cases identified during 1 January 2000 through 31 December 2012 from the Cancer Hospital of the Chinese Academy of Medical Sciences were collected. The International Classification of Diseases for Oncology system was used to classify the histological subtypes. Relative frequencies (RF) were estimated for major histological subtypes and compared by the years of diagnosis and birth, and among residential areas. Statistical differences were tested for RFs in the time periods with a trend test and with Pearson Chi square tests for distribution. Results: Of 7070 female Chinese lung cancer cases, the major histological subtypes were adenocarcinoma (ADC) 65.79%; squamous cell carcinoma (SCC) 10.21%; small cell cancer 8.12%; large cell carcinoma, 2.79%; and adeno-squamous carcinoma (ASC), 2.19%. ADC increased, with RFs from 46.72% in the cases identified in 2000-2002 to 76.49% in 2011-2012 (Z = 16.998, P < 0.0001); SCC decreased from 15.69% to 5.97% (Z=-8.750, P < 0.0001). Compared to the cases identified in 20002006, the age-adjusted RFs of ADC in 2007-2012 consistently increased in all study areas. Conclusion: The significant increase of ADC of the lung in Chinese women suggests that a persistently strong exposure to potential carcinogens in the Chinese population should be further and fully investigated. C1 [Zou, Xiao Nong] Chinese Acad Med Sci, Canc Inst Hosp, Natl Off Canc Prevent & Control, Beijing 100005, Peoples R China. [Lin, Dongmei; Lv, Ning] Chinese Acad Med Sci, Canc Inst Hosp, Natl Canc Ctr, Dept Pathol, Beijing 100005, Peoples R China. [Chao, Ann] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Wan, Xia; Yang, Gong Huan] Chinese Acad Med Sci, Inst Basic Med, Beijing 100005, Peoples R China. [Feng, Qinfu] Chinese Acad Med Sci, Canc Inst Hosp, Dept Radiat Oncol, Beijing 100005, Peoples R China. [Li, Junling] Chinese Acad Med Sci, Canc Inst Hosp, Dept Med Oncol, Beijing 100005, Peoples R China. [Yang, Jie] Chinese Ctr Dis Control & Prevent, Off Tobacco Control, Beijing, Peoples R China. RP Yang, GH (reprint author), Chinese Acad Med Sci, Inst Basic Med, 5 Dongdansantiao, Beijing 100005, Peoples R China. EM yangghuan@vip.sina.com; nlu03@126.com FU NIH project "Epidemiology and Intervention Research for Tobacco Control in China" [R01RFA-TW-06-006]; Beijing Hope Run Fund [YF2010-48] FX This work was supported by the NIH project "Epidemiology and Intervention Research for Tobacco Control in China" (R01RFA-TW-06-006) and the Beijing Hope Run Fund (YF2010-48). NR 38 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1759-7706 EI 1759-7714 J9 THORAC CANCER JI Thorac. Cancer PD SEP PY 2014 VL 5 IS 5 BP 447 EP 454 DI 10.1111/1759-7714.12121 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AO3NX UT WOS:000341239500012 PM 26767037 ER PT J AU Peters, DE Hoover, B Cloud, LG Liu, SH Molinolo, AA Leppla, SH Bugge, TH AF Peters, Diane E. Hoover, Benjamin Cloud, Loretta Grey Liu, Shihui Molinolo, Alfredo A. Leppla, Stephen H. Bugge, Thomas H. TI Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Prodrug; Cancer; Melanoma; Bacterial cytotoxin; Protease ID ATHYMIC NUDE-MICE; CAPILLARY MORPHOGENESIS PROTEIN-2; THERAPY PRODUCES REGRESSIONS; PROTECTIVE ANTIGEN; TUMOR ANGIOGENESIS; KINASE-KINASE; RECEPTOR; SPECIFICITY; INHIBITION; SEQUENCE AB We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. Published by Elsevier Inc. C1 [Peters, Diane E.; Cloud, Loretta Grey; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Peters, Diane E.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. [Hoover, Benjamin; Liu, Shihui; Leppla, Stephen H.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Molinolo, Alfredo A.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. EM thomas.bugge@nih.go FU NIDCR Intramural Research Program; NIAID Intramural Research Program FX Supported by the NIDCR Intramural Research Program (T.H.B.) and the NIAID Intramural Research Program (S.H.L). NR 39 TC 6 Z9 6 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 1 PY 2014 VL 279 IS 2 BP 220 EP 229 DI 10.1016/j.taap.2014.06.010 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AN6HL UT WOS:000340695500014 PM 24971906 ER PT J AU Barker, DJ Bercovicz, D Servilio, LC Simmons, SJ Ma, SS Root, DH Pawlak, AP West, MO AF Barker, David J. Bercovicz, Danielle Servilio, Lisa C. Simmons, Steven J. Ma, Sisi Root, David H. Pawlak, Anthony P. West, Mark O. TI Rat ultrasonic vocalizations demonstrate that the motivation to contextually reinstate cocaine-seeking behavior does not necessarily involve a hedonic response SO ADDICTION BIOLOGY LA English DT Article DE Affect; cocaine; dopamine; ultrasonic vocalizations ID SELF-REPORT; INCENTIVE-SENSITIZATION; NUCLEUS-ACCUMBENS; LABORATORY RATS; DRUG-ADDICTION; BRAIN; CALLS; AMPHETAMINE; WITHDRAWAL; EXPOSURE AB Human self-reports often indicate that changes in mood are a major contributor to drug relapse. Still, arguments have been made that instances of drug-seeking following abstinence in animal models (i.e. relapse/reinstatement) may be outside of hedonic control. Therefore, the present study utilized ultrasonic vocalizations in the rat in order to evaluate affect during cocaine self-administration and contextual reinstatement of cocaine-seeking in a pre-clinical model of drug relapse (abstinence-reinstatement model). Results show that while subjects effectively reinstated drug-seeking (lever pressing) following 30 days of abstinence, and spontaneously recovered/reinstated drug-seeking following 60 days of abstinence, ultrasonic vocalizations did not increase over baseline levels during either reinstatement session. These results are consistent with previous results from our laboratory and current theories of addiction suggesting that cues that are weakly associated with drug consumption can motivate drug-seeking behavior that is outside of hedonic processing. C1 [Barker, David J.; Bercovicz, Danielle; Servilio, Lisa C.; Simmons, Steven J.; Ma, Sisi; Pawlak, Anthony P.; West, Mark O.] Rutgers State Univ, Dept Psychol, Piscataway, NJ 08854 USA. [Servilio, Lisa C.] Univ Calif San Diego, Div Biol Sci, San Diego, CA 92103 USA. [Simmons, Steven J.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Root, David H.] NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, Baltimore, MD USA. RP West, MO (reprint author), Rutgers State Univ, Dept Psychol, 152 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM markwest@rutgers.edu RI Ma, Sisi/E-6367-2015; OI Root, David/0000-0002-1927-2175; Simmons, Steven/0000-0002-6982-4740 FU National Institute on Drug Abuse [DA006886, DA029873, DA026252, DA032270] FX This article was dedicated to the memory of Linda King, a colleague whose character and commitment to students will not be forgotten. We thank Linda King, Thomas Grace Sr., Jackie Thomas and Kevin Coffey for technical assistance. This study was supported by the National Institute on Drug Abuse Grants DA006886 (MOW), DA029873 (MOW), DA026252 (DHR) and DA032270 (DJB). The authors have no financial interests to be disclosed. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All coauthors have seen and approve of the contents of the manuscript. NR 69 TC 9 Z9 9 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD SEP PY 2014 VL 19 IS 5 BP 781 EP 790 DI 10.1111/adb.12044 PG 10 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA AN4BM UT WOS:000340532600004 PM 23506088 ER PT J AU Dore, R Valenza, M Wang, XF Rice, KC Sabino, V Cottone, P AF Dore, Riccardo Valenza, Marta Wang, Xiaofan Rice, Kenner C. Sabino, Valentina Cottone, Pietro TI The inverse agonist of CB1 receptor SR141716 blocks compulsive eating of palatable food SO ADDICTION BIOLOGY LA English DT Article DE Compulsive eating; food intake; palatability; rimonabant; risk-taking behavior; SR141716 ID CANNABINOID RECEPTOR; PREFERRED FOOD; LIMITED ACCESS; INTERMITTENT ACCESS; SEEKING BEHAVIOR; FEMALE RATS; SR 141716; WITHDRAWAL; BRAIN; ANTAGONIST AB Dieting and the increased availability of highly palatable food are considered major contributing factors to the large incidence of eating disorders and obesity. This study was aimed at investigating the role of the cannabinoid (CB) system in a novel animal model of compulsive eating, based on a rapid palatable diet cycling protocol. Male Wistar rats were fed either continuously a regular chow diet (Chow/Chow, control group) or intermittently a regular chow diet for 2 days and a palatable, high-sucrose diet for 1 day (Chow/Palatable). Chow/Palatable rats showed spontaneous and progressively increasing hypophagia and body weight loss when fed the regular chow diet, and excessive food intake and body weight gain when fed the palatable diet. Diet-cycled rats dramatically escalated the intake of the palatable diet during the first hour of renewed access (7.5-fold compared to controls), and after withdrawal, they showed compulsive eating and heightened risk-taking behavior. The inverse agonist of the CB1 receptor, SR141716 reduced the excessive intake of palatable food with higher potency and the body weight with greater efficacy in Chow/Palatable rats, compared to controls. Moreover, SR141716 reduced compulsive eating and risk-taking behavior in Chow/Palatable rats. Finally, consistent with the behavioral and pharmacological observations, withdrawal from the palatable diet decreased the gene expression of the enzyme fatty acid amide hydrolase in the ventromedial hypothalamus while increasing that of CB1 receptors in the dorsal striatum in Chow/Palatable rats, compared to controls. These findings will help understand the role of the CB system in compulsive eating. C1 [Dore, Riccardo; Valenza, Marta; Wang, Xiaofan; Sabino, Valentina; Cottone, Pietro] Boston Univ, Sch Med, Dept Pharmacol, Lab Addict Disorders, Boston, MA 02118 USA. [Dore, Riccardo; Valenza, Marta; Wang, Xiaofan; Sabino, Valentina; Cottone, Pietro] Boston Univ, Sch Med, Dept Psychiat, Lab Addict Disorders, Boston, MA 02118 USA. [Valenza, Marta] Univ Bari Aldo Moro, Dept Biomed Sci & Human Oncol, Bari, Italy. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, Kenner C.] NIAAA, Rockville, MD 20852 USA. RP Cottone, P (reprint author), Boston Univ, Sch Med, Dept Pharmacol, Lab Addict Disorders, 72 E Concord St,R-618, Boston, MA 02118 USA. EM cottone@bu.edu RI Sabino, Valentina/F-5290-2012; Cottone, Pietro/F-5291-2012 OI Sabino, Valentina/0000-0002-6680-1279; Cottone, Pietro/0000-0003-1320-1672 FU National Institute on Drug Abuse (NIDA) [DA023680, DA030425, MH091945, MH093650, AA016731]; National Institute of Mental Health (NIMH); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Peter Paul Career Development Professorship; Boston University's Undergraduate Research Opportunities Program (UROP); NIH Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS FX We thank Stephen St Cyr and Patrick De Souza for technical assistance and Rahul Rao for editorial assistance. This publication was made possible by grant numbers DA023680, DA030425, MH091945, MH093650 and AA016731 from the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), by the Peter Paul Career Development Professorship (P. C.) and by Boston University's Undergraduate Research Opportunities Program (UROP). This research was also supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 52 TC 11 Z9 11 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD SEP PY 2014 VL 19 IS 5 BP 849 EP 861 DI 10.1111/adb.12056 PG 13 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA AN4BM UT WOS:000340532600010 PM 23587012 ER PT J AU Corneli, A Pettifor, A Kamanga, G Golin, C McKenna, K Ou, SS Hamela, G Massa, C Martinson, F Tharaldson, J Hilgenberg, D Yu, XS Chege, W Hoffman, I AF Corneli, Amy Pettifor, Audrey Kamanga, Gift Golin, Carol McKenna, Kevin Ou, San-San Hamela, Gloria Massa, Cecelia Martinson, Francis Tharaldson, Jenae Hilgenberg, Deborah Yu, Xuesong Chege, Wairimu Hoffman, Irving CA HPTN 062 Study Team TI HPTN 062: A Feasibility and Acceptability Pilot Intervention to Reduce HIV Transmission Risk Behaviors Among Individuals with Acute and Early HIV Infection in Lilongwe, Malawi SO AIDS AND BEHAVIOR LA English DT Article DE Acute HIV infection; HIV prevention; Motivational Interviewing; Counseling; Malawi ID UNPROTECTED SEXUAL-BEHAVIOR; PROGRAM; OPPORTUNITIES; PREVENTION; HIV/AIDS; SAFETALK; AFRICA AB Acute HIV infection (AHI) is a relatively brief period of time when individuals are highly infectious and the opportunity to intervene to prevent forward transmission is extremely limited. HPTN 062 partnered with CHAVI 001 to evaluate the feasibility and acceptability of a motivational interviewing (MI)-based counseling intervention to reduce HIV-transmission risk behaviors among individuals with acute and early HIV infection in Lilongwe, Malawi. Participants were randomized to receive either (1) brief education sessions about HIV and AHI; or (2) the same brief education sessions plus an MI-based counseling intervention called Uphungu Wanga. Although Uphungu Wanga was determined to be feasible and acceptable, few major differences existed between the two arms with regard to acceptability, feasibility, and self-reported sexual behaviors. We therefore conclude that an additional MI-based counseling intervention may not be needed during the short period of AHI. Instead, we recommend that individuals with AHI receive frequent, but brief, counseling immediately after diagnosis and then transition to receiving counseling at less frequent intervals until they can initiate antiretroviral therapy. Other recommendations are provided. C1 [Corneli, Amy; McKenna, Kevin; Tharaldson, Jenae] FHI 360, Social & Behav Hlth Sci, Durham, NC 27701 USA. [Pettifor, Audrey] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Kamanga, Gift; Hamela, Gloria; Massa, Cecelia; Martinson, Francis] Univ North Carolina Project Malawi, UNC Project, Lilongwe, Malawi. [Golin, Carol] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Golin, Carol] Univ N Carolina, Dept Hlth Behav, Chapel Hill, NC USA. [Ou, San-San; Yu, Xuesong] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Hilgenberg, Deborah] FHI 360, Sci Facilitat, Durham, NC USA. [Chege, Wairimu] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Hoffman, Irving] Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. RP Corneli, A (reprint author), FHI 360, Social & Behav Hlth Sci, 359 Blackwell St,Suite 200, Durham, NC 27701 USA. EM acorneli@fhi360.org FU NIAID NIH HHS [P30 AI050410, UM1 AI068619]; NICHD NIH HHS [K24 HD069204] NR 28 TC 3 Z9 3 U1 3 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2014 VL 18 IS 9 BP 1785 EP 1800 DI 10.1007/s10461-014-0707-1 PG 16 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AN3HD UT WOS:000340476000018 PM 24523007 ER PT J AU Aldo, PB Racicot, K Craviero, V Guller, S Romero, R Mor, G AF Aldo, Paulomi B. Racicot, Karen Craviero, Vinicius Guller, Seth Romero, Roberto Mor, Gil TI Trophoblast Induces Monocyte Differentiation Into CD14+/CD16+ Macrophages SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Decidua; inflammation; macropahge; placenta; trophoblast ID HUMAN DECIDUAL MACROPHAGES; ALTERNATIVE ACTIVATION; PRETERM PARTURITION; GENE-EXPRESSION; IMMUNE-SYSTEM; PREGNANCY; CELLS; INFLAMMATION; LABOR; CHORIOAMNIONITIS AB Problem During early pregnancy, macrophages and trophoblast come into close contact during placenta development, and regulated cross talk between these cellular compartments is crucial for maintaining a healthy pregnancy. As trophoblast cells constitutively secrete many chemokines and cytokines, we hypothesize that trophoblast-secreted factors can differentiate monocytes into a decidual phenotype. In this study, we describe a unique macrophage phenotype, following monocytes' exposure to trophoblast-soluble factors. Method of study Peripheral blood monocytes were treated with or without conditioned media ( CM) from first trimester trophoblast cells. Phenotypic changes and phagocytic capacity were determined by flow cytometry. Cytokine and chemokine production was determined by multiplex analysis. Results Monocytes exposed to trophoblast factors undergo morphologic changes characterized by a gain in size and complexity and acquire a unique phenotype characterized by gain of CD14 surface expression as well as CD16. The presence of CD14+/CD16+ macrophages was confirmed in normal decidua. These cells secrete higher levels of IL-1b, IL-10, and IP-10 and have increased capacity for phagocytosis. Conclusion We demonstrate that trophoblast-secreted factors can induce monocyte differentiation into a unique macrophage phenotype. These findings suggest that the microenvironment of the placenta can modulate the phenotype of macrophages present at the decidua. C1 [Aldo, Paulomi B.; Racicot, Karen; Craviero, Vinicius; Guller, Seth; Mor, Gil] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06520 USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RP Mor, G (reprint author), Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, Div Reprod Sci, 333 Cedar St,LSOG 305A, New Haven, CT 06520 USA. EM gil.mor@yale.edu FU National Institutes of Health; NICDH [P01HD054713, 3N01 HD23342]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX This study is in part funded by grants from the National Institutes of Health, NICDH P01HD054713 and 3N01 HD23342 and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 51 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD SEP PY 2014 VL 72 IS 3 BP 270 EP 284 DI 10.1111/aji.12288 PG 15 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA AN4AN UT WOS:000340530100004 PM 24995492 ER PT J AU Mackay, D AF Mackay, Douglas TI STANDARD OF CARE, PROFESSIONAL OBLIGATIONS, AND DISTRIBUTIVE JUSTICE SO BIOETHICS LA English DT Article DE standard-of-care; professional obligations; distributive justice ID CLINICAL RESEARCH; ETHICS; EQUIPOISE; TRIALS AB The problem of standard-of-care in clinical research concerns the level of care that investigators ought to provide to research subjects in the control arm of their clinical trials. Commentators differ sharply on whether subjects in trials conducted in lower income countries should be provided with the same level of care as subjects in trials conducted in higher income countries. I consider an argument that commentators have employed on both sides of this debate: professional role arguments. These arguments claim to justify a conclusion to the standard-of-care problem solely by appeal to the professional obligations that investigators possess. I argue that prominent versions of professional role arguments cannot justify a solution to the problem of standard-of-care that is both determinate and reasonable simply by appeal to the professional obligations of investigators. Instead, to do so, one must also (1) determine the level of care or types of treatment that individuals are entitled to as a matter of distributive justice, and (2) identify which agents possess the duties that correspond to these entitlements. The level of care that investigators owe to subjects in the control arm of their clinical trials is thus in part dependent on the level of care that these subjects are entitled to as a matter of distributive justice, and whether it is the investigators who possess the corresponding distributive obligation to provide them with the care that they are entitled to. C1 NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Mackay, D (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM doug.mackay@nih.gov OI MacKay, Douglas/0000-0003-2563-0458 NR 27 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD SEP PY 2014 VL 28 IS 7 BP 352 EP 359 DI 10.1111/j.1467-8519.2012.02003.x PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AN3ZD UT WOS:000340526500005 PM 22978692 ER PT J AU Su, P Cheng, QQ Wang, XJ Cheng, XQ Zhang, M Tong, YR Li, F Gao, W Huang, LQ AF Su, Ping Cheng, Qiqing Wang, Xiujuan Cheng, Xiaoqing Zhang, Meng Tong, Yuru Li, Fei Gao, Wei Huang, Luqi TI Characterization of eight terpenoids from tissue cultures of the Chinese herbal plant, Tripterygium wilfordii, by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry SO BIOMEDICAL CHROMATOGRAPHY LA English DT Article DE tissue culture; HPLC-ESI-MS; terpenoid; Tripterygium wilfordii Hook. F. ID HOOK.-F; TRIPTOLIDE; TRIPDIOLIDE; TRITERPENES; MS; ALKALOIDS; MEDICINE; EXTRACTS; THERAPY; PLASMA AB In this study, a reliable method for analysis and identification of eight terpenoids in tissue cultures of Tripterygium wilfordii has been established using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS). Our study indicated that sterile seedlings, callus cultures and cell-suspension cultures can rapidly increase the amount of biological materials. HPLC-ESI-MS was used to identify terpenoids from the extracts of these tissue cultures. Triptolide, triptophenolide, celastrol and wilforlide A were unambiguously determined by comparing the retention times, UV spectral data, and mass fragmentation behaviors with those of the reference compounds. Another four compounds were tentatively identified as triptonoterpenol, triptonoterpene, 22 beta-hydroxy-3-oxoolean-12-en-29-oic acid and wilforlide B, based on their UV and mass spectrometry spectra. The quantitative analysis showed that all three materials contain triptolide, triptophenolide, celastrol, wilforlide A, and the contents of the four compounds in the cell-suspension cultures were 53.1, 240, 129 and 964 mu g/g, respectively, which were at least 2.0-fold higher than these in the sterile seedlings and callus cultures. Considering the known pharmacological activity of triptolide and celastrol, we recommend the cell-suspension cultures as biological materials for future studies, such as clinical and toxicological studies. The developed method was validated by the evaluation of its precision, linearity, detection limits and recovery, and it was successfully used to identify and quantify the terpenoids in the tissue cultures. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Su, Ping; Cheng, Qiqing; Wang, Xiujuan; Cheng, Xiaoqing; Zhang, Meng; Tong, Yuru; Gao, Wei] Capital Med Univ, Sch Tradit Chinese Med, Beijing 100069, Peoples R China. [Su, Ping; Cheng, Qiqing; Tong, Yuru; Huang, Luqi] China Acad Chinese Med Sci, Natl Resource Ctr Chinese Mat Med, Beijing, Peoples R China. [Li, Fei] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD USA. RP Gao, W (reprint author), Capital Med Univ, Sch Tradit Chinese Med, Beijing 100069, Peoples R China. EM weigao@ccmu.edu.cn; huangluqi01@126.com FU National Natural Science Foundation of China [81373906]; Foundation for the Author of National Excellent Doctoral Dissertation of China [201188]; Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality [CITTCD201304174]; Special Foundation for the Research of Capital Traditional Chinese Medicine [13ZY03] FX This work was supported by the National Natural Science Foundation of China (81373906) and the Foundation for the Author of National Excellent Doctoral Dissertation of China (201188) and the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality (CIT&TCD201304174) to W. G. and the Special Foundation for the Research of Capital Traditional Chinese Medicine (13ZY03). We also thank Professors Wei Hong and Chengzhen Wu of Fujian Agriculture and Forestry University, for providing plant material of Tripterygium wilfordii Hook. F. NR 42 TC 8 Z9 13 U1 5 U2 38 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-3879 EI 1099-0801 J9 BIOMED CHROMATOGR JI Biomed. Chromatogr. PD SEP PY 2014 VL 28 IS 9 BP 1183 EP 1192 DI 10.1002/bmc.3140 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA AN3ZZ UT WOS:000340528700004 PM 25237706 ER PT J AU Ilinskaya, AN Dobrovolskaia, MA AF Ilinskaya, A. N. Dobrovolskaia, M. A. TI Immunosuppressive and anti-inflammatory properties of engineered nanomaterials SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review DE nanoparticles; immune system; immunosuppression; inflammation; anti-inflammatory properties; immune inhibition ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; DELAYED-TYPE HYPERSENSITIVITY; SOLID LIPID NANOPARTICLES; ENCAPSULATING BETAMETHASONE PHOSPHATE; RHEUMATOID-ARTHRITIS; OXIDE NANOPARTICLES; DENDRITIC CELLS; CYCLOSPORINE-A; CONCISE GUIDE; IN-VIVO AB Nanoparticle interactions with various components of the immune system are determined by their physicochemical properties such as size, charge, hydrophobicity and shape. Nanoparticles can be engineered to either specifically target the immune system or to avoid immune recognition. Nevertheless, identifying their unintended impacts on the immune system and understanding the mechanisms of such accidental effects are essential for establishing a nanoparticle's safety profile. While immunostimulatory properties have been reviewed before, little attention in the literature has been given to immunosuppressive and anti-inflammatory properties. The purpose of this review is to fill this gap. We will discuss intended immunosuppression achieved by either nanoparticle engineering, or the use of nanoparticles to carry immunosuppressive or anti-inflammatory drugs. We will also review unintended immunosuppressive properties of nanoparticles per se and consider how such properties could be either beneficial or adverse. C1 [Ilinskaya, A. N.; Dobrovolskaia, M. A.] Leidos Biomed Res Inc, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Dobrovolskaia, MA (reprint author), Leidos Biomed Res Inc, Nanotechnol Characterizat Lab, Frederick Natl Lab Canc Res, POB B, Frederick, MD 21702 USA. EM marina@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We are grateful to Rachael Crist for help in manuscript preparation. The study was supported in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 135 TC 17 Z9 17 U1 8 U2 48 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD SEP PY 2014 VL 171 IS 17 SI SI BP 3988 EP 4000 DI 10.1111/bph.12722 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AN3SS UT WOS:000340509600004 PM 24724793 ER PT J AU Hiramoto, K Murata, T Shimizu, K Morita, H Inui, M Manganielle, VC Tagawa, T Arai, N AF Hiramoto, Kenichi Murata, Taku Shimizu, Kasumi Morita, Hiroshi Inui, Madoka Manganielle, Vincent C. Tagawa, Toshiro Arai, Naoya TI Role of phosphodiesterase 2 in growth and invasion of human malignant melanoma cells SO CELLULAR SIGNALLING LA English DT Article DE Human malignant melanoma; Phosphodiesterase 2; Cell growth; Invasion; Cyclic AMP ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; POTENTIAL TARGET; THERAPEUTIC AGENTS; BOVINE-TISSUES; C-MYC; AMP; INHIBITION; ADENOSINE; DIFFERENTIATION; EXPRESSION AB Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a CAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PICA inhibitor, and inhibited by N-6-benzoyl-c AMP, a PICA specific cAMP analog, whereas 8-(4-chlorophenylthio)-2'-O-methyl-cAMP, an Epac specific cAMP analog, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines. (C) 2014 Published by Elsevier Inc. C1 [Hiramoto, Kenichi; Murata, Taku; Shimizu, Kasumi; Morita, Hiroshi; Inui, Madoka; Tagawa, Toshiro; Arai, Naoya] Mie Univ, Grad Sch Med, Dept Clin Sci Med Life Sci, Dept Oral & Maxillofacial Surg, Tsu, Mie 5148507, Japan. [Manganielle, Vincent C.] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Shimizu, K (reprint author), Mie Univ, Grad Sch Med, Dept Clin Sci Med Life Sci, Dept Oral & Maxillofacial Surg, 2-74 Edobashi, Tsu, Mie 5148507, Japan. EM skasumi@clin.medic.mie-u.ac.jp FU Japan Society for the Promotion of Science [16390585, 18390537]; Intramural Research Program in National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by Grants-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science 16390585 (T.T.) and 18390537 (T.M.) and the Intramural Research Program in National Heart, Lung, and Blood Institute, National Institutes of Health (V.C.M.). NR 43 TC 2 Z9 2 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD SEP PY 2014 VL 26 IS 9 BP 1807 EP 1817 DI 10.1016/j.cellsig.2014.03.031 PG 11 WC Cell Biology SC Cell Biology GA AN0XZ UT WOS:000340308600006 PM 24705027 ER PT J AU Chang, C Sheikh, V Sereti, I French, M AF Chang, C. C. Sheikh, V. Sereti, I. French, M. A. TI Immune Reconstitution Disorders in Patients With HIV Infection: From Pathogenesis to Prevention and Treatment SO CURRENT HIV/AIDS REPORTS LA English DT Article DE HIV; Immune reconstitution disorders; Immune reconstitution inflammatory syndrome (IRIS) ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; T-CELL RESPONSES; COMBINATION ANTIRETROVIRAL THERAPY; NATALIZUMAB-ASSOCIATED PML; CENTRAL-NERVOUS-SYSTEM; INFLAMMATORY SYNDROME; CRYPTOCOCCAL MENINGITIS; KAPOSI-SARCOMA; RESTORATION DISEASE; CEREBROSPINAL-FLUID AB An immune reconstitution disorder occurs in up to 40 % of severely immunodeficient HIV patients who commence antiretroviral therapy (ART), with an immune reconstitution inflammatory syndrome (IRIS) being encountered most commonly. Differences in the immunopathogenesis of an IRIS associated with different types of pathogen have become apparent but common features have also been defined. These include severe immunodeficiency prior to commencing ART associated with a high pathogen load and 'compensatory' immune responses, particularly innate immune responses, which inadequately control the pathogen and increase the risk of immunopathology as the immune system recovers on ART. Prevention of an IRIS may be achieved by optimising therapy for opportunistic infections before ART is commenced, delaying ART or using immunomodulatory therapy to prevent or suppress the immune response that causes the immunopathology. However, further clinical studies are required to examine these options in a systematic manner for the various types of IRIS. C1 [Chang, C. C.] Monash Univ, Melbourne, Vic 3000, Australia. [Chang, C. C.] Alfred Hosp, Dept Infect Dis, Melbourne, Vic 3000, Australia. [Chang, C. C.] Biomed Res Ctr, Burnet Inst, Melbourne, Vic 3000, Australia. [Sheikh, V.; Sereti, I.] NIAID, Immunoregulat Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [French, M. A.] Univ Western Australia, Sch Pathol, Perth, WA 6009, Australia. [French, M. A.] Royal Perth Hosp, Dept Clin Immunol, Perth, WA 6000, Australia. [French, M. A.] PathWest Lab Med, Perth, WA 6000, Australia. RP French, M (reprint author), Univ Western Australia, Sch Pathol, Perth, WA 6009, Australia. EM martyn.french@uwa.edu.au OI Chang, Christina Catherine/0000-0003-0109-0725 FU Intramural Research Program of the National Institutes of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, MD, USA FX The work of IS and VS was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, MD, USA. NR 92 TC 10 Z9 10 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1548-3568 EI 1548-3576 J9 CURR HIV-AIDS REP JI Curr. Hiv/Aids Rep. PD SEP PY 2014 VL 11 IS 3 BP 223 EP 232 DI 10.1007/s11904-014-0213-0 PG 10 WC Infectious Diseases SC Infectious Diseases GA AN1UF UT WOS:000340368500004 PM 24950732 ER PT J AU Teicher, BA AF Teicher, Beverly A. TI Antibody drug conjugates SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE antibody drug conjugates; brentuximab vedotin; trastuzumab emtansine ID BRENTUXIMAB VEDOTIN SGN-35; INOTUZUMAB OZOGAMICIN; CANCER-THERAPY; ANTITUMOR-ACTIVITY; ALPHA-AMANITIN; TRASTUZUMAB EMTANSINE; TARGETED CHEMOTHERAPY; PHASE-II; CALICHEAMICIN; THERAPEUTICS AB Purpose of review Antibody conjugates are a diverse complex class of therapeutics, consisting of a potent cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells or an extracellular target, that are having impact in the clinic. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The more than 30-year history of antibody conjugates is marked by hurdles that have been identified and overcome. Recent findings Technology is continuing to evolve the protein and small molecule components, and it is likely that soon single-chemical entities will be the norm for antibody drug conjugates. More than 20 antibody conjugates are currently in clinical trials. Summary The time has arrived for this technology to become a major contributor to improving treatment for cancer patients. C1 [Teicher, Beverly A.] NCI, Bethesda, MD 20892 USA. RP Teicher, BA (reprint author), NCI, Mol Pharmacol Branch, RM 4-W602,MSC 9735,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM Beverly.Teicher@nih.gov NR 74 TC 6 Z9 7 U1 6 U2 77 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD SEP PY 2014 VL 26 IS 5 BP 476 EP 483 DI 10.1097/CCO.0000000000000108 PG 8 WC Oncology SC Oncology GA AN4MZ UT WOS:000340563400003 PM 25024051 ER PT J AU Geers, AL Miller, FG AF Geers, Andrew L. Miller, Franklin G. TI Understanding and translating the knowledge about placebo effects: the contribution of psychology SO CURRENT OPINION IN PSYCHIATRY LA English DT Review DE clinical intervention; expectation; placebo effect; psychological process; verbal suggestion ID MECHANISMS; ANALGESIA; EXPECTATIONS; PAIN; EXPECTANCY; CHOICE; ACTIVATION; RESPONSES; CONTEXT; NOCEBO AB Purpose of review Recent articles have summarized the literature on the neurobiological mechanisms involved in placebo effects. In this article, we review and evaluate the status of the psychological mechanisms in theory and research regarding placebo effects. Recent findings Currently, the placebo effect literature concentrates more on neurobiological mechanisms than on psychological mechanisms. Both theoretical and empirical coverage of the psychological mechanisms are typically limited to two variables: conditioning and verbally induced expectations. Because psychological processes take center stage in mediating the link between the therapeutic context and placebo responding, greater effort is needed to build empirically derived and theoretically complex psychological process models. Such models would include a broader array of psychological constructs and mechanisms. Summary Research and theory on placebo effects has illuminated much regarding the neurobiological mechanisms. The psychological mechanisms, however, have received much less attention. Expanding our knowledge regarding the psychological processes involved in placebo responding would open up opportunities for developing nondeceptive intervention techniques that encourage placebo responses. Ultimately, a concerted empirical effort to clarify the psychological model underlying placebo effects could merge with the evolving neurobiological model to fulfill the promise that placebo effects have for improving patient outcomes. C1 [Geers, Andrew L.] Univ Toledo, Toledo, OH USA. [Miller, Franklin G.] NIH, Bethesda, MD 20892 USA. RP Geers, AL (reprint author), Univ Toledo, Dept Psychol, Toledo, OH USA. EM Andrew.geers@utoledo.edu NR 51 TC 2 Z9 2 U1 3 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 EI 1473-6578 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD SEP PY 2014 VL 27 IS 5 BP 326 EP 331 DI 10.1097/YCO.0000000000000082 PG 6 WC Psychiatry SC Psychiatry GA AN1UN UT WOS:000340369300003 PM 25046081 ER PT J AU Kahlenberg, JM Kaplan, MJ AF Kahlenberg, J. Michelle Kaplan, Mariana J. TI The inflammasome and lupus: another innate immune mechanism contributing to disease pathogenesis? SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE caspase-1; IL-18; inflammasome; lupus; NLRP3 ID INHIBITING NLRP3 INFLAMMASOME; PLASMACYTOID DENDRITIC CELLS; HUMAN MONOCYTES; CHOLESTEROL CRYSTALS; AUTOIMMUNE-DISEASE; IFN-ALPHA; ACTIVATION; ERYTHEMATOSUS; NEPHRITIS; INTERLEUKIN-18 AB Purpose of review The role of innate immunity in systemic lupus erythematosus (SLE) has been a rapidly expanding area of research over the last decade. Included in this rubric is the concept that activation of the inflammasome, a molecular complex that activates caspase-1 and in turn the cytokines IL-1 beta and IL-18, is important in lupus pathogenesis. This review will summarize the recent discoveries exploring the role of the inflammasome machinery in SLE. Recent findings Immune complexes can activate the NLRP3 inflammasome, and SLE-derived macrophages are hyper-responsive to innate immune stimuli, leading to enhanced activation of the inflammasome and production of inflammatory cytokines. Work in several murine models suggests an important role for the NLRP3 inflammasome in mediating lupus nephritis. Caspase-1, the central enzyme of the inflammasome, is essential for the development of type I interferon responses, autoantibody production, and nephritis in the pristane model of lupus. The absence of melanoma 2 inflammasome may have protective and pathogenic roles in SLE. Summary Recent evidence suggests that the inflammasome machinery is dysregulated in SLE, plays an important role in promotion of organ damage, and may mediate cross-talk between environmental triggers and the development of lupus. Further research should focus on whether inhibition of inflammasome components may serve as a viable target for therapeutic development in SLE. C1 [Kahlenberg, J. Michelle] Univ Michigan, Div Rheumatol, Dept Internal Med, Ann Arbor, MI 48109 USA. [Kaplan, Mariana J.] NIAMSD, Syst Autoimmun Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Kahlenberg, JM (reprint author), Univ Michigan, Div Rheumatol, 1150 West Med Ctr Dr,MSRB 1 A520A, Ann Arbor, MI 48109 USA. EM mkahlenb@umich.edu OI Kahlenberg, J. Michelle/0000-0002-4006-8945 FU Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health; Alliance for Lupus Research; PHS [ARK08AR063668] FX This work was supported by the Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and by the Alliance for Lupus Research. J.M.K. was supported by the PHS grant ARK08AR063668. NR 67 TC 25 Z9 25 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 EI 1531-6963 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD SEP PY 2014 VL 26 IS 5 BP 475 EP 481 DI 10.1097/BOR.0000000000000088 PG 7 WC Rheumatology SC Rheumatology GA AN1RL UT WOS:000340361200003 PM 24992143 ER PT J AU Metwalli, AR Linehan, WM AF Metwalli, Adam R. Linehan, William M. TI Nephron-sparing surgery for multifocal and hereditary renal tumors SO CURRENT OPINION IN UROLOGY LA English DT Review DE Birt-Hogg-Dube; hereditary leiomyomatosis and renal cell carcinoma; hereditary renal tumors; multifocal kidney tumors; partial nephrectomy; renal cell carcinoma; von Hippel-Lindau ID HOGG-DUBE-SYNDROME; VONHIPPEL-LINDAU-DISEASE; LONG-TERM SURVIVAL; LAPAROSCOPIC PARTIAL NEPHRECTOMY; BAP1 MUTATIONS PREDISPOSE; TYROSINE KINASE DOMAIN; CELL-CARCINOMA; SPONTANEOUS PNEUMOTHORAX; RADICAL NEPHRECTOMY; BILATERAL-NEPHRECTOMY AB Purpose of review Despite the controversy surrounding the benefits of nephron-sparing surgery, multiple absolute indications for nephron-sparing surgery still exist, including the classic indications of hereditary and bilateral kidney tumors. Recent findings Multiple genetic mutations have been identified which lead to hereditary kidney cancer conditions. These are briefly reviewed because the surgical management of hereditary kidney tumors depends on the genetic and histologic subtypes involved. Clear understanding of these hereditary conditions is crucial for proper surgical management of these tumors. Summary Complex partial nephrectomy for multiple renal tumors, or multiplex partial nephrectomy, requires not only exceptional surgical skills but expertise of numerous nonsurgical methodologies, such as hands-on intraoperative ultrasonography and interpretation of multiple imaging modalities. In addition, multidisciplinary management is crucial for optimal outcomes in patient care. This review evaluates the most advanced surgical techniques and perioperative management required to successfully care for these challenging cases. C1 [Metwalli, Adam R.; Linehan, William M.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), Urol Oncol Branch, Bldg 10,Room 1W-5940,10 Ctr Dr,MSC 1211, Bethesda, MD 20892 USA. FU NIH, NCI, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 78 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0963-0643 EI 1473-6586 J9 CURR OPIN UROL JI Curr. Opin. Urol. PD SEP PY 2014 VL 24 IS 5 BP 466 EP 473 DI 10.1097/MOU.0000000000000094 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AN1TY UT WOS:000340367700007 PM 25014245 ER PT J AU Korzeniewski, SJ AF Korzeniewski, Steven J. TI Single-cause attribution in a multifactorial world: cerebral palsy attributed to or associated with congenital cytomegalovirus? SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Editorial Material ID CAUSATION C1 [Korzeniewski, Steven J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Bethesda, MD USA. [Korzeniewski, Steven J.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Korzeniewski, Steven J.] Michigan State Univ, Coll Human Med, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Korzeniewski, SJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Bethesda, MD USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 EI 1469-8749 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD SEP PY 2014 VL 56 IS 9 BP 802 EP 803 DI 10.1111/dmcn.12514 PG 3 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AN3NM UT WOS:000340495200003 PM 25040907 ER PT J AU Cross, AJ Major, JM Rothman, N Sinha, R AF Cross, Amanda J. Major, Jacqueline M. Rothman, Nathaniel Sinha, Rashmi TI Urinary 1-methylhistidine and 3-methylhistidine, meat intake, and colorectal adenoma risk SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE colorectal adenoma; meat; methylhistidine; urine ID EXCRETION; QUESTIONNAIRE; CONSUMPTION; CALIFORNIA; PROTEIN; FOOD AB Self-reported red and processed meat intake has been positively associated with colorectal adenoma and cancer; however, measurement error in self-reported data can attenuate risk estimates, increasing the need for improved exposure assessment methods to better understand this association. A controlled feeding study revealed that urinary 1-methylhistidine and 3-methylhistidine levels were dose-dependently associated with meat intake; our aim was to examine these analytes in relation to colorectal adenoma. Individuals undergoing routine cancer screening by sigmoidoscopy or colonoscopy were recruited for a colorectal adenoma case-control study; participants completed a food frequency questionnaire and a meat questionnaire, and donated urine. Urinary 1-methylhistidine and 3-methylhistidine levels were measured in 131 case-control pairs (age, sex, and smoking matched); odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Although the mean self-reported red meat intake was higher in cases (59 g/day) than in controls (48 g/day), the mean urinary 1-methylhistidine and 3-methylhistidine levels did not differ by case status (P = 0.72). Neither urinary 1-methylhistidine nor urinary 3-methylhistidine was associated with colorectal adenoma (ORcontinuous = 0.90, 95% CI: 0.53-1.54; ORcontinuous = 0.90, 95% CI: 0.69-1.17, respectively). A variable combining self-reported red meat intake with urinary 1-methylhistidine and 3-methylhistidine levels was not associated with colorectal adenoma. Analyzing urine samples from multiple days from 17 individuals revealed intraclass correlations of 0.52 and 0.49 for 1-methylhistidine and 3-methylhistidine, respectively; this variability could result in attenuated risks. Urinary 1-methylhistidine and 3-methylhistidine levels, measured in one sample, were not associated with colorectal adenoma. (c) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Cross, Amanda J.; Major, Jacqueline M.; Rothman, Nathaniel; Sinha, Rashmi] NCI, US Dept HHS, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Cross, AJ (reprint author), 9609 Med Ctr Dr, Rockville, MD 20852 USA. EM crossa@mail.nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Intramural Research Program of the National Cancer Institute, Department of Health and Human Services, National Institutes of Health, Rockville, Maryland FX This work was supported by the Intramural Research Program of the National Cancer Institute, Department of Health and Human Services, National Institutes of Health, Rockville, Maryland. NR 15 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 EI 1473-5709 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD SEP PY 2014 VL 23 IS 5 BP 385 EP 390 DI 10.1097/CEJ.0000000000000027 PG 6 WC Oncology SC Oncology GA AN4LL UT WOS:000340559200007 PM 24681531 ER PT J AU Efthymiou, AG Chen, GB Rao, M Chen, GK Boehm, M AF Efthymiou, Anastasia G. Chen, Guibin Rao, Mahendra Chen, Guokai Boehm, Manfred TI Self-renewal and cell lineage differentiation strategies in human embryonic stem cells and induced pluripotent stem cells SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE differentiation; hESC; hiPSC; self-renewal; stem cells ID SERUM-FREE MEDIUM; DEFINED CULTURE-CONDITIONS; GROWTH-FACTOR; IN-VITRO; DEFINITIVE ENDODERM; CARDIOMYOCYTE DIFFERENTIATION; DIRECTED DIFFERENTIATION; RECOMBINANT VITRONECTIN; HUMAN BLASTOCYSTS; ACTIVIN-A AB Introduction: Since the initial discoveries of human embryonic and induced pluripotent stem cells, many strategies have been developed to utilize the potential of these cells for translational research and disease modeling. The success of these aims and the development of future applications in this area will depend on the ability to generate high-quality and large numbers of differentiated cell types that genetically, epigenetically, and functionally mimic the cells found in the body. Areas covered: In this review, we highlight the current strategies used to maintain stem cell pluripotency (a measure of stem cell quality), as well as provide an overview of the various differentiation strategies being used to generate cells from all three germ lineages. We also discuss the particular considerations that must be addressed when utilizing these cells for translational therapy, and provide an example of a cell type currently used in clinical trials. Expert opinion: The major challenge in regenerative medicine and disease modeling will be in generating functional cells of sufficient quality that are physiologically and epigenetically similar to the diverse cells that they are modeled after. By meeting these criteria, these differentiated products can be successfully used in disease modeling, drug/toxicology screens, and cellular replacement therapy. C1 [Efthymiou, Anastasia G.; Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Efthymiou, Anastasia G.; Rao, Mahendra] NIH, Natl Inst Arthrit & Musculoskeletal & Skin Dis, Bethesda, MD 20892 USA. [Chen, Guibin; Chen, Guokai; Boehm, Manfred] NHLBI, NIH, Ctr Mol Med, Bethesda, MD 20892 USA. RP Boehm, M (reprint author), NHLBI, NIH, Ctr Mol Med, 10 Ctr Dr,MSC1454,Bldg 10-CRC,RM 5 East 3132, Bethesda, MD 20892 USA. EM boehmm@nhlbi.nih.gov OI Efthymiou, Anastasia/0000-0002-1769-5078 NR 98 TC 4 Z9 5 U1 2 U2 38 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 EI 1744-7682 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD SEP PY 2014 VL 14 IS 9 BP 1333 EP 1344 DI 10.1517/14712598.2014.922533 PG 12 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA AN3BN UT WOS:000340460000010 PM 24881868 ER PT J AU Coyne, GO Burotto, M AF Coyne, Geraldine O'Sullivan Burotto, Mauricio TI Clinical experience with ramucirumab: outcomes in breast cancer SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Article DE angiogenesis; breast cancer; cancer; clinical trials; mAb; ramucirumab; VEGF; VEGFR-2 ID PHASE-III TRIAL; METASTATIC COLORECTAL-CANCER; ENDOTHELIAL GROWTH-FACTOR; PACLITAXEL PLUS BEVACIZUMAB; 1ST-LINE TREATMENT; DOUBLE-BLIND; DOCETAXEL; PLACEBO; COMBINATION; SUNITINIB AB Introduction: Monoclonal antibodies and small molecules targeting the VEGF pathway are part of the arsenal to treat malignant tumors. Antiangiogenesis therapies has been studied in breast cancer with partial success, reflected by the approval of bevacizumab in Europe but not in United States, for metastatic breast cancer (mBC). Ramucirumab is a mAb against VEGFR-2 interfering with the normal activation of this receptor by its natural ligand VEGF. Areas covered: This article will review the preclinical data available to date for ramucirumab, as well as survey the main clinical trials of antiangiogenic agents reported in breast cancer, focusing on Phase III clinical trials. It will also review the clinical trial data for ramucirumab in mBC, including the design of the Phase II trials, and report on the preliminary results of the TRIO-012 trial. This trial did not meet its primary end point in progression-free survival and has to be considered as a negative trial. Expert opinion: Despite preliminary positive data with ramucirumab in other metastatic solid tumors reported to date, the results of TRIO-012 discourage pursuing more efforts with ramucirumab in mBC unless predictive and reproducible biomarkers can be established to select those patients who are most likely to benefit from it. C1 [Coyne, Geraldine O'Sullivan; Burotto, Mauricio] NCI, Natl Inst Hlth Natl, Ctr Canc Res, Med Oncol Serv, Bethesda, MD 20892 USA. RP Coyne, GO (reprint author), NCI, Natl Inst Hlth Natl, Ctr Canc Res, Med Oncol Serv, 12N226, Bethesda, MD 20892 USA. EM geraldine.o'sullivancoyne@nih.gov OI O'Sullivan Coyne, Geraldine/0000-0002-2918-6326 NR 45 TC 3 Z9 3 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 EI 1744-7682 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD SEP PY 2014 VL 14 IS 9 BP 1351 EP 1360 DI 10.1517/14712598.2014.939069 PG 10 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA AN3BN UT WOS:000340460000012 ER PT J AU Schwender, H Li, Q Neumann, C Taub, MA Younkin, SG Berger, P Scharpf, RB Beaty, TH Ruczinski, I AF Schwender, Holger Li, Qing Neumann, Christoph Taub, Margaret A. Younkin, Samuel G. Berger, Philipp Scharpf, Robert B. Beaty, Terri H. Ruczinski, Ingo TI Detecting Disease Variants in Case-Parent Trio Studies Using the Bioconductor Software Package trio SO GENETIC EPIDEMIOLOGY LA English DT Article DE software; case-parent trios; transmission disequilibrium tests; gene-environment interactions; parent-of-origin effects ID GENE-ENVIRONMENT INTERACTIONS; WITH/WITHOUT CLEFT-PALATE; GENOME-WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; EPISTATIC INTERACTIONS; RISK; LIP; FAMILY; TESTS; MARKERS AB Case-parent trio studies are commonly employed in genetics to detect variants underlying common complex disease risk. Both commercial and freely available software suites for genetic data analysis usually contain methods for case-parent trio designs. A user might, however, experience limitations with these packages, which can include missing functionality to extend the software if a desired analysis has not been implemented, and the inability to programmatically capture all the software versions used for low-level processing and high-level inference of genomic data, a critical consideration in particular for high-throughput experiments. Here, we present a software vignette (i.e., a manual with step by step instructions and examples to demonstrate software functionality) for reproducible genome-wide analyses of case-parent trio data using the open source Bioconductor package trio. The workflow for the practitioner uses data from previous genetic trio studies to illustrate functions for marginal association tests, assessment of parent-of-origin effects, power and sample size calculations, and functions to detect gene-gene and gene-environment interactions associated with disease. (C) 2014 Wiley Periodicals, Inc. C1 [Schwender, Holger; Berger, Philipp] Univ Dusseldorf, Math Inst, D-40225 Dusseldorf, Germany. [Li, Qing] NHGRI, Inherited Dis Res Branch, Baltimore, MD USA. [Neumann, Christoph] TU Dortmund Univ, Fac Stat, Dortmund, Germany. [Taub, Margaret A.; Ruczinski, Ingo] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Younkin, Samuel G.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Scharpf, Robert B.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Beaty, Terri H.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. RP Schwender, H (reprint author), Univ Dusseldorf, Math Inst, Univ Str 1, D-40225 Dusseldorf, Germany. EM holger.schwender@uni-duesseldorf.de FU Deutsche Forschungsgemeinschaft [SCHW 1508/3-1, SFB 823]; National Institute of Health [R01 HL090577, R01 GM083084, R03 DE021437, U01 DE018993, R01 DE014581]; CTSA FX We gratefully acknowledge the financial support provided by the Deutsche Forschungsgemeinschaft (SCHW 1508/3-1 to HS; SFB 823 "Statistical Modelling of Nonlinear Dynamic Processes" to C.N.), the National Institute of Health (R01 HL090577 to Q.L. and I.R.; R01 GM083084 to I.R.; R03 DE021437 to S.G.Y., T.H.B., and I.R.; U01 DE018993 and R01 DE014581 to T.H.B.), and a CTSA grant to the Johns Hopkins Medical Institutions. We particularly acknowledge Jeffrey C. Murray, Mary L. Marazita, and Alan F. Scott who played critical roles in generating the data for the International Cleft Consortium, used in this manuscript. The manuscript is dedicated to the late Trio member Gert "Kralle" Krawinkel. NR 37 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD SEP PY 2014 VL 38 IS 6 BP 516 EP 522 DI 10.1002/gepi.21836 PG 7 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA AN4KP UT WOS:000340556900004 PM 25048299 ER PT J AU Hammond, P McKee, S Suttie, M Allanson, J Cobben, JM Maas, SM Quarrell, O Smith, ACM Lewis, S Tassabehji, M Sisodiya, S Mattina, T Hennekam, R AF Hammond, Peter McKee, Shane Suttie, Michael Allanson, Judith Cobben, Jan-Maarten Maas, Saskia M. Quarrell, Oliver Smith, Ann C. M. Lewis, Suzanne Tassabehji, May Sisodiya, Sanjay Mattina, Teresa Hennekam, Raoul TI Opposite effects on facial morphology due to gene dosage sensitivity SO HUMAN GENETICS LA English DT Article ID SOTOS SYNDROME DELETION; PHENOTYPE; MICRODUPLICATION; HUMANS; REGION; DELAY; ARRAY AB Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individual's face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The ability to visualise and quantify face shape effects of gene dosage is of major benefit for determining whether a CNV is the cause of the phenotype of an individual and for predicting reciprocal consequences. It enables face shape to be used as a relatively simple and inexpensive functional analysis of the gene(s) involved. C1 [Hammond, Peter; Suttie, Michael] UCL Inst Child Hlth, Mol Med Unit, London WC1N 1EH, England. [McKee, Shane] Belfast City Hosp Trust, Belfast, Antrim, North Ireland. [Allanson, Judith] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada. [Cobben, Jan-Maarten; Maas, Saskia M.; Hennekam, Raoul] Univ Amsterdam, Acad Med Ctr, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands. [Quarrell, Oliver] Sheffield Childrens Hosp, Dept Clin Genet, Sheffield, S Yorkshire, England. [Smith, Ann C. M.] NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. [Lewis, Suzanne] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Tassabehji, May] Univ Manchester, Fac Med & Human Sci, Inst Human Dev, Manchester Ctr Genom Med, Manchester, Lancs, England. [Tassabehji, May] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester, Lancs, England. [Sisodiya, Sanjay] UCL Inst Neurol, Dept Clin & Expt Epilepsy, London, England. [Mattina, Teresa] Univ Catania, Catania, Italy. RP Hammond, P (reprint author), UCL Inst Child Hlth, Mol Med Unit, 30 Guilford St, London WC1N 1EH, England. EM p.hammond@ucl.ac.uk FU US National Institute on Alcoholism and Alcohol Abuse as part of the CIFASD consortium [2U01AA014809] FX This work was partly supported by the US National Institute on Alcoholism and Alcohol Abuse with a grant to PH (2U01AA014809) as part of the CIFASD consortium (www.cifasd.org). NR 28 TC 6 Z9 6 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD SEP PY 2014 VL 133 IS 9 BP 1117 EP 1125 DI 10.1007/s00439-014-1455-z PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AN3WT UT WOS:000340520100005 PM 24889830 ER PT J AU Shih, HY Sciume, G Poholek, AC Vahedi, G Hirahara, K Villarino, AV Bonelli, M Bosselut, R Kanno, Y Muljo, SA O'Shea, JJ AF Shih, Han-Yu Sciume, Giuseppe Poholek, Amanda C. Vahedi, Golnaz Hirahara, Kiyoshi Villarino, Alejandro V. Bonelli, Michael Bosselut, Remy Kanno, Yuka Muljo, Stefan A. O'Shea, John J. TI Transcriptional and epigenetic networks of helper T and innate lymphoid cells SO IMMUNOLOGICAL REVIEWS LA English DT Review DE transcription factors; gene regulation; epigenetics; T cells; ILCs; cell identity ID NATURAL-KILLER-CELLS; ROR-GAMMA-T; ARYL-HYDROCARBON RECEPTOR; PATHOGENIC T(H)17 CELLS; GERMINAL-CENTER FORMATION; CYTOKINE GENE-EXPRESSION; GROWTH-FACTOR-BETA; HYPER-IGE SYNDROME; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ANTI-INTERLEUKIN-17 MONOCLONAL-ANTIBODY AB The discovery of the specification of CD4(+) helper T cells to discrete effector 'lineages' represented a watershed event in conceptualizing mechanisms of host defense and immunoregulation. However, our appreciation for the actual complexity of helper T-cell subsets continues unabated. Just as the Sami language of Scandinavia has 1000 different words for reindeer, immunologists recognize the range of fates available for a CD4(+) T cell is numerous and may be underestimated. Added to the crowded scene for helper T-cell subsets is the continuously growing family of innate lymphoid cells (ILCs), endowed with common effector responses and the previously defined 'master regulators' for CD4(+) helper T-cell subsets are also shared by ILC subsets. Within the context of this extraordinary complexity are concomitant advances in the understanding of transcriptomes and epigenomes. So what do terms like 'lineage commitment' and helper T-cell 'specification' mean in the early 21st century? How do we put all of this together in a coherent conceptual framework? It would be arrogant to assume that we have a sophisticated enough understanding to seriously answer these questions. Instead, we review the current status of the flexibility of helper T-cell responses in relation to their genetic regulatory networks and epigenetic landscapes. Recent data have provided major surprises as to what master regulators can or cannot do, how they interact with other transcription factors and impact global genome-wide changes, and how all these factors come together to influence helper cell function. C1 [Shih, Han-Yu; Sciume, Giuseppe; Poholek, Amanda C.; Vahedi, Golnaz; Hirahara, Kiyoshi; Villarino, Alejandro V.; Bonelli, Michael; Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Hirahara, Kiyoshi] Chiba Univ, Dept Adv Allergol Airway, Chiba, Japan. [Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Muljo, Stefan A.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Kanno, Yuka/B-5802-2013; Muljo, Stefan/F-5671-2015; Sciume, Giuseppe/K-8985-2016; Hirahara, Kiyoshi/E-2460-2017; OI Muljo, Stefan/0000-0003-1013-446X; Sciume, Giuseppe/0000-0003-0131-512X; Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319; Villarino, Alejandro/0000-0001-8068-2176 FU NIH Intramural Research Program of NIAMS; NIH Intramural Research Program of NIAID; NIH Intramural Research Program of NCI FX This study was supported by the NIH Intramural Research Programs of NIAMS, NIAID, and NCI. The authors have no conflicts of interest to declare. NR 454 TC 15 Z9 16 U1 0 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD SEP PY 2014 VL 261 IS 1 SI SI BP 23 EP 49 DI 10.1111/imr.12208 PG 27 WC Immunology SC Immunology GA AN4HB UT WOS:000340547200003 PM 25123275 ER PT J AU Li, P Spolski, R Liao, W Leonard, WJ AF Li, Peng Spolski, Rosanne Liao, Wei Leonard, Warren J. TI Complex interactions of transcription factors in mediating cytokine biology in T cells SO IMMUNOLOGICAL REVIEWS LA English DT Review DE transcription factors; cell differentiation; T cells; Th1/Th2/Th17 cells; cytokines; gene regulation ID INTERFERON-REGULATORY FACTOR-4; ROR-GAMMA-T; LONG NONCODING RNAS; CLASS-SWITCH RECOMBINATION; ALLERGIC AIRWAYS DISEASE; BATF-IRF INTERACTIONS; TH1 IMMUNE-RESPONSES; HELPER TYPE-1 CELLS; GERMINAL CENTER B; TGF-BETA AB T-helper (Th) cells play critical roles within the mammalian immune system, and the differentiation of naive CD4(+) T cells into distinct T-helper subsets is critical for normal immunoregulation and host defense. These carefully regulated differentiation processes are controlled by networks of cytokines, transcription factors, and epigenetic modifications, resulting in the generation of multiple CD4(+) T-cell subsets, including Th1, Th2, Th9, Th17, Treg, and Tfh cells. In this review, we discuss the roles of transcription factors in determining the specific type of differentiation and in particular the role of interleukin-2 (IL-2) in promoting or inhibiting Th differentiation. In addition to discussing master regulators and subset-specific transcription factors for distinct T-helper cell populations, we focus on signal transducer and activator of transcription (STAT) proteins and on the cooperative action of interferon regulatory factor 4 (IRF4) with activator protein 1 (AP-1) family proteins and STAT3 in the assembly of complexes that broadly influence T-cell differentiation. C1 [Li, Peng; Spolski, Rosanne; Liao, Wei; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Li, Peng; Spolski, Rosanne; Liao, Wei; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. RP Li, P (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM peng.li@nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD FX We thank Dr. Jian-Xin Lin, NHLBI, for critical comments. Supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD. The authors have no conflicts of interest to declare. NR 201 TC 18 Z9 20 U1 1 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD SEP PY 2014 VL 261 IS 1 SI SI BP 141 EP 156 DI 10.1111/imr.12199 PG 16 WC Immunology SC Immunology GA AN4HB UT WOS:000340547200010 PM 25123282 ER PT J AU Liu, YQ Chen, LY Sokolowska, M Eberlein, M Alsaaty, S Martinez-Anton, A Logun, C Qi, HY Shelhamer, JH AF Liu, Yueqin Chen, Li-Yuan Sokolowska, Milena Eberlein, Michael Alsaaty, Sara Martinez-Anton, Asuncion Logun, Carolea Qi, Hai-Yan Shelhamer, James H. TI The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A(2) via GPR120 receptor to produce prostaglandin E-2 and plays an anti-inflammatory role in macrophages SO IMMUNOLOGY LA English DT Article DE cytokines; inflammation; lipid mediators; signal transduction ID POLYUNSATURATED FATTY-ACIDS; ARACHIDONIC-ACID; EICOSAPENTAENOIC ACID; ANTI-INFLAMMATION; LIPID MEDIATORS; HUMAN MONOCYTES; ETHYL-ESTERS; OMEGA-3-FATTY-ACIDS; EXPRESSION; CELLS AB Docosahexaenoic acid (DHA) is one of the major ingredients of fish oil and has been reported to have anti-inflammatory properties mediated through the GPR120 receptor. Whether cytosolic phospholipase A(2) (cPLA(2)) and lipid mediators produced from cPLA(2) activation are involved in the anti-inflammatory role of DHA in macrophages has not been reported. We report here that DHA and the GPR120 agonist, GW9508, activate cPLA(2) and cyclooxygenase 2 (COX-2), and cause prostaglandin E-2 (PGE(2)) release in a murine macrophage cell line RAW264.7 and in human primary monocyte-derived macrophages. DHA and GW9508 activate cPLA(2) via GPR120 receptor, G protein G alpha q and scaffold protein beta-arrestin 2. Extracellular signal-regulated kinase 1/2 activation is involved in DHA- and GW9508-induced cPLA(2) activation, but not p38 mitogen-activated protein kinase. The anti-inflammatory role of DHA and GW9508 is in part via activation of cPLA(2), COX-2 and production of PGE(2) as a cPLA(2) inhibitor or a COX-2 inhibitor partially reverses the DHA- and GW9508-induced inhibition of lipopolysaccharide-induced interleukin-6 secretion. The cPLA(2) product arachidonic acid and PGE(2) also play an anti-inflammatory role. This effect of PGE(2) is partially through inhibition of the nuclear factor-kappa B signalling pathway and through the EP4 receptor of PGE(2) because an EP4 inhibitor or knock-down of EP4 partially reverses DHA inhibition of lipopolysaccharide-induced interleukin-6 secretion. Hence, DHA has an anti-inflammatory effect partially through induction of PGE(2). C1 [Liu, Yueqin; Chen, Li-Yuan; Sokolowska, Milena; Eberlein, Michael; Alsaaty, Sara; Martinez-Anton, Asuncion; Logun, Carolea; Qi, Hai-Yan; Shelhamer, James H.] NIH, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. [Eberlein, Michael] Univ Iowa, Sch Med, Iowa City, IA 52242 USA. RP Shelhamer, JH (reprint author), NIH, Crit Care Med Dept, Ctr Clin, Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM jshelhamer@nih.gov RI Martinez Anton, Asuncion/A-5806-2017 OI Martinez Anton, Asuncion/0000-0001-9758-5911 NR 67 TC 30 Z9 30 U1 2 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD SEP PY 2014 VL 143 IS 1 BP 81 EP 95 DI 10.1111/imm.12296 PG 15 WC Immunology SC Immunology GA AN2AH UT WOS:000340385000009 PM 24673159 ER PT J AU Kerkar, SP Chinnasamy, D Hadi, N Melenhorst, J Muranski, P Spyridonidis, A Ito, S Weber, G Yin, F Hensel, N Wang, E Marincola, FM Barrett, AJ AF Kerkar, Sid P. Chinnasamy, Dhanalakshmi Hadi, Neima Melenhorst, Jan Muranski, Pawel Spyridonidis, Alexandros Ito, Sawa Weber, Gerrit Yin, Fang Hensel, Nancy Wang, Ena Marincola, Francesco M. Barrett, Austin John TI Timing and intensity of exposure to interferon-gamma critically determines the function of monocyte-derived dendritic cells SO IMMUNOLOGY LA English DT Article DE antigen presentation; dendritic cells; inflammation; interferon-gamma; T lymphocytes ID CD4(+) T-CELLS; IFN-GAMMA; CANCER-IMMUNOTHERAPY; IMMUNE-RESPONSES; ADOPTIVE IMMUNOTHERAPY; THERAPY; BIOLOGY; DIFFERENTIATION; MECHANISMS; MATURATION AB A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects of interferon-gamma (IFN-gamma) on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of monocytes into moDC with granulocyte-macrophage colony-stimulating factor and interleukin-4, IFN-gamma induces moDC maturation and up-regulates the co-stimulatory markers CD80/CD86/CD95 and MHC Class I, enabling moDC to effectively generate antigen-specific CD4(+) and CD8(+) T-cell responses for multiple viral and tumour antigens. Early exposure of monocytes to high concentrations of IFN-gamma during differentiation promotes the formation of macrophages. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma or lipopolysaccharide and an inability to generate effective antigen-specific CD4(+) and CD8(+) T-cell responses. These findings demonstrate that IFN-gamma imparts differential programmes on moDC that shape the antigen-specific T-cell responses they induce. Timing and intensity of exposure to IFN-gamma can therefore determine the functional capacity of moDC. C1 [Kerkar, Sid P.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chinnasamy, Dhanalakshmi; Hadi, Neima; Melenhorst, Jan; Muranski, Pawel; Spyridonidis, Alexandros; Ito, Sawa; Yin, Fang; Hensel, Nancy; Barrett, Austin John] NHLBI, Stem Cell Allogene Transplantat Lab, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Weber, Gerrit] Baylor Coll Med, Ctr Cell & Gene Therapy, Dept Pediat, Houston, TX 77030 USA. [Weber, Gerrit] Baylor Coll Med, Ctr Cell & Gene Therapy, Dept Med, Houston, TX 77030 USA. [Weber, Gerrit] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Wang, Ena] Trans NIH Ctr Human Immunol Autoimmun & Inflammat, NIH, Bethesda, MD USA. [Wang, Ena] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. RP Kerkar, SP (reprint author), NIH, Ctr Clin, Room 2B38,10 Ctr Dr, Bethesda, MD 20892 USA. EM kerkars@mail.nih.gov; barrettj@nhlbi.nih.gov FU NIH, National Heart Lung and Blood Institute FX This research was supported by the Intramural Research Program of the NIH, National Heart Lung and Blood Institute. NR 56 TC 4 Z9 4 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD SEP PY 2014 VL 143 IS 1 BP 96 EP 108 DI 10.1111/imm.12292 PG 13 WC Immunology SC Immunology GA AN2AH UT WOS:000340385000010 PM 24678989 ER PT J AU Schrama, D Groesser, L Haffner, C Ugurel, S Pastrana, D Buck, C Cerroni, L Theiler, A Becker, JC AF Schrama, D. Groesser, L. Haffner, C. Ugurel, S. Pastrana, D. Buck, C. Cerroni, L. Theiler, A. Becker, J. C. TI Presence of human polyomavirus 6 in mutation-specific BRAF inhibitor induced epithelial proliferations SO JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT LA English DT Meeting Abstract C1 [Schrama, D.; Cerroni, L.; Theiler, A.] Med Univ Graz, Graz, Austria. [Groesser, L.; Haffner, C.] Univ Hosp Regensburg, Regensburg, Germany. [Ugurel, S.] Univ Hosp Wurzburg, Wurzburg, Germany. [Pastrana, D.; Buck, C.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Becker, J. C.] Univ Hosp Essen, West German Tumor Ctr, German Consortium Translat Canc Res DKTK, Essen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1610-0379 EI 1610-0387 J9 J DTSCH DERMATOL GES JI J. Dtsch. Dermatol. Ges. PD SEP PY 2014 VL 12 SU 3 SI SI MA P91 BP 42 EP 42 PG 1 WC Dermatology SC Dermatology GA AN4BL UT WOS:000340532500117 ER PT J AU Blanch-Hartigan, D Blake, KD Viswanath, K AF Blanch-Hartigan, Danielle Blake, Kelly D. Viswanath, Kasisomayajula TI Cancer Survivors' Use of Numerous Information Sources for Cancer-Related Information: Does More Matter? SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Health information-seeking behavior; Cancer survivors; Cancer; Numerous source seekers; Patient-provider communication ID NATIONAL TRENDS SURVEY; HEALTH PRIORITIES; UNITED-STATES; SEEKING; BEHAVIORS; CARE; PERCEPTIONS; PREVENTION; AVOIDANCE; BELIEFS AB A large proportion of the 14 million cancer survivors in the USA are actively seeking health information. This study builds on the informed- and shared-decision making literature, examining cancer survivors' health information seeking behaviors to (1) quantify the number of health information sources used; (2) create a demographic profile of patients who report seeking cancer information from numerous sources versus fewer sources in five areas: cancer information overall, disease/treatment, self-care/management, health services, and work/finances; and (3) examine whether seeking cancer information from numerous sources is associated with self-efficacy, fear of recurrence, perceptions of information seeking difficulty, and resultant patient-provider communication. Data came from a survey of post-treatment cancer survivors (N = 501) who responded to a mailed questionnaire about health information seeking. Participants were divided into two groups using a median split: those who sought health information from more than five sources (numerous source seekers) and those that sought information from less than five sources (fewer source seekers). Multivariable logistic regression was used to model differential information seeking behaviors and outcomes for numerous versus fewer source seekers. On average, survivors sought cancer-related information from five different sources. Numerous source seekers were more likely to be women, have higher levels of education, and report fewer problems with cancer information-seeking. Overall, numerous source seekers were no more or less likely to discuss information with their providers or bring conflicting information to their providers. Understanding the characteristics, behaviors, and experiences of survivors who seek cancer-related information from numerous sources can contribute to informed decision making and patient-centered care. C1 [Blanch-Hartigan, Danielle] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Blake, Kelly D.] NCI, Behav Res Program, Hlth Commun & Informat Res Branch, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02215 USA. RP Blanch-Hartigan, D (reprint author), NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,MSC 9764, Rockville, MD 20850 USA. EM danielleblanch@gmail.com NR 26 TC 6 Z9 6 U1 2 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD SEP PY 2014 VL 29 IS 3 BP 488 EP 496 DI 10.1007/s13187-014-0642-x PG 9 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA AN4AK UT WOS:000340529800016 PM 24699921 ER PT J AU Brozyna, AA Jozwicki, W Takeda, Y Jetten, AM Slominski, AT AF Brozyna, A. A. Jozwicki, W. Takeda, Y. Jetten, A. M. Slominski, A. T. TI Changes in ROR alpha expression during progression of melanocytic tumors SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 10-13, 2014 CL Copenhagen, DENMARK SP European Soc Dermatol Res C1 [Brozyna, A. A.; Jozwicki, W.] NCU, Rydygier Coll Med, Ctr Oncol, Dept Tumor Pathol & Pathomorphol, Bydgoszcz, Poland. [Takeda, Y.; Jetten, A. M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Slominski, A. T.] Univ Tennessee HSC, Dept Pathol & Lab Med, Memphis, TN USA. [Slominski, A. T.] Univ Tennessee HSC, Dept Med, Memphis, TN USA. RI Brozyna, Anna/D-4902-2014; Jozwicki, Wojciech/I-1948-2014 OI Brozyna, Anna/0000-0002-3195-9965; NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2014 VL 134 SU 2 MA 517 BP S91 EP S91 PG 1 WC Dermatology SC Dermatology GA AN1OB UT WOS:000340352100511 ER PT J AU Palazzo, E Kellett, M Cataisson, C Bible, P Pietroni, V Radoja, N Hwang, J Blumenberg, M Yuspa, SH Morasso, M AF Palazzo, E. Kellett, M. Cataisson, C. Bible, P. Pietroni, V. Radoja, N. Hwang, J. Blumenberg, M. Yuspa, S. H. Morasso, M. TI DLX3-PKC-p53 functional axis controls keratinocyte cell cycle and differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 10-13, 2014 CL Copenhagen, DENMARK SP European Soc Dermatol Res C1 [Palazzo, E.; Kellett, M.; Bible, P.; Pietroni, V.; Radoja, N.; Hwang, J.; Morasso, M.] NIAMS, DSBU, NIH, Bethesda, MD USA. [Cataisson, C.; Yuspa, S. H.] NCI, CCR, LCBG, NIH, Bethesda, MD 20892 USA. [Blumenberg, M.] NYU, Dept Dermatol, New York, NY 10016 USA. RI Palazzo, Elisabetta/J-5287-2016 OI Palazzo, Elisabetta/0000-0002-0812-5524 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2014 VL 134 SU 2 MA 253 BP S44 EP S44 PG 1 WC Dermatology SC Dermatology GA AN1OB UT WOS:000340352100250 ER PT J AU Smith, SH Peredo, CE Takeda, Y Neil, J Therrien, J Nicodeme, E Brusq, J Viviani, F Jetten, AM Cote-Sierra, J AF Smith, S. H. Peredo, C. E. Takeda, Y. Neil, J. Therrien, J. Nicodeme, E. Brusq, J. Viviani, F. Jetten, A. M. Cote-Sierra, J. TI Topical Delivery of a Potent and Selective RORg Inhibitor Abrogates Th17 Cytokines from Human Skin Resident Immune Cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 10-13, 2014 CL Copenhagen, DENMARK SP European Soc Dermatol Res C1 [Takeda, Y.; Jetten, A. M.] NIEHS, NIH, Durham, NC USA. [Smith, S. H.; Peredo, C. E.; Neil, J.; Therrien, J.; Cote-Sierra, J.] Stiefel, Durham, NC USA. [Nicodeme, E.; Brusq, J.; Viviani, F.] GSK, Les Ulis, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2014 VL 134 SU 2 MA 407 BP S71 EP S71 PG 1 WC Dermatology SC Dermatology GA AN1OB UT WOS:000340352100403 ER PT J AU Takeshita, J Wang, S Shin, DB Mehta, NN Kimmel, SE Margolis, DJ Troxel, AB Gelfand, JM AF Takeshita, J. Wang, S. Shin, D. B. Mehta, N. N. Kimmel, S. E. Margolis, D. J. Troxel, A. B. Gelfand, J. M. TI Impact of psoriasis severity on uncontrolled hypertension: a population-based study in the United Kingdom SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 10-13, 2014 CL Copenhagen, DENMARK SP European Soc Dermatol Res C1 [Takeshita, J.; Shin, D. B.; Kimmel, S. E.; Margolis, D. J.; Troxel, A. B.; Gelfand, J. M.] Univ Penn, Philadelphia, PA 19104 USA. [Mehta, N. N.] NHLBI, Bethesda, MD 20892 USA. [Wang, S.] Rutgers Robert Wood Johnson, Piscataway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2014 VL 134 SU 2 MA 227 BP S39 EP S39 PG 1 WC Dermatology SC Dermatology GA AN1OB UT WOS:000340352100225 ER PT J AU Jing, X Kay, S Marley, T Hardiker, NR AF Jing, Xia Kay, Stephen Marley, Tom Hardiker, Nicholas R. TI Integration of an OWL-DL Knowledge Base with an EHR Prototype and Providing Customized Information SO JOURNAL OF MEDICAL SYSTEMS LA English DT Article DE Electronic health record (EHR) applications; Knowledge bases; Web ontology language (OWL); Ontology application; Intelligent systems; Knowledge base integration ID CYSTIC-FIBROSIS; CLINICAL-DATA; SYSTEM; DOCTORS; RECORD; NEEDS AB When clinicians use electronic health record (EHR) systems, their ability to obtain general knowledge is often an important contribution to their ability to make more informed decisions. In this paper we describe a method by which an external, formal representation of clinical and molecular genetic knowledge can be integrated into an EHR such that customized knowledge can be delivered to clinicians in a context-appropriate manner. Web Ontology Language-Description Logic (OWL-DL) is a formal knowledge representation language that is widely used for creating, organizing and managing biomedical knowledge through the use of explicit definitions, consistent structure and a computer-processable format, particularly in biomedical fields. In this paper we describe: 1) integration of an OWL-DL knowledge base with a standards-based EHR prototype, 2) presentation of customized information from the knowledge base via the EHR interface, and 3) lessons learned via the process. The integration was achieved through a combination of manual and automatic methods. Our method has advantages for scaling up to and maintaining knowledge bases of any size, with the goal of assisting clinicians and other EHR users in making better informed health care decisions. C1 [Jing, Xia] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. [Jing, Xia] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Kay, Stephen] Univ Salford, Sch Hlth Sport & Rehabil Sci, Salford M5 4WT, Lancs, England. [Hardiker, Nicholas R.] Univ Salford, Sch Nursing Midwifery & SocialWork, Salford M5 4WT, Lancs, England. [Jing, Xia] Ohio Univ, Grover Dept Social & Publ Hlth W357, Coll Hlth Sci & Profess, Athens, OH 45701 USA. RP Jing, X (reprint author), Ohio Univ, Grover Dept Social & Publ Hlth W357, Coll Hlth Sci & Profess, Athens, OH 45701 USA. EM jingx@ohio.edu OI Jing, Xia/0000-0002-1916-4588 FU Overseas Research Students Awards Scheme (UK); University of Salford in the UK; National Library of Medicine; Clinical Center of the National Institutes of Health in the USA FX This work was supported by the Overseas Research Students Awards Scheme (UK), University of Salford in the UK, and partially through intramural research funds from the National Library of Medicine and the Clinical Center of the National Institutes of Health in the USA. The authors thank Dr. James J Cimino, Yongsheng Gao for very constructive discussions and suggestions, Dr. Judith Effken for helpful comments and suggestions. The authors thank Ms. Cindy Clark, NIH Library Writing Center, for manuscript editing assistance and Ms. Jennifer White for English editing. NR 23 TC 1 Z9 1 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0148-5598 EI 1573-689X J9 J MED SYST JI J. Med. Syst. PD SEP PY 2014 VL 38 IS 9 AR 75 DI 10.1007/s10916-014-0075-4 PG 14 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AN2XY UT WOS:000340450500016 PM 24997857 ER PT J AU Purohit, V Rapaka, RS Rutter, J AF Purohit, Vishnudutt Rapaka, Rao S. Rutter, Joni TI Cannabinoid Receptor-2 and HIV-Associated Neurocognitive Disorders SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE HIV-associated neurocognitive disorders; Highly active antiretroviral therapy; Cannabinoid receptor type 2; Neuroinflammation; Macrophages and microglia; Blood brain barrier ID CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; RAT MICROGLIAL CELLS; TAT PROTEIN; SYNAPSE LOSS; MONOCYTE CHEMOTAXIS; CYTOKINE EXPRESSION; IMMUNE ACTIVATION AB Despite the wide spread use of highly active antiretroviral therapy (HAART), mild forms of HIV-associated neuro cognitive disorders (HAND) remain commonplace. HAART treated patients now show low levels of viremia and more subtle yet biologically important signs of brain macrophage and microglial activation. Adjunctive therapeutic strategies are required to eliminate HIV-1 infection and suppress immune activation and its associated neuroinflammation. In this regard, cannabinoid receptor-2(CB2) activation is a promising means to attenuate HAND by inhibiting HIV replication, down regulating inflammation, and suppressing chemokine-like activity of viral neurotoxic proteins (for example, Tat and HIV-1gp120), and thereby prevent neuronal and synaptic loss. Inhibiting even low level HIV replication can attenuate neuronal injury by decreasing the production of neurotoxins. Down regulation of inflammation by CB2 activation is mediated through blunted activation of peri vascular macrophages and microglia; decreased production of tumor necrosis factor-alpha, chemokines and virotoxins. Down regulated neuroinflammation can decrease blood brain barrier permeability and leukocyte infiltration resulting in reduced neuronal injury. It is suggested that CB2 agonists may further attenuate HAND in HIV-infected patients on HAART. In addition, CB2 activation may also blunt brain injury by attenuating drug addiction. C1 [Purohit, Vishnudutt; Rapaka, Rao S.; Rutter, Joni] NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. RP Purohit, V (reprint author), NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, 6001 Execut Blvd,NSC Bldg,Rm 4275, Bethesda, MD 20892 USA. EM vpurohit@nida.nih.gov OI Rutter, Joni/0000-0002-6502-2361 NR 69 TC 4 Z9 4 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD SEP PY 2014 VL 9 IS 4 BP 447 EP 453 DI 10.1007/s11481-014-9554-0 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AN1XO UT WOS:000340377500001 PM 25015040 ER PT J AU Anderson, MR Enose-Akahata, Y Massoud, R Ngouth, N Tanaka, Y Oh, U Jacobson, S AF Anderson, Monique R. Enose-Akahata, Yoshimi Massoud, Raya Ngouth, Nyater Tanaka, Yuetsu Oh, Unsong Jacobson, Steven TI Epigenetic Modification of the FoxP3 TSDR in HAM/TSP Decreases the Functional Suppression of Tregs SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE Regulatory T cells; HTLV-1; Treg specific demethylation region (TSDR); Epigenetic regulation; Suppressive capacity; Demethylation ID REGULATORY T-CELLS; MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; I-ASSOCIATED MYELOPATHY; HUMAN PERIPHERAL-BLOOD; NEUROLOGIC DISEASE; DNA METHYLATION; GENE-EXPRESSION; PROVIRAL LOAD; HTLV-1; POPULATION AB HTLV-1 is a human retrovirus that is associated with the neuroinflammatory disorder HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). In these patients, HTLV-1 is primarily found in the CD4(+)CD25(+) T cell subset (Regulatory T cells:Tregs), which is responsible for peripheral immune tolerance and is known to be dysfunctional in HAM/TSP. Recent evidence suggests that FoxP3 expression and function is determined epigenetically through DNA demethylation in the Treg-specific demethylated region (TSDR). We analyzed the methylation of the TSDR in PBMCs, CD4(+) T cells, and CD4(+)CD25(+) T cells from normal healthy donors (NDs) and HAM/TSP patients. We demonstrated that there is decreased demethylation in analyzed PBMCs and CD4(+)CD25(+) T cells from HAM/TSP patients as compared to NDs. Furthermore, decreased TSDR demethylation was associated with decreased functional suppression by Tregs. Additionally, increased HTLV-1 Tax expression in HAM/TSP PBMC culture correlated with a concomitant decline in FoxP3 TSDR demethylation. Overall, we suggest that HTLV-1 infection decreases Treg functional suppressive capacity in HAM/TSP through modification of FoxP3 TSDR demethylation and that dysregulated Treg function may contribute to HAM/TSP disease pathogenesis. C1 [Anderson, Monique R.; Enose-Akahata, Yoshimi; Massoud, Raya; Ngouth, Nyater; Jacobson, Steven] NINDS, Neuroimmunol Branch, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. [Anderson, Monique R.] Howard Hughes Med Inst, Howard Hughes Med Inst Natl Inst Hlth Res Scholar, Chevy Chase, MD 20815 USA. [Anderson, Monique R.] Univ ofVirginia, Sch Med, Dept Pathol, Mol & Cellular Basis Dis Grad Program, Charlottesville, VA 22908 USA. [Tanaka, Yuetsu] Univ Ryukyus, Grad Sch Med, Dept Immunol, Nishihara, Okinawa 9030125, Japan. [Oh, Unsong] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA 23298 USA. RP Jacobson, S (reprint author), NINDS, Neuroimmunol Branch, Viral Immunol Sect, NIH, 10 Ctr Dr,Rm 5C103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural NIH HHS [ZIA NS002817-24]; NCATS NIH HHS [KL2 TR000057] NR 52 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD SEP PY 2014 VL 9 IS 4 BP 522 EP 532 DI 10.1007/s11481-014-9547-z PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AN1XO UT WOS:000340377500008 PM 24845974 ER PT J AU Ofrat, S Krueger, RF Eaton, NR Keyes, KM Skodol, AE Grant, BF Hasin, DS AF Ofrat, Shani Krueger, Robert F. Eaton, Nicholas R. Keyes, Katherine M. Skodol, Andrew E. Grant, Bridget F. Hasin, Deborah S. TI Nonmedical Prescription Drug Use Comorbidity: Developing a Cohesive Risk Model SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Comorbidity; Nonmedical prescription drug use; Internalizing; Externalizing ID NATIONAL EPIDEMIOLOGIC SURVEY; ANXIETY DISORDERS; COLLEGE-STUDENTS; UNITED-STATES; FIT INDEXES; PREVALENCE; ALCOHOL; GENDER; MOOD; DEPENDENCE AB Nonmedical Prescription Drug Use (NMPDU) is a growing issue world-wide. Previously, NMPDU comorbidity has been investigated using bivariate approaches, providing a piecemeal understanding of NMPDU's relationship to other mental disorders. We investigate how NMPDU fits within the multivariate meta-structure of psychiatric comorbidity and how this might vary as a function of gender. Data were collected as part of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) in 2001-2002 on 43,093 individuals 18 years or older living in the US. The Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV version IV (AUDADIS-IV) assessed psychiatric diagnoses and sedative, tranquilizer, opioid, and amphetamine NMPDU. Using confirmatory factor analysis, NMPDU was introduced into the internalizing-externalizing model of common mental disorders to determine where it best fits. Models were examined separately for men and women and tested for gender invariance. NMPDU was strongly associated with the externalizing factor, and also showed a very small secondary association with the fear subfactor of internalizing. This structure was gender invariant. Differences between men and women's prevalence rates originate at the level of the latent factors. Results indicate a shared liability to NMPDU and other forms of externalizing psychopathology such as other substance use disorders, as well as antisocial behaviors. Research on NMPDU can benefit from focusing on the externalizing factor, aiming to understand how risk factors for diverse externalizing disorders may also manifest as NMPDU. Prescribers should be particularly attentive to the presence of the entire spectrum of externalizing disorders, as they may signal risk for NMPDU. C1 [Ofrat, Shani; Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Eaton, Nicholas R.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Keyes, Katherine M.; Skodol, Andrew E.; Hasin, Deborah S.] Columbia Univ, New York, NY USA. [Skodol, Andrew E.] Univ Arizona, Phoenix, AZ USA. [Grant, Bridget F.] NIAAA, Bethesda, MD USA. RP Krueger, RF (reprint author), Univ Minnesota, Dept Psychol, 75 East River Rd, Minneapolis, MN 55455 USA. EM ofrat001@umn.edu; krueg038@umn.edu; nreaton@gmail.com; kmk2104@mail.cumc.columbia.edu; askodol@gmail.com; bgrant@willco.niaaa.nih.gov; deborah.hasin@gmail.com NR 25 TC 4 Z9 4 U1 1 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 EI 1573-3505 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD SEP PY 2014 VL 36 IS 3 BP 371 EP 379 DI 10.1007/s10862-014-9409-2 PG 9 WC Psychology, Clinical SC Psychology GA AN1RA UT WOS:000340360100004 ER PT J AU Hennessy, E Oh, A Agurs-Collins, T Chriqui, JF Masse, LC Moser, RP Perna, F AF Hennessy, Erin Oh, April Agurs-Collins, Tanya Chriqui, Jamie F. Masse, Louise C. Moser, Richard P. Perna, Frank TI State-Level School Competitive Food and Beverage Laws Are Associated With Children's Weight Status SO JOURNAL OF SCHOOL HEALTH LA English DT Article DE policy; legislation; child and adolescent health; nutrition and diet ID US PUBLIC-SCHOOLS; CHILDHOOD OVERWEIGHT; VENDING MACHINES; YOUTH OBESITY; JUNK FOOD; NUTRITION; POLICY; CONSUMPTION; ENVIRONMENTS; ADOLESCENTS AB BACKGROUND: This study attempted to determine whether state laws regulating low nutrient, high energy-dense foods and beverages sold outside of the reimbursable school meals program referred to as "competitive foods'') are associated with children's weight status. METHODS: We use the Classification of Laws Associated with School Students CLASS) database of state codified laws) relevant to school nutrition. States were classified as having strong, weak, or no competitive food laws in 2005 based on strength and comprehensiveness. Parent-reported height and weight along with demographic, behavioral, family, and household characteristics were obtained from the 2007 National Survey of Children's Health. Bivariate and logistic regression analyses estimated the association between states' competitive food laws and children's overweight and obesity status body mass index [BMI]-for-age >= 85th percentile). Children N = 16,271) between the ages of 11-14 years with a BMI for age >= 5th percentile who attended public school were included. RESULTS: Children living in states with weak competitive food laws for middle schools had over a 20% higher odds of being overweight or obese than children living in states with either no or strong school competitive food laws. CONCLUSION: State-level school competitive food and beverage laws merit attention with efforts to address the childhood obesity epidemic. Attention to the specificity and requirements of these laws should also be considered. C1 [Hennessy, Erin] NCI, Leidos Biomed Res Inc, Frederick Nat Lab Canc Res, Support Behav Res Program,Div Canc Control & Popu, Bethesda, MD 20892 USA. [Oh, April] NCI, Hlth Commun & Informat Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Agurs-Collins, Tanya; Perna, Frank] NCI, Hlth Behav Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Chriqui, Jamie F.] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL 60608 USA. [Masse, Louise C.] Univ British Columbia, Sch Populat & Publ Hlth, BC Childrens Hosp, Vancouver, BC V6H 3V4, Canada. [Masse, Louise C.] BC Womens Hosp & Hlth Ctr, Vancouver, BC V6H 3V4, Canada. [Moser, Richard P.] NCI, Sci Res & Technol Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Hennessy, E (reprint author), NCI, Leidos Biomed Res Inc, Frederick Nat Lab Canc Res, Support Behav Res Program,Div Canc Control & Popu, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM erin.hennessy@fnlcr.nih.gov; ohay@mail.nih.gov; collinsta@mail.nih.gov; jchriqui@uic.edu; lmasse@cfri.ubc.ca; moserr@mail.nih.gov; pernafm@mail.nih.gov FU Cancer Research Training Award from the Cancer Prevention Fellowship Program, National Cancer Institute FX At the time of this study Dr. Erin Hennessy was supported by a Cancer Research Training Award from the Cancer Prevention Fellowship Program, National Cancer Institute. NR 35 TC 7 Z9 7 U1 4 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4391 EI 1746-1561 J9 J SCHOOL HEALTH JI J. Sch. Health PD SEP PY 2014 VL 84 IS 9 BP 609 EP 616 DI 10.1111/josh.12181 PG 8 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA AN3MX UT WOS:000340493500009 PM 25117896 ER PT J AU Rudloff, U Langan, RC Mullinax, JE Beane, JD Steinberg, SM Beresnev, T Webb, CC Walker, M Toomey, MA Schrump, D Pandalai, P Stojadinovic, A Avital, I AF Rudloff, Udo Langan, Russell C. Mullinax, John E. Beane, Joal D. Steinberg, Seth M. Beresnev, Tatiana Webb, Carole C. Walker, Melissa Toomey, Mary Ann Schrump, David Pandalai, Prakash Stojadinovic, Alexander Avital, Itzhak TI Impact of Maximal Cytoreductive Surgery Plus Regional Heated Intraperitoneal Chemotherapy (HIPEC) on Outcome of Patients With Peritoneal Carcinomatosis of Gastric Origin: Results of the GYMSSA Trial SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE metastatic gastric cancer; cytoreductive surgery; heated intraperitoneal chemotherapy (HIPEC); metastasectomy ID PHASE-II TRIAL; COLORECTAL-CANCER; RANDOMIZED-TRIAL; MITOMYCIN-C; HYPERTHERMIC CHEMOTHERAPY; INFUSIONAL FLUOROURACIL; SYSTEMIC CHEMOTHERAPY; 1ST-LINE TREATMENT; COMPLETE RESECTION; DIFFUSE-TYPE AB BackgroundA prospective randomized trial was conducted to compare the impact of systemic chemotherapy versus multi-modality therapy (complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic chemotherapy) on overall survival (OS) in patients with gastric carcinomatosis. MethodsPatients with measurable metastatic gastric adenocarcinoma involving the peritoneum, and resectable to no evidence of disease were randomized to gastrectomy, metastasectomy, HIPEC, and systemic FOLFOXIRI (GYMS arm) or FOLFOXIRI alone (SA arm). ResultsSeventeen patients were enrolled (16 evaluable); 7 of 9 patients in the multi-modality GYMS arm achieved complete cytoreduction (CCR0). Median OS was 11.3 months in the GYMS arm and 4.3 months in the SA arm. Four patients in the GYMS arm survived >12 months, 2 patients close to 2 years at last follow-up, and 1 patient more than 4 years, with 2 of these patients still alive. No patient in the SA arm lived beyond 11 months. All patients surviving beyond 12 months in the surgery arm achieved complete cytoreduction and had an initial Peritoneal Cancer Index (PCI) of 15. ConclusionMaximal cytoreductive surgery combined with regional (HIPEC) and systemic chemotherapy in selected patients with gastric carcinomatosis and limited disease burden can achieve prolonged survival. J. Surg. Oncol. 2014 110:275-284. (c) 2014 Wiley Periodicals, Inc. C1 [Rudloff, Udo; Langan, Russell C.; Mullinax, John E.; Beane, Joal D.; Beresnev, Tatiana; Webb, Carole C.; Walker, Melissa; Toomey, Mary Ann; Pandalai, Prakash] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Langan, Russell C.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Mullinax, John E.] Univ S Florida, Tampa Gen Hosp, Tampa, FL USA. [Steinberg, Seth M.] NIH, Biostat & Data Management Sect, Off Clin Director, Bethesda, MD 20892 USA. [Schrump, David] NCI, Thorac Oncol Sect, NIH, Bethesda, MD 20892 USA. [Stojadinovic, Alexander; Avital, Itzhak] Bon Secours Canc Inst, Richmond, VA 23226 USA. [Stojadinovic, Alexander; Avital, Itzhak] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Rudloff, U (reprint author), NCI, NIH, 10 Ctr Dr,CCR 4 West 4-5940, Bethesda, MD 20892 USA. EM rudloffu@mail.nih.gov; Itzhak_Avital@BSHSI.com RI Mullinax, John/L-2509-2014 FU NIH FX Grant sponsor: NIH. NR 44 TC 27 Z9 28 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD SEP PY 2014 VL 110 IS 3 BP 275 EP 284 DI 10.1002/jso.23633 PG 10 WC Oncology; Surgery SC Oncology; Surgery GA AN2EQ UT WOS:000340397300011 PM 25042700 ER PT J AU Mughal, TI Girnius, S Rosen, ST Kumar, S Wiestner, A Abdel-Wahab, O Kiladjian, JJ Wilson, WH Van Etten, RA AF Mughal, Tariq I. Girnius, Saulius Rosen, Steven T. Kumar, Shaji Wiestner, Adrian Abdel-Wahab, Omar Kiladjian, Jean-Jacques Wilson, Wyndham H. Van Etten, Richard A. TI Emerging therapeutic paradigms to target the dysregulated Janus kinase/signal transducer and activator of transcription pathway in hematological malignancies SO LEUKEMIA & LYMPHOMA LA English DT Review DE JAK/STAT pathway; JAK inhibitors; hematological malignancies ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; B-CELL LYMPHOMA; DNA-BINDING ACTIVITY; JAK2 V617F MUTATION; OF-FUNCTION MUTATIONS; TYROSINE KINASE JAK2; FACTOR-KAPPA-B; MULTIPLE-MYELOMA; MYELOPROLIFERATIVE-DISORDERS AB Over the past decade, there has been increasing biochemical evidence that the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is aberrantly activated in malignant cells from patients with a wide spectrum of cancers of the blood and immune systems. The emerging availability of small molecule inhibitors of JAK and other signaling molecules in the JAK/STAT pathway has allowed preclinical studies validating an important role of this pathway in the pathogenesis of many hematologic malignancies, and provided motivation for new strategies for treatment of these diseases. Here, a round-table panel of experts review the current preclinical and clinical landscape of the JAK/STAT pathway in acute lymphoid and myeloid leukemias, lymphomas and myeloma, and chronic myeloid neoplasms. C1 [Mughal, Tariq I.] Tufts Med Ctr, Boston, MA USA. [Girnius, Saulius] Boston Med Center VA Hosp, Boston, MA USA. [Rosen, Steven T.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Kumar, Shaji] Mayo Clin, Ctr Canc, Rochester, MN USA. [Wiestner, Adrian; Wilson, Wyndham H.] NCI, Lymphoma Therapeut Sect, NIH, Bethesda, MD 20892 USA. [Abdel-Wahab, Omar] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kiladjian, Jean-Jacques] Hop St Louis, Paris, France. [Van Etten, Richard A.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA 92697 USA. RP Van Etten, RA (reprint author), Univ Calif Irvine, Chao Family Comprehens Canc Ctr, 839 Med Sci Court,Sprague Hall,Room 124, Irvine, CA 92697 USA. EM vanetten@uci.edu RI Kumar, Shaji/A-9853-2008; OI Kumar, Shaji/0000-0001-5392-9284; Abdel-Wahab, Omar/0000-0002-3907-6171 FU NIH [HL089747] FX This work was supported in part by NIH grant HL089747 to R.A.V. NR 148 TC 7 Z9 7 U1 4 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD SEP PY 2014 VL 55 IS 9 BP 1968 EP 1979 DI 10.3109/10428194.2013.863307 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA AN3BP UT WOS:000340460200005 PM 24206094 ER PT J AU Simpson, R Keegan, J Gatehouse, P Hansen, M Firmin, D AF Simpson, Robin Keegan, Jennifer Gatehouse, Peter Hansen, Michael Firmin, David TI Spiral Tissue Phase Velocity Mapping in a Breath-Hold with Non-Cartesian SENSE SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE tissue phase velocity mapping; spiral; myocardial mechanics ID CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL MOTION; DETAILED ANALYSIS; MRI; QUANTIFICATION; RECONSTRUCTION; TRAJECTORIES; VOLUNTEERS; GRAPPA AB Purpose: Tissue phase velocity mapping (TPVM) is capable of reproducibly measuring regional myocardial velocities. However acquisition durations of navigator gated techniques are long and unpredictable while current breath-hold techniques have low temporal resolution. This study presents a spiral TPVM technique which acquires high resolution data within a clinically acceptable breath-hold duration. Methods: Ten healthy volunteers are scanned using a spiral sequence with temporal resolution of 24 ms and spatial resolution of 1.7 x 1.7 mm. Retrospective cardiac gating is used to acquire data over the entire cardiac cycle. The acquisition is accelerated by factors of 2 and 3 by use of non-Cartesian SENSE implemented on the Gadgetron GPU system resulting in breath-holds of 17 and 13 heartbeats, respectively. Systolic, early diastolic, and atrial systolic global and regional longitudinal, circumferential, and radial velocities are determined. Results: Global and regional velocities agree well with those previously reported. The two acceleration factors show no significant differences for any quantitative parameter and the results also closely match previously acquired higher spatial resolution navigator-gated data in the same subjects. Conclusion: By using spiral trajectories and non-Cartesian SENSE high resolution, TPVM data can be acquired within a clinically acceptable breath-hold. (C) 2013 Wiley Periodicals, Inc. C1 [Simpson, Robin; Keegan, Jennifer; Gatehouse, Peter; Firmin, David] NIHR Royal Brompton Cardiovasc Biomed Res Unit, London, England. [Simpson, Robin; Keegan, Jennifer; Firmin, David] Univ London Imperial Coll Sci Technol & Med, London, England. [Hansen, Michael] NHLBI, NIH, Bethesda, MD 20892 USA. RP Simpson, R (reprint author), Royal Brompton Hosp, CBRU, Sydney St, London SW3 6NP, England. EM r.simpson@rbht.nhs.uk RI Hansen, Michael/J-5391-2015; OI Hansen, Michael/0000-0002-8087-8731; Gatehouse, Peter/0000-0002-0260-4719 FU Intramural NIH HHS [Z99 HL999999] NR 23 TC 7 Z9 7 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD SEP PY 2014 VL 72 IS 3 BP 659 EP 668 DI 10.1002/mrm.24971 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AN4JB UT WOS:000340552700007 PM 24123135 ER PT J AU Kang, PB Gooch, CL McDermott, MP Darras, BT Finkel, RS Yang, ML Sproule, DM Chung, WK Kaufmann, P De Vivo, DC AF Kang, Peter B. Gooch, Clifton L. McDermott, Michael P. Darras, Basil T. Finkel, Richard S. Yang, Michele L. Sproule, Douglas M. Chung, Wendy K. Kaufmann, Petra De Vivo, Darryl C. CA Muscle Study Grp Pediat Neuromuscular Clinical Res TI THE MOTOR NEURON RESPONSE TO SMN1 DEFICIENCY IN SPINAL MUSCULAR ATROPHY REPLY SO MUSCLE & NERVE LA English DT Letter C1 [Kang, Peter B.] Univ Florida, Coll Med, Div Pediat Neurol, Gainesville, FL 32611 USA. [Gooch, Clifton L.] Univ S Florida, Coll Med, Dept Neurol, Tampa, FL USA. [McDermott, Michael P.] Univ Rochester, Dept Biostat & Computat Biol, Rochester, NY USA. [McDermott, Michael P.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Darras, Basil T.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Finkel, Richard S.] Nemours Childrens Hosp, Div Neurol, Orlando, FL USA. [Yang, Michele L.] Childrens Hosp Colorado, Div Neurol, Aurora, CO USA. [Sproule, Douglas M.; De Vivo, Darryl C.] Columbia Univ, Dept Neurol, New York, NY USA. [Chung, Wendy K.] Columbia Univ, Dept Pediat, New York, NY 10027 USA. [Chung, Wendy K.] Columbia Univ, Dept Med, New York, NY USA. [Kaufmann, Petra] NINDS, Bethesda, MD 20892 USA. RP Kang, PB (reprint author), Univ Florida, Coll Med, Div Pediat Neurol, Gainesville, FL 32611 USA. NR 3 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD SEP PY 2014 VL 50 IS 3 BP 458 EP 459 DI 10.1002/mus.24317 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN4BE UT WOS:000340531800027 PM 24935909 ER PT J AU Xie, LK Subashi, E Qi, Y Knepper, MA Johnson, GA AF Xie, Luke Subashi, Ergys Qi, Yi Knepper, Mark A. Johnson, G. Allan TI Four-dimensional MRI of renal function in the developing mouse SO NMR IN BIOMEDICINE LA English DT Article DE small-animal preclinical imaging; MRI; MR microscopy; mouse kidney development; 3D dynamic contrast enhancement; radial keyhole imaging; cryogenic surface coil ID POLYCYSTIC KIDNEY-DISEASE; POSITRON-EMISSION-TOMOGRAPHY; GLOMERULAR-FILTRATION-RATE; CONTRAST AGENT; TOXICOLOGIC PATHOLOGY; DYNAMIC MRI; BIOMARKERS; FAILURE; INJURY; MICE AB The major roles of filtration, metabolism and high blood flow make the kidney highly vulnerable to drug-induced toxicity and other renal injuries. A method to follow kidney function is essential for the early screening of toxicity and malformations. In this study, we acquired high spatiotemporal resolution (four dimensional) datasets of normal mice to follow changes in kidney structure and function during development. The data were acquired with dynamic contrast-enhanced MRI (via keyhole imaging) and a cryogenic surface coil, allowing us to obtain a full three-dimensional image (isotropic resolution, 125 microns) every 7.7 s over a 50-min scan. This time course permitted the demonstration of both contrast enhancement and clearance. Functional changes were measured over a 17-week course (at 3, 5, 7, 9, 13 and 17 weeks). The time dimension of the MRI dataset was processed to produce unique image contrasts to segment the four regions of the kidney: cortex (CO), outer stripe (OS) of the outer medulla (OM), inner stripe (IS) of the OM and inner medulla (IM). Local volumes, time-to-peak (TTP) values and decay constants (DC) were measured in each renal region. These metrics increased significantly with age, with the exception of DC values in the IS and OS. These data will serve as a foundation for studies of normal renal physiology and future studies of renal diseases that require early detection and intervention. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Xie, Luke; Subashi, Ergys; Qi, Yi; Johnson, G. Allan] Duke Univ, Med Ctr, Dept Radiol, Ctr In Vivo Microscopy, Durham, NC 27710 USA. [Xie, Luke; Johnson, G. Allan] Duke Univ, Dept Biomed Engn, Durham, NC 27710 USA. [Subashi, Ergys] Duke Univ, Med Ctr, Med Phys Grad Program, Durham, NC 27710 USA. [Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Johnson, GA (reprint author), Duke Univ, Med Ctr, Dept Radiol, Ctr In Vivo Microscopy, Box 3302, Durham, NC 27710 USA. EM gjohnson@duke.edu FU National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB) National Biomedical Technology Resource Center [P41 EB015897] FX This work was supported by the National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB) National Biomedical Technology Resource Center (P41 EB015897 to GAJ). NR 54 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD SEP PY 2014 VL 27 IS 9 BP 1094 EP 1102 DI 10.1002/nbm.3162 PG 9 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA AN3OV UT WOS:000340498700010 PM 25066408 ER PT J AU Widemann, BC Babovic-Vuksanovic, D Dombi, E Wolters, PL Goldman, S Martin, S Goodwin, A Goodspeed, W Kieran, MW Cohen, B Blaney, SM King, A Solomon, J Patronas, N Balis, FM Fox, E Steinberg, SM Packer, RJ AF Widemann, Brigitte C. Babovic-Vuksanovic, Dusica Dombi, Eva Wolters, Pamela L. Goldman, Stewart Martin, Staci Goodwin, Anne Goodspeed, Wendy Kieran, Mark W. Cohen, Bruce Blaney, Susan M. King, Allison Solomon, Jeffrey Patronas, Nicholas Balis, Frank M. Fox, Elizabeth Steinberg, Seth M. Packer, Roger J. TI Phase II Trial of Pirfenidone in Children and Young Adults With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas SO PEDIATRIC BLOOD & CANCER LA English DT Article DE neurofibromatosis type 1; phase II trial; plexiform neurofibroma; progression free survival; time to progression; volumetric MRI analysis ID IDIOPATHIC PULMONARY-FIBROSIS; FREQUENCY; DEFICITS; CELLS AB Background. Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN. Procedure. Patients (3-21 years) with NF1-related progressive PNreceived pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as >= 20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated. Results. Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed. Conclusions. Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN. (c) 2014 Wiley Periodicals, Inc. C1 [Widemann, Brigitte C.; Dombi, Eva; Wolters, Pamela L.; Martin, Staci; Goodwin, Anne; Goodspeed, Wendy; Balis, Frank M.; Fox, Elizabeth] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Babovic-Vuksanovic, Dusica] Mayo Coll Med, Dept Med Genet, Rochester, MN USA. [Goldman, Stewart] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Kieran, Mark W.] Dana Farber Childrens Hosp Canc Ctr, Boston, MA USA. [Cohen, Bruce] Cleveland Clin, Cleveland, OH 44106 USA. [Blaney, Susan M.] Texas Childrens Hosp, Houston, TX 77030 USA. [King, Allison] St Louis Childrens Hosp, St Louis, MO 63178 USA. [Solomon, Jeffrey] Expert Image Anal LLC, Potomac, MD USA. [Patronas, Nicholas] NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Balis, Frank M.; Fox, Elizabeth] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Packer, Roger J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10 CRC,Room 1-5750,MSC 1101, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov OI Kieran, Mark/0000-0003-2184-7692; King, Allison/0000-0002-1951-6176 FU Department of Defense [NF01000042]; FDA Orphan Fund Program Grant FX Grant sponsor: Department of Defense; Grant number: NF01000042; Grant sponsor: FDA Orphan Fund Program Grant NR 27 TC 12 Z9 14 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2014 VL 61 IS 9 BP 1598 EP 1602 DI 10.1002/pbc.25041 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AN4EO UT WOS:000340540600014 PM 24753394 ER PT J AU Carol, H Maris, JM Kang, MH Reynolds, CP Kolb, EA Gorlick, R Keir, ST Wu, JR Lyalin, D Kurmasheva, RT Houghton, PJ Smith, MA Lock, RB AF Carol, Hernan Maris, John M. Kang, Min H. Reynolds, C. Patrick Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Wu, Jianrong Lyalin, Dmitry Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI Initial Testing (Stage 1) of the Notch Inhibitor PF-03084014, by the Pediatric Preclinical Testing Program (vol 61, pg 1493, 2014) SO PEDIATRIC BLOOD & CANCER LA English DT Correction C1 [Carol, Hernan; Lock, Richard B.] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Wu, Jianrong] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Lyalin, Dmitry; Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Childrens Canc Inst Australia, Leukaemia Biol Program, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Lock, Richard/G-4253-2013 NR 1 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2014 VL 61 IS 9 BP 1716 EP 1716 DI 10.1002/pbc.25186 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AN4EO UT WOS:000340540600035 ER PT J AU Gilman, SE Bromet, EJ Cox, KL Colpe, LJ Fullerton, CS Gruber, MJ Heeringa, SG Lewandowski-Romps, L Millikan-Bell, AM Naifeh, JA Nock, MK Petukhova, MV Sampson, NA Schoenbaum, M Stein, MB Ursano, RJ Wessely, S Zaslavsky, AM Kessler, RC AF Gilman, S. E. Bromet, E. J. Cox, K. L. Colpe, L. J. Fullerton, C. S. Gruber, M. J. Heeringa, S. G. Lewandowski-Romps, L. Millikan-Bell, A. M. Naifeh, J. A. Nock, M. K. Petukhova, M. V. Sampson, N. A. Schoenbaum, M. Stein, M. B. Ursano, R. J. Wessely, S. Zaslavsky, A. M. Kessler, R. C. CA Army STARRS Collaborators TI Sociodemographic and career history predictors of suicide mortality in the United States Army 2004-2009 SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Army; Army STARRS; epidemiology; military; risk factors; suicide ID ACTIVE-DUTY PERSONNEL; US MILITARY PERSONNEL; MENTAL-HEALTH; RISK-FACTORS; LIFE-COURSE; DEPLOYMENT; COMBAT; IRAQ; BEHAVIOR; GENDER AB Background. The US Army suicide rate has increased sharply in recent years. Identifying significant predictors of Army suicides in Army and Department of Defense (DoD) administrative records might help focus prevention efforts and guide intervention content. Previous studies of administrative data, although documenting significant predictors, were based on limited samples and models. A career history perspective is used here to develop more textured models. Method. The analysis was carried out as part of the Historical Administrative Data Study (HADS) of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). De-identified data were combined across numerous Army and DoD administrative data systems for all Regular Army soldiers on active duty in 2004-2009. Multivariate associations of sociodemographics and Army career variables with suicide were examined in subgroups defined by time in service, rank and deployment history. Results. Several novel results were found that could have intervention implications. The most notable of these were significantly elevated suicide rates (69.6-80.0 suicides per 100000 person-years compared with 18.5 suicides per 100000 person-years in the total Army) among enlisted soldiers deployed either during their first year of service or with less than expected (based on time in service) junior enlisted rank; a substantially greater rise in suicide among women than men during deployment; and a protective effect of marriage against suicide only during deployment. Conclusions. A career history approach produces several actionable insights missed in less textured analyses of administrative data predictors. Expansion of analyses to a richer set of predictors might help refine understanding of intervention implications. C1 [Gilman, S. E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, S. E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bromet, E. J.] Stony Brook Sch Med, Dept Psychiat & Behav Sci, Stony Brook, NY USA. [Cox, K. L.; Millikan-Bell, A. M.] US Army Publ Hlth Command, Aberdeen Proving Ground, MD USA. [Colpe, L. J.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Fullerton, C. S.; Naifeh, J. A.; Ursano, R. J.] Uniformed Serv Univ Sch Med, Ctr Study Traumat Stress, Dept Psychiat, Bethesda, MD USA. [Gruber, M. J.; Petukhova, M. V.; Sampson, N. A.; Zaslavsky, A. M.; Kessler, R. C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Heeringa, S. G.; Lewandowski-Romps, L.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Nock, M. K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Schoenbaum, M.] NIMH, Off Sci Policy Planning & Commun, Bethesda, MD 20892 USA. [Stein, M. B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, M. B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, M. B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Wessely, S.] Kings Coll London, Kings Ctr Mil Hlth Res, London WC2R 2LS, England. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM ncs@hcp.med.harvard.edu RI Gilman, Stephen/E-7632-2010; Wessely, Simon/A-8713-2008 OI Gilman, Stephen/0000-0002-8331-6419; FU Department of the Army; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981] FX The study received the following financial support. Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Department of the Army, or the DoD. NR 47 TC 17 Z9 17 U1 3 U2 7 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 SEP PY 2014 VL 44 IS 12 BP 2579 EP 2592 DI 10.1017/S003329171400018X PG 14 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AN2GV UT WOS:000340403400012 PM 25055175 ER PT J AU Zheng, G Li, QZ Yuan, A AF Zheng, Gang Li, Qizhai Yuan, Ao TI Some Statistical Properties of Efficiency Robust Tests with Applications to Genetic Association Studies SO SCANDINAVIAN JOURNAL OF STATISTICS LA English DT Article DE boundary; constrained parameter space; genetic studies; maximin efficiency; MAX; nuisance parameter; score test ID TREND TESTS; LINKAGE DISEQUILIBRIUM; AFFECTED SIBS; SAMPLE-SIZE; SURVIVAL; SCORES; POWER; RANK; MAX AB Although efficiency robust tests are preferred for genetic association studies when the genetic model is unknown, their statistical properties have been studied for different study designs separately under special situations. We study some statistical properties of the maximin efficiency robust test and a maximum-type robust test (MAX3) under a general setting and obtain unified results. The results can also be applied to testing hypothesis with a constrained two-dimensional parameter space. The results are applied to genetic association studies using case-parents trio data. C1 [Zheng, Gang] NHLBI, Off Biostat Res, Bethesda, MD USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Beijing, Peoples R China. [Yuan, Ao] Howard Univ, Natl Human Genome Ctr, Washington, DC USA. RP Li, QZ (reprint author), Chinese Acad Sci, Acad Math & Syst Sci, Beijing, Peoples R China. EM liqz@amss.ac.cn FU National Science Foundation of China [61134013, 11371353]; National Institute on Minority Health and Health Disparities of the National Institutes of Health [G12MD007597] FX Q. Li was supported in part by the National Science Foundation of China (grant nos. 61134013 and 11371353). A. Yuan was supported in part by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under award number G12MD007597. We thank two reviewers for their very careful readings and helpful suggestions that greatly improved our presentations. We also thank Xin Tian for extracting the data used in the application and James Troendle and Joseph Gastwirth for their helpful comments. NR 28 TC 3 Z9 3 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6898 EI 1467-9469 J9 SCAND J STAT JI Scand. J. Stat. PD SEP PY 2014 VL 41 IS 3 BP 762 EP 774 DI 10.1111/sjos.12060 PG 13 WC Statistics & Probability SC Mathematics GA AN3NA UT WOS:000340493800011 ER PT J AU Uehara, S Murayama, N Nakanishi, Y Nakamura, C Hashizume, T Zeldin, DC Yamazaki, H Uno, Y AF Uehara, Shotaro Murayama, Norie Nakanishi, Yasuharu Nakamura, Chika Hashizume, Takanori Zeldin, Darryl C. Yamazaki, Hiroshi Uno, Yasuhiro TI Immunochemical detection of cytochrome P450 enzymes in small intestine microsomes of male and female untreated juvenile cynomolgus monkeys SO XENOBIOTICA LA English DT Article DE CYP; drug metabolism; jejunum ID LIVER-MICROSOMES; DRUG-METABOLISM; CYP2C76; CYP2J2; IDENTIFICATION; INVOLVEMENT; EXPRESSION; ENCODES; GENE AB 1. The expression of small intestinal cytochromes P450 (P450s) has not been systematically measured in cynomolgus monkeys, which are widely used in preclinical drug studies to predict pharmacokinetics and toxicity in humans: therefore, P450 content of small intestine was quantified in 35 cynomolgus monkeys by immunoblotting using 11 selective antibodies. 2. CYP2D, CYP2J2, CYP3A4 and CYP3A5 were detected in all 35 animals, while CYP1A and CYP2C9/19 were detected in 31 and 17 animals, respectively. CYP2C9 and CYP2C19 were detected with the same antibody. CYP1D, CYP2A, CYP2B6, CYP2C76 and CYP2E1 were not detected in any of the 35 animals examined. 3. On analysis of pooled microsomes (35 animals), CYP3A (3A4 + 3A5) was most abundant (79% of total immunoquantified CYP1-3 proteins), followed by CYP2J2 (13%), CYP2C9/19 (4%), CYP1A (3%) and CYP2D (0.4%). On the analysis of individual microsome samples, each P450 content varied 2-to-6-fold between animals, and no sex differences were observed in any P450 content. 4. These findings should help to increase the understanding of drug metabolism, especially the first-pass effect, in cynomolgus monkey small intestines. C1 [Uehara, Shotaro; Nakanishi, Yasuharu; Nakamura, Chika; Uno, Yasuhiro] Shin Nippon Biomed Labs Ltd, Pharmacokinet & Bioanal Ctr, Kainan, Wakayama 6420017, Japan. [Murayama, Norie; Yamazaki, Hiroshi] Showa Pharmaceut Univ, Lab Drug Metab & Pharmacokinet, Machida, Tokyo, Japan. [Hashizume, Takanori] Osaka Ohtani Univ, Fac Pharm, Tondabayashi, Osaka, Japan. [Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Res, Res Triangle Pk, NC USA. RP Uno, Y (reprint author), Shin Nippon Biomed Labs Ltd, Pharmacokinet & Bioanal Ctr, Genome Res Grp, 16-1 Minami Akasaka, Kainan, Wakayama 6420017, Japan. EM uno-yasuhiro@snbl.co.jp OI Yamazaki, Hiroshi/0000-0002-1068-4261 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This work was supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 28 TC 10 Z9 10 U1 0 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 EI 1366-5928 J9 XENOBIOTICA JI Xenobiotica PD SEP PY 2014 VL 44 IS 9 BP 769 EP 774 DI 10.3109/00498254.2014.895882 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AN3CN UT WOS:000340462600001 PM 24593267 ER PT J AU Bisagno, V Cadet, JL AF Bisagno, Veronica Cadet, Jean Lud TI Stress, sex, and addiction: potential roles of corticotropin-releasing factor, oxytocin, and arginine-vasopressin SO BEHAVIOURAL PHARMACOLOGY LA English DT Review DE addiction; arginine-vasopressin; corticotropin-releasing factor; oxytocin; sex; stress ID CONDITIONED PLACE PREFERENCE; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; MESSENGER-RIBONUCLEIC-ACID; MEDIAL PREFRONTAL CORTEX; ESTROGEN-RECEPTOR-BETA; COCAINE-INDUCED REINSTATEMENT; SUBSTANCE USE DISORDERS; PITUITARY-ADRENAL AXIS; CUE-INDUCED DRUG; GENDER-DIFFERENCES AB Stress sensitivity and sex are predictive factors for the development of neuropsychiatric disorders. Life stresses are not only risk factors for the development of addiction but also are triggers for relapse to drug use. Therefore, it is imperative to elucidate the molecular mechanisms underlying the interactions between stress and drug abuse, as an understanding of this may help in the development of novel and more effective therapeutic approaches to block the clinical manifestations of drug addiction. The development and clinical course of addiction-related disorders do appear to involve neuroadaptations within neurocircuitries that modulate stress responses and are influenced by several neuropeptides. These include corticotropin-releasing factor, the prototypic member of this class, as well as oxytocin and arginine-vasopressin that play important roles in affiliative behaviors. Interestingly, these peptides function to balance emotional behavior, with sexual dimorphism in the oxytocin/arginine-vasopressin systems, a fact that might play an important role in the differential responses of women and men to stressful stimuli and the specific sex-based prevalence of certain addictive disorders. Thus, this review aims to summarize (i) the contribution of sex differences to the function of dopamine systems, and (ii) the behavioral, neurochemical, and anatomical changes in brain stress systems. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Bisagno, Veronica] Consejo Nacl Invest Cient & Tecn, UBA, ININFA, Inst Invest Farmacol, RA-1033 Buenos Aires, DF, Argentina. [Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Res Branch, Intramural Res Program, NIH,DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov FU National Institute on Drug Abuse (NIDA), NIH; DHHS; [PIP11420100100072]; [PICT 2012-0924] FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), NIH, and DHHS (J.L.C.). V. Bisagno was supported by grants PIP11420100100072 and PICT 2012-0924, Argentina. NR 222 TC 14 Z9 15 U1 4 U2 62 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8810 EI 1473-5849 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2014 VL 25 IS 5-6 SI SI BP 445 EP 457 DI 10.1097/FBP.0000000000000049 PG 13 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA AM9PG UT WOS:000340212900010 PM 24949572 ER PT J AU Yavin, E Lin, YH Brand, A Salem, N AF Yavin, Ephraim Lin, Yu Hong Brand, Annette Salem, Norman, Jr. TI Metabolic conversion of intra-amniotically-injected deuterium-labeled essential fatty acids by fetal rats following maternal n-3 fatty acid deficiency SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE Brain; Docosahexaenoic acid; n-3 PUFA deficiency; Phospholipids; Fetal metabolism; Amniotic fluid ID ALPHA-LINOLENIC-ACID; DIETARY DOCOSAHEXAENOIC ACID; IN-VIVO; PRETERM INFANTS; BRAIN-FUNCTION; LIVER; RETINA; DESATURATION; ACCRETION; GROWTH AB Accumulation of polyunsaturated fatty acids (PUPA) in the fetal brain is accomplished predominantly via a highly selective flow of docosahexaenoic acid (22:6n-3, DHA) and arachidonic acid (20:4n-6, AA) through the placenta. Little is known regarding the endogenous capability of the fetus to generate its own DHA and AA from lower homologues such as linolenic (18:3n-3, ALA) and linoleic (18:2n-6, LA) acids, respectively. Deuterium-labeled d5-ALA and d5-LA at millimolar concentrations were injected directly into the amniotic fluid in order to investigate maternal-independent metabolic conversion of the stable isotopes in brain and liver of the fetus near delivery. After 48 h under adequate maternal diet, the levels of d5-ALA metabolites in the fetal brain and fetal liver were 45 +/- 2.2 pmol/mg and 86 +/- 4 pmol/mg of which 79% and 63.6% were comprised of d5-DHA. At this time point, incorporation of d5-LA metabolites was 103 +/- 5 pmol/mg and 772 +/- 46 pmol/mg for brain and liver, of which 50% and 30% were comprised of d5-AA. Following sustained maternal dietary ALA deficiency, the levels of total d5-ALA derived metabolites in the fetal brain and fetal liver were increased to 231 pmol/mg and 696 pmol/mg of which 71% and 26% were comprised of d5-DHA. From the time course and relative rates of d5-ALA precursor displacement by d5-DHA in cellular phosphoglycerides, it is concluded that the fetal rat brain can generate its own DHA from its d5-ALA precursors particularly under dietary stress. (C) 2014 Elsevier B.V. All rights reserved. C1 [Yavin, Ephraim; Lin, Yu Hong; Brand, Annette; Salem, Norman, Jr.] NIAAA, NIH, Bethesda, MD USA. [Yavin, Ephraim; Brand, Annette] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. [Salem, Norman, Jr.] DSM Nutr Prod, Kaiseraugst, Switzerland. RP Yavin, E (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. EM ephraim.yavin@gmail.com FU Gulton Foundation (EY) New York FX The contribution of Sharon Majchrzak with GC analyses is greatly appreciated. The fellowship of A Brand was made possible through a grant from the Gulton Foundation (EY) New York. NR 54 TC 0 Z9 0 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 EI 0006-3002 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD SEP PY 2014 VL 1841 IS 9 BP 1336 EP 1344 DI 10.1016/j.bbalip.2014.06.008 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AM7BN UT WOS:000340019800015 PM 24960100 ER PT J AU Haverkamp, MH van de Vosse, E Goldbach-Mansky, R Holland, SM AF Haverkamp, M. H. van de Vosse, E. Goldbach-Mansky, R. Holland, S. M. TI Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS) SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE Anakinra; cytokine; CAPS; NOMID ID INTERFERON-GAMMA-RECEPTOR; COLD AUTOINFLAMMATORY SYNDROME; MUCKLE-WELLS-SYNDROME; CIAS1 MUTATIONS; MYCOBACTERIAL INFECTION; ARTICULAR SYNDROME; GENETIC-HETEROGENEITY; CLINICAL-FEATURES; SOMATIC MOSAICISM; DISEASE AB Cryopyrin-associated periodic syndrome (CAPS) is characterized by dysregulated inflammation with excessive interleukin (IL)-1 beta activation and secretion. Neonatal-onset multi-system inflammatory disease (NOMID) is the most severe form. We explored cytokine responses in 32 CAPS patients before and after IL-1 beta blocking therapy. We measured cytokines produced by activated peripheral blood monuclear cells (PBMCs) from treated and untreated CAPS patients after stimulation for 48 h with phytohaemagglutinin (PHA), PHA plus IL-12, lipopolysaccharide (LPS) or LPS plus interferon (IFN)-gamma. We measured IL-1 beta, IL-6, IL-10, tumour necrosis factor (TNF), IL-12p70 and IFN-gamma in the supernatants. PBMCs from three untreated CAPS patients were cultured in the presence of the IL-1 beta blocker Anakinra. Fifty healthy individuals served as controls. CAPS patients had high spontaneous production of IL-1 beta, IL-6, TNF and IFN-gamma by unstimulated cells. However, stimulation indexes (SIs, ratio of stimulated to unstimulated production) of these cytokines to PHA and LPS were low in NOMID patients compared to controls. Unstimulated IL-10 and IL-12p70 production was normal, but up-regulation after PHA and LPS was also low. LPS plus IFN-gamma inadequately up-regulated the production of IL-1 beta, IL-6, TNF and IL-10 in CAPS patients. In-vitro but not in-vivo treatment with Anakinra improved SIs by lowering spontaneous cytokine production. However, in-vitro treatment did not improve the low stimulated cytokine levels. Activating mutations in NLRP3 in CAPS are correlated with poor SIs to PHA, LPS and IFN-gamma. The impairment in stimulated cytokine responses in spite of IL-1 beta blocking therapy suggests a broader intrinsic defect in CAPS patients, which is not corrected by targeting IL-1 beta. C1 [Haverkamp, M. H.; van de Vosse, E.] Leiden Univ, Med Ctr, Dept Infect Dis, NL-2333 ZA Leiden, Netherlands. [Haverkamp, M. H.; Holland, S. M.] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Goldbach-Mansky, R.] NIH, Translat Autoinflammatory Dis Sect, Bethesda, MD 20892 USA. RP Haverkamp, MH (reprint author), Leiden Univ, Med Ctr, Dept Infect Dis, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands. EM M.H.Haverkamp@lumc.nl RI van de Vosse, Esther/B-7285-2009 OI van de Vosse, Esther/0000-0001-5199-3426 FU Fulbright/Netherlands-America Foundation; NIH, National Institute of Allergy and Infectious Diseases; Netherlands Organization for Scientific Research (NWO); Stichting Fonds Doctor Catharine van Tussenbroek; Prins Bernhard Cultuurfonds; Leids Universiteits Fonds; Stichting Dr Hendrik Muller's Vaderlandsch Fonds; Stichting Fundatie Vrijvrouwe van Renswoude; Stichting Algemeen Studiefonds FX M. H. H. was supported by grants from the Fulbright/Netherlands-America Foundation; the intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases; the Netherlands Organization for Scientific Research (NWO); the Stichting Fonds Doctor Catharine van Tussenbroek; the Prins Bernhard Cultuurfonds; the Leids Universiteits Fonds; the Stichting Dr Hendrik Muller's Vaderlandsch Fonds; the Stichting Fundatie Vrijvrouwe van Renswoude; and the Stichting Algemeen Studiefonds. NR 35 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 EI 1365-2249 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD SEP PY 2014 VL 177 IS 3 BP 720 EP 731 DI 10.1111/cei.12361 PG 12 WC Immunology SC Immunology GA AM7JW UT WOS:000340044000018 PM 24773462 ER PT J AU Taieb, D Kebebew, E Castinetti, F Chen, CC Henry, JF Pacak, K AF Taieb, David Kebebew, Electron Castinetti, Frederic Chen, Clara C. Henry, Jean-Francois Pacak, Karel TI Diagnosis and preoperative imaging of multiple endocrine neoplasia type 2: current status and future directions SO CLINICAL ENDOCRINOLOGY LA English DT Review ID MEDULLARY-THYROID CARCINOMA; POSITRON-EMISSION-TOMOGRAPHY; SUBTOTAL ADRENALECTOMY; SPARING SURGERY; F-18-DOPA PET; F-18-FDG PET; PHEOCHROMOCYTOMA; RECURRENT; CANCER; MANAGEMENT AB Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant syndrome caused by mutations in the RET protooncogene and is characterized by a strong penetrance of medullary thyroid carcinoma (all subtypes) and is often accompanied by pheochromocytoma (MEN2A/2B) and primary hyperparathyroidism (MEN2A). The evaluation and management of MEN2-related tumours is often different from that of sporadic counterparts. This review article provides an overview of clinical manifestations, diagnosis and surgical management of MEN2 patients. This review also presents applications of the most up-to-date imaging modalities to MEN2 patients that are tightly linked to the clinical management and aims to guide physicians towards a rationale for the use of imaging prior to prophylactic thyroidectomy, initial surgery and reoperations for persistent/recurrent disease. This review also concludes that, in the near future, it is expected that these patients will indeed benefit from newly developed positron emission tomography approaches which will target peptide receptors and protein kinases. Identification of MEN2-specific radiopharmaceuticals will also soon arise from molecular profiling studies. Furthermore, subtotal (cortical-sparing) adrenalectomy, which is a valid option in MEN2 for avoiding long-term steroid replacement, will benefit from an accurate estimation through imaging of differential adrenocortical function. C1 [Taieb, David] Aix Marseille Univ, CERIMED, Dept Nucl Med, La Timone Univ Hosp, F-13385 Marseille, France. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Castinetti, Frederic] Aix Marseille Univ, Dept Endocrinol, La Timone Univ Hosp, F-13385 Marseille, France. [Chen, Clara C.] NIH, Dept Radiol, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Chen, Clara C.] NIH, Imaging Sci Dept, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Henry, Jean-Francois] Aix Marseille Univ, Dept Endocrine Surg, La Timone Univ Hosp, F-13385 Marseille, France. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Taieb, D (reprint author), Aix Marseille Univ, European Ctr Res Med Imaging, Dept Nucl Med, La Timone Univ Hosp, 264 Rue St Pierre, F-13385 Marseille, France. EM david.taieb@ap-hm.fr; karel@mail.nih.gov OI Castinetti, Frederic/0000-0002-1808-8800 NR 44 TC 10 Z9 10 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2014 VL 81 IS 3 BP 317 EP 328 DI 10.1111/cen.12513 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AM9GG UT WOS:000340188300001 PM 24889858 ER PT J AU van Berkel, A Pacak, K Lenders, JWM AF van Berkel, A. Pacak, K. Lenders, J. W. M. TI Should every patient diagnosed with a phaeochromocytoma have a I-123-MIBG scintigraphy? SO CLINICAL ENDOCRINOLOGY LA English DT Editorial Material ID POSITRON-EMISSION-TOMOGRAPHY; METASTATIC PHEOCHROMOCYTOMA; MIBG SCINTIGRAPHY; METAIODOBENZYLGUANIDINE SCINTIGRAPHY; IN-111-PENTETREOTIDE SCINTIGRAPHY; SPECT-CT; PARAGANGLIOMA; LOCALIZATION; I-123-METAIODOBENZYLGUANIDINE; PET AB Localization of phaeochromocytomas and paragangliomas (PPGLs) should involve functional imaging as anatomical imaging modalities can either fail to locate the tumour or can be suboptimal due to an anatomical abnormality or previous surgery. Functional imaging is particularly useful to fully delineate the extent of disease using the whole-body scan and the evaluation of multifocality, metastatic or recurrent disease. An increasing number of radiolabeled tracers have become available for tumour visualization during the past decade. I-123-meta-iodobenzylguanidine scintigraphy is the most widely used functional imaging modality, and its sensitivity to identify chromaffin cell tumours varies from 85 to 88% for phaeochromocytomas and 56-76% for paragangliomas, while specificity ranges between 70 and 100% and 84-100%, respectively. C1 [van Berkel, A.; Lenders, J. W. M.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Pacak, K.] NICHD, NIH, Bethesda, MD USA. [Lenders, J. W. M.] Univ Hosp Carl Gustav Carus, Dept Med 3, Dresden, Germany. RP Lenders, JWM (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Geert Grootepl Zuid 8, NL-6525 GA Nijmegen, Netherlands. EM Jacques.Lenders@radboudumc.nl RI Lenders, J.W.M./L-4487-2015 NR 34 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2014 VL 81 IS 3 BP 329 EP 333 DI 10.1111/cen.12482 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AM9GG UT WOS:000340188300002 PM 24796657 ER PT J AU Abd-Elmoniem, KZ Bakalov, VK Matta, JR Muldoon, N Hanover, JA Bondy, CA Gharib, AM AF Abd-Elmoniem, Khaled Z. Bakalov, Vladimir K. Matta, Jatin R. Muldoon, Nancy Hanover, John A. Bondy, Carolyn A. Gharib, Ahmed M. TI X chromosome parental origin and aortic stiffness in turner syndrome SO CLINICAL ENDOCRINOLOGY LA English DT Article ID ARTERIAL STIFFNESS; COMPUTED-TOMOGRAPHY; VASCULAR FUNCTION; MORTALITY; WOMEN; DYSFUNCTION; DILATATION; PREVALENCE; DISSECTION; PHENOTYPE AB Introduction Aortic abnormalities contribute to increased morbidity and mortality of women with Turner syndrome (TS). Impaired aortic stiffness may prove to have clinical prognostic value in TS as is the case in other diseases such as Marfan syndrome, diabetes and hypertension. Additionally, the parental origin of the X chromosome in TS may influence aortic stiffness. Objective To assess the relation between X chromosome parental origin and aortic stiffness in TS patients. Methods Twenty-four subjects with TS participated in this cross-sectional study at a tertiary care centre. The parental origin of the X chromosome was determined. Cardiac-gated multidetector computerized tomography (MDCT) was performed and distensibility of the ascending aorta (AA), a measure of aortic stiffness, was calculated. Results Fourteen women were Xm (maternal origin) and 10 were Xp (paternal origin) for their inheritance of the single X chromosome. Age, body size, blood pressure and AA areas were similar in the two groups. However, the calculated AA distensibility was significantly lower in the Xm group (2.8 +/- 1.1 mm/Hg) than in the Xp group (4.1 +/- 1.5 mm/Hg); P < 0.05. Conclusion This study demonstrates that TS subjects that inherit their single X chromosome from their mother (Xm) have a significantly stiffer aorta compared with the TS with a paternally originating X chromosome (Xp), consistent with a potentially greater risk for cardiovascular complications. These findings suggest that parental chromosomal analysis and aortic stiffness measurements would be useful for the risk assessment and clinical management of TS patients. C1 [Abd-Elmoniem, Khaled Z.; Matta, Jatin R.; Gharib, Ahmed M.] NIDDK, Biomed & Metab Imaging Branch, NIH, Bethesda, MD USA. [Bakalov, Vladimir K.; Bondy, Carolyn A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Epigenet, NIH, Bethesda, MD USA. [Muldoon, Nancy] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Hanover, John A.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD USA. RP Gharib, AM (reprint author), NIH, Bldg 10,Rm 3-5340,MSC 1263,10 Ctr Dr, Bethesda, MD 20892 USA. EM agharib@mail.nih.gov RI Gharib, Ahmed/O-2629-2016; Abd-Elmoniem, Khaled/B-9289-2008 OI Gharib, Ahmed/0000-0002-2476-481X; Abd-Elmoniem, Khaled/0000-0002-1001-1702 NR 32 TC 3 Z9 3 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2014 VL 81 IS 3 BP 467 EP 470 DI 10.1111/cen.12481 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AM9GG UT WOS:000340188300022 PM 24796499 ER PT J AU DiCuccio, M AF DiCuccio, Michael TI Letter to the Editor: Safety in Surgery and Overall Health: What is the Responsibility of the Patient? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Letter C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20852 USA. RP DiCuccio, M (reprint author), NIH, Natl Ctr Biotechnol Informat, 9000 Rockville Pike, Bethesda, MD 20852 USA. EM dicuccio@gmail.com NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD SEP PY 2014 VL 472 IS 9 BP 2895 EP 2896 DI 10.1007/s11999-014-3748-x PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AM7LR UT WOS:000340049200053 PM 24964890 ER PT J AU Liu, CT Buchkovich, ML Winkler, TW Heid, IM Borecki, IB Fox, CS Mohlke, KL North, KE Cupples, LA AF Liu, Ching-Ti Buchkovich, Martin L. Winkler, Thomas W. Heid, Iris M. Borecki, Ingrid B. Fox, Caroline S. Mohlke, Karen L. North, Kari E. Cupples, L. Adrienne CA African Ancestry Anthropometry Gen GIANT Consortium TI Multi-ethnic fine-mapping of 14 central adiposity loci SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; WAIST-HIP RATIO; TRANSETHNIC METAANALYSIS; FAT DISTRIBUTION; POPULATIONS; WOMEN; RISK AB The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within +/- 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality. C1 [Liu, Ching-Ti; Cupples, L. Adrienne] Boston Univ, Dept Biostat, Boston, MA 02118 USA. [Buchkovich, Martin L.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Winkler, Thomas W.; Heid, Iris M.] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany. [Heid, Iris M.] Helmholtz ZentrumMuenchen German Res Ctr Environm, Inst Epidemiol, Neuherberg, Germany. [Borecki, Ingrid B.] Washington Univ, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Fox, Caroline S.; Cupples, L. Adrienne] NHLBI Framingham Heart Study, Framingham, MA USA. [North, Kari E.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Gillings Sch Global Publ Hlth, Carolina Populat Ctr, Chapel Hill, NC USA. RP Liu, CT (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Massachusetts Ave,CT3, Boston, MA 02118 USA. EM ctliu@bu.edu; adrienne@bu.edu RI Palmer, Lyle/K-3196-2014; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Polasek, Ozren/B-6002-2011; Bandera, Elisa/M-4169-2014; Deloukas, Panos/B-2922-2013; Meitinger, Thomas/O-1318-2015; Witte, Daniel/C-1722-2008; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; kinnunen, leena/B-7059-2012; Beckmann, Jacques S /A-9772-2008; Krzelj, Vjekoslav/D-6491-2017; Colaus, PsyColaus/K-6607-2013; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014 OI Tuomi, Tiinamaija/0000-0002-8306-6202; Vandenput, Liesbeth/0000-0002-1712-6131; Jorgensen, Torben/0000-0001-9453-2830; Assimes, Themistocles/0000-0003-2349-0009; Hattersley, Andrew/0000-0001-5620-473X; de Geus, Eco/0000-0001-6022-2666; Palmer, Lyle/0000-0002-1628-3055; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Zondervan, Krina/0000-0002-0275-9905; Magi, Reedik/0000-0002-2964-6011; Lango Allen, Hana/0000-0002-7803-8688; Esko, Tonu/0000-0003-1982-6569; Zgaga, Lina/0000-0003-4089-9703; Luben, Robert/0000-0002-5088-6343; Adeyemo, Adebowale/0000-0002-3105-3231; Polasek, Ozren/0000-0002-5765-1862; Bandera, Elisa/0000-0002-8789-2755; Deloukas, Panos/0000-0001-9251-070X; Witte, Daniel/0000-0002-0769-2922; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; kinnunen, leena/0000-0001-8739-4812; Beckmann, Jacques S /0000-0002-9741-1900; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202 FU National Institutes of Health (NIH) [R01DK8925601, R01DK072193, R21DA027040, T32GM067553]; American Heart Association [13PRE16930025]; [NGFNPLUS 01GS0823] FX This work is partially supported by grant NGFNPLUS 01GS0823 (T.W.W. and I.M.H.), National Institutes of Health (NIH) R01DK8925601 (I.B.B., L.A.C. and C.T.L.), R01DK072193 (K.L.M.), R21DA027040 (K. L. M.), T32GM067553 (M.L.B.) and American Heart Association 13PRE16930025 (M.L.B.). NR 21 TC 21 Z9 21 U1 1 U2 37 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 1 PY 2014 VL 23 IS 17 BP 4738 EP 4744 DI 10.1093/hmg/ddu183 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AM9YU UT WOS:000340238200023 PM 24760767 ER PT J AU Yu, DZ Swaroop, M Wang, MQ Baxa, U Yang, RZ Yan, YP Coksaygan, T DeTolla, L Marugan, JJ Austin, CP McKew, JC Gong, DW Zheng, W AF Yu, Daozhan Swaroop, Manju Wang, Mengqiao Baxa, Ulrich Yang, Rongze Yan, Yiping Coksaygan, Turhan DeTolla, Louis Marugan, Juan J. Austin, Christopher P. McKew, John C. Gong, Da-Wei Zheng, Wei TI Niemann-Pick Disease Type C: Induced Pluripotent Stem Cell-Derived Neuronal Cells for Modeling Neural Disease and Evaluating Drug Efficacy SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE Niemann-Pick disease type C; NPC1; induced pluripotent stem cells; differentiated neurons; cyclodextrin; delta-tocopherol; drug combination therapy ID CHOLESTEROL REDUCTION; PHENOTYPIC SCREENS; STORAGE; CYCLODEXTRIN; PATHOGENESIS; DIFFERENTIATION; IDENTIFICATION; ACCUMULATION; MODULATORS; HALLMARKS AB Niemann-Pick disease type C (NPC) is a rare neurodegenerative disorder caused by recessive mutations in the NPC1 or NPC2 gene that result in lysosomal accumulation of unesterified cholesterol in patient cells. Patient fibroblasts have been used for evaluation of compound efficacy, although neuronal degeneration is the hallmark of NPC disease. Here, we report the application of human NPC1 neural stem cells as a cell-based disease model to evaluate nine compounds that have been reported to be efficacious in the NPC1 fibroblasts and mouse models. These cells are differentiated from NPC1 induced pluripotent stem cells and exhibit a phenotype of lysosomal cholesterol accumulation. Treatment of these cells with hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, and delta-tocopherol significantly ameliorated the lysosomal cholesterol accumulation. Combined treatment with cyclodextrin and delta-tocopherol shows an additive or synergistic effect that otherwise requires 10-fold higher concentration of cyclodextrin alone. In addition, we found that hydroxypropyl-beta-cyclodextrin is much more potent and efficacious in the NPC1 neural stem cells compared to the NPC1 fibroblasts. Miglustat, suberoylanilide hydroxamic acid, curcumin, lovastatin, pravastatin, and rapamycin did not, however, have significant effects in these cells. The results demonstrate that patient-derived NPC1 neural stem cells can be used as a model system for evaluation of drug efficacy and study of disease pathogenesis. C1 [Yu, Daozhan; Yang, Rongze; Gong, Da-Wei] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA. [Swaroop, Manju; Wang, Mengqiao; Marugan, Juan J.; Austin, Christopher P.; McKew, John C.; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Baxa, Ulrich] NCI, Electron Microscopy Lab, NIH, Bethesda, MD 20892 USA. [Yan, Yiping; DeTolla, Louis] Life Technol, Frederick, MD USA. [Coksaygan, Turhan] Univ Maryland, Sch Med, Comparat Med Program, Dept Pathol, Baltimore, MD 21201 USA. [Gong, Da-Wei] Baltimore Vet Affairs Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. RP Gong, DW (reprint author), Univ Maryland, Sch Med, Baltimore, MD 21201 USA. EM dgong@medicine.umaryland.edu; wzheng@mail.nih.gov OI Zheng, Wei/0000-0003-1034-0757 FU Maryland Stem Cell Research Fund; Maryland Clinical Nutrition Research Unit [DK072488]; Baltimore Diabetes Research and Training Center [P60-DK-079637]; NIH Center for Regenerative Medicine; National Center for Advancing Translational Sciences; National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was partially supported by grants from Maryland Stem Cell Research Fund, Maryland Clinical Nutrition Research Unit (DK072488), the Baltimore Diabetes Research and Training Center (P60-DK-079637), and NIH Center for Regenerative Medicine. This work is also supported by the Intramural Research Programs of the National Center for Advancing Translational Sciences and federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. NR 35 TC 15 Z9 15 U1 0 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD SEP PY 2014 VL 19 IS 8 BP 1164 EP 1173 DI 10.1177/1087057114537378 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA AM9YA UT WOS:000340235700004 PM 24907126 ER PT J AU Hassig, CA Zeng, FY Kung, P Kiankarimi, M Kim, S Diaz, PW Zhai, DY Welsh, K Morshedian, S Su, Y O'Keefe, B Newman, DJ Rusman, Y Kaur, H Salomon, CE Brown, SG Baire, B Michel, AR Hoye, TR Francis, S Georg, GI Walters, MA Divlianska, DB Roth, GP Wright, AE Reed, JC AF Hassig, Christian A. Zeng, Fu-Yue Kung, Paul Kiankarimi, Mehrak Kim, Sylvia Diaz, Paul W. Zhai, Dayong Welsh, Kate Morshedian, Shana Su, Ying O'Keefe, Barry Newman, David J. Rusman, Yudi Kaur, Harneet Salomon, Christine E. Brown, Susan G. Baire, Beeraiah Michel, Andrew R. Hoye, Thomas R. Francis, Subhashree Georg, Gunda I. Walters, Michael A. Divlianska, Daniela B. Roth, Gregory P. Wright, Amy E. Reed, John C. TI Ultra-High-Throughput Screening of Natural Product Extracts to Identify Proapoptotic Inhibitors of Bcl-2 Family Proteins SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE ultra-high-throughput screening; fluorescence polarization; natural product extracts; Bcl-2 family; apoptosis; bioassay-guided fractionation ID CANCER-THERAPY; ALTERTOXIN II; ANTAGONISTS; DISCOVERY; EFFICACY; ABT-199; ASSAY AB Antiapoptotic Bcl-2 family proteins are validated cancer targets composed of six related proteins. From a drug discovery perspective, these are challenging targets that exert their cellular functions through protein-protein interactions (PPIs). Although several isoform-selective inhibitors have been developed using structure-based design or high-throughput screening (HTS) of synthetic chemical libraries, no large-scale screen of natural product collections has been reported. A competitive displacement fluorescence polarization (FP) screen of nearly 150,000 natural product extracts was conducted against all six antiapoptotic Bcl-2 family proteins using fluorochrome-conjugated peptide ligands that mimic functionally relevant PPIs. The screens were conducted in 1536-well format and displayed satisfactory overall HTS statistics, with Z'-factor values ranging from 0.72 to 0.83 and a hit confirmation rate between 16% and 64%. Confirmed active extracts were orthogonally tested in a luminescent assay for caspase-3/7 activation in tumor cells. Active extracts were resupplied, and effort toward the isolation of pure active components was initiated through iterative bioassay-guided fractionation. Several previously described altertoxins were isolated from a microbial source, and the pure compounds demonstrate activity in both Bcl-2 FP and caspase cellular assays. The studies demonstrate the feasibility of ultra-high-throughput screening using natural product sources and highlight some of the challenges associated with this approach. C1 [Hassig, Christian A.; Zeng, Fu-Yue; Kung, Paul; Kiankarimi, Mehrak; Kim, Sylvia; Diaz, Paul W.; Zhai, Dayong; Welsh, Kate; Morshedian, Shana; Su, Ying; Reed, John C.] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [O'Keefe, Barry; Newman, David J.] NCI, Frederick, MD 21701 USA. [Rusman, Yudi; Kaur, Harneet; Salomon, Christine E.] Univ Minnesota, Ctr Drug Design, Minneapolis, MN USA. [Brown, Susan G.; Baire, Beeraiah; Michel, Andrew R.; Hoye, Thomas R.] Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. [Francis, Subhashree; Georg, Gunda I.; Walters, Michael A.] Univ Minnesota, Dept Med Chem, Inst Therapeut Discovery & Dev, Minneapolis, MN 55455 USA. [Divlianska, Daniela B.; Roth, Gregory P.] Sanford Burnham Med Res Inst Lake Nona, Orlando, FL USA. [Wright, Amy E.] Florida Atlantic Univ, Harbor Branch Oceanog Inst, Ft Pierce, FL USA. RP Hassig, CA (reprint author), Sanford Burnham Med Res Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM chassig@sanfordburnham.org RI Divlianska, Daniela/I-3567-2016 OI Divlianska, Daniela/0000-0002-6871-2122 FU National Cancer Institute NExT Program, National Institutes of Health [HHSN261200800001E] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project has been funded in whole or in part with federal funds from the National Cancer Institute NExT Program, National Institutes of Health, under contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 28 TC 3 Z9 3 U1 0 U2 24 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD SEP PY 2014 VL 19 IS 8 BP 1201 EP 1211 DI 10.1177/1087057114536227 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA AM9YA UT WOS:000340235700008 PM 24870016 ER PT J AU Van Liew, JR Christensen, AJ de Moor, JS AF Van Liew, Julia R. Christensen, Alan J. de Moor, Janet S. TI Psychosocial factors in adjuvant hormone therapy for breast cancer: an emerging context for adherence research SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Review DE Psychosocial; Breast cancer survivorship; Adjuvanthormone therapy; Tamoxifen; Aromatase inhibitor; Adherence ID ENDOCRINE THERAPY; EARLY DISCONTINUATION; TAMOXIFEN THERAPY; CLINICAL-PRACTICE; OLDER WOMEN; PATIENT; MORTALITY; BELIEFS; DEPRESSION; MANAGEMENT AB Purpose For patients with hormone receptor positive breast cancer, survivorship entails prolonged self-management of adjuvant treatment in the form of daily hormone therapy. Although sustained daily adherence across the 5-year course of therapy is associated with improved recurrence-free survival outcomes, adherence is suboptimal and many women discontinue hormone therapy prematurely. Factors associated with breast cancer survivors' nonadherence and nonpersistence are not comprehensively understood. Furthermore, psychosocial variables have only received limited research attention, despite their documented relationships with adherence in other chronic illness populations. Methods A systematic literature review identified 14 studies that analyzed relationships between psychosocial factors and breast cancer survivors' adherence and/or persistence with adjuvant hormone therapy. Results Although identified relationships were complex and at times inconsistent, salient conclusions emerged. Interpersonal factors, in the form of positive social support and patient-centered interactions with medical providers, as well as intrapersonal factors, such as anxiety and beliefs about the relative benefits of medication use, were reliably associated with better adherence and persistence. Depression did not demonstrate the negative impact on adherence that has been observed in other medical populations. No relationships between quality of life and adherence were identified. Conclusions Adjuvant hormone therapy appears to be a unique context for medication adherence, which warrants further attention and more rigorous analysis in future research. Implications for Cancer Survivors Individual patients' psychosocial characteristics and health care preferences should be considered when striving to optimize medication adherence. C1 [Van Liew, Julia R.] Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. [Christensen, Alan J.] Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. [Christensen, Alan J.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [de Moor, Janet S.] NCI, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Van Liew, JR (reprint author), Univ Iowa, Dept Psychol, E11 SSH, Iowa City, IA 52242 USA. EM julia-vanliew@uiowa.edu FU Behavioral Research Program in the Division of Cancer Control and Population Sciences, National Cancer Institute; Office of Social and Behavioral Sciences Research at the National Institutes of Health FX Alan J. Christensen's time in preparation of this article was supported, in part, by the Behavioral Research Program in the Division of Cancer Control and Population Sciences, National Cancer Institute and the Office of Social and Behavioral Sciences Research at the National Institutes of Health. NR 42 TC 6 Z9 6 U1 2 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD SEP PY 2014 VL 8 IS 3 BP 521 EP 531 DI 10.1007/s11764-014-0374-2 PG 11 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA AM9WR UT WOS:000340232200020 PM 24986227 ER PT J AU Bertelsen, RJ Engel, SM Jusko, TA Calafat, AM Hoppin, JA London, SJ Eggesbo, M Aase, H Zeiner, P Reichborn-Kjennerud, T Knudsen, GR Guidry, VT Longnecker, MR AF Bertelsen, Randi J. Engel, Stephanie M. Jusko, Todd A. Calafat, Antonia M. Hoppin, Jane A. London, Stephanie J. Eggesbo, Merete Aase, Heidi Zeiner, Pal Reichborn-Kjennerud, Ted Knudsen, Gun R. Guidry, Virginia T. Longnecker, Matthew R. TI Reliability of triclosan measures in repeated urine samples from Norwegian pregnant women SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE biomarkers; MoBa; intraclass correlation coefficient; pregnancy; reliability; triclosan ID BISPHENOL-A; ENVIRONMENTAL PHENOLS; TEMPORAL VARIABILITY; US POPULATION; SENSITIZATION; EXPOSURE; PARABENS; CHILDREN AB Triclosan (TCS) is a synthetic antibacterial chemical that is used in personal care products and is measurable in urine. Urinary TCS has been associated with allergy in children in Norway and the United States. A reasonable degree of temporal reliability of TCS urinary concentrations has been reported among US children as well as for Puerto Rican pregnant women. We examined the reliability of TCS measures in urine among Norwegian pregnant women. TCS was measured in spot urine samples collected in gestational weeks 17, 23, and 29 from 45 women in The Norwegian Mother and Child Cohort Study (MoBa) enrolled in 2007 and 2008. Spearman's rank correlation coefficient (r(s)) and intraclass correlation coefficient (ICC) statistics were calculated. Fifty-six percent of the 45 women had a least one sample with a value above the method limit of detection (2.3 mu g/l). The correlation coefficients were 0.61 for TCS concentrations at 17 and 23 weeks and 0.49 for concentrations at 17 and 29 weeks. For the three time points, the ICC was 0.49. The reliability of TCS concentrations in repeated urine samples from pregnant Norwegian women was reasonably good, suggesting a single urine sample can adequately represent TCS exposure during pregnancy. C1 [Bertelsen, Randi J.; Jusko, Todd A.; Hoppin, Jane A.; London, Stephanie J.; Longnecker, Matthew R.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Bertelsen, Randi J.] Norwegian Inst Publ Hlth, Dept Food Water & Cosmet, N-0403 Oslo, Norway. [Engel, Stephanie M.; Guidry, Virginia T.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Jusko, Todd A.] Univ Rochester, Sch Med & Dent, Dept Publ Hlth Sci, Rochester, NY USA. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Div Sci Lab, Atlanta, GA USA. [Eggesbo, Merete] Norwegian Inst Publ Hlth, Dept Genes & Environm, N-0403 Oslo, Norway. [Aase, Heidi] Norwegian Inst Publ Hlth, Dept Childhood Dev & Cultural Divers, N-0403 Oslo, Norway. [Zeiner, Pal] Univ Oslo, Dept Genet, Inst Clin Med, Oslo, Norway. [Reichborn-Kjennerud, Ted; Knudsen, Gun R.] Norwegian Inst Publ Hlth, N-0403 Oslo, Norway. RP Bertelsen, RJ (reprint author), Norwegian Inst Publ Hlth, Dept Food Water & Cosmet, N-0403 Oslo, Norway. EM randi.jacobsen.bertelsen@helse-bergen.no OI Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336; London, Stephanie/0000-0003-4911-5290 FU Norwegian Ministry of Health; Ministry of Education and Research; NIH/NIEHS [N01-ES-75558]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10]; National Institute of Environmental Health Sciences [P30-ES010126, R01-ES021777, K12-ES019852]; Intramural Research Program of the National Institute of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no. 1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (grant no. 151918/S10). This study was supported in part by the grants from the National Institute of Environmental Health Sciences (P30-ES010126, R01-ES021777, and K12-ES019852), the Intramural Research Program of the National Institute of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). The involvement of the CDC was determined not to constitute engagement in human subject research. Human subjects committees at NIEHS and at the University of North Carolina also approved this study protocol. We acknowledge X. Ye, X. Zhou, J. Kramer, and T. Jia (CDC) for technical assistance in measuring TCS. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC. NR 22 TC 11 Z9 12 U1 1 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 EI 1559-064X J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD SEP-OCT PY 2014 VL 24 IS 5 BP 517 EP 521 DI 10.1038/jes.2013.95 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AN1AX UT WOS:000340316200010 PM 24472755 ER PT J AU Jusko, TA Shaw, PA Snijder, CA Pierik, FH Koch, HM Hauser, R Jaddoe, VWV Burdorf, A Hofman, A Tiemeier, H Longnecker, MR AF Jusko, Todd A. Shaw, Pamela A. Snijder, Claudia A. Pierik, Frank H. Koch, Holger M. Hauser, Russ Jaddoe, Vincent W. V. Burdorf, Alex Hofman, Albert Tiemeier, Henning Longnecker, Matthew R. TI Reproducibility of urinary bisphenol A concentrations measured during pregnancy in the Generation R Study SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE endocrine disruptor; epidemiology; environmental exposure; intraclass correlation coefficient; misclassification ID EXPOSURE; CHILDREN; VARIABILITY; METABOLITE; BEHAVIOR; COHORT; WOMEN AB The potential human health effects of bisphenol A (BPA) exposure are a public health concern. In order to design adequately powered epidemiological studies to address potential health effects, data on the reproducibility of BPA concentration in serial urine specimens taken during pregnancy are needed. To provide additional data on the reproducibility of maternal urine specimens, 80 women in the Generation R Study (Rotterdam, The Netherlands) contributed a spot urine specimen at <18, 18-25, and >25 weeks of pregnancy. Reproducibility, estimated by the intraclass correlation coefficient (ICC), was 0.32 (95% confidence interval: 0.18-0.46), and, on a creatinine basis, 0.31 (95% confidence interval: 0.16-0.47). Although the ICC observed in the Generation R Study is slightly higher than previous reproducibility studies of BPA, it nevertheless indicates a high degree of within-person variability that presents challenges for designing well-powered epidemiologic studies. C1 [Jusko, Todd A.] Univ Rochester, Sch Med & Dent, Dept Publ Hlth Sci, Rochester, NY 14642 USA. [Shaw, Pamela A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Snijder, Claudia A.; Burdorf, Alex] Erasmus MC, Dept Publ Hlth, NL-3000 CA Rotterdam, Netherlands. [Snijder, Claudia A.; Jaddoe, Vincent W. V.] Erasmus MC, Generat Study Grp R, NL-3000 CA Rotterdam, Netherlands. [Pierik, Frank H.] TNO Netherlands Org Appl Sci Res, Dept Urban Environm & Safety, NL-3584 CB Utrecht, Netherlands. [Koch, Holger M.] Inst Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accid In, D-44789 Bochum, Germany. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Jaddoe, Vincent W. V.; Hofman, Albert] Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands. [Jaddoe, Vincent W. V.] Erasmus MC, Dept Pediat, NL-3000 DR Rotterdam, Netherlands. [Tiemeier, Henning] Erasmus MC, Dept Child & Adolescent Psychiat, NL-3000 DR Rotterdam, Netherlands. [Longnecker, Matthew R.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Jusko, TA (reprint author), Univ Rochester, Sch Med & Dent, Dept Publ Hlth Sci, 265 Crittenden Blvd,Box CU420644, Rochester, NY 14642 USA. EM todd_jusko@urmc.rochester.edu RI Koch, Holger/B-3277-2011; OI Koch, Holger/0000-0002-8328-2837; Tiemeier, Henning/0000-0002-4395-1397; Longnecker, Matthew/0000-0001-6073-5322 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); NIH [K12 ES019852, P30 ES001247] FX We thank Joe Braun for providing additional results from the EARTH study, and Walter Rogan and Jane Hoppin who provided comments on an earlier draft of the manuscript. We also thank Kelly Thevenet-Morrison who provided programming assistance. This research received support from the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, the Erasmus Medical Center and Erasmus University Rotterdam, The Netherlands Organization for Health Research and Development (ZonMw), and from NIH grants K12 ES019852 and P30 ES001247. NR 21 TC 11 Z9 11 U1 0 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 EI 1559-064X J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD SEP-OCT PY 2014 VL 24 IS 5 BP 532 EP 536 DI 10.1038/jes.2014.23 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AN1AX UT WOS:000340316200012 PM 24736100 ER PT J AU Prickett, TD Zerlanko, BJ Hill, VK Gartner, JJ Qutob, N Jiang, JJ Simaan, M Wunderlich, J Gutkind, JS Rosenberg, SA Samuels, Y AF Prickett, Todd D. Zerlanko, Brad J. Hill, Victoria K. Gartner, Jared J. Qutob, Nouar Jiang, Jiji Simaan, May Wunderlich, John Gutkind, J. Silvio Rosenberg, Steven A. Samuels, Yardena TI Somatic Mutation of GRIN2A in Malignant Melanoma Results in Loss of Tumor Suppressor Activity via Aberrant NMDAR Complex Formation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID RECEPTORS; GLUTAMATE; REVEALS; GROWTH; SCHIZOPHRENIA; NEUROGENESIS; MIGRATION; SUBUNITS; EPILEPSY; APHASIA AB The ionotropic glutamate receptors (N-methyl-D-aspartate receptors (NMDARs)) are composed of large complexes of multi-protein subunits creating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca2+) important for synaptic transmissions, cellular migration, and survival. Recently, we discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma. Functional characterization of a subset of GRIN2A mutants demonstrated a loss of NMDAR complex formation between GRIN1 and GRIN2A, increased anchorage-independent growth in soft agar, and increased migration. Somatic mutation of GRIN2A results in a dominant negative effect inhibiting the tumor-suppressive phenotype of wild-type (WT) GRIN2A in melanoma. Depletion of endogenous GRIN2A in melanoma cells expressing WT GRIN2A resulted in increased proliferation compared with control. In contrast, short-hairpin RNA depletion of GRIN2A in mutant cell lines slightly reduced proliferation. Our data show that somatic mutation of GRIN2A results in increased survival, and we demonstrate the functional importance of GRIN2A mutations in melanoma and the significance that ionotropic glutamate receptor signaling has in malignant melanoma. C1 [Prickett, Todd D.; Zerlanko, Brad J.; Hill, Victoria K.; Gartner, Jared J.; Jiang, Jiji; Samuels, Yardena] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Qutob, Nouar; Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Simaan, May; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Wunderlich, John; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Samuels, Y (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM Yardena.samuels@weizmann.ac.il FU National Human Genome Research Institute; National Institute of Dental and Craniofacial Research; National Cancer Institute; Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; estate of Alice Schwarz-Gardos; estate of John Hunter; Knell Family; Israel Science Foundation [1604/13, 877/13]; ERC [StG-335377] FX We thank UR for acquiring tumor specimens, CS and PP for establishment of the majority of melanoma cell lines, and VM, HA, and PC for generating the sequence data analyzed here. We thank VG Prieto for pathologic review of the biospecimens from the Melanoma Informatics, Tissue Resource, and Pathology Core (MelCore) at MD Anderson. We thank TW for bioinformatics help and JF and DL for graphical assistance. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Dental and Craniofacial Research, the National Cancer Institute, by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the estate of Alice Schwarz-Gardos, the estate of John Hunter, and the Knell Family. YS is supported by the Israel Science Foundation grant numbers 1604/13 and 877/13 and the ERC (StG-335377). NR 30 TC 10 Z9 10 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2014 VL 134 IS 9 BP 2390 EP 2398 DI 10.1038/jid.2014.190 PG 9 WC Dermatology SC Dermatology GA AN1OC UT WOS:000340352200017 PM 24739903 ER PT J AU Lin, Q Wesson, RN Maeda, H Wang, YC Cui, Z Liu, JO Cameron, AM Gao, B Montgomery, RA Williams, GM Sun, ZL AF Lin, Qing Wesson, Russell N. Maeda, Hiromichi Wang, Yongchun Cui, Zhu Liu, Jun O. Cameron, Andrew M. Gao, Bin Montgomery, Robert A. Williams, George M. Sun, Zhaoli TI Pharmacological Mobilization of Endogenous Stem Cells Significantly Promotes Skin Regeneration after Full-Thickness Excision: The Synergistic Activity of AMD3100 and Tacrolimus SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID DYSTROPHIC EPIDERMOLYSIS-BULLOSA; BONE-MARROW-TRANSPLANTATION; CXCR4 ANTAGONIST AMD3100; WOUND REPAIR; CHEMOKINE RECEPTOR; RAPID MOBILIZATION; PROGENITOR CELLS; MODEL; FK506; MURINE AB Stem cell therapy has shown promise in treating a variety of pathologies including skin wounds, but practical applications remain elusive. Here, we demonstrate that endogenous stem cell mobilization produced by AMD3100 and low-dose tacrolimus is able to reduce by 25% the time of complete healing of full-thickness wounds created by surgical excision. Equally important, healing was accompanied by reduced scar formation and regeneration of hair follicles. Searching for mechanisms, we found that AMD3100 combined with low-dose tacrolimus mobilized increased number of lineage-negative c-Kit+, CD34+, and CD133+ stem cells. Low-dose tacrolimus also increased the number of SDF-1-bearing macrophages in the wound sites amplifying the "pull" of mobilized stem cells into the wound. Lineage tracing demonstrated the critical role of CD133 stem cells in enhanced capillary and hair follicle neogenesis, contributing to more rapid and perfect healing. Our findings offer a significant therapeutic approach to wound healing and tissue regeneration. C1 [Lin, Qing; Wesson, Russell N.; Maeda, Hiromichi; Wang, Yongchun; Cui, Zhu; Cameron, Andrew M.; Montgomery, Robert A.; Williams, George M.; Sun, Zhaoli] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Liu, Jun O.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Gao, Bin] NIAAA, Lab Liver Dis, Bethesda, MD USA. RP Sun, ZL (reprint author), Johns Hopkins Univ, Sch Med, Dept Surg, 720 Rutland Ave,Ross 771, Baltimore, MD 21205 USA. EM zsun2@jhmi.edu OI Lin, Qing/0000-0002-8890-800X FU NIDDK NIH HHS [T32 DK007713] NR 45 TC 16 Z9 16 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2014 VL 134 IS 9 BP 2458 EP 2468 DI 10.1038/jid.2014.162 PG 11 WC Dermatology SC Dermatology GA AN1OC UT WOS:000340352200024 PM 24682043 ER PT J AU Wertheimer, A Miller, FG AF Wertheimer, A. Miller, F. G. TI There are (STILL) no coercive offers SO JOURNAL OF MEDICAL ETHICS LA English DT Editorial Material C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Wertheimer, A (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM wertheimera@cc.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD SEP PY 2014 VL 40 IS 9 DI 10.1136/medethics-2013-101510 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AN0BI UT WOS:000340246100003 ER PT J AU Negro, A Boehm, M AF Negro, Alejandra Boehm, Manfred TI Cardiomyocyte maturation: It takes a village to raise a kid SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material ID EMBRYONIC STEM-CELLS; PROMOTES CARDIAC DIFFERENTIATION; THYROID-HORMONE; HEART; MYOCYTES; HYPERTROPHY; PHENOTYPE; LINES; GROWTH; MOUSE C1 [Negro, Alejandra; Boehm, Manfred] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Boehm, M (reprint author), NHLBI, Ctr Mol Med, NIH, 10 Ctr Dr,MSC 1454,Bldg 10-CRC,RM 5 East 3132, Bethesda, MD 20892 USA. EM boehmm@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL006079-05] NR 37 TC 0 Z9 0 U1 0 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD SEP PY 2014 VL 74 BP 193 EP 195 DI 10.1016/j.yjmcc.2014.05.012 PG 3 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA AM7VX UT WOS:000340077900022 PM 24874422 ER PT J AU Ostlund, SB LeBlanc, KH Kosheleff', AR Wassum, KM Maidment, NT AF Ostlund, Sean B. LeBlanc, Kimberly H. Kosheleff', Alisa R. Wassum, Kate M. Maidment, Nigel T. TI Phasic Mesolimbic Dopamine Signaling Encodes the Facilitation of Incentive Motivation Produced by Repeated Cocaine Exposure SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID TO-INSTRUMENTAL TRANSFER; RAT NUCLEUS-ACCUMBENS; REWARD-SEEKING; NATURAL-REWARD; CORE DOPAMINE; D-AMPHETAMINE; DRUG-ABUSE; SENSITIZATION; BEHAVIOR; SHELL AB Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking. C1 [Ostlund, Sean B.; Maidment, Nigel T.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Ostlund, Sean B.; Kosheleff', Alisa R.; Wassum, Kate M.; Maidment, Nigel T.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. [Ostlund, Sean B.] Univ Calif Irvine, Dept Anesthesiol & Perioperat Care, Irvine, CA 92697 USA. [LeBlanc, Kimberly H.] NIDDK, NIH, Bethesda, MD 20892 USA. [Kosheleff', Alisa R.; Wassum, Kate M.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. RP Ostlund, SB (reprint author), Univ Calif Irvine, Sch Med, Dept Anesthesiol & Perioperat Care, Gillespie Neurosci Res Facil 3111, 837 Hlth Sci Rd, Irvine, CA 92697 USA. EM sostlund@ucla.edu RI Ostlund, Sean/D-6000-2017 FU [DA029035]; [DA09359]; [DA05010]; [DA035443] FX We thank Drs Mimi Liljeholm and Niall Murphy for valuable comments and discussions, and Dr Scott Ng-Evans for technical assistance. This work was supported by research grant DA029035 to SBO, DA09359 and DA05010 to NTM, and DA035443 to KMW. NR 49 TC 20 Z9 20 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2014 VL 39 IS 10 BP 2441 EP 2449 DI 10.1038/npp.2014.96 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AN0XX UT WOS:000340308400019 PM 24804846 ER PT J AU Starling, AP Umbach, DM Kamel, F Long, S Sandler, DP Hoppin, JA AF Starling, Anne P. Umbach, David M. Kamel, Freya Long, Stuart Sandler, Dale P. Hoppin, Jane A. TI Pesticide use and incident diabetes among wives of farmers in the Agricultural Health Study SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID PERSISTENT ORGANIC POLLUTANTS; DEVELOPMENTAL EXPOSURE; SERUM CONCENTRATIONS; NATIONAL-HEALTH; ASSOCIATION; MORTALITY; MELLITUS; DIOXIN; CHLORPYRIFOS; APPLICATORS AB Objective To estimate associations between use of specific agricultural pesticides and incident diabetes in women. Methods We used data from the Agricultural Health Study, a large prospective cohort of pesticide applicators and their spouses in Iowa and North Carolina. For comparability with previous studies of farmers, we limited analysis to 13 637 farmers' wives who reported ever personally mixing or applying pesticides at enrolment (1993-1997), who provided complete data on required covariates and diabetes diagnosis and who reported no previous diagnosis of diabetes at enrolment. Participants reported ever-use of 50 specific pesticides at enrolment and incident diabetes at one of two follow-up interviews within an average of 12 years of enrolment. We fit Cox proportional hazards models with age as the time scale and adjusting for state and body mass index to estimate HRs and 95% CIs for each of the 45 pesticides with sufficient users. Results Five pesticides were positively associated with incident diabetes (n=688; 5%): three organophosphates, fonofos (HR=1.56, 95% CI 1.11 to 2.19), phorate (HR=1.57, 95% CI 1.14 to 2.16) and parathion (HR=1.61, 95% CI 1.05 to 2.46); the organochlorine dieldrin (HR=1.99, 95% CI 1.12 to 3.54); and the herbicide 2,4,5-T/2,4,5-TP (HR=1.59, 95% CI 1.00 to 2.51). With phorate and fonofos together in one model to account for their correlation, risks for both remained elevated, though attenuated compared with separate models. Conclusions Results are consistent with previous studies reporting an association between specific organochlorines and diabetes and add to growing evidence that certain organophosphates also may increase risk. C1 [Starling, Anne P.; Kamel, Freya; Sandler, Dale P.; Hoppin, Jane A.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Starling, Anne P.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Long, Stuart] Westat Corp, Durham, NC USA. RP Hoppin, JA (reprint author), N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. EM jahoppin@ncsu.edu RI Tuomisto, Jouko/J-7450-2012; OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES049030]; National Cancer Institute [Z01 CP044008]; National Institute of Environmental Health Sciences [1-F30-ES022126-01] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES049030) and National Cancer Institute (Z01 CP044008). APS was supported by an extramural award (1-F30-ES022126-01) from the National Institute of Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 30 TC 14 Z9 14 U1 2 U2 17 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD SEP PY 2014 VL 71 IS 9 BP 629 EP 635 DI 10.1136/oemed-2013-101659 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM9YT UT WOS:000340238100009 PM 24727735 ER PT J AU Powell-Wiley, TM Ayers, C Agyemang, P Leonard, T Berrigan, D Ballard-Barbash, R Lian, M Das, SR Hoehner, CM AF Powell-Wiley, Tiffany M. Ayers, Colby Agyemang, Priscilla Leonard, Tammy Berrigan, David Ballard-Barbash, Rachel Lian, Min Das, Sandeep R. Hoehner, Christine M. TI Neighborhood-level socioeconomic deprivation predicts weight gain in a multi-ethnic population: Longitudinal data from the Dallas Heart Study SO PREVENTIVE MEDICINE LA English DT Article DE Neighborhood environment; Socioeconomic status; Socioeconomic deprivation; Obesity ID BODY-MASS INDEX; CARDIOMETABOLIC RISK-FACTORS; PSYCHOSOCIAL STRESS; PHYSICAL-ACTIVITY; OBESITY; HEALTH; BMI; ASSOCIATIONS; ENVIRONMENT; MULTILEVEL AB Objective. The aim of this study is to examine a relationship between neighborhood-level socioeconomic deprivation and weight change in a multi-ethnic cohort from Dallas County, Texas and whether behavioral/psychosocial factors attenuate the relationship. Methods. Non-movers (those in the same neighborhood throughout the study period) aged 18-65 (N = 939) in Dallas Heart Study (DHS) underwent weight measurements between 2000 and 2009 (median 7-year follow-up). Geocoded home addresses defined block groups; a neighborhood deprivation index (NDI) was created (higher NDI = greater deprivation). Multi-level modeling determined weight change relative to NDI. Model fit improvement was examined with adding physical activity and neighborhood environment perceptions (higher score = more unfavorable perceptions) as covariates. A significant interaction between residence length and NDI was found (p-interaction = 0.04); results were stratified by median residence length (11 years). Results. Adjusting for age, sex, race/ethnicity, smoking, and education/income, those who lived in neighborhood > 11 years gained 1.0 kg per one-unit increment of NDI (p = 0.03), or 6 kg for those in highest NDI tertile compared with those in the lowest tertile. Physical activity improved model fit; NDI remained associated with weight gain after adjustment for physical activity and neighborhood environment perceptions. There was no significant relationship between NDI and weight change for those in their neighborhood <= 11 years. Conclusions. Living in more socioeconomically deprived neighborhoods over a longer time period was associated with weight gain in DHS. Published by Elsevier Inc. C1 [Powell-Wiley, Tiffany M.; Agyemang, Priscilla] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Ayers, Colby; Das, Sandeep R.] Univ Texas Dallas, SW Med Ctr, Dept Med, Div Cardiol, Dallas, TX 75235 USA. [Leonard, Tammy] Univ Texas Dallas, Dept Econ, Richardson, TX 75080 USA. [Powell-Wiley, Tiffany M.; Berrigan, David; Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Lian, Min; Hoehner, Christine M.] Washington Univ, St Louis, MO 63130 USA. RP Powell-Wiley, TM (reprint author), NCI, Cardiovasc & Pulm Branch, Div Intramural Res,NHLBI,Appl Res Program, Div Canc Control & Populat Studies,NIH, Bldg 10,Room 5E3340, Bethesda, MD 20892 USA. EM tiffany.powell@nih.gov; colby.ayers@utsouthwestern.edu; pagyeman169@gmail.com; Leonard@utdallas.edu; berrigad@mail.nih.gov; barbashr@mail.nih.gov; mlian@dom.wustl.edu; Sandeep.das@utsouthwestem.edu; christyhoehner@gmail.com OI Powell-Wiley, Tiffany/0000-0001-9488-4131; Leonard, Tammy/0000-0002-8621-9358 FU Division of Intramural Research of NHLBI at NIH [ZIA HL006148-02, HHSN268201300173P] FX Funding for Dr. Powell-Wiley and Ms. Agyemang is provided by the Division of Intramural Research of NHLBI at NIH (ZIA HL006148-02). Funding for Mr. Ayers is provided through a professional services contract (contract # HHSN268201300173P) through the Division of Intramural Research of NHLBI at NIH. The funding source had no role in the study design, collection, analysis, and interpretation of data, in writing of the report, or in the decision to submit the article for publication. NR 45 TC 6 Z9 6 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD SEP PY 2014 VL 66 BP 22 EP 27 DI 10.1016/j.ypmed.2014.05.011 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM9RB UT WOS:000340217600005 PM 24875231 ER PT J AU McClain, JJ Lewin, DS Laposky, AD Kahle, L Berrigan, D AF McClain, James J. Lewin, Daniel S. Laposky, Aaron D. Kahle, Lisa Berrigan, David TI Associations between physical activity, sedentary time, sleep duration and daytime sleepiness in US adults SO PREVENTIVE MEDICINE LA English DT Article DE Sleep; Sedentary time; Physical activity; Accelerometry sleepiness; Sleep duration; Age; Sex ID UNITED-STATES; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; QUALITY INDEX; OLDER-ADULTS; EXERCISE; OBESITY; VALIDITY; WOMEN; SCALE AB Objective. To examine the associations between objectively measured physical activity (PA) or sedentary behavior and self-reported sleep duration or daytime sleepiness in a nationally representative sample of healthy US adults (N = 2128). Methods. We report analyses of four aspects of sedentary behavior and PA derived from accelerometry data (minutes of sedentary time, activity counts/minute, Minutes of Moderate and Vigorous PA [MVPA], and MVPA in 10-minute bouts) versus self-report of sleep duration and frequency of daytime sleepiness from the 2005-2006 National Health and Nutrition Examination Survey. Results. Age and sex dependence of associations between PA and sleep were observed. Aspects of PA were significantly lower in adults reporting more frequent daytime sleepiness in younger (20-39) and older (>= 60) age groups, but not in middle-aged (40-59), respondents. In younger respondents, PA increased with sleep duration, but in middle aged and older respondents PA was either unrelated to sleep duration or lower in those reporting >= 8 h of sleep. Objectively measured sedentary time showed limited evidence of associations with sleep duration. Conclusions. Further research delineating the relationships between sleep and PA is important because both activities have been implicated in diverse health outcomes as well as in the etiology of obesity. Published by Elsevier Inc. C1 [McClain, James J.; Berrigan, David] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Lewin, Daniel S.] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Washington, DC 20310 USA. [Laposky, Aaron D.] NHLBI, Natl Ctr Sleep Disorders Res, Bethesda, MD 20892 USA. [Kahle, Lisa] Information Management Serv Inc, Calverton, MD USA. RP McClain, JJ (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr 8609, Bethesda, MD 20892 USA. EM james.mcclain@nih.gov NR 40 TC 20 Z9 20 U1 3 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD SEP PY 2014 VL 66 BP 68 EP 73 DI 10.1016/j.ypmed.2014.06.003 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM9RB UT WOS:000340217600014 PM 24931432 ER PT J AU Coakley, MF Hurt, DE Weber, N Mtingwa, M Fincher, EC Alekseyev, V Chen, DT Yun, A Gizaw, M Swan, J Yoo, TS Huyen, Y AF Coakley, Meghan F. Hurt, Darrell E. Weber, Nick Mtingwa, Makazi Fincher, Erin C. Alekseyev, Vsevelod Chen, David T. Yun, Alvin Gizaw, Metasebia Swan, Jeremy Yoo, Terry S. Huyen, Yentram TI The NIH 3D Print Exchange: A Public Resource for Bioscientific and Biomedical 3D Prints SO 3D PRINTING AND ADDITIVE MANUFACTURING LA English DT Article AB The National Institutes of Health (NIH) has launched the NIH 3D Print Exchange, an online portal for discovering and creating bioscientifically relevant 3D models suitable for 3D printing, to provide both researchers and educators with a trusted source to discover accurate and informative models. There are a number of online resources for 3D prints, but there is a paucity of scientific models, and the expertise required to generate and validate such models remains a barrier. The NIH 3D Print Exchange fills this gap by providing novel, web-based tools that empower users with the ability to create ready-to-print 3D files from molecular structure data, microscopy image stacks, and computed tomography scan data. The NIH 3D Print Exchange facilitates open data sharing in a community-driven environment, and also includes various interactive features, as well as information and tutorials on 3D modeling software. As the first government-sponsored website dedicated to 3D printing, the NIH 3D Print Exchange is an important step forward to bringing 3D printing to the mainstream for scientific research and education. C1 [Coakley, Meghan F.; Hurt, Darrell E.; Weber, Nick; Mtingwa, Makazi; Huyen, Yentram] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Alekseyev, Vsevelod; Gizaw, Metasebia] NIAID, Software Engn Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Yun, Alvin] NIAID, Operat Engn Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Fincher, Erin C.; Swan, Jeremy] NICHHD, Biovisualizat Grp, Unit Comp Support Serv, NIH, Bethesda, MD 20892 USA. [Chen, David T.; Yoo, Terry S.] NIH, Informat Grp 3D, Off High Performance Comp & Commun, Natl Lib Med, Bethesda, MD 20892 USA. RP Hurt, DE (reprint author), Off Cyber Infrastruct & Computat Biol, Bioinformat & Computat Biosci Branch, Bldg 31,Room 3B62B,31 Ctr Dr, Bethesda, MD 20814 USA. EM darrellh@mail.nih.gov OI Coakley McCarthy, Meghan/0000-0002-0916-9692 FU HHS Ignite and HHS Ventures; HHS IDEA Lab of the Office of Technology, U.S. Department of Health and Human Services FX The Exchange is owned and operated by the National Institute of Allergy and Infectious Diseases under guidance from Mr. Mike Tartakovsky, chief information officer. The Exchange is funded in part by HHS Ignite and HHS Ventures, initiatives sponsored by the HHS IDEA Lab of the Office of Technology, U.S. Department of Health and Human Services. The Exchange gratefully acknowledges the time and feedback from members of our Advisory Team. Special recognition goes to Tom Ferrin, PhD, and the Chimera Team at the University of California San Francisco for help in optimizing 3D modeling workflows, and Nicholas Polys, PhD, Virginia Tech, for X3D and WebGL development support. For valuable feedback and special contributions, we also thank the NIH Library Office of Research Services, Eric Jones and Sam Michael of the National Center for Advancing Translational Sciences, the White House Office of Science and Technology Policy, and Jordan Miller, PhD, Rice University. NR 14 TC 3 Z9 3 U1 2 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2329-7662 EI 2329-7670 J9 3D PRINT ADDIT MANUF JI 3D Print. Addit. Manuf. PD SEP PY 2014 VL 1 IS 3 BP 137 EP 140 DI 10.1089/3dp.2014.1503 PG 4 WC Engineering, Manufacturing; Materials Science, Multidisciplinary SC Engineering; Materials Science GA V43BV UT WOS:000209657800005 PM 28367477 ER PT J AU Boudreaux, ED Horowitz, LM AF Boudreaux, Edwin D. Horowitz, Lisa M. TI Suicide Risk Screening and Assessment Designing Instruments with Dissemination in Mind SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article AB This paper summarizes recommendations made regarding the National Action Alliance for Suicide Prevention Research Prioritization Task Force's Aspirational Goal 2, to "determine the degree of suicide risk (e.g., imminent, near-term, long-term) among individuals in diverse populations and in diverse settings through feasible and effective screening and assessment approaches." We recommend that researchers shift to using "design for dissemination" principles to maximize both the goodness of fit and validity of screening and assessment measures for a given setting. Three specific recommendations to guide research efforts are made to achieve this shift: (1) the parameters related to each setting, including the logistics, scope of practice, infrastructure, and decision making required, should be identified and used to choose or design screening and assessment instruments that have a good fit; (2) to the greatest feasible extent, technology should be used to support screening and assessment; and (3) researchers should study the best methods for translating validated instruments into routine clinical practice. We discuss the potential barriers to implementing these recommendations and illustrate the paradigm shift within the emergency department setting. (Am J Prev Med 2014;47(3S2):S163-S169) (C) 2014 American Journal of Preventive Medicine. All rights reserved. C1 [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Psychiat, Dept Emergency Med, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Horowitz, Lisa M.] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Boudreaux, ED (reprint author), Dept Emergency Med, LA-189,55 Lake Ave North, Worcester, MA 01655 USA. EM edwin.boudreaux@umassmed.edu OI Boudreaux, Edwin/0000-0002-3223-6371 FU Centers for Disease Control and Prevention; National Institutes of Health Office of Behavioral and Social Sciences; National Institutes of Health Office of Disease Prevention; National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention FX Publication of this article was supported by the Centers for Disease Control and Prevention, the National Institutes of Health Office of Behavioral and Social Sciences, and the National Institutes of Health Office of Disease Prevention. This support was provided as part of the National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention. NR 15 TC 11 Z9 11 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2014 VL 47 IS 3 SU 2 BP S163 EP S169 DI 10.1016/j.amepre.2014.06.005 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CP0ZK UT WOS:000359605400010 PM 25145734 ER PT J AU Bridge, JA Horowitz, LM Fontanella, CA Grupp-Phelan, J Campo, JV AF Bridge, Jeffrey A. Horowitz, Lisa M. Fontanella, Cynthia A. Grupp-Phelan, Jackie Campo, John V. TI Prioritizing Research to Reduce Youth Suicide and Suicidal Behavior SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PRIMARY-CARE PATIENTS; ADOLESCENT DEPRESSION; SELF-HARM; COLLABORATIVE CARE; MENTAL-HEALTH; UNITED-STATES; YOUNG-PEOPLE; GLAD-PC; PREVENTION AB The goal of the National Action Alliance for Suicide Prevention is to reduce suicide and suicide attempts in the U.S. by 40% in the next decade. In this paper, a public health approach is applied to suicide prevention to illustrate how reductions in youth suicide and suicidal behavior might be achieved by prioritizing research in two areas: (1) increasing access to primary care-based behavioral health interventions for depressed youth and (2) improving continuity of care for youth who present to emergency departments after a suicide attempt. Finally, some scientific, clinical, and methodologic breakthroughs needed to achieve rapid, substantial, and sustained reductions in youth suicide and suicidal behavior are discussed. C1 [Bridge, Jeffrey A.] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Bridge, Jeffrey A.] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA. [Fontanella, Cynthia A.; Campo, John V.] Ohio State Univ, Coll Med, Dept Psychiat, Columbus, OH 43210 USA. [Grupp-Phelan, Jackie] Cincinnati Childrens Hosp Med Ctr, Div Emergency Med, Cincinnati, OH 45229 USA. [Horowitz, Lisa M.] NIMH, Off Clin Director, Bethesda, MD 20892 USA. RP Bridge, JA (reprint author), Nationwide Childrens Hosp, Res Inst, Ctr Innovat Pediat Practice, 700 Childrens Dr, Columbus, OH 43205 USA. EM jeff.bridge@nationwidechildrens.org FU Centers for Disease Control and Prevention; National Institutes of Health Office of Behavioral and Social Sciences; National Institutes of Health Office of Disease Prevention; National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention FX Publication of this article was supported by the Centers for Disease Control and Prevention, the National Institutes of Health Office of Behavioral and Social Sciences, and the National Institutes of Health Office of Disease Prevention. This support was provided as part of the National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention. NR 42 TC 10 Z9 10 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2014 VL 47 IS 3 SU 2 BP S229 EP S234 DI 10.1016/j.amepre.2014.06.001 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CP0ZK UT WOS:000359605400020 PM 25145744 ER PT J AU Colpe, LJ Pringle, BA AF Colpe, Lisa J. Pringle, Beverly A. TI Data for Building a National Suicide Prevention Strategy What We Have and What We Need SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID MENTAL-ILLNESS; HEALTH; MORTALITY; RISK AB Suicide is a leading cause of death in the U.S. As both the rate and number of suicides continue to climb, the country struggles with how to reverse this alarming trend. Using population-based data from publically available sources including the Web-based Injury Statistics Query and Reporting System, National Survey on Drug Use and Health, the authors identified patterns of suicide that can be used to steer a public health-based suicide prevention strategy. That most suicide deaths occur upon the first attempt, for example, suggests that a greater investment in primary prevention is needed. The fact that definable subgroups receiving care through identifiable service systems, such as individuals in specialty substance use treatment, exhibit greater concentrations of suicide risk than the general public suggests that integrating suicide prevention strategies into those service system platforms is an efficient way to deliver care to those with heightened need. The data sets that reveal these patterns have both strengths (e.g., population-level) and weaknesses (e.g., lack of longitudinal data linking changing health status, intervention encounters, suicidal behavior, and death records). Some of the data needed for crafting a comprehensive, public health-based approach for dramatically reducing suicide are currently available or may be available in the near term. Other resources will have to be built, perhaps by enhancing existing federal surveillance systems or constructing new ones. The article concludes with suggestions for immediate and longer-term actions that can strengthen public data resources in the service of reducing suicide in the U.S. (Am J PrevMed 2014;47(3S2):S130 S136) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Colpe, Lisa J.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Pringle, Beverly A.] NIMH, Off Res Dispar & Global Mental Hlth, Bethesda, MD 20892 USA. RP Colpe, LJ (reprint author), 6001 Execut Blvd,Room 7138 MSC9629, Bethesda, MD 20892 USA. EM lisa.colpe@nih.gov FU Centers for Disease Control and Prevention; National Institutes of Health Office of Behavioral and Social Sciences; National Institutes of Health Office of Disease Prevention; National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention FX Publication of this article was supported by the Centers for Disease Control and Prevention, the National Institutes of Health Office of Behavioral and Social Sciences, and the National Institutes of Health Office of Disease Prevention. This support was provided as part of the National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention. The views expressed in this manuscript do not necessarily represent the views of the National Institute of Mental Health or the Federal Government. NR 31 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2014 VL 47 IS 3 SU 2 BP S130 EP S136 DI 10.1016/j.amepre.2014.05.024 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CP0ZK UT WOS:000359605400006 PM 25145730 ER PT J AU Griffiths, JJ Zarate, CA Rasimas, JJ AF Griffiths, Joshua J. Zarate, Carlos A., Jr. Rasimas, J. J. TI Existing and Novel Biological Therapeutics in Suicide Prevention SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID MAJOR DEPRESSIVE DISORDER; RANDOMIZED CLINICAL-TRIAL; D-ASPARTATE ANTAGONIST; LITHIUM TREATMENT; PSYCHOLOGICAL AUTOPSY; CLOZAPINE TREATMENT; MOOD DISORDERS; DOUBLE-BLIND; BEHAVIOR; RISK AB We summarize outcomes for several pharmacologic and neurostimulatory approaches that have been considered potential treatments to reduce suicide risk, namely, by reducing suicide deaths, attempts, and ideation in various clinical populations. Available treatments include clozapine, lithium, antidepressants, antipsychotics, electroconvulsive therapy, and transcranial magnetic stimulation. The novel repurposing of ketamine as a potential suicide risk-mitigating agent in the acute setting is also discussed. Research pathways to better understand and treat suicidal ideation and behavior from a neurobiological perspective are proposed in light of this foundation of information and the limitations and challenges inherent in suicide research. Such pathways include trials of fast-acting medications, registry approaches to identify appropriate patients for trials, identification of biomarkers, neuropsychological vulnerabilities, and endophenotypes through the study of known suicide risk-mitigating agents in hope of determining mechanisms of pathophysiology and the action of protective biological interventions. (Am J Prev Med 2014;47(3S2):S195-S203) (C) 2014 American Journal of Preventive Medicine. All rights reserved. C1 [Griffiths, Joshua J.] Univ Colorado, Dept Psychiat, Denver, CO 80202 USA. [Zarate, Carlos A., Jr.; Rasimas, J. J.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Rasimas, J. J.] Penn State Coll Med, Dept Psychiat, Hershey, PA USA. [Rasimas, J. J.] Penn State Coll Med, Dept Emergency Med, Hershey, PA USA. RP Rasimas, JJ (reprint author), Univ Minnesota, Psychiat & Emergency Med, 640 Jackson St,Mailstop 12002A, St Paul, MN 55101 USA. EM joseph.j.rasimas@healthpartners.com FU Centers for Disease Control and Prevention; National Institutes of Health Office of Behavioral and Social Sciences; National Institutes of Health Office of Disease Prevention; National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention FX Publication of this article was supported by the Centers for Disease Control and Prevention, the National Institutes of Health Office of Behavioral and Social Sciences, and the National Institutes of Health Office of Disease Prevention. This support was provided as part of the National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention. NR 56 TC 14 Z9 14 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2014 VL 47 IS 3 SU 2 BP S195 EP S203 DI 10.1016/j.amepre.2014.06.012 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CP0ZK UT WOS:000359605400015 PM 25145739 ER PT J AU Horowitz, LM Bridge, JA Pao, M Boudreaux, ED AF Horowitz, Lisa M. Bridge, Jeffrey A. Pao, Maryland Boudreaux, Edwin D. TI Screening Youth for Suicide Risk in Medical Settings Time to Ask Questions SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID COMORBIDITY-SURVEY-REPLICATION; EMERGENCY-DEPARTMENT; PEDIATRIC EMERGENCY; ADOLESCENT SUICIDE; BEHAVIOR; PREVENTION; PREVALENCE; VALIDITY; CHILDREN; CARE AB This paper focuses on the National Action Alliance for Suicide Prevention's Research Prioritization Task Force's Aspirational Goal 2 (screening for suicide risk) as it pertains specifically to children, adolescents, and young adults. Two assumptions are forwarded: (1) strategies for screening youth for suicide risk need to be tailored developmentally; and (2) we must use instruments that were created and tested specifically for suicide risk detection and developed specifically for youth. Recommendations for shifting the current paradigm include universal suicide screening for youth in medical settings with validated instruments. (Am J Prev Med 2014;47(3S2):S170-S175) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Horowitz, Lisa M.; Pao, Maryland] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Bridge, Jeffrey A.] Nationwide Childrens Hosp, Res Inst, Ctr Innovat Pediat Practice, Columbus, OH USA. Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Psychiat, Dept Emergency Med, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. RP Horowitz, LM (reprint author), NIMH, Clin Res Ctr, Bldg 10,Room 6-5362, Bethesda, MD 20892 USA. EM horowitzl@mail.nih.gov OI Boudreaux, Edwin/0000-0002-3223-6371 FU Centers for Disease Control and Prevention; National Institutes of Health Office of Behavioral and Social Sciences; National Institutes of Health Office of Disease Prevention; National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention FX Publication of this article was supported by the Centers for Disease Control and Prevention, the National Institutes of Health Office of Behavioral and Social Sciences, and the National Institutes of Health Office of Disease Prevention. This support was provided as part of the National Institute of Mental Health-staffed Research Prioritization Task Force of the National Action Alliance for Suicide Prevention. NR 27 TC 7 Z9 7 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2014 VL 47 IS 3 SU 2 BP S170 EP S175 DI 10.1016/j.amepre.2014.06.002 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CP0ZK UT WOS:000359605400011 PM 25145735 ER PT J AU Pearson, JL Phd, CAC Booth, CL AF Pearson, Jane L. Claassen, Cynthia A. Booth, Chelsea L. CA National Action Alliance For Suici TI Introduction to the Suicide Prevention Research Prioritization Task Force Special Supplement The Topic Experts SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material ID NATIONAL ACTION ALLIANCE C1 [Pearson, Jane L.] Natl Inst Mental Hlth, Div Serv & Intervent Res, Rockville, MD 20892 USA. [Booth, Chelsea L.] Subst Abuse & Mental Hlth Serv Adm, Suicide Prevent Branch, Div Prevent Traumat Stress & Special Programs, Rockville, MD USA. [Claassen, Cynthia A.] Univ N Texas, Hlth Sci Ctr, Ft Worth, TX USA. RP Pearson, JL (reprint author), Natl Inst Mental Hlth, 6001 Execut Blvd,Room 7133, Rockville, MD 20892 USA. EM jpearson@mail.nih.gov NR 9 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2014 VL 47 IS 3 SU 2 BP S102 EP S105 DI 10.1016/j.amepre.2014.05.027 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CP0ZK UT WOS:000359605400002 PM 25145726 ER PT J AU Silverman, MM Pirkis, JE Pearson, JL Sherrill, JT AF Silverman, Morton M. Pirkis, Jane E. Pearson, Jane L. Sherrill, Joel T. TI Reflections on Expert Recommendations for US Research Priorities in Suicide Prevention SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material C1 [Silverman, Morton M.] Suicide Prevent Resource Ctr, Waltham, MA USA. [Pearson, Jane L.; Sherrill, Joel T.] Natl Inst Mental Hlth, Rockville, MD 20892 USA. [Pirkis, Jane E.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Australia. RP Sherrill, JT (reprint author), Natl Inst Mental Hlth, 6001 Execut Blvd, Rockville, MD 20892 USA. EM jsherril@mail.nih.gov NR 25 TC 1 Z9 1 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2014 VL 47 IS 3 SU 2 BP S97 EP S101 DI 10.1016/j.amepre.2014.05.025 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CP0ZK UT WOS:000359605400001 PM 25145750 ER PT J AU Grimes, WN Hoon, M Briggman, KL Wong, RO Rieke, F AF Grimes, William N. Hoon, Mrinalini Briggman, Kevin L. Wong, Rachel O. Rieke, Fred TI Cross-synaptic synchrony and transmission of signal and noise across the mouse retina SO ELIFE LA English DT Article ID MAMMALIAN RIBBON SYNAPSE; AII AMACRINE CELLS; ROD BIPOLAR CELLS; GANGLION-CELLS; CAT RETINA; MULTIVESICULAR RELEASE; CORRELATED ACTIVITY; PLEXIFORM LAYER; RABBIT RETINA; FIRING RATE AB Cross-synaptic synchrony-correlations in transmitter release across output synapses of a single neuron-is a key determinant of how signal and noise traverse neural circuits. The anatomical connectivity between rod bipolar and A17 amacrine cells in the mammalian retina-specifically that neighboring A17s often receive input from many of the same rod bipolar cells-provides a rare technical opportunity to measure cross-synaptic synchrony under physiological conditions. This approach reveals that synchronization of rod bipolar cell synapses is near perfect in the dark and decreases with increasing light level. Strong synaptic synchronization in the dark minimizes intrinsic synaptic noise and allows rod bipolar cells to faithfully transmit upstream signal and noise to downstream neurons. Desynchronization in steady light lowers the sensitivity of the rod bipolar output to upstream voltage fluctuations. This work reveals how cross-synaptic synchrony shapes retinal responses to physiological light inputs and, more generally, signaling in complex neural networks. C1 [Grimes, William N.; Rieke, Fred] Univ Washington, Dept Physiol & Biophys, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Hoon, Mrinalini; Wong, Rachel O.] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Briggman, Kevin L.] NINDS, Circuit Dynam & Connect Unit, Bethesda, MD 20892 USA. RP Rieke, F (reprint author), Univ Washington, Dept Physiol & Biophys, Howard Hughes Med Inst, 1705 NE Pacific St, Seattle, WA 98195 USA. EM rieke@u.washington.edu FU HHMI; NIH [EY11850, EY10699]; NINDS Intramural Research Program FX We thank Sid Kuo, Gautam Awatramani, Gabe Murphy for helpful comments on earlier versions of the paper, Felice Dunn for assistance with preliminary data collection and Mike Ahlquist, Mark Cafaro, Shellee Cunnington and Paul Newman for outstanding technical assistance. Support provided by HHMI (FR), NIH Extramural Funding (EY11850 to FR, EY10699 to ROW) and the NINDS Intramural Research Program (KLB). NR 62 TC 7 Z9 7 U1 0 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 1 PY 2014 VL 3 AR e03892 DI 10.7554/eLife.03892 PG 29 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AO3TY UT WOS:000341260000001 PM 25180102 ER PT J AU Nguyen, AB Breen, N Clark, TT Moser, R AF Anh Bao Nguyen Breen, Nancy Clark, Trenette T. Moser, Richard TI THE BIRACIAL ASIAN POPULATION IN CALIFORNIA: AN EXAMINATION OF HEALTH PROFILES AND CHRONIC CONDITIONS SO ETHNICITY & DISEASE LA English DT Article DE Biracial; Asians; Chronic Conditions; Ethnicity ID SOCIOECONOMIC-STATUS; US; DISEASE AB Objectives: To examine health outcomes and chronic conditions for the biracial Asian population in California. We hypothesized that the biracial population will display intermediate (or an average of) outcomes in comparison to their monoracial counterparts. Design: The study was cross-sectional. After adjusting for sociodemographic variables, multivariable regression models predicted health outcomes (ie, diabetes, heart disease, high blood pressure, disability status, BMI, and general health) and compared health outcomes among various (mono- and bi-) racial and ethnic groups. Participants: Data were collected from 238,897 adult (aged >= 18 years) respondents after merging iterations of the California Health Interview Survey (CHIS) administered in 2001, 2003, 2005, 2007, and 2009. Results: Multivariate results revealed that Whites reported better health overall than biracial Asians and other monoracial groups. Biracial Asians displayed BMI ranges that were intermediate between their monoracial constituents. Conclusions: BMI is a more proximal health outcome and is more sensitive to lifestyles and behaviors. As a result, BMI may be a better indicator than chronic diseases in showing that biracial Asians have adopted health behaviors and practices that fall between their monoracial counterparts. Future epidemiological research should examine the prevalence of more proximal health outcomes among biracial Asians and assess how it differs by developmental age. C1 [Anh Bao Nguyen; Breen, Nancy; Moser, Richard] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Clark, Trenette T.] Univ N Carolina, Sch Social Work, Chapel Hill, NC USA. RP Nguyen, AB (reprint author), 9609 Med Ctr Dr,Rm 3e638, Rockville, MD 20850 USA. EM bao2no1@gmail.com NR 25 TC 0 Z9 0 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2014 VL 24 IS 4 BP 481 EP 487 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CU7KU UT WOS:000363717400016 PM 25417433 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, J. TI Cell biological mechanisms underlying HIV-1 viral particle assembly and release SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO 2014 Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP FEBS, EMBO C1 [Lippincott-Schwartz, J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA CS-I-3-1 BP 12 EP 12 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666800034 ER PT J AU Goktuna, SI Canli, O Bollrath, J Fingerle, AA Horst, D Diamanti, MA Pallangyo, C Bennecke, M Nebelsiek, T Mankan, AK Lang, R Artis, D Hu, Y Patzelt, T Ruland, J Kirchner, T Taketo, MM Chariot, A Arkan, MC Greten, FR AF Goktuna, S. I. Canli, O. Bollrath, J. Fingerle, A. A. Horst, D. Diamanti, M. A. Pallangyo, C. Bennecke, M. Nebelsiek, T. Mankan, A. K. Lang, R. Artis, D. Hu, Y. Patzelt, T. Ruland, J. Kirchner, T. Taketo, M. M. Chariot, A. Arkan, M. C. Greten, F. R. TI IKK alpha promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO 2014 Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP FEBS, EMBO DE colorectal cancer; Macrophage activation; tumor microenvironment C1 [Goktuna, S. I.; Chariot, A.] Univ Liege, CHU Sart Timan, GIGA ST, Liege, Belgium. [Goktuna, S. I.; Canli, O.; Bollrath, J.; Fingerle, A. A.; Diamanti, M. A.; Bennecke, M.; Nebelsiek, T.; Mankan, A. K.; Arkan, M. C.; Greten, F. R.] Tech Univ Munich, Klinikum Rechts Isar, Inst Mol Immunol, D-80290 Munich, Germany. [Canli, O.; Greten, F. R.] Inst Tumor Biol & Expt Therapy, Frankfurt, Germany. [Horst, D.; Kirchner, T.] Univ Munich, Inst Pathol, D-80539 Munich, Germany. [Pallangyo, C.] Tech Univ Munich, Klinikum Rechts Isar, Med Klin 2, D-80290 Munich, Germany. [Lang, R.] Univ Hosp Erlangen, Inst Clin Microbiol Immunol & Hyg, Erlangen, Germany. [Artis, D.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Artis, D.] Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hu, Y.] NCI, Lab Expt Biol, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Patzelt, T.; Ruland, J.] Tech Univ Munich, Klinikum Rechts Isar, Dept Clin Chem, D-80290 Munich, Germany. [Ruland, J.; Kirchner, T.; Greten, F. R.] German Canc Consortium DKTK, Heidelberg, Germany. [Ruland, J.; Kirchner, T.; Greten, F. R.] German Canc Res Ctr, Heidelberg, Germany. [Taketo, M. M.] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto, Japan. [Chariot, A.] Walloon Exellence Lifesci & Biotechnol WELBI, Liege, Belgium. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA SUN-193 BP 130 EP 131 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666801180 ER PT J AU Wlodawer, A Zhou, D Gustchina, A Ferreira, RDS Lobo, YA Hansen, D Oliva, MLV AF Wlodawer, A. Zhou, D. Gustchina, A. Ferreira, R. D. S. Lobo, Y. A. Hansen, D. Oliva, M. L. V. TI Plant proteins with medically important properties: structural studies of three members of the beta-trefoil family that function as serine protease inhibitors and/or as lectins SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO 2014 Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP FEBS, EMBO DE inhibitor; lectin; protease C1 [Wlodawer, A.; Zhou, D.; Gustchina, A.] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Ferreira, R. D. S.; Lobo, Y. A.; Hansen, D.; Oliva, M. L. V.] Univ Fed Sao Paulo, Dept Bioquim, Sao Paulo, SP, Brazil. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA SUN-260 BP 153 EP 154 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666801243 ER PT J AU Gustchina, A Wlodawer, A Rotanova, T AF Gustchina, A. Wlodawer, A. Rotanova, T. TI Structural similarity between the N-terminal domain of LonA proteases and the highly conserved RNA-binding PUA domains SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO 2014 Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP FEBS, EMBO DE ATPase activity; Protein structure; Proteolysis C1 [Gustchina, A.; Wlodawer, A.] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Rotanova, T.] Shemyakin Ovchinnikov Inst, Moscow, Russia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA SUN-308 BP 170 EP 170 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666801287 ER PT J AU Chang, YS Siu, MK Abou-Kheir, W Yin, JJ Chien, IH Suau, F Casey, O Kelly, K Liu, YN AF Chang, Y. -S. Siu, M. K. Abou-Kheir, W. Yin, J. J. Chien, I. -H. Suau, F. Casey, O. Kelly, K. Liu, Y. -N. TI A role for miRNAs regulate prostate cancer metastasis and tyrosine kinase inhibitors (TKIs) resistance by targeting EGFR signaling pathway SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO 2014 Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP FEBS, EMBO DE bone metastasis; prostate cancer; tyrosine kinase inhibitors (TKIs) resistance C1 [Chang, Y. -S.; Siu, M. K.; Chien, I. -H.; Liu, Y. -N.] Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan. [Abou-Kheir, W.] Amer Univ Beirut, Dept Anat, Beirut, Lebanon. [Yin, J. J.; Suau, F.; Casey, O.; Kelly, K.] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA MON-030 BP 261 EP 262 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666802027 ER PT J AU Anderluh, A Klotzsch, E Newman, AH Sitte, HH Schutz, GJ AF Anderluh, A. Klotzsch, E. Newman, A. H. Sitte, H. H. Schuetz, G. J. TI Single molecule analysis reveals coexistence of stable serotonin transporter monomers and oligomers in the live cell plasma membrane SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO 2014 Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP FEBS, EMBO DE Serotonin Transporter; Single Molecule Analysis; Stoichiometry C1 [Anderluh, A.; Klotzsch, E.; Schuetz, G. J.] Vienna Univ Technol, Appl Phys, A-1040 Vienna, Austria. [Newman, A. H.] NIDA, Baltimore, MD USA. [Sitte, H. H.] Med Univ Vienna, Vienna, Austria. RI Klotzsch, Enrico/J-8831-2012; Schutz, Gerhard/B-1243-2008 OI Klotzsch, Enrico/0000-0002-7577-9042; Schutz, Gerhard/0000-0003-1542-1089 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA MON-385 BP 381 EP 381 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666802352 ER PT J AU Jaremko, M Jaremko, L Kim, HY Cho, MK Schwieters, CD Giller, K Becker, S Zweckstetter, M AF Jaremko, M. Jaremko, L. Kim, H. -Y. Cho, M. -K. Schwieters, C. D. Giller, K. Becker, S. Zweckstetter, M. TI Cold-denaturation of a protein dimer monitored at atomic resolution SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP Federat European Biochemical Soc, European Mol Biol Org DE cold denaturation; Protein structure; protein unfolding C1 [Jaremko, M.; Kim, H. -Y.; Cho, M. -K.; Giller, K.; Becker, S.] Max Planck Inst Biophys Chem, NMR Based Struct Biol, D-37077 Gottingen, Germany. [Jaremko, L.; Zweckstetter, M.] DZNE eV, Gottingen, Germany. [Schwieters, C. D.] NIH, Div Computat Biosci, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA WED-013 BP 620 EP 620 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666804013 ER PT J AU Miao, Z Blanchet, MF Boniecki, M Bujnicki, JM Chen, SJ Cheng, C Chou, FC Cordero, P Cruz, JA Das, R Ding, F Dokholyan, NV Dunin-Horkawicz, S Ferre-D'Amare, A Kladwang, W Krokhotin, A Magnus, M Major, F Mann, TH Matelska, D Peselis, A Serganov, A Tandon, A Tian, S Xu, X Zhang, J Zhao, P Westhof, E AF Miao, Z. Blanchet, M. -F. Boniecki, M. Bujnicki, J. M. Chen, S. -J. Cheng, C. Chou, F. -C. Cordero, P. Cruz, J. A. Das, R. Ding, F. Dokholyan, N. V. Dunin-Horkawicz, S. Ferre-D'Amare, A. Kladwang, W. Krokhotin, A. Magnus, M. Major, F. Mann, T. H. Matelska, D. Peselis, A. Serganov, A. Tandon, A. Tian, S. Xu, X. Zhang, J. Zhao, P. Westhof, E. TI RNA-Puzzles Round II: assessment of RNA structure prediction of two large riboswitches SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO 2014 Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP FEBS, EMBO DE 3D structure prediciton; Bioinformatics; RNA structure prediction C1 [Miao, Z.; Cruz, J. A.; Westhof, E.] Univ Strasbourg, Architecture & React ARN, Inst Biol Mol & Cellulaire, CNRS, Strasbourg, France. [Blanchet, M. -F.; Major, F.] Univ Montreal, Dept Comp Sci & Operat Res, Montreal, PQ, Canada. [Boniecki, M.; Bujnicki, J. M.; Dunin-Horkawicz, S.; Magnus, M.; Matelska, D.] Int Inst Mol & Cell Biol Warsaw, Lab Bioinformat & Prot Engn, Warsaw, Poland. [Bujnicki, J. M.] Adam Mickiewicz Univ, Inst Mol Biol & Biotechnol, Lab Bioinformat, Fac Biol, Poznan, Poland. [Chen, S. -J.; Xu, X.; Zhao, P.] Univ Missouri, Dept Phys, Columbia, MO 65211 USA. [Chen, S. -J.; Xu, X.; Zhao, P.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Cheng, C.; Chou, F. -C.; Cordero, P.; Das, R.; Kladwang, W.; Mann, T. H.; Tian, S.] Stanford Univ, Dept Phys, Stanford, CA 94305 USA. [Ding, F.] Clemson Univ, Coll Engn & Sci, Dept Phys & Astron, Clemson, SC 29631 USA. [Dokholyan, N. V.; Krokhotin, A.; Tandon, A.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27515 USA. [Ferre-D'Amare, A.; Zhang, J.] NHLBI, Bethesda, MD USA. [Peselis, A.; Serganov, A.] New York Univ Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA WED-067 BP 638 EP 639 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666804061 ER PT J AU Cruz-Gallardo, I Angulo, J Del Conte, R Gorospe, M Karlsson, BG Wilce, JA De la Rosa, MA Diaz-Moreno, I AF Cruz-Gallardo, I. Angulo, J. Del Conte, R. Gorospe, M. Karlsson, B. G. Wilce, J. A. De la Rosa, M. A. Diaz-Moreno, I. TI The binding of TIA-1 to RNA C-rich sequences is driven by its pH dependent C-terminal RRM domain SO FEBS JOURNAL LA English DT Meeting Abstract CT FEBS EMBO 2014 Conference CY AUG 30-SEP 04, 2014 CL Paris, FRANCE SP FEBS, EMBO DE RNA Binding Protein (RBP); RNA Recognition Motif (RRM); TIA-1 protein C1 [Cruz-Gallardo, I.; De la Rosa, M. A.; Diaz-Moreno, I.] Univ Seville, CSIC, Inst Plant Biochem & Photosynth IBVF, cicCartuja, Seville, Spain. [Angulo, J.] Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk, England. [Del Conte, R.] Univ Florence, CERM, Florence, Italy. [Gorospe, M.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Karlsson, B. G.] Univ Gothenburg, Swedish NMR Ctr, Gothenburg, Sweden. [Wilce, J. A.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. RI Diaz-Moreno, Irene/E-7181-2010; Karlsson, Goran/E-8686-2011 OI Diaz-Moreno, Irene/0000-0002-5318-7644; NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD SEP PY 2014 VL 281 SU 1 SI SI MA WED-464 BP 775 EP 775 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP1WE UT WOS:000359666804428 ER PT J AU Sidharthan, S Kottilil, S AF Sidharthan, Sreetha Kottilil, Shyam TI Mechanisms of alcohol-induced hepatocellular carcinoma SO HEPATOLOGY INTERNATIONAL LA English DT Article DE Alcohol; HCC; Carcinogenesis AB Chronic alcohol abuse is a major risk factor for hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide. Alcohol can also function synergistically with other risk factors to cause HCC. Hence, alcohol consumption is a major factor affecting hepatic carcinogenesis in millions and the cause of a substantial public health burden. Chronic alcohol consumption interferes with several host anti-tumor mechanisms, thereby facilitating hepatocyte proliferation and tumorigenesis. This review summarizes the major mechanisms of alcoholinduced HCC. These include pathways of ethanol metabolism, alcohol-induced oxidative stress and hypomethylation of DNA, and interplay of alcohol with iron elevation, retinoid metabolism, the immune system, inflammatory pathways, and neoangiogenesis. The relevance of each pathway in affecting HCC transformation is a topic of intense investigation. Ongoing research will enhance our insight into the alcohol-induced occurrence of HCC and offer hope in developing better therapeutics. C1 [Sidharthan, Sreetha] NIH, Dept Crit Care Med, Dept Hlth & Human Serv, Ctr Clin, Bethesda, MD 20892 USA. [Kottilil, Shyam] NIAID, Immunoregulat Lab, Dept Hlth & Human Serv, NIH, Bldg10,Rm 11N204, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, Dept Hlth & Human Serv, NIH, Bldg10,Rm 11N204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov FU Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases, and the Clinical Research Center) FX This research was supported by the Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases, and the Clinical Research Center). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 55 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1936-0533 EI 1936-0541 J9 HEPATOL INT JI Hepatol. Int. PD SEP PY 2014 VL 8 SU 2 BP S452 EP S457 DI 10.1007/s12072-013-9494-4 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V42PG UT WOS:000209625100009 PM 25383134 ER PT J AU Xu, MJ Chang, BX Mathews, S Gao, B AF Xu, Mingjiang Chang, Binxia Mathews, Stephanie Gao, Bin TI New drug targets for alcoholic liver disease SO HEPATOLOGY INTERNATIONAL LA English DT Article DE Prednisolone; Interleukin-22; Inflammation; Liver; Ethanol AB Alcoholic liver disease (ALD) represents a spectrum of disorders, ranging from simple steatosis to severe alcoholic hepatitis and cirrhosis. The severe form of ALD comprises multiple problems in the liver, including inflammation, hepatocellular damage, fibrosis, and impaired liver regeneration, and likely requires combinational therapies. In this review, we discuss recently identified therapeutic targets that inhibit inflammation, ameliorate hepatocyte death, and promote liver repair in ALD, with a focus on our recent studies on the immunosuppressive drug prednisolone and the hepatoprotective cytokine interleukin-22. Clinical trials examining prednisolone plus interleukin-22 therapy for severe alcoholic hepatitis are currently under consideration. C1 [Xu, Mingjiang; Chang, Binxia; Mathews, Stephanie; Gao, Bin] NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov NR 41 TC 1 Z9 1 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1936-0533 EI 1936-0541 J9 HEPATOL INT JI Hepatol. Int. PD SEP PY 2014 VL 8 SU 2 BP S475 EP S480 DI 10.1007/s12072-014-9516-x PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V42PG UT WOS:000209625100013 ER PT J AU Littlejohns, TJ Kos, K Henley, WE Cherubini, A Ferrucci, L Lang, IA Langa, KM Melzer, D Llewellyn, DJ AF Littlejohns, T. J. Kos, K. Henley, W. E. Cherubini, A. Ferrucci, L. Lang, I. A. Langa, K. M. Melzer, D. Llewellyn, D. J. TI SERUM LEPTIN AND RISK OF COGNITIVE DECLINE IN ELDERLY ITALIANS: A PROSPECTIVE COHORT STUDY SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Meeting Abstract C1 [Littlejohns, T. J.; Kos, K.; Henley, W. E.; Lang, I. A.; Melzer, D.; Llewellyn, D. J.] Univ Exeter, Sch Med, Exeter, Devon, England. [Cherubini, A.] Univ Perugia, Sch Med, Perugia, Italy. [Ferrucci, L.] NIA, NIH, Baltimore, MD 21224 USA. [Langa, K. M.] Vet Affairs Ann Arbor Ctr Clin Management Res, Div Gen Med, Ann Arbor, MI USA. [Langa, K. M.] Univ Michigan, Inst Social Res, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD SEP PY 2014 VL 68 SU 1 MA OP01 BP A4 EP A4 DI 10.1136/jech-2014-204726.4 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V45AH UT WOS:000209789000005 ER PT J AU Canadell, MP Moreno-Delgado, D Rodriguez-Ruiz, M Moreno, E Botta, J Gasperini, P Cordom, A Howell, LA Navarro, G Casado, V Ferre, S Guzman, M Pardo, L Alberch, J Canela, EI Lluis, C McCormick, PJ Gines, S AF Canadell, M. P. Moreno-Delgado, D. Rodriguez-Ruiz, M. Moreno, E. Botta, J. Gasperini, P. Cordom, A. Howell, L. A. Navarro, G. Casado, V. Ferre, S. Guzman, M. Pardo, L. Alberch, J. Canela, E. I. Lluis, C. McCormick, P. J. Gines, S. TI TARGETING DOPAMINE D1-HISTAMINE H3 RECEPTOR HETEROMERS AS A THERAPEUTICAL STRATEGY TO PREVENT COGNITIVE DEFICITS AND NEURODEGENERATION IN HUNTINGTON'S DISEASE SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract CT 8th European-Huntington's-Disease-Network Plenary Meeting CY SEP 19-21, 2014 CL Barcelona, SPAIN SP European Huntingtons Disease Network C1 [Canadell, M. P.; Gines, S.] Univ Barcelona, Fac Med, Dept Cellular Biol Immunol & Neurosci, E-08007 Barcelona, Spain. [Canadell, M. P.; Moreno-Delgado, D.; Rodriguez-Ruiz, M.; Moreno, E.; Botta, J.; Gasperini, P.; Navarro, G.; Casado, V.; Guzman, M.; Alberch, J.; Canela, E. I.; Lluis, C.; McCormick, P. J.; Gines, S.] Univ Barcelona, Ctr Invest Biomed Red Sobre Enfermedades Neurodeg, E-08007 Barcelona, Spain. [Moreno-Delgado, D.; Rodriguez-Ruiz, M.; Moreno, E.; Botta, J.; Gasperini, P.; Navarro, G.; Casado, V.; Canela, E. I.; Lluis, C.; McCormick, P. J.] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08007 Barcelona, Spain. [Gasperini, P.; Howell, L. A.; McCormick, P. J.] Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk, England. [Cordom, A.; Ferre, S.] NIDA, Intramural Res Program, NIH, US Dept HHS, Baltimore, MD 21224 USA. [Guzman, M.] Univ Complutense Madrid, Sch Biol, Dept Biochem & Mol Biol 1, E-28040 Madrid, Spain. [Pardo, L.] Autonomous Univ Barcelona, Fac Med, Computat Med Lab, Bellaterra, Spain. NR 0 TC 0 Z9 0 U1 3 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD SEP PY 2014 VL 85 SU 1 MA M17 BP A100 EP A100 DI 10.1136/jnnp-2014-309032.289 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA CS3KF UT WOS:000361971900290 ER PT J AU Jeffrey, BG Cukras, CA Vitale, S Turriff, A Bowles, K Sieving, PA AF Jeffrey, Brett G. Cukras, Catherine A. Vitale, Susan Turriff, Amy Bowles, Kristin Sieving, Paul A. TI Test-Retest Intervisit Variability of Functional and Structural Parameters in X-Linked Retinoschisis SO TRANSLATIONAL VISION SCIENCE & TECHNOLOGY LA English DT Article DE XLRS; retinoschisis; electroretinogram; OCT; MP1 AB Purpose: To examine the variability of four outcome measures that could be used to address safety and efficacy in therapeutic trials with X-linked juvenile retinoschisis. Methods: Seven men with confirmed mutations in the RS1 gene were evaluated over four visits spanning 6 months. Assessments included visual acuity, full-field electroretinograms (ERG), microperimetric macular sensitivity, and retinal thickness measured by optical coherence tomography (OCT). Eyes were separated into Better or Worse Eye groups based on acuity at baseline. Repeatability coefficients were calculated for each parameter and jackknife resampling used to derive 95% confidence intervals (CIs). Results: The threshold for statistically significant change in visual acuity ranged from three to eight letters. For ERG a-wave, an amplitude reduction greater than 56% would be considered significant. For other parameters, variabilities were lower in the Worse Eye group, likely a result of floor effects due to collapse of the schisis pockets and/or retinal atrophy. The criteria for significant change (Better/Worse Eye) for three important parameters were: ERG b/a-wave ratio (0.44/0.23), point wise sensitivity (10.4/7.0 dB), and central retinal thickness (31%/18%). Conclusions: The 95% CI range for visual acuity, ERG, retinal sensitivity, and central retinal thickness relative to baseline are described for this cohort of participants with X-linked juvenile retinoschisis (XLRS). Translational Relevance: A quantitative understanding of the variability of outcome measures is vital to establishing the safety and efficacy limits for therapeutic trials of XLRS patients. C1 [Jeffrey, Brett G.; Cukras, Catherine A.; Vitale, Susan; Turriff, Amy; Bowles, Kristin; Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. [Bowles, Kristin] Univ Houston, Coll Optometry, Houston, TX 77004 USA. RP Jeffrey, BG (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. EM jeffreybg@nei.nih.gov NR 66 TC 6 Z9 6 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 2164-2591 J9 TRANSL VIS SCI TECHN JI Transl. Vis. Sci. Technol. PD SEP PY 2014 VL 3 IS 5 AR 5 DI 10.1167/tvst.3.5.5 PG 15 WC Ophthalmology SC Ophthalmology GA V45JV UT WOS:000209813800005 ER PT J AU Fodor, A Barsvari, B Aliczki, M Balogh, Z Zelena, D Goldberg, SR Haller, J AF Fodor, Anna Barsvari, Beata Aliczki, Mano Balogh, Zoltan Zelena, Dora Goldberg, Steven R. Haller, Jozsef TI The effects of vasopressin deficiency on aggression and impulsiveness in male and female rats SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Aggression; Brattleboro rat; Impulsiveness; Maternal aggression; Resident-intruder test; Vasopressin ID GOLDEN-HAMSTERS; ARGININE-VASOPRESSIN; HYPOTHALAMIC VASOPRESSIN; INTERMALE AGGRESSION; OFFENSIVE AGGRESSION; MATERNAL AGGRESSION; RECEPTOR ANTAGONIST; BRATTLEBORO RATS; SOCIAL-BEHAVIOR; SEROTONIN AB The role of vasopressin in aggression received much attention in recent years. However, vasopressin has complex roles on social behavior, which are affected by social experience, motivation and hormonal background, suggesting that its effects depend on the condition of subjects. This hypothesis was tested here by studying the impact of vasopressin deficiency on aggressiveness in reproductively naive and reproductively experienced males, as well as in Lactating females, with special reference to the patterns and contexts of attack behavior. We also studied effects on impulsiveness, a behavioral feature strongly related to aggression. Vasopressin deficiency did not affect aggressiveness in reproductively experienced males, decreased the share of violent attacks in reproductively inexperienced males without affecting total attack counts, and suppressed maternal aggression in both early and late phases of lactation; violent forms of attack were decreased in the latter but not the former phase. Changes in aggression appeared unrelated to general changes in maternal behaviors. Impulsivity in the delay discounting task was markedly decreased by vasopressin deficiency in lactating females but not males. Taken together, our findings confirm that vasopressin has an impact on aggressiveness, but show that this impact depends on the condition of subjects, and suggest that the effects of vasopressin on maternal aggression develop in conjunction with impulsivity. Interestingly, overall effects on aggression and specific effects on violent attacks dissociated in both males and females, which hints to the possibility that vasopressin has distinct roles in the development of escalated forms of aggression. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Fodor, Anna; Barsvari, Beata; Aliczki, Mano; Balogh, Zoltan; Zelena, Dora; Haller, Jozsef] Hungarian Acad Sci, Inst Expt Med, Dept Behav Neurobiol, H-1450 Budapest, Hungary. [Fodor, Anna] Semmelweis Univ, Janos Szentagothai Sch Neurosci, H-1085 Budapest, Hungary. [Goldberg, Steven R.] NIDA, Dept Hlth & Human Serv, Preclin Pharmacol Sect, Intramural Res Program,NIH,Biomed Res Ctr, Baltimore, MD USA. RP Aliczki, M (reprint author), Hungarian Acad Sci, Inst Expt Med, Dept Behav Neurobiol, POB 67, H-1450 Budapest, Hungary. EM aliczki.mano@koki.mta.hu RI Balogh, Zoltan/O-9645-2014; OI Balogh, Zoltan/0000-0002-1020-4694; Haller, Jozsef/0000-0002-1953-3726 FU Hungarian National Science and Research Fund (OTKA) [82069]; Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS FX This study was supported by the Hungarian National Science and Research Fund (OTKA) contract grant number: 82069 and by the Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS. NR 55 TC 5 Z9 6 U1 1 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD SEP PY 2014 VL 47 BP 141 EP 150 DI 10.1016/j.psyneuen.2014.05.010 PG 10 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA AM2PY UT WOS:000339694500016 PM 25001964 ER PT J AU Wang, Y Resnick, SM Davatzikos, C AF Wang, Ying Resnick, Susan M. Davatzikos, Christos CA Baltimore Longitudinal Study Aging TI Analysis of Spatio-Temporal Brain Imaging Patterns by Hidden Markov Models and Serial MRI Images SO HUMAN BRAIN MAPPING LA English DT Article DE Spatio-temporal analysis; HMM; spatial brain patterns; MRI series; mild cognitive impairment; early MCI detection ID MILD COGNITIVE IMPAIRMENT; VOXEL-BASED MORPHOMETRY; ALZHEIMERS-DISEASE; OLDER-ADULTS; BASE-LINE; CLASSIFICATION; PREDICTION; MCI; SEGMENTATION; REGISTRATION AB Brain changes due to development and maturation, normal aging, or degenerative disease are continuous, gradual, and variable across individuals. To quantify the individual progression of brain changes, we propose a spatio-temporal methodology based on Hidden Markov Models (HMM), and apply it on four-dimensional structural brain magnetic resonance imaging series of older individuals. First, regional brain features are extracted in order to reduce image dimensionality. This process is guided by the objective of the study or the specific imaging patterns whose progression is of interest, for example, the evaluation of Alzheimer-like patterns of brain change in normal individuals. These regional features are used in conjunction with HMMs, which aim to measure the dynamic association between brain structure changes and progressive stages of disease over time. A bagging framework is used to obtain models with good generalization capability, since in practice the number of serial scans is limited. An application of the proposed methodology was to detect individuals with the risk of developing MCI, and therefore it was tested on modeling the progression of brain atrophy patterns in older adults. With HMM models, the state-transition paths corresponding to longitudinal brain changes were constructed from two completely independent datasets, the Alzheimer Disease Neuroimaging Initiative and the Baltimore Longitudinal Study of Aging. The statistical analysis of HMM-state paths among the normal, progressive MCI, and MCI groups indicates that, HMM-state index 1 is likely to be a predictor of the conversion from cognitively normal to MCI, potentially many years before clinical symptoms become measurable. (C) 2014 Wiley Periodicals, Inc. C1 [Wang, Ying; Davatzikos, Christos] Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. RP Wang, Y (reprint author), Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. EM ying.wang@uphs.upenn.edu FU NIH [R01AG14971, P30 AG010129, K01 AG030514]; Intramural Research Program of the National Institute on Aging (NIA) [N01-AG-3-2124]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant) [U01 AG024904]; Dana Foundation FX Contract grant sponsor: NIH; Contract grant number: R01AG14971; Contract grant sponsor: Intramural Research Program of the National Institute on Aging (NIA); Contract grant number: N01-AG-3-2124; Contract grant sponsor: Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant); Contract grant number: U01 AG024904; Contract grant sponsor: NIH grant; Contract grant number: P30 AG010129, K01 AG030514; Contract grant sponsor: the Dana Foundation. NR 53 TC 4 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2014 VL 35 IS 9 BP 4777 EP 4794 DI 10.1002/hbm.22511 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AM0VZ UT WOS:000339567000039 PM 24706564 ER PT J AU Tang, M Slud, EV Pfeiffer, RM AF Tang, Min Slud, Eric V. Pfeiffer, Ruth M. TI Goodness of fit tests for linear mixed models SO JOURNAL OF MULTIVARIATE ANALYSIS LA English DT Article DE Asymptotic efficiency; Information matrix; Maximum likelihood estimators; Method of moments; Model fit; Random effects ID LIKELIHOOD RATIO TESTS; ASYMPTOTIC PROPERTIES; LIMITED-INFORMATION; CONTINGENCY-TABLES; SELECTION; VARIANCE AB Linear mixed models (LMMs) are widely used for regression analysis of data that are assumed to be clustered or correlated. Assessing model fit is important for valid inference but to date no confirmatory tests are available to assess the adequacy of the fixed effects part of LMMs against general alternatives. We therefore propose a class of goodness-of-fit tests for the mean structure of LMMs. Our test statistic is a quadratic form of the difference between observed values and the values expected under the estimated model in cells defined by a partition of the covariate space. We show that this test statistic has an asymptotic chi-squared distribution when model parameters are estimated by maximum likelihood or by least squares and method of moments, and study its power under local alternatives both analytically and in simulations. Data on repeated measurements of thyroglobulin from individuals exposed to the accident at the Chernobyl power plant in 1986 are used to illustrate the proposed test. Published by Elsevier Inc. C1 [Tang, Min] Novartis Pharmaceut, E Hanover, NJ 07936 USA. [Slud, Eric V.] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Slud, Eric V.] US Bur Census, Ctr Stat Res & Methodol, Suitland, MD USA. [Pfeiffer, Ruth M.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Tang, M (reprint author), Novartis Pharmaceut, E Hanover, NJ 07936 USA. EM amethyst1984tm@gmail.com; pfeiffer@mail.nih.gov NR 30 TC 2 Z9 2 U1 2 U2 16 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0047-259X J9 J MULTIVARIATE ANAL JI J. Multivar. Anal. PD SEP PY 2014 VL 130 BP 176 EP 193 DI 10.1016/j.jmva.2014.03.012 PG 18 WC Statistics & Probability SC Mathematics GA AL8TR UT WOS:000339413100012 ER PT J AU Han, TU Park, J Domingues, CF Moretti-Ferreira, D Paris, E Sainz, E Gutierrez, J Drayna, D AF Han, Tae-Un Park, John Domingues, Carlos F. Moretti-Ferreira, Danilo Paris, Emily Sainz, Eduardo Gutierrez, Joanne Drayna, Dennis TI A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Stuttering; Genetics; FOXP2; CNTNAP2; Gene expression; Human brain ID REAL-TIME PCR; HUMAN BRAIN; LANGUAGE IMPAIRMENT; HOUSEKEEPING GENES; EXPRESSION DATA; SEVERE SPEECH; RT-PCR; IDENTIFICATION; NORMALIZATION; VALIDATION AB A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p = 0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p = 0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI. Published by Elsevier Inc. C1 [Han, Tae-Un; Domingues, Carlos F.; Sainz, Eduardo; Gutierrez, Joanne; Drayna, Dennis] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Park, John] NINDS, NIH, Bethesda, MD 20892 USA. [Domingues, Carlos F.; Moretti-Ferreira, Danilo] Sao Paulo State Univ UNESP, Inst Biosci, Dept Genet, Botucatu, SP, Brazil. RP Drayna, D (reprint author), NIDCD, NIH, 5 Res Court,Room 2B-46, Rockville, MD 20850 USA. EM drayna@nidcd.nih.gov OI FRIGERIO DOMINGUES, CARLOS EDUARDO/0000-0002-0598-4956; Moretti-Ferreira, Danilo/0000-0002-9256-7623 FU NIDCD [Z01-000046-13]; NINDS [1ZIANS003124] FX We thank the National Disease Research Interchange for providing normal human brain samples, and the stuttering subjects who participated in this study. We thank Rachel Rahn for assistance with DNA sequencing, and Drs. Thomas Friedman and Robert Morell for helpful comments on the manuscript. This research was supported by NIDCD intramural grant # Z01-000046-13 and by the NINDS (1ZIANS003124). NR 44 TC 4 Z9 4 U1 2 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD SEP PY 2014 VL 69 BP 23 EP 31 DI 10.1016/j.nbd.2014.04.019 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AM0ME UT WOS:000339538900003 PM 24807205 ER PT J AU Costa, VD Averbeck, BB AF Costa, Vincent D. Averbeck, Bruno B. TI VALUE DRIVEN MODULATION OF SACCADE-BASED PROBABILISTIC DECISION MAKING SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 54h Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 10-14, 2014 CL Atlanta, GA SP Soc Psychophysiol Res C1 [Costa, Vincent D.; Averbeck, Bruno B.] NIMH, Unit Learning & Decis Making, Neuropsychol Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2014 VL 51 SU 1 SI SI BP S8 EP S8 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA AL9RX UT WOS:000339479500044 ER PT J AU Engelmann, JM Versace, F Gewirtz, JC Cuthbert, BN Cinciripini, PM AF Engelmann, Jeffrey M. Versace, Francesco Gewirtz, Jonathan C. Cuthbert, Bruce N. Cinciripini, Paul M. TI INDIVIDUAL DIFFERENCES IN BRAIN RESPONSES TO CIGARETTE-RELATED CUES AND PLEASANT STIMULI IN YOUNG SMOKERS SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 54h Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 10-14, 2014 CL Atlanta, GA SP Soc Psychophysiol Res DE smoking; late positive potential; cue reactivity C1 [Engelmann, Jeffrey M.; Versace, Francesco; Cinciripini, Paul M.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Gewirtz, Jonathan C.] Univ Minnesota, Minneapolis, MN 55455 USA. [Cuthbert, Bruce N.] NIMH, Bethesda, MD USA. RI Cinciripini, Paul/I-5773-2012 OI Cinciripini, Paul/0000-0003-2877-9928 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2014 VL 51 SU 1 SI SI MA 2-11 BP S32 EP S32 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA AL9RX UT WOS:000339479500174 ER PT J AU Lu, HB Jenkins, BG Stein, EA AF Lu, Hanbing Jenkins, Bruce G. Stein, Elliot A. TI Introduction to the special issue on neuroimaging in neuropharmacology SO NEUROPHARMACOLOGY LA English DT Editorial Material C1 [Lu, Hanbing; Stein, Elliot A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, NIH, Bethesda, MD 20852 USA. [Jenkins, Bruce G.] Harvard Univ, Sch Med, MGH Martinos Ctr Biomed Imaging, Cambridge, MA 02138 USA. [Jenkins, Bruce G.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. RP Lu, HB (reprint author), Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, NIH, Bethesda, MD 20852 USA. EM luha@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2014 VL 84 SI SI BP 63 EP 64 DI 10.1016/j.neuropharm.2014.05.017 PG 2 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AK7OC UT WOS:000338616600007 PM 24859606 ER PT J AU Mandeville, JB Liu, CH Vanduffel, W Marota, JJA Jenkins, BG AF Mandeville, Joseph B. Liu, Christina H. Vanduffel, Wim Marota, John J. A. Jenkins, Bruce G. TI Data collection and analysis strategies for phMRI SO NEUROPHARMACOLOGY LA English DT Article DE phMRI; fMRI; General linear model; Remifentanil; Dopamine; PET/MRI ID CEREBRAL BLOOD-VOLUME; INDEPENDENT COMPONENT ANALYSIS; EXOGENOUS CONTRAST AGENT; HUMAN BRAIN ACTIVITY; EVENT-RELATED FMRI; PHARMACOLOGICAL MRI; SPIN-ECHO; DOPAMINE CONCENTRATION; SPATIAL NORMALIZATION; TEMPORAL RESPONSES AB Although functional MRI traditionally has been applied mainly to study changes in task-induced brain function, evolving acquisition methodologies and improved knowledge of signal mechanisms have increased the utility of this method for studying responses to pharmacological stimuli, a technique often dubbed "phMRI". The proliferation of higher magnetic field strengths and the use of exogenous contrast agent have boosted detection power, a critical factor for successful phMRI due to the restricted ability to average multiple stimuli within subjects. Receptor-based models of neurovascular coupling, including explicit pharmacological models incorporating receptor densities and affinities and data-driven models that incorporate weak biophysical constraints, have demonstrated compelling descriptions of phMRI signal induced by dopaminergic stimuli. This report describes phMRI acquisition and analysis methodologies, with an emphasis on data-driven analyses. As an example application, statistically efficient data-driven regressors were used to describe the biphasic response to the mu-opioid agonist remifentanil, and antagonism using dopaminergic and GABAergic ligands revealed modulation of the mesolimbic pathway. Results illustrate the power of phMRI as well as our incomplete understanding of mechanisms underlying the signal. Future directions are discussed for phMRI acquisitions in human studies, for evolving analysis methodologies, and for interpretative studies using the new generation of simultaneous PET/MRI scanners. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Mandeville, Joseph B.; Vanduffel, Wim; Marota, John J. A.; Jenkins, Bruce G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Liu, Christina H.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20817 USA. RP Mandeville, JB (reprint author), Martinos Ctr Biomed Imaging, Suite 2301,Bldg 149,13th St, Charlestown, MA 02129 USA. EM jbm@nmr.mgh.harvard.edu OI Vanduffel, Wim/0000-0002-9399-343X; Liu, Christina/0000-0002-5723-177X FU NIH [P41RR14075, P20DA026002, R01-EB001782] FX This research was supported by NIH grants P41RR14075, P20DA026002, and R01-EB001782. NR 95 TC 2 Z9 2 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2014 VL 84 SI SI BP 65 EP 78 DI 10.1016/j.neuropharm.2014.02.018 PG 14 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AK7OC UT WOS:000338616600008 PM 24613447 ER PT J AU Lu, HB Stein, EA AF Lu, Hanbing Stein, Elliot A. TI Resting state functional connectivity: Its physiological basis and application in neuropharmacology SO NEUROPHARMACOLOGY LA English DT Review DE Functional connectivity; Spontaneous fluctuation; Nicotine; Cocaine; Vasomotion ID LOW-FREQUENCY FLUCTUATIONS; DEFAULT-MODE NETWORK; INDEPENDENT COMPONENT ANALYSIS; SIMULTANEOUS EEG-FMRI; MONKEY VISUAL-CORTEX; ECHO-PLANAR MRI; HUMAN BRAIN; RAT-BRAIN; CINGULATE CORTEX; MOTOR CORTEX AB Brain structures do not work in isolation; their work in concert to produce sensory perception, motivation and behavior. Systems-level network activity can be investigated by resting state magnetic resonance imaging (rsMRI), an emerging neuroimaging technique that assesses the synchrony of the brain's ongoing spontaneous activity. Converging evidence reveals that rsMRI is able to consistently identify distinct spatiotemporal patterns of large-scale brain networks. Dysregulation within and between these networks has been implicated in a number of neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease and drug addiction. Despite wide application of this approach in systems neuroscience, the physiological basis of these fluctuations remains incompletely understood. Here we review physiological studies in electrical, metabolic and hemodynamic fluctuations that are most pertinent to the rsMRI signal. We also review recent applications to neuropharmacology - specifically drug effects on resting state fluctuations. We speculate that the mechanisms governing spontaneous fluctuations in regional oxygenation availability likely give rise to the observed rsMRI signal. We conclude by identifying several open questions surrounding this technique. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. Published by Elsevier Ltd. C1 [Lu, Hanbing; Stein, Elliot A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lu, HB (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Neuroimaging Res Branch, 251 Bayview Blvd,Suite 200,RM7A514, Baltimore, MD 21224 USA. EM luha@mail.nih.gov FU NIDA Intramural Research Program of NIH FX This work is supported by the NIDA Intramural Research Program of NIH. NR 165 TC 16 Z9 16 U1 7 U2 61 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2014 VL 84 SI SI BP 79 EP 89 DI 10.1016/j.neuropharm.2013.08.023 PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AK7OC UT WOS:000338616600009 PM 24012656 ER PT J AU Bjork, JM Gilman, JM AF Bjork, James M. Gilman, Jodi M. TI The effects of acute alcohol administration on the human brain: Insights from neuroimaging SO NEUROPHARMACOLOGY LA English DT Review DE Alcohol; Neuroimaging; fMRI; Positron Emission Tomography; Addiction ID CEREBRAL-BLOOD-FLOW; MAGNETIC-RESONANCE-SPECTROSCOPY; TERM ABSTINENT ALCOHOLICS; CENTRAL-NERVOUS-SYSTEM; CORTICAL GRAY-MATTER; GLUCOSE-METABOLISM; DOPAMINE RELEASE; DECISION-MAKING; FUNCTIONAL CONNECTIVITY; DETOXIFIED ALCOHOLICS AB Over the last quarter century, researchers have peered into the living human brain to develop and refine mechanistic accounts of alcohol-induced behavior, as well as neurobiological mechanisms for development and maintenance of addiction. These in vivo neuroimaging studies generally show that acute alcohol administration affects brain structures implicated in motivation and behavior control, and that chronic intoxication is correlated with structural and functional abnormalities in these same structures, where some elements of these decrements normalize with extended sobriety. In this review, we will summarize recent findings about acute human brain responses to alcohol using neuroimaging techniques, and how they might explain behavioral effects of alcohol intoxication. We then briefly address how chronic alcohol intoxication (as inferred from cross-sectional differences between various drinking populations and controls) may yield individual brain differences between drinking subjects that may confound interpretation of acute alcohol administration effects. This article is part of the Special Issue Section entitled Neuroimaging in Neuropharmacology'. Published by Elsevier Ltd. C1 [Bjork, James M.] NIDA, Div Clin Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. [Gilman, Jodi M.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, MGH Div Psychiat Neurosci, Lab Neuroimaging & Genet, Boston, MA 02114 USA. RP Bjork, JM (reprint author), NIDA, Div Clin Neurosci & Behav Res, NIH, 6001 Executive Blvd,Room 3163, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU National Institute on Alcohol Abuse and Alcoholism FX We are indebted to the training, fellowship, and inspiration of our former mentor, Dr. Daniel W. Hommer. Cited original research performed by the authors was funded by intramural funding of the National Institute on Alcohol Abuse and Alcoholism. NR 121 TC 14 Z9 16 U1 6 U2 46 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2014 VL 84 SI SI BP 101 EP 110 DI 10.1016/j.neuropharm.2013.07.039 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AK7OC UT WOS:000338616600011 PM 23978384 ER PT J AU Jasinska, AJ Zorick, T Brody, AL Stein, EA AF Jasinska, Agnes J. Zorick, Todd Brody, Arthur L. Stein, Elliot A. TI Dual role of nicotine in addiction and cognition: A review of neuroimaging studies in humans SO NEUROPHARMACOLOGY LA English DT Review DE Nicotine; Tobacco; Smoking; Dopamine; PET; SPECT; fMRI; Addiction; Cognition ID CEREBRAL-BLOOD-FLOW; STRIATAL DOPAMINE RELEASE; ACETYLCHOLINE-RECEPTOR OCCUPANCY; STATE FUNCTIONAL CONNECTIVITY; POSITRON-EMISSION-TOMOGRAPHY; WORKING-MEMORY TASK; HUMAN-BRAIN; SMOKING-CESSATION; CIGARETTE-SMOKING; TOBACCO SMOKERS AB Substantial evidence demonstrates both nicotine's addiction liability and its cognition-enhancing effects. However, the neurobiological mechanisms underlying nicotine's impact on brain function and behavior remain incompletely understood. Elucidation of these mechanisms is of high clinical importance and may lead to improved therapeutics for smoking cessation as well as for a number of cognitive disorders such as schizophrenia. Neuroimaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPEC), and functional magnetic resonance imaging (fMRI), which make it possible to study the actions of nicotine in the human brain in vivo, play an increasingly important role in identifying these dual mechanisms of action. In this review, we summarize the current state of knowledge and discuss outstanding questions and future directions in human neuroimaging research on nicotine and tobacco. This research spans from receptor-level PET and SPECT studies demonstrating nicotine occupancy at nicotinic acetylcholine receptors (nAChRs) and upregulation of nAChRs induced by chronic smoking; through nicotine's interactions with the mesocorticolimbic dopamine system believed to mediate nicotine's reinforcing effects leading to dependence; to functional activity and connectivity fMRI studies documenting nicotine's complex behavioral and cognitive effects manifest by its actions on large-scale brain networks engaged both during task performance and at rest. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. Published by Elsevier Ltd. C1 [Jasinska, Agnes J.; Stein, Elliot A.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Zorick, Todd; Brody, Arthur L.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90095 USA. [Zorick, Todd; Brody, Arthur L.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Jasinska, AJ (reprint author), NIDA, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jasinskaaj@mail.nih.gov; abrody@ucla.edu; EStein@intra.nida.nih.gov FU Intramural Research Program of NIDA; National Institute on Drug Abuse [R01 DA20872]; Tobacco-Related Disease Research Program [19XT-0135]; Merit Review Award from the Department of Veterans Affairs, Office of Research and Development FX Supported by the Intramural Research Program of NIDA (E.A.S., NJ.) and grants R01 DA20872 from the National Institute on Drug Abuse (A.L.B.), 19XT-0135 from the Tobacco-Related Disease Research Program (A.L.B.), and a Merit Review Award from the Department of Veterans Affairs, Office of Research and Development (A.L.B.). NR 156 TC 24 Z9 27 U1 5 U2 55 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2014 VL 84 SI SI BP 111 EP 122 DI 10.1016/j.neuropharm.2013.02.015 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AK7OC UT WOS:000338616600012 PM 23474015 ER PT J AU Fitzgerald, PJ Whittle, N Flynn, SM Graybeal, C Pinard, CR Gunduz-Cinar, O Kravitz, AV Singewald, N Holmes, A AF Fitzgerald, Paul J. Whittle, Nigel Flynn, Shaun M. Graybeal, Carolyn Pinard, Courtney R. Gunduz-Cinar, Ozge Kravitz, Alexxai V. Singewald, Nicolas Holmes, Andrew TI Prefrontal single-unit firing associated with deficient extinction in mice SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE Fear extinction; Retrieval; C57BL/6J; 129E1/SvImJ; Picrotoxin; Fluoxetine; Infralimbic cortex; Prelimbic cortex ID MEDIATED FEAR EXTINCTION; GENETIC MOUSE MODEL; INFRALIMBIC CORTEX; CONDITIONED FEAR; BASOLATERAL AMYGDALA; GAMMA OSCILLATIONS; NEURONAL CIRCUITS; MEMORY; STRESS; ACTIVATION AB The neural circuitry mediating fear extinction has been increasingly well studied and delineated. The rodent infralimbic subregion (IL) of the ventromedial prefrontal cortex (vmPFC) has been found to promote extinction, whereas the prelimbic cortex (PL) demonstrates an opposing, pro-fear, function. Studies employing in vivo electrophysiological recordings have observed that while increased IL single-unit firing and bursting predicts robust extinction retrieval, increased PL firing can correlate with sustained fear and poor extinction. These relationships between single-unit firing and extinction do not hold under all experimental conditions, however. In the current study, we further investigated the relationship between vmPFC and PL single-unit firing and extinction using inbred mouse models of intact (C57BL/6J, B6) and deficient (129S1/SvImJ, S1) extinction strains. Simultaneous single-unit recordings were made in the PL and vmPFC (encompassing IL) as B6 and S1 mice performed extinction training and retrieval. Impaired extinction retrieval in S1 mice was associated with elevated PL single-unit firing, as compared to firing in extinguishing 86 mice, consistent with the hypothesized pro-fear contribution of PL Analysis of local field potentials also revealed significantly higher gamma power in the PL of S1 than B6 mice during extinction training and retrieval. In the vmPFC, impaired extinction in Si mice was also associated with exaggerated single-unit firing, relative to B6 mice. This is in apparent contradiction to evidence that IL activity promotes extinction, but could reflect a (failed) compensatory effort by the vmPFC to mitigate fear-promoting activity in other regions, such as the PL or amygdala. In support of this hypothesis, augmenting IL activity via direct infusion of the GABA(A) receptor antagonist picrotoxin rescued impaired extinction retrieval in S1 mice. Chronic fluoxetine treatment produced modest reductions in fear during extinction retrieval and increased the number of Zif268-labeled cells in layer II of IL, but failed to increase vmPFC single-unit firing. Collectively, these findings further support the important contribution these cortical regions play in determining the balance between robust extinction on the one hand, and sustained fear on the other. Elucidating the precise nature of these roles could help inform understanding of the pathophysiology of fear-related anxiety disorders. Published by Elsevier Inc. C1 [Fitzgerald, Paul J.; Flynn, Shaun M.; Graybeal, Carolyn; Pinard, Courtney R.; Gunduz-Cinar, Ozge; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20892 USA. [Whittle, Nigel; Singewald, Nicolas] Univ Innsbruck, Inst Pharm, Dept Pharmacol & Toxicol, A-6020 Innsbruck, Austria. [Whittle, Nigel; Singewald, Nicolas] Univ Innsbruck, CMBI, A-6020 Innsbruck, Austria. [Kravitz, Alexxai V.] NIDDKD, NIH, Bethesda, MD USA. RP Fitzgerald, PJ (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20892 USA. EM pfitz@mbi.mb.jhu.edu FU National Institute on Alcohol Abuse and Alcoholism; Austrian Science Fund [SFB F4410-B19] FX We are grateful to Dr. Cara Wellman for valuable comments. Research supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program and the Austrian Science Fund (SFB F4410-B19). NR 58 TC 18 Z9 18 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 EI 1095-9564 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD SEP PY 2014 VL 113 BP 69 EP 81 DI 10.1016/j.nlm.2013.11.002 PG 13 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AJ6DR UT WOS:000337780400009 PM 24231425 ER PT J AU Bush, A AF Bush, Andrew TI GRANT APPLICATION WRITING FOR NOVICES SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Bush, Andrew] Imperial Coll, London, England. [Bush, Andrew] Natl Heart & Lung Inst, Bethesda, MD USA. EM a.bush@imperial.ac.uk NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD SEP PY 2014 VL 49 SU 37 BP S43 EP S44 PG 2 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA AJ9DE UT WOS:000338006200041 ER PT J AU Bush, A AF Bush, Andrew TI EVIDENCE BASED MANAGEMENT OF VIRAL INDUCED WHEEZE IN THE YOUNG SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract ID PRESCHOOL-CHILDREN C1 [Bush, Andrew] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Bush, Andrew] Natl Heart & Lung Inst, Bethesda, MD USA. EM a.bush@imperial.ac.uk NR 5 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD SEP PY 2014 VL 49 SU 37 BP S11 EP S12 PG 2 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA AJ9DE UT WOS:000338006200012 ER PT J AU Bush, A AF Bush, Andrew TI PAEDIATRIC PULMONOLOGY: YEAR IN REVIEW SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract ID TUBERCULOSIS; CHILDREN; PRETERM; ASTHMA; BURDEN; BIRTHS C1 [Bush, Andrew] Natl Heart & Lung Inst, Bethesda, MD USA. [Bush, Andrew] Royal Brompton Harefield NHS Fdn Trust, London, England. EM a.bush@imperial.ac.uk NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD SEP PY 2014 VL 49 SU 37 BP S2 EP S3 PG 2 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA AJ9DE UT WOS:000338006200003 ER PT J AU Chen, L Yuan, A Liu, AY Chen, GJ AF Chen, Le Yuan, Ao Liu, Aiyi Chen, Guanjie TI Longitudinal data analysis using Bayesian-frequentist hybrid random effects model SO JOURNAL OF APPLIED STATISTICS LA English DT Article DE hybrid; longitudinal data; simulation AB The mixed random effect model is commonly used in longitudinal data analysis within either frequentist or Bayesian framework. Here we consider a case, in which we have prior knowledge on partial parameters, while no such information on the rest of the parameters. Thus, we use the hybrid approach on the random-effects model with partial parameters. The parameters are estimated via Bayesian procedure, and the rest of parameters by the frequentist maximum likelihood estimation (MLE), simultaneously on the same model. In practice, we often know partial prior information such as, covariates of age, gender, etc. These information can be used, and accurate estimations in mixed random-effects model can be obtained. A series of simulation studies were performed to compare the results with the commonly used random-effects model with and without partial prior information. The results in hybrid estimation (HYB) and MLE were very close to each other. The estimated values in with partial prior information model (HYB) were more closer to true values, and showed less variances than without partial prior information in MLE. To compare with true values, the mean square of errors are much less in HYB than in MLE. This advantage of HYB is very obvious in longitudinal data with a small sample size. The methods of HYB and MLE are applied to a real longitudinal data for illustration purposes. C1 [Chen, Le; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, BBB, DIPHR, NIH, Bethesda, MD USA. [Yuan, Ao] Georgetown Univ, Dept Biostat Bioinformat & Biomath, Washington, DC USA. [Chen, Guanjie] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Chen, GJ (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM chengu@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU Intramural NIH HHS [Z99 HG999999] NR 11 TC 0 Z9 0 U1 0 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0266-4763 EI 1360-0532 J9 J APPL STAT JI J. Appl. Stat. PD SEP PY 2014 VL 41 IS 9 BP 2001 EP 2010 DI 10.1080/02664763.2014.898137 PG 10 WC Statistics & Probability SC Mathematics GA AH8ER UT WOS:000336368300009 PM 25143663 ER PT J AU Park, JW Piknova, B Nghiem, K Lozier, JN Schechter, AN AF Park, J. W. Piknova, B. Nghiem, K. Lozier, J. N. Schechter, A. N. TI Inhibitory effect of nitrite on coagulation processes demonstrated by thrombelastography SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Nitric oxide; Nitrites; Hypoxia; Platelet; Erythrocytes; Thrombelastography ID HUMAN-PLATELET-AGGREGATION; DIETARY NITRATE; RELAXING FACTOR; IN-VITRO; HYPOXIC CONDITIONS; RED-CELL; OXIDE; BLOOD; THROMBOELASTOGRAPHY; REDUCTION AB Nitric oxide (NO) can be generated by two-step reduction pathway in which nitrate is converted first into nitrite and then into NO via several mechanisms, as well as from arginine by endogenous nitric oxide synthase (NOS). We have recently shown that nitrite ions in the presence of erythrocytes inhibit platelet aggregation and activation, as measured by aggregometry and flow cytometric analysis of P-selectin, through its reduction to NO under partially deoxygenated conditions. In the current study, we investigated how nitrite may affect overall clotting processes via modulating platelet function using thrombe-lastography (TEG). We measured three major TEG parameters, reaction time (R, time to initial fibrin formation), alpha angle (velocity of clot growth) and maximum amplitude (MA, maximum clot strength) using blood from healthy volunteers. An NO donor (DEANONOate) showed inhibitory effects on all TEG parameters in platelet rich plasma (PRP) and whole blood, resulting in delayed R, decreased angle, and reduced MA in a dose dependent manner. Nitrite ions also exhibited inhibitory effects in whole blood at 20% hematocrit, and this was greatly enhanced under hypoxic conditions, being demonstrable at 0.1 mu M concentration. Neither compound changed any TEG parameters in plasma. Our results suggest that nitrite affects overall blood clotting and that TEG may be used to follow this process. Further the physiological effects of factors which determine NO bioavailability, such as endogenous levels of blood and tissue nitrite, may be useful as biomarkers for predicting hemostatic potential. Published by Elsevier Inc. C1 [Park, J. W.; Piknova, B.; Schechter, A. N.] Natl Inst Diabet & Digest & Kidney Dis, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Nghiem, K.; Lozier, J. N.] NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Mol Med Branch, NIH, 10 Ctr Dr,9N314, Bethesda, MD 20892 USA. EM alans@intra.niddk.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 FU Intramural NIH HHS [ZIA DK025104-07] NR 34 TC 5 Z9 5 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 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG 31 PY 2014 VL 40 BP 45 EP 51 DI 10.1016/j.niox.2014.05.006 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN6JQ UT WOS:000340701200007 PM 24858214 ER PT J AU Rifkind, JM Nagababu, E Dobrosielski, DA Salgado, MT Lima, M Ouyang, P Silber, HA AF Rifkind, Joseph M. Nagababu, Enika Dobrosielski, Devon A. Salgado, Maria T. Lima, Michael Ouyang, Pamela Silber, Harry A. TI The effect of intermittent pneumatic compression of legs on the levels of nitric oxide related species in blood and on arterial function in the arm SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Intermittent pneumatic compression; Nitric oxide; Nitrite; Flow mediated dilation; Low-flow mediated constriction; Occlusion-mediated constriction ID ENDOTHELIAL FUNCTION; HYPOXIC VASODILATION; HEALTHY-VOLUNTEERS; FOOT COMPRESSION; CALF COMPRESSION; WALKING ABILITY; BRACHIAL-ARTERY; S-NITROSOTHIOLS; REDUCED SHEAR; FOLLOW-UP AB Background: Intermittent pneumatic compression (IPC) of legs exerts beneficial local vascular effects, possibly through local release of nitric oxide (NO). However, studies demonstrating systemic transport of nitrogen oxide species and release of NO prompt the question of whether IPC could also exert nonlocal effects. We tested whether IPC (1) affects systemic levels of nitrite, S-nitrosothiols and red blood cell (RBC) NO, and (2) exerts vasoactive effects in the brachial artery (BA), although this hypothesis-generating pilot study did not investigate cause and effect relationship between (1) and (2). Methods: In 10 healthy subjects, ages 24-39 years, we measured plasma nitrite, plasma S-nitrosothiols and RBC-NO from venous blood samples drawn before and after IPC treatment. We also measured BA responses to 5 min of upper arm occlusion at rest and duringl h of leg IPC. Results: There was a significant decrease in plasma nitrite (112 +/- 26 nM to 90 +/- 15 nM, p = 0.0008) and RBC-NO (129 +/- 72 nM to 102 +/- 41 nM, p = 0.02). Plasma S-nitrosothiols were unchanged (5.79 +/- 4.81 nM to 6.27 +/- 5.79 nM, p = 0.3). BA occlusion-mediated constriction (OMC) was significantly attenuated with IPC treatment (-43 +/- 13% to -33 +/- 12%, p = 0.003). High-flow mediated BA dilation was unchanged (13.3 +/- 9.4% to 11.5 +/- 7.2%, p = 0.2). Conclusion: Plasma nitrite, RBC-NO, and BA OMC decreased with leg IPC. We hypothesize that this decrease in circulatory pool of plasma nitrite and RBC-NO may result from the transfer of their NO-bioactivity from blood to the hypoxic arm tissue, to be stored and released under hypoxic stress and oppose OMC. Future studies should investigate whether IPC-induced decreases in brachial OMC are caused by the changes in systemic NO activity, and whether leg IPC could benefit distant arterial function in systemic cardiovascular disease. (C) 2014 Published by Elsevier Inc. C1 [Lima, Michael; Ouyang, Pamela; Silber, Harry A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21224 USA. [Rifkind, Joseph M.; Nagababu, Enika; Salgado, Maria T.] NIA, Mol Dynam Sect, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Dobrosielski, Devon A.] Towson Univ, Dept Kinesiol, Towson, MD 21252 USA. RP Silber, HA (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Suite 2400,301 Bldg,4940 Eastern Ave, Baltimore, MD 21224 USA. EM rifkindj@grc.nia.nih.gov; nenika1@jhmi.edu; ddobrosielski@towson.edu; salgadomt@yahoo.com; michaeljdlima@gmail.com; pouyang@jhmi.edu; hsilber@jhmi.edu FU Johns Hopkins Cardiology Division; Intramural Research Program of the NIH, National Institutes of Aging; National Center for Research Resources (NCRR) [UL1 RR 025005]; National Institutes of Health (NIH); NIH Roadmap for Medical Research FX The authors gratefully acknowledge Sandra Lima for acquiring the ultrasound images, and ACI Medical for providing the ArtAssist Intermittent Pneumatic Compression devices. This research was supported in part by the Johns Hopkins Cardiology Division and by the Intramural Research Program of the NIH, National Institutes of Aging. This work was also made possible by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroad-map.nih.gov/clinical research/overview-translational.asp. NR 50 TC 1 Z9 1 U1 3 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG 31 PY 2014 VL 40 BP 117 EP 122 DI 10.1016/j.niox.2014.06.007 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN6JQ UT WOS:000340701200017 PM 24973574 ER PT J AU Emenaker, NJ Zudaire, E Croix, BS AF Emenaker, Nancy J. Zudaire, Enrique Croix, Brad St. TI Chemoprevention of metastasis SO ONCOTARGET LA English DT Editorial Material ID COLORECTAL-CANCER; ASPIRIN C1 [Croix, Brad St.] NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. RP Croix, BS (reprint author), NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. EM stcroix@ncifcrf.gov NR 7 TC 1 Z9 1 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 30 PY 2014 VL 5 IS 16 BP 6556 EP 6557 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ0EX UT WOS:000347920100003 PM 25179303 ER PT J AU Feldinger, K Generali, D Kramer-Marek, G Gijsen, M Ng, TB Wong, JH Strina, C Cappelletti, M Andreis, D Li, JL Bridges, E Turley, H Leek, R Roxanis, I Capala, J Murphy, G Harris, AL Kong, A AF Feldinger, Katharina Generali, Daniele Kramer-Marek, Gabriela Gijsen, Merel Ng, Tzi Bun Wong, Jack Ho Strina, Carla Cappelletti, Mariarosa Andreis, Daniele Li, Ji-Liang Bridges, Esther Turley, Helen Leek, Russell Roxanis, Ioannis Capala, Jacek Murphy, Gillian Harris, Adrian L. Kong, Anthony TI ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer SO ONCOTARGET LA English DT Article DE Trastuzumab; resistance; ADAM10; HER2; survival ID EPIDERMAL-GROWTH-FACTOR; CELL-CELL ADHESION; ADJUVANT CHEMOTHERAPY; MONOCLONAL-ANTIBODY; FACTOR RECEPTOR; ACTIVATION; EXPRESSION; INHIBITION; EFFICACY; CLEAVAGE AB Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p <= 0.001 in BT474; p <= 0.01 in SKBR3) and in vivo (p <= 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naive and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p <= 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p <= 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p <= 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients. C1 [Feldinger, Katharina; Gijsen, Merel; Kong, Anthony] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Human Epidermal Growth Factor Grp,Dept Oncol, Oxford OX3 9DU, England. [Li, Ji-Liang; Bridges, Esther; Turley, Helen; Leek, Russell; Harris, Adrian L.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Growth Factor Grp,Dept Oncol, Oxford OX3 9DU, England. [Generali, Daniele; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele] AO Inst Ospitalieri Cremona, US Terapia Mol & Farmacogenom, UO Multidisciplinare Patol Mammaria, Cremona, Italy. [Kramer-Marek, Gabriela; Capala, Jacek] NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Ng, Tzi Bun; Wong, Jack Ho] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Roxanis, Ioannis] Oxford Univ Hosp, Dept Cellular Pathol, Oxford, England. [Roxanis, Ioannis] Oxford Biomed Res Ctr, Oxford, England. [Murphy, Gillian] Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Cambridge, England. RP Kong, A (reprint author), Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Human Epidermal Growth Factor Grp,Dept Oncol, Oxford OX3 9DU, England. EM anthony.kong@oncology.ox.ac.uk RI Andreis, Daniele/J-8333-2016; OI Andreis, Daniele/0000-0001-6686-5662; Harris, Adrian/0000-0003-1376-8409 FU Breakthrough Breast Cancer Clinician Scientist Fellowship through Holbeck Charitable trust; Cancer Research UK; Oxford Biomedical Research Centre; Oxford Experimental Cancer Medicine Centre; Oxford Cancer Research Centre; ARCO onlus, Cremona, Italy; Imaging Probe Development Center, National Heart, Lung, and Blood Institute; Breast Cancer Research Stamp Fund; National Cancer Institute; National Institutes of Health FX This work was supported by Breakthrough Breast Cancer Clinician Scientist Fellowship through Holbeck Charitable trust. Other UK funders include Cancer Research UK, Oxford Biomedical Research Centre, Oxford Experimental Cancer Medicine Centre, and Oxford Cancer Research Centre. The Italian co-authors are funded by ARCO onlus, Cremona, Italy. The US coauthors are supported by the Imaging Probe Development Center, National Heart, Lung, and Blood Institute; the Breast Cancer Research Stamp Fund, the National Cancer Institute, and the National Institutes of Health. NR 49 TC 18 Z9 19 U1 0 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 30 PY 2014 VL 5 IS 16 BP 6633 EP 6646 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ0EX UT WOS:000347920100012 PM 24952873 ER PT J AU Ng, M Fleming, T Robinson, M Thomson, B Graetz, N Margono, C Mullany, EC Biryukov, S Abbafati, C Abera, SF Abraham, JP Abu-Rmeileh, NME Achoki, T AlBuhairan, FS Alemu, ZA Alfonso, R Ali, MK Ali, R Guzman, NA Ammar, W Anwari, P Banerjee, A Barquera, S Basu, S Bennett, DA Bhutta, Z Blore, J Cabral, N Nonato, IC Chang, JC Chowdhury, R Courville, KJ Criqui, MH Cundiff, DK Dabhadkar, KC Dandona, L Davis, A Dayama, A Dharmaratne, SD Ding, EL Durrani, AM Esteghamati, A Farzadfar, F Fay, DFJ Feigin, VL Flaxman, A Forouzanfar, MH Goto, A Green, MA Gupta, R Hafezi-Nejad, N Hankey, GJ Harewood, HC Havmoeller, R Hay, S Hernandez, L Husseini, A Idrisov, BT Ikeda, N Islami, F Jahangir, E Jassal, SK Jee, SH Jeffreys, M Jonas, JB Kabagambe, EK Khalifa, SEAH Kengne, AP Khader, YS Khang, YH Kim, D Kimokoti, RW Kinge, JM Kokubo, Y Kosen, S Kwan, G Lai, T Leinsalu, M Li, YC Liang, XF Liu, SW Logroscino, G Lotufo, PA Lu, Y Ma, JX Mainoo, NK Mensah, GA Merriman, TR Mokdad, AH Moschandreas, J Naghavi, M Naheed, A Nand, D Narayan, KMV Nelson, EL Neuhouser, ML Nisar, MI Ohkubo, T Oti, SO Pedroza, A Prabhakaran, D Roy, N Sampson, U Seo, H Sepanlou, SG Shibuya, K Shiri, R Shiue, I Singh, GM Singh, JA Skirbekk, V Stapelberg, NJC Sturua, L Sykes, BL Tobias, M Tran, BX Trasande, L Toyoshima, H van de Vijver, S Vasankari, TJ Veerman, JL Velasquez-Melendez, G Vlassov, VV Vollset, SE Vos, T Wang, C Wang, XR Weiderpass, E Werdecker, A Wright, JL Yang, YC Yatsuya, H Yoon, J Yoon, SJ Zhao, Y Zhou, MG Zhu, SK Lopez, AD Murray, CJL Gakidou, E AF Ng, Marie Fleming, Tom Robinson, Margaret Thomson, Blake Graetz, Nicholas Margono, Christopher Mullany, Erin C. Biryukov, Stan Abbafati, Cristiana Abera, Semaw Ferede Abraham, Jerry P. Abu-Rmeileh, Niveen M. E. Achoki, Tom AlBuhairan, Fadia S. Alemu, Zewdie A. Alfonso, Rafael Ali, Mohammed K. Ali, Raghib Alvis Guzman, Nelson Ammar, Walid Anwari, Palwaslia Banerjee, Amitava Barquera, Simon Basu, Sanjay Bennett, Derrick A. Bhutta, Zulfiqar Blore, Jed Cabral, Norberto Campos Nonato, Ismael Chang, Jung-Chen Chowdhury, Rajiv Courville, Karen J. Criqui, Michael H. Cundiff, David K. Dabhadkar, Kaustubh C. Dandona, Lalit Davis, Adrian Dayama, Anand Dharmaratne, Samath D. Ding, Eric L. Durrani, Adnan M. Esteghamati, Alireza Farzadfar, Farshad Fay, Derek F. J. Feigin, Valery L. Flaxman, Abraham Forouzanfar, Mohammad H. Goto, Atsushi Green, Mark A. Gupta, Rajeev Hafezi-Nejad, Nima Hankey, Graeme J. Harewood, Heather C. Havmoeller, Rasmus Hay, Simon Hernandez, Lucia Husseini, Abdullatif Idrisov, Bulot T. Ikeda, Nayu Islami, Farhad Jahangir, Eiman Jassal, Simerjot K. Jee, Sun Ha Jeffreys, Mona Jonas, Jost B. Kabagambe, Edmond K. Khalifa, Shams Eldin Ali Hassan Kengne, Andre Pascal Khader, Yousef Saleh Khang, Young-Ho Kim, Daniel Kimokoti, Ruth W. Kinge, Jonas M. Kokubo, Yoshihiro Kosen, Soewarta Kwan, Gene Lai, Taavi Leinsalu, Mall Li, Yichong Liang, Xiaofeng Liu, Shiwei Logroscino, Giancarlo Lotufo, Paulo A. Lu, Yuan Ma, Jixiang Mainoo, Nana Kwaku Mensah, George A. Merriman, Tony R. Mokdad, Ali H. Moschandreas, Joanna Naghavi, Mohsen Naheed, Aliya Nand, Devina Narayan, K. M. Venkat Nelson, Erica Leigh Neuhouser, Marian L. Nisar, Muhammad Imran Ohkubo, Takayoshi Oti, Samuel O. Pedroza, Andrea Prabhakaran, Dorai Roy, Nobhojit Sampson, Uchechukwu Seo, Hyeyoung Sepanlou, Sadaf G. Shibuya, Kenji Shiri, Rahman Shiue, Ivy Singh, Gitanjali M. Singh, Jasvinder A. Skirbekk, Vegard Stapelberg, Nicolas J. C. Sturua, Lela Sykes, Bryan L. Tobias, Martin Tran, Bach X. Trasande, Leonardo Toyoshima, Hideaki van de Vijver, Steven Vasankari, Tommi J. Veerman, J. Lennert Velasquez-Melendez, Gustavo Vlassov, Vasiliy Victorovich Vollset, Stein Emil Vos, Theo Wang, Claire Wang, XiaoRong Weiderpass, Elisabete Werdecker, Andrea Wright, Jonathan L. Yang, Y. Claire Yatsuya, Hiroshi Yoon, Jihyun Yoon, Seok-Jon Zhao, Yong Zhou, Maigeng Zhu, Shankuan Lopez, Alan D. Murray, Christopher J. L. Gakidou, Emmanuela TI Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013 SO LANCET LA English DT Article ID BODY-MASS INDEX; PHYSICAL-ACTIVITY; GUT MICROBIOME; UNITED-STATES; 187 COUNTRIES; CARDIOVASCULAR-DISEASE; NUTRITION TRANSITION; RISK-FACTORS; TRENDS; MORTALITY AB Background In 2010, overweight and obesity were estimated to cause 3.4 million deaths, 3.9% of years of life lost, and 3.8% of disability-adjusted life-years (DALYs) worldwide. The rise in obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013. Methods We systematically identified surveys, reports, and published studies (n = 1769) that included data for height and weight, both through physical measurements and self-reports. We used mixed effects linear regression to correct for bias in self-reports. We obtained data for prevalence of obesity and overweight by age, sex, country, and year (n = 19 244) with a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs). Findings Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/m(2) or greater increased between 1980 and 2013 from 28.8% (95% UI 28.4-29.3) to 36.9% (36.3-37.4) in men, and from 29.8% (29.3-30.2) to 38.0% (37.5-38.5) in women. Prevalence has increased substantially in children and adolescents in developed countries; 23.8% (22.9-24.7) of boys and 22.6% (21.7-23.6) of girls were overweight or obese in 2013. The prevalence of overweight and obesity has also increased in children and adolescents in developing countries, from 8.1% (7.7-86) to 12.9% (12.3-13.5) in 2013 for boys and from 8.4% (8.1-8.8) to 13.4% (13.0-13.9) in girls. In adults, estimated prevalence of obesity exceeded 50% in men in Tonga and in women in Kuwait, Kiribati, Federated States of Micronesia, Libya, Qatar, Tonga, and Samoa. Since 2006, the increase in adult obesity in developed countries has slowed down. Interpretation Because of the established health risks and substantial increases in prevalence, obesity has become a major global health challenge. Not only is obesity increasing, but no national success stories have been reported in the past 33 years. Urgent global action and leadership is needed to help countries to more effectively intervene. Funding Bill & Melinda Gates Foundation. C1 [Fleming, Tom; Robinson, Margaret; Thomson, Blake; Graetz, Nicholas; Margono, Christopher; Mullany, Erin C.; Biryukov, Stan; Achoki, Tom; Dandona, Lalit; Flaxman, Abraham; Forouzanfar, Mohammad H.; Mokdad, Ali H.; Naghavi, Mohsen; Nelson, Erica Leigh; Tobias, Martin; Vos, Theo; Murray, Christopher J. L.; Gakidou, Emmanuela] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Wright, Jonathan L.] Univ Washington, Sch Med, Seattle, WA 98121 USA. [Abbafati, Cristiana] Univ Roma La Sapienza, I-00185 Rome, Italy. [Abera, Semaw Ferede] Mekelle Univ, Sch Publ Hlth, Coll Hlth Sci, Mekelle, Ethiopia. [Abraham, Jerry P.] Univ Texas San Antonio, Sch Med, San Antonio, TX USA. [Abu-Rmeileh, Niveen M. E.] Birzeti Univ, Inst Community & Publ Hlth, Ramallah, West Bank, Israel. [Achoki, Tom] Minist Hlth, Gaborone, Botswana. [AlBuhairan, Fadia S.] King Saud bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City, Riyadh, Saudi Arabia. [AlBuhairan, Fadia S.] King Abdullah Int Med Res Ctr, Riyadh, Saudi Arabia. [Alemu, Zewdie A.] Debre Markos Univ, Debre Markos, Ethiopia. [Ali, Mohammed K.; Dabhadkar, Kaustubh C.; Dayama, Anand; Narayan, K. M. Venkat] Emory Univ, Atlanta, GA USA. [Ali, Raghib; Bennett, Derrick A.; Hay, Simon] Univ Oxford, Oxford, England. [Alvis Guzman, Nelson] Univ Cartagena, Cartagena De Indias, Colombia. [Ammar, Walid] Minist Publ Hlth, Beirut, Lebanon. [Anwari, Palwaslia] UNFPA, Kabul, Afghanistan. [Banerjee, Amitava] Univ Birmingham, Birmingham, W Midlands, England. [Barquera, Simon; Campos Nonato, Ismael; Hernandez, Lucia; Pedroza, Andrea] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Basu, Sanjay] Stanford Univ, Stanford, CA 94305 USA. [Bhutta, Zulfiqar; Nisar, Muhammad Imran] Aga Khan Univ, Med Ctr, Karachi, Pakistan. [Blore, Jed; Lopez, Alan D.] Univ Melbourne, Melbourne, Vic, Australia. [Cabral, Norberto] Univ Joinville Univille, Joinville, Brazil. [Chang, Jung-Chen] Natl Taiwan Univ, Taipei 10764, Taiwan. [Chowdhury, Rajiv] Univ Cambridge, Cambridge, England. [Courville, Karen J.] Hosp Dr Gustavo N Collado, Chitre, Herrera, Panama. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Dandona, Lalit] Publ Hlth Fdn India, New Delhi, India. [Davis, Adrian; Fay, Derek F. J.] Publ Hlth England, London, England. [Dharmaratne, Samath D.] Univ Peradeniya, Peradeniya, Sri Lanka. [Ding, Eric L.; Lu, Yuan; Singh, Gitanjali M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mensah, George A.] NHLBI, CTRIS, Bethesda, MD 20892 USA. [Mensah, George A.] NHLBI, CTRIS, Montgomery, MD USA. [Durrani, Adnan M.] NIH, Bethesda, MD 20892 USA. [Durrani, Adnan M.] NIH, Montgomery, MD USA. [Esteghamati, Alireza; Farzadfar, Farshad; Hafezi-Nejad, Nima] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran. [Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Feigin, Valery L.] AUT Univ, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Goto, Atsushi] Natl Ctr Global Hlth & Med, Dept Diabet Res, Tokyo, Japan. [Green, Mark A.] Univ Sheffield, Sheffield, S Yorkshire, England. [Gupta, Rajeev] Fortis Escorts Hosp, Jaipur, Rajasthan, India. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Harewood, Heather C.] Eunice Gibson Polyclin, Bridgetown, Barbados. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Husseini, Abdullatif] Birzeit Univ, Birzeit, Ramallah, Israel. [Idrisov, Bulot T.] Brandeis Univ, Waltham, MA USA. [Ikeda, Nayu] Natl Inst Hlth & Nutr, Tokyo 162, Japan. [Islami, Farhad] Amer Canc Soc, Atlanta, GA 30329 USA. [Jahangir, Eiman] Ochsner Med Ctr, New Orleans, LA USA. [Jassal, Simerjot K.] Univ Calif San Diego, VA San Diego, San Diego, CA 92103 USA. [Jee, Sun Ha] Yonsei Univ, Grad Sch Publ Hlth, Seoul 120749, South Korea. [Jeffreys, Mona] Univ Bristol, Bristol, Avon, England. [Jonas, Jost B.] Heidelberg Univ, Dept Ophthalmol, Med Fac Mannheim, Mannheim, Germany. [Kabagambe, Edmond K.] Vanderbilt Univ, Nashville, TN 37235 USA. [Khalifa, Shams Eldin Ali Hassan] Supreme Council Hlth, Doha, Qatar. [Kengne, Andre Pascal] South African Med Res Council, Cape Town, South Africa. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Alramtha, Jordan. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Inst Hlth Policy & Management, Seoul, South Korea. [Kim, Daniel] Northeastern Univ, Boston, MA 02115 USA. [Kimokoti, Ruth W.] Simmons Coll, Boston, MA 02115 USA. [Kinge, Jonas M.; Skirbekk, Vegard; Vollset, Stein Emil] Norwegian Inst Publ Hlth, Oslo, Norway. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Dept Prevent Med & Epidemiol Informat, Osaka, Japan. [Kosen, Soewarta] NIHRD, Ctr Community Empowerment Hlth Policy& Informat, Jakarta, Indonesia. [Kwan, Gene] Boston Med Ctr, Boston, MA USA. [Lai, Taavi] Fourth View Consulting, Tallinn, Estonia. [Leinsalu, Mall] Natl Inst Hlth Dev, Tallinn, Estonia. [Li, Yichong; Zhou, Maigeng] Natl Ctr Chron Noncommunicable Dis Control & Prev, Beijing, Peoples R China. [Liang, Xiaofeng; Liu, Shiwei; Ma, Jixiang] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Lotufo, Paulo A.] Univ Sao Paulo, Sao Paulo, Brazil. [Mainoo, Nana Kwaku] Xpharmconsult, Kumasi, Ghana. [Merriman, Tony R.] Univ Otago, Dunedin, New Zealand. [Moschandreas, Joanna] Univ Crete, Iraklion, Greece. [Naheed, Aliya] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Nand, Devina] Minist Hlth, Suva, Fiji. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo 173, Japan. [Oti, Samuel O.] African Populat & Hlth Res Ctr, Nairobi, Kenya. [Prabhakaran, Dorai] Ctr Chron Dis Control, New Delhi, India. [Roy, Nobhojit] BARC Hosp, Bombay, Maharashtra, India. [Seo, Hyeyoung] Korea Univ, Dept Publ Hlth, Grad Sch, Seoul, South Korea. [Yoon, Jihyun] Korea Univ, Dept Prevent Med, Seoul, South Korea. [Yoon, Seok-Jon] Korea Univ, Seoul, South Korea. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Shiri, Rahman] Finnish Inst Occupat Hlth, Helsinki, Finland. [Shiue, Ivy] Heriot Watt Univ, Edinburgh, Midlothian, Scotland. [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Stapelberg, Nicolas J. C.] Griffith Univ, Southport, Qld 4215, Australia. [Sturua, Lela] Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. [Sykes, Bryan L.] Univ Calif Irvine, Irvine, CA USA. [Tran, Bach X.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Trasande, Leonardo] NYU, Sch Med, New York, NY USA. [Toyoshima, Hideaki] Anjo Kosei Hosp, Hlth Care Ctr, Anjo City, Japan. [van de Vijver, Steven] African Populat & Hlth Res Ctr, Nairobi, Kenya. [Vasankari, Tommi J.] UKK Inst Hlth Promot Res, Tampere, Finland. [Veerman, J. Lennert] Univ Queensland, Brisbane, Qld, Australia. Univ Fed Minas Gerais, Escola Enfermagem Belo Horizonte, Belo Horizonte, MG, Brazil. [Vlassov, Vasiliy Victorovich] Natl Res Univ, Higher Sch Econ, Moscow, Russia. [Vollset, Stein Emil] Univ Bergen, Bergen, Norway. [Wang, Claire] Columbia Univ, New York, NY USA. [Wang, XiaoRong] Shandong Univ, Jinan Cent Hosp, Jinan 250100, Peoples R China. [Werdecker, Andrea] Inst Med Sociol & Social Med, Marburg, Hessen, Germany. [Yang, Y. Claire] Univ N Carolina, Chapel Hill, NC USA. [Yatsuya, Hiroshi] Fujita Hlth Univ, Toyoake, Aichi, Japan. [Zhao, Yong] Chongqing Med Univ, Chongqing, Peoples R China. [Zhu, Shankuan] Zhejiang Univ, Sch Publ Hlth, Hangzhou 310003, Zhejiang, Peoples R China. RP Gakidou, E (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. EM gakidou@uw.edu RI Davis, Adrian/E-6022-2015; Hankey, Graeme /H-4968-2014; Banerjee, Amitava/D-4381-2014; Sepanlou, Sadaf/H-9343-2016; Jahangir, Eiman/P-1053-2015; LOGROSCINO, GIANCARLO/K-5148-2016; Hay, Simon/F-8967-2015; Weiderpass, Elisabete/M-4029-2016; Lotufo, Paulo/A-9843-2008; OI Kwan, Gene/0000-0002-0929-6800; Goto, Atsushi/0000-0003-0669-654X; Veerman, Lennert/0000-0002-3206-8232; Cundiff, David/0000-0002-3206-9665; Vlassov, Vasiliy/0000-0001-5203-549X; Husseini, Abdullatif/0000-0001-8767-5956; Prabhakaran, Dorairaj/0000-0002-3172-834X; Khang, Young-Ho/0000-0002-9585-8266; Merriman, Tony/0000-0003-0844-8726; Davis, Adrian/0000-0001-7134-7528; Hankey, Graeme /0000-0002-6044-7328; Banerjee, Amitava/0000-0001-8741-3411; Sepanlou, Sadaf/0000-0002-3669-5129; Jahangir, Eiman/0000-0001-6944-5321; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Hay, Simon/0000-0002-0611-7272; Weiderpass, Elisabete/0000-0003-2237-0128; Lotufo, Paulo/0000-0002-4856-8450; Ding, Eric/0000-0002-5881-8097 FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation.r This trial was funded by the Bill & Melinda Gates Foundation. We thank the following individuals for their support of this research: Hideki Higashi, Maziar Moradi-Lakeh, Hmwe Hmwe Kyu, and Matthew Israelson, all from IHME, for their assistance acquiring data for analysis; Gulnoza Usmanova, Hyo Young Lee, and Hoang T Dieu-Hien, for translation of surveys into English; Casey M Graves (IHME) for helping to extract data for analysis. No individuals acknowledged received additional compensation for their efforts. NR 71 TC 1448 Z9 1525 U1 132 U2 545 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 30 PY 2014 VL 384 IS 9945 BP 766 EP 781 DI 10.1016/S0140-6736(14)60460-8 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA AO5DD UT WOS:000341361500037 PM 24880830 ER PT J AU Proschan, MA Dodd, LE AF Proschan, Michael A. Dodd, Lori E. TI A modest proposal for dropping poor arms in clinical trials SO STATISTICS IN MEDICINE LA English DT Article DE comparisons with control; multi-arm multi-stage (MAMS) design; multiple comparisons; family-wise error (FWE) rate; sequentially rejective methods; estimation bias ID MULTIPLE TESTS; DESIGNS; CANCER; OUTCOMES AB This paper presents a simple procedure for clinical trials comparing several arms with control. Demand for streamlining the evaluation of new treatments has led to phase III clinical trials with more arms than would have been used in the past. In such a setting, it is reasonable that some arms may not perform as well as an active control. We introduce a simple procedure that takes advantage of negative results in some comparisons to lessen the required strength of evidence for other comparisons. We evaluate properties analytically and use them to support claims made about multi-arm multi-stage designs. Published 2014. This article is a U. S. Government work and is in the public domain in the USA. C1 [Proschan, Michael A.; Dodd, Lori E.] NIAID, Bethesda, MD 20892 USA. RP Dodd, LE (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM proscham@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 14 TC 3 Z9 3 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2014 VL 33 IS 19 BP 3241 EP 3252 DI 10.1002/sim.6169 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA AL9AE UT WOS:000339430800001 PM 24757049 ER PT J AU Cullen, KR Eberly, LE Heller, MD Schlesinger, A Gold, PW Martinez, PE Klimes-Dougan, B AF Cullen, Kathryn R. Eberly, Lynn E. Heller, Monika D. Schlesinger, Amanda Gold, Phillip W. Martinez, Pedro E. Klimes-Dougan, Bonnie TI Personality disorders in offspring of mothers with mood disorders: Results from a longitudinal family study SO PSYCHIATRY RESEARCH LA English DT Article DE Bipolar; Depression; Personality disorders; Familial risk; Offspring; Development; Mothers ID BIPOLAR DISORDER; ADAPTIVE PERSONALITY; YOUNG-CHILDREN; FOLLOW-UP; PARENTS; TEMPERAMENT; PSYCHOPATHOLOGY; STABILITY; UNIPOLAR; ADOLESCENCE AB Offspring of mothers with mood disorders are known to be at risk for a range of adverse outcomes, but the prevalence of personality disorders (PDs) in this group is unknown. The goal of this study was to assess risk of PD diagnoses and symptoms in offspring of mothers with and without mood disorders, and to explore contributing factors to this risk. This longitudinal study assessed PDs and symptoms of PDs in offspring of mothers with bipolar disorder (O-BD), major depression (O-MDD), and no psychiatric diagnosis (O-WELL) in mid-adolescence and in early adulthood. O-BD were more likely to develop a Cluster B PD than O-MDD or O-WELL in adolescence, and more likely to develop a Cluster B PD then O-WELL in early adulthood. Dimensional analyses revealed that O-BD had elevated symptoms in PDs across all PD clusters at mid-adolescence and young adulthood. O-MDD showed elevated symptoms of antisocial PD at both time points, and of obsessive-compulsive PD at young adulthood. Offspring of mothers with mood disorders, especially O-BD, are at increased risk for PD diagnoses and symptoms in mid-adolescence and early adulthood. Contributing factors to risk of PD symptoms in at-risk offspring are discussed. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Cullen, Kathryn R.; Heller, Monika D.; Schlesinger, Amanda] Univ Minnesota, Dept Psychiat, Sch Med, Minneapolis, MN 55454 USA. [Eberly, Lynn E.] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55454 USA. [Gold, Phillip W.; Martinez, Pedro E.] NIMH, Bethesda, MD 20892 USA. [Klimes-Dougan, Bonnie] Univ Minnesota, Dept Psychol, Minneapolis, MN 55454 USA. RP Cullen, KR (reprint author), Univ Minnesota, Dept Psychiat, Sch Med, F256-2B West Bldg,2450 Riverside Ave, Minneapolis, MN 55454 USA. EM rega0026@umn.edu OI Eberly, Lynn/0000-0003-4763-330X FU National Institute of Mental Health; John D. and Catherine T. MacArthur Foundation FX The authors would like to thank the families that participated in this study, which has contributed such valuable information to our field over the past several decades. This study was supported by the National Institute of Mental Health and by the John D. and Catherine T. MacArthur Foundation. NR 46 TC 1 Z9 1 U1 4 U2 15 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 AUG 30 PY 2014 VL 218 IS 3 BP 303 EP 310 DI 10.1016/j.psychres.2014.04.044 PG 8 WC Psychiatry SC Psychiatry GA AK7GZ UT WOS:000338598000007 PM 24844978 ER PT J AU Martin, E Carlson, JM Le, AQ Chopera, DR McGovern, R Rahman, MA Ng, C Jessen, H Kelleher, AD Markowitz, M Allen, TM Milloy, MJ Carrington, M Wainberg, MA Brumme, ZL AF Martin, Eric Carlson, Jonathan M. Le, Anh Q. Chopera, Denis R. McGovern, Rachel Rahman, Manal A. Ng, Carmond Jessen, Heiko Kelleher, Anthony D. Markowitz, Martin Allen, Todd M. Milloy, M-J Carrington, Mary Wainberg, Mark A. Brumme, Zabrina L. TI Early immune adaptation in HIV-1 revealed by population-level approaches SO RETROVIROLOGY LA English DT Article DE Human immunodeficiency virus type-1 (HIV-1); Human leukocyte antigen (HLA) class I; CD8+cytotoxic T-lymphocytes (CTL); Immune escape; HLA-associated polymorphism; Adaptation; Evolution; Acute/early infection; Population-level analysis; Statistical association with phylogenetic correction ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-LYMPHOCYTE RESPONSE; ESCAPE MUTATIONS; PRIMARY INFECTION; CELL RESPONSES; SUBTYPE B; P24 GAG; HLA; EPITOPE; PATHWAYS AB Background: The reproducible nature of HIV-1 escape from HLA-restricted CD8+ T-cell responses allows the identification of HLA-associated viral polymorphisms "at the population level" - that is, via analysis of cross-sectional, linked HLA/HIV-1 genotypes by statistical association. However, elucidating their timing of selection traditionally requires detailed longitudinal studies, which are challenging to undertake on a large scale. We investigate whether the extent and relative timecourse of immune-driven HIV adaptation can be inferred via comparative cross-sectional analysis of independent early and chronic infection cohorts. Results: Similarly-powered datasets of linked HLA/HIV-1 genotypes from individuals with early (median < 3 months) and chronic untreated HIV-1 subtype B infection, matched for size (N > 200/dataset), HLA class I and HIV-1 Gag/Pol/Nef diversity, were established. These datasets were first used to define a list of 162 known HLA-associated polymorphisms detectable at the population level in cohorts of the present size and host/viral genetic composition. Of these 162 known HLA-associated polymorphisms, 15% (occurring at 14 Gag, Pol and Nef codons) were already detectable via statistical association in the early infection dataset at p <= 0.01 (q < 0.2) - identifying them as the most consistently rapidly escaping sites in HIV-1. Among these were known rapidly-escaping sites (e. g. B*57-Gag-T242N) and others not previously appreciated to be reproducibly rapidly selected (e. g. A*31:01-associated adaptations at Gag codons 397, 401 and 403). Escape prevalence in early infection correlated strongly with first-year escape rates (Pearson's R = 0.68, p = 0.0001), supporting cross-sectional parameters as reliable indicators of longitudinally-derived measures. Comparative analysis of early and chronic datasets revealed that, on average, the prevalence of HLA-associated polymorphisms more than doubles between these two infection stages in persons harboring the relevant HLA (p < 0.0001, consistent with frequent and reproducible escape), but remains relatively stable in persons lacking the HLA (p = 0.15, consistent with slow reversion). Published HLA-specific Hazard Ratios for progression to AIDS correlated positively with average escape prevalence in early infection (Pearson's R = 0.53, p = 0.028), consistent with high early within-host HIV-1 adaptation (via rapid escape and/or frequent polymorphism transmission) as a correlate of progression. Conclusion: Cross-sectional host/viral genotype datasets represent an underutilized resource to identify reproducible early pathways of HIV-1 adaptation and identify correlates of protective immunity. C1 [Martin, Eric; Le, Anh Q.; Chopera, Denis R.; Rahman, Manal A.; Brumme, Zabrina L.] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Martin, Eric; McGovern, Rachel; Ng, Carmond; Milloy, M-J; Brumme, Zabrina L.] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Carlson, Jonathan M.] Microsoft Res, Los Angeles, CA USA. [Chopera, Denis R.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, KwaZulu Natal Res Inst TB & HIV, Durban, South Africa. [Jessen, Heiko] Jessen Praxis, Berlin, Germany. [Kelleher, Anthony D.] Univ New S Wales, Kirby Inst, Sydney, NSW, Australia. [Markowitz, Martin] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Allen, Todd M.; Carrington, Mary] MIT, Ragon Inst MGH, Cambridge, MA USA. [Allen, Todd M.; Carrington, Mary] Harvard Univ, Cambridge, MA 02138 USA. [Milloy, M-J] Univ British Columbia, Fac Med, Vancouver, BC, Canada. [Carrington, Mary] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Wainberg, Mark A.] McGill Univ, Lady Davis Inst, Montreal, PQ, Canada. RP Brumme, ZL (reprint author), Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. EM zbrumme@sfu.ca RI Allen, Todd/F-5473-2011 FU Canadian Institutes for Health Research (CIHR) [MOP-93536, HOP-115700]; National Institute on Drug Abuse, NIH [RO1DA011591, RO1DA021525]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH, Frederick National Lab, Center for Cancer Research; Canadian Association of HIV Research; Abbott Virology; CIHR Frederick Banting and Charles Best Masters award; CIHR CANADA-HOPE fellowship; CIHR; Michael Smith Foundation for Health Research (MSFHR); CIHR New Investigator Award; MSFHR Scholar Award FX We thank Colin Shen and Zhixing (Samuel) Tan for laboratory assistance. We thank Chanson Brumme, Conan Woods and Daniel MacMillan for database assistance. We thank Richard Harrigan and Bruce D. Walker for data access and mentorship. We thank Mark Brockman for helpful discussions. This work was supported by operating grants from the Canadian Institutes for Health Research (CIHR) MOP-93536 and HOP-115700 to ZLB. The VIDUS and ACCESS projects are funded by the National Institute on Drug Abuse, NIH (RO1DA011591 and RO1DA021525). This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. EM was supported by a Master's Scholarship from the Canadian Association of HIV Research and Abbott Virology. AQL is the recipient of a CIHR Frederick Banting and Charles Best Masters award. DRC was the recipient of a CIHR CANADA-HOPE fellowship. M-JM is supported by post-doctoral fellowships from CIHR and the Michael Smith Foundation for Health Research (MSFHR). ZLB is a recipient of a CIHR New Investigator Award and a MSFHR Scholar Award. NR 56 TC 1 Z9 1 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD AUG 29 PY 2014 VL 11 AR 64 DI 10.1186/s12977-014-0064-1 PG 16 WC Virology SC Virology GA AS8MX UT WOS:000344503900001 PM 25212686 ER PT J AU Iyer, S Han, L Bartell, SM Kim, HN Gubrij, I de Cabo, R O'Brien, CA Manolagas, SC Almeida, M AF Iyer, Srividhya Han, Li Bartell, Shoshana M. Kim, Ha-Neui Gubrij, Igor de Cabo, Rafael O'Brien, Charles A. Manolagas, Stavros C. Almeida, Maria TI Sirtuin1 (Sirt1) Promotes Cortical Bone Formation by Preventing beta-Catenin Sequestration by FoxO Transcription Factors in Osteoblast Progenitors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Animal Model; Apoptosis; Cell Proliferation; Osteoporosis; Wnt Signaling ID LIFE-SPAN; MUSCLE ATROPHY; DISEASE; REGULATOR; MAINTENANCE; RESVERATROL; PROTEINS; ESTROGEN; INSIGHTS; PROTECTS AB Background: Sirt1 activity, like osteoblast number and bone mass, declines with age. Results: Mice with Sirt1 deletion in osteoprogenitor cells have low cortical bone mass due to decreased bone formation resulting from increased -catenin sequestration by FoxOs. Conclusion: Sirt1 increases Wnt signaling and bone formation by a mechanism involving FoxOs. Significance: Sirt1 in osteoprogenitor cells could be a therapeutic target for osteoporosis. A decline of the levels and activity of Sirtuin1 (Sirt1), a NAD(+) class III histone deacetylase, with age contributes to the development of several diseases including type 2 diabetes, neurodegeneration, inflammation, and cancer. The anti-aging effects of Sirt1 evidently result from the deacetylation of many transcription factors and co-factors including members of the Forkhead box O (FoxO) family and -catenin. Wnt/-catenin is indispensable for osteoblast generation. FoxOs, on the other hand, sequester -catenin and inhibit osteoprogenitor proliferation. Here, we have deleted Sirt1 in osteoprogenitors expressing Osterix1 (Osx1)-Cre and their descendants. Sirt1(Osx1) mice had lower cortical thickness in femora and vertebrae because of reduced bone formation at the endocortical surface. In line with this, osteoprogenitor cell cultures from the Sirt1(Osx1) mice exhibited lower alkaline phosphatase activity and mineralization, as well as decreased proliferation and increased apoptosis. These changes were associated with decreased Wnt/-catenin signaling and expression of cyclin D1 and resulted from increased binding of FoxOs to -catenin. These findings demonstrate that Sirt1-induced deacetylation of FoxOs unleashes Wnt signaling. A decline in Sirt1 activity in osteoblast progenitors with aging may, therefore, contribute to the age-related loss of bone mass. Together with evidence that Sirt1 activators increase bone mass in aged mice, our results also suggest that Sirt1 could be a therapeutic target for osteoporosis. C1 [Iyer, Srividhya; Han, Li; Bartell, Shoshana M.; Kim, Ha-Neui; O'Brien, Charles A.; Manolagas, Stavros C.; Almeida, Maria] Univ Arkansas Med Sci, Div Endocrinol & Metab, Ctr Osteoporosis & Metab Bone Dis, Little Rock, AR 72205 USA. [Gubrij, Igor] Univ Arkansas Med Sci, Div Pulm & Crit Care, Little Rock, AR 72205 USA. [de Cabo, Rafael] Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA. [de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Almeida, M (reprint author), Univ Arkansas Med Sci, Div Endocrinol & Metab, 4301 W Markham St 587, Little Rock, AR 72205 USA. EM schullermaria@uams.edu RI de Cabo, Rafael/J-5230-2016 OI de Cabo, Rafael/0000-0002-3354-2442 FU National Institutes of Health Grants [R01 AR56679, P01 AG13918, F32 AR061956-02]; Biomedical Laboratory Research and Development Service of the Veteran's Administration Office of Research and Development Grant [I01 BX001405]; University of Arkansas for Medical Sciences Tobacco Funds; Translational Research Institute Grant [1UL1RR029884]; Intramural Research Program of the NIA, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 AR56679 (to M. A.), P01 AG13918 (to S. C. M.), F32 AR061956-02 (to S. M. B.); Biomedical Laboratory Research and Development Service of the Veteran's Administration Office of Research and Development Grant I01 BX001405 (to S. C. M.); and University of Arkansas for Medical Sciences Tobacco Funds and Translational Research Institute Grant 1UL1RR029884.; Supported by the Intramural Research Program of the NIA, National Institutes of Health. NR 45 TC 19 Z9 21 U1 0 U2 7 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 AUG 29 PY 2014 VL 289 IS 35 BP 24069 EP 24078 DI 10.1074/jbc.M114.561803 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO7AY UT WOS:000341505600007 PM 25002589 ER PT J AU Groveman, BR Dolan, MA Taubner, LM Kraus, A Wickner, RB Caughey, B AF Groveman, Bradley R. Dolan, Michael A. Taubner, Lara M. Kraus, Allison Wickner, Reed B. Caughey, Byron TI Parallel In-register Intermolecular beta-Sheet Architectures for Prion-seeded Prion Protein (PrP) Amyloids SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Amyloid; Molecular Dynamics; Nuclear Magnetic Resonance (NMR); Prion; Protein Structure ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; C-TERMINAL DOMAIN; SCRAPIE PRION; SECONDARY STRUCTURE; MASS-SPECTROMETRY; CONVERSION; FIBRILS; CONFORMATION; STRAIN AB Background: The structures of infectious mammalian prions remain unclear. Results: Based in part on NMR data, we developed models with single PrP molecules spanning the entire cross-section of prion fibrils. Conclusion: These models are consistent with many empirical features of prion amyloids. Significance: We provide a new basis for conceptualizing and experimentally evaluating the structures and propagation of infectious prions. Structures of the infectious form of prion protein (e.g. PrPSc or PrP-Scrapie) remain poorly defined. The prevalent structural models of PrPSc retain most of the native -helices of the normal, noninfectious prion protein, cellular prion protein (PrPC), but evidence is accumulating that these helices are absent in PrPSc amyloid. Moreover, recombinant PrPC can form amyloid fibrils in vitro that have parallel in-register intermolecular -sheet architectures in the domains originally occupied by helices 2 and 3. Here, we provide solid-state NMR evidence that the latter is also true of initially prion-seeded recombinant PrP amyloids formed in the absence of denaturants. These results, in the context of a primarily -sheet structure, led us to build detailed models of PrP amyloid based on parallel in-register architectures, fibrillar shapes and dimensions, and other available experimentally derived conformational constraints. Molecular dynamics simulations of PrP(90-231) octameric segments suggested that such linear fibrils, which are consistent with many features of PrPSc fibrils, can have stable parallel in-register -sheet cores. These simulations revealed that the C-terminal residues approximate to 124-227 more readily adopt stable tightly packed structures than the N-terminal residues approximate to 90-123 in the absence of cofactors. Variations in the placement of turns and loops that link the -sheets could give rise to distinct prion strains capable of faithful template-driven propagation. Moreover, our modeling suggests that single PrP monomers can comprise the entire cross-section of fibrils that have previously been assumed to be pairs of laterally associated protofilaments. Together, these insights provide a new basis for deciphering mammalian prion structures. C1 [Groveman, Bradley R.; Taubner, Lara M.; Kraus, Allison; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Dolan, Michael A.] NIAID, Computat Biol Sect, Bioinformat & Computat Biosci Branch, Bethesda, MD 20892 USA. [Wickner, Reed B.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM bcaughey@nih.gov FU National Institutes of Health Intramural Program of the NIAID; National Institutes of Health Intramural Program of the NIDDK FX This work was supported, in whole or in part, by National Institutes of Health Intramural Programs of the NIAID and the NIDDK. NR 68 TC 41 Z9 41 U1 6 U2 41 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 AUG 29 PY 2014 VL 289 IS 35 BP 24129 EP 24142 DI 10.1074/jbc.M114.578344 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO7AY UT WOS:000341505600012 PM 25028516 ER PT J AU Vassilopoulos, A Xiao, CY Chisholm, C Chen, WP Xu, XL Lahusen, TJ Bewley, C Deng, CX AF Vassilopoulos, Athanassios Xiao, Cuiying Chisholm, Cristine Chen, Weiping Xu, Xiaoling Lahusen, Tyler J. Bewley, Carole Deng, Chu-Xia TI Synergistic Therapeutic Effect of Cisplatin and Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Cancer Growth and Metastasis of Brca1 Mutant Tumors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Breast Cancer; Cancer Stem Cells; Cytoskeleton; Drug Resistance; Tumor Metastases; PI3K Signaling ID EPITHELIAL-MESENCHYMAL TRANSITION; NEGATIVE BREAST-CANCER; STEM-CELLS; ACTIN CYTOSKELETON; INITIATING CELLS; MAMMARY-TUMORS; ERM PROTEINS; MOUSE MODELS; IN-VITRO; RESISTANCE AB Background: Metastasis is a serious problem that claims the lives of breast cancer patients. Results: Rapamycin and cisplatin synergistically inhibit CSC-mediated primary and metastatic cancer growth by blocking mTOR signaling and cytoskeletal remodeling. Conclusion: Cancer stem cells are involved in both primary and metastatic cancer growth of Brca1 tumors through distinct signaling pathways. Significance: Targeting cancer stem cell-specific pathways may reveal new therapeutic strategies. Drug resistance and cancer metastasis are two major problems in cancer research. During a course of therapeutic treatment in Brca1-associated tumors, we found that breast cancer stem cells (CSCs) exhibit an intrinsic ability to metastasize and acquire drug resistance through distinct signaling pathways. Microarray analysis indicated that the cytoskeletal remodeling pathway was differentially regulated in CSCs, and this was further evidenced by the inhibitory role of reagents that impair this pathway in the motility of cancer cells. We showed that cisplatin treatment, although initially inhibiting cancer growth, preventing metastasis through blocking cytoskeletal remodeling, and retarding CSC motility, eventually led to drug resistance associated with a marked increase in the number of CSCs. This event was at least partially attributed to the activation of PI3K signaling, and it could be significantly inhibited by co-treatment with rapamycin. These results provide strong evidence that cytoskeletal rearrangement and PI3K/AKT signaling play distinct roles in mediating CSC mobility and viability, respectively, and blocking both pathways synergistically may inhibit primary and metastatic cancer growth. C1 [Vassilopoulos, Athanassios; Xiao, Cuiying; Chisholm, Cristine; Xu, Xiaoling; Lahusen, Tyler J.; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDK, Microarray Core Facil, NIH, Bethesda, MD 20892 USA. [Bewley, Carole] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), Bldg 10,Rm 9N105,10 Ctr Dr, Bethesda, MD 20814 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU National Institutes of Health Intramural Research Program of the NIDDK FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program of the NIDDK. NR 49 TC 4 Z9 4 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 AUG 29 PY 2014 VL 289 IS 35 BP 24202 EP 24214 DI 10.1074/jbc.M114.567552 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO7AY UT WOS:000341505600018 PM 25006250 ER PT J AU Michailidis, E Huber, AD Ryan, EM Ong, YT Leslie, MD Matzek, KB Singh, K Marchand, B Hagedorn, AN Kirby, KA Rohan, LC Kodama, EN Mitsuya, H Parniak, MA Sarafianos, SG AF Michailidis, Eleftherios Huber, Andrew D. Ryan, Emily M. Ong, Yee T. Leslie, Maxwell D. Matzek, Kayla B. Singh, Kamalendra Marchand, Bruno Hagedorn, Ariel N. Kirby, Karen A. Rohan, Lisa C. Kodama, Eiichi N. Mitsuya, Hiroaki Parniak, Michael A. Sarafianos, Stefan G. TI 4 '-Ethynyl-2-fluoro-2 '-deoxyadenosine (EFdA) Inhibits HIV-1 Reverse Transcriptase with Multiple Mechanisms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE AIDS; Enzyme Inhibitor; Human Immunodeficiency Virus (HIV); Nucleoside; Nucleotide Analogue; Reverse Transcription; EFdA; NRTIs; Antivirals; Reverse Transcriptase ID HUMAN IMMUNODEFICIENCY VIRUSES; CONNECTION SUBDOMAIN; NUCLEOTIDE ANALOGS; DRUG-RESISTANCE; HEPATITIS-B; IN-VITRO; DNA; TRANSLOCATION; PRIMER; TENOFOVIR AB Background: 4-Ethynyl-2-fluoro-2-deoxyadenosine (EFdA) is a highly potent nucleoside analog reverse transcriptase (RT) inhibitor with a 3-OH. Results: EFdA inhibits RT as an immediate or delayed chain terminator depending on the DNA substrate sequence. RT efficiently misincorporates EFdA, producing non-extendable mismatched primers protected from excision. Conclusion: EFdA blocks RT by multiple mechanisms. Significance: Understanding the EFdA inhibition mechanism will help develop better antivirals. 4-Ethynyl-2-fluoro-2-deoxyadenosine (EFdA) is a nucleoside analog that, unlike approved anti-human immunodeficiency virus type 1 (HIV-1) nucleoside reverse transcriptase inhibitors, has a 3-OH and exhibits remarkable potency against wild-type and drug-resistant HIVs. EFdA triphosphate (EFdA-TP) is unique among nucleoside reverse transcriptase inhibitors because it inhibits HIV-1 reverse transcriptase (RT) with multiple mechanisms. (a) EFdA-TP can block RT as a translocation-defective RT inhibitor that dramatically slows DNA synthesis, acting as a de facto immediate chain terminator. Although non-translocated EFdA-MP-terminated primers can be unblocked, they can be efficiently converted back to the EFdA-MP-terminated form. (b) EFdA-TP can function as a delayed chain terminator, allowing incorporation of an additional dNTP before blocking DNA synthesis. In such cases, EFdA-MP-terminated primers are protected from excision. (c) EFdA-MP can be efficiently misincorporated by RT, leading to mismatched primers that are extremely hard to extend and are also protected from excision. The context of template sequence defines the relative contribution of each mechanism and affects the affinity of EFdA-MP for potential incorporation sites, explaining in part the lack of antagonism between EFdA and tenofovir. Changes in the type of nucleotide before EFdA-MP incorporation can alter its mechanism of inhibition from delayed chain terminator to immediate chain terminator. The versatility of EFdA in inhibiting HIV replication by multiple mechanisms may explain why resistance to EFdA is more difficult to emerge. C1 [Michailidis, Eleftherios; Huber, Andrew D.; Ryan, Emily M.; Ong, Yee T.; Leslie, Maxwell D.; Matzek, Kayla B.; Singh, Kamalendra; Marchand, Bruno; Hagedorn, Ariel N.; Kirby, Karen A.; Sarafianos, Stefan G.] Univ Missouri, Christopher Bond Life Sci Ctr, Columbia, MO 65211 USA. [Huber, Andrew D.] Univ Missouri, Dept Vet Pathobiol, Columbia, MO 65211 USA. [Sarafianos, Stefan G.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Michailidis, Eleftherios; Ryan, Emily M.; Ong, Yee T.; Leslie, Maxwell D.; Matzek, Kayla B.; Singh, Kamalendra; Marchand, Bruno; Hagedorn, Ariel N.; Kirby, Karen A.; Sarafianos, Stefan G.] Univ Missouri, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. [Rohan, Lisa C.] Univ Pittsburgh, Sch Pharm, Magee Womens Res Inst, Pittsburgh, PA 15213 USA. [Rohan, Lisa C.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15213 USA. [Kodama, Eiichi N.] Tohoku Univ, Div Emerging Infect Dis, Sendai, Miyagi 9808575, Japan. [Mitsuya, Hiroaki] Kumamoto Univ, Dept Internal Med, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NIH, Expt Retrovirol Sect, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Parniak, Michael A.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Sch Med, Pittsburgh, PA 15219 USA. RP Sarafianos, SG (reprint author), Univ Missouri, Dept Mol Microbiol & Immunol, Christopher Bond Life Sci Ctr, Columbia, MO 65211 USA. EM sarafianoss@missouri.edu RI Kodama, Eiichi /C-4032-2009; OI Kodama, Eiichi /0000-0002-6622-2752; Kirby, Karen A./0000-0003-2468-4796 FU National Institutes of Health [R01AI076119, R01AI076119-S1, R01AI076119-02S1, R01AI099284, R01AI100890, R21AI112417, P01GM103368, AI079801]; Mizzou Advantage; Ministry of Knowledge and Economy, Bilateral International Collaborative Research and Development Program, Republic of Korea FX This work was supported, in whole or in part, by National Institutes of Health Grants R01AI076119, R01AI076119-S1, R01AI076119-02S1, R01AI099284, R01AI100890, R21AI112417, and P01GM103368 (to S. G. S.) and AI079801 (to M. A. P.). This work was also supported by Mizzou Advantage and the Ministry of Knowledge and Economy, Bilateral International Collaborative Research and Development Program, Republic of Korea. Coauthors Drs. Hiroaki Mitsuya and Eiichi N. Kodama are inventors of EFdA, and thus there is a potential conflict of interest. NR 49 TC 12 Z9 12 U1 3 U2 13 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 AUG 29 PY 2014 VL 289 IS 35 BP 24533 EP 24548 DI 10.1074/jbc.M114.562694 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO7AY UT WOS:000341505600045 PM 24970894 ER PT J AU Quenet, D Dalal, Y AF Quenet, Delphine Dalal, Yamini TI A long non-coding RNA is required for targeting centromeric protein A to the human centromere SO ELIFE LA English DT Article ID CENP-A; POLYMERASE-II; HJURP; TRANSCRIPTION; DNA; DEPOSITION; DISTINCT AB The centromere is a specialized chromatin region marked by the histone H3 variant CENP-A. Although active centromeric transcription has been documented for over a decade, the role of centromeric transcription or transcripts has been elusive. Here, we report that centromeric a-satellite transcription is dependent on RNA Polymerase II and occurs at late mitosis into early G1, concurrent with the timing of new CENP-A assembly. Inhibition of RNA Polymerase II-dependent transcription abrogates the recruitment of CENP-A and its chaperone HJURP to native human centromeres. Biochemical characterization of CENP-A associated RNAs reveals a 1.3 kb molecule that originates from centromeres, which physically interacts with the soluble pre-assembly HJURP/CENP-A complex in vivo, and whose down-regulation leads to the loss of CENP-A and HJURP at centromeres. This study describes a novel function for human centromeric long non-coding RNAs in the recruitment of HJURP and CENP-A, implicating RNA-based chaperone targeting in histone variant assembly. C1 [Quenet, Delphine; Dalal, Yamini] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dalal, Y (reprint author), NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov FU National Cancer Institute Center for Cancer Research, Intramural Research Program FX National Cancer Institute Center for Cancer Research, Intramural Research Program Yamini Dalal NR 35 TC 33 Z9 34 U1 1 U2 15 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD AUG 29 PY 2014 VL 3 AR e03254 DI 10.7554/eLife.03254 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AO3TF UT WOS:000341258100001 PM 25117489 ER PT J AU Petrie, RJ Koo, H Yamada, KM AF Petrie, Ryan J. Koo, Hyun Yamada, Kenneth M. TI Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix SO SCIENCE LA English DT Article ID BLEBBING CELLS; MIGRATION; NESPRIN-3; FORCE AB Cells use actomyosin contractility to move through three-dimensional (3D) extracellular matrices. Contractility affects the type of protrusions cells use to migrate in 3D, but the mechanisms are unclear. In this work, we found that contractility generated high-pressure lobopodial protrusions in human cells migrating in a 3D matrix. In these cells, the nucleus physically divided the cytoplasm into forward and rear compartments. Actomyosin contractility with the nucleoskeleton-intermediate filament linker protein nesprin-3 pulled the nucleus forward and pressurized the front of the cell. Reducing expression of nesprin-3 decreased and equalized the intracellular pressure. Thus, the nucleus can act as a piston that physically compartmentalizes the cytoplasm and increases the hydrostatic pressure between the nucleus and the leading edge of the cell to drive lamellipodia-independent 3D cell migration. C1 [Petrie, Ryan J.; Koo, Hyun; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Koo, Hyun] Univ Rochester, Med Ctr, Dept Microbiol & Immunol, Ctr Oral Biol, Rochester, NY 14642 USA. [Koo, Hyun] Univ Penn, Sch Dent Med, Dept Orthodont, Biofilm Res Labs,Levy Ctr Oral Hlth, Philadelphia, PA 19104 USA. RP Petrie, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM petrier@mail.nih.gov; kyamada@mail.nih.gov FU National Institute of Dental and Craniofacial Research, NIH FX We thank K. Carver for helping to characterize various primary human cells; D. Starr for providing the nesprin-3 antibody; and M. Hoffman, A. Doyle, W. Daley, and K. Holmberg for critical comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH. The data presented in this manuscript are found in the main paper and the supplementary materials and methods. NR 16 TC 63 Z9 63 U1 6 U2 47 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 29 PY 2014 VL 345 IS 6200 BP 1062 EP 1065 DI 10.1126/science.1256965 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN8RE UT WOS:000340870900043 PM 25170155 ER PT J AU Carneiro, M Rubin, CJ Di Palma, F Albert, FW Alfoldi, J Barrio, AM Pielberg, G Rafati, N Sayyab, S Turner-Maier, J Younis, S Afonso, S Aken, B Alves, JM Barrell, D Bolet, G Boucher, S Burbano, HA Campos, R Chang, JL Duranthon, V Fontanesi, L Garreau, H Heiman, D Johnson, J Mage, RG Peng, Z Queney, G Rogel-Gaillard, C Ruffier, M Searle, S Villafuerte, R Xiong, AQ Young, S Forsberg-Nilsson, K Good, JM Lander, ES Ferrand, N Lindblad-Toh, K Andersson, L AF Carneiro, Miguel Rubin, Carl-Johan Di Palma, Federica Albert, Frank W. Alfoeldi, Jessica Barrio, Alvaro Martinez Pielberg, Gerli Rafati, Nima Sayyab, Shumaila Turner-Maier, Jason Younis, Shady Afonso, Sandra Aken, Bronwen Alves, Joel M. Barrell, Daniel Bolet, Gerard Boucher, Samuel Burbano, Hernan A. Campos, Rita Chang, Jean L. Duranthon, Veronique Fontanesi, Luca Garreau, Herve Heiman, David Johnson, Jeremy Mage, Rose G. Peng, Ze Queney, Guillaume Rogel-Gaillard, Claire Ruffier, Magali Searle, Steve Villafuerte, Rafael Xiong, Anqi Young, Sarah Forsberg-Nilsson, Karin Good, Jeffrey M. Lander, Eric S. Ferrand, Nuno Lindblad-Toh, Kerstin Andersson, Leif TI Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication SO SCIENCE LA English DT Article ID SELECTION; GENETICS; SWEEPS AB The genetic changes underlying the initial steps of animal domestication are still poorly understood. We generated a high-quality reference genome for the rabbit and compared it to resequencing data from populations of wild and domestic rabbits. We identified more than 100 selective sweeps specific to domestic rabbits but only a relatively small number of fixed (or nearly fixed) single-nucleotide polymorphisms (SNPs) for derived alleles. SNPs with marked allele frequency differences between wild and domestic rabbits were enriched for conserved noncoding sites. Enrichment analyses suggest that genes affecting brain and neuronal development have often been targeted during domestication. We propose that because of a truly complex genetic background, tame behavior in rabbits and other domestic animals evolved by shifts in allele frequencies at many loci, rather than by critical changes at only a few domestication loci. C1 [Carneiro, Miguel; Afonso, Sandra; Alves, Joel M.; Campos, Rita; Ferrand, Nuno] Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal. [Rubin, Carl-Johan; Barrio, Alvaro Martinez; Pielberg, Gerli; Rafati, Nima; Younis, Shady; Lindblad-Toh, Kerstin; Andersson, Leif] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab Uppsala, Uppsala, Sweden. [Di Palma, Federica; Alfoeldi, Jessica; Turner-Maier, Jason; Chang, Jean L.; Heiman, David; Johnson, Jeremy; Young, Sarah; Lander, Eric S.; Lindblad-Toh, Kerstin] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Di Palma, Federica] Genome Anal Ctr, Norwich, Norfolk, England. [Albert, Frank W.; Burbano, Hernan A.; Good, Jeffrey M.] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Leipzig, Germany. [Sayyab, Shumaila; Andersson, Leif] Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden. [Younis, Shady] Ain Shams Univ, Dept Anim Prod, Cairo, Egypt. [Aken, Bronwen; Barrell, Daniel; Ruffier, Magali; Searle, Steve] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Aken, Bronwen; Barrell, Daniel; Ruffier, Magali] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England. [Alves, Joel M.] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Bolet, Gerard; Garreau, Herve] INRA, Genet Physiol & Syst Elevage UMR1388, F-31326 Castanet Tolosan, France. [Boucher, Samuel] Labovet Conseil, F-85505 Les Herbiers, France. [Duranthon, Veronique] INRA, Biol Dev & Reprod UMR1198, F-78350 Jouy En Josas, France. [Fontanesi, Luca] Univ Bologna, Div Anim Sci, Dept Agr & Food Sci, I-40127 Bologna, Italy. [Mage, Rose G.] NIAID, Lab Immunol, NIH, Bethesda, MD 20892 USA. [Peng, Ze] US Dept Energy Joint Genome Inst, Lawrence Berkeley Natl Lab, Walnut Creek, CA 94598 USA. [Queney, Guillaume] ANTAGENE, Anim Genom Lab, Lyon, France. [Rogel-Gaillard, Claire] INRA, Genet Anim & Biol Integrat UMR1313, F-78350 Jouy En Josas, France. [Villafuerte, Rafael] IESA CSIC Campo Santo Martires 7, Inst Estudios Sociales Avanzados, Cordoba, Spain. [Xiong, Anqi; Forsberg-Nilsson, Karin] Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Good, Jeffrey M.] Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. [Ferrand, Nuno] Univ Porto, Fac Ciencias, Dept Biol, P-4169007 Oporto, Portugal. [Andersson, Leif] Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. RP Lindblad-Toh, K (reprint author), Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab Uppsala, Uppsala, Sweden. EM kersli@broadinstitute.org; leif.andersson@imbim.uu.se RI Fontanesi, Luca/L-1770-2014; Ferrand, Nuno /E-6085-2014; Afonso, Sandra/M-5702-2013; Carneiro, Miguel/L-7864-2013; OI Fontanesi, Luca/0000-0001-7050-3760; Ferrand, Nuno /0000-0002-2408-4195; Campos, Rita/0000-0003-4184-3269; Aken, Bronwen/0000-0002-3032-4095; Afonso, Sandra/0000-0001-7212-991X; Carneiro, Miguel/0000-0001-9882-7775; Ruffier, Magali/0000-0002-8386-1580; Burbano, Hernan A./0000-0003-3433-719X FU National Human Genome Research Institute [U54 HG003067]; European Research Council; Wellcome Trust [WT095908, WT098051]; NIH, NIAID; European Molecular Biology Laboratory; European Social Fund; Portuguese Ministerio da Ciencia, Tecnologia e Ensino Superior [SFRH/BPD/72343/2010, SFRH/BPD/64365/2009, SFRH/BD/72381/2010]; NSF [OISE-0754461]; FEDER through COMPETE program; Fundacao para a Ciencia e a Tecnologia [PTDC/CVT/122943/2010, PTDC/BIA-EVF/115069/2009, PTDC/BIA-BDE/72304/2006, PTDC/BIA-BDE/72277/2006]; project "Genomics and Evolutionary Biology" - North Portugal Regional Operational Programme (ON.2 - O Novo Norte) under National Strategic Reference Framework; project "Genomics Applied to Genetic Resources" - North Portugal Regional Operational Programme (ON.2 - O Novo Norte) under National Strategic Reference Framework; European Regional Development Fund (COST Action) [TD1101]; Higher Education Commission in Pakistan FX This work was supported by grants from the National Human Genome Research Institute (U54 HG003067 to E. S. L.), European Research Council project BATESON to L. A., the Wellcome Trust (grants WT095908 and WT098051), the intramural research program of the NIH, NIAID (R. G. M.), the European Molecular Biology Laboratory, Programa Operacional Potencial Humano-Quadro de Referencia Estrategica Nacional funds from the European Social Fund and Portuguese Ministerio da Ciencia, Tecnologia e Ensino Superior [postdoc grants to M. C. (SFRH/BPD/72343/2010) and R. C. (SFRH/BPD/64365/2009) and Ph.D. grant to J.M.A. (SFRH/BD/72381/2010)], a NSF international postdoctoral fellowship to J.M.G. (OISE-0754461), FEDER funds through the COMPETE program and Portuguese national funds through the Fundacao para a Ciencia e a Tecnologia (PTDC/CVT/122943/2010, PTDC/BIA-EVF/115069/2009, PTDC/BIA-BDE/72304/2006, and PTDC/BIA-BDE/72277/2006), the projects "Genomics and Evolutionary Biology" and "Genomics Applied to Genetic Resources" cofinanced by North Portugal Regional Operational Programme 2007/2013 (ON.2 - O Novo Norte) under the National Strategic Reference Framework and the European Regional Development Fund, travel grants to M. C. (COST Action TD1101), and Higher Education Commission in Pakistan (support for Sh.S.). We are grateful to L. Gaffney for assistance with figure preparation, P. C. Alves and S. Mills for providing the snowshoe hare sample, and S. Paabo for hosting M. C., S. A., and R. C. Sequencing was performed by the Broad Institute Genomics Platform. Computer resources were supplied by BITS and UPPNEX at Science for Life Laboratory. The O. cuniculus genome assembly has been deposited in GenBank under the accession number AAGW02000000. The RNA sequencing data have been deposited in GenBank under the bioproject PRJNA78323, the rabbit genome resequencing data under the bioproject PRJNA242290, and the sequence capture data under the bioproject PRJNA221358. NR 18 TC 49 Z9 51 U1 12 U2 93 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 29 PY 2014 VL 345 IS 6200 BP 1074 EP 1079 DI 10.1126/science.1253714 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN8RE UT WOS:000340870900046 PM 25170157 ER PT J AU Prabakaran, P Chen, WZ Dimitrov, DS AF Prabakaran, Ponraj Chen, Weizao Dimitrov, Dimiter S. TI The antibody germline/maturation hypothesis, elicitation of broadly neutralizing antibodies against HIV-1 and cord blood IgM repertoires SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE HIV-1; vaccine; broadly neutralizing antibody; cord blood IgM; germline antibody; 454 sequencing ID B-CELL DEVELOPMENT; 2F5-LIKE ANTIBODIES; MATURATION PATHWAY; IMMUNOGEN DESIGN; STRUCTURAL BASIS; ENVELOPE TRIMER; AMINO-ACIDS; GERMLINE; RECEPTORS; BINDING AB We have previously observed that all known potent broadly neutralizing antibodies (bnAbs) against HIV-1 are highly divergent from their putative germline predecessors in contrast to bnAbs against viruses causing acute infections such as henipaviruses and SARS CoV, which are much less divergent from their germline counterparts. Consequently, we have hypothesized that germline antibodies may not bind to the HIV-1 envelope glycoprotein (Env) because they are so different compared to the highly somatically mutated HIV-1-specific bnAbs. We have further hypothesized that the immunogenicity of highly conserved epitopes on the HIV-1 envelope glycoproteins (Envs) may be reduced or eliminated by their very weak or absent interactions with germline antibodies and immune responses leading to the elicitation of bnAbs may not be initiated and/or sustained. Even if such responses are initiated, the maturation pathways are so extraordinarily complex that prolonged periods of time may be required for elicitation of bnAbs with defined unique sequences. We provided the initial evidence supporting this antibody germline/maturation hypothesis, which prompted a number of studies to design vaccine immunogens that could bind putative germline predecessors of known bnAbs and to explore complex B cell lineages. However, guiding the immune system through the exceptionally complex antibody maturation pathways to elicit known bnAbs remains a major challenge. Here, we discuss studies exploring the antibody germline/maturation hypothesis as related to elicitation of bnAbs against HIV-1 and present our recent data demonstrating the existence of germline-like precursors of VRC01 antibodies in a human cord blood IgM library. C1 [Prabakaran, Ponraj; Chen, Weizao; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Expt Immunol Lab, Canc & Inflammat Program,NIH, Frederick, MD 21702 USA. [Prabakaran, Ponraj] Leidos Biomed Res Inc, Basic Sci Program, Frederick, MD USA. RP Prabakaran, P (reprint author), NCI, Prot Interact Grp, Expt Immunol Lab, Canc & Inflammat Program,NIH, Bldg 576,Room 103, Frederick, MD 21702 USA. EM prabakaran.ponraj@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Intramural AIDS Targeted Antiviral Program (IATAP) of the NIH; NIH, National Cancer Institute [NO1-CO-12400, HHSN261200800001E] FX We thank the Laboratory of Molecular Technology of SAIC-Frederick, Inc., for providing Roche 454 sequencing service. We thank Tina Ju for critically reading the manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, the Intramural AIDS Targeted Antiviral Program (IATAP) of the NIH and by Federal funds from the NIH, National Cancer Institute, under Contract Nos. NO1-CO-12400 and HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 51 TC 4 Z9 4 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD AUG 28 PY 2014 VL 5 BP 1 EP 9 AR 398 DI 10.3389/fimmu.2014.00398 PG 9 WC Immunology SC Immunology GA CI0BP UT WOS:000354400900001 PM 25221552 ER PT J AU Dimopoulos, MA Kastritis, E Owen, RG Kyle, RA Landgren, O Morra, E Leleu, X Garcia-Sanz, R Munshi, N Anderson, KC Terpos, E Ghobrial, IM Morel, P Maloney, D Rummel, M Leblond, V Advani, RH Gertz, MA Kyriakou, C Thomas, SK Barlogie, B Gregory, SA Kimby, E Merlini, G Treon, SP AF Dimopoulos, Meletios A. Kastritis, Efstathios Owen, Roger G. Kyle, Robert A. Landgren, Ola Morra, Enrica Leleu, Xavier Garcia-Sanz, Ramon Munshi, Nikhil Anderson, Kenneth C. Terpos, Evangelos Ghobrial, Irene M. Morel, Pierre Maloney, David Rummel, Mathias Leblond, Veronique Advani, Ranjana H. Gertz, Morie A. Kyriakou, Charalampia Thomas, Sheeba K. Barlogie, Bart Gregory, Stephanie A. Kimby, Eva Merlini, Giampaolo Treon, Steven P. TI Treatment recommendations for patients with Waldenstrom macroglobulinemia (WM) and related disorders: IWWM-7 consensus SO BLOOD LA English DT Review ID 2ND INTERNATIONAL WORKSHOP; PHASE-II TRIAL; BORTEZOMIB-MELPHALAN-PREDNISONE; RANDOMIZED CONTROLLED-TRIAL; PROGNOSTIC SCORING SYSTEM; PLACEBO-CONTROLLED TRIAL; PANEL RECOMMENDATIONS; AL AMYLOIDOSIS; WAIDENSTROMS MACROGLOBULINEMIA; MULTIPLE-MYELOMA AB Waldenstrom macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM(IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged. C1 [Dimopoulos, Meletios A.; Kastritis, Efstathios; Terpos, Evangelos] Univ Athens, Dept Clin Therapeut, Sch Med, Athens 11528, Greece. [Owen, Roger G.] St Jamess Inst Oncol, Leeds, W Yorkshire, England. [Kyle, Robert A.; Gertz, Morie A.] Mayo Clin, Rochester, MN USA. [Landgren, Ola] NCI, Bethesda, MD 20892 USA. [Morra, Enrica] Osped Niguarda Ca Granda, Dept Hematol, Milan, Italy. [Leleu, Xavier] CHRU Lille, Serv Malad Sang, Hop Huriez, F-59037 Lille, France. [Garcia-Sanz, Ramon] Hosp Univ Salamanca, Serv Hematol, Inst Invest Biomed Salamanca, Salamanca, Spain. [Munshi, Nikhil; Anderson, Kenneth C.; Ghobrial, Irene M.; Treon, Steven P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Morel, Pierre] Ctr Hosp Schaffner, Serv Hematol Clin, Lens, France. [Maloney, David] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Rummel, Mathias] Hosp Justus Liebig Univ Giessen, Med Klin 4, Giessen, Germany. [Leblond, Veronique] Univ Paris 06, AP HP, Hop La Pitie Salpetriere, GRC 11,Grp Rech Clin Hemopathie Lymphoide, Paris, France. [Advani, Ranjana H.] Stanford Canc Inst, Stanford, CA USA. [Kyriakou, Charalampia] Royal Free Hosp, London NW3 2QG, England. [Thomas, Sheeba K.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Barlogie, Bart] Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. [Gregory, Stephanie A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Kimby, Eva] Karolinska Univ Hosp, Dept Hematol, Solna, Sweden. [Merlini, Giampaolo] Univ Pavia, Amyloidosis Res & Treatment Ctr, Fdn Ist Ricovero & Cura Carattere Sci Policlin Sa, Dept Mol Med, I-27100 Pavia, Italy. RP Dimopoulos, MA (reprint author), Univ Athens, Dept Clin Therapeut, Sch Med, 80 Vas Sofias Ave, Athens 11528, Greece. EM mdimop@med.uoa.gr RI Merlini, Giampaolo/A-3817-2008; Garcia-Sanz, Ramon/B-7986-2017 OI Merlini, Giampaolo/0000-0001-7680-3254; Garcia-Sanz, Ramon/0000-0003-4120-2787 FU Celgene; Onyx; Janssen; Onyx/Amgen; Millenium/Takeda; Novartis; LeoPahrma; GSK; MundiPharma; Pharmacyclics; Amgen; Astellas; Roche; Gilead; BMS; Seattle Genetics; Onyx and Pharmacyclics FX M.D. has received honoraria from Celgene and Orthobiotech; R.G.O. has received research funding from Celgene and Onyx, is on the advisory board for Pharmacyclics and Celgene, and receives honoraria and lecture fees from Janssen and Celgene; R.A.K. sits on the disease monitoring committees for Celgene, Novartis, Merck, Bristol-Myers Squibb, AeternaZentaris, and Onyx and has received honoraria from Binding Site; X. L. has received honoraria and lecture fees from Celgene, Janssen, Onyx/Amgen, Millenium/Takeda, Novartis, and LeoPahrma; R.G.-S. has received honoraria and lecture fees from Janssen, Millenium/Takeda, GSK, MundiPharma, and Pharmacyclics; K. C. A. is on the advisory bard for Celgene, Millennium, Onyx, Gilead, and Sanofi Aventis and is a scientific founder of AcetylonOncopep; I. M. G. is on the advisory board for BMS, Celgene, Millennium, and Onyx; D. M. is a consultant for Roche/Genentech; M. R. has received honoraria and lecture fees from Amgen, Astellas, Celgene, GSK, Janssen, Mundipharma, and Roche; V. L. has received honoraria and lecture fees from Roche, GSK, Mundipharma, Janssen, Gilead, and BMS; R. H. A. has received research funding from Pharmacyclics, Celgene, Genentech, Millennium, and Seattle Genetics; M. A. G. has received honoraria from Onyx, Celgene, and Neotope; S. K. T. has received research funding from Novartis, Celgene, Millenium, and Idera Pharmaceuticals and is a consultant/advisor for Celgene and Pharmacyclics; S. A. G. is the chair of the safety data monitoring board for Genentech; is part of the speakers bureau for Celgene and Pharmacyclics, and is a consultant for Gilead; G. M. has received honoraria from Millennium; and S. P. T. has received research funding from Onyx and Pharmacyclics. The remaining authors declare no competing financial interests. NR 59 TC 41 Z9 42 U1 1 U2 11 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 AUG 28 PY 2014 VL 124 IS 9 BP 1404 EP 1411 DI 10.1182/blood-2014-03-565135 PG 8 WC Hematology SC Hematology GA AQ4JM UT WOS:000342762100012 PM 25027391 ER PT J AU Lee-Chang, C Bodogai, M Moritoh, K Olkhanud, PB Chan, AC Croft, M Mattison, JA Holst, PJ Gress, RE Ferrucci, L Hakim, F Biragyn, A AF Lee-Chang, Catalina Bodogai, Monica Moritoh, Kanako Olkhanud, Purevdorj B. Chan, Andrew C. Croft, Michael Mattison, Julie A. Holst, Peter Johannes Gress, Ronald E. Ferrucci, Luigi Hakim, Fran Biragyn, Arya TI Accumulation of 4-1BBL(+) B cells in the elderly induces the generation of granzyme-B+ CD8(+) T cells with potential antitumor activity SO BLOOD LA English DT Article ID ANTIGEN-PRESENTING CELLS; HEMATOPOIETIC STEM-CELLS; IN-VIVO; RHEUMATOID-ARTHRITIS; OLD MICE; CANCER; IMMUNE; SURVIVAL; EXPANSION; AGE AB Although the accumulation of highly-differentiated and granzyme B (GrB)-expressing CD8(+) CD28(-) T cells has been associated with aging, the mechanism for their enrichment and contribution to immune function remains poorly understood. Here we report a novel B-cell subset expressing 4-1BBL, which increases with age in humans, rhesus macaques, and mice, and with immune reconstitution after chemotherapy and autologous progenitor cell transplantation. These cells (termed 4BL cells) induce GrB(+) CD8(+) T cells by presenting endogenous antigens and using the 4-1BBL/4-1BB axis. We found that the 4BL cells increase antitumor responses in old mice, which may explain in part the paradox of retarded tumor growth in the elderly. 4BL cell accumulation and its capacity to evoke the generation of GrB(+) CD8(+) T cells can be eliminated by inducing reconstitution of B cells in old mice, suggesting that the age-associated skewed cellular immune responses are reversible. We propose that 4BL cells and the 4-1BBL signaling pathway are useful targets for improved effectiveness of natural antitumor defenses and therapeutic immune manipulations in the elderly. C1 [Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako; Olkhanud, Purevdorj B.; Biragyn, Arya] Lab Mol Biol & Immunol, Immunoregulat Sect, Baltimore, MD USA. [Chan, Andrew C.] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA. [Croft, Michael] La Jolla Inst Allergy & Immunol, Div Immune Regulat, La Jolla, CA USA. [Mattison, Julie A.] NIA, Nonhuman Primate Core Facil, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Holst, Peter Johannes] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Lab Expt Vaccinol, DK-1168 Copenhagen, Denmark. [Gress, Ronald E.; Hakim, Fran] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Biragyn, A (reprint author), NIA, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov RI Lee-Chang, Catalina/A-5580-2015 OI Lee-Chang, Catalina/0000-0002-7675-2124 FU NIH, Intramural Research Program of the NIA FX This research was supported by the NIH, Intramural Research Program of the NIA. NR 50 TC 6 Z9 6 U1 0 U2 4 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 AUG 28 PY 2014 VL 124 IS 9 BP 1450 EP 1459 DI 10.1182/blood-2014-03-563940 PG 10 WC Hematology SC Hematology GA AQ4JM UT WOS:000342762100017 PM 25037628 ER PT J AU Castellar, ERP Jaffe, ES Said, JW Swerdlow, SH Ketterling, RP Knudson, RA Sidhu, JS Hsi, ED Karikehalli, S Jiang, LY Vasmatzis, G Gibson, SE Ondrejka, S Nicolae, A Grogg, KL Allmer, C Ristow, KM Wilson, WH Macon, WR Law, ME Cerhan, JR Habermann, TM Ansell, SM Dogan, A Maurer, MJ Feldman, AL AF Castellar, Edgardo R. Parrilla Jaffe, Elaine S. Said, Jonathan W. Swerdlow, Steven H. Ketterling, Rhett P. Knudson, Ryan A. Sidhu, Jagmohan S. Hsi, Eric D. Karikehalli, Shridevi Jiang, Liuyan Vasmatzis, George Gibson, Sarah E. Ondrejka, Sarah Nicolae, Alina Grogg, Karen L. Allmer, Cristine Ristow, Kay M. Wilson, Wyndham H. Macon, William R. Law, Mark E. Cerhan, James R. Habermann, Thomas M. Ansell, Stephen M. Dogan, Ahmet Maurer, Matthew J. Feldman, Andrew L. TI ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes SO BLOOD LA English DT Article ID PERIPHERAL T-CELL; TRANSLOCATIONS; DIAGNOSIS; LOCUS AB Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 x 10(-5)). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management. C1 [Castellar, Edgardo R. Parrilla; Ketterling, Rhett P.; Knudson, Ryan A.; Grogg, Karen L.; Macon, William R.; Law, Mark E.; Dogan, Ahmet; Feldman, Andrew L.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Jaffe, Elaine S.; Nicolae, Alina] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Said, Jonathan W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA. [Swerdlow, Steven H.; Gibson, Sarah E.] Univ Pittsburgh, Med Ctr, Div Hematopathol, Pittsburgh, PA USA. [Sidhu, Jagmohan S.] United Hlth Serv Hosp, Dept Pathol & Lab Med, Johnson City, NY USA. [Hsi, Eric D.; Ondrejka, Sarah] Cleveland Clin, Dept Clin Pathol, Cleveland, OH 44106 USA. [Karikehalli, Shridevi] Centrex Clin Labs, Dept Pathol & Lab Med, Utica, NY USA. [Jiang, Liuyan] Mayo Clin, Dept Lab Med & Pathol, Jacksonville, FL 32224 USA. [Vasmatzis, George] Mayo Clin, Ctr Individualized Med, Rochester, MN 55905 USA. [Allmer, Cristine; Cerhan, James R.; Maurer, Matthew J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Ristow, Kay M.; Habermann, Thomas M.; Ansell, Stephen M.] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Feldman, AL (reprint author), Mayo Clin, Dept Lab Med & Pathol, Hilton Bldg,Room 8-00F,200 First St SW, Rochester, MN 55905 USA. EM feldman.andrew@mayo.edu OI Jaffe, Elaine/0000-0003-4632-0301; Cerhan, James/0000-0002-7482-178X FU Center for Individualized Medicine; Department of Laboratory Medicine and Pathology, Mayo Clinic (Rochester, MN); National Cancer Institute [R01 CA177734, P50 CA97274]; Damon Runyon Cancer Research Foundation [CI-48-09] FX This work was supported by the Center for Individualized Medicine and the Department of Laboratory Medicine and Pathology, Mayo Clinic (Rochester, MN) and National Cancer Institute awards R01 CA177734 (to A. L. F.) and P50 CA97274 (University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence [SPORE]). A. L. F. is a Damon Runyon Clinical Investigator supported by the Damon Runyon Cancer Research Foundation (CI-48-09). NR 26 TC 24 Z9 24 U1 0 U2 1 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 AUG 28 PY 2014 VL 124 IS 9 BP 1473 EP 1480 DI 10.1182/blood-2014-04-571091 PG 8 WC Hematology SC Hematology GA AQ4JM UT WOS:000342762100019 ER PT J AU Kovtunovych, G Ghosh, MC Ollivierre, W Weitzel, RP Eckhaus, MA Tisdale, JF Yachie, A Rouault, TA AF Kovtunovych, Gennadiy Ghosh, Manik C. Ollivierre, Wade Weitzel, R. Patrick Eckhaus, Michael A. Tisdale, John F. Yachie, Akihiro Rouault, Tracey A. TI Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; SCAVENGER RECEPTOR CD163; ACUTE KIDNEY INJURY; HEMOGLOBIN; DEFICIENCY; INFLAMMATION; EXPRESSION; COMPLEXES; MONOCYTES; HEMOLYSIS AB Loss-of-function mutation in the heme oxygenase 1 (Hmox1) gene causes a rare and lethal disease in children, characterized by severe anemia and intravascular hemolysis, with damage to endothelia and kidneys. Previously, we found that macrophages engaged in recycling of red cells were depleted from the tissues of Hmox1(-/-) mice, which resulted in intravascular hemolysis and severe damage to the endothelial system, kidneys, and other organs. Here, we report that subablative bone marrow transplantation (BMT) has a curative effect for disease in Hmox1(-/-) animals as a result of restoration of heme recycling by repopulation of the tissues with wild-type macrophages. Although engraftment was transient, BMT reversed anemia, normalized blood chemistries and iron metabolism parameters, and prevented renal damage. The largest proportion of donor-derived cells was observed in the livers of transplanted animals. These cells, identified as Kupffer cells with high levels of Hmox1 expression, persisted months after transient engraftment of the donor bone marrow and were responsible for the full restoration of heme-recycling ability in Hmox1(-/-) mice and reversing Hmox1-deficient phenotype. Our findings suggest that BMT or the development of specific cell therapies to repopulate patients' tissues with wild-type or reengineered macrophages represent promising approaches for HMOX1 deficiency treatment in humans. C1 [Kovtunovych, Gennadiy; Ghosh, Manik C.; Ollivierre, Wade; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. [Weitzel, R. Patrick; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Eckhaus, Michael A.] NIH, Div Vet Resources, Off Res Serv, Off Director, Bethesda, MD 20892 USA. [Yachie, Akihiro] Kanazawa Univ, Inst Med Pharmaceut & Hlth Sci, Kanazawa, Ishikawa, Japan. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, NIH, 35 Convent Dr,MSC3755, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov RI Yachie, Akihiro/C-4660-2015 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program; National Institute of Heart Lung and Blood Disorders; Division of Veterinary Resources, Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program, by the National Institute of Heart Lung and Blood Disorders, and the Division of Veterinary Resources, Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD. NR 38 TC 10 Z9 10 U1 2 U2 5 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 AUG 28 PY 2014 VL 124 IS 9 BP 1522 EP 1530 DI 10.1182/blood-2014-02-554162 PG 9 WC Hematology SC Hematology GA AQ4JM UT WOS:000342762100024 PM 24963040 ER PT J AU Baydyuk, M Xu, BJ AF Baydyuk, Maryna Xu, Baoji TI BDNF signaling and survival of striatal neurons SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE neurotrophins; BDNF; TrkB; striatum; Huntington's disease; DRD1a; DRD2; dopaminergic neurons ID LATERAL GANGLIONIC EMINENCE; HUNTINGTONS-DISEASE PHENOTYPES; CEREBELLAR GRANULE NEURONS; NEUROTROPHIC FACTOR; MOUSE MODEL; SYNAPTIC PLASTICITY; PROJECTION NEURONS; BASAL GANGLIA; IN-VIVO; STRIATOPALLIDAL NEURONS AB The striatum, a major component of the basal ganglia, performs multiple functions including control of movement, reward, and addiction. Dysfunction and death of striatal neurons are the main causes for the motor disorders associated with Huntington's disease (HD). Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family, is among factors that promote survival and proper function of this neuronal population. Here, we review recent studies showing that BDNF determines the size of the striatum by supporting survival of the immature striatal neurons at their origin, promotes maturation of striatal neurons, and facilitates establishment of striatal connections during brain development. We also examine the role of BDNF in maintaining proper function of the striatum during adulthood, summarize the mechanisms that lead to a deficiency in BDNF signaling and subsequently striatal degeneration in HD, and highlight a potential role of BDNF as a therapeutic target for HD treatment. C1 [Baydyuk, Maryna] NINDS, NIH, Bethesda, MD 20892 USA. [Xu, Baoji] Scripps Res Inst Florida, Dept Neurosci, Jupiter, FL 33458 USA. RP Xu, BJ (reprint author), Scripps Res Inst Florida, Dept Neurosci, 130 Scripps Way,3C1, Jupiter, FL 33458 USA. EM bxu@scripps.edu FU National Institutes of Health [R01 NS050596]; NINDS Intramural Research Program FX We thank the NIH Fellows Editorial Board for the editorial assistance, This work was supported by National Institutes of Health Grant R01 NS050596 (Baoji Xu) and NINDS Intramural Research Program (Maryna Baydyuk). NR 106 TC 23 Z9 24 U1 3 U2 21 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD AUG 28 PY 2014 VL 8 AR UNSP 254 DI 10.3389/fncel.2014.00254 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AP3AB UT WOS:000341946200001 PM 25221473 ER PT J AU Killeen, GF Kiware, SS Seyoum, A Gimnig, JE Corliss, GF Stevenson, J Drakeley, CJ Chitnis, N AF Killeen, Gerry F. Kiware, Samson S. Seyoum, Aklilu Gimnig, John E. Corliss, George F. Stevenson, Jennifer Drakeley, Christopher J. Chitnis, Nakul TI Comparative assessment of diverse strategies for malaria vector population control based on measured rates at which mosquitoes utilize targeted resource subsets SO MALARIA JOURNAL LA English DT Article DE Plasmodium; Anopheles; Vector control; Mosquito; Malaria; Target product profile ID ANOPHELES-GAMBIAE ATTRACTION; INSECTICIDE-TREATED NETS; TOXIC SUGAR BAITS; WESTERN KENYA; ENTOMOPATHOGENIC FUNGUS; ELECTROCUTING GRIDS; FEEDING-BEHAVIOR; HUMAN EXPOSURE; EAST ZAMBIA; CLAY POTS AB Background: Eliminating malaria requires vector control interventions that dramatically reduce adult mosquito population densities and survival rates. Indoor applications of insecticidal nets and sprays are effective against an important minority of mosquito species that rely heavily upon human blood and habitations for survival. However, complementary approaches are needed to tackle a broader diversity of less human-specialized vectors by killing them at other resource targets. Methods: Impacts of strategies that target insecticides to humans or animals can be rationalized in terms of biological coverage of blood resources, quantified as proportional coverage of all blood resources mosquito vectors utilize. Here, this concept is adapted to enable impact prediction for diverse vector control strategies based on measurements of utilization rates for any definable, targetable resource subset, even if that overall resource is not quantifiable. Results: The usefulness of this approach is illustrated by deriving utilization rate estimates for various blood, resting site, and sugar resource subsets from existing entomological survey data. Reported impacts of insecticidal nets upon human-feeding vectors, and insecticide-treated livestock upon animal-feeding vectors, are approximately consistent with model predictions based on measured utilization rates for those human and animal blood resource subsets. Utilization rates for artificial sugar baits compare well with blood resources, and are consistent with observed impact when insecticide is added. While existing data was used to indirectly measure utilization rates for a variety of resting site subsets, by comparison with measured rates of blood resource utilization in the same settings, current techniques for capturing resting mosquitoes underestimate this quantity, and reliance upon complex models with numerous input parameters may limit the applicability of this approach. Conclusions: While blood and sugar consumption can be readily quantified using existing methods for detecting natural markers or artificial tracers, improved techniques for labelling mosquitoes, or other arthropod pathogen vectors, will be required to assess vector control measures which target them when they utilize non-nutritional resources such as resting, oviposition, and mating sites. C1 [Killeen, Gerry F.; Kiware, Samson S.] Ifakara Hlth Inst, Environm Hlth & Ecol Sci Themat Grp, Morogoro, Tanzania. [Killeen, Gerry F.; Seyoum, Aklilu] Univ Liverpool, Liverpool Sch Trop Med, Vector Biol Dept, Liverpool L3 5QA, Merseyside, England. [Gimnig, John E.] Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Atlanta, GA 30333 USA. [Kiware, Samson S.; Corliss, George F.] Marquette Univ, Dept Elect & Comp Engn, Milwaukee, WI 53201 USA. [Stevenson, Jennifer; Drakeley, Christopher J.] Univ London London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London WC1E 7HT, England. [Stevenson, Jennifer] Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Malaria Res Inst, Baltimore, MD 21205 USA. [Chitnis, Nakul] Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland. [Chitnis, Nakul] Univ Basel, Basel, Switzerland. [Chitnis, Nakul] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Killeen, GF (reprint author), Ifakara Hlth Inst, Environm Hlth & Ecol Sci Themat Grp, Morogoro, Tanzania. EM gkilleen@ihi.or.tz RI Smith, Thomas/B-5569-2015; Chitnis, Nakul/B-3105-2013 OI Smith, Thomas/0000-0002-3650-9381; FU Bill & Melinda Gates Foundation [45114, 52644, OPP1032350] FX We thank Dr. K Aultman and Dr. D Malone for discussions that stimulated and influenced the content of this manuscript. We thank Prof T A Smith for guidance on the probablistic basis of exponential decay models, and Dr. T R Burkot for critical comments on the manuscript, as well as providing population size data for Haleta. We are also grateful to three anonymous reviewers, whose comments had a substantive influence on the final interpretation and conclusions. This work was funded by the Bill & Melinda Gates Foundation (Award numbers 45114, 52644 and OPP1032350). NR 93 TC 5 Z9 5 U1 0 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD AUG 28 PY 2014 VL 13 AR 338 DI 10.1186/1475-2875-13-338 PG 15 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AP0CJ UT WOS:000341728300001 PM 25168421 ER PT J AU Gaglio, B Phillips, SM Heurtin-Roberts, S Sanchez, MA Glasgow, RE AF Gaglio, Bridget Phillips, Siobhan M. Heurtin-Roberts, Suzanne Sanchez, Michael A. Glasgow, Russell E. TI How pragmatic is it? Lessons learned using PRECIS and RE-AIM for determining pragmatic characteristics of research SO IMPLEMENTATION SCIENCE LA English DT Article DE Pragmatic trials; External validity; Research translation; PRECIS; RE-AIM ID CONSORT STATEMENT; CLINICAL-TRIALS; HEALTH; SCIENCE; TOOL; INTERVENTIONS; TRANSLATION; FRAMEWORK; SYSTEMS AB Background: The need for high-quality evidence that is applicable in real-world, routine settings continues to increase. Pragmatic trials are designed to evaluate the effectiveness of interventions in real-world settings, whereas explanatory trials aim to test whether an intervention works under optimal situations. There is a continuum between explanatory and pragmatic trials. Most trials have aspects of both, making it challenging to label and categorize a trial and to evaluate its potential for translation into practice. Methods: We summarize our experience applying the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) combined with external validity items based on the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to three studies to provide a more robust and comprehensive assessment of trial characteristics related to translation of research. We summarize lessons learned using domains from the combined frameworks for use in study planning, evaluating specific studies, and reviewing the literature and make recommendations for future use. Results: A variety of coders can be trained to use the PRECIS and RE-AIM domains. These domains can also be used for diverse purposes, content areas, and study types, but are not without challenges. Both PRECIS and RE-AIM domains required modification in two of the three studies to evaluate and rate domains specific to study type. Lessons learned involved: dedicating enough time for training activities related to the domains; use of reviewers with a range of familiarity with specific study protocols; how to best adapt ratings that reflect complex study designs; and differences of opinion regarding the value of creating a composite score for these criteria. Conclusions: Combining both frameworks can specifically help identify where and how a study is and is not pragmatic. Using both PRECIS and RE-AIM allows for standard reporting of key study characteristics related to pragmatism and translation. Such measures should be used more consistently to help plan more pragmatic studies, evaluate progress, increase transparency of reporting, and integrate literature to facilitate translation of research into practice and policy. C1 [Gaglio, Bridget] Kaiser Permanente Midatlantic States, Midatlantic Permanente Res Inst, Rockville, MD 20852 USA. [Phillips, Siobhan M.; Heurtin-Roberts, Suzanne; Sanchez, Michael A.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Glasgow, Russell E.] Univ Colorado, Sch Med, Colorado Hlth Outcomes Program, Aurora, CO 80045 USA. [Glasgow, Russell E.] Univ Colorado, Sch Med, Dept Family Med, Aurora, CO 80045 USA. RP Gaglio, B (reprint author), Kaiser Permanente Midatlantic States, Midatlantic Permanente Res Inst, 2101 E Jefferson St,Suite 300, Rockville, MD 20852 USA. EM bridget.gaglio@kp.org FU National Heart, Lung, Blood Institute (NHLBI) [5 U01 HL087071-01, U01 HL087085-01, U01 HL 087072-01]; National Cancer Institute (NCI) [CA124401, CA140959, CA163526, CA154549] FX Funding Sources: Partially supported by National Heart, Lung, Blood Institute (NHLBI) - Grant #5 U01 HL087071-01, U01 HL087085-01, and U01 HL 087072-01 and the National Cancer Institute (NCI) - Grant # CA124401, CA140959, CA163526, and CA154549. The opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or views of the National Cancer Institute. NR 39 TC 13 Z9 13 U1 2 U2 20 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 AUG 28 PY 2014 VL 9 AR 96 DI 10.1186/s13012-014-0096-x PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AO2LQ UT WOS:000341154500001 PM 25163664 ER PT J AU Lee, KSS Liu, JY Wagner, KM Pakhomova, S Dong, H Morisseau, C Fu, SH Yang, J Wang, P Ulu, A Mate, CA Nguyen, LV Hwang, SH Edin, ML Mara, AA Wulff, H Newcomer, ME Zeldin, DC Hammock, BD AF Lee, Kin Sing Stephen Liu, Jun-Yan Wagner, Karen M. Pakhomova, Svetlana Dong, Hua Morisseau, Christophe Fu, Samuel H. Yang, Jun Wang, Peng Ulu, Arzu Mate, Christina A. Nguyen, Long V. Hwang, Sung Hee Edin, Matthew L. Mara, Alexandria A. Wulff, Heike Newcomer, Marcia E. Zeldin, Darryl C. Hammock, Bruce D. TI Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PAINFUL DIABETIC-NEUROPATHY; PLASMA-PROTEIN BINDING; INFLAMMATORY PAIN; THERAPEUTIC TARGET; RAT MODEL; X-RAY; ACID; PHARMACOKINETICS; DISCOVERY; CRYSTALLOGRAPHY AB Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans. C1 [Lee, Kin Sing Stephen; Liu, Jun-Yan; Wagner, Karen M.; Dong, Hua; Morisseau, Christophe; Fu, Samuel H.; Yang, Jun; Wang, Peng; Ulu, Arzu; Mate, Christina A.; Nguyen, Long V.; Hwang, Sung Hee; Hammock, Bruce D.] Univ Calif Davis, UCD Comprehens Canc Ctr, Dept Entomol & Nematol, Davis, CA 95616 USA. [Wulff, Heike] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Wang, Peng] China Agr Univ, Dept Appl Chem, Beijing 100193, Peoples R China. [Pakhomova, Svetlana; Newcomer, Marcia E.] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. [Edin, Matthew L.; Mara, Alexandria A.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Hammock, BD (reprint author), Univ Calif Davis, UCD Comprehens Canc Ctr, Dept Entomol & Nematol, One Shields Ave, Davis, CA 95616 USA. EM bdhammock@ucdavis.edu RI Lee, Kin Sing Stephen/I-9476-2012; OI Lee, Kin Sing Stephen/0000-0003-4541-3063; Edin, Matthew/0000-0002-7042-500X FU NIEHS [R01 ES002710]; NIAMS [R21 AR062866]; NIH CounterAct [U54 NS079202]; NIEHS Superfund Research Program [P42 ES004699]; NIH [R01 HL107887]; Louisiana Governors' Biotechnology Initiative; National Science Foundation [DBI-9871464]; National Institute of General Medical Sciences; National Center for Research Resources [P41RR015301-10]; National Institute of General Medical Sciences from the National Institutes of Health [P41 GM103403-10]; U.S. DOE [DE-AC02-06CH11357] FX This work was partially funded by NIEHS grant R01 ES002710, NIAMS grant R21 AR062866, NIH CounterAct U54 NS079202, and NIEHS Superfund Research Program grant P42 ES004699. B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Foundation. This work was supported in part by NIH R01 HL107887 (M.E.N.) and by the Louisiana Governors' Biotechnology Initiative. Data for the structure TPPU (UC1770) were collected at the Gulf Coast Protein Crystallography Beamline at the Center for Advanced Microstructures and Devices. This beamline is supported by the National Science Foundation grant DBI-9871464 with cofunding from the National Institute of General Medical Sciences. Data for the structure of inhibitor 4 (UC2389) were collected at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines, which are supported by grants from the National Center for Research Resources (P41RR015301-10) and the National Institute of General Medical Sciences (P41 GM103403-10) from the National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under contract no. DE-AC02-06CH11357. We thank Dr. Henry Bellami and Dr. David Neau for assistance with data collection. NR 63 TC 15 Z9 15 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD AUG 28 PY 2014 VL 57 IS 16 BP 7016 EP 7030 DI 10.1021/jm500694p PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AO2BV UT WOS:000341121400010 PM 25079952 ER PT J AU Zhang, WH DeRyckere, D Hunter, D Liu, J Stashko, MA Minson, KA Cummings, CT Lee, M Glaros, TG Newton, DL Sather, S Zhang, DH Kireev, D Janzen, WP Earp, HS Graham, DK Frye, SV Wang, XD AF Zhang, Weihe DeRyckere, Deborah Hunter, Debra Liu, Jing Stashko, Michael A. Minson, Katherine A. Cummings, Christopher T. Lee, Minjung Glaros, Trevor G. Newton, Dianne L. Sather, Susan Zhang, Dehui Kireev, Dmitri Janzen, William P. Earp, H. Shelton Graham, Douglas K. Frye, Stephen V. Wang, Xiaodong TI UNC2025, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RECEPTOR TYROSINE KINASE; ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; INTERNAL TANDEM DUPLICATION; CLINICAL CANDIDATE; THERAPEUTIC TARGET; DRUG DESIGN; RISK GROUP; MER; DISCOVERY AB We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined. C1 [Zhang, Weihe; Liu, Jing; Stashko, Michael A.; Zhang, Dehui; Kireev, Dmitri; Janzen, William P.; Frye, Stephen V.; Wang, Xiaodong] Univ N Carolina, Eshelman Sch Pharm, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Earp, H. Shelton] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Hunter, Debra; Earp, H. Shelton; Frye, Stephen V.] Univ N Carolina, Sch Med, Dept Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [DeRyckere, Deborah; Minson, Katherine A.; Cummings, Christopher T.; Lee, Minjung; Sather, Susan; Graham, Douglas K.] Univ Colorado Denver, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [Glaros, Trevor G.; Newton, Dianne L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Biol Testing Branch, Dev Therapeut Program, Frederick, MD 21702 USA. RP Frye, SV (reprint author), Univ N Carolina, Eshelman Sch Pharm, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. EM svfrye@email.unc.edu; xiaodonw@unc.edu FU University Cancer Research Fund; Federal Funds from the National Cancer Institute, National Institute of Health [HHSN261200800001E]; NIH [1R01CA137078]; BCRF FX We thank Dr. Nancy Cheng, Ms. Wendy M. Stewart, and Ms. Yingqiu Zhou for their help with MCE assays. This work was supported by the University Cancer Research Fund and Federal Funds from the National Cancer Institute, National Institute of Health, under Contract HHSN261200800001E. Additional support was provided by NIH 1R01CA137078 (D.G.) and the BCRF (H.S.E.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 54 TC 18 Z9 18 U1 2 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD AUG 28 PY 2014 VL 57 IS 16 BP 7031 EP 7041 DI 10.1021/jm500749d PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AO2BV UT WOS:000341121400011 PM 25068800 ER PT J AU Brown, JB Boley, N Eisman, R May, GE Stoiber, MH Duff, MO Booth, BW Wen, JY Park, S Suzuki, AM Wan, KH Yu, C Zhang, DY Carlson, JW Cherbas, L Eads, BD Miller, D Mockaitis, K Roberts, J Davis, CA Frise, E Hammonds, AS Olson, S Shenker, S Sturgill, D Samsonova, AA Weiszmann, R Robinson, G Hernandez, J Andrews, J Bickel, PJ Carninci, P Cherbas, P Gingeras, TR Hoskins, RA Kaufman, TC Lai, EC Oliver, B Perrimon, N Graveley, BR Celniker, SE AF Brown, James B. Boley, Nathan Eisman, Robert May, Gemma E. Stoiber, Marcus H. Duff, Michael O. Booth, Ben W. Wen, Jiayu Park, Soo Suzuki, Ana Maria Wan, Kenneth H. Yu, Charles Zhang, Dayu Carlson, Joseph W. Cherbas, Lucy Eads, Brian D. Miller, David Mockaitis, Keithanne Roberts, Johnny Davis, Carrie A. Frise, Erwin Hammonds, Ann S. Olson, Sara Shenker, Sol Sturgill, David Samsonova, Anastasia A. Weiszmann, Richard Robinson, Garret Hernandez, Juan Andrews, Justen Bickel, Peter J. Carninci, Piero Cherbas, Peter Gingeras, Thomas R. Hoskins, Roger A. Kaufman, Thomas C. Lai, Eric C. Oliver, Brian Perrimon, Norbert Graveley, Brenton R. Celniker, Susan E. TI Diversity and dynamics of the Drosophila transcriptome SO NATURE LA English DT Article ID GENOME-WIDE ANALYSIS; LONG NONCODING RNAS; MELANOGASTER GENOME; EXPRESSION ANALYSIS; ENDOGENOUS SIRNAS; GENE-EXPRESSION; CAP-ANALYSIS; IDENTIFICATION; LANDSCAPE; COMPLEX AB Animal transcriptomes are dynamic with each cell type, tissue and organ system expressing an ensemble of transcript forms that give rise to substantial diversity. Here we have identified new genes, transcripts and proteins using poly(A)(+) RNA sequencing from Drosophila melanogaster in cultured cell lines, dissected organ systems and under environmental perturbations. We found that a small set of mostly neural-specific genes has the potential to encode thousands of transcripts each through extensive alternative promoter usage and RNA splicing. The magnitudes of splicing changes are larger between tissues than between developmental stages, and most sex-specific splicing is gonad-specific. Gonads express hundreds of previously unknown coding and long non-coding RNAs (lncRNAs), some of which are antisense to protein-coding genes and produce short regulatory RNAs. Furthermore, previously identified pervasive intergenic transcription occurs primarily within newly identified introns. The fly transcriptome is substantially more complex than previously recognized, with this complexity arising from combinatorial usage of promoters splice sites and polyaclenylation sites. C1 [Brown, James B.; Boley, Nathan; Stoiber, Marcus H.; Robinson, Garret; Hernandez, Juan; Bickel, Peter J.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Brown, James B.; Booth, Ben W.; Park, Soo; Wan, Kenneth H.; Yu, Charles; Carlson, Joseph W.; Frise, Erwin; Hammonds, Ann S.; Weiszmann, Richard; Hoskins, Roger A.; Celniker, Susan E.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Dept Genome Dynam, Berkeley, CA 94720 USA. [Eisman, Robert; Cherbas, Lucy; Eads, Brian D.; Miller, David; Mockaitis, Keithanne; Andrews, Justen; Cherbas, Peter; Kaufman, Thomas C.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [May, Gemma E.; Duff, Michael O.; Olson, Sara; Graveley, Brenton R.] Univ Connecticut, Ctr Hlth, Inst Syst Genom, Dept Genet & Dev Biol, Farmington, CT 06030 USA. [Wen, Jiayu; Shenker, Sol; Lai, Eric C.] Sloan Kettering Inst, Rockefeller Res Labs 1017C, New York, NY 10065 USA. [Suzuki, Ana Maria; Carninci, Piero] RIKEN Omics Sci Ctr, Yokohama, Kanagawa 2300045, Japan. [Suzuki, Ana Maria; Carninci, Piero] RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa 2300045, Japan. [Zhang, Dayu; Roberts, Johnny; Cherbas, Peter] Indiana Univ, Ctr Genom & Bioinformat, Bloomington, IN 47405 USA. [Davis, Carrie A.; Gingeras, Thomas R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Sturgill, David; Oliver, Brian] NIDDK, Sect Dev Genom, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Samsonova, Anastasia A.; Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Samsonova, Anastasia A.; Perrimon, Norbert] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Brown, JB (reprint author), Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. EM benbrownofberkeley@gmail.com; graveley@neuron.uchc.edu; celniker@fruitfly.org RI Brown, James/H-2971-2015; Carninci, Piero/K-1568-2014; Samsonova, Anastasia/Q-7591-2016; OI Carninci, Piero/0000-0001-7202-7243; Samsonova, Anastasia/0000-0002-9353-9173; Gingeras, Thomas/0000-0001-9106-3573; Graveley, Brenton/0000-0001-5777-5892 FU National Human Genome Research Institute; Department of Energy [U01 HG004271, U54 HG006944, R01 GM076655, DE-AC02-05CH11231]; NHGRI [K99 HG006698]; modENCODE DAC sub-award [5710003102, 1U01HG007031-01]; ENCODE DAC [5U01HG004695-04]; Indiana METACyt Initiative of Indiana University - Lilly Endowment; [U01-HG004261]; [RC2-HG005639] FX We thank the members of the modENCODE transcription consortium, especially J. Landolin and J. Sandler for their early contributions to these studies. We also thank A. Kundaje and H. Huang for helpful discussions. This work was funded by a contract from the National Human Genome Research Institute modENCODE Project, contract U01 HG004271 and U54 HG006944, to S.E.C. (principal investigator) and P.C., T.R.G., R.A.H. and B.R.G. (co-principal investigators) with additional support from R01 GM076655 (S.E.C.) both under Department of Energy contract no. DE-AC02-05CH11231. J.B.B.'s work was supported by NHGRI K99 HG006698. Work in P.J.B.'s group was supported by the modENCODE DAC sub-award 5710003102, 1U01HG007031-01 and the ENCODE DAC 5U01HG004695-04. Work in Bloomington was supported in part by the Indiana METACyt Initiative of Indiana University, funded by an award from the Lilly Endowment. Work in E.C.L.'s group was supported by U01-HG004261 and RC2-HG005639. NR 50 TC 126 Z9 128 U1 15 U2 92 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 28 PY 2014 VL 512 IS 7515 BP 393 EP 399 DI 10.1038/nature12962 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN8GC UT WOS:000340840600025 PM 24670639 ER PT J AU Gerstein, MB Rozowsky, J Yan, KK Wang, DF Cheng, C Brown, JB Davis, CA Hillier, L Sisu, C Li, JJ Pei, BK Harmanci, AO Duff, MO Djebali, S Alexander, RP Alver, BH Auerbach, R Bell, K Bickel, PJ Boeck, ME Boley, NP Booth, BW Cherbas, L Cherbas, P Di, C Dobins, A Drenkows, J Ewing, B Fang, G Fastucas, M Feingold, EA Frankish, A Gao, GJ Good, PJ Guigo, R Hammonds, A Harrow, J Hoskins, RA Howald, C Hu, L Huang, HY Hubbard, TJP Huynh, C Jhas, S Kasper, D Kato, M Kaufman, TC Kitchen, RR Ladewig, E Lagarde, J Lai, E Leng, L Lu, Z MacCoss, M May, G McWhirter, R Merrihew, G Miller, DM Mortazavi, A Murad, R Oliver, B Olson, S Park, PJ Pazin, MJ Perrimon, N Pervouchine, D Reinke, V Reymond, A Robinson, G Samsonova, A Saunders, GI Schlesingers, F Sethi, A Slack, FJ Spencer, WC Stoiber, MH Strasbourger, P Tanzer, A Thompson, OA Wan, KH Wang, GL Wang, H Watkins, KL Wen, JY Wen, KJ Xue, CH Yang, L Yip, K Zaleskis, C Zhang, Y Zheng, H Brenner, SE Graveley, BR Ceniker, SE Gingeras, TR Waterston, R AF Gerstein, Mark B. Rozowsky, Joel Yan, Koon-Kiu Wang, Daifeng Cheng, Chao Brown, James B. Davis, Carrie A. Hillier, LaDeana Sisu, Cristina Li, Jingyi Jessica Pei, Baikang Harmanci, Arif O. Duff, Michael O. Djebali, Sarah Alexander, Roger P. Alver, Burak H. Auerbach, Raymond Bell, Kimberly Bickel, Peter J. Boeck, Max E. Boley, Nathan P. Booth, Benjamin W. Cherbas, Lucy Cherbas, Peter Di, Chao Dobins, Alex Drenkows, Jorg Ewing, Brent Fang, Gang Fastucas, Megan Feingold, Elise A. Frankish, Adam Gao, Guanjun Good, Peter J. Guigo, Roderic Hammonds, Ann Harrow, Jen Hoskins, Roger A. Howald, Cedric Hu, Long Huang, Haiyan Hubbard, Tim J. P. Huynh, Chau Jhas, Sonali Kasper, Dionna Kato, Masaomi Kaufman, Thomas C. Kitchen, Robert R. Ladewig, Erik Lagarde, Julien Lai, Eric Leng, Ling Lu, Zhi MacCoss, Michael May, Gemma McWhirter, Rebecca Merrihew, Gennifer Miller, David M. Mortazavi, Ali Murad, Rabi Oliver, Brian Olson, Sara Park, Peter J. Pazin, Michael J. Perrimon, Norbert Pervouchine, Dmitri Reinke, Valerie Reymond, Alexandre Robinson, Garrett Samsonova, Anastasia Saunders, Gary I. Schlesingers, Felix Sethi, Anurag Slack, Frank J. Spencer, William C. Stoiber, Marcus H. Strasbourger, Pnina Tanzer, Andrea Thompson, Owen A. Wan, Kenneth H. Wang, Guilin Wang, Huaien Watkins, Kathie L. Wen, Jiayu Wen, Kejia Xue, Chenghai Yang, Li Yip, Kevin Zaleskis, Chris Zhang, Yan Zheng, Henry Brenner, Steven E. Graveley, Brenton R. Ceniker, Susan E. Gingeras, Thomas R. Waterston, Robert TI Comparative analysis of the transcriptome across distant species SO NATURE LA English DT Article ID GENE-EXPRESSION; LANDSCAPE; EVOLUTION; TISSUES; GENOME; CELLS AB The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features(1-6). Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters. C1 [Gerstein, Mark B.; Rozowsky, Joel; Yan, Koon-Kiu; Wang, Daifeng; Sisu, Cristina; Pei, Baikang; Harmanci, Arif O.; Alexander, Roger P.; Auerbach, Raymond; Fang, Gang; Kitchen, Robert R.; Leng, Ling; Mortazavi, Ali; Sethi, Anurag; Zhang, Yan; Zheng, Henry] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Gerstein, Mark B.; Rozowsky, Joel; Yan, Koon-Kiu; Wang, Daifeng; Sisu, Cristina; Pei, Baikang; Harmanci, Arif O.; Alexander, Roger P.; Auerbach, Raymond; Fang, Gang; Kitchen, Robert R.; Leng, Ling; Mortazavi, Ali; Sethi, Anurag; Zhang, Yan; Zheng, Henry] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Gerstein, Mark B.] Yale Univ, Dept Comp Sci, New Haven, CT 06511 USA. [Cheng, Chao] Geisel Sch Med Dartmouth, Dept Genet, Hanover, NH 03755 USA. [Cheng, Chao] Geisel Sch Med Dartmouth, Inst Quantitat Biomed Sci, Norris Cotton Canc Ctr, Lebanon, NH 03766 USA. [Brown, James B.; Boley, Nathan P.; Booth, Benjamin W.; Hammonds, Ann; Hoskins, Roger A.; Stoiber, Marcus H.; Wan, Kenneth H.; Ceniker, Susan E.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Dept Genome Dynam, Berkeley, CA 94720 USA. [Brown, James B.; Li, Jingyi Jessica; Bickel, Peter J.; Huang, Haiyan; Robinson, Garrett] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Davis, Carrie A.; Bell, Kimberly; Dobins, Alex; Drenkows, Jorg; Fastucas, Megan; Jhas, Sonali; Schlesingers, Felix; Wang, Huaien; Xue, Chenghai; Zaleskis, Chris; Gingeras, Thomas R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Hillier, LaDeana; Boeck, Max E.; Ewing, Brent; Huynh, Chau; MacCoss, Michael; Merrihew, Gennifer; Strasbourger, Pnina; Thompson, Owen A.; Waterston, Robert] Dept Genome Sci, Seattle, WA 98195 USA. [Hillier, LaDeana; Boeck, Max E.; Ewing, Brent; Huynh, Chau; MacCoss, Michael; Merrihew, Gennifer; Strasbourger, Pnina; Thompson, Owen A.; Waterston, Robert] Univ Washington, Sch Med, Seattle, WA 98195 USA. [Li, Jingyi Jessica] Univ Calif Los Angeles, Dept Stat, Los Angeles, CA 90095 USA. [Li, Jingyi Jessica] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Duff, Michael O.; May, Gemma; Olson, Sara; Yang, Li; Graveley, Brenton R.] Univ Connecticut, Ctr Hlth, Inst Syst Genom, Dept Genet & Dev Biol, Farmington, CT 06030 USA. [Djebali, Sarah; Guigo, Roderic; Lagarde, Julien; Pervouchine, Dmitri] Ctr Genom Regulat, Barcelona 08003, Catalonia, Spain. [Djebali, Sarah; Guigo, Roderic; Lagarde, Julien; Pervouchine, Dmitri] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona 08003, Catalonia, Spain. [Alver, Burak H.; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Boley, Nathan P.; Stoiber, Marcus H.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Cherbas, Lucy; Cherbas, Peter; Kaufman, Thomas C.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Cherbas, Lucy; Cherbas, Peter] Indiana Univ, Ctr Genom & Bioinformat, Bloomington, IN 47405 USA. [Di, Chao; Gao, Guanjun; Hu, Long; Lu, Zhi; Wen, Kejia] Tsinghua Univ, Sch Life Sci, MOE Key Lab Bioinformat, Beijing 100084, Peoples R China. [Feingold, Elise A.; Good, Peter J.; Pazin, Michael J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Frankish, Adam; Harrow, Jen; Hubbard, Tim J. P.; Saunders, Gary I.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Howald, Cedric; Reymond, Alexandre] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland. [Howald, Cedric] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Hubbard, Tim J. P.] Kings Coll London, London WC2R 2LS, England. [Kasper, Dionna; Reinke, Valerie; Wang, Guilin] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Kato, Masaomi; Slack, Frank J.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. [Ladewig, Erik; Lai, Eric; Wen, Jiayu] Sloan Kettering Inst, New York, NY 10065 USA. [May, Gemma] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. [McWhirter, Rebecca; Miller, David M.; Spencer, William C.; Watkins, Kathie L.] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 USA. [Mortazavi, Ali; Murad, Rabi] Univ Calif Irvine, Irvine, CA 92697 USA. [Mortazavi, Ali; Murad, Rabi] Univ Calif Irvine, Ctr Complex Biol Syst, Irvine, CA 92697 USA. [Oliver, Brian] NIDDK, Sect Dev Genom, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Perrimon, Norbert; Samsonova, Anastasia] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Perrimon, Norbert; Samsonova, Anastasia] Harvard Univ, Sch Med, Drosophila RNAi Screening Ctr, Boston, MA 02115 USA. [Perrimon, Norbert; Samsonova, Anastasia] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Saunders, Gary I.] European Bioinformat Inst, Hinxton CB10 1SD, England. [Tanzer, Andrea] Univ Pompeu Fabra, Ctr Genom Regulat, Bioinformat & Genom Programme, Barcelona 08003, Catalonia, Spain. [Tanzer, Andrea] Univ Vienna, Theoret Biochem Grp TBI, Inst Theoret Chem, A-1090 Vienna, Austria. [Yang, Li] Chinese Acad Sci, Shanghai Inst Biol Sci, CAS MPG Partner Inst Computat Biol, Key Lab Computat Biol, Shanghai 200031, Peoples R China. [Yip, Kevin] Chinese Univ Hong Kong, Hong Kong Bioinformat Ctr, Shatin, Hong Kong, Peoples R China. [Yip, Kevin] Chinese Univ Hong Kong, CUHK BGI Innovat Inst Trans Omics 5, Shatin, Hong Kong, Peoples R China. [Brenner, Steven E.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Brenner, Steven E.] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA. RP Gerstein, MB (reprint author), Yale Univ, Program Computat Biol & Bioinformat, Bass 432,266 Whitney Ave, New Haven, CT 06520 USA. EM cmptxn@gersteinlab.org RI Djebali, Sarah/O-9817-2014; Di, Chao/G-1130-2015; Brown, James/H-2971-2015; Pervouchine, Dmitri/H-5252-2015; Guigo, Roderic/D-1303-2010; Hubbard, Tim/C-2567-2008; Tanzer, Andrea/L-3147-2015; Brenner, Steven/A-8729-2008; Samsonova, Anastasia/Q-7591-2016; OI Djebali, Sarah/0000-0002-0599-1267; Pervouchine, Dmitri/0000-0003-0543-9760; Guigo, Roderic/0000-0002-5738-4477; Hubbard, Tim/0000-0002-1767-9318; Tanzer, Andrea/0000-0003-2873-4236; Brenner, Steven/0000-0001-7559-6185; Samsonova, Anastasia/0000-0002-9353-9173; Sisu, Cristina/0000-0001-9371-0797; Saunders, Gary/0000-0002-7468-0008; Gerstein, Mark/0000-0002-9746-3719; Graveley, Brenton/0000-0001-5777-5892; Slack, Frank/0000-0001-8263-0409; Rozowsky, Joel/0000-0002-3565-0762; Alver, Burak/0000-0002-5019-7652; Pazin, Michael/0000-0002-7561-3640 FU NHGRI; ENCODE; modENCODE project; National Human Genome Research Institute modENCODE Project under Department of Energy [U01 HG004271, U54 HG006944]; Department of Energy [R01 GM076655, DE-AC02-05CH11231, U54 HG007005]; NHGRI [K99 HG006698]; DOE [DE-AC02-05CH11231]; modENCODE DAC sub award [5710003102, 1 U01HG007031-01]; ENCODE DAC [5U01HG004695-04]; NIH [HG007000, HG007355]; Indiana METACyt Initiative of Indiana University - Lilly Endowment, Inc.; National Institutes of Health [U01HG004258, 5U54HG004555]; Wellcome Trust [WT098051]; Spanish Ministry of Education [BIO2011-26205]; [U01-HG004261]; [RC2-HG005639]; [U01 HG 004263] FX The authors thank the NHGRI and the ENCODE and modENCODE projects for support. In particular, this work was funded by a contract from the National Human Genome Research Institute modENCODE Project, contract U01 HG004271 and U54 HG006944, to S.E.C. (principal investigator) and P.C., T.R.G., R.A.H. and B.R.G. (co-principal investigators) with additional support from R01 GM076655 (S.E.C.) both under Department of Energy contract no. DE-AC02-05CH11231, and U54 HG007005 to B.R.G. J.B.B.'s work was supported by NHGRI K99 HG006698 and DOE DE-AC02-05CH11231. Work in P.J.B.'s group was supported by the modENCODE DAC sub award 5710003102, 1 U01HG007031-01 and the ENCODE DAC 5U01HG004695-04. Work in M.B.G.'s group was supported by NIH grants HG007000 and HG007355. Work in Bloomington was supported in part by the Indiana METACyt Initiative of Indiana University, funded by an award from the Lilly Endowment, Inc. Work in E.C.L.'s group was supported by U01-HG004261 and RC2-HG005639. P.J.P. acknowledges support from the National Institutes of Health (grant no. U01HG004258). We thank the HAVANA team for providing annotation of the human reference genome, whose work is supported by National Institutes of Health (grant no. 5U54HG004555), the Wellcome Trust (grant no. WT098051). R.G. acknowledges support from the Spanish Ministry of Education (grant BIO2011-26205). We also acknowledge use of the Yale University Biomedical High Performance Computing Center. R.W.'s lab was supported by grant no. U01 HG 004263. NR 19 TC 69 Z9 69 U1 11 U2 102 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 28 PY 2014 VL 512 IS 7515 BP 445 EP + DI 10.1038/nature13424 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN8GC UT WOS:000340840600037 PM 25164755 ER PT J AU Ho, JWK June, YL Liu, T Alver, BH Lee, S Ikegami, K Sohn, KA Minoda, A Tolstorukov, MY Appert, A Parker, SCJ Gu, TT Kundaje, A Riddle, NC Bishop, E Egelhofer, TA Hu, SS Alekseyenko, AA Rechtsteiner, A Asker, D Belsky, JA Bowmanm, SK Chens, QB Chen, RAJ Day, DS Dong, Y Dose, AC Duan, XK Epstein, CB Ercan, S Feingold, EA Ferrari, F Garrigues, JM Gehlenborg, N Good, PJ Haseley, P He, D Herrmann, M Hoffman, MM Jeffers, TE Kharchenko, PV Kolasinska-Zwierz, P Kotwaliwale, CV Kumar, N Langley, SA Larschan, EN Latorre, I Libbrecht, MW Lin, XQ Park, R Pazin, MJ Pham, HN Plachetka, A Qin, B Schwartz, YB Shoresh, N Stempor, P Vielle, A Wang, CY Whittle, CM Xue, HL Kingstonm, RE Kim, JH Bernstein, BE Dernburg, AF Pirrotta, V Kuroda, MI Noble, WS Tullius, TD Kellis, M MacAlpine, DM Strome, S Elgin, SCR Liu, XS Lieb, JD Ahringer, J Karpen, GH Park, PJ AF Ho, Joshua W. K. June, Youngsook L. Liu, Tao Alver, Burak H. Lee, Soohyun Ikegami, Kohta Sohn, Kyung-Ah Minoda, Aki Tolstorukov, Michael Y. Appert, Alex Parker, Stephen C. J. Gu, Tingting Kundaje, Anshul Riddle, Nicole C. Bishop, Eric Egelhofer, Thea A. Hu, Sheng'en Shawn Alekseyenko, Artyom A. Rechtsteiner, Andreas Asker, Dalal Belsky, Jason A. Bowmanm, Sarah K. Chens, Q. Brent Chen, Ron A. -J. Day, Daniel S. Dong, Yan Dose, Andrea C. Duan, Xikun Epstein, Charles B. Ercan, Sevinc Feingold, Elise A. Ferrari, Francesco Garrigues, Jacob M. Gehlenborg, Nils Good, Peter J. Haseley, Psalm He, Daniel Herrmann, Moritz Hoffman, Michael M. Jeffers, Tess E. Kharchenko, Peter V. Kolasinska-Zwierz, Paulina Kotwaliwale, Chitra V. Kumar, Nischay Langley, Sasha A. Larschan, Erica N. Latorre, Isabel Libbrecht, Maxwell W. Lin, Xueqiu Park, Richard Pazin, Michael J. Pham, Hoang N. Plachetka, Annette Qin, Bo Schwartz, Yuri B. Shoresh, Noam Stempor, Przemyslaw Vielle, Anne Wang, Chengyang Whittle, Christina M. Xue, Huiling Kingstonm, Robert E. Kim, Ju Han Bernstein, Bradley E. Dernburg, Abby F. Pirrotta, Vincenzo Kuroda, Mitzi I. Noble, William S. Tullius, Thomas D. Kellis, Manolis MacAlpine, David M. Strome, Susan Elgin, Sarah C. R. Liu, Xiaole Shirley Lieb, Jason D. Ahringer, Julie Karpen, Gary H. Park, Peter J. TI Comparative analysis of metazoan chromatin organization SO NATURE LA English DT Article ID CENTROMERIC CHROMATIN; DROSOPHILA GENOME; MODENCODE; ELEMENTS; ELEGANS; STATE; TRANSCRIPTION; METHYLATION; DOMAINS; ENCODE AB Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms(1-3). Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths(4,5). To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function. C1 [Ho, Joshua W. K.; June, Youngsook L.; Alver, Burak H.; Lee, Soohyun; Tolstorukov, Michael Y.; Bishop, Eric; Day, Daniel S.; Ferrari, Francesco; Gehlenborg, Nils; Haseley, Psalm; Kharchenko, Peter V.; Park, Richard; Xue, Huiling; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Ho, Joshua W. K.; June, Youngsook L.; Tolstorukov, Michael Y.; Alekseyenko, Artyom A.; Haseley, Psalm; Plachetka, Annette; Xue, Huiling; Kuroda, Mitzi I.; Park, Peter J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA. [Liu, Tao; Liu, Xiaole Shirley] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Liu, Tao; Liu, Xiaole Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Liu, Tao; Liu, Xiaole Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Ikegami, Kohta; Chens, Q. Brent; Ercan, Sevinc; Jeffers, Tess E.; Lieb, Jason D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Ikegami, Kohta; Chens, Q. Brent; Ercan, Sevinc; Jeffers, Tess E.; Lieb, Jason D.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Sohn, Kyung-Ah] Ajou Univ, Dept Informat & Comp Engn, Suwon 443749, South Korea. [Sohn, Kyung-Ah; Kim, Ju Han] Seoul Natl Univ, Coll Med, Syst Biomed Informat Res Ctr, Seoul 110799, South Korea. [Minoda, Aki; Langley, Sasha A.; Pham, Hoang N.; Vielle, Anne; Dernburg, Abby F.; Karpen, Gary H.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Dept Genome Dynam, Berkeley, CA 94720 USA. [Minoda, Aki; He, Daniel; Kotwaliwale, Chitra V.; Langley, Sasha A.; Pham, Hoang N.; Whittle, Christina M.; Dernburg, Abby F.; Karpen, Gary H.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Tolstorukov, Michael Y.; Bowmanm, Sarah K.; Kingstonm, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Tolstorukov, Michael Y.; Bowmanm, Sarah K.; Kingstonm, Robert E.; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Appert, Alex; Chen, Ron A. -J.; Dong, Yan; Herrmann, Moritz; Kolasinska-Zwierz, Paulina; Latorre, Isabel; Stempor, Przemyslaw; Vielle, Anne; Ahringer, Julie] Univ Cambridge, Gurdon Inst, Cambridge CB2 1QN, England. [Appert, Alex; Chen, Ron A. -J.; Dong, Yan; Herrmann, Moritz; Kolasinska-Zwierz, Paulina; Latorre, Isabel; Stempor, Przemyslaw; Vielle, Anne; Ahringer, Julie] Univ Cambridge, Dept Genet, Cambridge CB2 1QN, England. [Parker, Stephen C. J.] NIGMS, NIH, Bethesda, MD 20892 USA. [Parker, Stephen C. J.; Feingold, Elise A.; Good, Peter J.; Pazin, Michael J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Gu, Tingting; Riddle, Nicole C.; Elgin, Sarah C. R.] Washington Univ, Dept Biol, St Louis, MO 63130 USA. [Kundaje, Anshul; Kumar, Nischay; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Alver, Burak H.; Kundaje, Anshul; Epstein, Charles B.; Gehlenborg, Nils; Kumar, Nischay; Shoresh, Noam; Vielle, Anne; Bernstein, Bradley E.; Kellis, Manolis; Liu, Xiaole Shirley] Broad Inst, Cambridge, MA 02141 USA. [Bishop, Eric; Park, Richard; Tullius, Thomas D.] Boston Univ, Program Bioinformat, Boston, MA 02215 USA. [Egelhofer, Thea A.; Rechtsteiner, Andreas; Garrigues, Jacob M.; Strome, Susan] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Hu, Sheng'en Shawn; Duan, Xikun; Lin, Xueqiu; Qin, Bo; Wang, Chengyang] Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China. [Alekseyenko, Artyom A.; Plachetka, Annette; Kuroda, Mitzi I.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Asker, Dalal; Schwartz, Yuri B.; Pirrotta, Vincenzo] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Asker, Dalal] Univ Alexandria, Fac Agr, Food Sci & Technol Dept, Alexandria 21545, Egypt. [Belsky, Jason A.; MacAlpine, David M.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Day, Daniel S.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Dose, Andrea C.] Univ Calif Davis, Dept Anat Physiol & Cell Biol, Davis, CA 95616 USA. [Ercan, Sevinc] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Hoffman, Michael M.] Princess Margaret Canc Ctr, Toronto, ON M6G 1L7, Canada. [Kotwaliwale, Chitra V.; Pham, Hoang N.; Whittle, Christina M.; Bernstein, Bradley E.; Dernburg, Abby F.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Larschan, Erica N.] Brown Univ, Dept Mol Biol Cellular Biol & Biochem, Providence, RI 02912 USA. [Libbrecht, Maxwell W.; Noble, William S.] Univ Washington, Dept Comp Sci & Engn, Seattle, WA 98195 USA. [Schwartz, Yuri B.] Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden. [Kim, Ju Han] Seoul Natl Univ, Coll Med, Div Biomed Informat, Seoul Natl Univ Biomed Informat, Seoul 110799, South Korea. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Noble, William S.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Tullius, Thomas D.] Boston Univ, Dept Chem, Boston, MA 02215 USA. [Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02215 USA. RP MacAlpine, DM (reprint author), Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. EM david.macalpine@duke.edu; sstrome@ucsc.edu; selgin@biology2.wustl.edu; xsliu@jimmy.harvard.edu; jdlieb@uchicago.edu; ja219@cam.ac.uk; ghkarpen@lbl.gov; peter_park@hms.harvard.edu RI Tullius, Thomas/A-9685-2008; Liu, Tao/G-3585-2010; Hoffman, Michael/I-1924-2012; Ferrari, Francesco/H-5007-2012; Asker, Dalal/B-5722-2009; Minoda, Aki/D-5335-2017; OI Stempor, Przemyslaw/0000-0002-9464-7475; Jeffers, Tess/0000-0003-4908-0796; Alver, Burak/0000-0002-5019-7652; Gehlenborg, Nils/0000-0003-0327-8297; Pazin, Michael/0000-0002-7561-3640; Latorre, Isabel/0000-0003-0638-1783; Tullius, Thomas/0000-0003-4425-796X; Liu, Tao/0000-0002-8818-8313; Hoffman, Michael/0000-0002-4517-1562; Ferrari, Francesco/0000-0002-9811-3753; Minoda, Aki/0000-0002-2927-5791; Belsky, Jason/0000-0003-2945-6282; Chen, Ron/0000-0001-9186-6747; Liu, Tao/0000-0003-0446-9001; Sohn, Kyung-Ah/0000-0001-8941-1188 FU NHGRI [U01HG004258, U01 HG004270, U01HG004279, U54HG004570, U01HG004695, K99HG006259]; NHBIB [5RL9EB008539]; NIGMS; NIH [U54CA121852]; NSF [1122374]; National Natural Science Foundation of China [31028011]; MEST Korea [MHW-2013-HI13C2164]; Wellcome Trust [54523]; [NRF-2012-0000994] FX This project was mainly funded by NHGRI U01HG004258 (G.H.K., S.C.R.E., M.I.K., P.J.P., V.P.), U01 HG004270 (J.D.L., J.A., A.F.D., X.S.L., S.S.), U01HG004279 (D.M.M.), U54HG004570 (B.E.B.) and U01HG004695 (W.S.N.). It is also supported by NHBIB 5RL9EB008539 (J.W.K.H.), NHGRI K99HG006259 (M.M.H.), NIGMS fellowships (S.C.J.P., E.N.L.), NIH U54CA121852 (T.D.T.), NSF 1122374 (D.S.D.), National Natural Science Foundation of China 31028011 (X.S.L.), MEST Korea MHW-2013-HI13C2164 (J.H.K.), NRF-2012-0000994 (K-AS.), and Wellcome Trust 54523 (J.A.). We thank D. Acevedo and C. Kennedy for technical assistance. NR 24 TC 79 Z9 81 U1 1 U2 57 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 28 PY 2014 VL 512 IS 7515 BP 449 EP U507 DI 10.1038/nature13415 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN8GC UT WOS:000340840600038 PM 25164756 ER PT J AU Boyle, AP Araya, CL Brdlik, C Cayting, P Cheng, C Cheng, Y Gardner, K Hillier, LW Janette, J Jiang, LX Kasper, D Kawli, T Kheradpour, P Kundaje, A Li, JJ Ma, LJ Niu, W Rehm, EJ Rozowsky, J Slattery, M Spokony, R Terrell, R Vafeados, D Wang, DF Weisdepp, P Wu, YC Xie, D Yan, KK Feingold, EA Good, PJ Pazin, MJ Huang, HY Bickel, PJ Brenner, SE Reinke, V Waterston, RH Gerstein, M White, KP Kellis, M Snyder, M AF Boyle, Alan P. Araya, Carlos L. Brdlik, Cathleen Cayting, Philip Cheng, Chao Cheng, Yong Gardner, Kathryn Hillier, LaDeana W. Janette, Judith Jiang, Lixia Kasper, Dionna Kawli, Trupti Kheradpour, Pouya Kundaje, Anshul Li, Jingyi Jessica Ma, Lijia Niu, Wei Rehm, E. Jay Rozowsky, Joel Slattery, Matthew Spokony, Rebecca Terrell, Robert Vafeados, Dionne Wang, Daifeng Weisdepp, Peter Wu, Yi-Chieh Xie, Dan Yan, Koon-Kiu Feingold, Elise A. Good, Peter J. Pazin, Michael J. Huang, Haiyan Bickel, Peter J. Brenner, Steven E. Reinke, Valerie Waterston, Robert H. Gerstein, Mark White, Kevin P. Kellis, Manolis Snyder, Michael TI Comparative analysis of regulatory information and circuits across distant species SO NATURE LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; CHIP-SEQ; HISTONE DEACETYLASE; CHROMATIN-IMMUNOPRECIPITATION; DROSOPHILA-MELANOGASTER; FACTOR COLOCALIZATION; MOTIF DISCOVERY; HIGH-THROUGHPUT; HUMAN-CELLS; RNA-SEQ AB Despite the large evolutionary distances between metazoan species, they can show remarkable commonalities in their biology, and this has helped to establish fly and worm as model organisms for human biology(1,2). Although studies of individual elements and factors have explored similarities in gene regulation, a large-scale comparative analysis of basic principles of transcriptional regulatory features is lacking. Here we map the genome-wide binding locations of 165 human, 93 worm and 52 fly transcription regulatory factors, generating a total of 1,019 data sets from diverse cell types, developmental stages, or conditions in the three species, of which 498 (48.9%) are presented here for the first time. We find that structural properties of regulatory networks are remarkably conserved and that orthologous regulatory factor families recognize similar binding motifs in vivo and show some similar co-associations. Our results suggest that gene-regulatory properties previously observed for individual factors are general principles of metazoan regulation that are remarkably well-preserved despite extensive functional divergence of individual network connections. The comparative maps of regulatory circuitry provided here will drive an improved understanding of the regulatory underpinnings of model organism biology and how these relate to human biology, development and disease. C1 [Boyle, Alan P.; Araya, Carlos L.; Brdlik, Cathleen; Cayting, Philip; Cheng, Yong; Jiang, Lixia; Kawli, Trupti; Xie, Dan; Snyder, Michael] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Cheng, Chao; Rozowsky, Joel; Wang, Daifeng; Yan, Koon-Kiu; Gerstein, Mark] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Gardner, Kathryn; Janette, Judith; Kasper, Dionna; Niu, Wei; Reinke, Valerie] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Hillier, LaDeana W.; Ma, Lijia; Terrell, Robert; Vafeados, Dionne; Waterston, Robert H.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Kundaje, Anshul] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Kheradpour, Pouya; Kundaje, Anshul; Wu, Yi-Chieh; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Li, Jingyi Jessica; Huang, Haiyan; Bickel, Peter J.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Li, Jingyi Jessica] Univ Calif Los Angeles, Dept Stat, Los Angeles, CA 90095 USA. [Rehm, E. Jay; Slattery, Matthew; Spokony, Rebecca; White, Kevin P.] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Feingold, Elise A.; Good, Peter J.; Pazin, Michael J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Brenner, Steven E.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Brenner, Steven E.] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA. RP Snyder, M (reprint author), Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. EM kpwhite@uchicago.edu; manoli@mit.edu; mpsnyder@stanford.edu RI Brenner, Steven/A-8729-2008; cheng, yong/I-4270-2012; Boyle, Alan/I-1848-2014 OI Brenner, Steven/0000-0001-7559-6185; Gerstein, Mark/0000-0002-9746-3719; Araya, Carlos/0000-0002-5512-3062; Rozowsky, Joel/0000-0002-3565-0762; Pazin, Michael/0000-0002-7561-3640; Boyle, Alan/0000-0002-2081-1105 FU NHGRI as part of the modENCODE; NHGRI as part of the ENCODE; [U01HG004264]; [RC2HG005679]; [P50GM081892]; [U54HG006996]; [U54HG004558]; [U01HG004267]; [F32GM101778] FX This work is supported by the NHGRI as part of the modENCODE and ENCODE projects. This work was funded by U01HG004264, RC2HG005679 and P50GM081892 to K.P.W., U54HG006996, U54HG004558 and U01HG004267 to M.S., and F32GM101778 to K.E.G. NR 54 TC 57 Z9 57 U1 3 U2 61 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 28 PY 2014 VL 512 IS 7515 BP 453 EP + DI 10.1038/nature13668 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN8GC UT WOS:000340840600039 PM 25164757 ER PT J AU Kotlyar, DS Shum, M Hsieh, J Blonski, W Greenwald, DA AF Kotlyar, David S. Shum, Mili Hsieh, Jennifer Blonski, Wojciech Greenwald, David A. TI Non-pulmonary allergic diseases and inflammatory bowel disease: A qualitative review SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Inflammatory bowel disease; Ulcerative colitis; Crohn's disease; Food intolerance; Food allergies; Biomarkers; Pathophysiology; Nutrition; Probiotics ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; ACTIVE CROHNS-DISEASE; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; ULCERATIVE-COLITIS; MAST-CELLS; DOUBLE-BLIND; MAINTAINING REMISSION; ESCHERICHIA-COLI AB While the etiological underpinnings of inflammatory bowel disease (IBD) are highly complex, it has been noted that both clinical and pathophysiological similarities exist between IBD and both asthma and non-pulmonary allergic phenomena. In this review, several key points on common biomarkers, pathophysiology, clinical manifestations and nutritional and probiotic interventions for both IBD and non-pulmonary allergic diseases are discussed. Histamine and mast cell activity show common behaviors in both IBD and in certain allergic disorders. IgE also represents a key immunoglobulin involved in both IBD and in certain allergic pathologies, though these links require further study. Probiotics remain a critically important intervention for both IBD subtypes as well as multiple allergic phenomena. Linked clinical phenomena, especially sinonasal disease and IBD, are discussed. In addition, nutritional interventions remain an underutilized and promising therapy for modification of both allergic disorders and IBD. Recommending new mothers breastfeed their infants, and increasing the duration of breastfeeding may also help prevent both IBD and allergic diseases, but requires more investigation. While much remains to be discovered, it is clear that non-pulmonary allergic phenomena are connected to IBD in a myriad number of ways and that the discovery of common immunological pathways may usher in an era of vastly improved treatments for patients. (C) 2014 Baishideng Publishing Group Inc. All rights reserved. C1 [Kotlyar, David S.] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Shum, Mili] New York Presbyterian Med Ctr, Dept Med, New York, NY 10021 USA. [Hsieh, Jennifer] SUNY Stony Brook, Dept Med, Div Gastroenterol, Stony Brook, NY 11790 USA. [Blonski, Wojciech] SUNY Upstate Med Univ, Dept Med, Binghamton, NY 13902 USA. [Blonski, Wojciech] Med Univ, PL-53111 Wroclaw, Poland. [Greenwald, David A.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Med, Div Gastroenterol & Liver Dis, Bronx, NY 10461 USA. RP Greenwald, DA (reprint author), Albert Einstein Coll Med, Montefiore Med Ctr, Dept Med, Div Gastroenterol & Liver Dis, 625 Ullman Bldg,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM dgreenwa@montefiore.org FU NIH Intramural Program; NCI Fellowship Program; NIH FX Supported by NIH Intramural Program to Kotlyar DS; NCI Fellowship Program, NIH NR 87 TC 0 Z9 0 U1 0 U2 10 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD AUG 28 PY 2014 VL 20 IS 32 BP 11023 EP 11032 DI 10.3748/wjg.v20.i32.11023 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO0RM UT WOS:000341019200001 PM 25170192 ER PT J AU Volkow, ND Compton, WM Weiss, SRB AF Volkow, Nora D. Compton, Wilson M. Weiss, Susan R. B. TI Adverse Health Effects of Marijuana Use REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Volkow, Nora D.; Compton, Wilson M.; Weiss, Susan R. B.] NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 2 TC 26 Z9 27 U1 3 U2 23 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 AUG 28 PY 2014 VL 371 IS 9 BP 879 EP 879 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AN7ZN UT WOS:000340819800024 PM 25162899 ER PT J AU Dean, M Bendfeldt, G Lou, H Giron, V Garrido, C Valverde, P Barnoya, M Castellanos, M Jimenez-Morales, S Luna-Fineman, S AF Dean, Michael Bendfeldt, Giovana Lou, Hong Giron, Veronica Garrido, Claudia Valverde, Patricia Barnoya, Margarita Castellanos, Mauricio Jimenez-Morales, Silvia Luna-Fineman, Sandra TI Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala SO CANCER LETTERS LA English DT Article DE RB1 gene; Mutations; Methylation; Guatemala; Ethnicity; Health disparity ID RB1 GENE; CANCER; MUTATIONS; HYPERMETHYLATION; ASSOCIATION; EXPRESSION; FREQUENCY; SPECTRUM AB Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population. Published by Elsevier Ireland Ltd. C1 [Dean, Michael; Bendfeldt, Giovana; Jimenez-Morales, Silvia] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Bendfeldt, Giovana] Univ San Carlos, Sch Med, Guatemala City, Guatemala. [Lou, Hong] Leidos Biomed Res Corp, Frederick, MD 21702 USA. [Giron, Veronica; Garrido, Claudia; Valverde, Patricia; Barnoya, Margarita; Castellanos, Mauricio; Jimenez-Morales, Silvia; Luna-Fineman, Sandra] Stanford Univ, Stanford, CA 94305 USA. [Giron, Veronica; Garrido, Claudia; Valverde, Patricia; Barnoya, Margarita; Castellanos, Mauricio; Luna-Fineman, Sandra] Unidad Nacl Oncol Pediat, Guatemala City, Guatemala. [Jimenez-Morales, Silvia] Natl Inst Genom Med, Lab Immunogen & Metab Dis, Mexico City, DF, Mexico. [Luna-Fineman, Sandra] Stanford Univ, Sch Med, Pediat Hematol Oncol SCT Canc Bio, Stanford, CA 94305 USA. RP Dean, M (reprint author), NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU Intermural Research Program, National Institutes of Health; St. Judes International Outreach Program; Department of Pediatrics, Stanford University FX The authors thank the patients and their families who participated in the present study, as well as the cancer registry and staff of UNOP, Patricia Zaid and Martha Balsells de Sechel for assistance in sample collection and shipping, and Bert Gold, Peggy Tucker, Carlos Rodriguez-Galindo and Federico Antillon-Klussmann for comments on the manuscript. Supported in part by the Intermural Research Program, National Institutes of Health; the St. Judes International Outreach Program, and the Department of Pediatrics, Stanford University. NR 19 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD AUG 28 PY 2014 VL 351 IS 1 BP 59 EP 63 DI 10.1016/j.canlet.2014.04.023 PG 5 WC Oncology SC Oncology GA AM3TI UT WOS:000339775300008 PM 24814393 ER PT J AU Schmiedt, JT Maier, A Fries, P Saunders, RC Leopold, DA Schmid, MC AF Schmiedt, Joscha T. Maier, Alexander Fries, Pascal Saunders, Richard C. Leopold, David A. Schmid, Michael C. TI Beta Oscillation Dynamics in Extrastriate Cortex after Removal of Primary Visual Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE blindsight; cortex; monkey; neurophysiology; oscillation; V4 ID LATERAL GENICULATE-NUCLEUS; MACAQUE AREA V4; SUPERIOR COLLICULUS; ATTENTIONAL MODULATION; PERCEPTUAL SUPPRESSION; NEURONAL MECHANISMS; ALPHA OSCILLATIONS; BAND OSCILLATIONS; VENTRAL STREAM; MONKEY AB The local field potential (LFP) in visual cortex is typically characterized by the following spectral pattern: before the onset of a visual stimulus, low-frequency oscillations(beta, 12-20 Hz) dominate, whereas during the presentation of a stimulus these oscillations diminish and are replaced by fluctuations at higher frequencies(gamma, >30 Hz). The origin of beta oscillations in vivo remains unclear, as is the basis of their suppression during visual stimulation. Here we investigate the contribution of ascending input from primary visual cortex (V1) to beta oscillation dynamics in extrastriate visual area V4 of behaving monkeys. We recorded LFP activity in V4 before and after resecting a portion of V1. After the surgery, the visually induced gamma LFP activity in the lesion projection zone of V4 was markedly reduced, consistent with previously reported spiking responses (Schmid etal., 2013). In the beta LFP range, the lesion had minimal effect on the normal pattern of spontaneous oscillations. However, the lesion led to a surprising and permanent reversal of the normal beta suppression during visual stimulation, with visual stimuli eliciting beta magnitude increases up to 50%, particularly in response to moving stimuli. This reversed beta activity pattern was specific to stimulus locations affected by the V1 lesion. Our results shed light on the mechanisms of beta activity in extrastriate visual cortex: The preserved spontaneous oscillations point to a generation mechanism independent of the geniculostriate pathway, whereas the positive beta responses support the contribution of visual information to V4 via direct thalamo-extrastriate projections. C1 [Schmiedt, Joscha T.; Fries, Pascal; Schmid, Michael C.] Max Planck Gesell, Ernst Strungmann Inst ESI Neurosci Cooperat, D-60528 Frankfurt, Germany. [Maier, Alexander] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Fries, Pascal] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 EN Nijmegen, Netherlands. [Saunders, Richard C.; Leopold, David A.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Leopold, David A.] NINDS, Neurophysiol Imaging Facil, NIMH, Bethesda, MD 20892 USA. [Leopold, David A.] NEI, Bethesda, MD 20892 USA. RP Schmid, MC (reprint author), Max Planck Gesell, Ernst Strungmann Inst ESI Neurosci Cooperat, Deutschordenstr 46, D-60528 Frankfurt, Germany. EM michael.schmid@esi-frankfurt.de RI Fries, Pascal/E-3196-2010; Maier, Alexander/B-7489-2009; Schmid, Michael/G-1867-2010; OI Fries, Pascal/0000-0002-4270-1468; Maier, Alexander/0000-0002-7250-502X; Schmid, Michael/0000-0003-1424-130X; Schmiedt, Joscha Tapani/0000-0001-6233-1866; Leopold, David/0000-0002-1345-6360 FU Intramural Research Program of the National Institute of Mental Health and Deutsche Forschungsgemeinschaft Emmy Noether [2806/1-1]; Whitehall; Alfred P. Sloan Foundation FX This work was supported by the Intramural Research Program of the National Institute of Mental Health and Deutsche Forschungsgemeinschaft Emmy Noether Grant Schm 2806/1-1 to M.C.S. and Whitehall and Alfred P. Sloan Foundation Grants to A.M. We thank Charles Zhu, David Hu, Alex Cummins, Andy Mitz, Katy Smith, and James Yu for technical assistance and Andy Peters for help with the experiments. NR 54 TC 8 Z9 8 U1 1 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 27 PY 2014 VL 34 IS 35 BP 11857 EP 11864 DI 10.1523/JNEUROSCI.0509-14.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AO4MX UT WOS:000341314900032 PM 25164679 ER PT J AU Nayak, RK Miller, FG AF Nayak, Rahul K. Miller, Franklin G. TI Cost-Related Motivations for Research Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Nayak, Rahul K.; Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 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 AUG 27 PY 2014 VL 312 IS 8 BP 847 EP 848 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AN7NX UT WOS:000340788500035 PM 25157736 ER PT J AU Valantine, HA Beckerle, MC Reed, KL Towner, D Zahniser, NR AF Valantine, Hannah A. Beckerle, Mary C. Reed, Kathryn L. Towner, Dena Zahniser, Nancy R. TI Teaching Corporate in College SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID LEADERSHIP AB By applying the strengths of corporate models for effective teamwork, academic scientists can drive transdisciplinary research and accelerate biomedical translation. C1 [Valantine, Hannah A.] NIH, Bethesda, MD 20892 USA. [Beckerle, Mary C.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Reed, Kathryn L.] Univ Arizona, Coll Med, Dept Obstet & Gynecol, Tucson, AZ 85724 USA. [Towner, Dena] Univ Hawaii, John A Burns Sch Medline, Dept Obstet Gynecol, Honolulu, HI 96826 USA. [Zahniser, Nancy R.] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. RP Valantine, HA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM hannah.valantine@nih.gov NR 11 TC 1 Z9 1 U1 0 U2 0 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 AUG 27 PY 2014 VL 6 IS 251 AR 251fs33 DI 10.1126/scitranslmed.3009450 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AO4JY UT WOS:000341304800001 PM 25163476 ER PT J AU Wang, MG He, BYJ AF Wang, Megan He, Biyu J. TI A cross-modal investigation of the neural substrates for ongoing cognition SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE ongoing cognition; semantic processing; linguistic processing; cross-modal; default-mode network; fMRI; conscious flow ID STIMULUS-INDEPENDENT THOUGHT; BRAINS DEFAULT NETWORK; TEMPORAL-LOBE; REPRESENTATION; KNOWLEDGE; SYSTEM; FMRI; CONSCIOUSNESS; DISSOCIATION; INTEGRATION AB What neural mechanisms underlie the seamless flow of our waking consciousness? A necessary albeit insufficient condition for such neural mechanisms is that they should be consistently modulated across time were a segment of the conscious stream to be repeated twice. In this study, we experimentally manipulated the content of a story followed by subjects during functional magnetic resonance imaging (fMRI) independently from the modality of sensory input (as visual text or auditory speech) as well as attentional focus. We then extracted brain activity patterns consistently modulated across subjects by the evolving content of the story regardless of whether it was presented visually or auditorily. Specifically, in one experiment we presented the same story to different subjects via either auditory or visual modality. In a second experiment, we presented two different stories simultaneously, one auditorily, one visually, and manipulated the subjects' attentional focus. This experimental design allowed us to dissociate brain activities underlying modality-specific sensory processing from modality-independent story processing. We uncovered a network of brain regions consistently modulated by the evolving content of a story regardless of the sensory modality used for stimulus input, including the superior temporal sulcus/gyrus (STS/STG), the inferior frontal gyrus (IFG), the posterior cingulate cortex (FCC), the medial frontal cortex (MFC), the temporal pole (TP), and the temporoparietal junction (TPJ). Many of these regions have previously been implicated in semantic processing. Interestingly, different stories elicited similar brain activity patterns, but with subtle differences potentially attributable to varying degrees of emotional valence and self-relevance. C1 [Wang, Megan; He, Biyu J.] NINDS, NIH, Bethesda, MD 20892 USA. RP He, BYJ (reprint author), NINDS, NIH, 10 Ctr Dr,Bldg 10,Room B1D728, Bethesda, MD 20892 USA. EM biyu.he@nih.gov OI He, Biyu/0000-0003-1549-1351 NR 41 TC 2 Z9 2 U1 0 U2 7 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD AUG 26 PY 2014 VL 5 AR 945 DI 10.3389/fpsyg.2014.00945 PG 10 WC Psychology, Multidisciplinary SC Psychology GA AO5ZB UT WOS:000341424700002 PM 25206347 ER PT J AU Katz, G Pobezinsky, LA Jeurling, S Shinzawa, M Van Laethem, F Singer, A AF Katz, Gil Pobezinsky, Leonid A. Jeurling, Susanna Shinzawa, Miho Van Laethem, Francois Singer, Alfred TI T cell receptor stimulation impairs IL-7 receptor signaling by inducing expression of the microRNA miR-17 to target Janus kinase 1 SO SCIENCE SIGNALING LA English DT Article ID DOUBLE-POSITIVE THYMOCYTES; DIFFERENTIATION; HOMEOSTASIS; MICE; INTERLEUKIN-7; INHIBITION; ACTIVATION; MECHANISMS; CYTOKINES; SELECTION AB T cell receptor (TCR)-mediated inhibition of interleukin-7 (IL-7) signaling is important for lineage fate determination in the thymus and for T cell survival in the periphery because uninterrupted IL-7 signaling results in T cell death. The initial event in IL-7 signaling is the transactivation of Janus kinases 1 and 3 (Jak1 and Jak3), which are associated with the cytosolic tails of the IL-7 receptor alpha chain (IL-7R alpha) and the gamma c subunit, the two cell surface proteins that constitute IL-7R. We found that Jak1 is a highly unstable protein with a half-life of only 1.5 hours, so that continuous Jak1 protein synthesis is required to maintain Jak1 protein in sufficient abundance to support IL-7 signaling. However, we also found that Jak1 protein synthesis was acutely reduced by TCR-responsive microRNAs in the miR-17 family, which targeted Jak1 mRNA (messenger RNA) to inhibit its translation. Thus, this study identifies a molecular mechanism by which TCR engagement acutely disrupts IL-7 signaling. C1 [Katz, Gil; Pobezinsky, Leonid A.; Jeurling, Susanna; Shinzawa, Miho; Van Laethem, Francois; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM singera@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 25 TC 9 Z9 9 U1 2 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD AUG 26 PY 2014 VL 7 IS 340 AR ra83 DI 10.1126/scisignal.2005221 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AO5ZK UT WOS:000341425900003 PM 25161318 ER PT J AU Fenollar-Ferrer, C Stockner, T Schwarz, TC Pal, A Gotovina, J Hofmaier, T Jayaraman, K Adhikary, S Kudlacek, O Mehdipour, AR Tavoulari, S Rudnick, G Singh, SK Konrat, R Sitte, HH Forrest, LR AF Fenollar-Ferrer, Cristina Stockner, Thomas Schwarz, Thomas C. Pal, Aritra Gotovina, Jelena Hofmaier, Tina Jayaraman, Kumaresan Adhikary, Suraj Kudlacek, Oliver Mehdipour, Ahmad Reza Tavoulari, Sotiria Rudnick, Gary Singh, Satinder K. Konrat, Robert Sitte, Harald H. Forrest, Lucy R. TI Structure and Regulatory Interactions of the Cytoplasmic Terminal Domains of Serotonin Transporter SO BIOCHEMISTRY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; DOPAMINE TRANSPORTER; SYNTAXIN 1A; NEUROTRANSMITTER TRANSPORTERS; MONOAMINE TRANSPORTERS; QUALITY ASSESSMENT; CRYSTAL-STRUCTURE; MEMBRANE-PROTEIN; C-TERMINUS; KINASE-C AB Uptake of neurotransmitters by sodium-coupled monoamine transporters of the NSS family is required for termination of synaptic transmission. Transport is tightly regulated by protein protein interactions involving the small cytoplasmic segments at the amino- and carboxy-terminal ends of the transporter. Although structures of homologues provide information about the transmembrane regions of these transporters, the structural arrangement of the terminal domains remains largely unknown. Here, we combined molecular modeling, biochemical, and biophysical approaches in an iterative manner to investigate the structure of the 82-residue N-terminal and 30-residue C-terminal domains of human serotonin transporter (SERT). Several secondary structures were predicted in these domains, and structural models were built using the Rosetta fragment-based methodology. One-dimensional H-1 nuclear magnetic resonance and circular dichroism spectroscopy supported the presence of helical elements in the isolated SERT N-terminal domain. Moreover, introducing helix-breaking residues within those elements altered the fluorescence resonance energy transfer signal between terminal cyan fluorescent protein and yellow fluorescent protein tags attached to full-length SERT, consistent with the notion that the fold of the terminal domains is relatively well-defined. Full-length models of SERT that are consistent with these and published experimental data were generated. The resultant models predict confined loci for the terminal domains and predict that they move apart during the transport-related conformational cycle, as predicted by structures of homologues and by the "rocking bundle" hypothesis, which is consistent with spectroscopic measurements. The models also suggest the nature of binding to regulatory interaction partners. This study provides a structural context for functional and regulatory mechanisms involving SERT terminal domains. C1 [Fenollar-Ferrer, Cristina; Mehdipour, Ahmad Reza; Forrest, Lucy R.] Max Planck Inst Biophys, Computat Struct Biol Grp, D-60438 Frankfurt, Germany. [Stockner, Thomas; Gotovina, Jelena; Hofmaier, Tina; Jayaraman, Kumaresan; Kudlacek, Oliver; Sitte, Harald H.] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, A-1090 Vienna, Austria. [Schwarz, Thomas C.; Konrat, Robert] Univ Vienna, Max F Perutz Labs, Dept Struct & Computat Chem, A-1030 Vienna, Austria. [Pal, Aritra; Adhikary, Suraj; Singh, Satinder K.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. [Tavoulari, Sotiria; Rudnick, Gary] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. RP Forrest, LR (reprint author), NINDS, Computat Struct Biol Sect, NIH, Bethesda, MD 20824 USA. EM harald.sitte@meduniwien.ac.at; lucy.forrest@nih.gov RI Stockner, Thomas/A-9509-2014; OI Stockner, Thomas/0000-0002-7071-8283; Sitte, Harald/0000-0002-1339-7444 FU Austrian Science Fund/FWF [F35, W1232]; Goodman Gilman Yale Scholar Award; Alfred P. Sloan Foundation; National Institutes of Health [R00MH083050, R21MH098180]; Max Planck Society; Division of Intramural Research of the National Institute of Neurological Disorder and Stroke, at the National Institutes of Health; [W-1221-B03] FX This work was supported by grants to H.H.S. from the Austrian Science Fund/FWF (F35 and W1232), to R.K. (Grant W-1221-B03), to S.K.S. from the Goodman Gilman Yale Scholar Award, the Alfred P. Sloan Foundation, and the National Institutes of Health (R00MH083050 and R21MH098180), and to L.R.F. from the Max Planck Society and the Division of Intramural Research of the National Institute of Neurological Disorder and Stroke, at the National Institutes of Health. NR 74 TC 13 Z9 13 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 26 PY 2014 VL 53 IS 33 BP 5444 EP 5460 DI 10.1021/bi500637f PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO0IW UT WOS:000340993300008 PM 25093911 ER PT J AU Hickman, AB Dyda, F AF Hickman, Alison B. Dyda, Fred TI CRISPR-Cas immunity and mobile DNA: a new superfamily of DNA transposons encoding a Cas1 endonuclease SO MOBILE DNA LA English DT Article DE DNA transposition; V(D)J recombination; CRISPR-Cas; Adaptive immunity; Casposon; Transposable elements; Cas1 nuclease protein ID ADAPTIVE IMMUNITY; EUKARYOTIC GENOMES; EVOLUTION; ELEMENTS; SYSTEMS; ACQUISITION AB Mobile genetic elements such as DNA transposons are a feature of most genomes. The existence of novel DNA transposons can be inferred when whole genome sequencing reveals the presence of hallmarks of mobile elements such as terminal inverted repeats (TIRs) flanked by target site duplications (TSDs). A recent report describes a new superfamily of DNA transposons in the genomes of a few bacteria and archaea that possess TIRs and TSDs, and encode several conserved genes including a cas1 endonuclease gene, previously associated only with CRISPR-Cas adaptive immune systems. The data strongly suggests that these elements, designated 'casposons', are likely to be bona fide DNA transposons and that their Cas1 nucleases act as transposases and are possibly still active. C1 [Hickman, Alison B.; Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hickman, AB (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM alisonh@helix.nih.gov FU NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This work was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 21 TC 7 Z9 7 U1 2 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1759-8753 J9 MOBILE DNA-UK JI Mob. DNA PD AUG 26 PY 2014 VL 5 AR 23 DI 10.1186/1759-8753-5-23 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA AO1BP UT WOS:000341047100001 PM 25180049 ER PT J AU Montine, TJ Koroshetz, WJ Babcock, D Dickson, DW Galpern, WR Glymour, MM Greenberg, SM Hutton, ML Knopman, DS Kuzmichev, AN Manly, JJ Marder, KS Miller, BL Phelps, CH Seeley, WW Sieber, BA Silverberg, NB Sutherland, M Torborg, CL Waddy, SP Zlokovic, BV Corriveau, RA AF Montine, Thomas J. Koroshetz, Walter J. Babcock, Debra Dickson, Dennis W. Galpern, Wendy R. Glymour, M. Maria Greenberg, Steven M. Hutton, Michael L. Knopman, David S. Kuzmichev, Andrey N. Manly, Jennifer J. Marder, Karen S. Miller, Bruce L. Phelps, Creighton H. Seeley, William W. Sieber, Beth-Anne Silverberg, Nina B. Sutherland, Margaret Torborg, Christine L. Waddy, Salina P. Zlokovic, Berislav V. Corriveau, Roderick A. CA ADRD 2013 Conference Organizing TI Recommendations of the Alzheimer's Disease-Related Dementias Conference SO NEUROLOGY LA English DT Review ID MILD COGNITIVE IMPAIRMENT; NATIONAL INSTITUTE; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES AB The National Alzheimer's Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimer's Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease ( AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease-related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan. C1 [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Koroshetz, Walter J.; Babcock, Debra; Galpern, Wendy R.; Kuzmichev, Andrey N.; Sieber, Beth-Anne; Sutherland, Margaret; Torborg, Christine L.; Waddy, Salina P.; Corriveau, Roderick A.] NINDS, Bethesda, MD 20892 USA. [Dickson, Dennis W.] Mayo Clin, Neuropathol Lab, Jacksonville, FL 32224 USA. [Glymour, M. Maria] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Greenberg, Steven M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hemorrhag Stroke Res Program,Dept Neurol, Boston, MA USA. [Hutton, Michael L.] Eli Lilly & Co, Lilly Res Ctr, Neurodegenerat Dis DHT, Windlesham, Surrey, England. [Knopman, David S.] Mayo Clin Rochester, Dept Neurol, Rochester, MN USA. [Manly, Jennifer J.; Marder, Karen S.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. [Manly, Jennifer J.; Marder, Karen S.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Miller, Bruce L.; Seeley, William W.] Univ Calif San Francisco, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Phelps, Creighton H.; Silverberg, Nina B.] NIA, Bethesda, MD 20892 USA. [Zlokovic, Berislav V.] Univ So Calif, Keck Sch Med, Zilhka Neurogenet Inst, Ctr Neurodegenerat & Regenerat, Los Angeles, CA 90033 USA. [Zlokovic, Berislav V.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. RP Corriveau, RA (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM roderick.corriveau@nih.gov FU NINDS; Alliance for Aging Research; Alzheimer's Association; Association for Frontotemporal Degeneration; USAgainstAlzheimer's FX This conference was supported by the NINDS, organized in collaboration with the NIA, with assistance from the FNIH, and with additional support from the Alliance for Aging Research, the Alzheimer's Association, the Association for Frontotemporal Degeneration and USAgainstAlzheimer's. NR 14 TC 23 Z9 23 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 26 PY 2014 VL 83 IS 9 BP 851 EP 860 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AO1SY UT WOS:000341096100019 PM 25080517 ER PT J AU Bird, JE Takagi, Y Billington, N Strub, MP Sellers, JR Friedman, TB AF Bird, Jonathan E. Takagi, Yasuharu Billington, Neil Strub, Marie-Paule Sellers, James R. Friedman, Thomas B. TI Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE deafness; DFNB3; myosin XV; UNC-45 ID SMOOTH-MUSCLE MYOSIN; HAIR-CELL STEREOCILIA; HYPERTROPHIC CARDIOMYOPATHY; HEAVY-MEROMYOSIN; DEAFNESS DFNB3; ACTIN-FILAMENT; POWER-STROKE; YEAST; XVA; PHOSPHORYLATION AB Unconventional myosin 15 is a molecular motor expressed in inner ear hair cells that transports protein cargos within developing mechanosensory stereocilia. Mutations of myosin 15 cause profound hearing loss in humans and mice; however, the properties of this motor and its regulation within the stereocilia organelle are unknown. To address these questions, we expressed a subfragment 1-like (S1) truncation of mouse myosin 15, comprising the predicted motor domain plus three light-chain binding sites. Following unsuccessful attempts to express functional myosin 15-S1 using the Spodoptera frugiperda (Sf9)-baculovirus system, we discovered that coexpression of the muscle-myosin-specific chaperone UNC45B, in addition to the chaperone heat-shock protein 90 (HSP90) significantly increased the yield of functional protein. Surprisingly, myosin 15-S1 did not bind calmodulin with high affinity. Instead, the IQ domains bound essential and regulatory light chains that are normally associated with class II myosins. We show that myosin 15-S1 is a barbed-end-directed motor that moves actin filaments in a gliding assay (similar to 430 nm center dot s(-1) at 30 degrees C), using a power stroke of 7.9 nm. The maximum ATPase rate (k(cat) similar to 6 s(-1)) was similar to the actin-detachment rate (k(det) = 6.2 s(-1)) determined in single molecule optical trapping experiments, indicating that myosin 15-S1 was rate limited by transit through strongly actin-bound states, similar to other processive myosin motors. Our data further indicate that in addition to folding muscle myosin, UNC45B facilitates maturation of an unconventional myosin. We speculate that chaperone coexpression may be a simple method to optimize the purification of other myosin motors from Sf9 insect cells. C1 [Bird, Jonathan E.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, Bethesda, MD USA. [Takagi, Yasuharu; Billington, Neil; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Strub, Marie-Paule] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov; friedman@nidcd.nih.gov OI Bird, Jonathan/0000-0001-5531-8794 FU intramural funds of the NHLBI [HL004243-12]; National Institute on Deafness and Other Communication Disorders [DC000039-17] FX We thank Attila Nagy for the gift of pFastbac-EGFP-FLAG; Lisa Cunningham, Dennis Drayna, and Melanie Barzik for critical review of our manuscript; Earl Homsher and Sarah Heissler for helpful discussions; Ming Zhou and DaRue Prieto at the Advanced Technology Program (National Cancer Institute) for core proteomic services; and the Electron Microscopy Core Facility at the National Heart, Lung, and Blood Institute (NHLBI) for their support, advice, and use of facilities. This work was funded by the intramural funds of the NHLBI (HL004243-12 to J.R.S.) and the National Institute on Deafness and Other Communication Disorders (DC000039-17 to T.B.F.). NR 55 TC 13 Z9 13 U1 5 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 26 PY 2014 VL 111 IS 34 BP 12390 EP 12395 DI 10.1073/pnas.1409459111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN7LA UT WOS:000340780300036 PM 25114250 ER PT J AU Lucas, M Gaspar, AH Pallara, C Rojas, AL Fernandez-Recio, J Machner, MP Hierro, A AF Lucas, Maria Gaspar, Andrew H. Pallara, Chiara Lucely Rojas, Adriana Fernandez-Recio, Juan Machner, Matthias P. Hierro, Aitor TI Structural basis for the recruitment and activation of the Legionella phospholipase VipD by the host GTPase Rab5 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pathogenic bacteria; allosteric modulation; membrane composition; X-ray crystallography ID RAY SOLUTION SCATTERING; SMALL-ANGLE SCATTERING; INTERFACIAL ACTIVATION; CRYSTAL-STRUCTURE; SWITCH REGIONS; PNEUMOPHILA; PROTEINS; COMPLEX; LIPASE; FAMILY AB A challenge for microbial pathogens is to assure that their translocated effector proteins target only the correct host cell compartment during infection. The Legionella pneumophila effector vacuolar protein sorting inhibitor protein D (VipD) localizes to early endosomal membranes and alters their lipid and protein composition, thereby protecting the pathogen from endosomal fusion. This process requires the phospholipase A1 (PLA(1)) activity of VipD that is triggered specifically on VipD binding to the host cell GTPase Rab5, a key regulator of endosomes. Here, we present the crystal structure of VipD in complex with constitutively active Rab5 and reveal the molecular mechanism underlying PLA(1) activation. An active site-obstructing loop that originates from the C-terminal domain of VipD is repositioned on Rab5 binding, thereby exposing the catalytic pocket within the N-terminal PLA(1) domain. Substitution of amino acid residues located within the VipD-Rab5 interface prevented Rab5 binding and PLA(1) activation and caused a failure of VipD mutant proteins to target to Rab5-enriched endosomal structures within cells. Experimental and computational analyses confirmed an extended VipD-binding interface on Rab5, explaining why this L. pneumophila effector can compete with cellular ligands for Rab5 binding. Together, our data explain how the catalytic activity of a microbial effector can be precisely linked to its subcellular localization. C1 [Lucas, Maria; Lucely Rojas, Adriana; Hierro, Aitor] Ctr Cooperat Res Biosci, Struct Biol Unit, Derio 48160, Spain. [Gaspar, Andrew H.; Machner, Matthias P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Pallara, Chiara; Fernandez-Recio, Juan] Barcelona Supercomp Ctr, Inst Res Biomed, Res Program Computat Biol, Barcelona 08034, Spain. [Hierro, Aitor] Basque Fdn Sci, IKERBASQUE, Bilbao 48011, Spain. RP Machner, MP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM machnerm@mail.nih.gov; ahierro@cicbiogune.es RI Hierro, Aitor/F-9998-2011; Rojas, Adriana/G-2403-2011; Machner, Matthias/G-2758-2015; Pallara, Chiara/F-9441-2016; Lucas, Maria/G-9788-2012; OI Hierro, Aitor/0000-0002-7721-1581; Rojas, Adriana/0000-0002-7358-3505; Pallara, Chiara/0000-0003-3005-343X; Lucas, Maria/0000-0002-7854-4249; Fernandez-Recio, Juan/0000-0002-3986-7686 FU Carlos III Health Institute [PI11/00121]; Basque Government [PI2011-26]; BioStruct-X program; European Synchrotron Radiation Facility (Grenoble, France) under the Block Allocation Group [MX1283/MX1420]; ALBA [BL13-XALOC] FX We thank A. Vidaurrazaga for technical assistance. We thank all the staff from the facilities where work was done for technical and human support. This work was supported by Carlos III Health Institute Grant PI11/00121 and Basque Government Grant PI2011-26 (to A. H.). This study made use of the Diamond Light Source (Oxfordshire, United Kingdom), partly funded by the BioStruct-X program (Proposal 2370), the European Synchrotron Radiation Facility (Grenoble, France) under the Block Allocation Group MX1283/MX1420, and ALBA synchrotron beamline BL13-XALOC under Proposal 2012100351. NR 52 TC 17 Z9 18 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 26 PY 2014 VL 111 IS 34 BP E3514 EP E3523 DI 10.1073/pnas.1405391111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN7LA UT WOS:000340780300006 PM 25114243 ER PT J AU Nicolaides, NC Charmandari, E Chrousos, GP Kino, T AF Nicolaides, Nicolas C. Charmandari, Evangelia Chrousos, George P. Kino, Tomoshige TI Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor SO BMC ENDOCRINE DISORDERS LA English DT Review DE Glucocorticoid receptor; Glucocorticoid resistance; Glucocorticoid hypersensitivity; Glucocorticoid signal transduction ID PRIMARY CORTISOL RESISTANCE; PITUITARY-ADRENAL AXIS; BINDING DOMAIN; POINT MUTATION; GENE-EXPRESSION; ER22/23EK POLYMORPHISM; RESPONSE ELEMENTS; IN-VIVO; STRESS; HORMONE AB Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor. C1 [Nicolaides, Nicolas C.; Charmandari, Evangelia; Chrousos, George P.] Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Div Endocrinol Metab & Diabet,Dept Pediat 1, GR-11527 Athens, Greece. [Nicolaides, Nicolas C.; Charmandari, Evangelia; Chrousos, George P.] Acad Athens, Biomed Res Fdn, Clin Res Ctr, Div Endocrinol & Metab, Athens 11527, Greece. [Chrousos, George P.] King Abdulaziz Univ, King Fahd Med Res Ctr, Saudi Diabet Study Res Grp, Jeddah 21413, Saudi Arabia. [Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Nicolaides, NC (reprint author), Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Div Endocrinol Metab & Diabet,Dept Pediat 1, GR-11527 Athens, Greece. EM nnicolaides@bioacademy.gr RI Charmandari, Evangelia/B-6701-2011 FU European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program: THALIS - University of Athens (UOA), Athens, Greece; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA FX This work was supported by i) the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program: THALIS - University of Athens (UOA), Athens, Greece; and ii) the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892, USA. NR 69 TC 14 Z9 15 U1 3 U2 24 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 AUG 25 PY 2014 VL 14 AR 71 DI 10.1186/1472-6823-14-71 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AO6GF UT WOS:000341447500001 PM 25155432 ER PT J AU Mao, YQ Van Auken, K Li, DH Arighi, CN McQuilton, P Hayman, GT Tweedie, S Schaeffer, ML Laulederkind, SJF Wang, SJ Gobeill, J Ruch, P Luu, AT Kim, JJ Chiang, JH Chen, YD Yang, CJ Liu, HF Zhu, DQ Li, YP Yu, H Emadzadeh, E Gonzalez, G Chen, JM Dai, HJ Lu, ZY AF Mao, Yuqing Van Auken, Kimberly Li, Donghui Arighi, Cecilia N. McQuilton, Peter Hayman, G. Thomas Tweedie, Susan Schaeffer, Mary L. Laulederkind, Stanley J. F. Wang, Shur-Jen Gobeill, Julien Ruch, Patrick Anh Tuan Luu Kim, Jung-jae Chiang, Jung-Hsien Chen, Yu-De Yang, Chia-Jung Liu, Hongfang Zhu, Dongqing Li, Yanpeng Yu, Hong Emadzadeh, Ehsan Gonzalez, Graciela Chen, Jian-Ming Dai, Hong-Jie Lu, Zhiyong TI Overview of the gene ontology task at BioCreative IV SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID ANNOTATION; EXTRACTION; TOOL AB Gene Ontology (GO) annotation is a common task among model organism databases (MODs) for capturing gene function data from journal articles. It is a time-consuming and labor-intensive task, and is thus often considered as one of the bottlenecks in literature curation. There is a growing need for semiautomated or fully automated GO curation techniques that will help database curators to rapidly and accurately identify gene function information in full-length articles. Despite multiple attempts in the past, few studies have proven to be useful with regard to assisting real-world GO curation. The shortage of sentence-level training data and opportunities for interaction between text-mining developers and GO curators has limited the advances in algorithm development and corresponding use in practical circumstances. To this end, we organized a text-mining challenge task for literature-based GO annotation in BioCreative IV. More specifically, we developed two subtasks: (i) to automatically locate text passages that contain GO-relevant information (a text retrieval task) and (ii) to automatically identify relevant GO terms for the genes in a given article (a concept-recognition task). With the support from five MODs, we provided teams with >4000 unique text passages that served as the basis for each GO annotation in our task data. Such evidence text information has long been recognized as critical for text-mining algorithm development but was never made available because of the high cost of curation. In total, seven teams participated in the challenge task. From the team results, we conclude that the state of the art in automatically mining GO terms from literature has improved over the past decade while much progress is still needed for computer-assisted GO curation. Future work should focus on addressing remaining technical challenges for improved performance of automatic GO concept recognition and incorporating practical benefits of text-mining tools into real-world GO annotation. C1 [Mao, Yuqing; Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat NCBI, Bethesda, MD 20817 USA. [Van Auken, Kimberly] CALTECH, Div Biol, WormBase, Pasadena, CA 91125 USA. [Li, Donghui] Carnegie Inst Sci, Dept Plant Biol, TAIR, Stanford, CA 94305 USA. [Arighi, Cecilia N.] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. [McQuilton, Peter; Tweedie, Susan] Univ Cambridge, Dept Genet, FlyBase, Cambridge CB2 3EH, England. [Hayman, G. Thomas; Laulederkind, Stanley J. F.; Wang, Shur-Jen] Med Coll Wisconsin, Rat Genome Database Human & Mol Genet Ctr, Milwaukee, WI 53226 USA. [Schaeffer, Mary L.] ARS, USDA, Plant Genet Res Unit, Columbia, MO 65211 USA. [Schaeffer, Mary L.] Univ Missouri, Div Plant Sci, Dept Agron, Columbia, MO 65211 USA. [Gobeill, Julien; Ruch, Patrick] HEG, HES SO, CH-1227 Carouge, Switzerland. [Gobeill, Julien; Ruch, Patrick] Swiss Inst Bioinformat, SIBtex, CH-1211 Geneva 4, Switzerland. [Anh Tuan Luu; Kim, Jung-jae] Nanyang Technol Univ, Sch Comp Engn, Singapore 639798, Singapore. [Chiang, Jung-Hsien; Chen, Yu-De; Yang, Chia-Jung] Natl Cheng Kung Univ, Dept Comp Sci & Informat Engn, Tainan 701, Taiwan. [Yang, Chia-Jung] Mackay Mem Hosp, Dept Radiol, Taitung Branch, Taitung, Taiwan. [Liu, Hongfang; Zhu, Dongqing] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Zhu, Dongqing] Univ Delaware, Dept Comp Sci, Newark, DE 19716 USA. [Li, Yanpeng; Yu, Hong] Univ Massachusetts, Dept Quantitat Hlth Sci, Sch Med, Worcester, MA 01655 USA. [Emadzadeh, Ehsan; Gonzalez, Graciela] Arizona State Univ, Dept Biomed Informat, Scottsdale, AZ 85259 USA. [Chen, Jian-Ming] Acad Sinica, Inst Informat Sci, Taipei 115, Taiwan. [Dai, Hong-Jie] Taipei Med Univ, Grad Inst BioMed Informat, Coll Med Sci & Technol, Taipei 110, Taiwan. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat NCBI, 8600 Rockville Pike, Bethesda, MD 20817 USA. EM Zhiyong.Lu@nih.gov RI Kim, Jung-jae/A-3738-2011; OI McQuilton, Peter/0000-0003-2687-1982; Tweedie, Susan/0000-0003-1818-8243; Gonzalez Hernandez, Graciela/0000-0002-6416-9556; Arighi, Cecilia/0000-0002-0803-4817 FU NIH Intramural Research Program, National Library of Medicine; National Human Genome Research Institute [U41-HG002223]; Gene Ontology Consortium by National Human Genome Research Institute (NHGRI) [U41-HG002273]; NHGRI/NIH [U41-HG000739]; UK Medical Research Council [G1000968]; NIH [R01LM009959A1]; SNF [153437]; European Union [257528]; [NSF/DBI-0850319]; [NSF/ABI-0845523] FX This research is supported by NIH Intramural Research Program, National Library of Medicine (Y.M. and Z.L.). The BioCreative IV Workshop is funded by NSF/DBI-0850319. WormBase is funded by National Human Genome Research Institute [U41-HG002223] and the Gene Ontology Consortium by National Human Genome Research Institute (NHGRI) [U41-HG002273]. FlyBase is funded by an NHGRI/NIH grant [U41-HG000739] and the UK Medical Research Council [G1000968]. Team 238 is funded by NSF/ABI-0845523 (H. L. and D.Z.), NIH R01LM009959A1 (H. L. and D.Z.). The SIBtex (Swiss Institute of Bioinformatics) team has been partially supported by the SNF (neXtpresso #153437) and the European Union (Khresmoi #257528). NR 67 TC 12 Z9 12 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD AUG 25 PY 2014 AR bau086 DI 10.1093/database/bau086 PG 14 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AO4KY UT WOS:000341308000001 ER PT J AU Nedvetsky, PI Emmerson, E Finley, JK Ettinger, A Cruz-Pacheco, N Prochazka, J Haddox, CL Northrup, E Hodges, C Mostov, KE Hoffman, MP Knox, SM AF Nedvetsky, Pavel I. Emmerson, Elaine Finley, Jennifer K. Ettinger, Andreas Cruz-Pacheco, Noel Prochazka, Jan Haddox, Candace L. Northrup, Emily Hodges, Craig Mostov, Keith E. Hoffman, Matthew P. Knox, Sarah M. TI Parasympathetic Innervation Regulates Tubulogenesis in the Developing Salivary Gland SO DEVELOPMENTAL CELL LA English DT Article ID MOUSE SUBMANDIBULAR-GLAND; LUMEN FORMATION; BRANCHING MORPHOGENESIS; CYSTIC-FIBROSIS; IN-VITRO; DUCTAL MORPHOGENESIS; ZEBRAFISH GUT; CELL-DEATH; MODEL; GENE AB A fundamental question in development is how cells assemble to form a tubular network during organ formation. In glandular organs, tubulogenesis is a multistep process requiring coordinated proliferation, polarization and reorganization of epithelial cells to form a lumen, and lumen expansion. Although it is clear that epithelial cells possess an intrinsic ability to organize into polarized structures, the mechanisms coordinating morphogenetic processes during tubulogenesis are poorly understood. Here, we demonstrate that parasympathetic nerves regulate tubulogenesis in the developing salivary gland. We show that vasoactive intestinal peptide (VIP) secreted by the innervating ganglia promotes ductal growth, leads to the formation of a contiguous lumen, and facilitates lumen expansion through a cyclic AMP/protein kinase A (cAMP/PKA)-dependent pathway. Furthermore, we provide evidence that lumen expansion is independent of apoptosis and involves the cystic fibrosis transnnembrane conductance regulator (CFTR), a cAMP-regulated Cl(-) channel. Thus, parasympathetic innervation coordinates multiple steps in tubulogenesis during organogenesis. C1 [Emmerson, Elaine; Finley, Jennifer K.; Ettinger, Andreas; Cruz-Pacheco, Noel; Northrup, Emily; Knox, Sarah M.] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA. [Nedvetsky, Pavel I.; Mostov, Keith E.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. [Prochazka, Jan] Univ Calif San Francisco, Dept Orofacial Sci, San Francisco, CA 94143 USA. [Haddox, Candace L.; Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Hodges, Craig] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. RP Knox, SM (reprint author), Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA. EM sarah.knox@ucsf.edu OI Emmerson, Elaine/0000-0002-5902-3368; Knox, Sarah/0000-0002-7567-083X; Ettinger, Andreas/0000-0001-6436-010X FU NIH [5R00DE018969, R21DE022951, 5R01DK074398, 5R01DK091530]; National Center for Research Resources of the NIH [S10 RR26758] FX We thank Drs. Ann Zovein, Ophir Klein, Jeff Bush, David Bryant, Volker Henn, Ross Metzger, and Li-Kun Phng for critical reading of the manuscript. This work was supported by NIH grants 5R00DE018969 and R21DE022951 to S.M.K. and 5R01DK074398 and 5R01DK091530 to K.E.M. Research was conducted on a spinning disc microscope system funded by Shared Equipment Grant S10 RR26758 from the National Center for Research Resources of the NIH. This paper is dedicated to the memory of Dr. Lynne M. Angerer. NR 48 TC 23 Z9 24 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD AUG 25 PY 2014 VL 30 IS 4 BP 449 EP 462 DI 10.1016/j.devcel.2014.06.012 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA AO1LL UT WOS:000341073500010 PM 25158854 ER PT J AU Kim, W Fiori, JL Shin, YK Okun, E Kim, JS Rapp, PR Egan, JM AF Kim, Wook Fiori, Jennifer L. Shin, Yu-Kyong Okun, Eitan Kim, Jung Seok Rapp, Peter R. Egan, Josephine M. TI Pancreatic polypeptide inhibits somatostatin secretion SO FEBS LETTERS LA English DT Article DE Pancreatic polypeptide; NPY4 receptor; Somatostatin secretion ID NEUROPEPTIDE-Y; PEPTIDE YY; FUNCTIONAL EXPRESSION; RECEPTOR SUBTYPES; BODY-WEIGHT; FOOD-INTAKE; RELEASE; BRAIN; CLONING; VITRO AB Pancreatic polypeptide (PP) is a major agonist for neuropeptide Y4 receptors (NPY4R). While NPY4R has been identified in various tissues, the cells on which it is expressed and its function in those cells has not been clearly delineated. Here we report that NPY4R is present in all somatostatin-containing cells of tissues that we tested, including pancreatic islets, duodenum, hippocampus, and hypothalamus. Its agonism by PP decreases somatostatin secretion from human islets. Mouse embryonic hippocampal (mHippo E18) cells expressed NPY4Rs and their activation by PP consistently decreased somatostatin secretion. Furthermore, central injection of PP in mice induced c-Fos immunoreactivity in somatostatin-containing cells in the hippocampus compared with PBS-injected mice. In sum, our results identify PP as a pivotal modulator of somatostatin secretion. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Kim, Wook; Kim, Jung Seok] Ajou Univ, Dept Mol Sci & Technol, Suwon 443749, South Korea. [Fiori, Jennifer L.; Shin, Yu-Kyong; Egan, Josephine M.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Okun, Eitan] Bar Ilan Univ, Leslie & Susan Gonda Multidisciplinary Brain Res, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Rapp, Peter R.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. RP Egan, JM (reprint author), NIA, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM eganj@grc.nia.nih.gov FU National Institute on Aging (NIA)/NIH; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT Future [NRF-2012R1A1A1041352]; Ministry of Education [2009-0093826] FX This work was supported by the Intramural Research Program of the National Institute on Aging (NIA)/NIH. W. K was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future (NRF-2012R1A1A1041352) and the Ministry of Education (No. 2009-0093826). NR 42 TC 2 Z9 2 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD AUG 25 PY 2014 VL 588 IS 17 BP 3233 EP 3239 DI 10.1016/j.febslet.2014.07.005 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AN8VI UT WOS:000340882900065 PM 25019573 ER PT J AU Safren, SA Biello, KB Smeaton, L Mimiaga, MJ Walawander, A Lama, JR Rana, A Nyirenda, M Kayoyo, VM Samaneka, W Joglekar, A Celentano, D Martinez, A Remmert, JE Nair, A Lalloo, UG Kumarasamy, N Hakim, J Campbell, TB AF Safren, Steven A. Biello, Katie B. Smeaton, Laura Mimiaga, Matthew J. Walawander, Ann Lama, Javier R. Rana, Aadia Nyirenda, Mulinda Kayoyo, Virginia M. Samaneka, Wadzanai Joglekar, Anjali Celentano, David Martinez, Ana Remmert, Jocelyn E. Nair, Aspara Lalloo, Umesh G. Kumarasamy, Nagalingeswaran Hakim, James Campbell, Thomas B. CA PEARLS ACTG A175 Study Team TI Psychosocial Predictors of Non-Adherence and Treatment Failure in a Large Scale Multi-National Trial of Antiretroviral Therapy for HIV: Data from the ACTG A5175/PEARLS Trial SO PLOS ONE LA English DT Article ID SELF-REPORTED ADHERENCE; QUALITY-OF-LIFE; CLINICAL-TRIALS; MEDICATIONS; BARRIERS; UGANDA AB Background: PEARLS, a large scale trial of antiretroviral therapy (ART) for HIV (n = 1,571, 9 countries, 4 continents), found that a once-daily protease inhibitor (PI) based regimen (ATV+DDI+FTC), but not a once-daily non-nucleoside reverse transcriptase inhibitor/nucleoside reverse transcriptase inhibitor (NNRTI/NRTI) regimen (EFV+FTC/TDF), had inferior efficacy compared to a standard of care twice-daily NNRTI/NRTI regimen (EFV+3TC/ZDV). The present study examined nonadherence in PEARLS. Methods: Outcomes: non-adherence assessed by pill count and by self-report, and time to treatment failure. Longitudinal predictors: regimen, quality of life (general health perceptions = QOL-health, mental health = QOL-mental health), social support, substance use, binge drinking, and sexual behaviors. "Life-Steps'' adherence counseling was provided. Results: In both pill-count and self-report multivariable models, both once-a-day regimens had lower levels of non-adherence than the twice-a-day standard of care regimen; although these associations attenuated with time in the self-report model. In both multivariable models, hard-drug use was associated with non-adherence, living in Africa and better QOL-health were associated with less nonadherence. According to pill-count, unprotected sex was associated with non-adherence. According to self-report, soft-drug use was associated with nonadherence and living in Asia was associated with less nonadherence. Both pill-count (HR = 1.55, 95% CI: 1.15, 2.09, p<.01) and self-report (HR = 1.13, 95% CI: 1.08, 1.13, p<.01) nonadherence were significant predictors of treatment failure over 72 weeks. In multivariable models (including pill-count or self-report nonadherence), worse QOL-health, age group (younger), and region were also significant predictors of treatment failure. Conclusion: In the context of a large, multi-national, multi-continent, clinical trial there were variations in adherence over time, with more simplified regimens generally being associated with better adherence. Additionally, variables such as QOL-health, regimen, drug-use, and region play a role. Self-report and pill-count adherence, as well as additional psychosocial variables, such QOL-health, age, and region, were, in turn, associated with treatment failure. C1 [Safren, Steven A.; Mimiaga, Matthew J.; Remmert, Jocelyn E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Safren, Steven A.; Mimiaga, Matthew J.] Harvard Univ, Sch Med, Boston, MA USA. [Safren, Steven A.; Biello, Katie B.; Mimiaga, Matthew J.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Biello, Katie B.; Smeaton, Laura; Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Walawander, Ann; Nair, Aspara] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Lama, Javier R.] Asociac Civil Impacta Salud & Educ, Lima, Peru. [Rana, Aadia] Miriam Hosp, Alpert Med Sch, Providence, RI 02906 USA. [Nyirenda, Mulinda] Johns Hopkins Res Project, Coll Med, Blantyre, Malawi. [Kayoyo, Virginia M.] Univ North Carolina Project, Lilongwe, Malawi. [Samaneka, Wadzanai] Univ Zimbabwe, Univ Calif San Francisco, Collaborat Res Program, Harare, Zimbabwe. [Joglekar, Anjali] Natl AIDS Res Inst, Pune, Maharashtra, India. [Celentano, David] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Martinez, Ana] NIH NIAD DAIDS Pharmaceut Affairs, Bethesda, MD USA. [Lalloo, Umesh G.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Durban, South Africa. [Kumarasamy, Nagalingeswaran] YRGCARE Med Ctr, Madras, Tamil Nadu, India. [Hakim, James] Univ Zimbabwe, Harare, Zimbabwe. [Campbell, Thomas B.] Univ Colorado Denver, Aurora, CO USA. RP Safren, SA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM ssafren@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR); General Clinical Research Center Units - National Center for Research Resources; AIDS Clinical Trials Group (ACTG) - National Institute of Allergy and Infectious Diseases, National Institutes of Health: grants [AI68636, AI68634, AI69450]; Clinical Trials Units (CTU): YRG CARE Medical Ctr., VHS CRS (Site 11701) CTU Grant [U01A1069432]; Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz CRS (Site 12101) CTU Grant [U01AI069476]; College of Med. JHU CRS (Site 30301) CTU Grant [1U01AI069518-01]; Durban Adult HIV CRS (Site 11201) CTU Grant [1U01AI069426-01]; UNC Project, Lilongwe (Site 12001) CTU Grant [5 U01 AI069518-04]; UZ-Parienyatwa CRS (Site 30313) CTU Grant [1U01AI069436-01]; Clinical HIV Research Unit University of Witwatersrand (Site 11101) CTU Grant [AI069463]; Chiang Mai Univ. ACTG CRS (Site 11501) CTU Grant [5 U01 AI069399-04]; Hospital Conceicao, Porto Alegre (Site 12201) CTU Grant [5U01AI069401]; Les Centres GHESKIO (Site 30022) CTU Grant [U01 AI069421-05]; National AIDS Research Institute (Site 11601); NARI Clinic at Gadikhana Dr. Kotnis Municipal Disp (Site 11602); NARI Clinic at NIV CRS (Site 11603) CTU Grant [5U01AI069417-04]; Asociacion Civil Impacta Salud y Educacion -Miraflores, CRS (Site 11301); Investigaciones Medicas en Salud -INMENSA. Lince CRS (Site 11302)-CTU Grant [5U01AI069438]; UT Southwestern Medical Center at Dallas (Site 3751) CTU Grant [3U01AI046376-05S4]; University of Cincinnati (Site 2401) CTU Grant [1U01AI069513-01]; UC Davis School of Medicine (Site 3851,3852) CTU Grant [AI38858-09S1]; University of Colorado Hospital (Site 6101) CTU Grant [AI69450, RR025780]; The Ohio State University (Site 2301) CTU Grant [AI069474]; Northwestern University CRS (Site 2701); Rush University Medical Center (Site 2702) CTU Grant [AI069471]; University of Minnesota (Site 1501) CTU Grant [AI27661]; Washington University (Site 2101) CTU Grant [U01AI069495]; Duke University Medical Center (Site 1601) CTU Grant [5U01 AI069 484-02]; Beth Israel Medical Center (Site 2851) CTU Grant [AI46370]; The Miriam Hospital (Site 2951) CTU Grant [AI069472]; University of Southern California (Site 1201) CTU Grant [AI069428]; UCLA CARE Center (Site 601); Harbor-UCLA (Site 603)-CTU Grant [AI069424]; GCRC Grant [RR00424]; University of North Carolina (Site 3201,3206) CTU Grant [AI069423-03]; CFAR Grant [AI050410, P30-AI045008-11]; CTSA Grant [UL 1RR 025747, UL1RR024156]; Vanderbilt Therapeutics (Site 3652) CTU Grant [AI-069439]; Hosp. of the Univ. of Pennsylvania (Site 6201) CTU Grant [001-AI069467-04]; Columbia University -HIV Prevention and Treatment CRS (Site 30329) CTU Grant [AI069470]; New York University/NYC HHC at Bellevue Hospital Center (Site 401) CTU Grant [AI27665, AI069532]; University of Texas Medical Branch, Galveston (Site 6301) CTU Grant [AI032782]; University of Rochester (Site 1101); AIDS Care (Site 1108) CTU Grant [U01AI069511-02]; Cook County Hospital Core Center (Site 2705) CTU Grant [AI25915]; University of Hawaii at Manoa (Site 5201) CTU Grant [AI34853]; Cornell CRS (Site 7804) CTU Grant [AI-69419]; Boehringer Ingelheim; Bristol-Myers Squibb; Gilead Sciences; GlaxoSmithKline; [MOI-RR00865]; [RR024996]; [K24 MH094214] FX The project described was supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). The project was also supported in part by the General Clinical Research Center Units funded by the National Center for Research Resources. This work was also supported in part by the AIDS Clinical Trials Group (ACTG), funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health: grants AI68636, AI68634, AI69450 and the following grants to individual Clinical Trials Units (CTU): YRG CARE Medical Ctr., VHS CRS (Site 11701) CTU Grant #U01A1069432; Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz CRS (Site 12101) CTU Grant # U01AI069476; College of Med. JHU CRS (Site 30301) CTU Grant # 1U01AI069518-01; Durban Adult HIV CRS (Site 11201) CTU Grant # 1U01AI069426-01; UNC Project, Lilongwe (Site 12001) CTU Grant # 5 U01 AI069518-04; UZ-Parienyatwa CRS (Site 30313) CTU Grant # 1U01AI069436-01; Clinical HIV Research Unit University of Witwatersrand (Site 11101) CTU Grant # AI069463; Chiang Mai Univ. ACTG CRS (Site 11501) CTU Grant # 5 U01 AI069399-04; Hospital Conceicao, Porto Alegre (Site 12201) CTU Grant # 5U01AI069401; Les Centres GHESKIO (Site 30022) CTU Grant # U01 AI069421-05; National AIDS Research Institute (Site 11601); NARI Clinic at Gadikhana Dr. Kotnis Municipal Disp (Site 11602); NARI Clinic at NIV CRS (Site 11603) CTU Grant # 5U01AI069417-04; Asociacion Civil Impacta Salud y Educacion -Miraflores, CRS (Site 11301); Investigaciones Medicas en Salud -INMENSA. Lince CRS (Site 11302)-CTU Grant # 5U01AI069438; UT Southwestern Medical Center at Dallas (Site 3751) CTU Grant # 3U01AI046376-05S4; University of Cincinnati (Site 2401) CTU Grant # 1U01AI069513-01; UC Davis School of Medicine (Site 3851,3852) CTU Grant # AI38858-09S1; University of Colorado Hospital (Site 6101) CTU Grant # AI69450; RR025780; The Ohio State University (Site 2301) CTU Grant # AI069474; Northwestern University CRS (Site 2701); Rush University Medical Center (Site 2702) CTU Grant # AI069471; University of Minnesota (Site 1501) CTU Grant # AI27661; Washington University (Site 2101) CTU Grant # U01AI069495; Duke University Medical Center (Site 1601) CTU Grant # 5U01 AI069 484-02; Beth Israel Medical Center (Site 2851) CTU Grant # AI46370; The Miriam Hospital (Site 2951) CTU Grant # AI069472; University of Southern California (Site 1201) CTU Grant # AI069428; UCLA CARE Center (Site 601); Harbor-UCLA (Site 603)-CTU Grant # AI069424; Grant # MOI-RR00865; GCRC Grant # RR00424; University of North Carolina (Site 3201,3206) CTU Grant # AI069423-03; CFAR Grant # AI050410; CTSA Grant # UL 1RR 025747; Vanderbilt Therapeutics (Site 3652) CTU Grant # AI-069439; Hosp. of the Univ. of Pennsylvania (Site 6201) CTU Grant # 001-AI069467-04; CFAR Grant # P30-AI045008-11; Columbia University -HIV Prevention and Treatment CRS (Site 30329) CTU Grant # AI069470; CTSA Grant # UL1RR024156; New York University/NYC HHC at Bellevue Hospital Center (Site 401) CTU Grant # AI27665 and AI069532; The University of Texas Medical Branch, Galveston (Site 6301) CTU Grant # AI032782; University of Rochester (Site 1101); AIDS Care (Site 1108) CTU Grant # U01AI069511-02; Cook County Hospital Core Center (Site 2705) CTU Grant # AI25915; University of Hawaii at Manoa (Site 5201) CTU Grant # AI34853; Cornell CRS (Site 7804) CTU Grant # AI-69419; Grant # RR024996.; Finally, some of the author time was supported by grant K24 MH094214 (Safren). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The NIAID provided recommendations on the study design and approved the final study design and provided editorial review as a substudy team member, but had no role in data collection or analysis, or decision to publish. The pharmaceutical sponsors (Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline) provided study drug and Gilead Sciences provided funding to purchase study drug that was not otherwise available. Bristol Myers Squibb provided atazanavir, didanosine-EC and efavirenz (with consent of Merck); Gilead Sciences, Inc. provided emtricitabine, tenofovir-DF, emtricitabine/tenofovirDF; GlaxoSmithKline provided lamivudine, zidovudine and lamivudine/zidovudine; and Boehringer Ingelheim Pharmaceuticals, Inc. provided nevirapine. Representatives of the pharmaceutical company sponsors participated as study team members and authors of this manuscript, but did not participate in data collection, data analyses, or interpretation. Bristol Myers Squibb, Gilead Sciences Inc., GlaxoSmithKline and Boehringer Ingelheim Pharmaceuticals, Inc. had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Finally, some of the author time was supported by grant K24 MH094214 (Safren). NR 22 TC 16 Z9 16 U1 0 U2 4 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 AUG 25 PY 2014 VL 9 IS 8 AR e104178 DI 10.1371/journal.pone.0104178 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN9TR UT WOS:000340952200015 PM 25153084 ER PT J AU Bachir, AI Zareno, J Moissoglu, K Plow, EF Gratton, E Horwitz, AR AF Bachir, Alexia I. Zareno, Jessica Moissoglu, Konstadinos Plow, Edward F. Gratton, Enrico Horwitz, Alan R. TI Integrin-Associated Complexes Form Hierarchically with Variable Stoichiometry in Nascent Adhesions SO CURRENT BIOLOGY LA English DT Article ID ALPHA-ACTININ; FOCAL ADHESIONS; CELL-MIGRATION; CYTOSKELETAL DYNAMICS; MYOSIN-II; TALIN; VINCULIN; ACTIVATION; MATURATION; BINDING AB Background: A complex network of putative molecular interactions underlies the architecture and function of cell-matrix adhesions. Most of these interactions are implicated from coimmunoprecipitation studies using expressed components, but few have been demonstrated or characterized functionally in living cells. Results: We introduce fluorescence fluctuation methods to determine, at high spatial and temporal resolution, "when" and "where" molecular complexes form and their stoichiometry in nascent adhesions (NAs). We focus on integrin-associated molecules implicated in integrin activation and in the integrin-actin linkage in NAs and show that these molecules form integrin-containing complexes hierarchically within the adhesion itself. Integrin and kindlin reside in a molecular complex as soon as adhesions are visible; talin, although also present early, associates with the integrin-kindlin complex only after NAs have formed and in response to myosin II activity. Furthermore, talin and vinculin association precedes the formation of the integrin-talin complex. Finally, alpha-actinin enters NAs periodically and in clusters that transiently associate with integrins. The absolute number and stoichiometry of these molecules varies among the molecules studied and changes as adhesions mature. Conclusions: These observations suggest a working model for NA assembly whereby transient a-actinin-integrin complexes help nucleate NAs within the lamellipodiunn. Subsequently, integrin complexes containing kindlin, but not talin, emerge. Once NAs have formed, myosin II activity promotes talin association with the integrin-kindlin complex in a stoichiometry consistent with each talin molecule linking two integrin-kindlin complexes. C1 [Bachir, Alexia I.; Zareno, Jessica; Horwitz, Alan R.] Univ Virginia, Dept Cell Biol, Charlottesville, VA 22908 USA. [Moissoglu, Konstadinos] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Plow, Edward F.] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44195 USA. [Gratton, Enrico] Univ Calif Irvine, Lab Fluorescence Dynam, Dept Biomed Engn, Irvine, CA 92697 USA. RP Bachir, AI (reprint author), Univ Virginia, Dept Cell Biol, Charlottesville, VA 22908 USA. EM ab8su@virginia.edu FU NIH [R01 GM023244, NIH P41-GM103540, NIH P50-GM076516]; Cell Migration Consortium [U54 GM064346] FX We thank D. Critchley for helpful comments and discussions. This research was supported by NIH grants R01 GM023244 and the Cell Migration Consortium (U54 GM064346) for A.R.H. and by NIH grants NIH P41-GM103540 and NIH P50-GM076516 for E.G. NR 56 TC 32 Z9 32 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD AUG 24 PY 2014 VL 24 IS 16 BP 1845 EP 1853 DI 10.1016/j.cub.2014.07.011 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN6DY UT WOS:000340686300022 PM 25088556 ER PT J AU Mattson, MP AF Mattson, Mark P. TI Superior pattern processing is the essence of the evolved human brain SO FRONTIERS IN NEUROSCIENCE LA English DT Review DE evolution; hippocampus; language disorders; religion and science; neuronal network ID ADULT HIPPOCAMPAL NEUROGENESIS; OBSESSIVE-COMPULSIVE DISORDER; DEFAULT MODE NETWORK; MENTAL TIME-TRAVEL; QUALITY-OF-LIFE; DENTATE GYRUS; EPISODIC MEMORY; SPATIAL LOCATIONS; MAGICAL THINKING; EVOLUTION AB Humans have long pondered the nature of their mind/brain and, particularly why its capacities for reasoning, communication and abstract thought are far superior to other species, including closely related anthropoids. This article considers superior pattern processing (SPP) as the fundamental basis of most, if not all, unique features of the human brain including intelligence, language, imagination, invention, and the belief in imaginary entities such as ghosts and gods. SPP involves the electrochemical, neuronal network-based, encoding, integration, and transfer to other individuals of perceived or mentally-fabricated patterns. During human evolution, pattern processing capabilities became increasingly sophisticated as the result of expansion of the cerebral cortex, particularly the prefrontal cortex and regions involved in processing of images. Specific patterns, real or imagined, are reinforced by emotional experiences, indoctrination and even psychedelic drugs. Impaired or dysregulated SPP is fundamental to cognitive and psychiatric disorders. A broader understanding of SPP mechanisms, and their roles in normal and abnormal function of the human brain, may enable the development of interventions that reduce irrational decisions and destructive behaviors. C1 [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIH, Biomed Res Ctr, 5C214,251 Bayview Blvd, Baltimore, MD 21214 USA. EM mark.mattson@nih.gov FU Intramural Research Program of the National Institute on Aging, NIH FX This work was supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 175 TC 3 Z9 3 U1 7 U2 36 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD AUG 22 PY 2014 VL 8 AR UNSP 265 DI 10.3389/fnins.2014.00265 PG 17 WC Neurosciences SC Neurosciences & Neurology GA AW8KY UT WOS:000346511900002 PM 25202234 ER PT J AU Im, HS Alter, KE Brochard, S Pons, C Sheehan, FT AF Im, Hyun Soo Alter, Katharine E. Brochard, Sylvain Pons, Christelle Sheehan, Frances T. TI In vivo pediatric shoulder muscle volumes and their relationship to 3D strength SO JOURNAL OF BIOMECHANICS LA English DT Article DE Torque; MRI; Children; Reliability; Rotator cuff; Injury ID BRACHIAL-PLEXUS PALSY; ROTATOR CUFF; GLENOHUMERAL JOINT; DELTOID MUSCLE; MOMENT ARMS; SPORTS INJURIES; UPPER EXTREMITY; CEREBRAL-PALSY; MRI; ARCHITECTURE AB In the pediatric shoulder, injury and pathology can disrupt the muscle force balance, resulting in severe functional losses. As little data exists pertaining to in vivo pediatric shoulder muscle function, musculoskeletal data are crucially needed to advance the treatment of pediatric shoulder pathology/injury. Therefore, the purpose of this study was to develop a pediatric database of in vivo volumes for the major shoulder muscles and correlate these volumes with maximum isometric flexion/extension, internal/external rotation, and abduction/adduction joint moments. A methodology was developed to derive 3D shoulder muscle volumes and to divide the deltoid into sub-units with unique torque producing capabilities, based on segmentation of three-dimensional magnetic resonance images. Eleven typically developing children/adolescents (4F/7M, 12.0 +/- 3.2 years, 150.8 +/- 16.7 cm, 49.2 +/- 16.4 kg) participated. Correlation and regression analyses were used to evaluate the relationship between volume and maximum, voluntary, isometric joint torques. The deltoid demonstrated the largest (30.4 +/- 1.2%) and the supraspinatus the smallest (4.8 +/- 0.5%) percent of the total summed volume of all six muscles evaluated. The anterior and posterior deltoid sections were 43.4 +/- 3.9% and 56.6 +/- 3.9% of the total deltoid volume. The percent volumes were highly consistent across subjects. Individual muscle volumes demonstrated moderate-high correlations with torque values (0.70-0.94, p<0.001). This study presents a comprehensive database documenting normative pediatric shoulder muscle volume. Using these data a clear relationship between shoulder volume and the torques they produce was established in all three rotational degrees-of-freedom. This study furthers the understanding of shoulder muscle function and serves as a foundation for evaluating shoulder injury/pathology in the pediatric/adolescent population. (C) 2014 Published by Elsevier Ltd. C1 [Im, Hyun Soo; Alter, Katharine E.; Brochard, Sylvain; Sheehan, Frances T.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. [Alter, Katharine E.] Mt Washington Pediat Hosp, Baltimore, MD USA. [Brochard, Sylvain; Pons, Christelle] Univ Hosp Brest, Dept Rehabil Med, Brest, France. [Brochard, Sylvain] INSERM, LaTIM, U1101, Brest, France. RP Sheehan, FT (reprint author), NIH, Bldg 10 CRC RM 1-1469,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov OI Pons, Christelle/0000-0003-3924-6035 FU National Institutes of Health Clinical Center, Bethesda, MD, USA; University Hospital of Brest; French Society of Physical Medicine and Rehabilitation (SOFMER); French Society of Research in Children with Disabilities (SFERHE) FX The authors would like to thank Diane Damiano, PhD, Christopher Hollingsworth, Lindsay Curatalo, Christopher Stanley, and Lauri Ohlrich for their help and support in the work. In addition, we would like to thank the Radiology Department, headed by Dr. David Bluemke at the Clinical Center of the National Institutes of Health. This work was funded by the Intramural Research Program of the National Institutes of Health Clinical Center, Bethesda, MD, USA. Drs. Brochard and Pons were supported by an award from the University Hospital of Brest, the French Society of Physical Medicine and Rehabilitation (SOFMER), and the French Society of Research in Children with Disabilities (SFERHE). All work for this study was done under protocol number 03-CC-0060, approved by the Institutional Review Board of the National Institute of Child Health and Human Services. NR 40 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD AUG 22 PY 2014 VL 47 IS 11 BP 2730 EP 2737 DI 10.1016/j.jbiomech.2014.04.049 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA AO6LF UT WOS:000341462900029 PM 24925254 ER PT J AU Teijido, O Rappaport, SM Chamberlin, A Noskov, SY Aguilella, VM Rostovtseva, TK Bezrukov, SM AF Teijido, Oscar Rappaport, Shay M. Chamberlin, Adam Noskov, Sergei Y. Aguilella, Vicente M. Rostovtseva, Tatiana K. Bezrukov, Sergey M. TI Acidification Asymmetrically Affects Voltage-dependent Anion Channel Implicating the Involvement of Salt Bridges SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Electrophysiology; Gating; Mitochondria; Molecular Dynamics; pH Regulation; Voltage-dependent Anion Channel (VDAC); -Barrel Channel Reconstitution ID MITOCHONDRIAL OUTER-MEMBRANE; ISCHEMIA-REPERFUSION INJURY; VDAC1 N-TERMINUS; CARDIAC MYOCYTES; ION-CHANNEL; PH PARADOX; MOLECULAR-DYNAMICS; SUCCINIC ANHYDRIDE; SELECTIVE CHANNEL; NEUROSPORA-CRASSA AB Background: VDAC voltage gating depends on pH. Results: Acidification asymmetrically and reversibly enhances VDAC closure. Conclusion: pH-sensitive formation of stable salt bridges in the cytosolic side of VDAC explains its asymmetrical response to acidification. Significance: The pronounced sensitivity of the cytosolic side of VDAC to acidification provides new insights into the protective effect of cytosolic acidification during ischemia. The voltage-dependent anion channel (VDAC) is the major pathway for ATP, ADP, and other respiratory substrates through the mitochondrial outer membrane, constituting a crucial point of mitochondrial metabolism regulation. VDAC is characterized by its ability to gate between an open and several closed states under applied voltage. In the early stages of tumorigenesis or during ischemia, partial or total absence of oxygen supply to cells results in cytosolic acidification. Motivated by these facts, we investigated the effects of pH variations on VDAC gating properties. We reconstituted VDAC into planar lipid membranes and found that acidification reversibly increases its voltage-dependent gating. Furthermore, both VDAC anion selectivity and single channel conductance increased with acidification, in agreement with the titration of the negatively charged VDAC residues at low pH values. Analysis of the pH dependences of the gating and open channel parameters yielded similar pK(a) values close to 4.0. We also found that the response of VDAC gating to acidification was highly asymmetric. The presumably cytosolic (cis) side of the channel was the most sensitive to acidification, whereas the mitochondrial intermembrane space (trans) side barely responded to pH changes. Molecular dynamic simulations suggested that stable salt bridges at the cis side, which are susceptible to disruption upon acidification, contribute to this asymmetry. The pronounced sensitivity of the cis side to pH variations found here in vitro might provide helpful insights into the regulatory role of VDAC in the protective effect of cytosolic acidification during ischemia in vivo. C1 [Teijido, Oscar; Rappaport, Shay M.; Noskov, Sergei Y.; Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver NICHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Chamberlin, Adam; Noskov, Sergei Y.] Univ Calgary, Ctr Mol Simulat, Dept Biol Sci, Calgary, AB T2N 2N4, Canada. [Aguilella, Vicente M.] Univ Jaume 1, Dept Phys, Castellon de La Plana 12080, Spain. RP Rostovtseva, TK (reprint author), NICHD, Program Phys Biol, NIH, 9000 Rockville Pike,Bldg 9,Rm 1E-106, Bethesda, MD 20892 USA. EM rostovtt@mail.nih.gov RI Aguilella, Vicente/B-7592-2008 OI Aguilella, Vicente/0000-0002-2420-2649 FU National Institutes of Health Intramural Research Program of the Eunice Kennedy Shriver NICHD; National Sciences and Engineering Research Council [RGPIN-315019]; Spanish MINECO [FIS2013-40473]; Universitat Jaume I-Fundacio Caixa Castello-Bancaixa [P1-1B2012-03]; Generalitat Valenciana [Prometeu/2012/069] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program of the Eunice Kennedy Shriver NICHD. This work was also supported by National Sciences and Engineering Research Council Discovery Grant RGPIN-315019 (to S. Y. N.).; Supported by Spanish MINECO Grant FIS2013-40473, Universitat Jaume I-Fundacio Caixa Castello-Bancaixa Grant P1-1B2012-03, and Generalitat Valenciana Grant Prometeu/2012/069. NR 71 TC 13 Z9 13 U1 1 U2 8 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 AUG 22 PY 2014 VL 289 IS 34 BP 23670 EP 23682 DI 10.1074/jbc.M114.576314 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO7AT UT WOS:000341505000035 PM 24962576 ER PT J AU Swenson, AM Trivedi, DV Rauscher, AA Wang, Y Takagi, Y Palmer, BM Malnasi-Csizmadia, A Debold, EP Yengo, CM AF Swenson, Anja M. Trivedi, Darshan V. Rauscher, Anna A. Wang, Yuan Takagi, Yasuharu Palmer, Bradley M. Malnasi-Csizmadia, Andras Debold, Edward P. Yengo, Christopher M. TI Magnesium Modulates Actin Binding and ADP Release in Myosin Motors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Actin; Contractile Protein; Enzyme Kinetics; Magnesium; Muscle; Myosin ID DEPENDENT ADENOSINE-TRIPHOSPHATASE; CYTOSOLIC-FREE MAGNESIUM; CROSS-BRIDGE CYCLE; SKELETAL-MUSCLE; ATPASE ACTIVITY; POWER STROKE; RAT-HEART; V MOTOR; MG2+; DISSOCIATION AB Background: Magnesium may be an important physiological regulator of myosin motor activity. Results: Mg2+ inhibits the ADP release rate constant in the subset of myosins examined and reduces actin affinity in the post-hydrolysis state in myosin V. Conclusion: Mg2+ alters contractile velocity without altering overall tension-generating capacity. Significance: Mg2+-dependent regulation of motor activity is conserved in myosin motors. We examined the magnesium dependence of five class II myosins, including fast skeletal muscle myosin, smooth muscle myosin, -cardiac myosin (CMIIB), Dictyostelium myosin II (DdMII), and nonmuscle myosin IIA, as well as myosin V. We found that the myosins examined are inhibited in a Mg2+-dependent manner (0.3-9.0 mm free Mg2+) in both ATPase and motility assays, under conditions in which the ionic strength was held constant. We found that the ADP release rate constant is reduced by Mg2+ in myosin V, smooth muscle myosin, nonmuscle myosin IIA, CMIIB, and DdMII, although the ADP affinity is fairly insensitive to Mg2+ in fast skeletal muscle myosin, CMIIB, and DdMII. Single tryptophan probes in the switch I (Trp-239) and switch II (Trp-501) region of DdMII demonstrate these conserved regions of the active site are sensitive to Mg2+ coordination. Cardiac muscle fiber mechanic studies demonstrate cross-bridge attachment time is increased at higher Mg2+ concentrations, demonstrating that the ADP release rate constant is slowed by Mg2+ in the context of an activated muscle fiber. Direct measurements of phosphate release in myosin V demonstrate that Mg2+ reduces actin affinity in the MADPP(i) state, although it does not change the rate of phosphate release. Therefore, the Mg2+ inhibition of the actin-activated ATPase activity observed in class II myosins is likely the result of Mg2+-dependent alterations in actin binding. Overall, our results suggest that Mg2+ reduces the ADP release rate constant and rate of attachment to actin in both high and low duty ratio myosins. C1 [Swenson, Anja M.; Trivedi, Darshan V.; Yengo, Christopher M.] Penn State Univ, Dept Cellular & Mol Physiol, Coll Med, Hershey, PA 17033 USA. [Rauscher, Anna A.; Malnasi-Csizmadia, Andras] Eotvos Lorand Univ, Dept Biochem, H-1117 Budapest, Hungary. [Wang, Yuan; Palmer, Bradley M.] Univ Vermont, Dept Mol Physiol & Biophys, Burlington, VT 05405 USA. [Takagi, Yasuharu] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Debold, Edward P.] Univ Massachusetts, Dept Kinesiol, Amherst, MA 02210 USA. [Malnasi-Csizmadia, Andras] Eotvos Lorand Univ, Hungarian Acad Sci, Mol Biophys Res Grp, H-1117 Budapest, Hungary. RP Yengo, CM (reprint author), Penn State Univ, Dept Cellular & Mol Physiol, Coll Med, 500 Univ Dr, Hershey, PA 17033 USA. EM cyengo@hmc.psu.edu OI Swenson, Anja/0000-0001-9953-9695 FU National Institutes of Health [R01 EY016419, R01 HL086902]; Pennsylvania Department of Health; National Science Foundation [EPS-1101317]; European Research Council [Ideas 208319] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 EY016419 and Grant R01 HL086902 (to B. M. P.). This work was also supported by a grant from the Pennsylvania Department of Health (to C. M. Y.), National Science Foundation Grant EPS-1101317, and European Research Council Ideas 208319 (to A. M. C.). NR 71 TC 5 Z9 5 U1 2 U2 16 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 AUG 22 PY 2014 VL 289 IS 34 BP 23977 EP 23991 DI 10.1074/jbc.M114.562231 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO7AT UT WOS:000341505000062 PM 25006251 ER PT J AU Wuest, SC Mexhitaj, I Chai, NR Romm, E Scheffel, J Xu, BY Lane, K Wu, TX Bielekova, B AF Wuest, Simone C. Mexhitaj, Ina Chai, Noo Ri Romm, Elena Scheffel, Joerg Xu, Biying Lane, Kelly Wu, Tianxia Bielekova, Bibiana TI A Complex Role of Herpes Viruses in the Disease Process of Multiple Sclerosis SO PLOS ONE LA English DT Article ID EPSTEIN-BARR-VIRUS; BLOOD-BRAIN-BARRIER; CEREBROSPINAL-FLUID; T-CELLS; DEMYELINATING DISEASES; ISLET AUTOANTIBODIES; DACLIZUMAB; PROGRESSION; SERUM; RISK AB Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). Neither the antigenic target(s) nor the cell population(s) responsible for CNS tissue destruction in MS have been fully defined. The objective of this study was to simultaneously determine the antigen (Ag)-specificity and phenotype of un-manipulated intrathecal CD4(+) and CD8(+) T cells of patients with relapsing-remitting and progressive MS compared to subjects with other inflammatory neurological diseases. We applied a novel Ag-recognition assay based on co-cultures of freshly obtained cerebrospinal fluid T cells and autologous dendritic cells pre-loaded with complex candidate Ag's. We observed comparably low T cell responses to complex auto-Ag's including human myelin, brain homogenate, and cell lysates of apoptotically modified oligodendroglial and neuronal cells in all cohorts and both compartments. Conversely, we detected a strong intrathecal enrichment of Epstein-Barr virus- and human herpes virus 6-specific (but not cytomegalovirus-specific) reactivities of the Th1-phenotype throughout all patients. Qualitatively, the intrathecal enrichment of herpes virus reactivities was more pronounced in MS patients. This enrichment was completely reversed by long-term treatment with the IL-2 modulating antibody daclizumab, which strongly inhibits MS disease activity. Finally, we observed a striking discrepancy between diminished intrathecal T cell proliferation and enhanced cytokine production of herpes virus-specific T cells among progressive MS patients, consistent with the phenotype of terminally differentiated cells. The data suggest that intrathecal administration of novel therapeutic agents targeting immune cells outside of the proliferation cycle may be necessary to effectively eliminate intrathecal inflammation in progressive MS. C1 [Wuest, Simone C.; Mexhitaj, Ina; Chai, Noo Ri; Romm, Elena; Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Scheffel, Joerg] NIAMSD, Mol Immunol Sect, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Xu, Biying; Lane, Kelly] NHLBI, Imaging Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov FU NINDS intramural program; NINDS competitive fellowship; AbbVie Biotherapeutics and Biogen/IDEC [CRADA 2010-0039] FX This work was funded by the NINDS intramural program, the NINDS competitive fellowship to S.C.W., and by AbbVie Biotherapeutics and Biogen/IDEC (CRADA# 2010-0039). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 7 Z9 7 U1 0 U2 5 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 AUG 22 PY 2014 VL 9 IS 8 AR e105434 DI 10.1371/journal.pone.0105434 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3LL UT WOS:000341230600046 PM 25148387 ER PT J AU Keller, SD Yang, MS Treadwell, MJ Werner, EM Hassell, KL AF Keller, San D. Yang, Manshu Treadwell, Marsha J. Werner, Ellen M. Hassell, Kathryn L. TI Patient reports of health outcome for adults living with sickle cell disease: development and testing of the ASCQ-Me item banks SO HEALTH AND QUALITY OF LIFE OUTCOMES LA English DT Article DE ASCQ-Me; Computer adaptive testing; CAT; Item response theory; IRT; Patient-reported outcomes; PROs; Sickle cell disease; Validity(up to 10 allowed) ID QUALITY-OF-LIFE; INFORMATION-SYSTEM PROMIS; UNIDIMENSIONALITY ASSUMPTION; HOSPITAL READMISSION; PISCES PROJECT; RISK-FACTORS; LEG ULCERS; ANEMIA; SEVERITY; NUMBER AB Background: Providers and patients have called for improved understanding of the health care requirements of adults with sickle cell disease (SCD) and have identified the need for a systematic, reliable and valid method to document the patient-reported outcomes (PRO) of adult SCD care. To address this need, the Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) was designed to complement the Patient Reported Outcome Measurement Information System (PROMIS (R)). Here we describe methods and results of the psychometric evaluation of ASCQ-Me item banks (IBs). Methods: At seven geographically-disbursed clinics within the US, 556 patients responded to questions generated to assess cognitive, emotional, physical and social impacts of SCD. We evaluated the construct validity of the hypothesized domains using exploratory factor analysis (EFA), parallel analysis (PA), and bi-factor analysis (Item Response Theory Graded Response Model, IRT-GRM). We used IRT-GRM and the Wald method to identify bias in responses across gender and age. We used IRT and Cronbach's alpha coefficient to evaluate the reliability of the IBs and then tested the ability of summary scores based on IRT calibrations to discriminate among tertiles of respondents defined by SCD severity. Results: Of the original 140 questions tested, we eliminated 48 that either did not form clean factors or provided biased measurement across subgroups defined by age and gender. Via EFA and PA, we identified three subfactors within physical impact: sleep, pain and stiffness impacts. Analysis of the resulting six item sets (sleep, pain, stiffness, cognitive, emotional and social impacts of SCD) supported their essential unidimensionality. With the exception of the cognitive impact IB, these item sets also were highly reliable across a broad range of values and highly significantly related to SCD disease severity. Conclusion: ASCQ-Me pain, sleep, stiffness, emotional and social SCD impact IBs demonstrated exceptional measurement properties using modern and classical psychometric methods of evaluation. Further development of the cognitive impact IB is required to improve its sensitivity to differences in SCD disease severity. Future research will evaluate the sensitivity of the ASCQ-Me IBs to change in SCD disease severity over time due to health interventions. C1 [Keller, San D.; Yang, Manshu] Amer Inst Res, Dept Hlth Policy & Res, Qual & Performance Measurement Program, Chapel Hill, NC 27517 USA. [Treadwell, Marsha J.] Childrens Hosp & Res Ctr Oakland, Oakland, CA 94609 USA. [Werner, Ellen M.] NHLBI, Bethesda, MD 20892 USA. [Hassell, Kathryn L.] Univ Colorado, Div Hematol, Aurora, CO 80045 USA. RP Keller, SD (reprint author), Amer Inst Res, Dept Hlth Policy & Res, Qual & Performance Measurement Program, 100 Europa Dr,Suite 315, Chapel Hill, NC 27517 USA. EM sankeller@air.org FU National Heart, Lung and Blood Institute, National Institutes of Health; American Institutes for Research FX This work was funded by a contract from the National Heart, Lung and Blood Institute, National Institutes of Health, to the American Institutes for Research and from a grant from the American Institutes for Research to the corresponding and second authors. NR 70 TC 7 Z9 7 U1 3 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7525 J9 HEALTH QUAL LIFE OUT JI Health Qual. Life Outcomes PD AUG 22 PY 2014 VL 12 AR 125 DI 10.1186/s12955-014-0125-0 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AO1CZ UT WOS:000341050800001 PM 25146160 ER PT J AU Chen, JD Gottesman, S AF Chen, Jiandong Gottesman, Susan TI RNA Riboswitch regulates RNA SO SCIENCE LA English DT Editorial Material ID ETHANOLAMINE UTILIZATION; LISTERIA-MONOCYTOGENES C1 [Chen, Jiandong; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Chen, JD (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM gottesms@helix.nih.gov FU Intramural NIH HHS NR 11 TC 3 Z9 5 U1 2 U2 23 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 22 PY 2014 VL 345 IS 6199 BP 876 EP 877 DI 10.1126/science.1258494 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN3YL UT WOS:000340524700023 PM 25146272 ER PT J AU Young, ME Ohm, DT Dumitriu, D Rapp, PR Morrison, JH AF Young, M. E. Ohm, D. T. Dumitriu, D. Rapp, P. R. Morrison, J. H. TI DIFFERENTIAL EFFECTS OF AGING ON DENDRITIC SPINES IN VISUAL CORTEX AND PREFRONTAL CORTEX OF THE RHESUS MONKEY SO NEUROSCIENCE LA English DT Article DE prefrontal cortex; visual cortex; dendritic spines; macaque; aging ID PYRAMIDAL NEURONS; COGNITIVE DECLINE; MACAQUE MONKEYS; ADULT CORTEX; AGED MONKEYS; AREA 46; LAYER 1; MEMORY; PLASTICITY; STABILITY AB Aging decreases the density of spines and the proportion of thin spines in the non-human primate (NHP) dorsolateral prefrontal cortex (dlPFC). In this study, we used confocal imaging of dye-loaded neurons to expand upon previous results regarding the effects of aging on spine density and morphology in the NHP dlPFC and compared these results to the effects of aging on pyramidal neurons in the primary visual cortex (V1). We confirmed that spine density, and particularly the density of thin spines, decreased with age in the dlPFC of rhesus monkeys. Furthermore, the average head diameter of non-stubby spines in the dlPFC was a better predictor than chronological age of the number of trials required to reach criterion on both the delayed response test of visuospatial working memory and the delayed nonmatching-to-sample test of recognition memory. By contrast, total spine density was lower on neurons in V1 than in dlPFC, and neither total spine density, thin spine density, nor spine size in V1 was affected by aging. Our results highlight the importance and selective vulnerability of dlPFC thin spines for optimal prefrontal-mediated cognitive function. Understanding the nature of the selective vulnerability of dlPFC thin spines as compared to the resilience of thin spines in V1 may be a promising area of research in the quest to prevent or ameliorate age-related cognitive decline. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Young, M. E.; Ohm, D. T.; Dumitriu, D.; Morrison, J. H.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, Friedman Brain Inst, Kastor Neurobiol Aging Lab, New York, NY 10029 USA. [Young, M. E.; Ohm, D. T.; Dumitriu, D.; Morrison, J. H.] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA. [Rapp, P. R.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Morrison, J. H.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Care, New York, NY 10029 USA. RP Morrison, JH (reprint author), Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, Box 1065,One Gustave L Levy Pl, New York, NY 10029 USA. EM john.morrison@mssm.edu FU NIA [AG016765, AG006647, AG010606]; Intramural Research Program of the NIA FX Acknowledgments-The authors thank William Janssen and Dr. Yuko Hara for their expert advice and assistance. This work is supported by AG016765, AG006647, and AG010606 to J.H.M. from the NIA, and in part by the Intramural Research Program of the NIA. NR 51 TC 4 Z9 4 U1 3 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD AUG 22 PY 2014 VL 274 BP 33 EP 43 DI 10.1016/j.neuroscience.2014.05.008 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AK8XO UT WOS:000338712300004 PM 24853052 ER PT J AU Puigbo, P Lobkovsky, AE Kristensen, DM Wolf, YI Koonin, EV AF Puigbo, Pere Lobkovsky, Alexander E. Kristensen, David M. Wolf, Yuri I. Koonin, Eugene V. TI Genomes in turmoil: quantification of genome dynamics in prokaryote supergenomes SO BMC BIOLOGY LA English DT Article ID HORIZONTAL GENE-TRANSFER; UNIVERSAL COMMON ANCESTOR; BACTERIAL PAN-GENOME; MAXIMUM-LIKELIHOOD; PHYLOGENETIC TREES; ORTHOLOGOUS GENES; PROTEIN FAMILIES; DELETIONAL BIAS; COG DATABASE; EVOLUTION AB Background: Genomes of bacteria and archaea (collectively, prokaryotes) appear to exist in incessant flux, expanding via horizontal gene transfer and gene duplication, and contracting via gene loss. However, the actual rates of genome dynamics and relative contributions of different types of event across the diversity of prokaryotes are largely unknown, as are the sizes of microbial supergenomes, i.e. pools of genes that are accessible to the given microbial species. Results: We performed a comprehensive analysis of the genome dynamics in 35 groups (34 bacterial and one archaeal) of closely related microbial genomes using a phylogenetic birth-and-death maximum likelihood model to quantify the rates of gene family gain and loss, as well as expansion and reduction. The results show that loss of gene families dominates the evolution of prokaryotes, occurring at approximately three times the rate of gain. The rates of gene family expansion and reduction are typically seven and twenty times less than the gain and loss rates, respectively. Thus, the prevailing mode of evolution in bacteria and archaea is genome contraction, which is partially compensated by the gain of new gene families via horizontal gene transfer. However, the rates of gene family gain, loss, expansion and reduction vary within wide ranges, with the most stable genomes showing rates about 25 times lower than the most dynamic genomes. For many groups, the supergenome estimated from the fraction of repetitive gene family gains includes about tenfold more gene families than the typical genome in the group although some groups appear to have vast, 'open' supergenomes. Conclusions: Reconstruction of evolution for groups of closely related bacteria and archaea reveals an extremely rapid and highly variable flux of genes in evolving microbial genomes, demonstrates that extensive gene loss and horizontal gene transfer leading to innovation are the two dominant evolutionary processes, and yields robust estimates of the supergenome size. C1 [Puigbo, Pere; Lobkovsky, Alexander E.; Kristensen, David M.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX The authors are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 86 TC 30 Z9 30 U1 1 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD AUG 21 PY 2014 VL 12 AR 66 DI 10.1186/s12915-014-0066-4 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AO9YJ UT WOS:000341716400001 PM 25141959 ER PT J AU Khurana, S Kruhlak, MJ Kim, J Tran, AD Liu, JP Nyswaner, K Shi, L Jailwala, P Sung, MH Hakim, O Oberdoerffer, P AF Khurana, Simran Kruhlak, Michael J. Kim, Jeongkyu Tran, Andy D. Liu, Jinping Nyswaner, Katherine Shi, Lei Jailwala, Parthav Sung, Myong-Hee Hakim, Ofir Oberdoerffer, Philipp TI A Macrohistone Variant Links Dynamic Chromatin Compaction to BRCA1-Dependent Genome Maintenance SO CELL REPORTS LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; BRCA1 TUMOR SUPPRESSION; REPAIR PATHWAY CHOICE; HOMOLOGOUS RECOMBINATION; END RESECTION; HISTONE ACETYLATION; MAMMALIAN-CELLS; ATM; PROTEIN AB Appropriate DNA double-strand break (DSB) repair factor choice is essential for ensuring accurate repair outcome and genomic integrity. The factors that regulate this process remain poorly understood. Here, we identify two repressive chromatin components, the macrohistone variant macroH2A1 and the H3K9 methyltransferase and tumor suppressor PRDM2, which together direct the choice between the antagonistic DSB repair mediators BRCA1 and 53BP1. The macroH2A1/PRDM2 module mediates an unexpected shift from accessible to condensed chromatin that requires the ataxia telangiectasia mutated (ATM)-dependent accumulation of both proteins at DSBs in order to promote DSB-flanking H3K9 dimethylation. Remarkably, loss of macroH2A1 or PRDM2, as well as experimentally induced chromatin decondensation, impairs the retention of BRCA1, but not 53BP1, at DSBs. As a result, macroH2A1 and/or PRDM2 depletion causes epistatic defects in DSB end resection, homology-directed repair, and the resistance to poly(ADP-ribose) polymerase (PARP) inhibition-all hallmarks of BRCA1-deficient tumors. Together, these findings identify dynamic, DSB-associated chromatin reorganization as a critical modulator of BRCA1-dependent genome maintenance. C1 [Khurana, Simran; Kim, Jeongkyu; Tran, Andy D.; Liu, Jinping; Sung, Myong-Hee; Oberdoerffer, Philipp] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Kruhlak, Michael J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Nyswaner, Katherine] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Jailwala, Parthav] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. [Shi, Lei] Tianjin Med Univ, Dept Biochem & Mol Biol, Tianjin 300070, Peoples R China. [Hakim, Ofir] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel. RP Oberdoerffer, P (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM philipp.oberdoerffer@nih.gov FU National Cancer Institute, NIH; NIH FX We thank Y. Dalal, T. Misteli, A. Nussenzweig, and S. Oberdoerffer for critical reading of the manuscript; S. Silver, T Nieland, and the Broad RNAi platform for assistance with RNAi screening; A. Mazumder for help with Cellomics high-content imaging; B. Tran and J. Shetty for Illumina sequencing; S. Burkett for FISH analysis; and C. Lukas, Y. Galanty, S. Jackson, D. Livingston, and A. Sartori for reagents. This work was supported by federal funds from the National Cancer Institute, NIH, and the NIH intramural research program. NR 66 TC 36 Z9 37 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD AUG 21 PY 2014 VL 8 IS 4 BP 1049 EP 1062 DI 10.1016/j.celrep.2014.07.024 PG 14 WC Cell Biology SC Cell Biology GA AO8AD UT WOS:000341573500015 PM 25131201 ER PT J AU Wang, H Kane, AW Lee, C Ahn, S AF Wang, Hui Kane, Anna W. Lee, Cheol Ahn, Sohyun TI Gli3 Repressor Controls Cell Fates and Cell Adhesion for Proper Establishment of Neurogenic Niche SO CELL REPORTS LA English DT Article ID NEURAL STEM-CELLS; CILIARY NEUROTROPHIC FACTOR; NERVOUS-SYSTEM; VASCULAR NICHE; DORSAL TELENCEPHALON; GENE-EXPRESSION; ADULT BRAIN; E-CADHERIN; SVZ NICHE; NUMB AB Neural stem cells (NSCs) in the subventricular zone (SVZ) rely on environmental signals provided by the neurogenic niche for their proper function. However, little is known about the initial steps of niche establishment, as embryonic radial glia transition to postnatal NSCs. Here, we identify Gli3 repressor (Gli3R), a component of the Sonic hedgehog (Shh) pathway, as a critical factor controlling both cell-type specification and structural organization of the developing SVZ. We demonstrate that Gli3R expressed in radial glia temporally regulates gp130/STAT3 signaling at the transcriptional level to suppress glial characteristics in differentiating ependymal cells. In addition, Gli3R maintains the proper level of Numb in ependymal cells to allow localization of cell adhesion molecules such as vascular cell adhesion molecule (VCAM) and E-cadherin. Thus, our findings reveal a role for Gli3R as a mediator of niche establishment and provide insights into the conditions required for proper SVZ neurogenic niche formation. C1 [Wang, Hui; Kane, Anna W.; Lee, Cheol; Ahn, Sohyun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Kane, Anna W.] Brown Univ, Dept Neurosci, Brown NIH Grad Partnership Program, Providence, RI 02912 USA. RP Ahn, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM ahnsohyun@mail.nih.gov FU NIH [1ZIHD008781] FX We would like to thank M. Song, M. Zervas, and J. Li for critical reading of the manuscript; I. Dawid and M. Won for helpful suggestions on the LNX2 study; M. Song for discussions on STAT3; members of the S. A. lab for discussion; and G. Ge and E. Karey for help during the initial stage of the study. We would also like to thank NICHD Microscopy Imaging Core and NCI Electron Microscopy Core Facilities for confocal microscopy and TEM analysis; and NHLBI Flow Cytometry Core Facility for FACS. This study was supported by the Intramural Research Program of NIH (1ZIHD008781 to S. A.). NR 45 TC 2 Z9 3 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD AUG 21 PY 2014 VL 8 IS 4 BP 1093 EP 1104 DI 10.1016/j.celrep.2014.07.006 PG 12 WC Cell Biology SC Cell Biology GA AO8AD UT WOS:000341573500018 PM 25127137 ER PT J AU Kang, H Kerloc'h, A Rotival, M Xu, XQ Zhang, Q D'Souza, Z Kim, M Scholz, JC Ko, JH Srivastava, PK Genzen, JR Cui, WG Aitman, TJ Game, L Melvin, JE Hanidu, A Dimock, J Zheng, J Souza, D Behera, AK Nabozny, G Cook, HT Bassett, JHD Williams, GR Li, J Vignery, A Petretto, E Behmoaras, J AF Kang, Heeseog Kerloc'h, Audrey Rotival, Maxime Xu, Xiaoqing Zhang, Qing D'Souza, Zelpha Kim, Michael Scholz, Jodi Carlson Ko, Jeong-Hun Srivastava, Prashant K. Genzen, Jonathan R. Cui, Weiguo Aitman, Timothy J. Game, Laurence Melvin, James E. Hanidu, Adedayo Dimock, Janice Zheng, Jie Souza, Donald Behera, Aruna K. Nabozny, Gerald Cook, H. Terence Bassett, J. H. Duncan Williams, Graham R. Li, Jun Vignery, Agnes Petretto, Enrico Behmoaras, Jacques TI Kcnn4 Is a Regulator of Macrophage Multinucleation in Bone Homeostasis and Inflammatory Disease SO CELL REPORTS LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; GIANT-CELL FORMATION; CRESCENTIC GLOMERULONEPHRITIS; OSTEOCLAST DIFFERENTIATION; INTERMEDIATE-CONDUCTANCE; RAT MODEL; ION CHANNELS; K+ CHANNEL; FUSION; ACTIVATION AB Macrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) as part of the immune response. We use a systems genetics approach in rat macrophages to unravel their genetic determinants of multinucleation and investigate their role in both bone homeostasis and inflammatory disease. We identify a trans-regulated gene network associated with macrophage multinucleation and Kcnn4 as being the most significantly trans-regulated gene in the network and induced at the onset of fusion. Kcnn4 is required for osteoclast and MGC formation in rodents and humans. Genetic deletion of Kcnn4 reduces macrophage multinucleation through modulation of Ca2+ signaling, increases bone mass, and improves clinical outcome in arthritis. Pharmacological blockade of Kcnn4 reduces experimental glomerulonephritis. Our data implicate Kcnn4 in macrophage multinucleation, identifying it as a potential therapeutic target for inhibition of bone resorption and chronic inflammation. C1 [Kang, Heeseog; Xu, Xiaoqing; Zhang, Qing; Kim, Michael; Vignery, Agnes] Yale Univ, Sch Med, Dept Orthopaed, New Haven, CT 06510 USA. [Kang, Heeseog; Xu, Xiaoqing; Zhang, Qing; Kim, Michael; Vignery, Agnes] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA. [Kerloc'h, Audrey; Ko, Jeong-Hun; Cook, H. Terence; Behmoaras, Jacques] Univ London Imperial Coll Sci Technol & Med, CCIR, London W12 0NN, England. [Rotival, Maxime; D'Souza, Zelpha; Srivastava, Prashant K.; Aitman, Timothy J.; Petretto, Enrico] Univ London Imperial Coll Sci Technol & Med, MRC Clin Sci Ctr, London W12 0NN, England. [Scholz, Jodi Carlson] Yale Univ, Sch Med, Comparat Med Sect, New Haven, CT 06510 USA. [Genzen, Jonathan R.] Univ Utah, Dept Pathol, Salt Lake City, UT 84108 USA. [Genzen, Jonathan R.] ARUP Labs, Salt Lake City, UT 84108 USA. [Cui, Weiguo] Blood Ctr Wisconsin, Milwaukee, WI 53213 USA. [Game, Laurence] Univ London Imperial Coll Sci Technol & Med, MRC Clin Sci Ctr, Genom Lab, London W12 0NN, England. [Melvin, James E.] NIDCR, NIH, Bethesda, MD 20892 USA. [Hanidu, Adedayo; Dimock, Janice; Zheng, Jie; Souza, Donald; Behera, Aruna K.; Nabozny, Gerald; Li, Jun] Boehringer Ingelheim Pharmaceut Inc, Dept Immunol & Inflammat, Ridgefield, CT 06877 USA. [Bassett, J. H. Duncan; Williams, Graham R.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Mol Endocrinol Grp, London W12 0NN, England. RP Vignery, A (reprint author), Yale Univ, Sch Med, Dept Orthopaed, New Haven, CT 06510 USA. EM agnes.vignery@yale.edu; enrico.petretto@imperial.ac.uk; jacquesb@imperial.ac.uk OI Rotival, Maxime/0000-0003-2519-8044; Scholz, Jodi/0000-0002-9571-5599 FU Kidney Research UK [RP9/2013]; Wellcome Trust [WT092523MA]; European Community [HEALTH-F4- 2010-241504]; Medical Research Council; Boehringer Ingelheim FX The authors are grateful to Veterinary Clinical Services at the Yale School of Medicine and to the Yale Core Center for Musculoskeletal Diseases, in particular, to Nancy Troiano for her assistance in processing the mouse bones for histomorphometry analysis. We also thank Bolder Biopath (Boulder, CO) for processing the arthritic mouse bones for histology, and grading the pathology. We would like to thank Jennifer Smith for her excellent technical assistance and Kathrin Saar (MDC, Berlin) for genotyping protocols and data analysis. We gratefully acknowledge funding from Kidney Research UK (RP9/2013) (J.B.), Wellcome Trust (WT092523MA) (J.B.). We also acknowledge funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. HEALTH-F4- 2010-241504 (EURATRANS) (E.P. and M .R.) and the Medical Research Council (E.P.). A.H., J.D., J.Z., D.S., A.K.B., G.N., and J.L. are employees of Boehringer Ingelheim. This work was supported in part by a grant from Boehringer Ingelheim. NR 65 TC 10 Z9 10 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD AUG 21 PY 2014 VL 8 IS 4 BP 1210 EP 1224 DI 10.1016/j.celrep.2014.07.032 PG 15 WC Cell Biology SC Cell Biology GA AO8AD UT WOS:000341573500027 PM 25131209 ER PT J AU Kwong, B Lazarevic, V AF Kwong, Brandon Lazarevic, Vanja TI T-bet Orchestrates CD8 alpha alpha IEL Differentiation SO IMMUNITY LA English DT Editorial Material ID INTRAEPITHELIAL LYMPHOCYTES; THYMOCYTES; CELL; FATE AB Very little is known about the transcription factor network that regulates the development of intestinal intraepithelial lymphocytes (IELs). In this issue of Immunity, Klose et al. (2014b) and Reis et al. (2014) demonstrate an essential role for T-bet in regulating the CD8 alpha alpha IEL differentiation program. C1 [Kwong, Brandon; Lazarevic, Vanja] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Lazarevic, V (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lazarevicv@mail.nih.gov NR 9 TC 2 Z9 3 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD AUG 21 PY 2014 VL 41 IS 2 BP 169 EP 171 DI 10.1016/j.immuni.2014.08.003 PG 3 WC Immunology SC Immunology GA AO6JA UT WOS:000341455300002 PM 25148017 ER PT J AU Vrisekoop, N Monteiro, JP Mandl, JN Germain, RN AF Vrisekoop, Nienke Monteiro, Joao P. Mandl, Judith N. Germain, Ronald N. TI Revisiting Thymic Positive Selection and the Mature T Cell Repertoire for Antigen SO IMMUNITY LA English DT Review ID MAJOR HISTOCOMPATIBILITY COMPLEX; SINGLE MHC/PEPTIDE LIGAND; MHC CLASS-II; RECEPTOR REPERTOIRE; NEGATIVE SELECTION; LYMPHOCYTIC CHORIOMENINGITIS; CROSS-REACTIVITY; IMMUNE-RESPONSE; MOLECULAR-BASIS; SELF-PEPTIDES AB To support effective host defense, the T cell repertoire must balance breadth of recognition with sensitivity for antigen. The concept that T lymphocytes are positively selected in the thymus is well established, but how this selection achieves such a repertoire has not been resolved. Here we suggest that it is direct linkage between self and foreign antigen recognition that produces the necessary blend of TCR diversity and specificity in the mature peripheral repertoire, enabling responses to a broad universe of unpredictable antigens while maintaining an adequate number of highly sensitive T cells in a population of limited size. Our analysis also helps to explain how diversity and frequency of antigen-reactive cells in a T cell repertoire are adjusted in animals of vastly different size scale to enable effective antipathogen responses and suggests a possible binary architecture in the TCR repertoire that is divided between germline-related optimal binding and diverse recognition. C1 [Vrisekoop, Nienke] Univ Med Ctr Utrecht, Dept Resp Med, Lab Translat Immunol, NL-3584 CT Utrecht, Netherlands. [Monteiro, Joao P.; Mandl, Judith N.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Mandl, JN (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. EM mandlj@niaid.nih.gov; rgermain@nih.gov FU Intramural Research Program of NIAID at the NIH FX We are grateful to D. van Baarle, C. Kesmir, K. Hogquist, and N. Singh for reading earlier versions of this manuscript and providing critical feedback. We would also like to thank J. Textor for immensely valuable discussions. This work was supported by the Intramural Research Program of NIAID at the NIH. NR 108 TC 19 Z9 19 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD AUG 21 PY 2014 VL 41 IS 2 BP 181 EP 190 DI 10.1016/j.immuni.2014.07.007 PG 10 WC Immunology SC Immunology GA AO6JA UT WOS:000341455300007 PM 25148022 ER PT J AU Melis, M Diaz, G Kleiner, DE Zamboni, F Kabat, J Lai, JP Mogavero, G Tice, A Engle, RE Becker, S Brown, CR Hanson, JC Rodriguez-Canales, J Emmert-Buck, M Govindarajan, S Kew, M Farci, P AF Melis, Marta Diaz, Giacomo Kleiner, David E. Zamboni, Fausto Kabat, Juraj Lai, Jinping Mogavero, Giulia Tice, Ashley Engle, Ronald E. Becker, Steven Brown, Charles R. Hanson, Jeffrey C. Rodriguez-Canales, Jaime Emmert-Buck, Michael Govindarajan, Sugantha Kew, Michael Farci, Patrizia TI Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Hepatocellular carcinoma; Hepatitis B virus; Gene expression profiling; Laser capture microdissection; Confocal microscopy ID GENE-EXPRESSION; DNA; TUMOR; MICROARRAY; AKR1B10; PROTEIN; FAMILY; OVEREXPRESSION; ANTIGEN; CANCER AB Background: The molecular mechanisms whereby hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) remain elusive. We used genomic and molecular techniques to investigate host-virus interactions by studying multiple areas of the same liver from patients with HCC. Methods: We compared the gene signature of whole liver tissue (WLT) versus laser capture-microdissected (LCM) hepatocytes along with the intrahepatic expression of HBV. Gene expression profiling was performed on up to 17 WLT specimens obtained at various distances from the tumor center from individual livers of 11 patients with HCC and on selected LCM samples. HBV markers in liver and serum were determined by real-time polymerase chain reaction (PCR) and confocal immunofluorescence. Results: Analysis of 5 areas of the liver showed a sharp change in gene expression between the immediate perilesional area and tumor periphery that correlated with a significant decrease in the intrahepatic expression of HB surface antigen (HBsAg). The tumor was characterized by a large preponderance of down-regulated genes, mostly involved in the metabolism of lipids and fatty acids, glucose, amino acids and drugs, with down-regulation of pathways involved in the activation of PXR/RXR and PPARa/RXRa nuclear receptors, comprising PGC-1a and FOXO1, two key regulators critically involved not only in the metabolic functions of the liver but also in the life cycle of HBV, acting as essential transcription factors for viral gene expression. These findings were confirmed by gene expression of microdissected hepatocytes. Moreover, LCM of malignant hepatocytes also revealed up-regulation of unique genes associated with cancer and signaling pathways, including two novel HCC-associated cancer testis antigen genes, NUF2 and TTK. Conclusions: Integrated gene expression profiling of whole liver tissue with that of microdissected hepatocytes demonstrated that HBV-associated HCC is characterized by a metabolism switch-off and by a significant reduction in HBsAg. LCM proved to be a critical tool to validate gene signatures associated with HCC and to identify genes that may play a role in hepatocarcinogenesis, opening new perspectives for the discovery of novel diagnostic markers and therapeutic targets. C1 [Melis, Marta; Tice, Ashley; Engle, Ronald E.; Farci, Patrizia] NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Diaz, Giacomo] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [Kleiner, David E.; Lai, Jinping] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zamboni, Fausto; Mogavero, Giulia] Brotzu Hosp, Liver Transplantat Ctr, Cagliari, Italy. [Kabat, Juraj; Becker, Steven] NIAID, Biol Imaging Facil, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Brown, Charles R.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Hanson, Jeffrey C.; Rodriguez-Canales, Jaime; Emmert-Buck, Michael] NCI, Laser Capture Microdissect Core Facil, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Govindarajan, Sugantha] Univ So Calif, Rancho Los Amigos Hosp, Dept Pathol, Downey, CA 90242 USA. [Kew, Michael] Groote Schuur Hosp, Dept Med, ZA-7925 Cape Town, South Africa. [Kew, Michael] Univ Cape Town, ZA-7925 Cape Town, South Africa. RP Farci, P (reprint author), NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pfarci@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases; NIH, National Cancer Institute; Fondazione Banco di Sardegna, Sassari, Italy [739/2011.1045] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases and National Cancer Institute. Giacomo Diaz was the recipient of a grant from Fondazione Banco di Sardegna (739/2011.1045), Sassari, Italy. NR 51 TC 4 Z9 4 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD AUG 21 PY 2014 VL 12 AR 230 DI 10.1186/s12967-014-0230-1 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AO3EY UT WOS:000341212900002 PM 25141867 ER PT J AU Lentz, MR Peterson, KL Ibrahim, WG Lee, DE Sarlls, J Lizak, MJ Maric, D Reid, WC Hammoud, DA AF Lentz, Margaret R. Peterson, Kristin L. Ibrahim, Wael G. Lee, Dianne E. Sarlls, Joelle Lizak, Martin J. Maric, Dragan Reid, William C. Hammoud, Dima A. TI Diffusion Tensor and Volumetric Magnetic Resonance Measures as Biomarkers of Brain Damage in a Small Animal Model of HIV SO PLOS ONE LA English DT Article ID VIRUS-POSITIVE PATIENTS; APPEARING WHITE-MATTER; CORPUS-CALLOSUM; ANTIRETROVIRAL THERAPY; COGNITIVE IMPAIRMENT; ANTIOXIDANT ENZYMES; TRANSGENIC RAT; AXONAL DAMAGE; DEMENTIA; INJURY AB Background: There are currently no widely accepted neuro-HIV small animal models. We wanted to validate the HIV-1 Transgenic rat (Tg) as an appropriate neuro-HIV model and then establish in vivo imaging biomarkers of neuropathology, within this model, using MR structural and diffusion tensor imaging (DTI). Methods: Young and middle-aged Tg and control rats were imaged using MRI. A subset of middle-aged animals underwent longitudinal repeat imaging six months later. Total brain volume (TBV), ventricular volume (VV) and parenchymal volume (PV = TBV-VV) were measured. Fractional anisotropy (FA) and mean diffusivity (MD) values of the corpus callosum (CC) were calculated from DTI data. Results: TBV and PV were smaller in Tg compared to control rats in young and middle-aged cohorts (p<0.0001). VV increased significantly (p = 0.005) over time in the longitudinal Tg cohort. There were lower FA (p<0.002) and higher MD (p<0.003) values in the CC of middle-aged Tg rats compared to age-matched controls. Longitudinally, MD significantly decreased over time in Tg rats (p<0.03) while it did not change significantly in the control cohort over the same period of time (p>0.05). Conclusions: We detected brain volume loss in the Tg rat, probably due to astrocytic dysfunction/loss, loss of structural/axonal matrix and striatal neuronal loss as suggested by immunofluorescence. Increased MD and decreased FA in the CC probably reflect microstructural differences between the Tg and Control rats which could include increased extracellular space between white matter tracts, demyelination and axonal degeneration, among other pathologies. We believe that the Tg rat is an adequate model of neuropathology in HIV and that volumetric MR and DTI measures can be potentially used as biomarkers of disease progression. C1 [Lentz, Margaret R.; Peterson, Kristin L.; Ibrahim, Wael G.; Lee, Dianne E.; Reid, William C.; Hammoud, Dima A.] NIH, Ctr Infect Dis Imaging CIDI Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Sarlls, Joelle] Natl Inst Child Hlth & Human Dev NICHD, NIH, Bethesda, MD USA. [Lizak, Martin J.] NINDS, Magnet Resonance Imaging Res Facil NMRF, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, DIR, NIH, Bethesda, MD 20892 USA. RP Hammoud, DA (reprint author), NIH, Ctr Infect Dis Imaging CIDI Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM hammoudd@cc.nih.gov RI Hammoud, Dima/C-2286-2015 FU Intramural National Institutes of Health program Center for Infectious Diseases Imaging, Radiology and Imaging Sciences, CC/NIAID FX Funding provided by Intramural National Institutes of Health program Center for Infectious Diseases Imaging, Radiology and Imaging Sciences, CC/NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 8 Z9 8 U1 2 U2 5 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 AUG 21 PY 2014 VL 9 IS 8 AR e105752 DI 10.1371/journal.pone.0105752 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1WL UT WOS:000341106100117 PM 25144656 ER PT J AU Rollan, A Arab, JP Camargo, MC Candia, R Harris, P Ferreccio, C Rabkin, CS Gana, JC Cortes, P Herrero, R Duran, L Garcia, A Toledo, C Espino, A Lustig, N Sarfatis, A Figueroa, C Torres, J Riquelme, A AF Rollan, Antonio Pablo Arab, Juan Camargo, M. Constanza Candia, Roberto Harris, Paul Ferreccio, Catterina Rabkin, Charles S. Cristobal Gana, Juan Cortes, Pablo Herrero, Rolando Duran, Luisa Garcia, Apolinaria Toledo, Claudio Espino, Alberto Lustig, Nicole Sarfatis, Alberto Figueroa, Catalina Torres, Javier Riquelme, Arnoldo TI Management of Helicobacter pylori infection in Latin America: A Delphi technique-based consensus SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Helicobacter pylori; Consensus development conference; Delphi technique; Latin America ID PROTON-PUMP INHIBITOR; RANDOMIZED CONTROLLED-TRIAL; C-13-UREA BREATH TEST; EARLY GASTRIC-CANCER; STANDARD TRIPLE THERAPY; COST-EFFECTIVENESS ANALYSIS; PEPTIC-ULCER DISEASE; SERVICES-TASK-FORCE; TERM-FOLLOW-UP; SEQUENTIAL THERAPY AB AIM: To optimize diagnosis and treatment guidelines for this geographic region, a panel of gastroenterologists, epidemiologists, and basic scientists carried out a structured evaluation of available literature. METHODS: Relevant questions were distributed among the experts, who generated draft statements for consideration by the entire panel. A modified three-round Delphi technique method was used to reach consensus. Critical input was also obtained from representatives of the concerned medical community. The quality of the evidence and level of recommendation supporting each statement was graded according to United States Preventive Services Task Force criteria. RESULTS: A group of ten experts was established. The survey included 15 open-ended questions that were distributed among the experts, who assessed the articles associated with each question. The levels of agreement achieved by the panel were 50% in the first round, 73.3% in the second round and 100% in the third round. Main consensus recommendations included: (1) when available, urea breath and stool antigen test (HpSA) should be used for non-invasive diagnosis; (2) detect and eradicate Helicobacter pylori (H. pylori) in all gastroscopy patients to decrease risk of peptic ulcer disease, prevent o retard progression in patients with preneoplastic lesions, and to prevent recurrence in patients treated for gastric cancer; (3) further investigate implementation issues and health outcomes of H. pylori eradication for primary prevention of gastric cancer in high-risk populations; (4) prescribe standard 14-d triple therapy or sequential therapy for first-line treatment; (5) routinely assess eradication success post-treatment in clinical settings; and (6) select second-and third-line therapies according to antibiotic susceptibility testing. CONCLUSION: These achievable steps toward better region-specific management can be expected to improve clinical health outcomes. (C) 2014 Baishideng Publishing Group Inc. All rights reserved. C1 [Rollan, Antonio; Cortes, Pablo; Duran, Luisa] Univ Desarrollo, Fac Med Clin Alemana, Clin Alemana Santiago, Santiago 7650568, Chile. [Pablo Arab, Juan; Candia, Roberto; Espino, Alberto; Lustig, Nicole; Sarfatis, Alberto; Figueroa, Catalina; Riquelme, Arnoldo] Pontificia Univ Catolica Chile, Fac Med, Dept Gastroenterol, Santiago 8330024, Chile. [Camargo, M. Constanza; Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Candia, Roberto] Pontificia Univ Catolica Chile, Programa Salud Basada Evidencia, Santiago 8330024, Chile. [Harris, Paul; Cristobal Gana, Juan] Pontificia Univ Catolica Chile, Fac Med, Dept Gastroenterol & Nutr Pediat, Santiago 8330024, Chile. [Ferreccio, Catterina] Pontificia Univ Catolica Chile, Fac Med, Dept Salud Publ, Santiago 8330024, Chile. [Herrero, Rolando] WHO, Int Agcy Res Canc, F-69372 Lyon, France. [Garcia, Apolinaria] Univ Concepcion, Fac Ciencias Biol, Dept Microbiol, Concepcion 4089100, Chile. [Toledo, Claudio] Univ Austral Chile, Fac Med, Hosp Valdivia, Unidad Gastroenterol, Valdivia 5090000, Chile. [Torres, Javier] Inst Mexicano Seguro Social, Unidad Invest Enfermedades Infecciosas, Mexico City 06600, DF, Mexico. RP Rollan, A (reprint author), Univ Desarrollo, Fac Med Clin Alemana, Clin Alemana Santiago, Ave Vitacura 5951, Santiago 7650568, Chile. EM arollan@alemana.cl RI Camargo, M. Constanza/R-9891-2016; OI Candia, Roberto/0000-0003-1856-7737 NR 125 TC 4 Z9 5 U1 1 U2 18 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD AUG 21 PY 2014 VL 20 IS 31 BP 10969 EP 10983 DI 10.3748/wjg.v20.i31.10969 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN6TL UT WOS:000340730400033 PM 25152601 ER PT J AU DeBaun, MR Gordon, M McKinstry, RC Noetzel, MJ White, DA Sarnaik, SA Meier, ER Howard, TH Majumdar, S Inusa, BPD Telfer, PT Kirby-Allen, M McCavit, TL Kamdem, A Airewele, G Woods, GM Berman, B Panepinto, JA Fuh, BR Kwiatkowski, JL King, AA Fixler, JM Rhodes, MM Thompson, AA Heiny, ME Redding-Lallinger, RC Kirkham, FJ Dixon, N Gonzalez, CE Kalinyak, KA Quinn, CT Strouse, JJ Miller, JP Lehmann, H Kraut, MA Ball, WS Hirtz, D Casella, JF AF DeBaun, M. R. Gordon, M. McKinstry, R. C. Noetzel, M. J. White, D. A. Sarnaik, S. A. Meier, E. R. Howard, T. H. Majumdar, S. Inusa, B. P. D. Telfer, P. T. Kirby-Allen, M. McCavit, T. L. Kamdem, A. Airewele, G. Woods, G. M. Berman, B. Panepinto, J. A. Fuh, B. R. Kwiatkowski, J. L. King, A. A. Fixler, J. M. Rhodes, M. M. Thompson, A. A. Heiny, M. E. Redding-Lallinger, R. C. Kirkham, F. J. Dixon, N. Gonzalez, C. E. Kalinyak, K. A. Quinn, C. T. Strouse, J. J. Miller, J. P. Lehmann, H. Kraut, M. A. Ball, W. S., Jr. Hirtz, D. Casella, J. F. TI Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CHILDREN; DISEASE; STROKE; BRAIN; HEMOGLOBINOPATHY; PREVENTION; STATE; BLOOD; RISK AB BACKGROUND Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood transfusion therapy than among those who received standard care. METHODS In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P = 0.04). CONCLUSIONS Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.) C1 [DeBaun, M. R.] Vanderbilt Univ, Sch Med, Vanderbilt Meharry Ctr Excellence Sickle Cell Dis, Dept Pediat,Div Hematol Oncol, Nashville, TN 37212 USA. [Gordon, M.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, Div Biostat, St Louis, MO 63130 USA. [McKinstry, R. C.] Washington Univ, Sch Med, Dept Radiol & Pediat, St Louis, MO 63130 USA. [Noetzel, M. J.] Washington Univ, Sch Med, Dept Neurol & Pediat, St Louis, MO 63130 USA. [White, D. A.] Washington Univ, Sch Med, Dept Psychol, St Louis, MO 63130 USA. [King, A. A.] Washington Univ, Sch Med, Program Occupat Therapy, St Louis, MO 63130 USA. [King, A. A.] Washington Univ, Sch Med, Dept Pediat Hematol Oncol, St Louis, MO 63130 USA. [Miller, J. P.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63130 USA. [Miller, J. P.] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63130 USA. [Sarnaik, S. A.] Wayne State Univ, Dept Pediat, Div Hematol Oncol, Detroit, MI 48202 USA. [Meier, E. R.] George Washington Univ, Dept Pediat, Med Ctr, Ctr Canc & Blood Disorders,Childrens Natl Med Ctr, Washington, DC 20052 USA. [Gonzalez, C. E.] Georgetown Univ Hosp, Dept Pediat, Div Hematol Oncol, Washington, DC 20007 USA. [Howard, T. H.] Univ Alabama Birmingham, Dept Pediat, Div Hematol Oncol, Birmingham, W Midlands, England. [Majumdar, S.] Univ Mississippi, Med Ctr, Dept Pediat, Div Hematol Oncol, Jackson, MS USA. [Inusa, B. P. D.] St Thomas Hosp NHS Trust, Evelina Childrens Hosp, Dept Paediat, London, England. [Telfer, P. T.] Barts Hlth NHS Trust, Royal London Hosp, Dept Pediat Hematol, London, England. [Kirkham, F. J.] UCL, Inst Child Hlth, Neurosci Unit, London WC1E 6BT, England. [Kirby-Allen, M.] Univ Toronto, Dept Paediat, Hosp Sick Children, Toronto, ON M5S 1A1, Canada. [McCavit, T. L.] UT Southwestern Med Ctr, Dept Pediat, Div Hematol Oncol, Dallas, TX USA. [Kamdem, A.] Hop Intercommunal Creteil, Dept Pediat, Creteil, France. [Airewele, G.] Baylor Coll Med, Dept Pediat, Div Hematol Oncol, Houston, TX 77030 USA. [Woods, G. M.] Univ Missouri Kansas City, Dept Pediat, Kansas City, MO USA. [Berman, B.] Case Western Reserve Univ, Dept Pediat, Div Hematol Oncol, Cleveland, OH 44106 USA. [Rhodes, M. M.] Ohio State Univ, Dept Pediat, Div Hematol Oncol, Columbus, OH 43210 USA. [Kalinyak, K. A.; Quinn, C. T.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Hematol, Cincinnati, OH 45229 USA. [Ball, W. S., Jr.] Cincinnati Childrens Hosp Med Ctr, Dept Radiol, Cincinnati, OH 45229 USA. [Panepinto, J. A.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Fuh, B. R.] Brody Sch Med, Dept Pediat, Greenville, NC USA. [Redding-Lallinger, R. C.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Dixon, N.] Wake Forest Univ Hlth Sci, Dept Pediat, Winston Salem, NC USA. [Kwiatkowski, J. L.] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. [Kwiatkowski, J. L.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Fixler, J. M.] Johns Hopkins Univ, Sch Med, Dept Pediat, Sinai Hosp, Baltimore, MD 21205 USA. [Strouse, J. J.] Johns Hopkins Univ, Sch Med, Dept Pediat & Med, Div Pediat Hematol, Baltimore, MD USA. [Casella, J. F.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Hematol, Baltimore, MD 21205 USA. [Kraut, M. A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Div Neuroradiol, Baltimore, MD 21205 USA. [Lehmann, H.] Johns Hopkins Bloomberg Sch Publ Hlth, Div Hlth Sci Informat, Baltimore, MD USA. [Hirtz, D.] NINDS, NIH, Bethesda, MD 20892 USA. [Thompson, A. A.] Northwestern Univ, Dept Pediat, Ann & Robert H Lurie Childrens Hosp Chicago, Div Hematol Oncol, Chicago, IL 60611 USA. [Heiny, M. E.] Indiana Univ Purdue Univ, Dept Pediat, Indianapolis, IN 46202 USA. RP DeBaun, MR (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Meharry Ctr Excellence Sickle Cell Dis, Dept Pediat,Div Hematol Oncol, Nashville, TN 37212 USA. EM m.debaun@vanderbilt.edu RI Quinn, Charles/J-6842-2012; Kirkham, Fenella/C-2442-2009; OI Quinn, Charles/0000-0002-2372-2175; Kirkham, Fenella/0000-0002-2443-7958; King, Allison/0000-0002-1951-6176 FU National Institute of Neurological Disorders and Stroke FX Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285. NR 27 TC 91 Z9 91 U1 1 U2 21 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 AUG 21 PY 2014 VL 371 IS 8 BP 699 EP 710 DI 10.1056/NEJMoa1401731 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AN3SV UT WOS:000340509900005 PM 25140956 ER PT J AU Belew, AT Meskauskas, A Musalgaonkar, S Advani, VM Sulima, SO Kasprzak, WK Shapiro, BA Dinman, JD AF Belew, Ashton Trey Meskauskas, Arturas Musalgaonkar, Sharmishtha Advani, Vivek M. Sulima, Sergey O. Kasprzak, Wojciech K. Shapiro, Bruce A. Dinman, Jonathan D. TI Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway SO NATURE LA English DT Article ID TRANSLATIONAL FIDELITY; SEQUENCE ALIGNMENT; CELLS; GENE; SIGNALS; MODEL; YEAST; EFFICIENCY; MICRORNAS; DATABASE AB Programmed -1 ribosomal frameshift (-1 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Although well characterizedin viruses, how these elements may regulate cellular gene expression is not understood. Here we describe a -1 PRF signal in the human mRNA encoding CCR5, the HIV-1 co-receptor. CCR5 mRNA-mediated -1 PRF is directed by an mRNA pseudoknot, and is stimulated by at least two microRNAs. Mapping the mRNA-miRNA interaction suggests that formation of a triplex RNA structure stimulates -1 PRF. A -1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay pathway. At least one additional mRNA decay pathway is also involved. Functional -1 PRF signals that seem to be regulated by miRNAs are also demonstrated in mRNAs encoding six other cytokine receptors, suggesting a novel mode through which immune responses may be fine-tuned in mammalian cells. C1 [Belew, Ashton Trey; Meskauskas, Arturas; Musalgaonkar, Sharmishtha; Advani, Vivek M.; Sulima, Sergey O.; Dinman, Jonathan D.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Meskauskas, Arturas] Vilnius State Univ, Dept Biotechnol & Microbiol, LT-03101 Vilnius, Lithuania. [Kasprzak, Wojciech K.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Shapiro, Bruce A.] NCI, Basic Res Lab, Frederick, MD 21702 USA. RP Dinman, JD (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. EM dinman@umd.edu OI Dinman, Jonathan/0000-0002-2402-9698 FU National Institutes of Health [5 R01GM058859, R21GM068123]; National Science Foundation [MCB-0084559]; University of Maryland College of CMNS Hockmeyer Fellowship; NIH/NIGMS [T32GM080201]; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; Intramural Research Program of the National Institutes of Health, Center for Cancer Research; [NIH/NIAIDT32AI051967] FX This work was supported by grants to J.D.D. from the National Institutes of Health (5 R01GM058859, R21GM068123) and from the National Science Foundation(MCB-0084559). A. T. B. was supported by NIH/NIAID T32AI051967, and a University of Maryland College of CMNS Hockmeyer Fellowship. S.O.S. was supported by NIH/NIGMS T32GM080201. This publication has also been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under Contract HHSN261200800001E to W. K. K. This research was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research to B. A. S. The content of this publication does not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 48 TC 38 Z9 38 U1 1 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 21 PY 2014 VL 512 IS 7514 BP 265 EP + DI 10.1038/nature13429 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN3SF UT WOS:000340508200025 PM 25043019 ER PT J AU Than, NG Balogh, A Romero, R Karpati, E Erez, O Szilagyi, A Kovalszky, I Sammar, M Gizurarson, S Matko, J Zavodszky, P Papp, Z Meiri, H AF Than, Nandor Gabor Balogh, Andrea Romero, Roberto Karpati, Eva Erez, Offer Szilagyi, Andras Kovalszky, Ilona Sammar, Marei Gizurarson, Sveinbjorn Matko, Janos Zavodszky, Peter Papp, Zoltan Meiri, Hamutal TI Placental Protein 13 (PP13) - a placental immunoregulatory galectin protecting pregnancy SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE actin cytoskeleton; biomarker; danger signal; evolution; extracellular vesicles; glycans; lectins; maternal-fetal interface ID UTERINE ARTERY DOPPLER; MATERNAL-FETAL INTERFACE; GALACTOSIDE-BINDING LECTINS; DEEP TROPHOBLAST INVASION; LEYDEN CRYSTAL PROTEIN; HUMAN CYTOTROPHOBLAST DIFFERENTIATION; EARLY-ONSET PREECLAMPSIA; VON-WILLEBRAND-FACTOR; BLOOD-GROUP ANTIGENS; FOR-GESTATIONAL-AGE AB Galectins are glycan-binding proteins that regulate innate and adaptive immune responses, and some confer maternal-fetal immune tolerance in eutherian mammals. A chromosome 19 cluster of galectins has emerged in anthropoid primates, species with deep placentation and long gestation. Three of the five human cluster galectins are solely expressed in the placenta, where they may confer additional immunoregulatory functions to enable deep placentation. One of these is galectin-13, also known as Placental Protein 13 (PP13). It has a "jelly-roll" fold, carbohydrate-recognition domain and sugar-binding preference resembling other mammalian galectins. PP13 is predominantly expressed by the syncytiotrophoblast and released from the placenta into the maternal circulation. Its ability to induce apoptosis of activated T cells in vitro, and to divert and kill T cells as well as macrophages in the maternal decidua in situ, suggests important immune functions. Indeed, mutations in the promoter and an exon of LGALS13 presumably leading to altered or non-functional protein expression are associated with a higher frequency of preeclampsia and other obstetrical syndromes, which involve immune dysregulation. Moreover, decreased placental expression of PP13 and its low concentrations in first trimester maternal sera are associated with elevated risk of preeclampsia. Indeed, PP13 turned to be a good early biomarker to assess maternal risk for the subsequent development of pregnancy complications caused by impaired placentation. Due to the ischemic placental stress in preterm preeclampsia, there is increased trophoblastic shedding of PP13 immunopositive microvesicles starting in the second trimester, which leads to high maternal blood PP13 concentrations. Our meta-analysis suggests that this phenomenon may enable the potential use of PP13 in directing patient management near to or at the time of delivery. Recent findings on the beneficial effects of PP13 on decreasing blood pressure due to vasodilatation in pregnant animals suggest its therapeutic potential in preeclampsia. C1 [Than, Nandor Gabor; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, US Dept Hlth & Human Serv, NIH, Bethesda, MD USA. [Than, Nandor Gabor; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, US Dept Hlth & Human Serv, NIH, Detroit, MI USA. [Than, Nandor Gabor] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Than, Nandor Gabor; Papp, Zoltan] Semmelweis Univ, Matern Private Dept, Kutvolgyi Clin Block, H-1085 Budapest, Hungary. [Than, Nandor Gabor; Szilagyi, Andras; Zavodszky, Peter] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, H-1117 Budapest, Hungary. [Karpati, Eva; Matko, Janos] Eotvos Lorand Univ, Dept Immunol, Budapest, Hungary. [Erez, Offer] Ben Gurion Univ Negev, Soroka Univ, Med Ctr, Dept Obstet & Gynecol, IL-84105 Beer Sheva, Israel. [Kovalszky, Ilona] Semmelweis Univ, Dept Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary. [Sammar, Marei] ORT Braude Coll, Prof Ephraim Katzir Dept Biotechnol Engn, Karmiel, Israel. [Gizurarson, Sveinbjorn] Univ Iceland, Fac Pharmaceut Sci, Sch Hlth Sci, Reykjavik, Iceland. [Meiri, Hamutal] TeleMarpe Ltd, Tel Aviv, Israel. [Meiri, Hamutal] Hylabs Ltd, Rehovot, Israel. RP Than, NG (reprint author), Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, Magyar Tudosok Korutja 2, H-1117 Budapest, Hungary. EM than.gabor@ttk.mta.hu; hamutal62@hotmail.com RI Gizurarson, Sveinbjorn/M-1489-2015; Szilagyi, Andras/A-3561-2008 OI Gizurarson, Sveinbjorn/0000-0001-7824-9752; Szilagyi, Andras/0000-0002-1773-6861 FU European Union [601852, 037244]; Hungarian OTKA-PD grant [104398]; Hungarian Academy of Sciences Momentum grant [LP20147/2014]; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS); Foundation of Helgu Jonsdottur and Sigurlida Kristjansson (Iceland) FX The preparation and publication of this manuscript was sponsored, in part, by the European Union FP7 "ASPRE" project (#601852 to Hamutal Meiri and Sveinbjorn Gizurarson), the Hungarian OTKA-PD grant (#104398 to Andrea Balogh), and the Hungarian Academy of Sciences Momentum grant (#LP20147/2014 to Nandor Gabor Than). Many of the published studies conducted between 2006 and 2010 were funded by the European Union FP6 "Pregenesys" project (#037244 to Hamutal Meiri and Nandor Gabor Than) and by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS). The Foundation of Helgu Jonsdottur and Sigurlida Kristjansson (Iceland) sponsored the animal studies with rats (to Sveinbjorn Gizurarson). PP13, anti-P P13 monoclonal antibodies and ELISA kits were produced by Hy-Laboratories for the animal studies along with some of the clinical studies about PP13 which were included in either the first or the third trimester meta-analysis. The authors thank Dr. Harvey J. Kliman (Yale University, New Haven, CT, USA) for helpful discussions, Dr. Ruth Cohen and Alla Tractenhaertz for providing unpublished information on the new generation of PP13 kits and their help with this publication, and for Sara Tipton (Wayne State University) for her critical reading of our manuscript. NR 186 TC 12 Z9 12 U1 2 U2 15 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD AUG 20 PY 2014 VL 5 BP 1 EP 25 AR 348 DI 10.3389/fimmu.2014.00348 PG 25 WC Immunology SC Immunology GA CI0AE UT WOS:000354397100001 PM 25191322 ER PT J AU Byun, K Bayarsaikhan, D Bayarsaikhan, E Son, M Oh, S Lee, J Son, HI Won, MH Kim, SU Song, BJ Lee, B AF Byun, Kyunghee Bayarsaikhan, Delger Bayarsaikhan, Enkhjargal Son, Myeongjoo Oh, Seyeon Lee, Jaesuk Son, Hye-in Won, Moo-Ho Kim, Seung U. Song, Byoung-Joon Lee, Bonghee TI Microglial AGE-Albumin Is Critical in Promoting Alcohol-Induced Neurodegeneration in Rats and Humans SO PLOS ONE LA English DT Article ID INDUCED OXIDATIVE STRESS; BINGE ETHANOL EXPOSURE; INDUCED BRAIN-DAMAGE; INCREASED MCP-1; ACTIVATION; NEUROINFLAMMATION; NEUROGENESIS; EXPRESSION; REGIONS; PROLIFERATION AB Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration. C1 [Byun, Kyunghee; Bayarsaikhan, Delger; Bayarsaikhan, Enkhjargal; Son, Myeongjoo; Oh, Seyeon; Lee, Jaesuk; Lee, Bonghee] Gachon Univ, Lee Gil Ya Canc & Diabet Inst, Ctr Genom & Prote, Inchon, South Korea. [Byun, Kyunghee; Lee, Bonghee] Gachon Univ, Grad Sch Med, Dept Anat & Cell Biol, Inchon, South Korea. [Son, Hye-in] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Won, Moo-Ho] Kangwon Natl Univ, Coll Med, Dept Anat & Neurobiol, Chunchon, South Korea. [Won, Moo-Ho] Kangwon Natl Univ, Coll Med, Inst Neurodegenerat & Neuroregenerat, Chunchon, South Korea. [Kim, Seung U.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM bj.song@nih.gov; bhlee@gachon.ac.kr FU National Research Foundation - Korean government [20120002979] FX This work was supported by the National Research Foundation grant funded by the Korean government (K. B.) (20120002979). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 3 Z9 3 U1 0 U2 5 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 AUG 20 PY 2014 VL 9 IS 8 AR e104699 DI 10.1371/journal.pone.0104699 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3JB UT WOS:000342687200027 PM 25140518 ER PT J AU Cizza, G Piaggi, P Rother, KI Csako, G AF Cizza, Giovanni Piaggi, Paolo Rother, Kristina I. Csako, Gyorgy CA Sleep Extension Study Grp TI Hawthorne Effect with Transient Behavioral and Biochemical Changes in a Randomized Controlled Sleep Extension Trial of Chronically Short-Sleeping Obese Adults: Implications for the Design and Interpretation of Clinical Studies SO PLOS ONE LA English DT Article ID DURATION; QUALITY; PLACEBO; IMPACT; INTERVENTION; METAANALYSIS; INDEX AB Objective: To evaluate the effects of study participation per se at the beginning of a sleep extension trial between screening, randomization, and the run-in visit. Design: Subjects were screened, returned for randomization (Comparison vs. Intervention) after 81 days (median), and attended run-in visit 121 days later. Setting: Outpatient. Patients: Obese (N = 125; M/F, 30/95; Blacks/Whites/Other, N = 73/44/8), mean weight 107.6 +/- 19.7 kg, <6.5 h sleep/night. Intervention: Non-pharmacological sleep extension. Measurements: Sleep duration (diaries and actigraphy watch), sleep quality (Pittsburgh Sleep Quality Index), daily sleepiness (Epworth Sleepiness Scale), fasting glucose, insulin and lipids. Results: Prior to any intervention, marked improvements occurred between screening and randomization. Sleep duration increased (diaries: 357.4 +/- 51.2 vs. 388.1 +/- 48.6 min/night; mean +/- SD; P < 0.001 screening vs. randomization; actigraphy: 344.3 +/- 41.9 vs. 358.6 +/- 48.2 min/night; P < 0.001) sleep quality improved (9.1 +/- 3.2 vs. 8.2 +/- 3.0 PSQI score; P < 0.001), sleepiness tended to improve (8.9 +/- 4.6 vs. 8.3 +/- 4.5 ESS score; P = 0.06), insulin resistance decreased (0.327 +/- 0.038 vs. 0.351 +/- 0.045; Quicki index; P < 0.001), and lipids improved, except for HDL-C. Abnormal fasting glucose (25% vs. 11%; P = 0.007), and metabolic syndrome (42% vs. 29%; P = 0.007) both decreased. In absence of intervention, the earlier metabolic improvements disappeared at the run-in visit. Limitations: Relatively small sample size. Conclusions: Improvements in biochemical and behavioral parameters between screening and randomization changed the "true'' study baseline, thereby potentially affecting outcome. While regression to the mean and placebo effect were considered, these findings are most consistent with the "Hawthorne effect'', according to which behavior measured in the setting of an experimental study changes in response to the attention received from study investigators. This is the first time that biochemical changes were documented with respect to the Hawthorne effect. The findings have implications for the design and conduct of clinical research. C1 [Cizza, Giovanni] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Piaggi, Paolo] Univ Hosp Pisa, Obes Res Ctr, Endocrinol Unit, Pisa, Italy. [Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. [Csako, Gyorgy] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. EM gcizza@gmail.com OI Piaggi, Paolo/0000-0003-2774-9161 FU intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases; Clinical Center, NIH FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and Clinical Center, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 4 Z9 4 U1 1 U2 10 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 AUG 20 PY 2014 VL 9 IS 8 AR e104176 DI 10.1371/journal.pone.0104176 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3JB UT WOS:000342687200013 PM 25141012 ER PT J AU Lakshminarayana, SB Boshoff, HIM Cherian, J Ravindran, S Goh, A Jiricek, J Nanjundappa, M Nayyar, A Gurumurthy, M Singh, R Dick, T Blasco, F Barry, CE Ho, PC Manjunatha, UH AF Lakshminarayana, Suresh B. Boshoff, Helena I. M. Cherian, Joseph Ravindran, Sindhu Goh, Anne Jiricek, Jan Nanjundappa, Mahesh Nayyar, Amit Gurumurthy, Meera Singh, Ramandeep Dick, Thomas Blasco, Francesca Barry, Clifton E., III Ho, Paul C. Manjunatha, Ujjini H. TI Pharmacokinetics-Pharmacodynamics Analysis of Bicyclic 4-Nitroimidazole Analogs in a Murine Model of Tuberculosis SO PLOS ONE LA English DT Article ID EARLY BACTERICIDAL ACTIVITY; EPITHELIAL LINING FLUID; AEROSOL INFECTION MODEL; PLASMA-PROTEIN BINDING; IN-VIVO EFFICACY; MYCOBACTERIUM-TUBERCULOSIS; INTRAPULMONARY PHARMACOKINETICS; NITROIMIDAZOPYRAN PA-824; TISSUE DISTRIBUTION; FIBEROPTIC BRONCHOSCOPY AB PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT(>MIC)). In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in vivo PK and efficacy studies. In an established murine TB model, the efficacy of diverse nitroimidazole analogs ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Further, a retrospective analysis was performed for a set of seven nitroimidazole analogs to identify the PK parameters that correlate with in vivo efficacy. Our findings show that the in vivo efficacy of bicyclic 4-nitroimidazoles correlated better with lung PK than with plasma PK. Further, nitroimidazole analogs with moderate-to-high volume of distribution and Lung to plasma ratios of >2 showed good efficacy. Among all the PK-PD indices, total lung T->MIC correlated the best with in vivo efficacy (r(s) = 0.88) followed by lung C-max/MIC and AUC/ MIC. Thus, lung drug distribution studies could potentially be exploited to guide the selection of compounds for efficacy studies, thereby accelerating the drug discovery efforts in finding new nitroimidazole analogs. C1 [Lakshminarayana, Suresh B.; Cherian, Joseph; Ravindran, Sindhu; Goh, Anne; Jiricek, Jan; Nanjundappa, Mahesh; Gurumurthy, Meera; Dick, Thomas; Blasco, Francesca; Manjunatha, Ujjini H.] Novartis Inst Trop Dis, Singapore, Singapore. [Boshoff, Helena I. M.; Nayyar, Amit; Singh, Ramandeep; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Ho, Paul C.] Natl Univ Singapore, Dept Pharm, Singapore 117548, Singapore. RP Lakshminarayana, SB (reprint author), Novartis Inst Trop Dis, Singapore, Singapore. EM suresh.b_lakshminarayana@novartis.com; manjunatha.ujjini@novartis.com RI Barry, III, Clifton/H-3839-2012; Ho, Paul/O-9652-2014; Cherian, Joseph/Q-2522-2016 OI Ho, Paul/0000-0001-9213-7116; FU NITD; NIAID; Bill and Melinda Gates Foundation; Wellcome Trust FX This work was funded in part by NITD, the Intramural Research Program of the NIAID to CEB, the Bill and Melinda Gates Foundation and the Wellcome Trust. NITD provided support in the form of salaries for authors SBL, JC, SR, AG, JJ, MN, MG, TD, FB and UHM but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 76 TC 9 Z9 9 U1 1 U2 7 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 AUG 20 PY 2014 VL 9 IS 8 AR e105222 DI 10.1371/journal.pone.0105222 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3JB UT WOS:000342687200061 PM 25141257 ER PT J AU Lin, P Bach, M Asquith, M Lee, AY Akileswaran, L Stauffer, P Davin, S Pan, YZ Cambronne, ED Dorris, M Debelius, JW Lauber, CL Ackermann, G Baeza, YV Gill, T Knight, R Colbert, RA Taurog, JD Van Gelder, RN Rosenbaum, JT AF Lin, Phoebe Bach, Mary Asquith, Mark Lee, Aaron Y. Akileswaran, Lakshmi Stauffer, Patrick Davin, Sean Pan, Yuzhen Cambronne, Eric D. Dorris, Martha Debelius, Justine W. Lauber, Christian L. Ackermann, Gail Baeza, Yoshiki V. Gill, Tejpal Knight, Rob Colbert, Robert A. Taurog, Joel D. Van Gelder, Russell N. Rosenbaum, James T. TI HLA-B27 and Human beta 2-Microglobulin Affect the Gut Microbiota of Transgenic Rats SO PLOS ONE LA English DT Article ID HUMAN MONOCYTIC CELLS; KLEBSIELLA-PNEUMONIAE NITROGENASE; ANKYLOSING-SPONDYLITIS; HLA-B27-TRANSGENIC RATS; SALMONELLA-ENTERITIDIS; BACTEROIDES-VULGATUS; INFLAMMATORY DISEASE; AUTOIMMUNE-DISEASE; REACTIVE ARTHRITIS; MOLECULAR MIMICRY AB The HLA-B27 gene is a major risk factor for clinical diseases including ankylosing spondylitis, acute anterior uveitis, reactive arthritis, and psoriatic arthritis, but its mechanism of risk enhancement is not completely understood. The gut microbiome has recently been shown to influence several HLA-linked diseases. However, the role of HLA-B27 in shaping the gut microbiome has not been previously investigated. In this study, we characterize the differences in the gut microbiota mediated by the presence of the HLA-B27 gene. We identified differences in the cecal microbiota of Lewis rats transgenic for HLA-B27 and human beta 2-microglobulin (h beta 2m), compared with wild-type Lewis rats, using biome representational in situ karyotyping (BRISK) and 16S rRNA gene sequencing. 16S sequencing revealed significant differences between transgenic animals and wild type animals by principal coordinates analysis. Further analysis of the data set revealed an increase in Prevotella spp. and a decrease in Rikenellaceae relative abundance in the transgenic animals compared to the wild type animals. By BRISK analysis, species-specific differences included an increase in Bacteroides vulgatus abundance in HLA-B27/h beta 2m and h beta 2m compared to wild type rats. The finding that HLA-B27 is associated with altered cecal microbiota has not been shown before and can potentially provide a better understanding of the clinical diseases associated with this gene. C1 [Lin, Phoebe; Stauffer, Patrick; Davin, Sean; Pan, Yuzhen; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Asquith, Mark; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Div Rheumatol, Portland, OR 97201 USA. [Bach, Mary] Univ Washington, Div Rheumatol, VA Med Ctr, Seattle, WA 98195 USA. [Lee, Aaron Y.] Moorfields Eye Inst London, London, England. [Akileswaran, Lakshmi; Van Gelder, Russell N.] Univ Washington, Dept Ophthalmol, Seattle, WA 98195 USA. [Dorris, Martha; Taurog, Joel D.] Univ Texas Southwestern, Dept Rheumatol, Dallas, TX USA. [Debelius, Justine W.; Lauber, Christian L.; Ackermann, Gail; Baeza, Yoshiki V.; Knight, Rob] Univ Colorado, Boulder, CO 80309 USA. [Rosenbaum, James T.] Devers Eye Inst, Portland, OR USA. [Cambronne, Eric D.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Gill, Tejpal; Colbert, Robert A.] NIAMSD, Pediat Translat Res Branch, NIH, Baltimore, MD USA. [Knight, Rob] Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. RP Lin, P (reprint author), Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. EM linp@ohsu.edu RI Knight, Rob/D-1299-2010 FU Research to Prevent Blindness Career Development Award; NIH [K08EY022948, P30 EY001730, T32 AR 007108]; Stan and Madelle Rosenfeld Family Trust; William and Mary Bauman Foundation; Burroughs-Wellcome Translational Scientist Award; Research to Prevent Blindness; NIAMS [Z01 AR041184] FX PL is supported by a Research to Prevent Blindness Career Development Award and an NIH award K08EY022948. JTR is supported by the Stan and Madelle Rosenfeld Family Trust and the William and Mary Bauman Foundation. RK is an HHMI Early Career Scientist. RVG and LA were supported by the Burroughs-Wellcome Translational Scientist Award, an unrestricted award from Research to Prevent Blindness, and by NIH P30 EY001730. MB was supported by NIH T32 AR 007108. TG and RAC were supported by the NIAMS Intramural Research Program Z01 AR041184. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 45 Z9 47 U1 2 U2 13 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 AUG 20 PY 2014 VL 9 IS 8 AR e105684 DI 10.1371/journal.pone.0105684 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3JB UT WOS:000342687200120 PM 25140823 ER PT J AU Crane, DD Bauler, TJ Wehrly, TD Bosio, CM AF Crane, Deborah D. Bauler, Timothy J. Wehrly, Tara D. Bosio, Catharine M. TI Mitochondrial ROS potentiates indirect activation of the AIM2 inflannmasome SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE inflammasome; tularemia; macrophage; reactive oxygen species ID VIRULENT FRANCISELLA-TULARENSIS; REACTIVE OXYGEN; INFLAMMASOME ACTIVATION; INNATE IMMUNITY; SUPPRESSION; INFECTION; NITROGEN; REVEALS; STRAINS; CELLS AB Activation of the inflammasome is important for the detection and clearance of cytosolic pathogens. In contrast to avirulent Francisella novicida (Fn), infection with virulent Francisella tularensis ssp tularensis does not trigger activation of the host AIM2 inflammasome. Here we show that differential activation of AIM2 following Francisella infection is due to sensitivity of each isolate to reactive oxygen species (ROS). ROS present at the outset of Fn infection contributes to activation of the AIM2 inflammasome, independent of NLRP3 and NADPH oxidase. Rather, mitochondrial ROS (mROS) is critical for Fn stimulation of the inflammasome. This study represents the first demonstration of the importance of mROS in the activation of the AIM2 inflammasome by bacteria. Our results also demonstrate that bacterial resistance to mROS is a mechanism of virulence for early evasion of detection by the host. C1 [Crane, Deborah D.; Bauler, Timothy J.; Wehrly, Tara D.; Bosio, Catharine M.] NIAID, Immun Pulmonary Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Bosio, CM (reprint author), NIAID, Immun Pulmonary Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 24 TC 11 Z9 11 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD AUG 20 PY 2014 VL 5 AR 438 DI 10.3389/fmicb.2014.00438 PG 7 WC Microbiology SC Microbiology GA AO7VN UT WOS:000341560800001 PM 25191316 ER PT J AU Di Bonaventura, MVM Ciccocioppo, R Romano, A Bossert, JM Rice, KC Ubaldi, M Laurent, RS Gaetani, S Massi, M Shaham, Y Cifani, C AF Di Bonaventura, Maria Vittoria Micioni Ciccocioppo, Roberto Romano, Adele Bossert, Jennifer M. Rice, Kenner C. Ubaldi, Massimo Laurent, Robyn St. Gaetani, Silvana Massi, Maurizio Shaham, Yavin Cifani, Carlo TI Role of Bed Nucleus of the Stria Terminalis Corticotrophin-Releasing Factor Receptors in Frustration Stress-Induced Binge-Like Palatable Food Consumption in Female Rats with a History of Food Restriction SO JOURNAL OF NEUROSCIENCE LA English DT Article DE binge eating; BNST; CRF1 receptor antagonist; palatable food; R121919; stress and food restriction ID MEDIAL PREFRONTAL CORTEX; ANXIOGENIC DRUG YOHIMBINE; INDUCED REINSTATEMENT; INDUCED RELAPSE; COCAINE SEEKING; EATING DISORDER; CRF RECEPTORS; HEROIN-SEEKING; LIMITED ACCESS; OBESE WOMEN AB We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This "frustration stress" manipulation also activates the hypothalamic-pituitary-adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a] pyrimidine) (10-20 mg/kg) and BNST (25-50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist D-Phe-CRF(12-41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders. C1 [Di Bonaventura, Maria Vittoria Micioni; Ciccocioppo, Roberto; Ubaldi, Massimo; Massi, Maurizio; Cifani, Carlo] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, MC, Italy. [Romano, Adele; Gaetani, Silvana] Univ Roma La Sapienza, Dept Physiol & Pharmacol, I-00185 Rome, Italy. [Bossert, Jennifer M.; Rice, Kenner C.; Laurent, Robyn St.; Shaham, Yavin; Cifani, Carlo] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Cifani, C (reprint author), Univ Camerino, Sch Pharm, Pharmacol Unit, Via Madonna Carceri 9, I-62032 Camerino, MC, Italy. EM carlo.cifani@unicam.it RI Gaetani, Silvana/D-3455-2009; OI Cifani, Carlo/0000-0001-6180-828X; Ubaldi, Massimo/0000-0002-4089-2483; Micioni Di Bonaventura, Maria Vittoria/0000-0002-8044-1206; ROMANO, ADELE/0000-0003-3874-2627 FU Italian Ministry of University and Research [FIRB-RBFR12DELS]; National Institute on Drug Abuse, Intramural Research Program [R121919]; National Institute on Alcoholism and Alcohol Abuse FX The behavioral and pharmacological part of the research was supported by Italian Ministry of University and Research Grant FIRB-RBFR12DELS (C.C., S.G.). The synthesis of R121919 and the immunohistochemistry part of the research were supported by the National Institute on Drug Abuse, Intramural Research Program, and the National Institute on Alcoholism and Alcohol Abuse. We thank Dr. David Epstein for helpful comments on the text. NR 75 TC 5 Z9 5 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 AUG 20 PY 2014 VL 34 IS 34 BP 11316 EP 11324 DI 10.1523/JNEUROSCI.1854-14.2014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AO4MI UT WOS:000341312600016 ER PT J AU Bae, M Patel, N Xu, HX Lee, M Tominaga-Yamanaka, K Nath, A Geiger, J Gorospe, M Mattson, MP Haughey, NJ AF Bae, Mihyun Patel, Neha Xu, Haoxing Lee, Mingwaoh Tominaga-Yamanaka, Kumiko Nath, Avindra Geiger, Jonathan Gorospe, Myriam Mattson, Mark P. Haughey, Norman J. TI Activation of TRPML1 Clears Intraneuronal A beta in Preclinical Models of HIV Infection SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amyloid; dementia; endosome; HIV; lysosome; neuron ID HUMAN-IMMUNODEFICIENCY-VIRUS; AMYLOID PRECURSOR PROTEIN; BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; APP MESSENGER-RNA; ALZHEIMERS-DISEASE; NEUROCOGNITIVE DISORDERS; LIPID RAFTS; MOUSE MODEL; ANTIRETROVIRAL TREATMENT AB Antiretroviral therapy extends the lifespan of human immunodeficiency virus (HIV)-infected patients, but many survivors develop premature impairments in cognition. These residual cognitive impairments may involve aberrant deposition of amyloid beta-peptides (A beta). By unknown mechanisms, A beta accumulates in the lysosomal and autophagic compartments of neurons in the HIV-infected brain. Here we identify the molecular events evoked by the HIV coat protein gp120 that facilitate the intraneuronal accumulation of A beta. We created a triple transgenic gp120/APP/PS1 mouse that recapitulates intraneuronal deposition of A beta in a manner reminiscent of the HIV-infected brain. In cultured neurons, we found that the HIV coat protein gp120 increased the transcriptional expression of BACE1 through repression of PPAR gamma, and increased APP expression by promoting interaction of the translation-activating RBP heterogeneous nuclear ribonucleoprotein C with APP mRNA. APP and BACE1 were colocalized into stabilized membrane microdomains, where the beta-cleavage of APP and A beta formation were enhanced. A beta-peptides became localized to lysosomes that were engorged with sphingomyelin and calcium. Stimulating calcium efflux from lysosomes with a TRPM1 agonist promoted calcium efflux, luminal acidification, and cleared both sphingomyelin and A beta from lysosomes. These findings suggest that therapeutics targeted to reduce lysosomal pH in neurodegenerative conditions may protect neurons by facilitating the clearance of accumulated sphingolipids and A beta-peptides. C1 [Bae, Mihyun; Patel, Neha; Haughey, Norman J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Div Neuroimmunol & Neurol Infect, Baltimore, MD 21287 USA. [Xu, Haoxing] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Lee, Mingwaoh; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Geiger, Jonathan] Univ N Dakota, Sch Med & Hlth Sci, Dept Pharmacol Physiol & Therapeut, Grand Forks, ND 58202 USA. [Tominaga-Yamanaka, Kumiko; Gorospe, Myriam] NIA, Genet Lab, IRP, NIH, Baltimore, MD 21224 USA. [Mattson, Mark P.] NIA, Neurosci Lab, IRP, NIH, Baltimore, MD 21224 USA. RP Haughey, NJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Meyer 6-109,600 North Wolfe St, Baltimore, MD 21287 USA. EM nhaughe1@jhmi.edu FU NIH [MH077542, AG034849, AA0017408, MH075673]; National Institute on Aging [GM103329]; [AG043338]; [P30GM103329]; [R01MH100972] FX This work was supported by NIH Grants MH077542, AG034849, AA0017408, and MH075673 to N.J.H., and by the intramural research program of the National Institute on Aging, GM103329 to M.G., K.T.-Y., and M.P.M., and AG043338, P30GM103329, and R01MH100972 to J.D.G. We thank Jacqueline Lovette for technical assistance. NR 115 TC 12 Z9 12 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 20 PY 2014 VL 34 IS 34 BP 11485 EP 11503 DI 10.1523/JNEUROSCI.0210-14.2014 PG 19 WC Neurosciences SC Neurosciences & Neurology GA AO4MI UT WOS:000341312600031 PM 25143627 ER PT J AU Jacob, CG Tan, JC Miller, BA Tan, A Takala-Harrison, S Ferdig, MT Plowe, CV AF Jacob, Christopher G. Tan, John C. Miller, Becky A. Tan, Asako Takala-Harrison, Shannon Ferdig, Michael T. Plowe, Christopher V. TI A microarray platform and novel SNP calling algorithm to evaluate Plasmodium falciparum field samples of low DNA quantity SO BMC GENOMICS LA English DT Article DE Plasmodium falciparum; Malaria; Microarray ID RESISTANT MALARIA; DIVERSITY; POPULATIONS AB Background: Analysis of single nucleotide polymorphisms (SNPs) derived from whole-genome studies allows for rapid evaluation of genome-wide diversity, and genomic epidemiology studies of Plasmodium falciparum provide insights into parasite population structure, gene flow, drug resistance and vaccine development. In areas with adequate cold chain facilities, large volumes of leukocyte-depleted patient blood can be frozen for use in parasite genomic analyses. In more remote endemic areas smaller volumes of infected blood are taken by finger prick, and dried and stored on filter paper. These dried blood spots do not generally yield enough concentrated parasite DNA for whole-genome sequencing. Results: A DNA microarray was designed for use on field samples to type a genome-wide set of SNPs which prior sequencing had shown to be variable in Africa, Southeast Asia, and Papua New Guinea. An algorithm was designed to call SNPs in samples with low parasite DNA. With this new algorithm SNP-calling accuracy of 98% was measured by hybridizing purified DNA from malaria lab strains and comparing calls with SNPs called from full genome sequences. An average accuracy of > 98% was likewise obtained for DNA extracted from malaria field samples collected in studies in Southeast Asia, with an average call rate of > 82%. Conclusion: This new high-density microarray provided high quality SNP calls from a wide range of parasite DNA quantities, and represents a robust tool for genome-wide analysis of malaria parasites in diverse settings. C1 [Jacob, Christopher G.; Takala-Harrison, Shannon; Plowe, Christopher V.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Howard Hughes Med Inst,Malaria Grp, Baltimore, MD 21201 USA. [Tan, John C.] Roche NimbleGen Inc, Madison, WI 53719 USA. [Tan, John C.; Miller, Becky A.; Tan, Asako; Ferdig, Michael T.] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Miller, Becky A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Plowe, CV (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Howard Hughes Med Inst,Malaria Grp, Baltimore, MD 21201 USA. EM cplowe@medicine.umaryland.edu RI Ferdig, Michael/C-6627-2016 FU Howard Hughes Medical Institute; Doris Duke Charitable Foundation; National Institutes of Health [R01AI10171302] FX This work was supported by the Howard Hughes Medical Institute, the Doris Duke Charitable Foundation and National Institutes of Health Grant R01AI10171302 (to S.T.-H). NR 16 TC 3 Z9 4 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 20 PY 2014 VL 15 AR 719 DI 10.1186/1471-2164-15-719 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AO0ZE UT WOS:000341040700001 PM 25159520 ER PT J AU Hurria, A Dale, W Mooney, M Rowland, JH Ballman, KV Cohen, HJ Muss, HB Schilsky, RL Ferrell, B Extermann, M Schmader, KE Mohile, SG AF Hurria, Arti Dale, William Mooney, Margaret Rowland, Julia H. Ballman, Karla V. Cohen, Harvey J. Muss, Hyman B. Schilsky, Richard L. Ferrell, Betty Extermann, Martine Schmader, Kenneth E. Mohile, Supriya G. TI Designing Therapeutic Clinical Trials for Older and Frail Adults With Cancer: U13 Conference Recommendations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID ACUTE MYELOID-LEUKEMIA; METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; BREAST-CANCER; ADJUVANT CHEMOTHERAPY; GERIATRIC ASSESSMENT; ELDERLY-PATIENTS; PROSTATE-CANCER; AGING RESEARCH; AGE AB A majority of cancer diagnoses and deaths occur in patients age >= 65 years. With the aging of the US population, the number of older adults with cancer will grow. Although the coming wave of older patients with cancer was anticipated in the early 1980s, when the need for more research on the cancer-aging interface was recognized, many knowledge gaps remain when it comes to treating older and/or frailer patients with cancer. Relatively little is known about the best way to balance the risks and benefits of existing cancer therapies in older patients; however, these patients continue to be underrepresented in clinical trials. Furthermore, the available clinical trials often do not include end points pertinent to the older adult population, such as preservation of function, cognition, and independence. As part of its ongoing effort to advance research in the field of geriatric oncology, the Cancer and Aging Research Group held a conference in November 2012 in collaboration with the National Cancer Institute, the National Institute on Aging, and the Alliance for Clinical Trials in Oncology. The goal was to develop recommendations and establish research guidelines for the design and implementation of therapeutic clinical trials for older and/or frail adults. The conference sought to identify knowledge gaps in cancer clinical trials for older adults and propose clinical trial designs to fill these gaps. The ultimate goal of this conference series is to develop research that will lead to evidence-based care for older and/or frail adults with cancer. (C) 2014 by American Society of Clinical Oncology C1 [Hurria, Arti; Ferrell, Betty] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Dale, William; Schilsky, Richard L.] Univ Chicago, Chicago, IL 60637 USA. [Mooney, Margaret; Rowland, Julia H.] NCI, Bethesda, MD 20892 USA. [Ballman, Karla V.] Mayo Clin, Rochester, MN USA. [Mohile, Supriya G.] Univ Rochester, Rochester, NY USA. [Cohen, Harvey J.; Schmader, Kenneth E.] Duke Univ, Durham, NC 27706 USA. [Schmader, Kenneth E.] Durham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, England. [Muss, Hyman B.] Univ N Carolina, Chapel Hill, NC USA. [Extermann, Martine] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. RP Hurria, A (reprint author), City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM ahurria@coh.org FU National Institute on Aging and National Cancer Institute (NCI; National Institutes of Health) [U13 AG038151]; Alliance for Clinical Trials in Oncology; City of Hope; NCI [CA31946]; Alliance Statistics and Data Center [CA33601] FX Supported by Grant No. U13 AG038151 from the National Institute on Aging and National Cancer Institute (NCI; National Institutes of Health); by the Alliance for Clinical Trials in Oncology; and by City of Hope and in part by Grants No. CA31946 from the NCI to the Alliance for Clinical Trials in Oncology and No. CA33601 to the Alliance Statistics and Data Center. NR 63 TC 36 Z9 37 U1 0 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2014 VL 32 IS 24 BP 2587 EP + DI 10.1200/JCO.2013.55.0418 PG 9 WC Oncology SC Oncology GA AN6TQ UT WOS:000340731100009 PM 25071116 ER PT J AU Rowland, JH Bellizzi, KM AF Rowland, Julia H. Bellizzi, Keith M. TI Cancer Survivorship Issues: Life After Treatment and Implications for an Aging Population SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID CLINICAL-PRACTICE GUIDELINE; PRIMARY-CARE PHYSICIANS; QUALITY-OF-LIFE; FOLLOW-UP CARE; BREAST-CANCER; AMERICAN SOCIETY; ADULT SURVIVORS; UNITED-STATES; CHILDHOOD-CANCER; RANDOMIZED-TRIAL AB The US population of cancer survivors age >= 65 years will continue to grow rapidly over the next few decades. This growth will be driven largely by the aging of the national population. With the diffusion of earlier detection and more effective therapies, the majority of these individuals can expect to live long term after diagnosis. This often vulnerable group of survivors poses significant challenges for both researchers and clinicians with regard to how best to document and address its unique health care needs. In this article, we briefly review the long-term and late-occurring effects of cancer and its treatment in older survivors, review information on current patterns of post-treatment care and the evolving guidelines for this care, and discuss opportunities for future research. C1 [Rowland, Julia H.] NCI, Bethesda, MD 20892 USA. [Bellizzi, Keith M.] Univ Connecticut, Storrs, CT USA. RP Rowland, JH (reprint author), Off Canc Survivorship, 9609 Med Ctr Dr,Room 4E450, Bethesda, MD 20892 USA. EM rowlandj@mail.nih.gov NR 70 TC 30 Z9 30 U1 1 U2 14 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2014 VL 32 IS 24 BP 2662 EP + DI 10.1200/JCO.2014.55.8361 PG 8 WC Oncology SC Oncology GA AN6TQ UT WOS:000340731100018 PM 25071099 ER PT J AU Liu, ZB Xu, KF Hu, CL Chen, RR Duan, J Shi, YZ Wang, YA Zhang, WH Moss, J Wu, J Zhang, HB AF Liu, Zhibo Xu, Kai-Feng Hu, Cailian Chen, Rongrong Duan, Jing Shi, Yuzhuo Wang, Yanan Zhang, Weihong Moss, Joel Wu, Jian Zhang, Hongbing TI Use of Whole-Exome Sequencing for the Diagnosis of Atypical Birte-Hogge-Dube Syndrome SO JOURNAL OF GENETICS AND GENOMICS LA English DT Letter ID SPONTANEOUS PNEUMOTHORAX; GENE; MUTATIONS C1 [Liu, Zhibo; Chen, Rongrong; Duan, Jing; Shi, Yuzhuo; Wang, Yanan; Zhang, Hongbing] Chinese Acad Med Sci, Inst Basic Med Sci, Peking Union Med Coll, Dept Physiol,Sch Basic Med,Grad Sch,State Key Lab, Beijing 100005, Peoples R China. [Xu, Kai-Feng] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Resp Med, Beijing 100730, Peoples R China. [Hu, Cailian] Yanan Univ, Affiliated Hosp, Dept Resp Med, Yanan 716000, Peoples R China. [Zhang, Weihong] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Radiol, Beijing 100730, Peoples R China. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Wu, Jian] MyGenostics Inc, Baltimore, MD 21201 USA. RP Zhang, HB (reprint author), Chinese Acad Med Sci, Inst Basic Med Sci, Peking Union Med Coll, Dept Physiol,Sch Basic Med,Grad Sch,State Key Lab, Beijing 100005, Peoples R China. EM hbzhang@ibms.pumc.edu.cn NR 14 TC 2 Z9 2 U1 1 U2 5 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1673-8527 EI 1873-5533 J9 J GENET GENOMICS JI J. Genet. Genomics PD AUG 20 PY 2014 VL 41 IS 8 BP 449 EP 451 DI 10.1016/j.jgg.2014.06.005 PG 3 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AN8GT UT WOS:000340842700004 PM 25160977 ER PT J AU Barr, IG Russell, C Besselaar, TG Cox, NJ Daniels, RS Donis, R Engelhardt, OG Grohmann, G Itamura, S Kelso, A McCauley, J Odagiri, T Schultz-Cherry, S Shu, YL Smith, D Tashiro, M Wang, DY Webby, R Xu, XY Ye, ZP Zhang, WQ AF Barr, Ian G. Russell, Colin Besselaar, Terry G. Cox, Nancy J. Daniels, Rod S. Donis, Ruben Engelhardt, Othmar G. Grohmann, Gary Itamura, Shigeyuki Kelso, Anne McCauley, John Odagiri, Takato Schultz-Cherry, Stacey Shu, Yuelong Smith, Derek Tashiro, Masato Wang, Dayan Webby, Richard Xu, Xiyan Ye, Zhiping Zhang, Wenqing CA Writing Comm World Hlth Org Consul TI WHO recommendations for the viruses used in the 2013-2014 Northern Hemisphere influenza vaccine: Epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and B influenza viruses collected from October 2012 to January 2013 SO VACCINE LA English DT Article DE Influenza; Vaccine; Human; Trivalent; Quadrivalent; Recommendation; Northern Hemisphere 2013-2014 ID SUBSTITUTION AB In February the World Health Organisation (WHO) recommends influenza viruses to be included in influenza vaccines for the forthcoming winter in the Northern Hemisphere. These recommendations are based on data collected by National Influenza Centres (NICs) through the WHO Global Influenza Surveillance and Response System (GISRS) and a more detailed analysis of representative and potential antigenically variant influenza viruses from the WHO Collaborating Centres for Influenza (WHO CCs) and Essential Regulatory Laboratories (ERLs). This article provides a detailed summary of the antigenic and genetic properties of viruses and additional background data used by WHO experts during development of the recommendations of the 2013-2014 Northern Hemisphere influenza vaccine composition. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Barr, Ian G.; Kelso, Anne] WHO Collaborating Ctr Reference & Res Influenza, Victorian Infect Dis Reference Lab, Melbourne, Vic, Australia. [Russell, Colin] Univ Cambridge, Cambridge CB2 1TN, England. [Besselaar, Terry G.; Zhang, Wenqing] WHO Global Influenza Programme GIP, Geneva, Switzerland. [Cox, Nancy J.; Donis, Ruben; Xu, Xiyan] Ctr Dis Control & Prevent, WHO Collaborating Ctr Surveillance Epidemiol & Co, Atlanta, GA USA. [Daniels, Rod S.; McCauley, John] Natl Inst Med Res, MRC, WHO Collaborating Ctr Reference & Res Influenza, London NW7 1AA, England. [Grohmann, Gary] Hlth Protect Agcy, Natl Inst Biol Stand & Control, Potters Bar, Herts, England. [Grohmann, Gary] Therapeut Goods Adm, Canberra, ACT, Australia. [Itamura, Shigeyuki; Odagiri, Takato; Tashiro, Masato] Natl Inst Infect Dis, WHO Collaborating Ctr Reference & Res Influenza, Tokyo, Japan. [Schultz-Cherry, Stacey; Webby, Richard] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Shu, Yuelong; Wang, Dayan] Chinese Natl Influenza Ctr, WHO Collaborating Ctr Reference & Res Influenza, Beijing, Peoples R China. [Smith, Derek] Univ Cambridge, Ctr Pathogen Evolut, Cambridge CB2 1TN, England. [Smith, Derek] Univ Cambridge, WHOCC Modelling Evolut & Control Emerging Infect, Cambridge CB2 1TN, England. [Smith, Derek] NIH, Fogarty Int Ctr, Bethesda, MD USA. [Ye, Zhiping] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Barr, IG (reprint author), WHO Collaborating Ctr Reference & Res Influenza, Victorian Infect Dis Reference Lab, Melbourne, Vic, Australia. EM Ian.Barr@influenzacentre.org FU Australian Government Department of Health; WHO Collaborating Centre for Reference and Research on Influenza at the MRC National Institute for Medical Research; Medical Research Programme [U1175512723]; NIH [HHSN266200700010C] FX The writing committee would like to thank all of their colleagues in their institutes, the WHO NICs and other laboratories and organisations for their efforts in supplying, testing and analysing the influenza viruses characterised in the course of generating the data for this report. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health and the WHO Collaborating Centre for Reference and Research on Influenza at the MRC National Institute for Medical Research, Mill Hill, is supported by Medical Research Programme U1175512723. DS is supported by NIH contract HHSN266200700010C. NR 9 TC 32 Z9 34 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD AUG 20 PY 2014 VL 32 IS 37 BP 4713 EP 4725 DI 10.1016/j.vaccine.2014.02.014 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AO0DR UT WOS:000340979800004 PM 24582632 ER PT J AU Seeher, S Atassi, T Mahdi, Y Carlson, BA Braun, D Wirth, EK Klein, MO Reix, N Miniard, AC Schomburg, L Hatfield, DL Driscoll, DM Schweizer, U AF Seeher, Sandra Atassi, Tarik Mahdi, Yassin Carlson, Bradley A. Braun, Doreen Wirth, Eva K. Klein, Marc O. Reix, Nathalie Miniard, Angela C. Schomburg, Lutz Hatfield, Dolph L. Driscoll, Donna M. Schweizer, Ulrich TI Secisbp2 Is Essential for Embryonic Development and Enhances Selenoprotein Expression SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID SELENOCYSTEINE INSERTION-SEQUENCE; THYROID-HORMONE METABOLISM; RNA-BINDING PROTEIN; TARGETED DISRUPTION; MESSENGER-RNA; THIOREDOXIN REDUCTASE; FORMATE DEHYDROGENASE; SELENIUM DEFICIENCY; MOUSE DEVELOPMENT; ELONGATION-FACTOR AB Aims: The selenocysteine insertion sequence (SECIS)-binding protein 2 (Secisbp2) binds to SECIS elements located in the 3'-untranslated region of eukaryotic selenoprotein mRNAs. Selenoproteins contain the rare amino acid selenocysteine (Sec). Mutations in SECISBP2 in humans lead to reduced selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display myopathy, hearing impairment, male infertility, increased photosensitivity, mental retardation, and ataxia. Mouse models are needed to understand selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes. Results: Unlike tRNA([Ser]Sec)-deficient embryos, homozygous Secisbp2-deleted embryos implant, but fail before gastrulation. Heterozygous inactivation of Secisbp2 reduced the amount of selenoprotein expressed, but did not affect the thyroid hormone axis or growth. Conditional deletion of Secisbp2 in hepatocytes significantly decreased selenoprotein expression. Unexpectedly, the loss of Secisbp2 reduced the abundance of many, but not all, selenoprotein mRNAs. Transcript-specific and gender-selective effects on selenoprotein mRNA abundance were greater in Secisbp2-deficient hepatocytes than in tRNA([Ser]Sec)-deficient cells. Despite the massive reduction of Dio1 and Sepp1 mRNAs, significantly more corresponding protein was detected in primary hepatocytes lacking Secisbp2 than in cells lacking tRNA([Ser]Sec). Regarding selenoprotein expression, compensatory nuclear factor, erythroid-derived, like 2 (Nrf2)-dependent gene expression, or embryonic development, phenotypes were always milder in Secisbp2-deficient than in tRNA([Ser]Sec)-deficient mice. Innovation: We report the first Secisbp2 mutant mouse models. The conditional mutants provide a model for analyzing Secisbp2 function in organs not accessible in patients. Conclusion: In hepatocyte-specific conditional mouse models, Secisbp2 gene inactivation is less detrimental than tRNA([Ser]Sec) inactivation. A role of Secisbp2 in stabilizing selenoprotein mRNAs in vivo was uncovered. C1 [Seeher, Sandra; Mahdi, Yassin; Braun, Doreen; Wirth, Eva K.; Schomburg, Lutz; Schweizer, Ulrich] Charite, Inst Expt Endokrinol, D-13353 Berlin, Germany. [Seeher, Sandra; Mahdi, Yassin; Braun, Doreen; Schweizer, Ulrich] Univ Bonn, Inst Biochem & Mol Biol, D-53115 Bonn, Germany. [Atassi, Tarik; Miniard, Angela C.; Driscoll, Donna M.] Cleveland Clin, Dept Cellular & Mol Med, Lerner Res Inst, Cleveland, OH 44106 USA. [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Klein, Marc O.] Ctr Hosp & Univ Nancy, Serv Endocrinol, Nancy, France. [Reix, Nathalie] Univ Strasbourg, CNRS, Labs Explorat Fonct Isotopes, Hop Univ Strasbourg,ICube UMR 7357, Strasbourg, France. RP Schweizer, U (reprint author), Univ Bonn, Inst Biochem & Mol Biol, Nussallee 11, D-53115 Bonn, Germany. EM uschweiz@uni-bonn.de OI Wirth, Eva Katrin/0000-0002-0491-9941; Schweizer, Ulrich/0000-0003-1380-4780 FU Deutsche Forschungsgemeinschaft DFG [Schw914/2-1, GK1208]; National Institutes of Health [R01DK085391, R01DK07859] FX The authors thank Antje Kretschmer, Anja Fischbach, Vartiter Seher, and Ursula Reuter for excellent technical assistance. Dr. Markus Schupp, Charite-Universitatsmedizin Berlin helped with primary hepatocyte cultures, Dr. Carmen Birchmeier provided FLPe and Cre deleter mice, Dr. Wolfgang Wurst prioritized Secisbp2 in EUCOMM. The study was funded by Deutsche Forschungsgemeinschaft DFG Schw914/2-1 and GK1208 to the U.S. and National Institutes of Health grants R01DK085391 and R01DK07859 to D.M.D. NR 61 TC 12 Z9 12 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD AUG 20 PY 2014 VL 21 IS 6 BP 835 EP 849 DI 10.1089/ars.2013.5358 PG 15 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AN4EZ UT WOS:000340541700002 PM 24274065 ER PT J AU Stojilkovic, SS Leiva-Salcedo, E Rokic, MB Coddou, C AF Stojilkovic, Stanko S. Leiva-Salcedo, Elias Rokic, Milos B. Coddou, Claudio TI Regulation of ATP-Gated P2X Channels: From Redox Signaling to Interactions with Other Proteins SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID GAMMA-AMINOBUTYRIC-ACID; ROOT GANGLION NEURONS; ZINC-BINDING SITE; RECEPTOR CHANNELS; REACTIVE-OXYGEN; RAT P2X(2); KINASE-C; DIVALENT-CATIONS; ION CHANNELS; EXTRACELLULAR PH AB Significance: The family of purinergic P2X receptors (P2XRs) is a part of ligand-gated superfamily of channels activated by extracellular adenosine-5'-triphosphate. P2XRs are present in virtually all mammalian tissues as well as in tissues of other vertebrate and nonvertebrate species and mediate a large variety of functions, including fast transmission at central synapses, contraction of smooth muscle cells, platelet aggregation, and macrophage activation to proliferation and cell death. Recent Advances: The recent solving of crystal structure of the zebrafish P2X4.1R is a major advance in the understanding of structural correlates of channel activation and regulation. Combined with growing information obtained in the post-structure era and the reinterpretation of previous work within the context of the tridimensional structure, these data provide a better understanding of how the channel operates at the molecular levels. Critical Issues: This review focuses on the relationship between redox signaling and P2XR function. We also discuss other allosteric modulation of P2XR gating in the physiological/pathophysiological context. This includes the summary of extracellular actions of trace metals, which can be released to the synaptic cleft, pH decrease that happens during ischemia and inflammation, and calcium, an extracellular and intracellular messenger. Future Directions: Our evolving understanding of activation and regulation of P2XRs is helpful in clarifying the mechanism by which these channels trigger and modulate cellular functions. Further research is required to identify the signaling pathways contributing to the regulation of the receptor activity and to develop novel and receptor-specific allosteric modulators, which could be used in vivo with therapeutic potential. C1 [Stojilkovic, Stanko S.; Leiva-Salcedo, Elias; Rokic, Milos B.; Coddou, Claudio] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Coddou, Claudio] Univ Catolica Norte, Fac Med, Dept Biomed Sci, Coquimbo, Chile. RP Stojilkovic, SS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bldg 49,Room 6A36, Bethesda, MD 20892 USA. EM stojilks@mail.nih.gov RI ROKIC, MILOS/O-7204-2014 OI ROKIC, MILOS/0000-0002-9148-2716 FU Intramural Research Program of the National Institute of Child Health and Human Development, NIH; FONDECYT Initiation [11121302] FX This research was funded by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH (S. S., E. L.-S., and C. C.) and the FONDECYT Initiation Grant 11121302 (C. C.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the article. NR 200 TC 4 Z9 4 U1 3 U2 18 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD AUG 20 PY 2014 VL 21 IS 6 BP 953 EP 970 DI 10.1089/ars.2013.5549 PG 18 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AN4EZ UT WOS:000340541700010 PM 23944253 ER PT J AU Ptak, CP Hsieh, CL Lin, YP Maltsev, AS Raman, R Sharma, Y Oswald, RE Chang, YF AF Ptak, Christopher P. Hsieh, Ching-Lin Lin, Yi-Pin Maltsev, Alexander S. Raman, Rajeev Sharma, Yogendra Oswald, Robert E. Chang, Yung-Fu TI NMR Solution Structure of the Terminal Immunoglobulin-like Domain from the Leptospira Host-Interacting Outer Membrane Protein, LigB SO BIOCHEMISTRY LA English DT Article ID ENTEROPATHOGENIC ESCHERICHIA-COLI; PATHOGENIC LEPTOSPIRA; EXTRACELLULAR-MATRIX; CRYSTAL-STRUCTURE; TRYPTOPHAN FLUORESCENCE; BINDING-PROTEIN; FIBRONECTIN; INTERROGANS; ADHESION; LIPL32 AB A number of surface proteins specific to pathogenic strains of Leptospira have been identified. The Lig protein family has shown promise as a marker in typing leptospiral isolates for pathogenesis and as an antigen in vaccines. We used NMR spectroscopy to solve the solution structure of the twelfth immunoglobulin-like (Ig-like) repeat domn from LigB (LigB-12). The fold is similar to that of other bacterial Ig-like domains and comprised mainly of beta-strands form a beta-sandwich based on a Greek-key folding arrangement. Based on sequence analysis and conservation of structurally important residues, homology models for the other LigB Ig-like domains were generated. The set of LigB models illustrates the electrostatic differences between the domains as well as the possible interactions between neighboring domains. Understanding the structure of the extracellular portion of LigB and related proteins is important for developing diagnostic methods and new therapeutics directed toward leptospirosis. C1 [Ptak, Christopher P.; Hsieh, Ching-Lin; Lin, Yi-Pin; Chang, Yung-Fu] Cornell Univ, Coll Vet Med, Dept Populat Med & Diagnost Sci, Ithaca, NY 14853 USA. [Ptak, Christopher P.; Oswald, Robert E.] Cornell Univ, Coll Vet Med, Dept Mol Med, Ithaca, NY 14853 USA. [Maltsev, Alexander S.] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Raman, Rajeev; Sharma, Yogendra] Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. RP Chang, YF (reprint author), Cornell Univ, Coll Vet Med, Dept Populat Med & Diagnost Sci, Ithaca, NY 14853 USA. EM reo1@cornell.edu; yc42@cornell.edu RI Ptak, Christopher/I-3126-2012 OI Ptak, Christopher/0000-0003-2752-0367 FU Biotechnology Research and Development Corp.; Cornell Center of Advanced Technology program; Zweig Foundation FX This work was supported by grants from the Biotechnology Research and Development Corp., the Cornell Center of Advanced Technology program, and the Zweig Foundation to Y.F.C. NR 57 TC 4 Z9 4 U1 5 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 19 PY 2014 VL 53 IS 32 BP 5249 EP 5260 DI 10.1021/bi500669u PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN6JS UT WOS:000340701400005 PM 25068811 ER PT J AU Guo, Y Weck, J Sundaram, R Goldstone, AE Louis, GB Kannan, K AF Guo, Ying Weck, Jennifer Sundaram, Rajeswari Goldstone, Alexandra E. Louis, Germaine Buck Kannan, Kurunthachalam TI Urinary Concentrations of Phthalates in Couples Planning Pregnancy and Its Association with 8-Hydroxy-2 '-deoxyguanosine, a Biomarker of Oxidative Stress: Longitudinal Investigation of Fertility and the Environment Study SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID DI(2-ETHYLHEXYL) PHTHALATE; HUMAN EXPOSURE; DNA-DAMAGE; WAIST CIRCUMFERENCE; UNITED-STATES; BISPHENOL-A; METABOLITES; POPULATION; 8-OHDG; MARKER AB Oxidative stress has been recognized as one of the most important contributors to infertility in both males and females. Exposure to many environmental chemicals, such as phthalates, has been shown to induce oxidative stress. In a longitudinal study designed to assess exposure to environmental chemicals and fecundity in couples who were planning pregnancy, 894 urine samples were collected from 469 couples from Michigan and Texas during 2005-2009. The concentrations of 14 phthalate metabolites and a marker of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG), were determined in these samples. Concentrations, profiles, and estimated daily intakes (DIs) of phthalates were positively associated with 8-OHdG. The median concentrations of monomethyl phthalate (mMP), monoethyl phthalate (mEP), mono(3-carboxypropyl) phthalate (mCPP), mono-n-butyl phthalate (mBP), mono(2-isobutyl) phthalate (miBP), monobenzyl phthalate (mBzP), Sigma(5)mEHP (sum of five metabolites of di(2-ethylhexyl) phthalate (DEHP)) and Sigma(14)phthalates (sum of 14 urinary phthalate metabolites) were 0.48, 85.2, 4.50, 7.66, 4.36, 3.80, 54.8, and 249 mu g/g creatinine, respectively. The estimated DI values for DEHP in 39 individuals were above the U.S. Environmental Protection Agency's (EPA) reference dose (RfD) of 20 mu g/kg-bw/clay. The mean and median concentrations of 8-OHdG were 6.02 and 3.13 mu g/g creatinine, respectively, which were significantly higher in females than in males. Statistically significant associations were found between 8-OHdG and urinary concentrations of mEP, and Sigma(5)mEHP for females. Similarly, a significant association was found between 8-OHdG and DIs estimated for select phthalates. Our results suggested that phthalate exposure increases oxidative stress, which can be a mechanism for the diminished fertility observed in couples who were highly exposed to select phthalates. C1 [Guo, Ying; Kannan, Kurunthachalam] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. [Guo, Ying; Kannan, Kurunthachalam] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12201 USA. [Weck, Jennifer; Sundaram, Rajeswari; Louis, Germaine Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Goldstone, Alexandra E.] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Environm & Occupat Hlth, Washington, DC 20052 USA. [Kannan, Kurunthachalam] King Abdulaziz Univ, King Fahd Med Res Ctr, Fac Sci, Dept Biochem, Jeddah 21589, Saudi Arabia. [Kannan, Kurunthachalam] King Abdulaziz Univ, King Fahd Med Res Ctr, Expt Biochem Unit, Jeddah 21589, Saudi Arabia. RP Kannan, K (reprint author), New York State Dept Hlth, Wadsworth Ctr, Empire State Plaza,POB 509, Albany, NY 12201 USA. EM kkannan@wadsworth.org OI Weck, Jennifer/0000-0002-3246-7380; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NICHD) [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358, HHSN27500001] FX This study was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NICHD; contract nos. N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358, HHSN27500001). NR 47 TC 16 Z9 17 U1 7 U2 37 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD AUG 19 PY 2014 VL 48 IS 16 BP 9804 EP 9811 DI 10.1021/es5024898 PG 8 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA AN6JW UT WOS:000340701800103 PM 25068827 ER PT J AU Koroshetz, WJ Landis, S AF Koroshetz, Walter J. Landis, Story TI Neurology's stake in foundational neuroscience research SO NEUROLOGY LA English DT Editorial Material C1 [Koroshetz, Walter J.; Landis, Story] NINDS, Bethesda, MD 20892 USA. RP Koroshetz, WJ (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM koroshetzw@ninds.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 19 PY 2014 VL 83 IS 8 BP 670 EP 671 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AN6SR UT WOS:000340727800003 PM 24991032 ER PT J AU Verghese, J Annweiler, C Ayers, E Barzilai, N Beauchet, O Bennett, DA Bridenbaugh, SA Buchman, AS Callisaya, ML Camicioli, R Capistrant, B Chatterji, S De Cock, AM Ferrucci, L Giladi, N Guralnik, JM Hausdorff, JM Holtzer, R Kim, KW Kowal, P Kressig, RW Lim, JY Lord, S Meguro, K Montero-Odasso, M Muir-Hunter, SW Noone, ML Rochester, L Srikanth, V Wang, CL AF Verghese, Joe Annweiler, Cedric Ayers, Emmeline Barzilai, Nir Beauchet, Olivier Bennett, David A. Bridenbaugh, Stephanie A. Buchman, Aron S. Callisaya, Michele L. Camicioli, Richard Capistrant, Benjamin Chatterji, Somnath De Cock, Anne-Marie Ferrucci, Luigi Giladi, Nir Guralnik, Jack M. Hausdorff, Jeffrey M. Holtzer, Roee Kim, Ki Woong Kowal, Paul Kressig, Reto W. Lim, Jae-Young Lord, Susan Meguro, Kenichi Montero-Odasso, Manuel Muir-Hunter, Susan W. Noone, Mohan L. Rochester, Lynn Srikanth, Velandai Wang, Cuiling TI Motoric cognitive risk syndrome Multicountry prevalence and dementia risk SO NEUROLOGY LA English DT Article ID OLDER-ADULTS; GAIT SPEED; ALZHEIMERS-DISEASE; MEMORY IMPAIRMENT; DECLINE; PERFORMANCE; HEALTH; ASSOCIATION; POPULATION; COUNTRIES AB Objectives: Our objective is to report prevalence of motoric cognitive risk syndrome (MCR), a newly described predementia syndrome characterized by slow gait and cognitive complaints, in multiple countries, and its association with dementia risk. Methods: Pooled MCR prevalence analysis of individual data from 26,802 adults without dementia and disability aged 60 years and older from 22 cohorts from 17 countries. We also examined risk of incident cognitive impairment (Mini-Mental State Examination decline >= 4 points) and dementia associated with MCR in 4,812 individuals without dementia with baseline Mini-Mental State Examination scores >= 25 from 4 prospective cohort studies using Cox models adjusted for potential confounders. Results: At baseline, 2,808 of the 26,802 participants met MCR criteria. Pooled MCR prevalence was 9.7% (95% confidence interval [CI] 8.2%-11.2%). MCR prevalence was higher with older age but there were no sex differences. MCR predicted risk of developing incident cognitive impairment in the pooled sample (adjusted hazard ratio [aHR] 2.0, 95% CI 1.7-2.4); aHRs were 1.5 to 2.7 in the individual cohorts. MCR also predicted dementia in the pooled sample (aHR 1.9, 95% CI 1.5-2.3). The results persisted even after excluding participants with possible cognitive impairment, accounting for early dementia, and diagnostic overlap with other predementia syndromes. Conclusion: MCR is common in older adults, and is a strong and early risk factor for cognitive decline. This clinical approach can be easily applied to identify high-risk seniors in a wide variety of settings. C1 [Verghese, Joe; Ayers, Emmeline; Holtzer, Roee] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. [Verghese, Joe; Barzilai, Nir] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Wang, Cuiling] Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10467 USA. [Annweiler, Cedric; Beauchet, Olivier] Angers Univ Hosp, Div Geriatr Med, Angers, France. [Annweiler, Cedric; Beauchet, Olivier] Angers Univ Hosp, Memory Clin, Angers, France. [Bennett, David A.; Buchman, Aron S.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Bridenbaugh, Stephanie A.; Kressig, Reto W.] Univ Basel, Univ Basel Hosp, Acute Geriatr Dept, CH-4003 Basel, Switzerland. [Callisaya, Michele L.; Srikanth, Velandai] Monash Univ, Dept Med, Southern Clin Sch, Clayton, Vic, Australia. [Callisaya, Michele L.] Menzies Res Inst, Hobart, Tas, Australia. [Camicioli, Richard] Univ Alberta, Glenrose Rehabil Hosp, Dept Med, Edmonton, AB, Canada. [Capistrant, Benjamin] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Chatterji, Somnath; Kowal, Paul] WHO, Dept Hlth Stat & Informat Syst, CH-1211 Geneva, Switzerland. [De Cock, Anne-Marie] AZ ST Maarten Mechelen, Dept Geriatr Med, Mechelen, Belgium. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Giladi, Nir; Hausdorff, Jeffrey M.] Tel Aviv Sourasky Med Ctr, Dept Neurol, Tel Aviv, Israel. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Div Gerontol, Baltimore, MD 21201 USA. [Holtzer, Roee] Yeshiva Univ, Ferkauf Sch Psychol, Bronx, NY USA. [Kim, Ki Woong] Seoul Natl Univ, Coll Med, Dept Neuropsychiat, Seoul 151, South Korea. [Lim, Jae-Young] Seoul Natl Univ, Coll Med, Dept Rehabil Med, Seoul 151, South Korea. [Kim, Ki Woong] Seoul Natl Univ, Coll Nat Sci, Dept Brain & Cognit Sci, Seoul 151, South Korea. [Lord, Susan; Rochester, Lynn] Newcastle Univ, Clin Ageing Res Unit, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Meguro, Kenichi] Tohoku Univ, Dept Geriatr Behav Neurol, Grad Sch Med, Sendai, Miyagi 980, Japan. [Montero-Odasso, Manuel] Univ Western Ontario, Dept Med, London, ON, Canada. [Montero-Odasso, Manuel] Univ Western Ontario, London, ON, Canada. [Montero-Odasso, Manuel] Univ Western Ontario, Div Geriatr Med, London, ON, Canada. [Montero-Odasso, Manuel] Univ Western Ontario, Gait & Brain Lab, London, ON, Canada. [Muir-Hunter, Susan W.] Univ Western Ontario, Sch Phys Therapy, London, ON, Canada. [Noone, Mohan L.] Baby Mem Hosp, Dept Neurosci, Kozhikode, India. RP Verghese, J (reprint author), Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. EM joe.verghese@einstein.yu.edu RI Callisaya, Michele/I-2333-2013; OI Callisaya, Michele/0000-0003-2122-1622; Kowal, Paul/0000-0002-6314-8753; Annweiler, Cedric/0000-0002-7199-8109; Camicioli, Richard/0000-0003-2977-8660; Lim, Jae-young/0000-0002-9454-0344 FU Australian National Health and Medical Research Council [403000]; Canadian Institutes of Health and Research [MOP 211220]; NIH; WHO (OGHA) [04034785, YA1323-08-CN-0020, Y1-AG-1005-01, R01 AG034479, 1R21AG034263]; French Ministry of Health (Projet Hospitalier de Recherche Clinique national) [2009-A00533-54]; NIH [R01 AG039330, AG-14100, 263 MD 916413, 263 MD 821336, 1ZIAAG001050, R00AG037574, 1P01AG034906, R01AG046949, 1R01AG042188, P30AG038072, NIH R37AG18381, R01AG036921, RO1AGO44007-01A1, P30AG10161, R01AG15819, R01AG17917, R01AG34374, R01AG33678, RO1 AG10939, RO3 AG026106]; Italian Ministry of Health [ICS 110.1/RS97.71]; Kurihara, Miyagi, Japan; Korean Health Technology R D Project [A092077, A070001]; National Research Foundation of Korea [2012-0000999]; UK NIHR Biomedical Research Centre for Ageing and Age-Related Disease award; Department of Health; Parkinson's UK programme grant [J-0802]; CTSA [KL2TR000088]; Einstein Glenn Center; Paul Glenn Foundation; American Federation for Aging Research; Illinois Department of Public Health FX No targeted funding is reported for the pooled analysis performed in this study. The individual studies were supported by the following agencies. The TASCOG Study was funded by the Australian National Health and Medical Research Council (403000). The Gait and Brain Study was funded by Canadian Institutes of Health and Research (MOP 211220). The SAGE Study was funded by NIH Interagency agreements with WHO (OGHA 04034785, YA1323-08-CN-0020, Y1-AG-1005-01, R01 AG034479, 1R21AG034263). The GAIT Study was funded by the French Ministry of Health (Projet Hospitalier de Recherche Clinique national 2009-A00533-54). The Kerala-Einstein Study was funded by NIH (R01 AG039330). The Israel studies were funded by NIH (AG-14100). The InCHIANTI Study was funded by the Italian Ministry of Health (grant ICS 110.1/RS97.71) and NIH (grants 263 MD 916413, 263 MD 821336, 1ZIAAG001050). Kurihara Project was funded by Kurihara, Miyagi, Japan (2008-2010) and by the Japanese Ministry of Health, Labour and Welfare (2009-2010). The KLoSHA project was funded by the Korean Health Technology R & D Project (grants A092077 and A070001) and the National Research Foundation of Korea grant (2012-0000999). The Newcastle Study was funded by a UK NIHR Biomedical Research Centre for Ageing and Age-Related Disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, Department of Health, and a Parkinson's UK programme grant (J-0802). The LonGenity Study was funded by NIH (R00AG037574, 1P01AG034906, R01AG046949, 1R01AG042188, P30AG038072, and NIH R37AG18381), CTSA KL2TR000088, Einstein Glenn Center, Paul Glenn Foundation, and the American Federation for Aging Research. The CCMA study was funded by NIH (R01AG036921, RO1AGO44007-01A1). The MAP and ROS cohorts were funded by NIH (P30AG10161, R01AG15819, R01AG17917, R01AG34374, R01AG33678) and the Illinois Department of Public Health. The H-EPESE Study was funded by NIH (RO1 AG10939, RO3 AG026106). NR 38 TC 44 Z9 44 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 19 PY 2014 VL 83 IS 8 BP 718 EP 726 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AN6SR UT WOS:000340727800012 PM 25031288 ER PT J AU Beydoun, MA Gamaldo, AA Canas, JA Beydoun, HA Shah, MT McNeely, JM Zonderman, AB AF Beydoun, May A. Gamaldo, Alyssa A. Canas, Jose A. Beydoun, Hind A. Shah, Mauli T. McNeely, Jessica M. Zonderman, Alan B. TI Serum Nutritional Biomarkers and Their Associations with Sleep among US Adults in Recent National Surveys SO PLOS ONE LA English DT Article ID PLASMA HOMOCYSTEINE LEVELS; RESTLESS LEGS SYNDROME; VITAMIN-D; DEPRESSIVE SYMPTOMS; OLDER-ADULTS; COGNITIVE IMPAIRMENT; ANTIOXIDANT STATUS; METABOLIC SYNDROME; SAMPLE SELECTION; CHRONIC DISEASE AB Background: The associations between nutritional biomarkers and measures of sleep quantity and quality remain unclear. Methods: Cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) 2005-2006 were used. We selected 2,459 adults aged 20-85, with complete data on key variables. Five sleep measures were constructed as primary outcomes: (A) Sleep duration; (B) Sleep disorder; (C) Three factors obtained from factor analysis of 15 items and labeled as "Poor sleep-related daytime dysfunction'' (Factor 1), "Sleepiness'' (Factor 2) and "Sleep disturbance'' (Factor 3). Main exposures were serum concentrations of key nutrients, namely retinol, retinyl esters, carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein+zeaxanthin, lycopene), folate, vitamin B-12, total homocysteine (tHcy), vitamin C, 25-hydroxyvitamin D (25(OH) D) and vitamin E. Main analyses consisted of multiple linear, logistic and multinomial logit models. Results: Among key findings, independent inverse associations were found between serum vitamin B-12 and sleep duration, 25(OH) D and sleepiness (as well as insomnia), and between folate and sleep disturbance. Serum total carotenoids concentration was linked to higher odds of short sleep duration (i.e. 5-6 h per night) compared to normal sleep duration (7-8 h per night). Conclusions: A few of the selected serum nutritional biomarkers were associated with sleep quantity and quality. Longitudinal studies are needed to ascertain temporality and assess putative causal relationships. C1 [Beydoun, May A.; Gamaldo, Alyssa A.; Shah, Mauli T.; McNeely, Jessica M.; Zonderman, Alan B.] NIA, NIH, IRP, Baltimore, MD 21224 USA. [Canas, Jose A.] Nemours Childrens Clin, Jacksonville, FL USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Shah, Mauli T.; McNeely, Jessica M.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. RP Beydoun, MA (reprint author), NIA, NIH, IRP, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging; Intramural Research Program (NIA/NIH/IRP) FX This study was entirely supported by the National Institute on Aging, Intramural Research Program (NIA/NIH/IRP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 89 TC 5 Z9 5 U1 6 U2 16 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 AUG 19 PY 2014 VL 9 IS 8 AR e103490 DI 10.1371/journal.pone.0103490 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6XM UT WOS:000340742100008 PM 25137304 ER PT J AU Peprah, E AF Peprah, Emmanuel TI Understanding decreased fertility in women carriers of the FMR1 premutation: a possible mechanism for Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) SO REPRODUCTIVE HEALTH LA English DT Editorial Material DE FXPOI; Ovarian insufficiency; FMR1; CGG repeat; Female reproductive health ID CGG REPEAT; FAILURE; TRANSLATION; TRANSCRIPTION; INTERMEDIATE; EXPANSIONS; MENOPAUSE; RANGE; SIZE; GENE AB Fragile X syndrome (FXS) and its associated disorders are caused by the expansion of the CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1). The full mutation, defined as >200 cytosine-guanine-guanine (CGG) triplet repeats, causes FXS. Individuals with 55-199 CGG repeats, classified as premutation carriers, are affected by two distinct disorders depending on their premutation status. Disorders associated with premutation carriers include: Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). The molecular similarities of FXTAS and FXPOI (e. g. overabundance of FMR1 transcript and intranuclear inclusions) suggest that similar molecular mechanisms underlie both FXTAS and FXPOI. The current hypothesis describes the underlying mechanism for FXTAS as an mRNA gain-of-function mutation, however the underlying mechanism for FXPOI remains unresolved. New data suggests that repeat associated non-AUG (RAN) translation could underlie FXPOI. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD 20852 USA. RP Peprah, E (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd RM 5Z00, Rockville, MD 20852 USA. EM peprahek@mail.nih.gov NR 28 TC 3 Z9 3 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PD AUG 19 PY 2014 VL 11 AR 67 DI 10.1186/1742-4755-11-67 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AO2AJ UT WOS:000341116700001 PM 25134882 ER PT J AU Ou-Yang, CW Siegel, RM AF Ou-Yang, Chih-Wen Siegel, Richard M. TI Outflanking RANK with a Designer Antagonist Cytokine SO SCIENCE SIGNALING LA English DT Article ID SINGLE-CHAIN TNF; RECEPTOR; CANCER AB Members of the tumor necrosis factor (TNF) superfamily of cytokines are noncovalently linked trimers that play important roles in regulating the immune system and have emerged as successful therapeutic targets in various rheumatic and autoimmune conditions. Traditionally, antibodies to cytokines or receptor-Fc fusion proteins have been used to block signaling by TNF family cytokines. In this issue of Science Signaling, Warren et al. have taken a new approach to blocking the action of the TNF superfamily member RANKL [receptor activator of nuclear factor kappa B (RANK) ligand], which plays an important role in regulating bone turnover through stimulation of its receptor RANK on osteoclasts. Beginning with a single-chain fusion protein of three RANKL subunits, the authors used directed mutagenesis to generate a trimer consisting of a nonreceptor binding subunit fused to two "super-agonist" subunits that have increased affinity for RANK. This molecule antagonized the osteoclastogenic activity of wild-type RANKL in vitro and in vivo, thus providing insights into RANK signaling and a paradigm for the development of other antagonists of TNF family cytokines. C1 [Ou-Yang, Chih-Wen; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM rsiegel@nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH FX This work was funded through the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. NR 10 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD AUG 19 PY 2014 VL 7 IS 339 AR pe20 DI 10.1126/scisignal.2005674 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AO2YA UT WOS:000341192700001 PM 25140052 ER PT J AU Hayashi, H Takamune, N Nirasawa, T Aoki, M Morishita, Y Das, D Koh, Y Ghosh, AK Misumi, S Mitsuya, H AF Hayashi, Hironori Takamune, Nobutoki Nirasawa, Takashi Aoki, Manabu Morishita, Yoshihiko Das, Debananda Koh, Yasuhiro Ghosh, Arun K. Misumi, Shogo Mitsuya, Hiroaki TI Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AIDS; thermal stability; two-step dimerization dynamics; protease precursor ID HUMAN-IMMUNODEFICIENCY; IN-VITRO; STABILITY; REPLICATION; RESISTANT; PRECURSOR; VARIANTS; ACQUISITION; MATURATION; RESIDUES AB Dimerization of HIV-1 protease (PR) subunits is an essential process for PR's acquisition of proteolytic activity, which plays a critical role in the maturation of HIV-1. Recombinant wild-type PR (PRWT) proved to dimerize, as examined with electrospray ionization mass spectrometry; however, two active site interface PR mutants (PRT26A and PRR87K) remained monomeric. On the other hand, two termini interface PR mutants (PR1-C95A and PR97/99) took both monomeric and dimeric forms. Differential scanning fluorimetry indicated that PR1-C95A and PR97/99 dimers were substantially less stable than PRWT dimers. These data indicate that intermolecular interactions of two monomers occur first at the active site interface, generating unstable or transient dimers, and interactions at the termini interface subsequently occur, generating stable dimers. Darunavir (DRV), an HIV-1 protease inhibitor, inhibits not only proteolytic activity but also PR dimerization. DRV bound to protease monomers in a one-to-one molar ratio, inhibiting the first step of PR dimerization, whereas conventional protease inhibitors (such as saquinavir) that inhibit enzymatic activity but not dimerization failed to bind to monomers. DRV also bound to mutant PRs containing the transframe region-added PR (TFR-PRD25N and TFR-PRD25N-7AA), whereas saquinavir did not bind to TFR-PRD25N or TFR-PRD25N-7AA. Notably, DRV failed to bind to mutant PR containing four amino acid substitutions (V32I, L33F, I54M, and I84V) that confer resistance to DRV on HIV-1. To our knowledge, the present report represents the first demonstration of the two-step PR dimerization dynamics and the mechanism of dimerization inhibition by DRV, which should help design further, more potent novel PIs. C1 [Hayashi, Hironori; Aoki, Manabu; Koh, Yasuhiro; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med, Dept Hematol, Chuo Ku, Kumamoto 8608556, Japan. [Hayashi, Hironori; Aoki, Manabu; Koh, Yasuhiro; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med, Dept Rheumatol, Chuo Ku, Kumamoto 8608556, Japan. [Hayashi, Hironori; Aoki, Manabu; Koh, Yasuhiro; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med, Dept Infect Dis, Chuo Ku, Kumamoto 8608556, Japan. [Hayashi, Hironori; Das, Debananda; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Takamune, Nobutoki; Misumi, Shogo] Kumamoto Univ, Dept Biochem, Grad Sch Pharmaceut Sci, Chuo Ku, Kumamoto 8620973, Japan. [Nirasawa, Takashi; Morishita, Yoshihiko] Bruker Dalton KK, Kanagawa Ku, Yokohama, Kanagawa 2210022, Japan. [Aoki, Manabu] Kumamoto Hlth Sci Univ, Dept Med Technol, Kita Ku, Kumamoto 8615598, Japan. [Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Grad Sch Med, Dept Hematol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8608556, Japan. EM hmitsuya@helix.nih.gov FU Monbu-Kagakusho; Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan; Kumamoto University [78]; Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health [GM53386] FX This work was supported in part by a grant for the Global Education and Research Center Aiming at the Control of AIDS (Global Center of Excellence, supported by Monbu-Kagakusho); Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan; a grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo, no. 78; Kumamoto University) of Monbu-Kagakusho (to H. M.); the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (H. M.); and by Extramural Grant GM53386 from the National Institutes of Health (to A.K.G.). NR 31 TC 5 Z9 5 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 AUG 19 PY 2014 VL 111 IS 33 BP 12234 EP 12239 DI 10.1073/pnas.1400027111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN2TS UT WOS:000340438800076 PM 25092296 ER PT J AU Ha, HL Wang, HS Pisitkun, P Kim, JC Tassi, I Tang, WH Morasso, MI Udey, MC Siebenlist, U AF Ha, Hye-Lin Wang, Hongshan Pisitkun, Prapaporn Kim, Jin-Chul Tassi, Ilaria Tang, Wanhu Morasso, Maria I. Udey, Mark C. Siebenlist, Ulrich TI IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ADAPTER PROTEIN CIKS/ACT1; SKIN INFLAMMATION; INTERLEUKIN-17 RECEPTOR; IN-VITRO; ANTIBODY; DIFFERENTIATION; KERATINOCYTES; CYTOKINES; TRAF3IP2; DISEASE AB Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory cells. The mechanisms underlying psoriasis in humans and in mouse models are poorly understood, although evidence strongly points to crucial contributions of IL-17 cytokines, which signal via the obligatory adaptor CIKS/Act1. Here we identify critical roles of CIKS/Act1-mediated signaling in imiquimod-induced psoriatic inflammation, a mouse model that shares features with the human disease. We found that IL-17 cytokines/CIKS-mediated signaling into keratinocytes is essential for neutrophilic microabscess formation and contributes to hyperproliferation and markedly attenuated differentiation of keratinocytes, at least in part via direct effects. In contrast, IL-17 cytokines/CIKS-mediated signaling into nonkeratinocytes, particularly into dermal fibroblasts, promotes cellular infiltration and, importantly, leads to enhanced the accumulation of IL-17-producing gamma delta T cells in skin, comprising a positive feed-forward mechanism. Thus, CIKS-mediated signaling is central in the development of both dermal and epidermal hallmarks of psoriasis, inducing distinct pathologies via target cell-specific effects. CIKS-mediated signaling represents a potential therapeutic target in psoriasis. C1 [Ha, Hye-Lin; Wang, Hongshan; Pisitkun, Prapaporn; Tassi, Ilaria; Tang, Wanhu; Siebenlist, Ulrich] NIAID, Immune Activat Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kim, Jin-Chul; Morasso, Maria I.] NIAMSD, Lab Skin Biol, NIH, Bethesda, MD 20892 USA. [Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pisitkun, Prapaporn] Mahidol Univ, Div Allergy Immunol & Rheumatol, Dept Med, Ramathibodi Hosp, Bangkok 10400, Thailand. RP Siebenlist, U (reprint author), NIAID, Immune Activat Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM usiebenlist@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Cancer Institute, National Institutes of Health FX We thank Sundar Ganesan for help with fluorescence microscopy and members of the U.S. laboratory for constructive input. This research was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Cancer Institute, National Institutes of Health. NR 43 TC 21 Z9 24 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 AUG 19 PY 2014 VL 111 IS 33 BP E3422 EP E3431 DI 10.1073/pnas.1400513111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN2TS UT WOS:000340438800011 PM 25092341 ER PT J AU Kellis, M Wold, B Snyder, MP Bernstein, BE Kundaje, A Marinov, GK Ward, LD Birney, E Crawford, GE Dekker, J Dunham, I Elnitski, LL Farnham, PJ Feingold, EA Gerstein, M Giddings, MC Gilbert, DM Gingeras, TR Green, ED Guigo, R Hubbard, T Kent, J Lieb, JD Myers, RM Pazin, MJ Ren, B Stamatoyannopoulos, J Weng, Z White, KP Hardison, RC AF Kellis, Manolis Wold, Barbara Snyder, Michael P. Bernstein, Bradley E. Kundaje, Anshul Marinov, Georgi K. Ward, Lucas D. Birney, Ewan Crawford, Gregory E. Dekker, Job Dunham, Ian Elnitski, Laura L. Farnham, Peggy J. Feingold, Elise A. Gerstein, Mark Giddings, Morgan C. Gilbert, David M. Gingeras, Thomas R. Green, Eric D. Guigo, Roderic Hubbard, Tim Kent, Jim Lieb, Jason D. Myers, Richard M. Pazin, Michael J. Ren, Bing Stamatoyannopoulos, John Weng, Zhiping White, Kevin P. Hardison, Ross C. TI Reply to Brunet and Doolittle: Both selected effect and causal role elements can influence human biology and disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID GENOME C1 [Kellis, Manolis; Kundaje, Anshul; Ward, Lucas D.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Kellis, Manolis; Bernstein, Bradley E.; Kundaje, Anshul; Ward, Lucas D.] Broad Inst, Cambridge, MA 02139 USA. [Wold, Barbara; Marinov, Georgi K.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Snyder, Michael P.; Kundaje, Anshul] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Birney, Ewan; Dunham, Ian] European Mol Biol Lab, European Bioinformat Inst, Cambridge CB10 1SD, England. [Crawford, Gregory E.] Duke Univ, Durham, NC 27708 USA. [Dekker, Job; Weng, Zhiping] Univ Massachusetts, Sch Med, Program Syst Biol, Worcester, MA 01605 USA. [Elnitski, Laura L.; Feingold, Elise A.; Green, Eric D.; Pazin, Michael J.] NIH, NHGRI, Bethesda, MD 20892 USA. [Farnham, Peggy J.] Univ So Calif, Los Angeles, CA 90089 USA. [Gerstein, Mark] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Giddings, Morgan C.] LLC, Marketing Your Sci, Boise, ID 83702 USA. [Gilbert, David M.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Gingeras, Thomas R.] Cold Spring Harbor Lab, Funct Genom Grp, Cold Spring Harbor, NY 11724 USA. [Guigo, Roderic] Ctr Genome Regulat, Bioinformat & Genom Program, E-08003 Barcelona, Catalonia, Spain. [Hubbard, Tim] Kings Coll London, Cambridge CB10 1SD, England. [Hubbard, Tim] Wellcome Trust Sanger Inst, Cambridge CB10 1SD, England. [Kent, Jim] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Lieb, Jason D.; White, Kevin P.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Myers, Richard M.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Ren, Bing] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Stamatoyannopoulos, John] Univ Washington, Seattle, WA 98195 USA. [Hardison, Ross C.] Penn State Univ, University Pk, PA 16802 USA. RP Kellis, M (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM manoli@mit.edu; rch8@psu.edu RI Guigo, Roderic/D-1303-2010; Hubbard, Tim/C-2567-2008; OI Guigo, Roderic/0000-0002-5738-4477; Hubbard, Tim/0000-0002-1767-9318; Ward, Lucas/0000-0002-8017-809X; Farnham, Peggy/0000-0003-4469-7914; Gerstein, Mark/0000-0002-9746-3719; Dunham, Ian/0000-0003-2525-5598; Birney, Ewan/0000-0001-8314-8497; Pazin, Michael/0000-0002-7561-3640 FU NHGRI NIH HHS [U41 HG007234, U54 HG007004]; NIGMS NIH HHS [P01 GM085354, R01 GM083337] NR 4 TC 1 Z9 1 U1 1 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 AUG 19 PY 2014 VL 111 IS 33 BP E3366 EP E3366 DI 10.1073/pnas.1410434111 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN2TS UT WOS:000340438800004 PM 25275169 ER PT J AU Yue, XM Pourladian, IS Tootell, RBH Ungerleider, LG AF Yue, Xiaomin Pourladian, Irene S. Tootell, Roger B. H. Ungerleider, Leslie G. TI Curvature-processing network in macaque visual cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE curvature patches; face patches; curved Gabor filters ID INFERIOR TEMPORAL CORTEX; POSTERIOR INFEROTEMPORAL CORTEX; FUSIFORM FACE AREA; STRIATE CORTEX; RETINOTOPIC ORGANIZATION; OBJECT REPRESENTATIONS; SHAPE REPRESENTATION; CARTESIAN GRATINGS; FUNCTIONAL-ANATOMY; NONHUMAN-PRIMATES AB Our visual environment abounds with curved features. Thus, the goal of understanding visual processing should include the processing of curved features. Using functional magnetic resonance imaging in behaving monkeys, we demonstrated a network of cortical areas selective for the processing of curved features. This network includes three distinct hierarchically organized regions within the ventral visual pathway: a posterior curvature-biased patch (PCP) located in the near-foveal representation of dorsal V4, a middle curvature-biased patch (MCP) located on the ventral lip of the posterior superior temporal sulcus (STS) in area TEO, and an anterior curvature-biased patch (ACP) located just below the STS in anterior area TE. Our results further indicate that the processing of curvature becomes increasingly complex from PCP to ACP. The proximity of the curvature-processing network to the well-known face-processing network suggests a possible functional link between them. C1 [Yue, Xiaomin; Pourladian, Irene S.; Tootell, Roger B. H.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Tootell, Roger B. H.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Yue, XM (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM yuex@mail.nih.gov; ungerlel@mail.nih.gov FU National Institute of Mental Health Intramural Research Program; National Institutes of Health [R01 EY017081] FX The study was supported by National Institute of Mental Health Intramural Research Program (X.Y., I.S.P., and L.G.U.) and National Institutes of Health Grant R01 EY017081 (to R.B.H.T.). NR 78 TC 10 Z9 10 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 19 PY 2014 VL 111 IS 33 BP E3467 EP E3475 DI 10.1073/pnas.1412616111 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN2TS UT WOS:000340438800016 PM 25092328 ER PT J AU Li, XL Jones, MF Subramanian, M Lal, A AF Li, Xiao Ling Jones, Matthew F. Subramanian, Murugan Lal, Ashish TI Mutant p53 exerts oncogenic effects through microRNAs and their target gene networks SO FEBS LETTERS LA English DT Review DE Mutant p53; microRNA; miRNA; Let-7; miR-130b; miR-128-2; miR-155; miR-223; miR-27a; miR-205; Gain-of-function; Invasion; Metastasis; Cancer ID LI-FRAUMENI-SYNDROME; GAIN-OF-FUNCTION; CELL-PROLIFERATION; COLORECTAL-CANCER; TUMOR-CELLS; TRANSFORMATION; MODULATION; EXPRESSION; APOPTOSIS; MIR-34A AB MicroRNAs are potent regulators of gene expression and modulate multiple cellular processes including proliferation, differentiation and apoptosis. A number of microRNAs have been shown to be regulated by p53, the most frequently mutated gene in human cancer. It is has been demonstrated that some mutant p53 proteins not only lose tumor suppressor activity, but also acquire novel oncogenic functions that are independent of wild-type p53. In this review, we highlight recent evidences suggesting that some mutant p53 proteins regulate the expression of specific microRNAs to gain oncogenic functions and identify a gene network regulated by the microRNAs downstream of mutant p53. (C) 2014 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Li, Xiao Ling; Jones, Matthew F.; Subramanian, Murugan; Lal, Ashish] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Lal, A (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM ashish.lal@nih.gov NR 85 TC 5 Z9 5 U1 0 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD AUG 19 PY 2014 VL 588 IS 16 SI SI BP 2610 EP 2615 DI 10.1016/j.febslet.2014.03.054 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AN1BN UT WOS:000340317800007 PM 24726728 ER PT J AU Puchner, SB Liu, T Mayrhofer, T Truong, QA Lee, H Fleg, JL Nagurney, JT Udelson, JE Hoffmann, U Ferencik, M AF Puchner, Stefan B. Liu, Ting Mayrhofer, Thomas Truong, Quynh A. Lee, Hang Fleg, Jerome L. Nagurney, John T. Udelson, James E. Hoffmann, Udo Ferencik, Maros TI High-Risk Plaque Detected on Coronary CT Angiography Predicts Acute Coronary Syndromes Independent of Significant Stenosis in Acute Chest Pain Results From the ROMICAT-II Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute chest pain; acute coronary syndrome; coronary atherosclerotic plaque; coronary computed tomography ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; RADIOFREQUENCY DATA-ANALYSIS; NAPKIN-RING SIGN; DUAL-SOURCE CT; INTRAVASCULAR ULTRASOUND; NONINVASIVE ASSESSMENT; ATHEROSCLEROTIC PLAQUE; MYOCARDIAL-INFARCTION; VIRTUAL HISTOLOGY; CULPRIT LESIONS AB BACKGROUND It is not known whether high-risk plaque, as detected by coronary computed tomography angiography (CTA), permits improved early diagnosis of acute coronary syndromes (ACS) independently to the presence of significant coronary artery disease (CAD) in patients with acute chest pain. OBJECTIVES The primary aim of this study was to determine whether high-risk plaque features, as detected by CTA in the emergency department (ED), may improve diagnostic certainty of ACS independently and incrementally to the presence of significant CAD and clinical risk assessment in patients with acute chest pain but without objective evidence of myocardial ischemia or myocardial infarction (MI). METHODS We included patients randomized to the coronary CTA arm of the ROMICAT-II (Rule Out Myocardial Infarction/Ischemia Using Computer-Assisted Tomography II) trial. Readers assessed coronary CTA qualitatively for the presence of nonobstructive CAD (1% to 49% stenosis), significant CAD (>= 50% or >= 70% stenosis), and the presence of at least 1 of the high-risk plaque features (positive remodeling, low <30 Hounsfield units plaque, napkin-ring sign, spotty calcium). In logistic regression analysis, we determined the association of high-risk plaque with ACS (MI or unstable angina pectoris) during the index hospitalization and whether this was independent of significant CAD and clinical risk assessment. RESULTS Overall, 37 of 472 patients who underwent coronary CTA with diagnostic image quality (mean age 53.9 +/- 8.0 years; 52.8% men) had ACS (7.8%; MI n = 5; unstable angina pectoris n = 32). CAD was present in 262 patients (55.5%; nonobstructive CAD in 217 patients [46.0%] and significant CAD with >= 50% stenosis in 45 patients [9.5%]). High-risk plaques were more frequent in patients with ACS and remained a significant predictor of ACS (odds ratio [OR]: 8.9; 95% CI: 1.8 to 43.3; p = 0.006) after adjustment for >= 50% stenosis (OR: 38.6; 95% CI: 14.2 to 104.7; p < 0.001) and clinical risk assessment (age, sex, number of cardiovascular risk factors). Similar results were observed after adjustment for >= 70% stenosis. CONCLUSIONS In patients presenting to the ED with acute chest pain but negative initial electrocardiogram and troponin, presence of high-risk plaques on coronary CTA increased the likelihood of ACS independent of significant CAD and clinical risk assessment (age, sex, and number of cardiovascular risk factors). (Multicenter Study to Rule Out Myocardial Infarction by Cardiac Computed Tomography [ROMICAT-II]) (C) 2014 by the American College of Cardiology Foundation. C1 [Puchner, Stefan B.; Liu, Ting; Mayrhofer, Thomas; Truong, Quynh A.; Hoffmann, Udo; Ferencik, Maros] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Puchner, Stefan B.; Liu, Ting; Mayrhofer, Thomas; Truong, Quynh A.; Hoffmann, Udo; Ferencik, Maros] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Puchner, Stefan B.; Liu, Ting; Mayrhofer, Thomas; Truong, Quynh A.; Lee, Hang; Nagurney, John T.; Hoffmann, Udo; Ferencik, Maros] Harvard Univ, Sch Med, Boston, MA USA. [Puchner, Stefan B.] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Vienna, Austria. [Liu, Ting] China Med Univ, Affiliated Hosp 1, Dept Radiol, Shenyang, Peoples R China. [Truong, Quynh A.; Lee, Hang; Hoffmann, Udo; Ferencik, Maros] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. [Ferencik, Maros] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97201 USA. RP Ferencik, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM maros_ferencik@hms.harvard.edu FU National Heart, Lung, and Blood Institute (NHLBI) [U01HL092040, U01HL092022]; National Institutes of Health/NHLBI [K23HL098370, L30HL093896]; Biosite/Allere; Brahms Limited/Thermo-Fisher; Nanosphere; NHLBI [U01HL092040, U01HL092022]; American Heart Association [13FTF16450001] FX This work was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) (U01HL092040 and U01HL092022). Dr. Truong has received support from the National Institutes of Health/NHLBI (K23HL098370 and L30HL093896), St. Jude Medical, American College of Radiology Imaging Network, and Duke Clinical Research Institute. Dr. Nagurney has received research grants from Biosite/Allere, Brahms Limited/Thermo-Fisher, and Nanosphere for work on cardiac biomarkers. Dr. Udelson has received research grants from the NHLBI (U01HL092040 and U01HL092022). Dr. Ferencik has received support from the American Heart Association (13FTF16450001). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 33 TC 57 Z9 58 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 19 PY 2014 VL 64 IS 7 BP 684 EP 692 DI 10.1016/j.jacc.2014.05.039 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN0AL UT WOS:000340243300009 PM 25125300 ER PT J AU Chen, QR Hu, Y Yan, CH Buetow, K Meerzaman, D AF Chen, Qing-Rong Hu, Ying Yan, Chunhua Buetow, Kenneth Meerzaman, Daoud TI Systematic Genetic Analysis Identifies Cis-eQTL Target Genes Associated with Glioblastoma Patient Survival SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; EXPRESSION; SUSCEPTIBILITY; CANCER; GLIOMA; CELLS; LOCI; POLYMORPHISMS; METAANALYSIS; POPULATION AB Prior expression quantitative trait locus (eQTL) studies have demonstrated heritable variation determining differences in gene expression. The majority of eQTL studies were based on cell lines and normal tissues. We performed cis-eQTL analysis using glioblastoma multiforme (GBM) data sets obtained from The Cancer Genome Atlas (TCGA) to systematically investigate germline variation's contribution to tumor gene expression levels. We identified 985 significant cis-eQTL associations (FDR<0.05) mapped to 978 SNP loci and 159 unique genes. Approximately 57% of these eQTLs have been previously linked to the gene expression in cell lines and normal tissues; 43% of these share cis associations known to be associated with functional annotations. About 25% of these cis-eQTL associations are also common to those identified in Breast Cancer from a recent study. Further investigation of the relationship between gene expression and patient clinical information identified 13 eQTL genes whose expression level significantly correlates with GBM patient survival (p<0.05). Most of these genes are also differentially expressed in tumor samples and organ-specific controls (p<0.05). Our results demonstrated a significant relationship of germline variation with gene expression levels in GBM. The identification of eQTLs-based expression associated survival might be important to the understanding of genetic contribution to GBM cancer prognosis. C1 [Chen, Qing-Rong; Hu, Ying; Yan, Chunhua; Buetow, Kenneth; Meerzaman, Daoud] NIH, Natl Canc Inst, Ctr Biomed Informat & Informat Technol, Bethesda, MD 20892 USA. RP Chen, QR (reprint author), NIH, Natl Canc Inst, Ctr Biomed Informat & Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM chenqi@mail.nih.gov NR 34 TC 8 Z9 8 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 18 PY 2014 VL 9 IS 8 AR e105393 DI 10.1371/journal.pone.0105393 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO4JF UT WOS:000341302700111 PM 25133526 ER PT J AU Dal Monte, O Noble, PL Turchi, J Cummins, A Averbeck, BB AF Dal Monte, Olga Noble, Pamela L. Turchi, Janita Cummins, Alex Averbeck, Bruno B. TI CSF and Blood Oxytocin Concentration Changes following Intranasal Delivery in Macaque SO PLOS ONE LA English DT Article ID CEREBROSPINAL-FLUID; PLASMA OXYTOCIN; RHESUS-MONKEYS; MACACA-MULATTA; DRUG-DELIVERY; BRAIN-BARRIER; SPINAL-CORD; VASOPRESSIN; RATS; HUMANS AB Oxytocin (OT) in the central nervous system (CNS) influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline) to 15 primates (Macaca mulatta), using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF) and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels. C1 [Dal Monte, Olga; Noble, Pamela L.; Turchi, Janita; Cummins, Alex; Averbeck, Bruno B.] NIH, NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Dal Monte, Olga] Univ Turin, Dept Neuropsychol, Turin, Italy. RP Averbeck, BB (reprint author), NIH, NIMH, Neuropsychol Lab, Bldg 10, Bethesda, MD 20892 USA. EM averbeckbb@mail.nih.gov OI dal monte, olga/0000-0002-7823-4769 FU Intramural Research Program of the NIMH/NIH/DHHS FX This research was supported by the Intramural Research Program of the NIMH/NIH/DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 38 Z9 38 U1 1 U2 23 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 AUG 18 PY 2014 VL 9 IS 8 AR e103677 DI 10.1371/journal.pone.0103677 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO4JF UT WOS:000341302700015 PM 25133536 ER PT J AU Nenseth, HZ Dezitter, X Tesikova, M Mueller, F Klokk, TI Hager, GL Saatcioglu, F AF Nenseth, Hatice Z. Dezitter, Xavier Tesikova, Martina Mueller, Florian Klokk, Tove I. Hager, Gordon L. Saatcioglu, Fahri TI Distinctly Different Dynamics and Kinetics of Two Steroid Receptors at the Same Response Elements in Living Cells SO PLOS ONE LA English DT Article ID LIGAND-SPECIFIC DYNAMICS; LONG TERMINAL REPEAT; ANDROGEN-RECEPTOR; GLUCOCORTICOID-RECEPTOR; DNA-BINDING; ACTINOMYCIN-D; TRANSCRIPTIONAL ELONGATION; IN-VITRO; P-TEFB; PROMOTER AB Closely related transcription factors (TFs) can bind to the same response elements (REs) with similar affinities and activate transcription. However, it is unknown whether transcription is similarly orchestrated by different TFs bound at the same RE. Here we have compared the recovery half time (t(1/2)), binding site occupancy and the resulting temporal changes in transcription upon binding of two closely related steroid receptors, the androgen and glucocorticoid receptors (AR and GR), to their common hormone REs (HREs). We show that there are significant differences at all of these levels between AR and GR at the MMTV HRE when activated by their ligands. These data show that two TFs bound at the same RE can have significantly different modes of action that can affect their responses to environmental cues. C1 [Nenseth, Hatice Z.; Dezitter, Xavier; Tesikova, Martina; Klokk, Tove I.; Saatcioglu, Fahri] Univ Oslo, Dept Biosci, Oslo, Norway. [Mueller, Florian] Inst Pasteur, Computat Imaging & Modeling Unit, Paris, France. [Hager, Gordon L.] Natl Inst Hlth, Natl Canc Inst, Lab Receptor Biol & Gene Express, Bethesda, MD USA. [Saatcioglu, Fahri] Oslo Univ Hosp, Inst Canc Genet & Informat, Oslo, Norway. RP Saatcioglu, F (reprint author), Univ Oslo, Dept Biosci, Oslo, Norway. EM fahris@ibv.uio.no RI Mueller, Florian/C-9075-2012 OI Mueller, Florian/0000-0002-9622-4396 FU Norwegian Research Council; Norwegian Cancer Society; University of Oslo FX This work was supported by funds from the Norwegian Research Council (www.forskningsradet.no), Norwegian Cancer Society (www.kreftforeningen.no), and University of Oslo (www.uio.no). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 6 Z9 6 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 AUG 18 PY 2014 VL 9 IS 8 AR e105204 DI 10.1371/journal.pone.0105204 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO4JF UT WOS:000341302700085 PM 25133404 ER PT J AU Viaud, S Daillere, R Boneca, IG Lepage, P Pittet, MJ Ghiringhelli, F Trinchieri, G Goldszmid, R Zitvogel, L AF Viaud, S. Daillere, R. Boneca, I. G. Lepage, P. Pittet, M. J. Ghiringhelli, F. Trinchieri, G. Goldszmid, R. Zitvogel, L. TI Harnessing the Intestinal Microbiome for Optimal Therapeutic Immunomodulation SO CANCER RESEARCH LA English DT Review ID HUMAN GUT MICROBIOME; REGULATORY T-CELLS; CYCLOPHOSPHAMIDE; RICHNESS; IMPACT; GENE AB Distinct cytotoxic agents currently used in the oncological armamentarium mediate their clinical benefit by influencing, directly or indirectly, the immune system in such a way that innate and adaptive immunity contributes to the tumoricidal activity. Now, we bring up evidence that both arms of anticancer immunity can be triggered through the intervention of the intestinal microbiota. Alkylating agents, such as cyclophosphamide, set up the stage for enhanced permeability of the small intestine, facilitating the translocation of selected arrays of Gram-positive bacteria against which the host mounts effector pTh17 cells and memory Th1 responses. In addition, gut commensals, through lipopolysaccharide and other bacterial components, switch the tumor microenvironment, in particular the redox equilibrium and the TNF production of intratumoral myeloid cells during therapies with platinum salts or intratumoral TLR9 agonists combined with systemic anti-IL10R Ab respectively. Consequently, antibiotics can compromise the efficacy of certain chemotherapeutic or immunomodulatory regimens. (C) 2014 AACR. C1 [Viaud, S.; Daillere, R.; Zitvogel, L.] INSERM, U1015, Villejuif, France. [Viaud, S.; Daillere, R.; Zitvogel, L.] Univ Paris 11, Le Kremlin Bicetre, France. [Boneca, I. G.] Inst Pasteur, Unit Biol & Genet Bacterial Cell Wall, Paris, France. [Boneca, I. G.] INSERM, Grp Avenir, Paris, France. [Lepage, P.] INRA, Micalis UMR1319, Jouy En Josas, France. [Lepage, P.] AgroParisTech, Micalis UMR1319, Jouy En Josas, France. [Pittet, M. J.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Pittet, M. J.] Harvard Univ, Sch Med, Boston, MA USA. [Ghiringhelli, F.] INSERM, U866, Ctr Georges Francois Leclerc, Dijon, France. [Ghiringhelli, F.] INSERM, Grp Avenir, Dijon, France. [Ghiringhelli, F.] Univ Bourgogne, Fac Med, Dijon, France. [Trinchieri, G.; Goldszmid, R.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Zitvogel, L.] Gustave Roussy, Ctr Invest Clin Biotherapie CICBT 507, Villejuif, France. RP Zitvogel, L (reprint author), 114 Rue Edouard Vaillant, F-94805 Villejuif, France. EM laurence.zitvogel@gustaveroussy.fr RI Boneca, Ivo/H-1677-2014 OI Boneca, Ivo/0000-0001-8122-509X FU Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labellisee); SIRIC Socrate; LABEX and PACRI Onco-Immunology; European Research Council (PGNfromSHAPEtoVIR) [202283]; ISREC Foundation FX This work was supported by the Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labellisee), SIRIC Socrate, LABEX and PACRI Onco-Immunology, European Research Council starting grant (PGNfromSHAPEtoVIR no202283, to I. G. Boneca), and the ISREC Foundation. NR 32 TC 12 Z9 12 U1 3 U2 28 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 16 PY 2014 VL 74 IS 16 BP 4217 EP 4221 DI 10.1158/0008-5472.CAN-14-0987 PG 5 WC Oncology SC Oncology GA AO2WH UT WOS:000341186700002 PM 25074615 ER PT J AU Yin, JJ Liu, YN Tillman, H Barrett, B Hewitt, S Ylaya, K Fang, L Lake, R Corey, E Morrissey, C Vessella, R Kelly, K AF Yin, JuanJuan Liu, Yen-Nien Tillman, Heather Barrett, Ben Hewitt, Stephen Ylaya, Kris Fang, Lei Lake, Ross Corey, Eva Morrissey, Colm Vessella, Robert Kelly, Kathleen TI AR-Regulated TWEAK-FN14 Pathway Promotes Prostate Cancer Bone Metastasis SO CANCER RESEARCH LA English DT Article ID FACTOR-KAPPA-B; NUCLEAR-LOCALIZATION; RECEPTOR; GROWTH; CELLS; PROGRESSION; EXPRESSION; PROGRAM; PTEN; FN14 AB The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKK beta-dependent, NF kappa B signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstream mechanism, via FN14 signaling, through which the NFkB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers. (C)2014 AACR. C1 [Yin, JuanJuan; Tillman, Heather; Barrett, Ben; Fang, Lei; Lake, Ross; Kelly, Kathleen] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Liu, Yen-Nien] Taipei Med Univ, Coll Med Sci & Technol, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan. [Hewitt, Stephen; Ylaya, Kris] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Corey, Eva; Morrissey, Colm; Vessella, Robert] Univ Washington, Dept Urol, Seattle, WA 98195 USA. RP Kelly, K (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, 37 Convent Dr,Room 1068, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU NIH, National Cancer Institute, Center for Cancer Research; New Staff Research Project Grant, Taipei Medical University, Taiwan [TMU101-AE1-B20]; Pacific Northwest Prostate Cancer SPORE [P50CA97186]; PO1 NIH grant [PO1CA085859]; Richard M. Lucas Foundation FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Y.-N. Liu was supported by the New Staff Research Project Grant, Taipei Medical University, Taiwan (TMU101-AE1-B20). The Prostate Cancer Donor Program is supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1CA085859), and the Richard M. Lucas Foundation. NR 43 TC 10 Z9 10 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 16 PY 2014 VL 74 IS 16 BP 4306 EP 4317 DI 10.1158/0008-5472.CAN-13-3233 PG 12 WC Oncology SC Oncology GA AO2WH UT WOS:000341186700011 PM 24970477 ER PT J AU Kang, HJ Park, JH Chen, WP Kang, SI Moroz, K Ladanyi, M Lee, SB AF Kang, Hong-Jun Park, Jun Hong Chen, WeiPing Kang, Soo Im Moroz, Krzysztof Ladanyi, Marc Lee, Sean Bong TI EWS-WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation SO CANCER RESEARCH LA English DT Article ID ROUND-CELL TUMOR; SARCOMA GENE EWS; TRANSLOCATION PRODUCT; EWINGS-SARCOMA; FUSION PROTEIN; WILMS-TUMOR; MULTIFUNCTIONAL PROTEIN; MOUSE MODEL; EXPRESSION; TARGET AB The oncogenic fusion gene EWS-WT1 is the defining chromosomal translocation in desmoplastic small round-cell tumors (DSRCT), a rare but aggressive soft tissue sarcoma with a high rate of mortality. EWS-WT1 functions as an aberrant transcription factor that drives tumorigenesis, but the mechanistic basis for its pathogenic activity is not well understood. To address this question, we created a transgenic mouse strain that permits physiologic expression of EWS-WT1 under the native murine Ews promoter. EWS-WT1 expression led to a dramatic induction of many neuronal genes in embryonic fibroblasts and primary DSRCT, most notably the neural reprogramming factor ASCL1. Mechanistic analyses demonstrated that EWS-WT1 directly bound the proximal promoter of ASCL1, activating its transcription through multiple WT1-responsive elements. Conversely, EWS-WT1 silencing in DSRCT cells reduced ASCL1 expression and cell viability. Notably, exposure of DSRCT cells to neuronal induction media increased neural gene expression and induced neurite-like projections, both of which were abrogated by silencing EWS-WT1. Taken together, our findings reveal that EWS-WT1 can activate neural gene expression and direct partial neural differentiation via ASCL1, suggesting agents that promote neural differentiation might offer a novel therapeutic approach to treat DSRCT. (C)2014 AACR. C1 [Kang, Hong-Jun; Park, Jun Hong; Kang, Soo Im; Moroz, Krzysztof; Lee, Sean Bong] Tulane Univ, Sch Med, Dept Pathol & Lab Med, New Orleans, LA 70112 USA. [Chen, WeiPing] Natl Inst Diabet & Digest & Kidney Dis, Genom Core Facil, NIH, Bethesda, MD USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Lee, SB (reprint author), Tulane Univ, Sch Med, Dept Pathol & Lab Med, 1700 Tulane Ave Room 808, New Orleans, LA 70112 USA. EM slee30@tulane.edu FU Intramural Research Program of the NIH; Tulane Startup Fund; NIDDK FX This research was supported in part by the Intramural Research Program of the NIH, NIDDK (S. B. Lee), and by the Tulane Startup Fund (S. B. Lee). NR 44 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 16 PY 2014 VL 74 IS 16 BP 4526 EP 4535 DI 10.1158/0008-5472.CAN-13-3663 PG 10 WC Oncology SC Oncology GA AO2WH UT WOS:000341186700030 PM 24934812 ER EF