FN Thomson Reuters Web of Science™
VR 1.0
PT J
AU Chang, IS
Jiang, SS
Yang, JCH
Su, WC
Chien, LH
Hsiao, CF
Lee, JH
Chen, CY
Chen, CH
Chang, GC
Wang, ZM
Lo, FY
Chen, KY
Wang, WC
Chen, YM
Huang, MS
Tsai, YH
Su, YC
Hsieh, WS
Shih, WC
Shieh, SH
Yang, TY
Lan, Q
Rothman, N
Chen, CJ
Chanock, SJ
Yang, PC
Hsiung, CA
AF Chang, I-Shou
Jiang, Shih Sheng
Yang, James Chih-Hsin
Su, Wu-Chou
Chien, Li-Hsin
Hsiao, Chin-Fu
Lee, Jih-Hsiang
Chen, Chih-Yi
Chen, Chung-Hsing
Chang, Gee-Chen
Wang, Zhaoming
Lo, Fang-Yi
Chen, Kuan-Yu
Wang, Wen-Chang
Chen, Yuh-Min
Huang, Ming-Shyan
Tsai, Ying-Huang
Su, Yu-Chun
Hsieh, Wan-Shan
Shih, Wen-Chi
Shieh, Shwn-Huey
Yang, Tsung-Ying
Lan, Qing
Rothman, Nathaniel
Chen, Chien-Jen
Chanock, Stephen J.
Yang, Pan-Chyr
Hsiung, Chao A.
TI Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung
Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase
Inhibitors
SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
LA English
DT Article
DE lung neoplasms; molecular targeted therapy; never-smokers; genome-wide
association study; single-nucleotide polymorphism
ID RANDOMIZED PHASE-3 TRIAL; GENOME-WIDE ASSOCIATION; EGFR MUTATIONS;
OPEN-LABEL; CANCER; GEFITINIB; CHEMOTHERAPY; ERLOTINIB; THERAPY;
MULTICENTER
AB Rationale: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patients with advanced NSCLC who have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS.
Objectives: The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs.
Methods: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). Measurements and Main Results: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P < 10(-8)) and with an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression of EGFR, which encodes the TKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene.
Conclusions: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.
C1 [Chang, I-Shou; Jiang, Shih Sheng; Chen, Chung-Hsing] Natl Inst Canc Res, Zhunan, Taiwan.
[Chien, Li-Hsin; Hsiao, Chin-Fu; Lo, Fang-Yi; Wang, Wen-Chang; Su, Yu-Chun; Hsieh, Wan-Shan; Shih, Wen-Chi; Hsiung, Chao A.] Natl Hlth Res Inst, Inst Populat Hlth Sci, 35 Keyan Rd, Zuhan 35053, Taiwan.
[Hsiao, Chin-Fu] Natl Hlth Res Inst, Taiwan Lung Canc Tissue Specimen Informat Resourc, Zhunan, Taiwan.
[Yang, James Chih-Hsin; Lee, Jih-Hsiang] Natl Taiwan Univ, Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan.
[Yang, Pan-Chyr] Natl Taiwan Univ, Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan.
[Yang, James Chih-Hsin; Chen, Kuan-Yu; Yang, Pan-Chyr] Natl Taiwan Univ, Coll Med, Taipei, Taiwan.
[Yang, James Chih-Hsin] Natl Taiwan Univ, Natl Cheng Kung Univ Hosp, Grant Inst Oncol, Taipei, Taiwan.
[Yang, James Chih-Hsin] Natl Taiwan Univ, Natl Cheng Kung Univ Hosp, Canc Res Ctr, Coll Med, Taipei, Taiwan.
[Chen, Kuan-Yu] Natl Taiwan Univ, Natl Cheng Kung Univ Hosp, Dept Internal Med, Div Pulm Med, Taipei, Taiwan.
[Su, Wu-Chou] Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Coll Med, Dept Internal Med, Tainan, Taiwan.
[Chen, Chih-Yi] Chung Shan Med Univ Hosp, Inst Med, Taichung, Taiwan.
[Hsiao, Chin-Fu] Chung Shan Med Univ Hosp, Dept Surg, Div Thorac Surg, Taichung, Taiwan.
[Chang, Gee-Chen] Natl Yang Ming Univ, Fac Med, Sch Med, Taipei, Taiwan.
[Chang, Gee-Chen; Yang, Tsung-Ying] Taichung Vet Gen Hosp, Dept Internal Med, Div Chest Med, Taichung, Taiwan.
[Wang, Zhaoming] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
[Lan, Qing; Rothman, Nathaniel; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
[Wang, Wen-Chang] Taipei Med Univ, Coll Med Sci & Technol, Ph D Program Translat Med, Taipei, Taiwan.
[Chen, Yuh-Min] Taipei Med Univ, Coll Med Sci & Technol, Taipei, Taiwan.
[Chen, Yuh-Min] Taipei Vet Gen Hosp, Dept Chest Med, Taipei, Taiwan.
[Huang, Ming-Shyan] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Sch Med, Dept Internal Med, Kaohsiung, Taiwan.
[Tsai, Ying-Huang] Chiayi Chang Gung Mem Hosp, Div Pulm & Crit Care Med, Chiayi, Taiwan.
[Shieh, Shwn-Huey] China Med Univ, Dept Hlth Serv Adm, Taichung, Taiwan.
[Shieh, Shwn-Huey] China Med Univ, Dept Nursing, Taichung, Taiwan.
[Chen, Chien-Jen] Acad Sinica, Gen Res Ctr, Taipei, Taiwan.
RP Hsiung, CA (reprint author), Natl Hlth Res Inst, Inst Populat Hlth Sci, 35 Keyan Rd, Zuhan 35053, Taiwan.
EM hsiung@nhri.org.tw
NR 31
TC 0
Z9 0
U1 1
U2 1
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 MAR 1
PY 2017
VL 195
IS 5
BP 663
EP 673
DI 10.1164/rccm.201602-0300OC
PG 11
WC Critical Care Medicine; Respiratory System
SC General & Internal Medicine; Respiratory System
GA EM5ND
UT WOS:000395357400016
PM 27669169
ER
PT J
AU Taubert, J
Weldon, KB
Parr, LA
AF Taubert, Jessica
Weldon, Kimberly B.
Parr, Lisa A.
TI Robust representations of individual faces in chimpanzees (Pan
troglodytes) but not monkeys (Macaca mulatta)
SO ANIMAL COGNITION
LA English
DT Article
DE Face recognition; Face perception; Chimpanzees; Rhesus monkeys;
Familiarity; Image averaging
ID SPLIT-BRAIN MONKEYS; UNFAMILIAR FACES; HEMISPHERIC-SPECIALIZATION;
NONHUMAN-PRIMATES; SELECTIVE REGIONS; MATCHING TASK; RECOGNITION;
FAMILIAR; PERCEPTION; VIEWPOINT
AB Being able to recognize the faces of our friends and family members no matter where we see them represents a substantial challenge for the visual system because the retinal image of a face can be degraded by both changes in the person (age, expression, pose, hairstyle, etc.) and changes in the viewing conditions (direction and degree of illumination). Yet most of us are able to recognize familiar people effortlessly. A popular theory for how face recognition is achieved has argued that the brain stabilizes facial appearance by building average representations that enhance diagnostic features that reliably vary between people while diluting features that vary between instances of the same person. This explains why people find it easier to recognize average images of people, created by averaging multiple images of the same person together, than single instances (i.e. photographs). Although this theory is gathering momentum in the psychological and computer sciences, there is no evidence of whether this mechanism represents a unique specialization for individual recognition in humans. Here we tested two species, chimpanzees (Pan troglodytes) and rhesus monkeys (Macaca mulatta), to determine whether average images of different familiar individuals were easier to discriminate than photographs of familiar individuals. Using a two-alternative forced-choice, match-to-sample procedure, we report a behaviour response profile that suggests chimpanzees encode the faces of conspecifics differently than rhesus monkeys and in a manner similar to humans.
C1 [Taubert, Jessica; Weldon, Kimberly B.; Parr, Lisa A.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA.
[Taubert, Jessica] NIMH, Bethesda, MD 20814 USA.
[Parr, Lisa A.] Emory Univ, Div Psychiat & Behav Sci, Atlanta, GA 30322 USA.
RP Taubert, J (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA.; Taubert, J (reprint author), NIMH, Bethesda, MD 20814 USA.
EM jesstaubert@gmail.com
FU NIH/NCRR [RR-00165, R01-MH068791]
FX This investigation was supported by RR-00165 from the NIH/NCRR to the
Yerkes National Primate Research Center and R01-MH068791 to L.A. Parr.
NR 68
TC 0
Z9 0
U1 5
U2 5
PU SPRINGER HEIDELBERG
PI HEIDELBERG
PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY
SN 1435-9448
EI 1435-9456
J9 ANIM COGN
JI Anim. Cogn.
PD MAR
PY 2017
VL 20
IS 2
BP 321
EP 329
DI 10.1007/s10071-016-1054-6
PG 9
WC Behavioral Sciences; Zoology
SC Behavioral Sciences; Zoology
GA EL0LH
UT WOS:000394313400018
PM 27864643
ER
PT J
AU Parsons, C
Lee, S
Jayeola, V
Kathariou, S
AF Parsons, Cameron
Lee, Sangmi
Jayeola, Victor
Kathariou, Sophia
TI Novel Cadmium Resistance Determinant in Listeria monocytogenes
SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY
LA English
DT Article
DE Listeria monocytogenes; cadmium resistance; cadA; biofilm; virulence
ID ESCHERICHIA-COLI O157-H7; PLASMID-BORNE CADMIUM; SEROTYPE 4B;
GENETIC-CHARACTERIZATION; BENZALKONIUM CHLORIDE; UNITED-STATES; STRAINS;
GENOME; OUTBREAK; SUSCEPTIBILITY
AB Listeria monocytogenes is a foodborne pathogen that can cause severe disease (listeriosis) in susceptible individuals. It is ubiquitous in the environment and often exhibits resistance to heavy metals. One of the determinants that enables Listeria to tolerate exposure to cadmium is the cadAC efflux system, with CadA being a P-type ATPase. Three different cadA genes (designated cadA1 to cadA3) were previously characterized in L. monocytogenes. A novel putative cadmium resistance gene (cadA4) was recently identified through whole-genome sequencing, but experimental confirmation for its involvement in cadmium resistance is lacking. In this study, we characterized cadA4 in L. monocytogenes strain F8027, a cadmium-resistant strain of serotype 4b. By screening a mariner-based transposon library of this strain, we identified a mutant with reduced tolerance to cadmium and that harbored a single transposon insertion in cadA4. The tolerance to cadmium was restored by genetic complementation with the cadmium resistance cassette (cadA4C), and enhanced cadmium tolerance was conferred to two unrelated cadmium-sensitive strains via heterologous complementation with cadA4C. Cadmium exposure induced cadA4 expression, even at noninhibitory levels. Virulence assessments in the Galleria mellonella model suggested that a functional cadA4 suppressed virulence, potentially promoting commensal colonization of the insect larvae. Biofilm assays suggested that cadA4 inactivation reduced biofilm formation. These data not only confirm cadA4 as a novel cadmium resistance determinant in L. monocytogenes but also provide evidence for roles in virulence and biofilm formation.
IMPORTANCE Listeria monocytogenes is an intracellular foodborne pathogen causing the disease listeriosis, which is responsible for numerous hospitalizations and deaths every year. Among the adaptations that enable the survival of Listeria in the environment are the abilities to persist in biofilms, grow in the cold, and tolerate toxic compounds, such as heavy metals. Here, we characterized a novel determinant that was recently identified on a larger mobile genetic island through whole-genome sequencing. This gene (cadA4) was found to be responsible for cadmium detoxification and to be a divergent member of the Cad family of cadmium efflux pumps. Virulence assessments in a Galleria mellonella model suggested that cadA4 may suppress virulence. Additionally, cadA4 may be involved in the ability of Listeria to form biofilms. Beyond the role in cadmium detoxification, the involvement of cadA4 in other cellular functions potentially explains its retention and wide distribution in L. monocytogenes.
C1 [Parsons, Cameron; Lee, Sangmi; Jayeola, Victor; Kathariou, Sophia] North Carolina State Univ, Dept Food Bioproc & Nutr Sci, Raleigh, NC 27695 USA.
[Lee, Sangmi] NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Kathariou, S (reprint author), North Carolina State Univ, Dept Food Bioproc & Nutr Sci, Raleigh, NC 27695 USA.
EM sophia_kathariou@ncsu.edu
FU USDA [2011-2012-67017-30218]
FX This study was partially funded by a USDA grant (no.
2011-2012-67017-30218).
NR 45
TC 0
Z9 0
U1 0
U2 0
PU AMER SOC MICROBIOLOGY
PI WASHINGTON
PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA
SN 0099-2240
EI 1098-5336
J9 APPL ENVIRON MICROB
JI Appl. Environ. Microbiol.
PD MAR
PY 2017
VL 85
IS 4
AR UNSP e02580
DI 10.1128/AEM.02580-16
PG 16
WC Biotechnology & Applied Microbiology; Microbiology
SC Biotechnology & Applied Microbiology; Microbiology
GA EK5JK
UT WOS:000393962500005
ER
PT J
AU Withisuphakorn, P
Jiraporn, P
AF Withisuphakorn, Pradit
Jiraporn, Pornsit
TI Co-opted directors and powerful CEOs: evidence from the CEO pay slice
(CPS)
SO APPLIED ECONOMICS LETTERS
LA English
DT Article
DE Co-opted directors; co-option; CEO power; powerful CEOs; corporate
governance; G30; G34
AB We explore the effect of co-opted directors on chief executive officer (CEO) power. Co-opted directors are those appointed after the incumbent CEO assumes office and are found by prior research to represent a weakened governance mechanism. Our evidence reveals that co-opted directors lead to less powerful CEOs, consistent with the substitution effect. Because co-opted directors impose less stringent oversight, the CEO is able to exercise a great deal of latitude in running the firm. Therefore, it is less necessary for the CEO to command so much power where more directors are co-opted, hence leading to less powerful CEOs. In other words, co-opted directors substitute for strong CEO power. Crucially, we find that board co-option exhibits much more explanatory power than does board independence, which has been the primary measure of board effectiveness in the literature.
C1 [Withisuphakorn, Pradit] NIDA, Bangkok, Thailand.
[Jiraporn, Pornsit] Penn State Univ, SGPS, Malvern, PA USA.
RP Jiraporn, P (reprint author), Penn State Univ, SGPS, Malvern, PA USA.
EM pxj11@psu.edu
NR 6
TC 0
Z9 0
U1 0
U2 0
PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND
SN 1350-4851
EI 1466-4291
J9 APPL ECON LETT
JI Appl. Econ. Lett.
PD MAR
PY 2017
VL 24
IS 6
BP 381
EP 386
DI 10.1080/13504851.2016.1194960
PG 6
WC Economics
SC Business & Economics
GA EK1QC
UT WOS:000393699600006
ER
PT J
AU You, L
Xie, RQ
Hu, HJ
Gu, GQ
Zheng, HM
Zhang, JD
Yang, XH
He, XM
Cui, W
AF You, Ling
Xie, Ruiqin
Hu, Haijuan
Gu, Guoqiang
Zheng, Hongmei
Zhang, Jidong
Yang, Xiaohong
He, Ximiao
Cui, Wei
TI High levels of serum beta 2-microglobulin predict severity of coronary
artery disease
SO BMC CARDIOVASCULAR DISORDERS
LA English
DT Article
DE beta 2-Microglobulin; Severity; Coronary artery disease
ID C-REACTIVE PROTEIN; ACUTE MYOCARDIAL-INFARCTION;
GLOMERULAR-FILTRATION-RATE; CHRONIC STABLE ANGINA; CYSTATIN-C;
PROGNOSTIC VALUE; HEART-DISEASE; NATRIURETIC PEPTIDE;
GENERAL-POPULATION; MULTIPLE-MYELOMA
AB Background: The identification of new risk factors for coronary artery disease (CAD) is increasingly sought in an effort to tackle this threatening disease. beta 2-microglobulin (B2M) is reported to associate with peripheral arterial disease and adverse cardiovascular outcomes. However, the association between B2M and cardiovascular disease remains under-researched. This study evaluated the effects of B2M on CAD without renal dysfunction.
Methods: One thousand seven hundred sixty-two subjects (403 non-CAD subjects and 1,359 CAD subjects) were investigated. Fasting samples were collected to determine B2M level. The Gensini and SYNTAX scores were used to assess the severity of CAD.
Results: CAD subjects were significantly higher in serum B2M level comparing with non-CAD subjects (1.25 +/- 0.46 vs 1.14 +/- 0.28 mg/L, p < 0.001). Serum B2M level was a risk factor of CAD after adjusting potential confounders (Odds Ratio (OR) = 2.363, 95% confidence interval (CI): 1.467-3.906, p = 0.001). Receiver operating characteristics (ROC) showed B2M level moderately predicted diagnosis of CAD (the area under the ROC curve (AUC) = 0.608, 95% CI: 0.577-0.639, p < 0.001). Furthermore, serum B2M level was positively associated with Gensini score system, SYNTAX score system and the number of disease vessels (NDV >= 2).
Conclusions: The significant association between serum B2M and CAD suggests that B2M could be a biomarker for CAD.
C1 [He, Ximiao] NCI, Lab Metab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA.
[You, Ling; Xie, Ruiqin; Hu, Haijuan; Gu, Guoqiang; Zheng, Hongmei; Zhang, Jidong; Yang, Xiaohong; Cui, Wei] Hebei Med Univ, Hosp 2, Div Cardiol, 215 Heping West Rd, Shijiazhuang 050000, Hebei, Peoples R China.
RP He, XM (reprint author), NCI, Lab Metab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA.; Cui, W (reprint author), Hebei Med Univ, Hosp 2, Div Cardiol, 215 Heping West Rd, Shijiazhuang 050000, Hebei, Peoples R China.
EM Ximiao.He@gmail.com; cuiwei@medmail.com.cn
FU Science and technology project of Hebei Province [15277715D]; key
project of medical science research in Hebei Province [20150208]
FX This work was generously supported by grants from the Science and
technology project of Hebei Province (Grant No. 15277715D to Ling You)
and grants from the key project of medical science research in Hebei
Province in 2015 (Grant No. 20150208 to Ling You).
NR 44
TC 0
Z9 0
U1 2
U2 2
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2261
J9 BMC CARDIOVASC DISOR
JI BMC Cardiovasc. Disord.
PD MAR 1
PY 2017
VL 17
AR 71
DI 10.1186/s12872-017-0502-9
PG 8
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EM7DH
UT WOS:000395471200001
PM 28249620
ER
PT J
AU Remaley, AT
AF Remaley, Alan T.
TI Undetectable HDL Cholesterol in a Patient with Flu-Like Illness
SO CLINICAL CHEMISTRY
LA English
DT Editorial Material
C1 [Remaley, Alan T.] NIH, 10 Ctr Dr, Bethesda, MD 20892 USA.
RP Remaley, AT (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20892 USA.
EM aremaley1@nhlbi.nih.gov
NR 0
TC 0
Z9 0
U1 0
U2 0
PU AMER ASSOC CLINICAL CHEMISTRY
PI WASHINGTON
PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA
SN 0009-9147
EI 1530-8561
J9 CLIN CHEM
JI Clin. Chem.
PD MAR
PY 2017
VL 63
IS 3
BP 645
EP 645
DI 10.1373/clinchem.2016.263541
PG 1
WC Medical Laboratory Technology
SC Medical Laboratory Technology
GA EL6LU
UT WOS:000394734900005
PM 28242832
ER
PT J
AU Newmeyer, MN
Swortwood, MJ
Andersson, M
Abulseoud, OA
Scheidweiler, KB
Huestis, MA
AF Newmeyer, Matthew N.
Swortwood, Madeleine J.
Andersson, Maria
Abulseoud, Osama A.
Scheidweiler, Karl B.
Huestis, Marilyn A.
TI Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and
Evaluation of Oral Fluid Screening Devices for Predicting
Delta(9)-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis
Brownie Administration
SO CLINICAL CHEMISTRY
LA English
DT Article
ID CONTROLLED SMOKED CANNABIS; TANDEM MASS-SPECTROMETRY; WHOLE-BLOOD;
DELTA-9-TETRAHYDROCANNABINOL CONCENTRATIONS; TESTING DEVICES; PLASMA;
DRUGS; DISPOSITION; DRIVERS; THC
AB BACKGROUND: Roadside oral fluid (OF) Delta(9)-tetrahycirocannabinol (THC) detection indicates recent cannabis intake. OF and blood THC pharmacokinetic data are limited and there are no on-site OF screening performance evaluations after controlled edible cannabis.
CONTENT: We reviewed OF and blood cannabinoid pharmacokinetics and performance evaluations of theDraeger DrugTest (R) 5000 (DT5000) and Alere (TM) DDS (R) 2 (DDS2) on -site OF screening devices. We also present data from a controlled oral cannabis administration session.
SUMMARY: OF THC maximum concentrations (C-max) were similar in freqUent as compared to occasional smokers, while blood THC C-max were higher in frequent [mean (range) 17.7 (8.0-36.1) mu g/L] smokers compared to occasional [8.2 (3.2-14.3) mu g/L] smokers. Minor cannabinoids Delta(9)-tetrahydrocannabivarin "and cannabigerol were never detected in blood, and not in OF by 5 or 8 h, respectively, with 0.3 mu g/L cutoffs. Recommended performance (analytical sensitivity, specificity, and efficiency) criteria for screening devices of >= 80% are difficult to meet when maximizing true positive (TP) results with confirmation cutoffs below the screening cutoff. TPs were greatest with OF confirmation cutoffs of THC >= 1 and >= 2 mu g/L, but analytical sensitivities were <80% due to false negative tests arising from confirmation cutoffs below the DT5000 and DDS2 screening cutoffs; all criteria were >80% with an OF THC >= mu g/L cutoff. Per- formance criteria also were >80% with a blood THC >= 5 mu g/L confirmation cutoff; however, positive OF screening results might not confirm due to the time required to collect blood after a crash or police stop. OF confirmation is recommended for roadside OF screening. (C) 2016 American Association for Clinical Chemistry
C1 [Newmeyer, Matthew N.; Swortwood, Madeleine J.; Andersson, Maria; Abulseoud, Osama A.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Bethesda, MD 20892 USA.
[Newmeyer, Matthew N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA.
[Swortwood, Madeleine J.] Sam Houston State Univ, Dept Forens Sci, Coll Criminal Justice, Huntsville, TX 77340 USA.
[Andersson, Maria] Karolinska Inst, Div Clin Pharmacol, Dept Lab Med, Stockholm, Sweden.
[Andersson, Maria] Univ Hosp, Stockholm, Sweden.
[Huestis, Marilyn A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA.
RP Huestis, MA (reprint author), Univ Maryland, Sch Med, 683 Shore Rd, Severna Pk, MD 21146 USA.
EM marilyn.huestis@gmail.com
FU Intramural Research Program, National Institute on Drug Abuse, NIH;
Graduate Partnership Program, NIH
FX M.N. Newmeyer, Intramural Research Program, National Institute on Drug
Abuse, NIH (to the institution); and Graduate Partnership Program, NIH;
M.A. Huestis, Quantisal, DT5000, and DDS2 devices provided by the
manufacturer to NIH through a Materials Transfer Agreement; and
Intramural Research Program, National Institute on Drug Abuse, NIH (to
the institution).
NR 59
TC 1
Z9 1
U1 5
U2 5
PU AMER ASSOC CLINICAL CHEMISTRY
PI WASHINGTON
PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA
SN 0009-9147
EI 1530-8561
J9 CLIN CHEM
JI Clin. Chem.
PD MAR
PY 2017
VL 63
IS 3
BP 647
EP 662
DI 10.1373/clinchem.2016.265371
PG 16
WC Medical Laboratory Technology
SC Medical Laboratory Technology
GA EL6LU
UT WOS:000394734900007
PM 28188235
ER
PT J
AU Illuzzi, JL
McNeill, DR
Bastian, P
Brenerman, B
Wersto, R
Russell, HR
Bunz, F
McKinnon, PJ
Becker, KG
Wilson, DM
AF Illuzzi, Jennifer L.
McNeill, Daniel R.
Bastian, Paul
Brenerman, Boris
Wersto, Robert
Russell, Helen R.
Bunz, Fred
McKinnon, Peter J.
Becker, Kevin G.
Wilson, David M., III
TI Tumor-Associated APE1 Variant Exhibits Reduced Complementation
Efficiency But Does Not Promote Cancer Cell Phenotypes
SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
LA English
DT Article
DE APE1/APEX1; haploinsufficiency; base excision repair; transformation;
cancer susceptibility
ID APURINIC/APYRIMIDINIC ENDONUCLEASE; ABASIC ENDONUCLEASE; OXIDATIVE
STRESS; REPAIR; DNA; PROTEIN; MOUSE; DAMAGE; REF-1; MICE
AB Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the nontransformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function, or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells. (C) 2017 Wiley Periodicals, Inc.
C1 [Illuzzi, Jennifer L.; McNeill, Daniel R.; Brenerman, Boris; Wilson, David M., III] NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA.
[Bastian, Paul; Becker, Kevin G.] NIA, Lab Genet, Intramural Res Program, NIH, Baltimore, MD 21224 USA.
[Wersto, Robert] NIA, Flow Cytometry Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA.
[Russell, Helen R.; McKinnon, Peter J.] St Jude Childrens Res Hosp, Genet Dept, 332 N Lauderdale St, Memphis, TN 38105 USA.
[Bunz, Fred] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA.
RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA.
EM wilsonda@mail.nih.gov
FU Intramural Research Program at the NIH, National Institute on Aging; NIH
[NS-37956, CA-21765, CA-157535, CA-158428]; American Lebanese and Syrian
Associated Charities of St. Jude Children's Research Hospital
FX Grant sponsor: Intramural Research Program at the NIH, National
Institute on Aging.; Grant sponsor: NIH; Grant numbers: NS-37956 and
CA-21765 (to P.J.M.), and CA-157535 and CA-158428 (to F.B.).; Grant
sponsor: American Lebanese and Syrian Associated Charities of St. Jude
Children's Research Hospital (to P.J.M.).
NR 40
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 MAR
PY 2017
VL 58
IS 2
BP 84
EP 98
DI 10.1002/em.22074
PG 15
WC Environmental Sciences; Genetics & Heredity; Toxicology
SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology
GA EL5SR
UT WOS:000394681700003
PM 28181292
ER
PT J
AU Schisterman, EF
Swanson, CW
Lu, YL
Mumford, SL
AF Schisterman, Enrique F.
Swanson, Chandra W.
Lu, Ya-Ling
Mumford, Sunni L.
TI The Changing Face of Epidemiology Gender Disparities in Citations?
SO EPIDEMIOLOGY
LA English
DT Article
ID MEDICAL SUBJECT-HEADINGS; RESEARCH PERFORMANCE; ACADEMIC POSITION; LIFE
SCIENCES; TEXT-WORD; IMPACT; PRODUCTIVITY; SUCCESS; INDIVIDUALS;
JOURNALS
AB Background: Female biomedical scientists tend to publish fewer articles as last author than their male colleagues and accrue fewer citations per publication. We seek to understand whether epidemiology follows this pattern.
Methods: We gathered aggregate information on the current gender distribution of epidemiology departments (n = 29 of 71 surveyed), societies (n = 4 of 8), and journal editorial boards (n = 6 of 6) using two online surveys and publicly available online information. Bibliometric data from 4,149 articles published between 2008 and 2012 in six high-impact epidemiology journals were drawn from Web of Science and PubMed.
Results: We observed a higher prevalence of female than male doctoral students and epidemiology faculty, particularly at lower faculty ranks. A total of 54% of society members were female. Among editorial boards, all current and emeritus editors-in-chief were male and board membership was largely male (64%). Females were more likely to be first authors, but less likely to be last authors. There were no differences in accrued citations at the 50th percentile by first or last author gender. However, articles with male first and last authors tend to accrue more citations (5.7 citations, 95% CI: 2.1, 9.4), mostly driven by the most highly cited articles. This disparity is not fully explained by potential confounders, including seniority.
Conclusions: We found a greater number of female epidemiologists in early-career positions and further evidence of potential gender disparity in publication metrics in epidemiology. If epidemiology continues to be practiced by a majority of women, it remains to be seen if these patterns will change over time.
C1 [Schisterman, Enrique F.; Swanson, Chandra W.; Lu, Ya-Ling; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6710B Rockledge Dr MSC 7004, Bethesda, MD 20892 USA.
[Lu, Ya-Ling] NIH, NIH Lib, Bldg 10, Bethesda, MD 20892 USA.
RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6710B Rockledge Dr MSC 7004, Bethesda, MD 20892 USA.
EM schistee@mail.nih.gov
OI Schisterman, Enrique/0000-0003-3757-641X
FU Intramural Research Program of the Eunice Kennedy Shriver National
Institute of Child Health and Human Development, National Institutes of
Health
FX This study was supported by the Intramural Research Program of the
Eunice Kennedy Shriver National Institute of Child Health and Human
Development, National Institutes of Health.
NR 36
TC 0
Z9 0
U1 3
U2 3
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1044-3983
EI 1531-5487
J9 EPIDEMIOLOGY
JI Epidemiology
PD MAR
PY 2017
VL 28
IS 2
BP 159
EP 168
DI 10.1097/EDE.0000000000000593
PG 10
WC Public, Environmental & Occupational Health
SC Public, Environmental & Occupational Health
GA EK5IB
UT WOS:000393959000011
PM 27930394
ER
PT J
AU Olsson, AC
Vermeulen, R
Schuz, J
Kromhout, H
Pesch, B
Peters, S
Behrens, T
Portengen, L
Mirabelli, D
Gustavsson, P
Kendzia, B
Almansa, J
Luzon, V
Vlaanderen, J
Stucker, I
Guida, F
Consonni, D
Caporaso, N
Landi, MT
Field, J
Bruske, I
Wichmann, HE
Siemiatycki, J
Parent, ME
Richiardi, L
Merletti, F
Jockel, KH
Ahrens, W
Pohlabeln, H
Plato, N
Tardon, A
Zaridze, D
McLaughlin, J
Demers, P
Szeszenia-Dabrowska, N
Lissowska, J
Rudnai, P
Fabianova, E
Dumitru, RS
Bencko, V
Foretova, L
Janout, V
Boffetta, P
Bueno-De-Mesquita, B
Forastiere, F
Bruning, T
Straif, K
AF Olsson, Ann C.
Vermeulen, Roel
Schuz, Joachim
Kromhout, Hans
Pesch, Beate
Peters, Susan
Behrens, Thomas
Portengen, Lutzen
Mirabelli, Dario
Gustavsson, Per
Kendzia, Benjamin
Almansa, Josue
Luzon, Veronique
Vlaanderen, Jelle
Stucker, Isabelle
Guida, Florence
Consonni, Dario
Caporaso, Neil
Landi, Maria Teresa
Field, John
Brueske, Irene
Wichmann, Heinz-Erich
Siemiatycki, Jack
Parent, Marie-Elise
Richiardi, Lorenzo
Merletti, Franco
Joeckel, Karl-Heinz
Ahrens, Wolfgang
Pohlabeln, Hermann
Plato, Nils
Tardon, Adonina
Zaridze, David
McLaughlin, John
Demers, Paul
Szeszenia-Dabrowska, Neonila
Lissowska, Jolanta
Rudnai, Peter
Fabianova, Eleonora
Dumitru, Rodica Stanescu
Bencko, Vladimir
Foretova, Lenka
Janout, Vladimir
Boffetta, Paolo
Bueno-de-Mesquita, Bas
Forastiere, Francesco
Bruening, Thomas
Straif, Kurt
TI Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a
Pooled Analysis of Case-Control Studies
SO EPIDEMIOLOGY
LA English
DT Article
ID MADE VITREOUS FIBERS; OCCUPATIONAL-EXPOSURE; CASE-REFERENT; SYN-JEM;
RISK; SMOKING; EUROPE; METAANALYSIS; CARCINOGENS; MATRIX
AB Background: Evidence is limited regarding risk and the shape of the exposure-response curve at low asbestos exposure levels. We estimated the exposure-response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies.
Methods: We pooled 14 case-control studies conducted in 19852010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends.
Results: The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs similar to two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women.
Conclusions: Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure-response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.)
C1 [Olsson, Ann C.; Schuz, Joachim; Luzon, Veronique; Vlaanderen, Jelle; Straif, Kurt] Int Agcy Res Canc, Lyon, France.
[Olsson, Ann C.; Gustavsson, Per; Plato, Nils] Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
[Vermeulen, Roel; Kromhout, Hans; Peters, Susan; Portengen, Lutzen; Almansa, Josue; Vlaanderen, Jelle] Inst Risk Assessment Sci, Utrecht, Netherlands.
[Pesch, Beate; Behrens, Thomas; Kendzia, Benjamin; Bruening, Thomas] Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance Inst, Bochum, Germany.
[Peters, Susan] Univ Western Australia, Sch Populat Hlth, Occupat Resp Epidemiol, Perth, WA, Australia.
[Richiardi, Lorenzo; Merletti, Franco] Univ Turin, Dept Med Sci, Canc Epidemiol Unit, Turin, Italy.
[Richiardi, Lorenzo; Merletti, Franco] CPO Piemonte, Turin, Italy.
[Stucker, Isabelle; Guida, Florence] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Environm Epidemiol Canc Team, U1018, Villejuif, France.
[Stucker, Isabelle; Guida, Florence] Univ Paris Sud, UMRS 1018, Villejuif, France.
[Consonni, Dario] Osped Maggiore Policlin, Fdn IRCS Ca Granda, Epidemiol Unit, Milan, Italy.
[Caporaso, Neil; Landi, Maria Teresa] NCI, Bethesda, MD 20892 USA.
[Field, John] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Canc Med, Roy Castle Lung Canc Res Programme,Canc Res Ctr, Liverpool, Merseyside, England.
[Brueske, Irene; Wichmann, Heinz-Erich] Deutsch Forschungszentrum Gesundheit & Umwelt, Inst Epidemiol, Neuherberg, Germany.
[Siemiatycki, Jack] Univ Montreal, Hosp Res Ctr CRCHUM, Montreal, PQ, Canada.
[Parent, Marie-Elise] Univ Quebec, Inst Armand Frappier, INRS, Laval, PQ, Canada.
[Joeckel, Karl-Heinz] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany.
[Ahrens, Wolfgang; Pohlabeln, Hermann] BIPS, Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany.
[Tardon, Adonina] Univ Oviedo, Biomed Res Ctr, Network Epidemiol & Publ Hlth CIBERESP, Oviedo, Spain.
[Zaridze, David] Russian Canc Res Ctr, Moscow, Russia.
[McLaughlin, John] Publ Hlth Ontario, 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.
[Lissowska, Jolanta] Inst Oncol, Warsaw, Poland.
[Rudnai, Peter] Natl Ctr Publ 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, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic.
[Foretova, Lenka] Masaryk Univ, Dept Canc Epidemiol & Genet, Masaryk Mem Canc Inst, Brno, Czech Republic.
[Foretova, Lenka] Masaryk Univ, Dept Canc Epidemiol & Genet, Fac Med, Brno, Czech Republic.
[Janout, Vladimir] Palacky Univ, Fac Med, Olomouc, Czech Republic.
[Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA.
[Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA.
[Bueno-de-Mesquita, Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands.
[Forastiere, Francesco] ASL RomaE, Dept Epidemiol, Rome, Italy.
RP Olsson, AC (reprint author), IARC, ENV, 150 Cours Albert Thomas, F-69372 Lyon 08, France.
EM olssona@iarc.fr
RI Bruning, Thomas/G-8120-2015
OI Bruning, Thomas/0000-0001-9560-5464
FU German Social Accident Insurance (DGUV) [FP 271]; Canada by Canadian
Institutes for Health Research and Guzzo-SRC Chair in Environment and
Cancer; National Cancer Institute of Canada; Canadian Cancer Society;
Occupational Cancer Research Centre; Workplace Safety and Insurance
Board; Cancer Care Ontario; Germany by Federal Ministry of Education,
Science, Research, and Technology [01 HK 173/0]; Federal Ministry of
Science [01 HK 546/8]; Ministry of Labour and Social Affairs
[IIb7-27/13]; Poland by Polish State Committee for Scientific Research
[SPUB-M-COPERNICUS/P-05/DZ-30/99/2000]; European Commission
[IC15-CT96-0313]
FX Joachim Schuz and Kurt Straif are part of a collaborative study with the
State Russian Institute of Occupational Health (SRIOH) on asbestos and
cancer risk, which includes financial support from SRIOH to IARC. Paolo
Boffetta acted as expert witness for Edison SpA in asbestos-related
litigation, outside the submitted work. Beate Pesch, Thomas Behrens,
Benjamin Kendzia, and Thomas Bruning, as staff of the Institute for
Prevention and Occupational Medicine (IPA), are employed at the
"Berufsgenossenschaft Rohstoffe und chemische Industrie" (BG RCI), a
public body, which is a member of the study's main sponsor, the German
Social Accident Insurance (DGUV). IPA is an independent research
institute of the Ruhr-Universitat Bochum. The authors are independent
from the German Social Accident Insurance in study design, access to the
collected data, responsibility for data analysis and interpretation, and
the right to publish. The views expressed in this article are those of
the authors and not necessarily those of the sponsor. The other authors
report no conflicts of interest. The SYNERGY project is funded by the
German Social Accident Insurance (DGUV), Grant FP 271. The original
studies were funded as follows: in Canada by Canadian Institutes for
Health Research and Guzzo-SRC Chair in Environment and Cancer, National
Cancer Institute of Canada, Canadian Cancer Society, Occupational Cancer
Research Centre, Workplace Safety and Insurance Board, Canadian Cancer
Society, and Cancer Care Ontario; in France by the French Agency of
Health Security (ANSES), Fondation de France, French National Research
Agency (ANR), National Institute of Cancer (INCA), Fondation pour la
Recherche Medicale, French Institute for Public Health Surveillance
(InVS), Health Ministry (DGS), Organization for the Research on Cancer
(ARC), and French Ministry of work, solidarity, and public function
(DGT); in Germany by Federal Ministry of Education, Science, Research,
and Technology (Grant 01 HK 173/0), Federal Ministry of Science (Grant
01 HK 546/8), and the Ministry of Labour and Social Affairs (Grant
IIb7-27/13); in Italy by Environmental Epidemiology Program of the
Lombardy Region, INAIL, Italian Association for Cancer Research, Region
Piedmont, Compagnia di San Paolo, and Lazio Region; in Poland by Polish
State Committee for Scientific Research (Grant
SPUB-M-COPERNICUS/P-05/DZ-30/99/2000); in Czech Republic by MH CZ - DRO
(MMCI, 00209805); in Spain by Instituto Universitario de Oncologia,
Universidad de Oviedo, Asturias, Fondo de Investigacion Sanitaria (FIS)
and Ciber de Epidemiologia y Salud Publica (CIBERESP); in Sweden by
Swedish Council for Work Life Research and Swedish Environmental
Protection Agency; in the Netherlands by Dutch Ministry of Health,
Welfare and Sports, National Institute of Public Health and the
Environment, and Europe Against Cancer Program; in the UK by Roy Castle
Foundation; in the USA by Intramural Research Program of the National
Institutes of Health, National Cancer Institute, Division of Cancer
Epidemiology and Genetics, Bethesda, MD; the IARC multicenter study in
Central and Eastern Europe was funded by the European Commission's INCO
Copernicus program (Contract IC15-CT96-0313).
NR 37
TC 0
Z9 0
U1 4
U2 4
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1044-3983
EI 1531-5487
J9 EPIDEMIOLOGY
JI Epidemiology
PD MAR
PY 2017
VL 28
IS 2
BP 288
EP 299
DI 10.1097/EDE.0000000000000604
PG 12
WC Public, Environmental & Occupational Health
SC Public, Environmental & Occupational Health
GA EK5IB
UT WOS:000393959000027
PM 28141674
ER
PT J
AU Imamachi, N
Salam, KA
Suzuki, Y
Akimitsu, N
AF Imamachi, Naoto
Salam, Kazi Abdus
Suzuki, Yutaka
Akimitsu, Nobuyoshi
TI A GC-rich sequence feature in the 3 ' UTR directs UPF1-dependent mRNA
decay in mammalian cells
SO GENOME RESEARCH
LA English
DT Article
ID EXON JUNCTION COMPLEX; UPF1 PHOSPHORYLATION; STABILITY; REVEALS;
SURVEILLANCE; EVOLUTION; BINDING; DEGRADATION; TRANSCRIPTS; ABUNDANCE
AB Up-frameshift protein 1 (UPF1) is an ATP-dependent RNA helicase that has essential roles in RNA surveillance and in post-transcriptional gene regulation by promoting the degradation of mRNAs. Previous studies revealed that UPF1 is associated with the 3' untranslated region (UTR) of target mRNAs via as-yet-unknown sequence features. Herein, we aimed to identify characteristic sequence features of UPF1 targets. We identified 246 UPF1 targets by measuring RNA stabilization upon UPF1 depletion and by identifying mRNAs that associate with UPF1. By analyzing RNA footprint data of phosphorylated UPF1 and two CLIP-seq data of UPF1, we found that 3' UTR but not 5' UTRs or open reading frames of UPF1 targets have GC-rich motifs embedded in high GC-content regions. Reporter gene experiments revealed that GC-rich motifs in UPF1 targets were indispensable for UPF1-mediated mRNA decay. These findings highlight the important features of UPF1 target 3' UTRs.
C1 [Imamachi, Naoto; Salam, Kazi Abdus; Akimitsu, Nobuyoshi] Univ Tokyo, Isotope Sci Ctr, Bunkyo Ku, Tokyo 1130032, Japan.
[Suzuki, Yutaka] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Kashiwa, Chiba 2778562, Japan.
[Salam, Kazi Abdus] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA.
RP Akimitsu, N (reprint author), Univ Tokyo, Isotope Sci Ctr, Bunkyo Ku, Tokyo 1130032, Japan.
EM akimitsu@ric.u-tokyo.ac.jp
OI Imamachi, Naoto/0000-0002-3503-7589
FU MEXT KAKENHI [221S0002, 21115001]; Funding Program for World-Leading
Innovative R&D on Science and Technology of the Japan Society for the
Promotion of Science; Japan Society for the Promotion of Science
FX This work was financially supported by MEXT KAKENHI (Grant Numbers
221S0002 and 21115001), the Funding Program for World-Leading Innovative
R&D on Science and Technology of the Japan Society for the Promotion of
Science and Research Fellowship of the Japan Society for the Promotion
of Science.
NR 47
TC 0
Z9 0
U1 1
U2 1
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1088-9051
EI 1549-5469
J9 GENOME RES
JI Genome Res.
PD MAR
PY 2017
VL 27
IS 3
BP 407
EP 418
DI 10.1101/gr.206060.116
PG 12
WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
Genetics & Heredity
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
Genetics & Heredity
GA EN0IR
UT WOS:000395694000007
PM 27940950
ER
PT J
AU Goldstein, I
Baek, S
Presman, DM
Paakinaho, V
Swinstead, EE
Hager, GL
AF Goldstein, Ido
Baek, Songjoon
Presman, Diego M.
Paakinaho, Ville
Swinstead, Erin E.
Hager, Gordon L.
TI Transcription factor assisted loading and enhancer dynamics dictate the
hepatic fasting response
SO GENOME RESEARCH
LA English
DT Article
ID ACTIVATED RECEPTOR-ALPHA; GLUCOCORTICOID-RECEPTOR; CHROMATIN
ACCESSIBILITY; REGULATORY ELEMENTS; IN-VIVO; CELLS; BINDING; GENOME;
GENE; EXCHANGE
AB Fasting elicits transcriptional programs in hepatocytes leading to glucose and ketone production. This transcriptional program is regulated by many transcription factors (TFs). To understand how this complex network regulates the metabolic response to fasting, we aimed at isolating the enhancers and TFs dictating it. Measuring chromatin accessibility revealed that fasting massively reorganizes liver chromatin, exposing numerous fasting-induced enhancers. By utilizing computational methods in combination with dissecting enhancer features and TF cistromes, we implicated four key TFs regulating the fasting response: glucocorticoid receptor (GR), cAMP responsive element binding protein 1 (CREB1), peroxisome proliferator activated receptor alpha (PPARA), and CCAAT/enhancer binding protein beta (CEBPB). These TFs regulate fuel production by two distinctly operating modules, each controlling a separate metabolic pathway. The gluconeogenic module operates through assisted loading, whereby GR doubles the number of sites occupied by CREB1 as well as enhances CREB1 binding intensity and increases accessibility of CREB1 binding sites. Importantly, this GR-assisted CREB1 binding was enhancer-selective and did not affect all CREB1-bound enhancers. Single-molecule tracking revealed that GR increases the number and DNA residence time of a portion of chromatin-bound CREB1 molecules. These events collectively result in rapid synergistic gene expression and higher hepatic glucose production. Conversely, the ketogenic module operates via a GR-induced TF cascade, whereby PPARA levels are increased following GR activation, facilitating gradual enhancer maturation next to PPARA target genes and delayed ketogenic gene expression. Our findings reveal a complex network of enhancers and TFs that dynamically cooperate to restore homeostasis upon fasting.
C1 [Goldstein, Ido; Baek, Songjoon; Presman, Diego M.; Paakinaho, Ville; Swinstead, Erin E.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA.
RP Goldstein, I; Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA.
EM goldstein.ido@gmail.com; hagerg@dce41.nci.nih.gov
FU Intramural Research Program of the National Institutes of Health (NIH);
National Cancer Institute (NCI); Center for Cancer Research (CCR);
Sigrid Juselius Foundation
FX We thank Lars Grontved, Tom Johnson, Lyuba Varticovski, Tom Misteli, and
Irwin Arias for their comments and help. This work was supported by the
Intramural Research Program of the National Institutes of Health (NIH),
the National Cancer Institute (NCI), and the Center for Cancer Research
(CCR). V.P. was supported, in part, by the Sigrid Juselius Foundation.
NR 49
TC 0
Z9 0
U1 1
U2 1
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1088-9051
EI 1549-5469
J9 GENOME RES
JI Genome Res.
PD MAR
PY 2017
VL 27
IS 3
BP 427
EP 439
DI 10.1101/gr.212175.116
PG 13
WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
Genetics & Heredity
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
Genetics & Heredity
GA EN0IR
UT WOS:000395694000009
PM 28031249
ER
PT J
AU Gupta, S
Jacobs, ET
Baron, JA
Lieberman, DA
Murphy, G
Ladabaum, U
Cross, AJ
Jover, R
Liu, L
Martinez, ME
AF Gupta, Samir
Jacobs, Elizabeth T.
Baron, John A.
Lieberman, David A.
Murphy, Gwen
Ladabaum, Uri
Cross, Amanda J.
Jover, Rodrigo
Liu, Lin
Martinez, Maria Elena
TI Risk stratification of individuals with low-risk colorectal adenomas
using clinical characteristics: a pooled analysis
SO GUT
LA English
DT Article
ID CANCER INCIDENCE; COLONOSCOPY SURVEILLANCE; TASK-FORCE; MORTALITY;
TRIAL; POLYPECTOMY; RECURRENCE; REMOVAL; SIGMOIDOSCOPY; GUIDELINES
AB Objective For individuals with 1- 2 small (<1 cm) low-risk colorectal adenomas, international guidelines range from no surveillance to offering surveillance colonoscopy in 5-10 years. We hypothesised that the risks for metachronous advanced neoplasia (AN) among patients with low-risk adenomas differ based on clinical factors distinct from those currently used.
Design We pooled data from seven prospective studies to assess the risk of metachronous AN. Two groups with 1- 2 small adenomas were defined based on guidelines from the UK (n=4516) or the European Union (EU)/US (n=2477).
Results Absolute risk of metachronous AN ranged from a low of 2.9% to a high of 12.2%, depending on specific risk factor and guideline used. For the UK group, the highest absolute risks for metachronous AN were found among individuals with a history of prior polyp (12.2%), villous histology (12.2%), age >= 70 years (10.9%), high- grade dysplasia (10.9%), any proximal adenoma (10.2%), distal and proximal adenoma (10.8%) or two adenomas (10.1%). For the EU/US group, the highest absolute risks for metachronous AN were among individuals with a history of prior polyp (11.5%) or the presence of both proximal and distal adenomas (11.0%). In multivariate analyses, strong associations for increasing age and history of prior polyps and odds of metachronous AN were observed, whereas more modest associations were shown for baseline proximal adenomas and those with villous features.
Conclusions Risks of metachronous AN among individuals with 1- 2 small adenomas vary according to readily available clinical characteristics. These characteristics may be considered for recommending colonoscopy surveillance and require further investigation.
C1 [Gupta, Samir] Veteran Affairs San Diego Healthcare Syst, Gastroenterol Sect, Dept Med, San Diego, CA USA.
[Gupta, Samir] Univ Calif San Diego, Div Gastroenterol, Dept Internal Med, La Jolla, CA 92093 USA.
[Gupta, Samir; Liu, Lin; Martinez, Maria Elena] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
[Jacobs, Elizabeth T.] Univ Arizona, Arizona Canc Ctr, Dept Epidemiol & Biostat, Arizona Coll Publ Hlth, Tucson, AZ USA.
[Baron, John A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA.
[Lieberman, David A.] Portland Vet Affairs Med Cente, Div Gastroenterol & Hepatol, Portland, OR USA.
[Lieberman, David A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA.
[Murphy, Gwen] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
[Ladabaum, Uri] Stanford Univ, Dept Med, Sch Med, Div Gastroenterol Hepatol, Stanford, CA 94305 USA.
[Cross, Amanda J.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD USA.
[Jover, Rodrigo] Hosp Gen Univ Alicante, Inst Invest Sanitaria ISABIAL, Unidad Gastroenterol, Alicante, Spain.
[Liu, Lin; Martinez, Maria Elena] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
RP Martinez, ME (reprint author), Univ Calif San Diego, Moores Canc Ctr, Dept Family Med & Publ Hlth, 3855 Hlth Sci Dr,0901, La Jolla, CA 92093 USA.
EM e8martinez@ucsd.edu
FU Public Health Service from the National Cancer Institute [CA-41108,
CA-23074, CA95060, CA37287, CA104869, CA23108, CA59005, CA26852];
Cooperative Studies Program, Department of Veterans Affairs; USA
Department of Veterans Affairs Health Services Research & Development
Service of the VA Office of Research and Development [1 I01
HX001574-01A1]; Instituto de Salud Carlos III; Fondos FEDER [PI11/2630,
INT-13-078, INT-14-196, UGP-13-221, PI14/01386]
FX This work was supported by Public Health Service grants CA-41108,
CA-23074, CA95060, CA37287, CA104869, CA23108, CA59005 and CA26852 from
the National Cancer Institute. Funding for the Veteran's Affairs Study
was supported by the Cooperative Studies Program, Department of Veterans
Affairs. Support was also provided in part by Merit Review Award number
1 I01 HX001574-01A1 (Gupta, PI) from the USA Department of Veterans
Affairs Health Services Research & Development Service of the VA Office
of Research and Development. The views expressed in this article are
those of the author(s) and do not necessarily represent the views of the
Department of Veterans Affairs. Additional support was provide by
Instituto de Salud Carlos III and Fondos FEDER (PI11/2630, INT-13-078,
INT-14-196, UGP-13-221, PI14/01386)..
NR 25
TC 1
Z9 1
U1 0
U2 0
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 MAR
PY 2017
VL 66
IS 3
SU 1
BP 446
EP 453
DI 10.1136/gutjnl-2015-310196
PG 8
WC Gastroenterology & Hepatology
SC Gastroenterology & Hepatology
GA EL3BY
UT WOS:000394495800010
PM 26658145
ER
PT J
AU Hussein, S
Green, A
Watane, A
Reiter, D
Chen, XJ
Papadakis, GZ
Wood, B
Cypess, A
Osman, M
Bagci, U
AF Hussein, Sarfaraz
Green, Aileen
Watane, Arjun
Reiter, David
Chen, Xinjian
Papadakis, Georgios Z.
Wood, Bradford
Cypess, Aaron
Osman, Medhat
Bagci, Ulas
TI Automatic Segmentation and Quantification of White and Brown Adipose
Tissues from PET/CT Scans
SO IEEE TRANSACTIONS ON MEDICAL IMAGING
LA English
DT Article
DE Visceral Fat Segmentation; Central Obesity Quantification; Segmentation
of Brown Fat; Brown Adipose Tissue; Abdominal Fat Quantification;
Co-Segmentation
ID VISCERAL FAT ACCUMULATION; ALL-CAUSE MORTALITY; IMAGE SEGMENTATION;
CARDIOVASCULAR-DISEASE; CT IMAGES; CANCER; ALGORITHM; TOMOGRAPHY;
OBESITY; HUMANS
AB In this paper, we investigate the automatic detection of white and brown adipose tissues using Positron Emission Tomography/Computed Tomography (PET/CT) scans, and develop methods for the quantification of these tissues at the whole-body and body-region levels. We propose a patient-specific automatic adiposity analysis system with two modules. In the first module, we detect white adipose tissue (WAT) and its two sub-types from CT scans: Visceral Adipose Tissue (VAT) and Subcutaneous Adipose Tissue (SAT). This process relies conventionally on manual or semi-automated segmentation, leading to inefficient solutions. Our novel framework addresses this challenge by proposing an unsupervised learning method to separate VAT from SAT in the abdominal region for the clinical quantification of central obesity. This step is followed by a context driven label fusion algorithm through sparse 3D Conditional Random Fields (CRF) for volumetric adiposity analysis. In the second module, we automatically detect, segment, and quantify brown adipose tissue (BAT) using PET scans because unlike WAT, BAT is metabolically active. After identifying BAT regions using PET, we perform a co-segmentation procedure utilizing asymmetric complementary information from PET and CT. Finally, we present a new probabilistic distance metric for differentiating BAT from non-BAT regions. Both modules are integrated via an automatic body-region detection unit based on one-shot learning. Experimental evaluations conducted on 151 PET/CT scans achieve state-of-the-art performances in both central obesity as well as brown adiposity quantification.
C1 [Hussein, Sarfaraz; Watane, Arjun; Bagci, Ulas] Univ Cent Florida, Ctr Res Comp Vis, Orlando, FL 32826 USA.
[Green, Aileen] Cardiol Clin Muskogee, Muskogee, OK 74401 USA.
[Reiter, David; Papadakis, Georgios Z.; Wood, Bradford; Cypess, Aaron] NIH, Bldg 10, Bethesda, MD 20892 USA.
[Chen, Xinjian] Soochow Univ, Suzhou 215006, Peoples R China.
[Osman, Medhat] St Louis Univ, Dept Nucl Med, St Louis, MO 63103 USA.
RP Bagci, U (reprint author), Univ Cent Florida, Ctr Res Comp Vis, Orlando, FL 32826 USA.
EM ulasbagci@gmail.com
OI Bagci, Ulas/0000-0001-7379-6829
NR 52
TC 0
Z9 0
U1 4
U2 4
PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC
PI PISCATAWAY
PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA
SN 0278-0062
EI 1558-254X
J9 IEEE T MED IMAGING
JI IEEE Trans. Med. Imaging
PD MAR
PY 2017
VL 36
IS 3
BP 734
EP 744
DI 10.1109/TMI.2016.2636188
PG 11
WC Computer Science, Interdisciplinary Applications; Engineering,
Biomedical; Engineering, Electrical & Electronic; Imaging Science &
Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging
SC Computer Science; Engineering; Imaging Science & Photographic
Technology; Radiology, Nuclear Medicine & Medical Imaging
GA EN6ME
UT WOS:000396117300005
PM 28114010
ER
PT J
AU Mao, L
Deng, WW
Yu, GT
Bu, LL
Liu, JF
Ma, SR
Wu, L
Kulkarni, AB
Zhang, WF
Sun, ZJ
AF Mao, Liang
Deng, Wei-Wei
Yu, Guang-Tao
Bu, Lin-Lin
Liu, Jian-Feng
Ma, Si-Rui
Wu, Lei
Kulkarni, Ashok B.
Zhang, Wen-Feng
Sun, Zhi-Jun
TI Inhibition of SRC family kinases reduces myeloid-derived suppressor
cells in head and neck cancer
SO INTERNATIONAL JOURNAL OF CANCER
LA English
DT Article
DE head and neck cancer; LYN kinase; myeloid-derived suppressor cell; SRC
family kinase
ID HPV-NEGATIVE HEAD; NUDE-MOUSE MODEL; BREAST-CANCER; MESENCHYMAL
TRANSITION; TUMOR MICROENVIRONMENT; IMMUNE SUPPRESSION; PROSTATE-CANCER;
DOWN-REGULATION; T-CELL; CARCINOMA
AB SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI+ SRT+) was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy.
C1 [Mao, Liang; Deng, Wei-Wei; Yu, Guang-Tao; Bu, Lin-Lin; Liu, Jian-Feng; Ma, Si-Rui; Wu, Lei; Sun, Zhi-Jun] Wuhan Univ, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan, Peoples R China.
[Mao, Liang; Deng, Wei-Wei; Yu, Guang-Tao; Bu, Lin-Lin; Liu, Jian-Feng; Ma, Si-Rui; Wu, Lei; Sun, Zhi-Jun] Wuhan Univ, Key Lab Oral Biomed, Minist Educ, Sch & Hosp Stomatol, Wuhan, Peoples R China.
[Bu, Lin-Lin; Zhang, Wen-Feng; Sun, Zhi-Jun] Wuhan Univ, Sch & Hosp Stomatol, Dept Oral Maxillofacial Head Neck Oncol, Wuhan, Peoples R China.
[Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA.
RP Sun, ZJ (reprint author), Wuhan Univ, Sch & Hosp Stomatol, Wuhan 430079, Peoples R China.
EM sunzj@whu.edu.cn
FU National Natural Science Foundation of China [81272963, 81472528,
81672668, 81272964, 81472529, 81672667]; program for new century
excellent talents in university, Ministry of Education of China
[NCET-13-0439]
FX This work was supported by National Natural Science Foundation of China
81272963, 81472528, 81672668 (Z.J S.), 81272964, 81472529, 81672667
(W.F.Z). Z.J.S. was supported by program for new century excellent
talents in university (NCET-13-0439), Ministry of Education of China.
NR 53
TC 0
Z9 0
U1 2
U2 2
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0020-7136
EI 1097-0215
J9 INT J CANCER
JI Int. J. Cancer
PD MAR 1
PY 2017
VL 140
IS 5
BP 1173
EP 1185
DI 10.1002/ijc.30493
PG 13
WC Oncology
SC Oncology
GA EK5OQ
UT WOS:000393976100019
PM 27798955
ER
PT J
AU Alvidrez, J
Perez-Stable, J
AF Alvidrez, Jennifer
Perez-Stable, J.
TI Diabetes Care in Latinos With Limited English Proficiency What Do
Language Concordant Clinicians Add?
SO JAMA INTERNAL MEDICINE
LA English
DT Editorial Material
C1 [Alvidrez, Jennifer; Perez-Stable, J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, 6707 Democracy Blvd,Ste 800, Bethesda, MD 20892 USA.
[Perez-Stable, J.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
RP Perez-Stable, J (reprint author), Natl Inst Minor Hlth & Hlth Dispar, NIH, 6707 Democracy Blvd,Ste 800, Bethesda, MD 20892 USA.
EM eliseo.perez-stable@nih.gov
NR 11
TC 0
Z9 0
U1 0
U2 0
PU AMER MEDICAL ASSOC
PI CHICAGO
PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA
SN 2168-6106
EI 2168-6114
J9 JAMA INTERN MED
JI JAMA Intern. Med.
PD MAR 1
PY 2017
VL 177
IS 3
BP 313
EP 315
DI 10.1001/jamainternmed.2016.8661
PG 3
WC Medicine, General & Internal
SC General & Internal Medicine
GA EN7RX
UT WOS:000396201000007
PM 28114669
ER
PT J
AU Jefferson, AA
Pearson, SD
AF Jefferson, Akilah A.
Pearson, Steven D.
TI Conflict of Interest in Seminal Hepatitis C Virus and Cholesterol
Management Guidelines
SO JAMA INTERNAL MEDICINE
LA English
DT Article
ID CLINICAL-PRACTICE GUIDELINES; AMERICAN-COLLEGE; DYSLIPIDEMIA
AB IMPORTANCE Little is known regarding whether Institute of Medicine (IOM) standards for managing conflicts of interest (COI) have been met in the development of recent important clinical guidelines.
OBJECTIVE To evaluate adherence to the IOM standards for limits on commercial COI, guideline development, and evaluation of evidence by the 2013 American College of Cardiology and American Heart Association cholesterol management guideline and the 2014 American Association for the Study of Liver Diseases and Infectious Diseases Society of America hepatitis C virus management guideline.
DESIGN, SETTING, AND PARTICIPANTS This study was a retrospective document review of the June 2014 print version of the cholesterol guideline and the final September 2015 print version of the hepatitis C virus guideline. Each guideline was assessed for adherence to the IOM standards for commercial COI published in the 2011 special report Clinical Practice Guidelines We Can Trust.
MAIN OUTCOMES AND MEASURES The IOM standards call for no commercial COI among guideline committee chairs and cochairs and for less than 50% of committee members to have commercial COI. Guideline and contemporaneous article disclosure statements were used to evaluate adherence to these standards. Each guideline was also reviewed for adherence to other IOM standards for guideline development and evidence review.
RESULTS Among the 16 cholesterol guideline committee members, 7 (44%) disclosed commercial COI, all 7 reported industry-sponsored research, and 6 (38%) also reported consultancy. Of 3 guideline chairs and cochairs, 1 (33%) disclosed commercial COI. Review of contemporaneous articles identified additional commercial COI. Among the 29 hepatitis C virus guideline committee members, 21 (72%) reported commercial COI. Eighteen (62%) disclosed industry-sponsored research, 10 (34%) served on advisory boards, 5 (17%) served on data safety monitoring boards, 3 (10%) were consultants, and 3 (10%) reported other honoraria. Of 6 guideline cochairs, 4 (67%) disclosed commercial COI. All 4 disclosed additional COI in other publications that were not listed in their guideline disclosures. Contemporaneous literature review revealed an additional cochair with commercial COI. Of the 9 IOM guideline development and evidence standards, the cholesterol guideline met 5 (56%), and the hepatitis C virus guideline met them all.
CONCLUSIONS AND RELEVANCE Neither the cholesterol guideline nor the hepatitis C virus guideline fully met the IOM standards for commercial COI management, and discordance between committee leader guideline disclosures and those in contemporaneous articles was common. Adherence to additional IOM standards for guideline development and evidence review was mixed. Adoption of consistent COI frameworks across specialty societies may help ensure that clinical guidelines are developed in a transparent and trustworthy manner.
C1 [Jefferson, Akilah A.; Pearson, Steven D.] NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Room 1C118, Bethesda, MD 20892 USA.
[Pearson, Steven D.] Inst Clin & Econ Review, Boston, MA USA.
RP Pearson, SD (reprint author), NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Room 1C118, Bethesda, MD 20892 USA.
EM pearsonsd@cc.nih.gov
FU National Institutes of Health
FX This study was supported by an intramural research grant from the
National Institutes of Health.
NR 24
TC 1
Z9 1
U1 1
U2 1
PU AMER MEDICAL ASSOC
PI CHICAGO
PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA
SN 2168-6106
EI 2168-6114
J9 JAMA INTERN MED
JI JAMA Intern. Med.
PD MAR 1
PY 2017
VL 177
IS 3
BP 352
EP 357
DI 10.1001/jamainternmed.2016.8439
PG 6
WC Medicine, General & Internal
SC General & Internal Medicine
GA EN7RX
UT WOS:000396201000017
PM 28114439
ER
PT J
AU Olfson, M
Blanco, C
Marcus, SC
AF Olfson, Mark
Blanco, Carlos
Marcus, Steven C.
TI Screening for Depression Through a Glass Darkly Reply
SO JAMA INTERNAL MEDICINE
LA English
DT Editorial Material
ID MAJOR DEPRESSION
C1 [Olfson, Mark] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY USA.
[Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA.
[Blanco, Carlos] NIDA, Bethesda, MD 20892 USA.
[Marcus, Steven C.] Univ Penn, Sch Social Practice & Policy, Philadelphia, PA 19104 USA.
RP Olfson, M (reprint author), Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Coll Phys & Surg, 1051 Riverside Dr, New York, NY 10032 USA.
EM mo49@cumc.columbia.edu
FU Agency for Healthcare Quality and Research [U19 HS02112]; National
Institute on Drug Abuse
FX This work was supported by the Agency for Healthcare Quality and
Research (grant No. U19 HS02112). Work by Dr Blanco was supported by the
National Institute on Drug Abuse; Dr Blanco had no role in the grant
from the Agency for Healthcare Quality and Research.
NR 6
TC 0
Z9 0
U1 1
U2 1
PU AMER MEDICAL ASSOC
PI CHICAGO
PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA
SN 2168-6106
EI 2168-6114
J9 JAMA INTERN MED
JI JAMA Intern. Med.
PD MAR 1
PY 2017
VL 177
IS 3
BP 447
EP 448
DI 10.1001/jamainternmed.2016.9287
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA EN7RX
UT WOS:000396201000048
PM 28264123
ER
PT J
AU Xue, YX
Deng, JH
Chen, YY
Zhang, LB
Wu, P
Huang, GD
Luo, YX
Bao, YP
Wang, YM
Shaham, Y
Shi, J
Lu, L
AF Xue, Yan-Xue
Deng, Jia-Hui
Chen, Ya-Yun
Zhang, Li-Bo
Wu, Ping
Huang, Geng-Di
Luo, Yi-Xiao
Bao, Yan-Ping
Wang, Yu-Mei
Shaham, Yavin
Shi, Jie
Lu, Lin
TI Effect of Selective Inhibition of Reactivated Nicotine-Associated
Memories With Propranolol on Nicotine Craving
SO JAMA PSYCHIATRY
LA English
DT Article
ID RETRIEVAL-EXTINCTION PROCEDURE; ADRENERGIC-RECEPTOR BLOCKADE; DRIVEN
TRAUMATIC IMAGERY; BASOLATERAL AMYGDALA; REINSTATEMENT MODEL; DEPENDENT
HUMANS; PLACE PREFERENCE; SMOKING RELAPSE; CUE REACTIVITY; DRUG RELAPSE
AB IMPORTANCE A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results.
OBJECTIVE To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke.
DESIGN, SETTING, AND PARTICIPANTS A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18-45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke.
INTERVENTION The study rats were injected noncontingently with the UCS (nicotine 0.15mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40mg, per os; Zhongnuo Pharma).
MAIN OUTCOMES AND MEASURES Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke.
RESULTS Sixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d=1.72, 95% CI, 0.63-2.77; operant seeking, d=1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d=1.46, 95% CI, 0.42-2.47; operant seeking: d=1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d=1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d=1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d=0.61, 95% CI, 0.02-1.19 and CS2, d=0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d=0.57, 95% CI, -0.02 to 1.15), and nicotine priming (CS1, d=0.82, 95% CI, 0.22-1.41 and CS2, d=0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d=0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d=0.64, 95% CI, 0.05-1.22), and nicotine priming (d=1.15, 95% CI, 0.52-1.76).
CONCLUSIONS AND RELEVANCE In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials. Copyright 2017 American Medical Association. All rights reserved.
C1 [Deng, Jia-Hui; Chen, Ya-Yun; Luo, Yi-Xiao; Wang, Yu-Mei; Lu, Lin] Peking Univ, Hosp 6, Inst Mental Hlth, 51 Huayuan Rd, Beijing 100191, Peoples R China.
[Xue, Yan-Xue; Deng, Jia-Hui; Chen, Ya-Yun; Zhang, Li-Bo; Wu, Ping; Huang, Geng-Di; Luo, Yi-Xiao; Bao, Yan-Ping; Shi, Jie; Lu, Lin] Peking Univ, Beijing Key Lab Drug Dependence, Natl Inst Drug Dependence, Beijing, Peoples R China.
[Lu, Lin] Peking Univ, Natl Clin Res Ctr Mental Disorders, Beijing, Peoples R China.
[Lu, Lin] Peking Univ, Key Lab Mental Hlth, Minist Hlth, Beijing, Peoples R China.
[Shaham, Yavin] NIDA, Intramural Res Program, NIH, Baltimore, MD USA.
[Lu, Lin] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China.
[Lu, Lin] Peking Univ, PKU IDG McGovern Inst Brain Res, Beijing, Peoples R China.
RP Lu, L (reprint author), Peking Univ, Hosp 6, Inst Mental Hlth, 51 Huayuan Rd, Beijing 100191, Peoples R China.
EM linlu@bjmu.edu.cn
FU National Basic Research Program of China [2015CB856400, 2015CB559200,
2015CB553503]; Natural Science Foundation of China [31230033, 91432303,
31300930, 81221002, 81201032]; Ten Thousand Youth Talents; Intramural
Research Program of the National Insitutue on Drug Abuse
FX This research was conducted with support from grants 2015CB856400,
2015CB559200, and 2015CB553503 from the National Basic Research Program
of China and grants 31230033, 91432303, 31300930, 81221002, and 81201032
from the Natural Science Foundation of China. This research also
received support from Ten Thousand Youth Talents and the Intramural
Research Program of the National Insitutue on Drug Abuse.
NR 72
TC 0
Z9 0
U1 0
U2 0
PU AMER MEDICAL ASSOC
PI CHICAGO
PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA
SN 2168-622X
EI 2168-6238
J9 JAMA PSYCHIAT
JI JAMA Psychiatry
PD MAR 1
PY 2017
VL 74
IS 3
BP 224
EP 232
DI 10.1001/jamapsychiatry.2016.3907
PG 9
WC Psychiatry
SC Psychiatry
GA EN5LP
UT WOS:000396047300005
PM 28146250
ER
PT J
AU Levine, AG
Hemmers, S
Baptista, AP
Schizas, M
Faire, MB
Moltedo, B
Konopacki, C
Schmidt-Supprian, M
Germain, RN
Treuting, PM
Rudensky, AY
AF Levine, Andrew G.
Hemmers, Saskia
Baptista, Antonio P.
Schizas, Michail
Faire, Mehlika B.
Moltedo, Bruno
Konopacki, Catherine
Schmidt-Supprian, Marc
Germain, Ronald N.
Treuting, Piper M.
Rudensky, Alexander Y.
TI Suppression of lethal autoimmunity by regulatory T cells with a single
TCR specificity
SO JOURNAL OF EXPERIMENTAL MEDICINE
LA English
DT Article
ID SELF-TOLERANCE; IN-VIVO; THYMUS; HOMEOSTASIS; GENERATION; DISEASE;
LINEAGE; LIMITS
AB The regulatory T cell (T reg cell) T cell receptor (TCR) repertoire is highly diverse and skewed toward recognition of self-antigens. TCR expression by T reg cells is continuously required for maintenance of immune tolerance and for a major part of their characteristic gene expression signature; however, it remains unknown to what degree diverse TCR -mediated interactions with cognate self-antigens are required for these processes. In this study, by experimentally switching the T reg cell TCR repertoire to a single T reg cell TCR, we demonstrate that T reg cell function and gene expression can be partially uncoupled from TCR diversity. An induced switch of the T reg cell TCR repertoire to a random repertoire also preserved, albeit to a limited degree, the ability to suppress lymphadenopathy and T helper cell type 2 activation. At the same time, these perturbations of the T reg cell TCR repertoire led to marked immune cell activation, tissue inflammation, and an ultimately severe autoimmunity, indicating the importance of diversity and specificity for optimal T reg cell function.
C1 [Levine, Andrew G.; Hemmers, Saskia; Schizas, Michail; Faire, Mehlika B.; Moltedo, Bruno; Konopacki, Catherine; Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Program Immunol, Ludwig Ctr, New York, NY 10065 USA.
[Baptista, Antonio P.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Schmidt-Supprian, Marc] Tech Univ Munich, Klinikum Rechts Isar, Hematol & Oncol, D-80333 Munich, Germany.
[Treuting, Piper M.] Univ Washington, Sch Med, Dept Comparat Med, Seattle, WA 98195 USA.
RP Rudensky, AY (reprint author), Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Program Immunol, Ludwig Ctr, New York, NY 10065 USA.
EM rudenska@mskcc.org
RI Schmidt-Supprian, Marc/F-5893-2011
OI Schmidt-Supprian, Marc/0000-0002-8543-6166
FU National Institutes of Health (NIH) Medical Scientist Training Program
grant [T32GM07739]; Frank Lappin Horsfall Jr. Student Fellowship; NIH
grant [R37AI034206]; Ludwig Center at Memorial Sloan-Kettering Cancer
Center; Hilton-Ludwig Cancer Prevention Initiative of the Conrad N.
Hilton Foundation; Ludwig Cancer Research; NIH/National Cancer Institute
Cancer Center Support [P30 CA008748]; Intramural Research Program of the
National Institute of Allergy and Infectious Diseases, NIH
FX This work was supported by a National Institutes of Health (NIH) Medical
Scientist Training Program grant (T32GM07739) to the Weill
Cornell/Rockefeller/SloanKettering Tri-Institutional MD-PhD Program
(A.G. Levine), the Frank Lappin Horsfall Jr. Student Fellowship (A.G.
Levine), an NIH grant (R37AI034206 to A.Y. Rudensky), the Ludwig Center
at Memorial Sloan-Kettering Cancer Center, the Hilton-Ludwig Cancer
Prevention Initiative of the Conrad N. Hilton Foundation and Ludwig
Cancer Research (A.Y. Rudensky), and the NIH/National Cancer Institute
Cancer Center Support Grant (P30 CA008748). This research was also
supported in part by the Intramural Research Program of the National
Institute of Allergy and Infectious Diseases, NIH (R.N. Germain and A.P.
Baptista). A.Y. Rudensky is an investigator with the Howard Hughes
Medical Institute.
NR 30
TC 0
Z9 0
U1 1
U2 1
PU ROCKEFELLER UNIV PRESS
PI NEW YORK
PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA
SN 0022-1007
EI 1540-9538
J9 J EXP MED
JI J. Exp. Med.
PD MAR
PY 2017
VL 214
IS 3
BP 609
EP 622
DI 10.1084/jem.20161318
PG 14
WC Immunology; Medicine, Research & Experimental
SC Immunology; Research & Experimental Medicine
GA EN2GS
UT WOS:000395828600004
PM 28130403
ER
PT J
AU Volpi, S
Yamazaki, Y
Brauer, PM
van Rooijen, E
Hayashida, A
Slavotinek, A
Kuehn, HS
Di Rocco, M
Rivolta, C
Bortolomai, I
Du, LK
Felgentreff, K
de Bruin, LO
Hayashida, K
Freedman, G
Marcovecchio, GE
Capuder, K
Rath, P
Luche, N
Hagedorn, EJ
Buoncompagni, A
Royer-Bertrand, B
Giliani, S
Poliani, PL
Imberti, L
Dobbs, K
Poulain, FE
Martini, A
Manis, J
Linhardt, RJ
Bosticardo, M
Rosenzweig, SD
Lee, H
Puck, JM
Zuniga-Pflucker, JC
Zon, L
Park, PW
Superti-Furga, A
Notarangelo, LD
AF Volpi, Stefano
Yamazaki, Yasuhiro
Brauer, Patrick M.
van Rooijen, Ellen
Hayashida, Atsuko
Slavotinek, Anne
Kuehn, Hye Sun
Di Rocco, Maja
Rivolta, Carlo
Bortolomai, Ileana
Du, Likun
Felgentreff, Kerstin
de Bruin, Lisa Ott
Hayashida, Kazutaka
Freedman, George
Marcovecchio, Genni Enza
Capuder, Kelly
Rath, Prisni
Luche, Nicole
Hagedorn, Elliott J.
Buoncompagni, Antonella
Royer-Bertrand, Beryl
Giliani, Silvia
Poliani, Pietro Luigi
Imberti, Luisa
Dobbs, Kerry
Poulain, Fabienne E.
Martini, Alberto
Manis, John
Linhardt, Robert J.
Bosticardo, Marita
Rosenzweig, Sergio Damian
Lee, Hane
Puck, Jennifer M.
Zuniga-Pflucker, Juan Carlos
Zon, Leonard
Park, Pyong Woo
Superti-Furga, Andrea
Notarangelo, Luigi D.
TI EXTL3 mutations cause skeletal dysplasia, immune deficiency, and
developmental delay
SO JOURNAL OF EXPERIMENTAL MEDICINE
LA English
DT Article
ID SEVERE COMBINED IMMUNODEFICIENCY; EMBRYONIC STEM-CELLS; SHORT-LIMBED
DWARFISM; HEPARAN-SULFATE; HEMATOPOIETIC STEM; TUMOR SUPPRESSORS;
B-LYMPHOPOIESIS; HSPG SYNTHESIS; IN-VITRO; DIFFERENTIATION
AB We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2 : green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.
C1 [Volpi, Stefano; Buoncompagni, Antonella; Martini, Alberto] Ist Giannina Gaslini, Dept Pediat, Unita Operat Pediat 2, I-16148 Genoa, Italy.
[Di Rocco, Maja] Ist Giannina Gaslini, Dept Pediat, Unit Rare Dis, I-16148 Genoa, Italy.
[Yamazaki, Yasuhiro; Dobbs, Kerry; Notarangelo, Luigi D.] NIAID, Lab Host Def, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Kuehn, Hye Sun; Rosenzweig, Sergio Damian] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA.
[Brauer, Patrick M.; Zuniga-Pflucker, Juan Carlos] Univ Toronto, Dept Immunol, Sunnybrook Res Inst, Toronto, ON M5S, Canada.
[van Rooijen, Ellen; Hagedorn, Elliott J.; Zon, Leonard] Harvard Med Sch, Stem Cell Program, Boston Childrens Hosp, Boston, MA 02115 USA.
[Hayashida, Atsuko; Hayashida, Kazutaka; Park, Pyong Woo] Harvard Med Sch, Div Resp Dis, Boston Childrens Hosp, Boston, MA 02115 USA.
[Du, Likun; Felgentreff, Kerstin; de Bruin, Lisa Ott; Capuder, Kelly; Luche, Nicole] Harvard Med Sch, Div Immunol, Boston Childrens Hosp, Boston, MA 02115 USA.
[Manis, John] Harvard Med Sch, Dept Lab Med, Boston Childrens Hosp, Boston, MA 02115 USA.
[Slavotinek, Anne] Univ Calif San Francisco, Dept Pediat, Div Genet, San Francisco, CA 94143 USA.
[Freedman, George; Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA.
[Rivolta, Carlo; Royer-Bertrand, Beryl] Univ Lausanne, Univ Lausanne Hosp, Dept Computat Biol, Unit Med Genet, CH-1015 Lausanne, Switzerland.
[Royer-Bertrand, Beryl; Superti-Furga, Andrea] Univ Lausanne, Univ Lausanne Hosp, Div Genet Med, CH-1015 Lausanne, Switzerland.
[Bortolomai, Ileana; Marcovecchio, Genni Enza; Bosticardo, Marita] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, Ist Ric & Cura Carattere Sci, I-20132 Milan, Italy.
[Rath, Prisni] Tata Consultancy Serv Innovat Labs, Hyderabad, Telangana, India.
[Giliani, Silvia] Univ Brescia, A Nocivelli Inst Mol Med, I-25123 Brescia, Italy.
[Poliani, Pietro Luigi] Univ Brescia, Dept Mol & Translat Med, I-25123 Brescia, Italy.
[Imberti, Luisa] Spedali Civil Brescia, Ctr Ric Ematooncol AIL, I-25123 Brescia, Italy.
[Poulain, Fabienne E.] Univ South Carolina, Dept Biol Sci, Columbia, SC 29208 USA.
[Linhardt, Robert J.] Rensselaer Polytech Inst, Dept Chem & Chem Biol, Troy, NY 12180 USA.
[Lee, Hane] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA.
[Bortolomai, Ileana] CNR, Ist Ric Genet & Biomed, Milan Unit, I-20138 Milan, Italy.
RP Notarangelo, LD (reprint author), NIAID, Lab Host Def, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Superti-Furga, A (reprint author), Univ Lausanne, Univ Lausanne Hosp, Div Genet Med, CH-1015 Lausanne, Switzerland.
EM asuperti@unil.ch; luigi.notarangelo2@nih.gov
OI Rivolta, Carlo/0000-0002-0733-9950
FU Telethon Network of Genetic Biobanks [GTB12001]; Intramural Research
Program of the National Institute of Allergy and Infectious Diseases
(NIAID), National Institutes of Health (NIH); NIAID, NIH [5R21AI113459];
Italian Ministry of Health [PE-2011-02347329]; Swiss National Science
Foundation [156260]; National Institute of Neurological Disorders and
Stroke, NIH [R00NS083714]; Faculte de Biologie et Medecine of the
University of Lausanne; Krembil Foundation; Canada Research Chair in
Developmental Immunology
FX We thank Drs. Steven E. Brenner, Rajgopal Srinivasan, Uma Sunderam, and
the UCLA Clinical Genomics Center Genomic Data Board for reviewing and
interpreting WES data and Maurizio Fazio, Julie Perlin, and Anne
Robertson for assistance with zebrafish experiments. The Cell Line and
DNA Biobank from Patients Affected by Genetic Diseases (Istituto G.
Gaslini; Telethon Network of Genetic Biobanks; project no. GTB12001)
provided specimens.; This work was supported by the Intramural Research
Program of the National Institute of Allergy and Infectious Diseases
(NIAID), National Institutes of Health (NIH) and by a grant from NIAID,
NIH (5R21AI113459 to L. D. Notarangelo), a grant from the Italian
Ministry of Health (PE-2011-02347329 to S. Giliani and L. D.
Notarangelo), a grant from the Swiss National Science Foundation (156260
to C. Rivolta), and a grant from the National Institute of Neurological
Disorders and Stroke, NIH (R00NS083714 to F. E. Poulain). A.
Superti-Furga is supported by the Faculte de Biologie et Medecine of the
University of Lausanne. J.C.Zuniga-Pflucker is supported by the Krembil
Foundation and by a Canada Research Chair in Developmental Immunology.
NR 55
TC 0
Z9 0
U1 4
U2 4
PU ROCKEFELLER UNIV PRESS
PI NEW YORK
PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA
SN 0022-1007
EI 1540-9538
J9 J EXP MED
JI J. Exp. Med.
PD MAR
PY 2017
VL 214
IS 3
BP 623
EP 637
DI 10.1084/jem.20161525
PG 15
WC Immunology; Medicine, Research & Experimental
SC Immunology; Research & Experimental Medicine
GA EN2GS
UT WOS:000395828600005
PM 28148688
ER
PT J
AU Lyons, JJ
Liu, Y
Ma, CA
Yu, X
O'Connell, MP
Lawrence, MG
Zhang, Y
Karpe, K
Zhao, M
Siegel, AM
Stone, KD
Nelson, C
Jones, N
DiMaggio, T
Darnell, DN
Mendoza-Caamal, E
Orozco, L
Hughes, JD
McElwee, J
Hohman, RJ
Frischmeyer-Guerrerio, PA
Rothenberg, ME
Freeman, AF
Holland, SM
Milner, JD
AF Lyons, J. J.
Liu, Y.
Ma, C. A.
Yu, X.
O'Connell, M. P.
Lawrence, M. G.
Zhang, Y.
Karpe, K.
Zhao, M.
Siegel, A. M.
Stone, K. D.
Nelson, C.
Jones, N.
DiMaggio, T.
Darnell, D. N.
Mendoza-Caamal, E.
Orozco, L.
Hughes, J. D.
McElwee, J.
Hohman, R. J.
Frischmeyer-Guerrerio, P. A.
Rothenberg, M. E.
Freeman, A. F.
Holland, S. M.
Milner, J. D.
TI ERBIN deficiency links STAT3 and TGF-beta pathway defects with atopy in
humans
SO JOURNAL OF EXPERIMENTAL MEDICINE
LA English
DT Article
ID GROWTH-FACTOR-BETA; REGULATORY T-CELLS; EOSINOPHILIC ESOPHAGITIS;
NEGATIVE REGULATION; CONNECTIVE-TISSUE; IN-VIVO; MUTATIONS; RECEPTOR;
GATA-3; EXPRESSION
AB Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-beta activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-beta signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3(mut)) or a loss-of-function mutation in ERBB2IP (ERBB2IP(mut)) have evidence of deregulated TGF-beta signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3-ERBIN-SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-beta. In turn, cell-intrinsic deregulation of TGF-beta signaling is associated with increased functional IL-4R alpha expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4R alpha/GATA3 axis in vitro. These findings link increased TGF-beta pathway activation in ERBB2IP(mut) and STAT3(mut) patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.
C1 [Lyons, J. J.; Liu, Y.; Ma, C. A.; Yu, X.; O'Connell, M. P.; Zhang, Y.; Karpe, K.; Siegel, A. M.; Stone, K. D.; Nelson, C.; DiMaggio, T.; Milner, J. D.] NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Zhao, M.; Hohman, R. J.] NIAID, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Darnell, D. N.; Freeman, A. F.; Holland, S. M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Frischmeyer-Guerrerio, P. A.] NIAID, Food Allergy Res Unit, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Lawrence, M. G.] Univ Virginia, Dept Med, Div Asthma Allergy & Immunol, Charlottesville, VA 22903 USA.
[Jones, N.] Leidos Biomed Res Inc, Clin Res Directorate CRMP, NCI Campus Frederick, Frederick, MD 21702 USA.
[Mendoza-Caamal, E.; Orozco, L.] Natl Inst Genom Med, Mexico City 14610, DF, Mexico.
[Hughes, J. D.; McElwee, J.] Merck & Co Inc, Merck Res Labs, Boston, MA 02115 USA.
[Rothenberg, M. E.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Allergy & Immunol, Cincinnati, OH 45229 USA.
RP Milner, JD (reprint author), NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
EM jdmilner@niaid.nih.gov
FU Intramural Research Programs of the National Institutes of Health (NIH),
National Cancer Institute (NCI), Center for Cancer Research; NIAID; NCI,
NIH [HHSN261200800001E]
FX This research was supported in part by the Intramural Research Programs
of the National Institutes of Health (NIH), National Cancer Institute
(NCI), Center for Cancer Research, and of the NIAID. This project has
been funded in whole or in part with federal funds from the NCI, NIH
under contract HHSN261200800001E. The content of this publication does
not necessarily reflect the views or policies of the Department of
Health and Human Services nor does mention of trade names, commercial
products, or organizations imply endorsement by the U.S. Government.
NR 45
TC 1
Z9 1
U1 0
U2 0
PU ROCKEFELLER UNIV PRESS
PI NEW YORK
PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA
SN 0022-1007
EI 1540-9538
J9 J EXP MED
JI J. Exp. Med.
PD MAR
PY 2017
VL 214
IS 3
BP 669
EP 680
DI 10.1084/jem.20161435
PG 12
WC Immunology; Medicine, Research & Experimental
SC Immunology; Research & Experimental Medicine
GA EN2GS
UT WOS:000395828600008
PM 28126831
ER
PT J
AU Gansler, DA
Huey, ED
Pan, JJ
Wasserman, E
Grafman, JH
AF Gansler, David A.
Huey, Edward D.
Pan, Jessica J.
Wasserman, Eric
Grafman, Jordan H.
TI Assessing the dysexecutive syndrome in dementia
SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
LA English
DT Article
ID CONFIRMATORY FACTOR-ANALYSIS; HUMAN CEREBRAL-CORTEX; FRONTOTEMPORAL
DEMENTIA; EXECUTIVE FUNCTION; DIAGNOSTIC-CRITERIA; ALZHEIMERS-DISEASE;
PROGRESSIVE APHASIA; BEHAVIOR; SCALE; DEGENERATION
AB Objective We compared performance on tests of dysexecutive behaviour (DB) and executive function (EF) in patients with behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and corticobasal syndrome (CBS).
Methods Patients diagnosed with bvFTD (n=124), PPA (n=34) and CBS (n=85) were recruited. EF was measured with the Delis-Kaplan Executive Function System (DKEFS: performance based), and DB was measured with the Frontal Systems Behavior Scale (FrSBe: caregiver-report based). Confirmatory factor analysis characterised the relationship between EF and DB, binary logistic regression evaluated the incremental diagnostic utility of the measures and neuroimaging data from 110 patients identified neural correlates.
Results EF was lowest and DB was highest in bvFTD participants. EF and DB were distinct but related (r=-0.48). Measures correctly classified 89% of bvFTD from CBS patients and 93% of bvFTD from PPA patients -30% and 13% above base rates (59%, 80%), respectively. All modalities were useful in identifying CBS and PPA, whereas DB alone was useful for identifying bvFTD. EF was uniquely associated with caudal left dorsolateral prefrontal and lateral temporo-parietal cortices. DB was uniquely associated with the cingulate (R>L), right subcallosal and right anterior frontal cortex. EF and DB were associated with the rostral dorsolateral prefrontal cortex bilaterally.
Conclusions EF and DB measures displayed criterion and construct validity, had incremental utility at low DB levels (CBS and PPA) and were associated with overlapping and distinct neural correlates. EF and DB procedures can conjointly provide useful diagnostic and descriptive information in identifying and ruling out the dysexecutive syndrome.
C1 [Gansler, David A.; Pan, Jessica J.] Suffolk Univ, Dept Psychol, 41 Temple St, Boston, MA 02114 USA.
[Huey, Edward D.] Columbia Univ, Dept Psychiat, New York, NY USA.
[Huey, Edward D.] Columbia Univ, Dept Neurol, New York, NY USA.
[Wasserman, Eric] NINDS, Behav Neurol Unit, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
[Grafman, Jordan H.] Northwestern Univ, Sch Med, Dept Phys Med & Rehabil, Chicago, IL USA.
[Grafman, Jordan H.] Northwestern Univ, Sch Med, Dept Psychiat & Behav Sci, Cognit Neurol, Chicago, IL 60611 USA.
[Grafman, Jordan H.] Rehabil Inst Chicago, Cognit Neurosci Lab, Chicago, IL 60611 USA.
RP Gansler, DA (reprint author), Suffolk Univ, Dept Psychol, 41 Temple St, Boston, MA 02114 USA.
EM dgansler@suffolk.edu
FU NINDS
FX This study was supported by NINDS intramural funding to JHG.
NR 42
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 MAR
PY 2017
VL 88
IS 3
BP 254
EP 261
DI 10.1136/jnnp-2016-313576
PG 8
WC Clinical Neurology; Psychiatry; Surgery
SC Neurosciences & Neurology; Psychiatry; Surgery
GA EL3ED
UT WOS:000394501500012
PM 27466358
ER
PT J
AU Kahin, SA
Wright, DS
Pejavara, A
Kim, SA
AF Kahin, Sahra A.
Wright, Demia S.
Pejavara, Anu
Kim, Sonia A.
TI State-Level Farmers Market Activities: A Review of CDC-Funded State
Public Health Actions That Support Farmers Markets
SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE
LA English
DT Review
DE Centers for Disease Control and Prevention; farmers markets; fruits and
vegetables; state health departments; state-level
ID FOOD DESERTS; FRUIT; COMMUNITIES; PROGRAM
AB Context: Introducing farmers markets to underserved areas, or supporting existing farmers markets, can increase access and availability of fruits and vegetables and encourage healthy eating. Since 2003, the Centers for Disease Control and Prevention (CDC)'s Division of Nutrition, Physical Activity, and Obesity (DNPAO) has provided guidance and funding to state health departments (SHDs) to support the implementation of interventions, including activities around farmers markets, to address healthy eating, and improve the access to and availability of fruits and vegetables at state and community levels.
Objective: For this project, we identified state-level farmers market activities completed with CDC's DNPAO funding from 2003 to 2013. State-level was defined as actions taken by the state health department that influence or support farmers market work across the state.
Design and Participants: We completed an analysis of SHD farmers market activities of 3 DNPAO cooperative agreements from 2003 to 2013: State Nutrition and Physical Activity Programs to Prevent Obesity and Other Chronic Diseases; Nutrition, Physical Activity and Obesity Program; and Communities Putting Prevention to Work. To identify state farmers market activities, data sources for each cooperative agreement were searched using the key words "farm," "market," " produce market," and "produce stand." State data with at least one state-level farmers market action present were then coded for the presence of itemized activities.
Results: Across all cooperative agreements, the most common activities identified through analysis included the following: working on existing markets and nutrition assistance benefit programs, supporting community action, and providing training and technical assistance. Common partners were nutrition assistance benefit program offices and state or regional Department of Agriculture or agricultural extension offices.
Implications for Policy & Practice: Common farmers market practices and evidence-based activities, such as nutrition assistance benefits programs and land-use policies, can be adopted as methods for farmers market policy and practice work.
Conclusion: The activities identified in this study can inform future planning at the state and federal levels on environment, policy, and systems approaches that improve the food environment through farmers markets.
C1 [Kahin, Sahra A.; Pejavara, Anu; Kim, Sonia A.] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, 4770 Buford Hwy,NE,MS F-77, Atlanta, GA 30341 USA.
[Wright, Demia S.] NIEHS, Worker Training Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.
RP Kahin, SA (reprint author), Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, 4770 Buford Hwy,NE,MS F-77, Atlanta, GA 30341 USA.
EM xfz9@cdc.gov
FU CDC
FX All authors were full-time CDC staff during the writing of this article.
The CDC funds authors' salaries to do this work.
NR 22
TC 0
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U1 4
U2 4
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1078-4659
EI 1550-5022
J9 J PUBLIC HEALTH MAN
JI J. Public Health Manag. Pract.
PD MAR-APR
PY 2017
VL 23
IS 2
BP 96
EP 103
DI 10.1097/PHH.0000000000000412
PG 8
WC Public, Environmental & Occupational Health
SC Public, Environmental & Occupational Health
GA EK1WM
UT WOS:000393716500007
PM 27798521
ER
PT J
AU Ashley, PJ
Freemer, M
Garbe, P
Rowson, D
AF Ashley, Peter J.
Freemer, Michelle
Garbe, Paul
Rowson, David
TI Coordinated Federal Actions Are Needed to Reduce Racial and Ethnic
Disparities in Childhood Asthma
SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE
LA English
DT Editorial Material
C1 [Ashley, Peter J.] US Dept Housing & Urban Dev, 451 7th St,SW,Room 8236, Washington, DC 20410 USA.
[Freemer, Michelle] NHLBI, Bldg 10, Bethesda, MD 20892 USA.
[Garbe, Paul] Ctr Dis Control & Prevent, Atlanta, GA USA.
[Rowson, David] US EPA, Washington, DC 20460 USA.
RP Ashley, PJ (reprint author), US Dept Housing & Urban Dev, 451 7th St,SW,Room 8236, Washington, DC 20410 USA.
EM Peter.J.Ashley@hud.gov
NR 4
TC 0
Z9 0
U1 0
U2 0
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1078-4659
EI 1550-5022
J9 J PUBLIC HEALTH MAN
JI J. Public Health Manag. Pract.
PD MAR-APR
PY 2017
VL 23
IS 2
BP 207
EP 209
DI 10.1097/PHH.0000000000000541
PG 3
WC Public, Environmental & Occupational Health
SC Public, Environmental & Occupational Health
GA EK1WM
UT WOS:000393716500025
PM 28121772
ER
PT J
AU Bennett, PH
Magliano, DJ
Alberti, KG
Zimmet, P
AF Bennett, Peter H.
Magliano, Dianna J.
Alberti, K. George
Zimmet, Paul
TI Challenges of monitoring global diabetes prevalence Reply
SO LANCET DIABETES & ENDOCRINOLOGY
LA English
DT Editorial Material
ID MELLITUS
C1 [Bennett, Peter H.] NIH, Phoenix, AZ 85014 USA.
[Magliano, Dianna J.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia.
[Alberti, K. George] Imperial Coll, St Marys Campus, London, England.
[Zimmet, Paul] Monash Univ, Dept Med, Melbourne, Vic, Australia.
RP Bennett, PH (reprint author), NIH, Phoenix, AZ 85014 USA.
EM pbennett@nih.gov
NR 5
TC 0
Z9 0
U1 0
U2 0
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 2213-8587
J9 LANCET DIABETES ENDO
JI Lancet Diabetes Endocrinol.
PD MAR
PY 2017
VL 5
IS 3
BP 162
EP 162
PG 1
WC Endocrinology & Metabolism
SC Endocrinology & Metabolism
GA EN9RZ
UT WOS:000396338600008
PM 28235491
ER
PT J
AU Chowell, G
Viboud, C
AF Chowell, Gerardo
Viboud, Cecile
TI Quantifying the fitness of antiviral-resistant influenza strains
SO LANCET INFECTIOUS DISEASES
LA English
DT Editorial Material
ID NEURAMINIDASE INHIBITORS; SURVEILLANCE
C1 [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA.
[Chowell, Gerardo; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA.
RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA.; Chowell, G (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA.
EM gchowell@gsu.edu
NR 12
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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 MAR
PY 2017
VL 17
IS 3
BP 250
EP 251
DI 10.1016/S1473-3099(16)30522-9
PG 2
WC Infectious Diseases
SC Infectious Diseases
GA EL6KX
UT WOS:000394732600009
PM 27914854
ER
PT J
AU Quaglio, G
Corbetta, M
Karapiperis, T
Amunts, K
Koroshetz, W
Yamamori, T
Draghia-Akli, R
AF Quaglio, Gianluca
Corbetta, Maurizio
Karapiperis, Theodoros
Amunts, Katrin
Koroshetz, Walter
Yamamori, Tetsuo
Draghia-Akli, Ruxandra
TI Understanding the brain through large, multidisciplinary research
initiatives
SO LANCET NEUROLOGY
LA English
DT Letter
ID NEUROSCIENCE
C1 [Quaglio, Gianluca; Karapiperis, Theodoros] European Parliament, European Parliamentary Res Serv, Sci Foresight Unit Sci & Technol Opt Assessment, Brussels, Belgium.
[Corbetta, Maurizio] Univ Padua, Padua, Italy.
[Corbetta, Maurizio] Washington Univ, Sch Med, St Louis, MO USA.
[Amunts, Katrin] Inst Neurosci & Med, INM 1, Julich Res Ctr, Julich, Germany.
[Amunts, Katrin] Univ Hosp Dusseldorf, Cecile & Oskar Vogt Brain Res, Dusseldorf, Germany.
Human Brain Project, Sci & Infrastruct Board, Vienna, Austria.
[Koroshetz, Walter] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
[Koroshetz, Walter] Natl Inst Hlth Brain Initiat, Bethesda, MD USA.
[Yamamori, Tetsuo] Riken Brain Sci Inst, Wako, Saitama, Japan.
[Yamamori, Tetsuo] Brain MINDS Project, Wako, Saitama, Japan.
[Draghia-Akli, Ruxandra] European Commiss, Directorate General Res & Innovat, Brussels, Belgium.
RP Quaglio, G (reprint author), European Parliament, European Parliamentary Res Serv, Sci Foresight Unit Sci & Technol Opt Assessment, Brussels, Belgium.
EM gianluca.quaglio@europarl.europa.eu
FU European Commission
FX KA reports grants from the European Commission. All other authors
declare no competing interests. The views expressed in this letter are
the sole responsibility of the authors and do not necessarily reflect
the views of their affiliated organisations.
NR 7
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PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 1474-4422
EI 1474-4465
J9 LANCET NEUROL
JI Lancet Neurol.
PD MAR
PY 2017
VL 16
IS 3
BP 183
EP 184
PG 2
WC Clinical Neurology
SC Neurosciences & Neurology
GA EK4ZC
UT WOS:000393935700014
PM 28229889
ER
PT J
AU Seymour, L
Bogaerts, J
Perrone, A
Ford, R
Schwartz, LH
Mandrekar, S
Lin, NU
Litiere, S
Dancey, J
Chen, A
Hodi, FS
Therasse, P
Hoekstra, OS
Shankar, LK
Wolchok, JD
Ballinger, M
Caramella, C
de Vries, EGE
AF Seymour, Lesley
Bogaerts, Jan
Perrone, Andrea
Ford, Robert
Schwartz, Lawrence H.
Mandrekar, Sumithra
Lin, Nancy U.
Litiere, Saskia
Dancey, Janet
Chen, Alice
Hodi, F. Stephen
Therasse, Patrick
Hoekstra, Otto S.
Shankar, Lalitha K.
Wolchok, Jedd D.
Ballinger, Marcus
Caramella, Caroline
de Vries, Elisabeth G. E.
CA RECIST Working Grp
TI iRECIST: guidelines for response criteria for use in trials testing
immunotherapeutics
SO LANCET ONCOLOGY
LA English
DT Review
ID CELL LUNG-CANCER; IMMUNE-RELATED RESPONSE; SOLID TUMORS; UNTREATED
MELANOMA; DOUBLE-BLIND; NIVOLUMAB; IPILIMUMAB; PEMBROLIZUMAB;
CARBOPLATIN; COMBINATION
AB Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.
C1 [Seymour, Lesley; Dancey, Janet] Queens Univ, Canadian Canc Trials Grp, Kingston, ON K7L 3N6, Canada.
[Bogaerts, Jan; Litiere, Saskia] EORTC Headquarters, Brussels, Belgium.
[Perrone, Andrea] Merck & Co Inc, Translat Med, Kenilworth, NJ USA.
[Ford, Robert] Clin Trials Imaging Consulting LLC, Belle Mead, NJ USA.
[Schwartz, Lawrence H.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA.
[Schwartz, Lawrence H.] New York Presbyterian Hosp, New York, NY USA.
[Mandrekar, Sumithra] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA.
[Lin, Nancy U.; Hodi, F. Stephen] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA.
[Chen, Alice] NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA.
[Therasse, Patrick] Inst Rech Int Servier, Paris, France.
[Hoekstra, Otto S.] Vrije Univ Amsterdam, Dept Radiol & Nucl Med, Med Ctr, Amsterdam, Netherlands.
[Shankar, Lalitha K.] NCI, Diagnost Imaging Branch, Bethesda, MD 20892 USA.
[Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA.
[Ballinger, Marcus] Weill Cornell Med & Grad Coll, New York, NY USA.
[Ballinger, Marcus] Ludwig Inst Canc Res, New York, NY USA.
[Ballinger, Marcus] Genentech Inc, 460 Point San Bruno Blvd, San Francisco, CA 94080 USA.
[Caramella, Caroline] Gustav Roussy Canc Campus, Dept Radiol, Villejuif, France.
[de Vries, Elisabeth G. E.] Univ Med Ctr Groningen, Dept Med Oncol, Groningen, Netherlands.
RP Seymour, L (reprint author), Queens Univ, Canadian Canc Trials Grp, Kingston, ON K7L 3N6, Canada.
EM lseymour@ctg.queensu.ca
FU Canadian Cancer Society Research Institute [021039]; EORTC Cancer
Research Fund; National Cancer Institute [5U10-CA11488-45]
FX AC and LKS are employees of the National Institutes of Health/National
Cancer Institute. This publication was supported by the Canadian Cancer
Society Research Institute (grant #021039), the EORTC Cancer Research
Fund, and the National Cancer Institute (grant number 5U10-CA11488-45).
The contents of this paper were presented in part at the EORTC-NCI-AACR
2016 Meeting (Munich, Germany; Nov 29-Dec 2, 2016). We gratefully
acknowledge the thoughtful participation of the following in this
initiative: Patricia Keegan (US Food and Drug Administration, Silver
Spring, MD, USA); Francesco Pignatti (European Medicine Agency, London,
UK); Wendy Hayes (Bristol-Myers Squibb, Princeton, NJ, USA); Eric Rubin
(Merck & Co, Kenilworth, NJ, USA). We also received written comments
from Darragh Halpenny, Jean-Yves Blay, Florian Lordick, Silke Gillessen,
Hirokazu Watanabe, Jose Pablo Maroto Rey, Pietro Quaglino, Howard
Kaufman, Denis Lacombe, Corneel Coens, Catherine Fortpied, Jessica
Menis, Francisco Vera-Badillo, Jean Powers, Michail Ignatiadis, Eric
Gauthier, Michael O'Neal, Caroline Malhaire, Laure Fournier, and Glen
Laird. We thank Anouk Funke for her assistance with this manuscript.
NR 35
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PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 1470-2045
EI 1474-5488
J9 LANCET ONCOL
JI Lancet Oncol.
PD MAR
PY 2017
VL 18
IS 3
BP E143
EP E152
PG 10
WC Oncology
SC Oncology
GA EN9UH
UT WOS:000396344600018
PM 28271869
ER
PT J
AU Ng, C
Goodenow, M
Greenshaw, A
Upshall, P
Lam, R
AF Ng, Chee
Goodenow, Maureen
Greenshaw, Andrew
Upshall, Phil
Lam, Raymond
TI APEC digital hub for mental health
SO LANCET PSYCHIATRY
LA English
DT Editorial Material
C1 [Ng, Chee] Univ Melbourne, Dept Psychiat, Richmond, Vic 3121, Australia.
[Ng, Chee] Univ Melbourne, Asia Australia Mental Hlth, Richmond, Vic 3121, Australia.
[Goodenow, Maureen] NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA.
Univ Alberta, Dept Psychiat, Edmonton, AB, Canada.
[Upshall, Phil] Mood Disorders Soc Canada, Guelph, ON, Canada.
[Lam, Raymond] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada.
RP Ng, C (reprint author), Univ Melbourne, Dept Psychiat, Richmond, Vic 3121, Australia.; Ng, C (reprint author), Univ Melbourne, Asia Australia Mental Hlth, Richmond, Vic 3121, Australia.
NR 1
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Z9 0
U1 0
U2 0
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 2215-0374
J9 LANCET PSYCHIAT
JI Lancet Psychiatry
PD MAR
PY 2017
VL 4
IS 3
BP E3
EP E4
PG 3
WC Psychiatry
SC Psychiatry
GA EN9VD
UT WOS:000396346800003
PM 28236959
ER
PT J
AU Goldberg, RB
Temprosa, M
Mele, L
Orchard, T
Mather, K
Bray, G
Horton, E
Kitabchi, A
Krakoff, J
Marcovina, S
Perreault, L
White, N
AF Goldberg, Ronald B.
Temprosa, Marinella
Mele, Lisa
Orchard, Trevor
Mather, Kieren
Bray, George
Horton, Edward
Kitabchi, Abbas
Krakoff, Jonathan
Marcovina, Santica
Perreault, Leigh
White, Neil
CA Diabet Prevention Program Res Grp
TI Change in adiponectin explains most of the change in HDL particles
induced by lifestyle intervention but not metformin treatment in the
diabetes prevention program (Vol 65, pg 764, 2016)
SO METABOLISM-CLINICAL AND EXPERIMENTAL
LA English
DT Correction
C1 [Goldberg, Ronald B.] Univ Miami, Diabet Res Inst, 1450 NW 10th Ave,Suite 2054, Miami, FL 33136 USA.
[Temprosa, Marinella; Mele, Lisa] George Washington Univ, Biostat Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA.
[Orchard, Trevor] Univ Pittsburgh, 3512 Fifth Ave, Pittsburgh, PA 15213 USA.
[Mather, Kieren] Indiana Univ, Dept Med, 541 Clin Dr CL 365, Indianapolis, IN 46202 USA.
[Bray, George] Louisiana State Univ, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA.
[Horton, Edward] Joslin Diabet Ctr, Sect Clin Behav & Outcomes Res, One Joslin Pl, Boston, MA 02215 USA.
[Horton, Edward] Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02115 USA.
[Kitabchi, Abbas] Univ Tennessee, Div Endocrinol, Hlth Sci Ctr, 920 Madison Ave Suite 300A, Memphis, TN 38163 USA.
[Krakoff, Jonathan] NIDDK, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA.
[Marcovina, Santica] Univ Washington, Northwest Lipid Res Labs, 401 Queen Anne Ave, North Seattle, WA 98109 USA.
[Perreault, Leigh] Univ Colorado, Div Endocrinol Metab & Diabet, Dept Med, Anschutz Med Campus,12801 E 17th Ave, Aurora, CO 80045 USA.
[White, Neil] Washington Univ, Sch Med, 660 South Euclid Ave, St Louis, MO 63110 USA.
RP Goldberg, RB (reprint author), George Washington Univ, Biostat Ctr, Diabet Prevent Program Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA.
EM dppmail@bsc.gwu.edu
NR 1
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PI PHILADELPHIA
PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA
SN 0026-0495
EI 1532-8600
J9 METABOLISM
JI Metab.-Clin. Exp.
PD MAR
PY 2017
VL 68
BP 184
EP 186
DI 10.1016/j.metabol.2016.11.007
PG 3
WC Endocrinology & Metabolism
SC Endocrinology & Metabolism
GA EK4WF
UT WOS:000393927600018
PM 28065437
ER
PT J
AU Zarate, CA
Machado-Vieira, R
AF Zarate, C. A., Jr.
Machado-Vieira, R.
TI Ketamine: translating mechanistic discoveries into the next generation
of glutamate modulators for mood disorders
SO MOLECULAR PSYCHIATRY
LA English
DT Editorial Material
ID RAPID-ACTING ANTIDEPRESSANTS; RESISTANT BIPOLAR DEPRESSION;
GLYCOGEN-SYNTHASE KINASE-3; D-ASPARTATE ANTAGONIST; AMPA RECEPTOR; NMDA
ANTAGONISTS; DOUBLE-BLIND; INHIBITION; TRIAL; METABOLITES
C1 [Zarate, C. A., Jr.; Machado-Vieira, R.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.
RP Zarate, CA (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.
EM zaratec@mail.nih.gov
FU Intramural Research Program at the National Institute of Mental Health;
National Institutes of Health (IRP-NIMH-NIH) [ZIA MH002857]; NARSAD
Independent Investigator Award; Brain and Behavior Mood Disorders
Research Award
FX Funding for this work was supported by the Intramural Research Program
at the National Institute of Mental Health, National Institutes of
Health (IRP-NIMH-NIH; ZIA MH002857), by a NARSAD Independent
Investigator Award to Dr Zarate Jr, and by a Brain and Behavior Mood
Disorders Research Award to Dr Zarate Jr. We thank the 7SE research unit
and staff for their support.
NR 38
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U1 2
U2 2
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1359-4184
EI 1476-5578
J9 MOL PSYCHIATR
JI Mol. Psychiatr.
PD MAR
PY 2017
VL 22
IS 3
BP 324
EP 327
DI 10.1038/mp.2016.249
PG 4
WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry
SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry
GA EL3RQ
UT WOS:000394537100001
PM 28070122
ER
PT J
AU Trampush, JW
Yang, MLZ
Yu, J
Knowles, E
Davies, G
Liewald, DC
Starr, JM
Djurovic, S
Melle, I
Sundet, K
Christoforou, A
Reinvang, I
DeRosse, P
Lundervold, AJ
Steen, VM
Espeseth, T
Raikkonen, K
Widen, E
Palotie, A
Eriksson, JG
Giegling, I
Konte, B
Roussos, P
Giakoumaki, S
Burdick, KE
Payton, A
Ollier, W
Horan, M
Chiba-Falek, O
Attix, DK
Need, AC
Cirulli, ET
Voineskos, AN
Stefanis, NC
Avramopoulos, D
Hatzimanolis, A
Arking, DE
Smyrnis, N
Bilder, RM
Freimer, NA
Cannon, TD
London, E
Poldrack, RA
Sabb, FW
Congdon, E
Conley, ED
Scult, MA
Dickinson, D
Straub, RE
Donohoe, G
Morris, D
Corvin, A
Gill, M
Hariri, AR
Weinberger, DR
Pendleton, N
Bitsios, P
Rujescu, D
Lahti, J
Le Hellard, S
Keller, MC
Andreassen, OA
Deary, IJ
Glahn, DC
Malhotra, AK
Lencz, T
AF Trampush, J. W.
Yang, M. L. Z.
Yu, J.
Knowles, E.
Davies, G.
Liewald, D. C.
Starr, J. M.
Djurovic, S.
Melle, I.
Sundet, K.
Christoforou, A.
Reinvang, I.
DeRosse, P.
Lundervold, A. J.
Steen, V. M.
Espeseth, T.
Raikkonen, K.
Widen, E.
Palotie, A.
Eriksson, J. G.
Giegling, I.
Konte, B.
Roussos, P.
Giakoumaki, S.
Burdick, K. E.
Payton, A.
Ollier, W.
Horan, M.
Chiba-Falek, O.
Attix, D. K.
Need, A. C.
Cirulli, E. T.
Voineskos, A. N.
Stefanis, N. C.
Avramopoulos, D.
Hatzimanolis, A.
Arking, D. E.
Smyrnis, N.
Bilder, R. M.
Freimer, N. A.
Cannon, T. D.
London, E.
Poldrack, R. A.
Sabb, F. W.
Congdon, E.
Conley, E. D.
Scult, M. A.
Dickinson, D.
Straub, R. E.
Donohoe, G.
Morris, D.
Corvin, A.
Gill, M.
Hariri, A. R.
Weinberger, D. R.
Pendleton, N.
Bitsios, P.
Rujescu, D.
Lahti, J.
Le Hellard, S.
Keller, M. C.
Andreassen, O. A.
Deary, I. J.
Glahn, D. C.
Malhotra, A. K.
Lencz, T.
TI GWAS meta-analysis reveals novel loci and genetic correlates for general
cognitive function: a report from the COGENT consortium
SO MOLECULAR PSYCHIATRY
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; SCOTTISH MENTAL SURVEY; UK BIOBANK N=112151;
EDUCATIONAL-ATTAINMENT; INTELLECTUAL DISABILITY; DEVELOPMENTAL DELAY;
EXECUTIVE FUNCTION; HUMAN INTELLIGENCE; PROVIDES INSIGHTS; ABILITY
AB The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (similar to 8M single-nucleotide polymorphisms (SNP) with minor allele frequency >= 1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5x10(-8)). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e. = 0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.
C1 [Trampush, J. W.; Yu, J.; DeRosse, P.; Lencz, T.] Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA.
[Yang, M. L. Z.] Inst Mental Hlth, Singapore, Singapore.
[Yu, J.; DeRosse, P.; Malhotra, A. K.; Lencz, T.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA.
[Knowles, E.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA.
[Davies, G.; Starr, J. M.; Deary, I. J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.
[Davies, G.; Liewald, D. C.; Deary, I. J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland.
[Starr, J. M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland.
[Djurovic, S.] Univ Bergen, Oslo Univ Hosp, Dept Med Genet, Oslo, Norway.
[Djurovic, S.; Melle, I.; Christoforou, A.; Le Hellard, S.] Univ Bergen, KG Jebsen Ctr Psychosis Res, NORMENT, Bergen, Norway.
[Melle, I.; Sundet, K.; Espeseth, T.] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway.
[Sundet, K.; Espeseth, T.] Univ Oslo, Dept Psychol, Oslo, Norway.
[Christoforou, A.] Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway.
[Lundervold, A. J.] Univ Bergen, Dept Biol & Med Psychol, Bergen, Norway.
[Raikkonen, K.] Univ Helsinki, Inst Behav Sci, Helsinki, Finland.
[Widen, E.; Palotie, A.] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.
[Palotie, A.] Wellcome Trust Genome Campus, Wellcome Trust Sanger Inst, Cambridge, England.
[Palotie, A.] Univ Helsinki, Dept Med Genet, Helsinki, Finland.
[Palotie, A.] Univ Cent Hosp, Helsinki, Finland.
[Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland.
[Eriksson, J. G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.
[Eriksson, J. G.] Univ Helsinki, Unit Gen Practice, Cent Hosp, Helsinki, Finland.
[Eriksson, J. G.] Folkhalsan Res Ctr, Helsinki, Finland.
[Giegling, I.; Konte, B.; Rujescu, D.] Martin Luther Univ Halle Wittenberg, Dept Psychiat, Halle, Germany.
[Roussos, P.; Burdick, K. E.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.
[Roussos, P.; Burdick, K. E.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
[Roussos, P.; Burdick, K. E.] Icahn Sch Med Mt Sinai, Inst Multiscale Biol, New York, NY 10029 USA.
[Roussos, P.] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN 3, Bronx, NY USA.
[Giakoumaki, S.] Univ Crete, Dept Psychol, Rethimnon, Greece.
[Payton, A.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester Ctr Audiol & Deafness, Manchester, Lancs, England.
[Payton, A.] Univ Manchester, Sch Biol Sci, Div Evolut & Genom Sci, Manchester, Lancs, England.
[Ollier, W.] Univ Manchester, Inst Populat Hlth, Ctr Integrated Genom Med Res, Manchester, Lancs, England.
[Horan, M.] Univ Manchester, Inst Brain Behav & Mental Hlth, Manchester Med Sch, Manchester, Lancs, England.
[Chiba-Falek, O.; Attix, D. K.] Duke Univ, Med Ctr, Div Neurol, Bryan Alzheimers Dis Res Ctr, Durham, NC 27710 USA.
[Chiba-Falek, O.; Attix, D. K.] Duke Univ, Med Ctr, Ctr Genom & Computat Biol, Durham, NC USA.
[Attix, D. K.] Duke Univ, Med Ctr, Dept Neurol Psychiat & Behav Sci, Div Med Psychol, Durham, NC USA.
[Need, A. C.] Imperial Coll, Dept Med, Div Brain Sci, London, England.
[Cirulli, E. T.] Duke Univ, Sch Med, Ctr Appl Genom & Precis Med, Durham, NC USA.
[Voineskos, A. N.] Univ Toronto, Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Inst, Toronto, ON, Canada.
[Stefanis, N. C.; Hatzimanolis, A.] Univ Athens, Sch Med, Eginit Hosp, Dept Psychiat, Athens, Greece.
[Stefanis, N. C.; Hatzimanolis, A.] Univ Mental Hlth Res Inst, Athens, Greece.
[Stefanis, N. C.; Hatzimanolis, A.] Theodor Theohari Cozzika Fdn, Neurobiol Res Inst, Athens, Greece.
[Avramopoulos, D.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.
[Avramopoulos, D.; Arking, D. E.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.
[Avramopoulos, D.; Arking, D. E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA.
[Bilder, R. M.; Freimer, N. A.; London, E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA.
[Cannon, T. D.] Yale Univ, Dept Psychol, New Haven, CT USA.
[Poldrack, R. A.] Stanford Univ, Dept Psychol, Palo Alto, CA 94304 USA.
[Sabb, F. W.] Univ Oregon, Robert & Beverly Lewis Ctr Neuroimaging, Eugene, OR 97403 USA.
[Conley, E. D.] 23andMe Inc, Mountain View, CA USA.
[Scult, M. A.; Hariri, A. R.] Duke Univ, Neurogenet Lab, Dept Psychol & Neurosci, Durham, NC USA.
[Congdon, E.; Dickinson, D.] NIMH, Clin & Translat Neurosci Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.
[Straub, R. E.; Weinberger, D. R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Med Campus, Baltimore, MD USA.
[Donohoe, G.] Natl Univ Ireland, Dept Psychol, Galway, Ireland.
[Morris, D.; Corvin, A.; Gill, M.] Trinity Coll Dublin, Trinity Coll Inst Neurosci, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin, Ireland.
[Bitsios, P.] Univ Crete, Fac Med, Dept Psychiat & Behav Sci, Iraklion, Greece.
[Rujescu, D.; Lahti, J.] Univ Helsinki, Helsinki Collegium Adv Studies, Helsinki, Finland.
[Keller, M. C.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA.
[Andreassen, O. A.] Univ Oslo, Inst Clin Med, Oslo, Norway.
[Malhotra, A. K.; Lencz, T.] Hofstra Northwell Sch Med, Dept Psychiat, Hempstead, NY USA.
RP Lencz, T (reprint author), Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA.
EM tlencz@northwell.edu
OI Sundet, Kjetil/0000-0003-2850-3673; Payton, Antony/0000-0003-0335-152X
FU National Institutes of Health [R01MH079800, P50 MH080173, R01 MH080912,
K23 MH077807, K01 MH085812, R01 DA033369, R01 AG049789]; Research
Council of Norway; South-East Norway Health Authority; KG Jebsen
Foundation; Research Council of Norway [154313/V50, 177458/V50]; Bergen
Research Foundation; University of Bergen; Research Council of Norway
(FUGE, Psykisk Helse); Helse Vest RHF and Dr Einar Martens Fund; Academy
of Finland; Finnish Diabetes Research Society; Folkhalsan Research
Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and
Ane Gyllenberg Foundation; University of Helsinki; Ministry of
Education; Ahokas Foundation; Emil Aaltonen Foundation; Disconnected
Mind project; UK Biotechnology and Biological Sciences Research Council
(BBSRC) [BB/F019394/1]; Medical Research Council; Biotechnology and
Biological Sciences Research Council [MR/K026992/1]; CAMH Foundation;
Canadian Institutes of Health Research; National Institute of Mental
Health of the National Institutes of Health [K01MH098126]; Ellison
Medical Foundation New Scholar award [AG-NS-0441-08]; NIH [UL1DE019580,
PL1MH083271, RL1MH083269, RL1DA024853, PL1NS062410]; National Institute
of Mental Health research [R01MH085018, R01MH092515]; National Science
Foundation Graduate Research Fellowship; Science Foundation Ireland
[12/IP/1670, 12/IP/1359, 08/IN. 1/B1916]
FX This work has been supported by grants from the National Institutes of
Health (R01MH079800 and P50 MH080173 to AKM; R01 MH080912 to DCG; K23
MH077807 to KEB; K01 MH085812 to MCK). Data collection for the TOP
cohort was supported by the Research Council of Norway, South-East
Norway Health Authority and KG Jebsen Foundation. The NCNG study was
supported by Research Council of Norway Grants 154313/V50 and
177458/V50. The NCNG GWAS was financed by grants from the Bergen
Research Foundation, the University of Bergen, the Research Council of
Norway (FUGE, Psykisk Helse), Helse Vest RHF and Dr Einar Martens Fund.
The Helsinki Birth Cohort Study has been supported by grants from the
Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan
Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet,
Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of
Education, Ahokas Foundation, Emil Aaltonen Foundation. For the LBC1936
cohort, phenotype collection was supported by The Disconnected Mind
project. Genotyping was funded by the UK Biotechnology and Biological
Sciences Research Council (BBSRC grant no. BB/F019394/1). The work was
undertaken by The University of Edinburgh Centre for Cognitive Ageing
and Cognitive Epidemiology, part of the cross council Lifelong Health
and Wellbeing Initiative, which is funded by the Medical Research
Council and the Biotechnology and Biological Sciences Research Council
(MR/K026992/1). The CAMH work was supported by the CAMH Foundation and
the Canadian Institutes of Health Research. The Duke Cognition Cohort
(DCC) acknowledges K Linney, JM McEvoy, P Hunt, V Dixon, T Pennuto, K
Cornett, D Swilling, L Phillips, M Silver, J Covington, N Walley, J
Dawson, H Onabanjo, P Nicoletti, A Wagoner, J Elmore, L Bevan, J Hunkin
and R Wilson for recruitment and testing of subjects. DCC also
acknowledges the Ellison Medical Foundation New Scholar award
AG-NS-0441-08 for partial funding of this study as well as the National
Institute of Mental Health of the National Institutes of Health under
award number K01MH098126. The UCLA Consortium for Neuropsychiatric
Phenomics (CNP) study acknowledges the following sources of funding from
the NIH: Grants UL1DE019580 and PL1MH083271 (RMB), RL1MH083269 (TDC),
RL1DA024853 (EL) and PL1NS062410. The ASPIS study was supported by
National Institute of Mental Health research grants R01MH085018 and
R01MH092515 to Dr Dimitrios Avramopoulos. Support for the Duke
Neurogenetics Study was provided the National Institutes of Health (R01
DA033369 and R01 AG049789 to ARH) and by a National Science Foundation
Graduate Research Fellowship to MAS. Recruitment, genotyping and
analysis of the TCD healthy control samples were supported by Science
Foundation Ireland (grants 12/IP/1670, 12/IP/1359 and 08/IN. 1/B1916).
NR 73
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U1 3
U2 3
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1359-4184
EI 1476-5578
J9 MOL PSYCHIATR
JI Mol. Psychiatr.
PD MAR
PY 2017
VL 22
IS 3
BP 336
EP 345
DI 10.1038/mp.2016.244
PG 10
WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry
SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry
GA EL3RQ
UT WOS:000394537100003
PM 28093568
ER
PT J
AU Haidar, G
Zerbe, CS
Cheng, M
Zelazny, AM
Holland, SM
Sheridan, KR
AF Haidar, Ghady
Zerbe, Christa S.
Cheng, Michelle
Zelazny, Adrian M.
Holland, Steven M.
Sheridan, Kathleen R.
TI Phellinus species: An emerging cause of refractory fungal infections in
patients with X-linked chronic granulomatous disease
SO MYCOSES
LA English
DT Review
DE basidiomycota; chronic granulomatous disease; internal transcribed
spacer; Phellinus
ID INVASIVE ASPERGILLOSIS; TROPICALIS; IDENTIFICATION; OSTEOMYELITIS
AB Aspergillus spp. are a leading cause of mortality in chronic granulomatous disease (CGD), but other fungi have emerged in the era of mould prophylaxis. Of these, Phellinus spp. are an under-recognised cause of invasive fungal infections (IFIs) in CGD, and data on their presentation and management are scarce. We present a patient with CGD who developed disseminated IFI involving the lungs and brain. Surgical specimens grew a basidiomycete which was disregarded as a contaminant. After three months of progressive disease despite antifungals, he was diagnosed with Phellinus tropicalis by internal transcribed spacer (ITS) sequencing. He improved with amphotericin B and isavuconazole but required haematopoietic stem cell transplantation (HSCT). We review the literature on Phellinus infections in CGD and conclude that: (i) these infections emerge on mould-active prophylaxis and are indolent; (ii) they typically cause locally destructive disease but can disseminate; (iii) diagnosis is delayed and requires molecular methods; (iv) amphotericin B is most active in vitro; and (v) treatment is protracted and requires surgery and possibly HSCT. In conclusion, Phellinus spp. are emerging pathogens in CGD. Every effort should be made to establish the diagnosis of non-Aspergillus IFIs in patients with CGD by sending tissue specimens for molecular diagnostics.
C1 [Haidar, Ghady; Sheridan, Kathleen R.] Univ Pittsburgh, Dept Med, Div Infect Dis, Med Ctr, Pittsburgh, PA USA.
[Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Cheng, Michelle] Univ Pittsburgh, Med Ctr, Dept Med, Pittsburgh, PA USA.
[Zelazny, Adrian M.] NIH, Dept Lab Med, Microbiol Serv, Bldg 10, Bethesda, MD 20892 USA.
[Cheng, Michelle] Univ Calif Davis, Dept Dermatol, Davis, CA 95616 USA.
RP Sheridan, KR (reprint author), Univ Pittsburgh, Med Ctr, Div Infect Dis, Pittsburgh, PA 15260 USA.
EM sheridank@upmc.edu
NR 19
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U1 1
U2 1
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0933-7407
EI 1439-0507
J9 MYCOSES
JI Mycoses
PD MAR
PY 2017
VL 60
IS 3
BP 155
EP 160
DI 10.1111/myc.12573
PG 6
WC Dermatology; Mycology
SC Dermatology; Mycology
GA EK5DM
UT WOS:000393947100002
PM 27781311
ER
PT J
AU Lerch, JP
van der Kouwe, AJW
Raznahan, A
Pans, T
Johansen-Berg, H
Miller, KL
Smith, SM
Fischl, B
Sotiropoulos, SN
AF Lerch, Jason P.
van der Kouwe, Andre J. W.
Raznahan, Armin
Pans, Tomas
Johansen-Berg, Heidi
Miller, Karla L.
Smith, Stephen M.
Fischl, Bruce
Sotiropoulos, Stamatios N.
TI Studying neuroanatomy using MRI
SO NATURE NEUROSCIENCE
LA English
DT Review
ID VOXEL-BASED MORPHOMETRY; HUMAN CONNECTOME PROJECT; BRAIN WHITE-MATTER;
NEURITE ORIENTATION DISPERSION; AXON DIAMETER DISTRIBUTION; HUMAN
CORTICAL DEVELOPMENT; DIFFUSION-WEIGHTED MRI; PULSED-FIELD GRADIENT;
HUMAN CEREBRAL-CORTEX; IN-VIVO
AB The study of neuroanatomy using imaging enables key insights into how our brains function, are shaped by genes and environment, and change with development, aging and disease. Developments in MRI acquisition, image processing and data modeling have been key to these advances. However, MRI provides an indirect measurement of the biological signals we aim to investigate. Thus, artifacts and key questions of correct interpretation can confound the readouts provided by anatomical MRI. In this review we provide an overview of the methods for measuring macro- and mesoscopic structure and for inferring microstructural properties; we also describe key artifacts and confounds that can lead to incorrect conclusions. Ultimately, we believe that, although methods need to improve and caution is required in interpretation, structural MRI continues to have great promise in furthering our understanding of how the brain works.
C1 [Lerch, Jason P.] Hosp Sick Children, Program Neurosci & Mental Hlth, Toronto, ON, Canada.
[Lerch, Jason P.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada.
[van der Kouwe, Andre J. W.; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Res, Charlestown, MA USA.
[van der Kouwe, Andre J. W.; Fischl, Bruce] Harvard Med Sch, Charlestown, MA USA.
[van der Kouwe, Andre J. W.; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA.
[van der Kouwe, Andre J. W.; Fischl, Bruce] Harvard Med Sch, Boston, MA USA.
[Raznahan, Armin] NIMH, Dev Neurogen Unit, Child Psychiat Branch, Bethesda, MD 20892 USA.
[Pans, Tomas] Rotman Res Inst, Toronto, ON, Canada.
[Pans, Tomas] Univ Toronto, Dept Psychol, Toronto, ON, Canada.
[Pans, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON, Canada.
[Pans, Tomas] Child Mind Inst, Ctr Developing Brain, New York, NY USA.
[Johansen-Berg, Heidi; Miller, Karla L.; Smith, Stephen M.; Sotiropoulos, Stamatios N.] Univ Oxford, Oxford Ctr Funct MRI Brain FMRIB, Oxford, MS USA.
[Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
[Sotiropoulos, Stamatios N.] Univ Nottingham, Sch Med, Sir Peter Mansfield Imaging Ctr, Nottingham NG7 2RD, England.
RP Lerch, JP (reprint author), Hosp Sick Children, Program Neurosci & Mental Hlth, Toronto, ON, Canada.; Lerch, JP (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON, Canada.
EM jason.lerch@utoronto.ca
FU Ontario Brain Institutes' POND grant
FX We thank C. Hammill for his assistance in the preparation of Figures 2
and 3, which contain data from The Ontario Brain Institutes' POND grant
(to J.P.L.), and we thank L. Wald (Massachusetts General Hospital) for
providing the images in Figure 6. Figure 1 contains data from
R0IMH085772-01A1 (to T.P.).
NR 176
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U1 8
U2 8
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 MAR
PY 2017
VL 20
IS 3
BP 314
EP 326
DI 10.1038/nn.4501
PG 13
WC Neurosciences
SC Neurosciences & Neurology
GA EL9DU
UT WOS:000394920400005
PM 28230838
ER
PT J
AU Edwards, NJ
Tejeda, HA
Pignatelli, M
Zhang, SL
McDevitt, RA
Wu, J
Bass, CE
Bettler, B
Morales, M
Bonci, A
AF Edwards, Nicholas J.
Tejeda, Hugo A.
Pignatelli, Marco
Zhang, Shiliang
McDevitt, Ross A.
Wu, Jocelyn
Bass, Caroline E.
Bettler, Bernhard
Morales, Marisela
Bonci, Antonello
TI Circuit specificity in the inhibitory architecture of the VTA regulates
cocaine-induced behavior
SO NATURE NEUROSCIENCE
LA English
DT Article
ID VENTRAL TEGMENTAL AREA; MIDBRAIN DOPAMINE NEURONS; RAT SUBSTANTIA-NIGRA;
GABA(B) RECEPTORS; SYNAPTIC INPUTS; REWARD; LOCALIZATION; ACTIVATION;
NUCLEUS; TRANSMISSION
AB Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABA(B) receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABA(B) receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.
C1 [Edwards, Nicholas J.; Tejeda, Hugo A.; Pignatelli, Marco; Zhang, Shiliang; McDevitt, Ross A.; Wu, Jocelyn; Morales, Marisela; Bonci, Antonello] NIDA, Intramural Res Program, US Natl Inst Hlth, Baltimore, MD 21224 USA.
[Bass, Caroline E.] Univ Buffalo, Dept Pharmacol & Toxicol, Buffalo, NY USA.
[Bettler, Bernhard] Univ Basel, Pharmazentrum, Dept Biomed, Basel, Switzerland.
[Bonci, Antonello] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA.
[Bonci, Antonello] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.
RP Bonci, A (reprint author), NIDA, Intramural Res Program, US Natl Inst Hlth, Baltimore, MD 21224 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.
EM antonello.bonci@nih.gov
FU Intramural Research Program at the National Institute on Drug Abuse
FX We thank members of the Bonci lab for insightful discussions and careful
reading of the manuscript. We thank the NIDA Histology Core for help
with in situ hybridization experiments, B. Sadacca for help with
statistical analysis, K. Deisseroth (Stanford University) for the
generation of optogenetic constructs, and B. Lowell (Beth Israel
Deaconess Medical Center) for Dyn-Cre and VGAT-Cre transgenic mice. This
work was supported by the Intramural Research Program at the National
Institute on Drug Abuse.
NR 50
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U1 5
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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 MAR
PY 2017
VL 20
IS 3
BP 438
EP 448
DI 10.1038/nn.4482
PG 11
WC Neurosciences
SC Neurosciences & Neurology
GA EL9DU
UT WOS:000394920400021
PM 28114294
ER
PT J
AU Duffy, AG
Greten, TF
AF Duffy, Austin G.
Greten, Tim F.
TI Regorafenib as second-line therapy in hepatocellular carcinoma
SO NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY
LA English
DT Editorial Material
ID SORAFENIB
AB Drug development in hepatocellular carcinoma had essentially stalled since 2008 when sorafenib was established as the modest standard of care. Now, a positive result in a phase III study evaluating regorafenib challenges us to weigh its clinical significance as well as its real-world benefits and potential harms.
C1 [Duffy, Austin G.; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA.
RP Greten, TF (reprint author), NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA.
EM tim.greten@nih.gov
NR 9
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U1 0
U2 0
PU NATURE PUBLISHING GROUP
PI NEW YORK
PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA
SN 1759-5045
EI 1759-5053
J9 NAT REV GASTRO HEPAT
JI Nat. Rev. Gastroenterol. Hepatol.
PD MAR
PY 2017
VL 14
IS 3
BP 141
EP 142
DI 10.1038/nrgastro.2017.7
PG 2
WC Gastroenterology & Hepatology
SC Gastroenterology & Hepatology
GA EN1YA
UT WOS:000395805200003
PM 28174418
ER
PT J
AU Prescott, JB
Marzi, A
Safronetz, D
Robertson, SJ
Feldmann, H
Best, SM
AF Prescott, Joseph B.
Marzi, Andrea
Safronetz, David
Robertson, Shelly J.
Feldmann, Heinz
Best, Sonja M.
TI Immunobiology of Ebola and Lassa virus infections
SO NATURE REVIEWS IMMUNOLOGY
LA English
DT Review
ID HUMAN DENDRITIC CELLS; DOUBLE-STRANDED-RNA; HEMORRHAGIC-FEVER; VP35
PROTEIN; WEST-AFRICA; NONHUMAN-PRIMATES; IMMUNE-RESPONSES; SIERRA-LEONE;
INTERFERON ANTAGONISM; NEUTRALIZING ANTIBODY
AB Two of the most important contemporary emerging viruses that affect human health in Africa are Ebola virus (EBOV) and Lassa virus (LASV). The 2013-2016 West African outbreak of EBOV was responsible for more than 11,000 deaths, primarily in Guinea, Sierra Leone and Liberia. LASV is constantly emerging in these and surrounding West African countries, with an estimate of more than 500,000 cases of Lassa fever, and approximately 5,000 deaths, annually. Both EBOV and LASV are zoonotic, and human infection often results in a severe haemorrhagic fever in both cases. However, the contribution of specific immune responses to disease differs between EBOV and LASV. This Review examines innate and adaptive immune responses to these viruses with the goal of delineating responses that are associated with protective versus pathogenic outcomes.
C1 [Prescott, Joseph B.; Marzi, Andrea; Robertson, Shelly J.; Feldmann, Heinz; Best, Sonja M.] NIAID, Virol Lab, Rocky Mt Labs, NIH, 903 S Fourth St, Hamilton, MT 59840 USA.
[Safronetz, David] Publ Hlth Agcy Canada, Zoonot Dis & Special Pathogens, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada.
[Safronetz, David; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, 745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada.
RP Feldmann, H; Best, SM (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, 903 S Fourth St, Hamilton, MT 59840 USA.; Feldmann, H (reprint author), Univ Manitoba, Dept Med Microbiol, 745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada.
EM feldmannh@niaid.nih.gov; sbest@niaid.nih.gov
FU Division of Intramural Research, National Institutes of Allergy and
Infectious Diseases, US National Institutes of Health
FX This work was supported by the Division of Intramural Research, National
Institutes of Allergy and Infectious Diseases, US National Institutes of
Health.
NR 140
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PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1474-1733
EI 1474-1741
J9 NAT REV IMMUNOL
JI Nat. Rev. Immunol.
PD MAR
PY 2017
VL 17
IS 3
BP 195
EP 207
DI 10.1038/nri.2016.138
PG 13
WC Immunology
SC Immunology
GA EN2GI
UT WOS:000395827600004
PM 28111475
ER
PT J
AU Chirenje, ZM
Gundacker, HM
Richardson, B
Rabe, L
Gaffoor, Z
Nair, G
Mirembe, BG
Piper, JM
Hillier, S
Marrazzo, J
AF Chirenje, Zvavahera Mike
Gundacker, Holly M.
Richardson, Barbra
Rabe, Lorna
Gaffoor, Zakir
Nair, Gonasagrie (Lulu)
Mirembe, Brenda Gati
Piper, Jeanna M.
Hillier, Sharon
Marrazzo, Jeanne
TI Risk Factors for Incidence of Sexually Transmitted Infections Among
Women in a Human Immunodeficiency Virus Chemoprevention Trial: VOICE
(MTN-003)
SO SEXUALLY TRANSMITTED DISEASES
LA English
DT Article
ID PELVIC-INFLAMMATORY-DISEASE; CHLAMYDIA-TRACHOMATIS; HIV-INFECTION;
SOUTH-AFRICA; SERVICES; HEALTH; TRANSMISSION; GONORRHEA
AB Background: In sub-Saharan Africa, there are limited data on the incidence of sexually transmitted infections (STIs) among women, largely because routine screening for asymptomatic infection is not performed. We conducted a secondary analysis to measure STI incidence rates and determine risk factors for new STI acquisition among women enrolled in the VOICE trial.
Methods: We analyzed data from 4843 women screened for chlamydia, gonorrhoea, syphilis, and trichomonas infection at baseline, annually, at interim visits when clinically indicated and at their study termination visit. Risk reduction counseling and condoms were provided throughout the trial.
Results: Twenty percent of evaluable participants had one or more curable STIs at baseline. Over 5660 person-years at risk (PYAR) of observation, incidence rates were 13.8%(95% confidence interval [CI], 12.7-14.8) PYAR for chlamydia, 3.5% (95% CI, 3.0-4.1) PYAR gonorrhea, 0.1% (95% CI, 0.6-1.1) PYAR syphilis, and 6.6% (95% CI, 5.8-7.2) PYAR trichomoniasis. South African sites had the highest incidence of chlamydia. The Uganda site had the highest incidence of gonorrhoea and syphilis, and Zimbabwe the lowest incidence overall. The majority of these cases were diagnosed at a routine scheduled testing visit. In multivariate analysis, positive baseline STI, younger than 25 years, being unmarried, and some alcohol consumption were associated with acquiring a new STI.
Conclusions: We observed high rates of STIs during follow up among women in the VOICE study. Women living in human immunodeficiency virus endemic countries should be screened for common STIs.
C1 [Chirenje, Zvavahera Mike] Univ Zimbabwe Univ Calif San Francisco Res Progra, Harare, Zimbabwe.
[Gundacker, Holly M.] Fred Hutchinson Canc Res Ctr, SCHARP, 1124 Columbia St, Seattle, WA 98104 USA.
[Richardson, Barbra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
[Rabe, Lorna; Hillier, Sharon] Magee Womens Res Inst, Pittsburgh, PA USA.
[Gaffoor, Zakir] MRC, HIV Prevent Res Unit, Durban, South Africa.
[Nair, Gonasagrie (Lulu)] Univ KwaZulu Natal, CAPRISA, Durban, South Africa.
[Mirembe, Brenda Gati] MU JHU Res Collaborat, Kampala, Uganda.
[Piper, Jeanna M.] NIAID, Div Aids, US Natl Inst Hlth, Bethesda, MD 20892 USA.
[Hillier, Sharon] Univ Pittsburgh, Pittsburgh, PA USA.
[Marrazzo, Jeanne] Univ Alabama Birmingham, Birmingham, AL USA.
RP Chirenje, ZM (reprint author), UZ UCSF Collaborat Res Programme, 15 Philips Rd, Harare, Zimbabwe.
EM chirenje@uz-ucsf.co.zw
FU National Institute of Allergy and Infectious Diseases [UM1AI068633,
UM1AI068615, UM1AI106707]; Eunice Kennedy Shriver National Institute of
Child Health and Human Development; National Institute of Mental Health
of the U.S. National Institutes of Health
FX The VOICE study (VOICE ClinicalTrials.gov number, NCT00705679) was
supported by MTN. MTN is funded by the National Institute of Allergy and
Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with
co-funding from the Eunice Kennedy Shriver National Institute of Child
Health and Human Development and the National Institute of Mental
Health, all components of the U.S. National Institutes of Health. The
content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institutes of
Health.
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PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0148-5717
EI 1537-4521
J9 SEX TRANSM DIS
JI Sex. Transm. Dis.
PD MAR
PY 2017
VL 44
IS 3
BP 135
EP 140
DI 10.1097/OLQ.0000000000000568
PG 6
WC Infectious Diseases
SC Infectious Diseases
GA EL1CX
UT WOS:000394359200001
PM 28178109
ER
PT J
AU Altan-Bonnett, N
AF Altan-Bonnett, Nihal
TI Lipid Tales of Viral Replication and Transmission
SO TRENDS IN CELL BIOLOGY
LA English
DT Review
ID RNA VIRUS-REPLICATION; HOST RETICULON PROTEINS; 4-KINASE III-BETA;
PHOSPHATIDYLINOSITOL 4-PHOSPHATE; PLASMA-MEMBRANE; IN-VITRO;
EXTRACELLULAR VESICLES; CELLULAR MEMBRANES; PHOSPHATIDYLSERINE;
AUTOPHAGY
AB Positive-strand RNA viruses are the largest group of RNA viruses on Earth and cellular membranes are critical for all aspects of their life cycle, from entry and replication to exit. In particular, membranes serve as platforms for replication and as carriers to transmit these viruses to other cells, the latter either as an envelope surrounding a single virus or as the vesicle containing a population of viruses. Notably, many animal and human viruses appear to induce and exploit phosphatidylinositol 4-phosphate/cholesterol-enriched membranes for replication, whereas many plant and insect-vectored animal viruses utilize phosphatidylethanolamine/cholesterol-enriched membranes for the same purpose; and phosphatidylserine-enriched membrane carriers are widely used by both single and populations of viruses for transmission. Here I discuss the implications for viral pathogenesis and therapeutic development of this remarkable convergence on specific membrane lipid blueprints for replication and transmission.
C1 [Altan-Bonnett, Nihal] NHLBI, Lab Host Pathogen Dynam, NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Altan-Bonnett, N (reprint author), NHLBI, Lab Host Pathogen Dynam, NIH, Bldg 10, Bethesda, MD 20892 USA.
EM nihal.altan-bonnet@nih.gov
FU Intramural NIH HHS [Z99 HL999999]
NR 99
TC 0
Z9 0
U1 3
U2 3
PU ELSEVIER SCIENCE LONDON
PI LONDON
PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND
SN 0962-8924
J9 TRENDS CELL BIOL
JI Trends Cell Biol.
PD MAR
PY 2017
VL 27
IS 3
SI SI
BP 201
EP 213
DI 10.1016/j.tcb.2016.09.011
PG 13
WC Cell Biology
SC Cell Biology
GA EN2NR
UT WOS:000395847700004
PM 27838086
ER
PT J
AU Belenko, S
Knight, D
Wasserman, GA
Dennis, ML
Wiley, T
Taxman, FS
Oser, C
Dembo, R
Robertson, AA
Sales, J
AF Belenko, Steven
Knight, Danica
Wasserman, Gail A.
Dennis, Michael L.
Wiley, Tisha
Taxman, Faye S.
Oser, Carrie
Dembo, Richard
Robertson, Angela A.
Sales, Jessica
TI The Juvenile Justice Behavioral Health Services Cascade: A new framework
for measuring unmet substance use treatment services needs among
adolescent offenders
SO JOURNAL OF SUBSTANCE ABUSE TREATMENT
LA English
DT Article
DE Substance abuse treatment; Juvenile justice; Delinquent youth; Barriers
to treatment access; Continuum of services; Evidence-based practices
ID ALCOHOL-USE DISORDERS; ABUSE TREATMENT; ADDICTION TREATMENT;
CRIMINAL-JUSTICE; DRUG COURT; HIV CARE; COMORBIDITY; YOUTH; RISK;
ENGAGEMENT
AB Overview: Substance use and substance use disorders are highly prevalent among youth under juvenile justice (JJ) supervision, and related to delinquency, psychopathology, social problems, risky sex and sexually transmitted infections, and health problems. However, numerous gaps exist in the identification of behavioral health (BH) problems and in the subsequent referral, initiation and retention in treatment for youth in community justice settings. This reflects both organizational and systems factors, including coordination between justice and BH agencies.
Methods and results: This paper presents a new framework, the Juvenile Justice Behavioral Health Services Cascade ("Cascade"), for measuring unmet substance use treatment needs to illustrate how the cascade approach can be useful in understanding service delivery issues and identifying strategies to improve treatment engagement and outcomes for youth under community JJ supervision. We discuss the organizational and systems barriers for linking delinquent youth to BH services, and explain how the Cascade can help understand and address these barriers. We provide a detailed description of the sequential steps and measures of the Cascade, and then offer an example of its application from the Juvenile Justice Translational Research on Interventions for Adolescents in the Legal System project (JJ-TRIALS), a multi-site research cooperative funded by the National Institute on Drug Abuse.
Conclusion: As illustrated with substance abuse treatment, the Cascade has potential for informing and guiding efforts to improve behavioral health service linkages for adolescent offenders, developing and testing interventions and policies to improve interagency and cross-systems coordination, and informing the development of measures and interventions for improving the implementation of treatment in complex multisystem service settings. (C) 2017 Elsevier Inc. All rights reserved.
C1 [Belenko, Steven] Temple Univ, 1115 Polett Walk, Philadelphia, PA 19122 USA.
[Knight, Danica] Texas Christian Univ, 3034 Sandage Ave, Ft Worth, TX 76129 USA.
[Wasserman, Gail A.] Columbia Univ, 1051 Riverside Dr,Unit 78, New York, NY 10032 USA.
[Dennis, Michael L.] Chestnut Hlth Syst, 448 Wylie Dr, Normal, IL 61701 USA.
[Wiley, Tisha] NIDA, 6001 Execut Blvd,Room 5191, Bethesda, MD 20892 USA.
[Taxman, Faye S.] George Mason Univ, 4087 Univ Dr,4100,MSN 6D3, Fairfax, VA 22030 USA.
[Oser, Carrie] Univ Kentucky, 1531 Patterson Off Tower, Lexington, KY 40506 USA.
[Dembo, Richard] Univ S Florida, 4202 E Fowler Ave, Tampa, FL 33620 USA.
[Robertson, Angela A.] Mississippi State Univ, 1 Res Blvd,Suite 103, Starkville, MS 39759 USA.
[Sales, Jessica] Emory Univ, Rollins Sch Publ Hlth, 1518 Clifton Rd,Room 570, Atlanta, GA 30322 USA.
RP Belenko, S (reprint author), Temple Univ, 1115 Polett Walk, Philadelphia, PA 19122 USA.
EM sbelenko@temple.edu; d.knight@tcu.edu; wassermg@nyspi.columbia.edu;
mdennis@chestnut.org; wileytr@nida.nih.gov; ftaxman@gmu.edu;
Carrie.oser@uky.edu; rdembo@usf.edu; Angela.robertson@ssrc.msstate.edu;
jmcderm@emory.edu
OI Dennis, Michael/0000-0002-2580-5345
FU Juvenile Justice Translational Research on Interventions for Adolescents
in the Legal System project (JJ-TRIALS); National Institute on Drug
Abuse (NIDA), National Institutes of Health (NIH); Chestnut Health
Systems [U01DA036221]; Columbia University [U01DA036226]; Emory
University [U01DA036233]; Mississippi State University [U01DA036176];
Temple University [U01DA036225]; Texas Christian University
[U01DA036224]; University of Kentucky [U01DA036158]
FX This study was funded under the Juvenile Justice Translational Research
on Interventions for Adolescents in the Legal System project (JJ-TRIALS)
cooperative agreement, funded by the National Institute on Drug Abuse
(NIDA), National Institutes of Health (NIH). The authors gratefully
acknowledge the collaborative contributions of NIDA and support from the
following grant awards: Chestnut Health Systems (U01DA036221); Columbia
University (U01DA036226); Emory University (U01DA036233); Mississippi
State University (U01DA036176); Temple University (U01DA036225); Texas
Christian University (U01DA036224); and University of Kentucky
(U01DA036158). The NIDA Science Officer on this project is Tisha Wiley.
The contents of this publication are solely the responsibility of the
authors and do not necessarily represent the official views of the NIDA,
NIH, or the participating universities or juvenile justice systems.
NR 84
TC 0
Z9 0
U1 5
U2 5
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0740-5472
J9 J SUBST ABUSE TREAT
JI J. Subst. Abus. Treat.
PD MAR
PY 2017
VL 74
BP 80
EP 91
DI 10.1016/j.jsat.2016.12.012
PG 12
WC Psychology, Clinical; Substance Abuse
SC Psychology; Substance Abuse
GA EK2CG
UT WOS:000393734400012
PM 28132705
ER
PT J
AU de Sousa, RT
Loch, AA
Carvalho, AF
Brunoni, AR
Haddad, MR
Henter, ID
Zarate, CA
Machado-Vieira, R
AF de Sousa, Rafael T.
Loch, Alexandre A.
Carvalho, Andre F.
Brunoni, Andre R.
Haddad, Marie Reine
Henter, Ioline D.
Zarate, Carlos A., Jr.
Machado-Vieira, Rodrigo
TI Genetic Studies on the Tripartite Glutamate Synapse in the
Pathophysiology and Therapeutics of Mood Disorders
SO NEUROPSYCHOPHARMACOLOGY
LA English
DT Review
ID MAJOR DEPRESSIVE DISORDER; BIPOLAR AFFECTIVE-DISORDER; GENOME-WIDE
ASSOCIATION; STAR-ASTERISK-D; CHINESE HAN POPULATION; 3 GRIN2B
POLYMORPHISMS; RECEPTOR GENE; ANTIDEPRESSANT TREATMENT; FUNCTIONAL
POLYMORPHISM; FLUVOXAMINE RESPONSE
AB Both bipolar disorder (BD) and major depressive disorder (MDD) have high morbidity and share a genetic background. Treatment options for these mood disorders are currently suboptimal for many patients; however, specific genetic variables may be involved in both pathophysiology and response to treatment. Agents such as the glutamatergic modulator ketamine are effective in treatment-resistant mood disorders, underscoring the potential importance of the glutamatergic system as a target for improved therapeutics. Here we review genetic studies linking the glutamatergic system to the pathophysiology and therapeutics of mood disorders. We screened 763 original genetic studies of BD or MDD that investigated genes encoding targets of the pathway/mediators related to the so-called tripartite glutamate synapse, including pre- and post-synaptic neurons and glial cells; 60 papers were included in this review. The findings suggest the involvement of glutamate-related genes in risk for mood disorders, treatment response, and phenotypic characteristics, although there was no consistent evidence for a specific gene. Target genes of high interest included GRIA3 and GRIK2 (which likely play a role in emergent suicidal ideation after antidepressant treatment), GRIK4 (which may influence treatment response), and GRM7 (which potentially affects risk for mood disorders). There was stronger evidence that glutamate-related genes influence risk for BD compared with MDD. Taken together, the studies show a preliminary relationship between glutamate-related genes and risk for mood disorders, suicide, and treatment response, particularly with regard to targets on metabotropic and ionotropic receptors.
C1 [de Sousa, Rafael T.; Henter, Ioline D.; Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Ctr Clin, 10 Ctr Dr,Room 2-D39C, Bethesda, MD 20892 USA.
[de Sousa, Rafael T.; Loch, Alexandre A.; Brunoni, Andre R.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, Neurosci Lab, LIM 27, Sao Paulo, Brazil.
[Carvalho, Andre F.] Univ Fed Ceara, Translat Psychiat Res Grp, Fac Med, Fortaleza, Ceara, Brazil.
[Carvalho, Andre F.] Univ Fed Ceara, Dept Clin Med, Fac Med, Fortaleza, Ceara, Brazil.
[Haddad, Marie Reine] NICHHD, Sect Translat Neurosci, NIH, Bethesda, MD 20892 USA.
[Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPN, Sao Paulo, Brazil.
RP de Sousa, RT (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Ctr Clin, 10 Ctr Dr,Room 2-D39C, Bethesda, MD 20892 USA.
EM rafael.desousa@nih.gov
RI Loch, Alexandre/C-8526-2011;
OI Loch, Alexandre/0000-0002-0006-8107; Russowsky Brunoni,
Andre/0000-0002-6310-3571; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190
FU Intramural Research Program at the National Institute of Mental Health,
National Institutes of Health (IRP-NIMH-NIH) [ZIA MH002857]; NARSAD
Independent Investigator; Brain & Behavior Mood Disorders Research Award
FX Funding for this work was supported by the Intramural Research Program
at the National Institute of Mental Health, National Institutes of
Health (IRP-NIMH-NIH; ZIA MH002857), by a NARSAD Independent
Investigator to Dr Zarate, and by a Brain & Behavior Mood Disorders
Research Award to Dr Zarate. Dr Zarate is listed as a co-inventor on a
patent for the use of, ketamine and its metabolites in major depression.
He has assigned his rights in the patent to the US government but will
share a percentage of any royalties that may be received by the
government. The remaining authors declare no conflict of interest.
NR 95
TC 1
Z9 1
U1 3
U2 3
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 MAR
PY 2017
VL 42
IS 4
BP 787
EP 800
DI 10.1038/npp.2016.149
PG 14
WC Neurosciences; Pharmacology & Pharmacy; Psychiatry
SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry
GA EK1ZC
UT WOS:000393725600002
PM 27510426
ER
PT J
AU Hui, WF
Betoko, A
Savant, JD
Abraham, AG
Greenbaum, LA
Warady, B
Moxey-Mims, MM
Furth, SL
AF Hui, Wun Fung
Betoko, Aisha
Savant, Jonathan D.
Abraham, Alison G.
Greenbaum, Larry A.
Warady, Bradley
Moxey-Mims, Marva M.
Furth, Susan L.
TI Assessment of dietary intake of children with chronic kidney disease
SO PEDIATRIC NEPHROLOGY
LA English
DT Article
DE Dietary assessment; Nutrient intake; Children; Chronic kidney disease
ID FOOD FREQUENCY QUESTIONNAIRE; PRESCHOOL-CHILDREN; SALT INTAKE; GROWTH;
REPRODUCIBILITY; ADOLESCENTS; PHOSPHORUS; OBESITY; WEIGHT; ENERGY
AB Our aim was to characterize the nutrient intake of children with chronic kidney disease (CKD) relative to recommended intake levels.
We conducted a cross-sectional study of dietary intake assessed by Food Frequency Questionnaire (FFQ) in The North American Chronic Kidney Disease in Children (CKiD) prospective cohort study. Nutrient intake was analyzed to estimate the daily consumption levels of various nutrients and compared with national guidelines for intake.
There were 658 FFQs available for analysis; 69.9 % of respondents were boys, with a median age [Interquartile range (IQR)] of 11 years (8-15). Median daily sodium, potassium, and phosphorus intake was 3089 mg (2294-4243), 2384 mg (1804-3076), and 1206 mg (894-1612) respectively. Sodium and phosphorus consumptions were higher than recommended in all age groups. Caloric intake decreased with dropping glomerular filtration rate (GFR) (p = 0.003). The median daily caloric intakes were 1307 kcal in male children 2-3 years old, 1875 kcal in children 4-8 years old, 1923 kcal in those 9-13 years old, and 2427 kcal in those 14-18 years old. Respective levels for girls were 1467 kcal, 1736 kcal, 1803 kcal, and 2281 kcal. Median protein intake exceeded recommended levels in all age groups, particularly among younger participants. Younger children were more likely than older children to exceed the recommended intakes for phosphorus (p < 0.001) and the age-specific recommended caloric intake (p < 0.001). Macronutrient distribution (carbohydrate:fat:protein) was consistent with recommendation.
Children in the CKiD cohort consumed more sodium, phosphorus, protein, and calories than recommended. The gap between actual consumption and recommendations indicates a need for improved nutritional counseling and monitoring.
C1 [Hui, Wun Fung; Savant, Jonathan D.; Furth, Susan L.] Childrens Hosp Philadelphia, Dept Pediat, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA.
[Betoko, Aisha; Abraham, Alison G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.
[Greenbaum, Larry A.] Emory Univ, Atlanta, GA 30322 USA.
[Greenbaum, Larry A.] Childrens Healthcare Atlanta, Atlanta, GA USA.
[Warady, Bradley] Childrens Mercy Hosp, Div Pediat Nephrol, Kansas City, MO 64108 USA.
[Moxey-Mims, Marva M.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA.
RP Furth, SL (reprint author), Childrens Hosp Philadelphia, Dept Pediat, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA.
EM furths@email.chop.edu
OI Betoko, Aisha/0000-0003-1245-8257
FU National Institute of Diabetes and Digestive and Kidney Diseases; Eunice
Kennedy Shriver National Institute of Child Health and Human
Development; National Heart, Lung and Blood Institute [U01-DK-66143,
U01-DK-66174, U01DK-082194, U01-DK-66116]
FX National Institute of Diabetes and Digestive and Kidney Diseases, with
additional funding from the Eunice Kennedy Shriver National Institute of
Child Health and Human Development and the National Heart, Lung and
Blood Institute (grants U01-DK-66143, U01-DK-66174, U01DK-082194, and
U01-DK-66116).
NR 39
TC 0
Z9 0
U1 3
U2 3
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 0931-041X
EI 1432-198X
J9 PEDIATR NEPHROL
JI Pediatr. Nephrol.
PD MAR
PY 2017
VL 32
IS 3
BP 485
EP 494
DI 10.1007/s00467-016-3491-5
PG 10
WC Pediatrics; Urology & Nephrology
SC Pediatrics; Urology & Nephrology
GA EK2MC
UT WOS:000393760400015
PM 27687620
ER
PT J
AU Thanos, PK
Kim, R
Delis, F
Rocco, MJ
Cho, J
Volkow, ND
AF Thanos, Panayotis K.
Kim, Ronald
Delis, Foteini
Rocco, Mark J.
Cho, Jacob
Volkow, Nora D.
TI Effects of chronic methamphetamine on psychomotor and cognitive
functions and dopamine signaling in the brain
SO BEHAVIOURAL BRAIN RESEARCH
LA English
DT Article
DE Chronic; Methamphetamine; Dopamine; Behavior; Brain; Reward deficiency
syndrome; Positron emission tomography
ID TRANSPORTER COMPLEX-FORMATION; IMPAIRS RECOGNITION MEMORY;
PLACEBO-CONTROLLED TRIAL; OBJECT RECOGNITION; RAT-BRAIN;
NUCLEUS-ACCUMBENS; D2 RECEPTORS; ABSTINENT METHAMPHETAMINE;
NEUROTRANSMITTER RELEASE; BEHAVIORAL-RESPONSES
AB Methamphetamine (MA) studies in animals usually involve acute, binge, or short-term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8 mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed. (C) 2016 Published by Elsevier B.V.
C1 [Thanos, Panayotis K.; Kim, Ronald; Rocco, Mark J.; Cho, Jacob] Univ Buffalo, Res Inst Addict, Behav Neuropharmacol & Neuroimaging Lab Addict, Buffalo, NY 14203 USA.
[Delis, Foteini; Volkow, Nora D.] Univ Ioannina, Sch Med, Dept Pharmacol, Ioannina 45100, Greece.
[Volkow, Nora D.] NIAAA, Lab Neuroimaging, Intramural Program, Bethesda, MD 20892 USA.
RP Thanos, PK (reprint author), 1021 Main St, Buffalo, NY 14203 USA.
EM pthanos@ria.buffalo.edu
FU Research Foundation of New York
FX This work was supported by the Research Foundation of New York. The
authors have no competing financial interests to declare.
NR 94
TC 0
Z9 0
U1 8
U2 8
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0166-4328
EI 1872-7549
J9 BEHAV BRAIN RES
JI Behav. Brain Res.
PD MAR 1
PY 2017
VL 320
BP 282
EP 290
DI 10.1016/j.bbr.2016.12.010
PG 9
WC Behavioral Sciences; Neurosciences
SC Behavioral Sciences; Neurosciences & Neurology
GA EJ5FV
UT WOS:000393244100032
PM 27993694
ER
PT J
AU Halladay, LR
Blair, HT
AF Halladay, Lindsay R.
Blair, Hugh T.
TI Prefrontal infralimbic cortex mediates competition between excitation
and inhibition of body movements during pavlovian fear conditioning
SO JOURNAL OF NEUROSCIENCE RESEARCH
LA English
DT Article
DE fear conditioning; freezing; flight; fear expression; defensive; RGD
ID:2308852
ID DORSOLATERAL PERIAQUEDUCTAL GRAY; BEHAVIORAL FLEXIBILITY; LATERAL
AMYGDALA; NUCLEUS-ACCUMBENS; DISSOCIABLE ROLES; DEFENSE REACTIONS;
PRELIMBIC CORTEX; AVERSIVE STIMULI; EXTINCTION; RAT
AB The infralimbic subregion of the prefrontal cortex (IL) is broadly involved in behavioral flexibility, risk assessment, and outcome reinforcement. In aversive conditioning tasks, the IL has been implicated in fear extinction and in mediating transitions between Pavlovian and instrumental responses. Here we examine the role of the IL in mediating transitions between two competing Pavlovian fear responses, conditioned motor inhibition (CMI) and conditioned motor excitation (CME). Rats were trained to fear an auditory conditioned stimulus (CS) by pairing it with periorbital shock to one eyelid (the unconditioned stimulus [US]). Trained animals exhibited CMI responses (movement suppression) to the CS when they had not recently encountered the US (>24 hr), but, after recent encounters with the US (<5 min), the CS evoked CME responses (turning in circles away from anticipated shock). Animals then received bilateral infusions of muscimol or picrotoxin to inactivate or hyperactivate the IL, respectively. Neither drug reliably affected CMI responses, but there was a bidirectional effect on CME responses; inactivation of the IL attenuated CME responses, whereas hyperactivation potentiated CME responses. These results provide evidence that activation of the IL may promote behavioral strategies that involve mobilizing the body and suppress strategies that involve immobilizing the body. (c) 2016 Wiley Periodicals, Inc.
C1 [Halladay, Lindsay R.; Blair, Hugh T.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA.
[Halladay, Lindsay R.] NIAAA, NIH, Bethesda, MD USA.
RP Halladay, LR (reprint author), 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA.
EM lindsay.halladay@nih.gov
FU National Institutes of Health [R01 MH073700, 5 T32 NS058280-03]
FX Contract grant sponsor: National Institutes of Health; Contract grant
numbers: R01 MH073700 (to H.T.B.); Contract grant number: 5 T32
NS058280-03 (to L.R.H.)
NR 57
TC 1
Z9 1
U1 3
U2 3
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0360-4012
EI 1097-4547
J9 J NEUROSCI RES
JI J. Neurosci. Res.
PD MAR
PY 2017
VL 95
IS 3
BP 853
EP 862
DI 10.1002/jnr.23736
PG 10
WC Neurosciences
SC Neurosciences & Neurology
GA EJ8DC
UT WOS:000393453800005
PM 26997207
ER
PT J
AU Carlin, JL
Jain, S
Gizewski, E
Wan, TC
Tosh, DK
Xiao, CY
Auchampach, JA
Jacobson, KA
Gavrilova, O
Reitman, ML
AF Carlin, Jesse Lea
Jain, Shalini
Gizewski, Elizabeth
Wan, Tina C.
Tosh, Dilip K.
Xiao, Cuiying
Auchampach, John A.
Jacobson, Kenneth A.
Gavrilova, Oksana
Reitman, Marc L.
TI Hypothermia in mouse is caused by adenosine A(1) and A(3) receptor
agonists and AMP via three distinct mechanisms
SO NEUROPHARMACOLOGY
LA English
DT Article
DE Hypothermia; Adenosine; A(1)AR; A(3)AR; AMP; Torpor
ID ADIPOSE-TISSUE THERMOGENESIS; BODY-TEMPERATURE; SPECIES-DIFFERENCES;
DAILY TORPOR; ISCHEMIA/REPERFUSION INJURY; NEUROPATHIC PAIN; A(2A)
RECEPTORS; SYRIAN-HAMSTERS; MAMMALIAN BRAIN; METABOLIC-RATE
AB Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adoral(-/-), Adora3(-/-)) mice. Confirming prior data, stimulation of the A(3) adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H-1 receptors. In contrast, A(1)AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A1AR agonists, including N-6-cyclopentyladenosine (CPA), N-6-cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A(1)AR and A(3)AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of CI-ENBA [(+/-)-5'-chloro-5'-deoxy-N-6-endo-norbornyladenosine], or using Adora3(-/-) mice allowed selective stimulation of A(1)AR. AMP-stimulated hypothermia can occur independently of A(1)AR, A(3)AR, and mast cells. A(1)AR and A(3)AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A(1)AR nor A(3)AR was required for fasting-induced torpor. A(1)AR and A(3)AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms. Published by Elsevier Ltd.
C1 [Carlin, Jesse Lea; Xiao, Cuiying; Reitman, Marc L.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.
[Jain, Shalini; Gavrilova, Oksana] Natl Inst Diabet & Digest & Kidney Dis, Mouse Metab Core, NIH, Bethesda, MD 20892 USA.
[Tosh, Dilip K.; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA.
[Gizewski, Elizabeth; Wan, Tina C.; Auchampach, John A.] Med Coll Wisconsin, Dept Pharmacol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA.
RP Reitman, ML (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.
EM marc.reitman@nih.gov
OI Reitman, Marc/0000-0002-0426-9475
FU Intramural Research Program of the National Institutes of Health,
National Institute of Diabetes and Digestive and Kidney Diseases [ZIA
DK075063, ZIA DK031117]; National Heart, Lung, and Blood Institute
[R01H1077707]
FX We thank Jurgen Schnermann for discussions. This research was supported
in part by the Intramural Research Program of the National Institutes of
Health, National Institute of Diabetes and Digestive and Kidney Diseases
[ZIA DK075063; ZIA DK031117] and by the National Heart, Lung, and Blood
Institute [R01H1077707].
NR 81
TC 0
Z9 0
U1 5
U2 5
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 MAR 1
PY 2017
VL 114
BP 101
EP 113
DI 10.1016/j.neuropharm.2016.11.026
PG 13
WC Neurosciences; Pharmacology & Pharmacy
SC Neurosciences & Neurology; Pharmacology & Pharmacy
GA EI8SW
UT WOS:000392779300010
PM 27914963
ER
PT J
AU Cocola, C
Molgora, S
Piscitelli, E
Veronesi, MC
Greco, M
Bragato, C
Moro, M
Crosti, M
Gray, B
Milanesi, L
Grieco, V
Luvoni, GC
Kehler, J
Bellipanni, G
Reinbold, R
Zucchi, I
Giordano, A
AF Cocola, Cinzia
Molgora, Stefano
Piscitelli, Eleonora
Veronesi, Maria Cristina
Greco, Marianna
Bragato, Cinzia
Moro, Monica
Crosti, Mariacristina
Gray, Brian
Milanesi, Luciano
Grieco, Valeria
Luvoni, Gaia Cecilia
Kehler, James
Bellipanni, Gianfranco
Reinbold, Rolland
Zucchi, Ileana
Giordano, Antonio
TI FGF2 and EGF Are Required for Self-Renewal and Organoid Formation of
Canine Normal and Tumor Breast Stem Cells
SO JOURNAL OF CELLULAR BIOCHEMISTRY
LA English
DT Article
DE CANINES; CANCER; STEM; ORGANOIDS; MAMMOSPHERE; ACINI; FGF2; MAMMARY;
BREAST
ID MAMMARY-GLAND; INITIATING CELLS; IN-VITRO; CANCER; CULTURE; SYSTEM;
MODEL
AB Recent studies suggest that human tumors are generated from cancer cells with stem cell (SC) properties. Spontaneously occurring cancers in dogs contain a diversity of cells that like for human tumors suggest that certain canine tumors are also generated from cancer stem cells (CSCs). CSCs, like normal SCs, have the capacity for self-renewal as mammospheres in suspension cultures. To understand how cells with SC properties contribute to canine mammary gland tumor development and progression, comparative analysis between normal SCs and CSCs, obtained from the same individual, is essential. We have utilized the property of sphere formation to develop culture conditions for propagating stem/progenitor cells from canine normal and tumor tissue. We show that cells from dissociated mammospheres retain sphere reformation capacity for several serial passages and have the capacity to generate organoid structures ex situ. Utilizing various culture conditions for passaging SCs and CSCs, fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) were found to positively or negatively regulate mammosphere regeneration, organoid formation, and multi-lineage differentiation potential. The response of FGF2 and EGF on SCs and CSCs was different, with increased FGF2 and EGF self-renewal promoted in SCs and repressed in CSCs. Our protocol for propagating SCs from normal and tumor canine breast tissue will provide new opportunities in comparative mammary gland stem cell analysis between species and anticancer treatment and therapies for dogs. J. Cell. Biochem. 118: 570-584, 2017. (c) 2016 Wiley Periodicals, Inc.
C1 [Cocola, Cinzia; Molgora, Stefano; Piscitelli, Eleonora; Greco, Marianna; Milanesi, Luciano; Reinbold, Rolland; Zucchi, Ileana] CNR, Ist Tecnol Biomed, Via Flli Cervi 93, I-20090 Milan, Italy.
[Veronesi, Maria Cristina; Grieco, Valeria] Univ Milan, Dept Vet Med, Via Celoria 10, I-20133 Milan, Italy.
[Bragato, Cinzia] Fdn IRCCS Ist Neurol C Besta, Neuromuscular Dis & Neuroimmunol Unit, Muscle Cell Biol Lab, Via Temolo 4, Milan, Italy.
[Moro, Monica; Crosti, Mariacristina] Fdn Ist Nazl Genet Mol Romeo & Enrica Invernizzi, Via Francesco Sforza 35, I-20122 Milan, Italy.
[Gray, Brian] Mol Targeting Technol Inc, W Chester, PA USA.
[Luvoni, Gaia Cecilia] Univ Milan, Dept Hlth Anim Sci & Food Safety, I-20133 Milan, Italy.
[Kehler, James] NIDDK, NIH, Bethesda, MD 20814 USA.
[Bellipanni, Gianfranco; Giordano, Antonio] NIDDK, NIH, Temple, TX 20814 USA.
[Bellipanni, Gianfranco; Giordano, Antonio] Temple Univ, Coll Sci & Technol, Dept Biol, Temple, TX USA.
[Bellipanni, Gianfranco; Giordano, Antonio] Temple Univ, Coll Sci & Technol, Sbarro Inst Canc Res & Mol Med, Philadelphia, PA 19122 USA.
EM rolland.reinbold@itb.cnr.it; ileana.zucchi@itb.cnr.it
OI Milanesi, Luciano/0000-0002-1201-3939
FU Cariplo Progetti-Internazionali; MIUR-FIRB [RBAP11-BYNP, RBAP11Z4Z9];
Progetto Bandiera MIUR-CNR Interomics; Progetto Bandiera MIUR-CNR Epigen
FX Grant sponsor: Cariplo Progetti-Internazionali 2008-2015; Grant sponsor:
MIUR-FIRB; Grant numbers: RBAP11-BYNP, RBAP11Z4Z9; Grant sponsor:
Progetto Bandiera MIUR-CNR Interomics 2015; Grant sponsor: Progetto
Bandiera MIUR-CNR Epigen 2016.
NR 35
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Z9 1
U1 20
U2 20
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0730-2312
EI 1097-4644
J9 J CELL BIOCHEM
JI J. Cell. Biochem.
PD MAR
PY 2017
VL 118
IS 3
BP 570
EP 584
DI 10.1002/jcb.25737
PG 15
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA EI4VR
UT WOS:000392492200015
PM 27632571
ER
PT J
AU Xu, T
Zhang, H
Xin, C
Kim, E
Long, LR
Xue, ZY
Antani, S
Huang, XL
AF Xu, Tao
Zhang, Han
Xin, Cheng
Kim, Edward
Long, L. Rodney
Xue, Zhiyun
Antani, Sameer
Huang, Xiaolei
TI Multi-feature based benchmark for cervical dysplasia classification
evaluation
SO PATTERN RECOGNITION
LA English
DT Article
DE Cervical cancer screening; Computer aided diagnosis; Image
classification; Pyramid histogram; Local binary patterns; Convolutional
neural network
ID IMAGING-SYSTEM; PATTERNS
AB Cervical cancer is one of the most common types of cancer in women worldwide. Most deaths due to the disease occur in less developed areas of the world. In this work, we introduce a new image dataset along with expert annotated diagnoses for evaluating image-based cervical disease classification algorithms. A large number of Cervigram (R) images are selected from a database provided by the US National Cancer Institute. For each image, we extract three complementary pyramid features: Pyramid histogram in L*A*B* color space (PLAB), Pyramid Histogram of Oriented Gradients (PHOG), and Pyramid histogram of Local Binary Patterns (PLBP). Other than hand-crafted pyramid features, we investigate the performance of convolutional neural network (CNN) features for cervical disease classification. Our experimental results demonstrate the effectiveness of both our handcrafted and our deep features. We intend to release this multi-feature dataset and our extensive evaluations using seven classic classifiers can serve as the baseline.
C1 [Xu, Tao; Xin, Cheng; Huang, Xiaolei] Lehigh Univ, Dept Comp Sci & Engn, Bethlehem, PA 18015 USA.
[Zhang, Han] Rutgers State Univ, Dept Comp Sci, Piscataway, NJ USA.
[Kim, Edward] Villanova Univ, Dept Comp Sci, Villanova, PA 19085 USA.
[Long, L. Rodney; Xue, Zhiyun; Antani, Sameer] NIH, Natl Lib Med, Bethesda, MD USA.
RP Huang, XL (reprint author), Lehigh Univ, Dept Comp Sci & Engn, Bethlehem, PA 18015 USA.
EM xih206@lehigh.edu
FU Intramural Research Program of the National Institutes of Health (NIH),
National Library of Medicine (NLM); Lister Hill National Center for
Biomedical Communications (LHNCBC) [HHSN276201000693P]
FX This research was supported in part by the Intramural Research Program
of the National Institutes of Health (NIH), National Library of Medicine
(NLM), and Lister Hill National Center for Biomedical Communications
(LHNCBC), under Contract HHSN276201000693P. We would also like to
acknowledge the expert advice and support from Dr. Mark Schiffman and
Dr. Nicolas Wentzensen of the National Cancer Institute (NCI) in the use
and interpretation of data from the NCI Guanacaste Project.
NR 31
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U1 30
U2 30
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0031-3203
EI 1873-5142
J9 PATTERN RECOGN
JI Pattern Recognit.
PD MAR
PY 2017
VL 63
BP 468
EP 475
DI 10.1016/j.patcog.2016.09.027
PG 8
WC Computer Science, Artificial Intelligence; Engineering, Electrical &
Electronic
SC Computer Science; Engineering
GA EE7HG
UT WOS:000389785900038
ER
PT J
AU Rajbhandari, N
Lin, WC
Wehde, BL
Triplett, AA
Wagner, KU
AF Rajbhandari, Nirakar
Lin, Wan-chi
Wehde, Barbara L.
Triplett, Aleata A.
Wagner, Kay-Uwe
TI Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the
Absence of Oncogenic Drivers
SO CELL REPORTS
LA English
DT Article
ID EPITHELIAL-CELLS; CANCER; MOUSE; KRAS; PROGRESSION; EXPRESSION;
RESISTANCE; RECEPTOR; MODELS; INITIATION
AB Mutant KRAS and c-MYC are oncogenic drivers and rational therapeutic targets for the treatment of pancreatic cancer. Although tumor growth and homeostasis are largely dependent on these oncogenes, a few residual cancer cells are able to survive the ablation of mutant KRAS and c-MYC. By performing a genome-wide gene expression analysis of in vivo-derived bulk tumor cells and residual cancer cells lacking the expression of mutant KRAS or c-MYC, we have identified an increase in autocrine IGF1/AKT signaling as a common survival mechanism in dormant cancer cells. The pharmacological inhibition of IGF-1R reduces residual disease burden and cancer recurrence, suggesting that this molecular pathway is crucial for the survival of cancer cells in the absence of the primary oncogenic drivers.
C1 [Rajbhandari, Nirakar; Lin, Wan-chi; Wehde, Barbara L.; Triplett, Aleata A.; Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA.
[Rajbhandari, Nirakar; Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA.
[Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA.
[Lin, Wan-chi] NIEHS, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA.
RP Wagner, KU (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA.; Wagner, KU (reprint author), Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA.; Wagner, KU (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA.
EM kuwagner@unmc.edu
FU Nebraska Cancer and Smoking Disease Research Program (NE DHHS) [LB506
2011-36, LB506 2016-54]; Public Health Service Grant [R21 CA155175,
CA202917]; UNMC Graduate Studies Office
FX The authors thank the UNMC Genomics Core Facility for assistance in
nextgeneration sequencing (NGS) service and the UNMC Cell Analysis Core
facility for flow cytometry. We are grateful to Karen K. Dulany for the
preparation of histological sections. Financial support provided to
K.-U.W. by the Nebraska Cancer and Smoking Disease Research Program (NE
DHHS LB506 2011-36 and LB506 2016-54) was imperative to finance the
maintenance of mutant mice and the collection of tumor tissues for
transcriptome analysis. Additional funding was provided by Public Health
Service Grant CA202917 (K.-U.W.). The work on the c-MYC-associated
pancreatic cancer model was supported by Public Health Service Grant R21
CA155175 (K.-U.W.). N.R. and W.-c. L. were supported through a research
assistantship from the UNMC Graduate Studies Office. The funders had no
role in study design, data collection and analysis, decision to publish,
or preparation of the manuscript.
NR 29
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U2 0
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 FEB 28
PY 2017
VL 18
IS 9
BP 2243
EP 2255
DI 10.1016/j.celrep.2017.02.013
PG 13
WC Cell Biology
SC Cell Biology
GA EP4CO
UT WOS:000397328400016
PM 28249168
ER
PT J
AU Wu, ZH
Plotnikov, SV
Moalim, AY
Waterman, CM
Liu, J
AF Wu, Zhanghan
Plotnikov, Sergey V.
Moalim, Abdiwahab Y.
Waterman, Clare M.
Liu, Jian
TI Two Distinct Actin Networks Mediate Traction Oscillations to Confer
Focal Adhesion Mechanosensing
SO BIOPHYSICAL JOURNAL
LA English
DT Article
ID FLUORESCENT SPECKLE MICROSCOPY; CELL-MATRIX ADHESIONS; MIGRATING CELLS;
NASCENT ADHESIONS; MECHANICAL FORCE; RETROGRADE FLOW; STRESS FIBERS;
ALPHA-ACTININ; MOTILE CELLS; DYNAMICS
AB Focal adhesions (FAs) are integrin-based transmembrane assemblies that connect a cell to its extracellular matrix (ECM). They are mechanosensors through which cells exert actin cytoskeleton-mediated traction forces to sense the ECM stiffness. Interestingly, FAs themselves are dynamic structures that adapt their growth in response to mechanical force. It is unclear how the cell manages the plasticity of the FA structure and the associated traction force to accurately sense ECM stiffness. Strikingly, FA traction forces oscillate in time and space, and govern the cell mechanosensing of ECM stiffness. However, precisely how and why the FA traction oscillates is unknown. We developed a model of FA growth that integrates the contributions of the branched actin network and stress fibers (SFs). Using the model in combination with experimental tests, we show that the retrograde flux of the branched actin network promotes the proximal growth of the FA and contributes to a traction peak near the FA's distal tip. The resulting traction gradient within the growing FA favors SF formation near the FA's proximal end. The SF-mediated actomyosin contractility further stabilizes the FA and generates a second traction peak near the center of the FA. Forminmediated SF elongation negatively feeds back with actomyosin contractility, resulting in central traction peak oscillation. This underpins the observed FA traction oscillation and, importantly, broadens the ECM stiffness range over which FAs can accurately adapt to traction force generation. Actin cytoskeleton-mediated FA growth and maturation thus culminate with FA traction oscillation to drive efficient FA mechanosensing.
C1 [Wu, Zhanghan; Liu, Jian] NHLBI, Theoret Cellular Phys Sect, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA.
[Plotnikov, Sergey V.; Moalim, Abdiwahab Y.] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON, Canada.
[Waterman, Clare M.] NHLBI, Lab Cell & Tissue Morphodynam, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Liu, J (reprint author), NHLBI, Theoret Cellular Phys Sect, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA.
EM jian.liu@nih.gov
FU Intramural Research Program of the National Heart, Lung, and Blood
Institute, National Institutes of Health; Connaught Fund New
Investigator Award; Canada Foundation for Innovation [34473]; Natural
Sciences and Engineering Research Council of Canada [RGPIN-2015-05114]
FX This work was supported by the Intramural Research Program of the
National Heart, Lung, and Blood Institute, National Institutes of
Health. This work was partially supported by a Connaught Fund New
Investigator Award to S.V.P. and by grants from the Canada Foundation
for Innovation (#34473) and the Discovery Grant Program of the Natural
Sciences and Engineering Research Council of Canada (RGPIN-2015-05114)
to S.V.P.
NR 65
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U1 0
U2 0
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 0006-3495
EI 1542-0086
J9 BIOPHYS J
JI Biophys. J.
PD FEB 28
PY 2017
VL 112
IS 4
BP 780
EP 794
DI 10.1016/j.bpj.2016.12.035
PG 15
WC Biophysics
SC Biophysics
GA EM9FU
UT WOS:000395617800022
PM 28256237
ER
PT J
AU Nash, RA
Hutton, GJ
Racke, MK
Popat, U
Devine, SM
Steinmiller, KC
Griffith, LM
Muraro, PA
Openshaw, H
Sayre, PH
Stuve, O
Arnold, DL
Wener, MH
Georges, GE
Wundes, A
Kraft, GH
Bowen, JD
AF Nash, Richard A.
Hutton, George J.
Racke, Michael K.
Popat, Uday
Devine, Steven M.
Steinmiller, Kaitlyn C.
Griffith, Linda M.
Muraro, Paolo A.
Openshaw, Harry
Sayre, Peter H.
Stuve, Olaf
Arnold, Douglas L.
Wener, Mark H.
Georges, George E.
Wundes, Annette
Kraft, George H.
Bowen, James D.
TI High-dose immunosuppressive therapy and autologous HCT for
relapsing-remitting MS
SO NEUROLOGY
LA English
DT Article
ID STEM-CELL TRANSPLANTATION; AGGRESSIVE MULTIPLE-SCLEROSIS;
DISEASE-ACTIVITY; NO EVIDENCE; MARROW-TRANSPLANTATION; CLINICAL-TRIAL;
MRI LESIONS; FOLLOW-UP; DISABILITY; EXPERIENCE
AB Objective: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT).
Methods: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0-5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE).
Results: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12-72). EFS was 69.2% (90% confidence interval [CI] 50.2-82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%-97.2%), 86.9% (90% CI 69.5%-94.7%), and 86.3% (90% CI 68.1%-94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of 20.5 (interquartile range -1.5 to 0.0; p = 0.001) among participants who survived and completed the study.
Conclusion: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years.
C1 [Nash, Richard A.] Colorado Blood Canc Inst, Denver, CO 80218 USA.
[Hutton, George J.] Baylor Coll Med, Houston, TX 77030 USA.
[Racke, Michael K.; Devine, Steven M.] Ohio State Univ, Columbus, OH 43210 USA.
[Popat, Uday] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
[Steinmiller, Kaitlyn C.] Rho Inc, Chapel Hill, NC USA.
[Griffith, Linda M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Muraro, Paolo A.] Imperial Coll London, Div Brain Sci, London, England.
[Openshaw, Harry] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA.
[Sayre, Peter H.] Univ Calif San Francisco, Immune Tolerance Network, San Francisco, CA 94143 USA.
[Stuve, Olaf] Univ Texas Southwestern, Dallas, TX USA.
[Arnold, Douglas L.] McGill Univ, NeuroRx, Montreal, PQ, Canada.
[Georges, George E.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
[Wener, Mark H.; Wundes, Annette; Kraft, George H.] Univ Washington, Seattle, WA 98195 USA.
[Bowen, James D.] Swedish Med Ctr, Med Ctr, Seattle, WA USA.
RP Nash, RA (reprint author), Colorado Blood Canc Inst, Denver, CO 80218 USA.
EM richard.nash@healthonecares.com
FU Division of Allergy, Immunology, and Transplantation, National Institute
of Allergy and Infectious Diseases (DAIT-NIAID), NIH,; DAIT; NIAID; NIH
FX This work was sponsored by the Division of Allergy, Immunology, and
Transplantation, National Institute of Allergy and Infectious Diseases
(DAIT-NIAID), NIH, and conducted by the Immune Tolerance Network (ITN)
(UM1 AI 109565) and DAIT-NIAID-funded statistical and clinical
coordinating centers (UM2 AI 117870). The funding organization and
sponsor, DAIT, NIAID, NIH, participated in design and conduct of the
study; collection, management, analysis, and interpretation of the data;
preparation, review, and approval of the manuscript; and the decision to
submit the manuscript for publication. Baxter Healthcare Corporation,
Deerfield, IL, supplied the Isolex 300i Magnetic Cell Selection System
machines, Disposable Sets, and CD34 Reagent Kits used for the HALT-MS
clinical trial to DAIT, NIAID, without charge. The opinions expressed
are those of the authors and do not represent the position of the
National Institute of Allergy and Infectious Diseases, the NIH, or the
US Government.
NR 38
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PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0028-3878
EI 1526-632X
J9 NEUROLOGY
JI Neurology
PD FEB 28
PY 2017
VL 88
IS 9
BP 842
EP 852
DI 10.1212/WNL.0000000000003660
PG 11
WC Clinical Neurology
SC Neurosciences & Neurology
GA EP4HH
UT WOS:000397341100014
PM 28148635
ER
PT J
AU Dimitriades, VR
Devlin, V
Pittaluga, S
Su, HC
Holland, SM
Wilson, W
Dunleavy, K
Shah, NN
Freeman, AF
AF Dimitriades, Victoria R.
Devlin, Vincent
Pittaluga, Stefania
Su, Helen C.
Holland, Steven M.
Wilson, Wyndham
Dunleavy, Kieron
Shah, Nirali N.
Freeman, Alexandra F.
TI DOCK 8 Deficiency, EBV+ Lymphomatoid Granulomatosis, and Intrafamilial
Variation in Presentation
SO FRONTIERS IN PEDIATRICS
LA English
DT Article
DE DOCK8; lymphomatoid granulomatosis; lymphomatous granulomatosis; eBV
lymphoproliferation; bone marrow transplantation
ID STEM-CELL TRANSPLANTATION; DEDICATOR; PHENOTYPE; MUTATIONS
AB Dedicator of cytokinesis 8 ( DOCK8) deficiency is an autosomal recessive, combined immunodeficiency within the spectrum of hyper-IgE syndromes. Epstein-Barr virus-positive lymphomatoid granulomatosis ( LYG) ( EBV+LYG) is a rare diagnosis and a previously unreported presentation of DOCK8 deficiency. A 10-year-old girl was initially evaluated for mild eczema and recurrent sinopulmonary infections. She had normal immunoglobulins with elevated IgE, poor polysaccharide response with low switched memory B cells, low CD4 count, and normal mitogen and antigen responses. Despite clinical improvement following immunoglobulin replacement, a prolonged cough prompted a CT scan, which showed nodules. Biopsy identified a Grade 2 EBV+LYG. Due to an inadequate response with chemotherapy, further workup for primary immunodeficiency was performed. With her symptoms of eczema and IgE elevation, along with her brother's history of recurrent sinopulmonary infections and warts, targeted sequencing of DOCK8 was performed revealing compound heterozygous mutations for the two siblings. Both patients were successfully transplanted with resolution of the LYG and warts, respectively. This is the first reported case of LYG in DOCK8 deficiency. The EBV-driven lymphoproliferative disease along with the infection history in the brother led to the diagnosis of DOCK8 deficiency and curative hematopoietic stem cell transplants.
C1 [Dimitriades, Victoria R.] Univ Calif Davis, Med Ctr, Dept Pediat, Div Infect Dis Immunol & Allergy, Sacramento, CA 95817 USA.
[Devlin, Vincent] Louisiana State Univ, Med Ctr, Dept Pediat, New Orleans, LA 70112 USA.
[Pittaluga, Stefania] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA.
[Su, Helen C.; Holland, Steven M.; Freeman, Alexandra F.] NIAID, NIH, Bethesda, MD 20892 USA.
[Wilson, Wyndham; Dunleavy, Kieron; Shah, Nirali N.] NCI, NIH, Bethesda, MD 20892 USA.
RP Freeman, AF (reprint author), NIAID, NIH, Bethesda, MD 20892 USA.
EM freemaal@mail.nih.gov
NR 12
TC 0
Z9 0
U1 2
U2 2
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 2296-2360
J9 FRONT PEDIATR
JI Front. Pediatr.
PD FEB 28
PY 2017
VL 5
AR 38
DI 10.3389/fped.2017.00038
PG 4
WC Pediatrics
SC Pediatrics
GA EL8UB
UT WOS:000394894500001
PM 28293550
ER
PT J
AU Dabelea, D
Stafford, JM
Mayer-Davis, EJ
D'Agostino, R
Dolan, L
Imperatore, G
Linder, B
Lawrence, JM
Marcovina, SM
Mottl, AK
Black, MH
Pop-Busui, R
Saydah, S
Hamman, RF
Pihoker, C
AF Dabelea, Dana
Stafford, Jeanette M.
Mayer-Davis, Elizabeth J.
D'Agostino, Ralph
Dolan, Lawrence
Imperatore, Giuseppina
Linder, Barbara
Lawrence, Jean M.
Marcovina, Santica M.
Mottl, Amy K.
Black, Mary Helen
Pop-Busui, Rodica
Saydah, Sharon
Hamman, Richard F.
Pihoker, Catherine
CA SEARCH Diabet Youth Res Grp
TI Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During
Childhood and Adolescence With Complications During Teenage Years and
Young Adulthood
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Article
ID PERIPHERAL NEUROPATHY; FUTURE-DIRECTIONS; ONSET TYPE-1; RISK-FACTORS;
YOUTH; SEARCH; PREVALENCE; COHORT; RETINOPATHY; MORTALITY
AB IMPORTANCE The burden and determinants of complications and comorbidities in contemporary youth-onset diabetes are unknown.
OBJECTIVE To determine the prevalence of and risk factors for complications related to type 1 diabetes vs type 2 diabetes among teenagers and young adults who had been diagnosed with diabetes during childhood and adolescence.
DESIGN, SETTING, AND PARTICIPANTS Observational study from 2002 to 2015 in 5 US locations, including 2018 participants with type 1 and type 2 diabetes diagnosed at younger than 20 years, with single outcome measures between 2011 and 2015.
EXPOSURES Type 1 and type 2 diabetes and established risk factors (hemoglobin A(1c) level, body mass index, waist-height ratio, and mean arterial blood pressure).
MAIN OUTCOMES AND MEASURES Diabetic kidney disease, retinopathy, peripheral neuropathy, cardiovascular autonomic neuropathy, arterial stiffness, and hypertension.
RESULTS Of 2018 participants, 1746 had type 1 diabetes (mean age, 17.9 years [SD 4.1]; 1327 non-Hispanic white [76.0%]; 867 female patients [49.7%]), and 272 had type 2 (mean age, 22.1 years [SD 3.5]; 72 non-Hispanic white [26.5%]; 181 female patients [66.5%]). Mean diabetes duration was 7.9 years (both groups). Patients with type 2 diabetes vs those with type 1 had higher age-adjusted prevalence of all measured complications except cardiovascular autonomic neuropathy. After adjustment for established risk factors measured over time, participants with type 2 diabetes vs those with type 1 had significantly higher odds of diabetic kidney disease, retinopathy, and peripheral neuropathy but no significant difference in the odds of arterial stiffness and hypertension.
[GRAPHICS]
CONCLUSIONS AND RELEVANCE Among teenagers and young adults who had been diagnosed with diabetes during childhood or adolescence, the prevalence of complications and comorbidities was higher among those with type 2 diabetes compared with type 1, but frequent in both groups. These findings support early monitoring of youth with diabetes for development of complications.
C1 [Dabelea, Dana; Hamman, Richard F.] Colorado Sch Publ Hlth, Dept Epidemiol, B-119, Aurora, CO 80045 USA.
[Stafford, Jeanette M.; D'Agostino, Ralph] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA.
[Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA.
[Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA.
[Dolan, Lawrence] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA.
[Imperatore, Giuseppina; Saydah, Sharon] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA.
[Linder, Barbara] Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, Bethesda, MD USA.
[Lawrence, Jean M.; Black, Mary Helen] Kaiser Permanente Southern Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA.
[Marcovina, Santica M.] Univ Washington, Northwest Lipid Res Lab, Seattle, WA USA.
[Mottl, Amy K.] Univ N Carolina, Sch Med, Div Nephrol & Hypertens, Chapel Hill, NC USA.
[Pop-Busui, Rodica] Univ Michigan, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA.
[Pihoker, Catherine] Univ Washington, Dept Pediat, Seattle, WA 98195 USA.
RP Dabelea, D (reprint author), Colorado Sch Publ Hlth, Dept Epidemiol, B-119, Aurora, CO 80045 USA.
EM dana.dabelea@ucdenver.edu
FU National Institutes of Health (NIH), National Institute of Diabetes and
Digestive and Kidney Diseases; Centers for Disease Control and
Prevention (CDC); CDC [RFP DP15-002]; NIH, National Institute of
Diabetes and Digestive and Kidney Diseases; Kaiser Permanente Southern
California [U18DP006133, U48/CCU919219, U01 DP000246, U18DP002714];
University of Colorado-Denver [U18DP006139, U48/CCU819241-3, U01
DP000247, U18DP000247-06A1]; Cincinnati's Children's Hospital Medical
Center [U18DP006134, U48/CCU519239, U01 DP000248, 1U18DP002709];
University of North Carolina at Chapel Hill [U18DP006138, U48/CCU419249,
U01 DP000254, U18DP002708]; Seattle Children's Hospital [U18DP006136,
U58/CCU019235-4, U01 DP000244, U18DP002710-01]; Wake Forest University
School of Medicine [U18DP006131, U48/CC U919219, U01 DP000250,
200-2010-35171]
FX The SEARCH for Diabetes in Youth Cohort Study (1UC4DK108173-01) is
funded by the National Institutes of Health (NIH), National Institute of
Diabetes and Digestive and Kidney Diseases and supported by the Centers
for Disease Control and Prevention (CDC). The Population Based Registry
of Diabetes in Youth Study (RFP DP15-002) is funded by the CDC and
supported by the NIH, National Institute of Diabetes and Digestive and
Kidney Diseases. Sites: Kaiser Permanente Southern California
(U18DP006133, U48/CCU919219, U01 DP000246, and U18DP002714), University
of Colorado-Denver (U18DP006139, U48/CCU819241-3, U01 DP000247, and
U18DP000247-06A1), Cincinnati's Children's Hospital Medical Center
(U18DP006134, U48/CCU519239, U01 DP000248, and 1U18DP002709), University
of North Carolina at Chapel Hill (U18DP006138, U48/CCU419249, U01
DP000254, and U18DP002708), Seattle Children's Hospital (U18DP006136,
U58/CCU019235-4, U01 DP000244, and U18DP002710-01), and Wake Forest
University School of Medicine (U18DP006131, U48/CC U919219, U01
DP000250, and 200-2010-35171).
NR 39
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U1 4
U2 4
PU AMER MEDICAL ASSOC
PI CHICAGO
PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA
SN 0098-7484
EI 1538-3598
J9 JAMA-J AM MED ASSOC
JI JAMA-J. Am. Med. Assoc.
PD FEB 28
PY 2017
VL 317
IS 8
BP 825
EP 835
DI 10.1001/jama.2017.0686
PG 11
WC Medicine, General & Internal
SC General & Internal Medicine
GA EM7PW
UT WOS:000395505600020
PM 28245334
ER
PT J
AU Varshney, A
Scott, LJ
Welch, RP
Erdos, MR
Chines, PS
Narisu, N
Albanus, RD
Orchard, P
Wolford, BN
Kursawe, R
Vadlamudi, S
Cannon, ME
Didion, JP
Hensley, J
Kirilusha, A
Bonnycastle, LL
Taylor, DL
Watanabe, R
Mohlke, KL
Boehnke, M
Collins, FS
Parker, SCJ
Stitzel, ML
AF Varshney, Arushi
Scott, Laura J.
Welch, Ryan P.
Erdos, Michael R.
Chines, Peter S.
Narisu, Narisu
Albanus, Ricardo D'O.
Orchard, Peter
Wolford, Brooke N.
Kursawe, Romy
Vadlamudi, Swarooparani
Cannon, Maren E.
Didion, John P.
Hensley, John
Kirilusha, Anthony
Bonnycastle, Lori L.
Taylor, D. Leland
Watanabe, Richard
Mohlke, Karen L.
Boehnke, Michael
Collins, Francis S.
Parker, Stephen C. J.
Stitzel, Michael L.
CA NISC Comparative Sequencing Progra
TI Genetic regulatory signatures underlying islet gene expression and type
2 diabetes
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE chromatin; diabetes; eQTL; epigenome; footprint
ID GENOME-WIDE ASSOCIATION; PANCREATIC BETA-CELL; INSULIN-SECRETION;
GENOTYPE IMPUTATION; VARIANTS; CHROMATIN; DISEASE; RFX6; DISCOVERY;
IDENTIFICATION
AB Genome-wide association studies (GWAS) have identified > 100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce dense cis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed that cis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATACseq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for islet cis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition.
C1 [Varshney, Arushi; Parker, Stephen C. J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.
[Scott, Laura J.; Welch, Ryan P.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.
[Scott, Laura J.; Welch, Ryan P.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
[Erdos, Michael R.; Chines, Peter S.; Narisu, Narisu; Didion, John P.; Kirilusha, Anthony; Bonnycastle, Lori L.; Taylor, D. Leland; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA.
[Albanus, Ricardo D'O.; Orchard, Peter; Wolford, Brooke N.; Hensley, John; Parker, Stephen C. J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
[Kursawe, Romy; Stitzel, Michael L.] Jackson Lab Genom Med, Farmington, CT 06032 USA.
[Vadlamudi, Swarooparani; Cannon, Maren E.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
[NISC Comparative Sequencing Progra] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA.
[Taylor, D. Leland] European Bioinformat Inst, Wellcome Trust Genome Campus, European Mol Biol Lab, Hinxton CB10 1SD, Cambs, England.
[Watanabe, Richard] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA.
[Watanabe, Richard] Univ Southern Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90089 USA.
RP Parker, SCJ (reprint author), Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.; Collins, FS (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA.; Parker, SCJ (reprint author), Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
EM collinsf@od.nih.gov; scjp@umich.edu
OI Taylor, Leland/0000-0001-6498-6970
FU National Institute of Diabetes and Digestive and Kidney Diseases Grants
[F31HL127984, U01DK062370, ZIAHG000024, R00DK099240, 5R00DK092251,
R01DK093757, U01DK105561, R01DK072193]; American Diabetes Association
Pathway to Stop Diabetes Grant [1-14-INI-07]; Intramural Research
Program of the National Human Genome Research Institute, NIH
FX We thank additional members of our laboratories and Finland-United
States Investigation of NIDDM Genetics (FUSION) Study investigators for
helpful comments on and critiques of the study and manuscript. This
study was supported by National Institute of Diabetes and Digestive and
Kidney Diseases Grants F31HL127984 (to M.E.C.), U01DK062370 (to M.B.),
ZIAHG000024 (to F.S.C.), R00DK099240 (to S.C.J.P.), 5R00DK092251 (to
M.L.S.), and R01DK093757, U01DK105561, and R01DK072193 (to K.L.M.) and
American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07
(to S.C.J.P.). This research was supported, in part, by the Intramural
Research Program of the National Human Genome Research Institute, NIH.
NR 56
TC 0
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U1 2
U2 2
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 28
PY 2017
VL 114
IS 9
BP 2301
EP 2306
DI 10.1073/pnas.1621192114
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1TZ
UT WOS:000395101200062
PM 28193859
ER
PT J
AU Lau, MSY
Dalziel, BD
Funk, S
McClelland, A
Tiffany, A
Riley, S
Metcalf, CJE
Grenfell, BT
AF Lau, Max S. Y.
Dalziel, Benjamin Douglas
Funk, Sebastian
McClelland, Amanda
Tiffany, Amanda
Riley, Steven
Metcalf, C. Jessica E.
Grenfell, Bryan T.
TI Spatial and temporal dynamics of superspreading events in the 2014-2015
West Africa Ebola epidemic
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE Ebola; superspreading; offspring distribution; Bayesian inference
ID VIRUS DISEASE; TRANSMISSION; OUTBREAK
AB The unprecedented scale of the Ebola outbreak in Western Africa (2014-2015) has prompted an explosion of efforts to understand the transmission dynamics of the virus and to analyze the performance of possible containment strategies. Models have focused primarily on the reproductive numbers of the disease that represent the average number of secondary infections produced by a random infectious individual. However, these population-level estimates may conflate important systematic variation in the number of cases generated by infected individuals, particularly found in spatially localized transmission and superspreading events. Although superspreading features prominently in first-hand narratives of Ebola transmission, its dynamics have not been systematically characterized, hindering refinements of future epidemic predictions and explorations of targeted interventions. We used Bayesian model inference to integrate individual-level spatial information with other epidemiological data of community-based (undetected within clinical-care systems) cases and to explicitly infer distribution of the cases generated by each infected individual. Our results show that super-spreaders play a key role in sustaining onward transmission of the epidemic, and they are responsible for a significant proportion (similar to 61%) of the infections. Our results also suggest age as a key demographic predictor for superspreading. We also show that community-based cases may have progressed more rapidly than those notified within clinical-care systems, and most transmission events occurred in a relatively short distance (with median value of 2.51 km). Our results stress the importance of characterizing superspreading of Ebola, enhance our current understanding of its spatiotemporal dynamics, and highlight the potential importance of targeted control measures.
C1 [Lau, Max S. Y.; Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA.
[Dalziel, Benjamin Douglas] Oregon State Univ, Dept Integrat Biol, Corvallis, OR 97331 USA.
[Dalziel, Benjamin Douglas] Oregon State Univ, Dept Math, Corvallis, OR 97331 USA.
[Funk, Sebastian] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1E 7HT, England.
[McClelland, Amanda] Int Federat Red Cross & Red Crescent Societies, CH-1211 Geneva 19, Switzerland.
[Tiffany, Amanda] Epicentre, CH-1211 Geneva 6, Switzerland.
[Riley, Steven] Imperial Coll London, Dept Infect Dis Epidemiol, Ctr Outbreak Anal & Modelling, MRC, London SW7 2AZ, England.
[Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA.
RP Lau, MSY (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA.
EM msylau@princeton.edu
FU Bill & Melinda Gates Foundation [OPP1091919]; RAPIDD program of the
Science and Technology Directorate Department of Homeland Security; UK
Medical Research Council (MRC); MRC Career Award in Biostatistics
[MR/K021680/1]; Fogarty International Center, National Institutes of
Health
FX This work was supported by Bill & Melinda Gates Foundation Grant
OPP1091919; the RAPIDD program of the Science and Technology Directorate
Department of Homeland Security and the Fogarty International Center,
National Institutes of Health; and the UK Medical Research Council
(MRC). S.F. was also supported by MRC Career Award in Biostatistics
MR/K021680/1.
NR 34
TC 0
Z9 0
U1 2
U2 2
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 28
PY 2017
VL 114
IS 9
BP 2337
EP 2342
DI 10.1073/pnas.1614595114
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1TZ
UT WOS:000395101200068
PM 28193880
ER
PT J
AU Feeley, EM
Pilla-Moffett, DM
Zwack, EE
Piro, AS
Finethy, R
Kolb, JP
Martinez, J
Brodsky, IE
Coers, J
AF Feeley, Eric M.
Pilla-Moffett, Danielle M.
Zwack, Erin E.
Piro, Anthony S.
Finethy, Ryan
Kolb, Joseph P.
Martinez, Jennifer
Brodsky, Igor E.
Coers, Joern
TI Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles
furnished with bacterial secretion systems
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE interferon; guanylate binding proteins; immunity-related GTPase;
galectin; ubiquitin
ID LEGIONELLA-PNEUMOPHILA; TOXOPLASMA-GONDII; HOST-DEFENSE;
YERSINIA-PSEUDOTUBERCULOSIS; PARASITOPHOROUS VACUOLE; AUTOPHAGY
PROTEINS; SALMONELLA; RESISTANCE; PATHOGENS; IMMUNITY
AB Many invasive bacteria establish pathogen-containing vacuoles (PVs) as intracellular niches for microbial growth. Immunity to these infections is dependent on the ability of host cells to recognize PVs as targets for host defense. The delivery of several host defense proteins to PVs is controlled by IFN-inducible guanylate binding proteins (GBPs), which themselves dock to PVs through poorly characterized mechanisms. Here, we demonstrate that GBPs detect the presence of bacterial protein secretion systems as "patterns of pathogenesis" associated with PVs. We report that the delivery of GBP2 to Legionella-containing vacuoles is dependent on the bacterial Dot/Icm secretion system, whereas the delivery of GBP2 to Yersiniacontaining vacuoles (YCVs) requires hypersecretion of Yersinia translocon proteins. We show that the presence of bacterial secretion systems directs cytosolic carbohydrate-binding protein Galectin-3 to PVs and that the delivery of GBP1 and GBP2 to Legionella-containing vacuoles or YCVs is substantially diminished in Galectin-3-deficient cells. Our results illustrate that insertion of bacterial secretion systems into PV membranes stimulates Galectin-3-dependent recruitment of antimicrobial GBPs to PVs as part of a coordinated host defense program.
C1 [Feeley, Eric M.; Pilla-Moffett, Danielle M.; Piro, Anthony S.; Finethy, Ryan; Coers, Joern] Duke Univ Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA.
[Zwack, Erin E.; Brodsky, Igor E.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA.
[Kolb, Joseph P.; Martinez, Jennifer] NIEHS, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA.
[Coers, Joern] Duke Univ Med Ctr, Dept Immunol, Durham, NC 27710 USA.
RP Coers, J (reprint author), Duke Univ Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA.; Coers, J (reprint author), Duke Univ Med Ctr, Dept Immunol, Durham, NC 27710 USA.
EM jorn.coers@duke.edu
FU National Institutes of Health [R21AI122048, R01AI103197, R01AI103062];
Investigators in the Pathogenesis of Infectious Disease Awards from the
Burroughs Wellcome Fund
FX We thank Dr. Gregory Taylor for sharing Irgm1-/Irgm3-/- mouse bone
marrow cells, Dr. Felix Randow for sharing YFP-Galectin expression
constructs, Dr. Sunny Shin for sharing the mCherry expression plasmid,
and Sarah Luoma for technical assistance. This work was supported by
National Institutes of Health Grants R21AI122048 (to J.C.), R01AI103197
(to J.C.), and R01AI103062 (to I. E. B.), and Investigators in the
Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome
Fund (to J.C. and I.E.B.).
NR 57
TC 0
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U1 0
U2 0
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 28
PY 2017
VL 114
IS 9
BP E1698
EP E1706
DI 10.1073/pnas.1615771114
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1TZ
UT WOS:000395101200016
PM 28193861
ER
PT J
AU Knudson, KM
Pritzl, CJ
Saxena, V
Altman, A
Daniels, MA
Teixeiro, E
AF Knudson, Karin M.
Pritzl, Curtis J.
Saxena, Vikas
Altman, Amnon
Daniels, Mark A.
Teixeiro, Emma
TI NF kappa B-Pim-1-Eomesodermin axis is critical for maintaining CD8
T-cell memory quality
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE CD8 T-cell memory; NFkB; Pim1; Eomesodermin
ID NF-KAPPA-B; KINASE C-THETA; TRANSCRIPTIONAL CONTROL; TERMINAL KINASE;
CUTTING EDGE; IKK COMPLEX; RECEPTOR; EFFECTOR; DIFFERENTIATION; SURVIVAL
AB T-cell memory is critical for long-term immunity. However, the factors involved in maintaining the persistence, function, and phenotype of the memory pool are undefined. Eomesodermin (Eomes) is required for the establishment of the memory pool. Here, we show that in T cells transitioning to memory, the expression of high levels of Eomes is not constitutive but rather requires a continuum of cell-intrinsic NF kappa B signaling. Failure to maintain NF kappa B signals after the peak of the response led to impaired Eomes expression and a defect in the maintenance of CD8 T-cell memory. Strikingly, we found that antigen receptor [T-cell receptor (TCR)] signaling regulates this process through expression of the NF(kappa)Bdependent kinase proviral integration site for Moloney murine leukemia virus-1 (PIM-1), which in turn regulates NF kappa B and Eomes. T cells defective in TCR-dependent NF kappa B signaling were impaired in late expression of Pim-1, Eomes, and CD8 memory. These defects were rescued when TCR-dependent NF kappa B signaling was restored. We also found that NF kappa B-Pim-1 signals were required at memory to maintain memory CD8 T-cell longevity, effector function, and Eomes expression. Hence, an NF kappa B-Pim-1Eomes axis regulates Eomes levels to maintain memory fitness.
C1 [Knudson, Karin M.; Pritzl, Curtis J.; Saxena, Vikas; Daniels, Mark A.; Teixeiro, Emma] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA.
[Knudson, Karin M.] Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD 20814 USA.
[Altman, Amnon] Jolla Inst Allergy & Immunol, Divis Cell Biol, San Diego, CA 92121 USA.
RP Teixeiro, E (reprint author), Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA.
EM teixeiropernase@missouri.edu
FU University of Missouri Mission Enhancement Fund; University of Missouri
Life Sciences Fellowship; National Institutes of Health [R01 AI110420,
R01 CA35299]
FX We thank S. Guerder, M. Croft, S. Reiner, and N. Kim for providing
retroviral constructs; S. S. Way, M. Bevan, and D. Zehn for providing
Listeria monocytogenes strains; B. Osborne, S. Jameson, and Sara
Hamilton for critical discussion; R. Kedl for performing experiments
with CD70-deficient mice; B. Hahm and M. Vijayan for providing the NF.B
reporter construct; and M. Johnson, D. Burke, and M. Lange for providing
the VSV-G construct. This work was supported by the University of
Missouri Mission Enhancement Fund, the University of Missouri Life
Sciences Fellowship (to K.M.K.), and the National Institutes of Health
Grants R01 AI110420 (to E.T.) and R01 CA35299 (to A.A.).
NR 56
TC 0
Z9 0
U1 2
U2 2
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 28
PY 2017
VL 114
IS 9
BP E1659
EP E1667
DI 10.1073/pnas.1608448114
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1TZ
UT WOS:000395101200012
PM 28193872
ER
PT J
AU Cubenas-Potts, C
Rowley, MJ
Lyu, XW
Li, G
Lei, EP
Corces, VG
AF Cubenas-Potts, Caelin
Rowley, M. Jordan
Lyu, Xiaowen
Li, Ge
Lei, Elissa P.
Corces, Victor G.
TI Different enhancer classes in Drosophila bind distinct architectural
proteins and mediate unique chromatin interactions and 3D architecture
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID INTEGRATIVE GENOMICS VIEWER; LONG-RANGE INTERACTIONS; GENE-EXPRESSION;
RNA-POLYMERASE; HI-C; INSULATOR FUNCTION; ACTIVE CHROMATIN; HUMAN-CELLS;
PROMOTER; ORGANIZATION
AB Eukaryotic gene expression is regulated by enhancer-promoter interactions but the molecular mechanisms that govern specificity have remained elusive. Genome-wide studies utilizing STARR-seq identified two enhancer classes in Drosophila that interact with different core promoters: housekeeping enhancers (hkCP) and developmental enhancers (dCP). We hypothesized that the two enhancer classes are occupied by distinct architectural proteins, affecting their enhancer-promoter contacts. By evaluating ChIP-seq occupancy of architectural proteins, typical enhancer-associated proteins, and histone modifications, we determine that both enhancer classes are enriched for RNA Polymerase II, CBP, and architectural proteins but there are also distinctions. hkCP enhancers contain H3K4me3 and exclusively bind Cap-H2, Chromator, DREF and Z4, whereas dCP enhancers contain H3K4me1 and are more enriched for Rad21 and Fs(1) h-L. Additionally, we map the interactions of each enhancer class utilizing a Hi-C dataset with <1 kb resolution. Results suggest that hkCP enhancers are more likely to form multi-TSS interaction networks and be associated with topologically associating domain (TAD) borders, while dCP enhancers are more often bound to one or two TSSs and are enriched at chromatin loop anchors. The data support a model suggesting that the unique architectural protein occupancy within en-hancers is one contributor to enhancer-promoter interaction specificity.
C1 [Cubenas-Potts, Caelin; Rowley, M. Jordan; Lyu, Xiaowen; Li, Ge; Corces, Victor G.] Emory Univ, Dept Biol, 1510 Clifton Rd NE, Atlanta, GA 30322 USA.
[Lei, Elissa P.] NIDDK, Nucl Org & Gene Express Sect, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA.
[Li, Ge] Emory Univ, Div Digest Dis, 1670 Clairmont Rd, Decatur, GA 30033 USA.
[Cubenas-Potts, Caelin] Ctr Dis Control & Prevent, Meningitis & Vaccine Preventable Dis Branch, Div Bacterial Dis, Natl Ctr Immunizat & Resp Dis, 1600 Clifton Rd, Atlanta, GA 30333 USA.
RP Corces, VG (reprint author), Emory Univ, Dept Biol, 1510 Clifton Rd NE, Atlanta, GA 30322 USA.
EM vgcorces@gmail.com
FU U.S. Public Health Service Award [R01 GM035463]; National Institutes of
Health; National Research Service Award [F32 GM113570]
FX U.S. Public Health Service Award R01 GM035463 (to V.G.C.); Intramural
Research Program of the NIDDK (to E.L.) from the National Institutes of
Health and Ruth L. Kirschstein National Research Service Award F32
GM113570 (to M.J.R.). Funding for open access charge: U.S. Public Health
Service Award [R01 GM035463]. Conflict of interest statement. None
declared.
NR 71
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U1 0
U2 0
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD FEB 28
PY 2017
VL 45
IS 4
BP 1714
EP 1730
DI 10.1093/nar/gkw1114
PG 17
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EN5OO
UT WOS:000396055400022
ER
PT J
AU Hamilton, WL
Claessens, A
Otto, TD
Kekre, M
Fairhurst, RM
Rayner, JC
Kwiatkowski, D
AF Hamilton, William L.
Claessens, Antoine
Otto, Thomas D.
Kekre, Mihir
Fairhurst, Rick M.
Rayner, Julian C.
Kwiatkowski, Dominic
TI Extreme mutation bias and high AT content in plasmodium falciparum
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID LOW-COMPLEXITY REGIONS; COPY NUMBER VARIATION; GENOME-WIDE VIEW; MALARIA
PARASITE; NUCLEOTIDE SUBSTITUTION; ESCHERICHIA-COLI; DNA-SEQUENCES; VAR
GENES; INFECTED ERYTHROCYTES; MOLECULAR-SPECTRUM
AB For reasons that remain unknown, the Plasmodium falciparum genome has an exceptionally high AT content compared to other Plasmodium species and eukaryotes in general - nearly 80% in coding regions and approaching 90% in non-coding regions. Here, we examine how this phenomenon relates to genome-wide patterns of de novo mutation. Mutation accumulation experiments were performed by sequential cloning of six P. falciparum isolates growing in human erythrocytes in vitro for 4 years, with 279 clones sampled for whole genome sequencing at different time points. Genome sequence analysis of these samples revealed a significant excess of G:C to A:T transitions compared to other types of nucleotide substitution, which would naturally cause AT content to equilibrate close to the level seen across the P. fal-ciparum reference genome (80.6% AT). These data also uncover an extremely high rate of small indel mutation relative to other species, primarily associated with repetitive AT-rich sequences, in addition to larger-scale structural rearrangements focused in antigen-coding var genes. In conclusion, high AT content in P. falciparum is driven by a systematic mutational bias and ultimately leads to an unusual level of microstructural plasticity, raising the question of whether this contributes to adaptive evolution.
C1 [Hamilton, William L.; Claessens, Antoine; Otto, Thomas D.; Kekre, Mihir; Rayner, Julian C.; Kwiatkowski, Dominic] Wellcome Trust Sanger Inst, Malaria Programme, Hinxton CB10 1SA, England.
[Hamilton, William L.] Univ Cambridge, Sch Clin Med, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0SP, England.
[Claessens, Antoine] Med Res Council Unit Gambia, Atlantic Rd,POB 273, Banjul, Gambia.
[Claessens, Antoine] London Sch Hyg & Trop Med, Dept Pathogen Mol Biol, London WC1E 7HT, England.
[Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA.
[Kwiatkowski, Dominic] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
RP Hamilton, WL (reprint author), Wellcome Trust Sanger Inst, Malaria Programme, Hinxton CB10 1SA, England.; Hamilton, WL (reprint author), Univ Cambridge, Sch Clin Med, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0SP, England.
EM will.l.hamilton@gmail.com
FU Wellcome Trust [098051]; Medical Research Council [G0600718]
FX Wellcome Trust [098051]; Medical Research Council [G0600718]. Funding
for open access charge: Wellcome Trust.
NR 100
TC 0
Z9 0
U1 0
U2 0
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD FEB 28
PY 2017
VL 45
IS 4
BP 1889
EP 1901
DI 10.1093/nar/gkw1259
PG 13
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EN5OO
UT WOS:000396055400035
ER
PT J
AU Kirby, TW
Gassman, NR
Smith, CE
Zhao, ML
Horton, JK
Wilson, SH
London, RE
AF Kirby, Thomas W.
Gassman, Natalie R.
Smith, Cassandra E.
Zhao, Ming-Lang
Horton, Julie K.
Wilson, Samuel H.
London, Robert E.
TI DNA polymerase beta contains a functional nuclear localization signal at
its N-terminus
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID BASE-EXCISION-REPAIR; IMPORTIN-ALPHA ISOFORMS; TRIPLE-A-SYNDROME;
OXIDATIVE-STRESS; IN-VITRO; MOUSE FIBROBLASTS; OVER-EXPRESSION;
BREAST-CANCER; CELL-CYCLE; LIGASE I
AB DNA polymerase beta (pol beta) requires nuclear localization to fulfil its DNA repair function. Although its small size has been interpreted to imply the absence of a need for active nuclear import, sequence and structural analysis suggests that a monopartite nuclear localization signal (NLS) may reside in the Nterminal lyase domain. Binding of this domain to Importin alpha 1 (Imp alpha 1) was confirmed by gel filtration and NMR studies. Affinity was quantified by fluorescence polarization analysis of a fluorescein-tagged peptide corresponding to pol beta residues 2-13. These studies indicate high affinity binding, characterized by a low micromolar K-d, that is selective for the murine Importin alpha 1 (mImp alpha 1) minor site, with the Kd strengthening to similar to 140 nM for the full lyase domain (residues 2-87). A further reduction in Kd obtains in binding studies with human Importin alpha 5 (hImp alpha 5), which in some cases has been demonstrated to bind small domains connected to the NLS. The role of this NLS was confirmed by fluorescent imaging of wild-type and NLS-mutated pol beta (R4S, K5S) in mouse embryonic fibroblasts lacking endogenous pol beta. Together these data demonstrate that pol beta contains a specific NLS sequence in the N-terminal lyase domain that promotes transport of the protein independent of its interaction partners. Active nuclear uptake allows development of a nuclear/cytosolic concentration gradient against a background of passive diffusion.
C1 [Kirby, Thomas W.; Gassman, Natalie R.; Smith, Cassandra E.; Zhao, Ming-Lang; Horton, Julie K.; Wilson, Samuel H.; London, Robert E.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.
[Gassman, Natalie R.] Univ S Alabama, Mitchell Canc Inst, Mol & Metab Oncol, 1660 Springhill Ave, Mobile, AL 36604 USA.
[Smith, Cassandra E.] Univ Colorado, Sch Med, Anschutz Med Campus,Campus Box C296 AMC, Aurora, CO 80045 USA.
RP London, RE (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.
EM london@niehs.nih.gov
FU Intramural Research Program of the NIH, National Institute of
Environmental Health Sciences [ZIA ES050111, Z01 ES050158, ES050159,
R00ES023813]
FX Intramural Research Program of the NIH, National Institute of
Environmental Health Sciences [project number ZIA ES050111 to R.E.L. and
project numbers Z01 ES050158 and ES050159 to S.H.W., R00ES023813 to
N.R.G., in part]. Funding for open access charge: Intramural Research
Program of the NIH, National Institute of Environmental Health Sciences
[project number ZIA ES050111].
NR 94
TC 0
Z9 0
U1 0
U2 0
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD FEB 28
PY 2017
VL 45
IS 4
BP 1958
EP 1970
DI 10.1093/nar/gkw1257
PG 13
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EN5OO
UT WOS:000396055400040
ER
PT J
AU Halman, JR
Satterwhite, E
Roark, B
Chandler, M
Viard, M
Ivanina, A
Bindewald, E
Kasprzak, WK
Panigaj, M
Bui, MN
Lu, JS
Miller, J
Khisamutdinov, EF
Shapiro, BA
Dobrovolskaia, MA
Afonin, KA
AF Halman, Justin R.
Satterwhite, Emily
Roark, Brandon
Chandler, Morgan
Viard, Mathias
Ivanina, Anna
Bindewald, Eckart
Kasprzak, Wojciech K.
Panigaj, Martin
Bui, My N.
Lu, Jacob S.
Miller, Johann
Khisamutdinov, Emil F.
Shapiro, Bruce A.
Dobrovolskaia, Marina A.
Afonin, Kirill A.
TI Functionally-interdependent shape-switching nanoparticles with
controllable properties
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID RNA-DNA HYBRIDS; SPLIT FUNCTIONALITIES; MAMMALIAN-CELLS; PH CHANGES;
PROTEIN; CYTOKINES; NANOTECHNOLOGY; INTERFERENCE; NANOMACHINE;
ACTIVATION
AB We introduce a new concept that utilizes cognate nucleic acid nanoparticles which are fully complementary and functionally-interdependent to each other. In the described approach, the physical interaction between sets of designed nanoparticles initiates a rapid isothermal shape change which triggers the activation of multiple functionalities and biological pathways including transcription, energy transfer, functional aptamers and RNA interference. The individual nanoparticles are not active and have controllable kinetics of re-association and fine-tunable chemical and thermodynamic stabilities. Computational algorithms were developed to accurately predict melting temperatures of nanoparticles of various compositions and trace the process of their re-association in silico. Additionally, tunable immunostimulatory properties of described nanoparticles suggest that the particles that do not induce pro-inflammatory cytokines and high levels of interferons can be used as scaffolds to carry therapeutic oligonucleotides, while particles with strong interferon and mild proinflammatory cytokine induction may qualify as vaccine adjuvants. The presented concept provides a simple, cost-effective and straightforward model for the development of combinatorial regulation of biological processes in nucleic acid nanotechnology.
C1 [Halman, Justin R.; Satterwhite, Emily; Roark, Brandon; Chandler, Morgan; Ivanina, Anna; Afonin, Kirill A.] Univ North Carolina Charlotte, Dept Chem, Nanoscale Sci Program, Charlotte, NC 28223 USA.
[Viard, Mathias; Lu, Jacob S.; Miller, Johann; Shapiro, Bruce A.] NCI, RNA Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA.
[Viard, Mathias; Bindewald, Eckart; Kasprzak, Wojciech K.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res Inc, RNA Biol Lab, Frederick, MD 21702 USA.
[Panigaj, Martin] Pavol Jozef Safarik Univ Kosice, Inst Biol & Ecol, Fac Sci, Kosice 04154, Slovakia.
[Bui, My N.; Khisamutdinov, Emil F.] Ball State Univ, Dept Chem, Muncie, IN 47306 USA.
[Dobrovolskaia, Marina A.] Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA.
[Afonin, Kirill A.] Univ North Carolina Charlotte, Ctr Biomed Engn & Sci, Charlotte, NC 28223 USA.
RP Afonin, KA (reprint author), Univ North Carolina Charlotte, Dept Chem, Nanoscale Sci Program, Charlotte, NC 28223 USA.; Afonin, KA (reprint author), Univ North Carolina Charlotte, Ctr Biomed Engn & Sci, Charlotte, NC 28223 USA.
EM kafonin@uncc.edu
RI Nanotechnology Characterization Lab, NCL/K-8454-2012
FU Department of Chemistry UNCC start-up funds; UNCC Faculty Research
Grant; Frederick National Laboratory for Cancer Research, National
Institutes of Health [HHSN26120080001E]; Intramural Research Program of
the NIH, National Cancer Institute, Center for Cancer Research; Slovak
Academic Information Agency (SAIA)
FX The research was supported by Department of Chemistry UNCC start-up
funds and UNCC Faculty Research Grant to KAA. MAD, MV, EB, WKK disclose
that this project has been funded in whole or in part with Federal funds
from the Frederick National Laboratory for Cancer Research, National
Institutes of Health, under contract HHSN26120080001E. This Research was
supported [in part] by the Intramural Research Program of the NIH,
National Cancer Institute, Center for Cancer Research. The content of
this publication does not necessarily reflect the views or policies of
the Department of Health and Human Services, nor does mention of trade
names, commercial products or organizations imply endorsement by the
U.S. Government. MP participation on the project was supported [in part]
by Slovak Academic Information Agency (SAIA).
NR 55
TC 0
Z9 0
U1 1
U2 1
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD FEB 28
PY 2017
VL 45
IS 4
BP 2210
EP 2220
DI 10.1093/nar/gkx008
PG 11
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EN5OO
UT WOS:000396055400060
ER
PT J
AU Chan, WV
Pearson, TA
Bennett, GC
Cushman, WC
Gaziano, TA
Gorman, PN
Handler, J
Krumholz, HM
Kushner, RF
MacKenzie, TD
Sacco, RL
Smith, SC
Stevens, VJ
Wells, BL
AF Chan, Wiley V.
Pearson, Thomas A.
Bennett, Glen C.
Cushman, William C.
Gaziano, Thomas A.
Gorman, Paul N.
Handler, Joel
Krumholz, Harlan M.
Kushner, Robert F.
MacKenzie, Thomas D.
Sacco, Ralph L.
Smith, Sidney C., Jr.
Stevens, Victor J.
Wells, Barbara L.
TI ACC/AHA Special Report: Clinical Practice Guideline Implementation
Strategies: A Summary of Systematic Reviews by the NHLBI Implementation
Science Work Group: A Report of the American College of
Cardiology/American Heart Association Task Force on Clinical Practice
Guidelines
SO CIRCULATION
LA English
DT Review
DE AHA Scientific Statements; cost; detailing; effectiveness;
evidence-based; incentives; interventions; reminders; systematic review
ID DECISION-SUPPORT-SYSTEMS; HEALTH-CARE; VENOUS THROMBOEMBOLISM; IMPROVE
PROPHYLAXIS; DISEASE MANAGEMENT; PATIENT OUTCOMES; MEDICATION USE;
INTERVENTIONS; METAANALYSIS; QUALITY
AB Background: In 2008, the National Heart, Lung, and Blood Institute convened an Implementation Science Work Group to assess evidence-based strategies for effectively implementing clinical practice guidelines. This was part of a larger effort to update existing clinical practice guidelines on cholesterol, blood pressure, and overweight/obesity.
Objectives: Review evidence from the published implementation science literature and identify effective or promising strategies to enhance the adoption and implementation of clinical practice guidelines.
Methods: This systematic review was conducted on 4 critical questions, each focusing on the adoption and effectiveness of 4 intervention strategies: (1) reminders, (2) educational outreach visits, (3) audit and feedback, and (4) provider incentives. A scoping review of the Rx for Change database of systematic reviews was used to identify promising guideline implementation interventions aimed at providers. Inclusion and exclusion criteria were developed a priori for each question, and the published literature was initially searched up to 2012, and then updated with a supplemental search to 2015. Two independent reviewers screened the returned citations to identify relevant reviews and rated the quality of each included review.
Results: Audit and feedback and educational outreach visits were generally effective in improving both process of care (15 of 21 reviews and 12 of 13 reviews, respectively) and clinical outcomes (7 of 12 reviews and 3 of 5 reviews, respectively). Provider incentives showed mixed effectiveness for improving both process of care (3 of 4 reviews) and clinical outcomes (3 reviews equally distributed between generally effective, mixed, and generally ineffective). Reminders showed mixed effectiveness for improving process of care outcomes (27 reviews with 11 mixed and 3 generally ineffective results) and were generally ineffective for clinical outcomes (18 reviews with 6 mixed and 9 generally ineffective results). Educational outreach visits (2 of 2 reviews), reminders (3 of 4 reviews), and provider incentives (1 of 1 review) were generally effective for cost reduction. Educational outreach visits (1 of 1 review) and provider incentives (1 of 1 review) were also generally effective for cost-effectiveness outcomes. Barriers to clinician adoption or adherence to guidelines included time constraints (8 reviews/overviews); limited staffing resources (2 overviews); timing (5 reviews/overviews); clinician skepticism (5 reviews/overviews); clinician knowledge of guidelines (4 reviews/overviews); and higher age of the clinician (1 overview). Facilitating factors included guideline characteristics such as format, resources, and end-user involvement (6 reviews/overviews); involving stakeholders (5 reviews/overviews); leadership support (5 reviews/overviews); scope of implementation (5 reviews/overviews); organizational culture such as multidisciplinary teams and low-baseline adherence (9 reviews/overviews); and electronic guidelines systems (3 reviews).
Conclusion: The strategies of audit and feedback and educational outreach visits were generally effective in improving both process of care and clinical outcomes. Reminders and provider incentives showed mixed effectiveness, or were generally ineffective. No general conclusion could be reached about cost effectiveness, because of limitations in the evidence. Important gaps exist in the evidence on effectiveness of implementation interventions, especially regarding clinical outcomes, cost effectiveness and contextual issues affecting successful implementation.
C1 [Chan, Wiley V.] Kaiser Permanente Northwest, Guidelines & Evidence Based Med, Portland, OR 97210 USA.
[Pearson, Thomas A.] Univ Rochester, Med Ctr, Res & Educ, Rochester, NY 14627 USA.
[Bennett, Glen C.] NHLBI, Bldg 10, Bethesda, MD 20892 USA.
[Cushman, William C.] Univ Tennessee, Hlth Sci Ctr, Preventat Med, Knoxville, TN 37996 USA.
[Gaziano, Thomas A.] Harvard Med Sch, Boston, MA USA.
[Gaziano, Thomas A.] Brigham & Womens Hosp, Cardiovasc Med, Boston, MA 02115 USA.
[Gorman, Paul N.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA.
[Handler, Joel] Southern Calif Permanente Med Grp, Portland, OR USA.
[Krumholz, Harlan M.] Yale New Haven Med Ctr, 20 York St, New Haven, CT 06504 USA.
[Kushner, Robert F.] Northwestern Univ, Med, Evanston, IL 60208 USA.
[MacKenzie, Thomas D.] Denver Hlth Fdn, Denver, CO USA.
[Sacco, Ralph L.] Univ Miami, Hlth Syst, Dept Neurol, Coral Gables, FL 33124 USA.
[Smith, Sidney C., Jr.] Univ North Carolina Chapel Hill, Med, Chapel Hill, NC USA.
[Stevens, Victor J.] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA.
[Wells, Barbara L.] NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Chan, WV (reprint author), Kaiser Permanente Northwest, Guidelines & Evidence Based Med, Portland, OR 97210 USA.
FU federal funds from the National Heart, Lung, and Blood Institute,
National Institutes of Health, US Department of Health and Human
Services, under GSA [GS-10F-0112J, HHSN2268201100098U]
FX This project was funded in whole or in part with federal funds from the
National Heart, Lung, and Blood Institute, National Institutes of
Health, US Department of Health and Human Services, under GSA contract
No. GS-10F-0112J, Order No. HHSN2268201100098U.
NR 54
TC 0
Z9 0
U1 3
U2 3
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD FEB 28
PY 2017
VL 135
IS 9
BP E122
EP E137
DI 10.1161/CIR.0000000000000481
PG 16
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
SC Cardiovascular System & Cardiology
GA EM8GO
UT WOS:000395549700002
PM 28126839
ER
PT J
AU Larson, CL
Heinzen, RA
AF Larson, Charles L.
Heinzen, Robert A.
TI High-Content Imaging Reveals Expansion of the Endosomal Compartment
during Coxiella burnetii Parasitophorous Vacuole Maturation
SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
LA English
DT Article
DE endosome; lysosome; intracellular pathogen; endocytic trafficking;
fluorescence microscopy; Chlamydia trachomatis; Coxiella burnetii
ID CHLAMYDIAL INCLUSION; LYSOSOMAL BIOGENESIS; HOST-CELL; PATHWAY;
TRAFFICKING; TRANSFERRIN; REPLICATE; INFECTION; AUTOPHAGY; PROTEINS
AB Coxiella burnetii is an obligate intracellular pathogen and the causative agent of human Q fever. Replication of the bacteriumwithin a large parasitophorous vacuole (PV) resembling a host phagolysosome is required for pathogenesis. PV biogenesis is a pathogen driven process that requires engagement of several host cell vesicular trafficking pathways to acquire vacuole components. The goal of this study was to determine if infection by C. burnetii modulates endolysosomal flux to potentially benefit PV formation. HeLa cells, infected with C. burnetii or left uninfected, were incubated with fluorescent transferrin (Tf) for 0-30 min, and the amount of Tf internalized by cells quantitated by high-content imaging. At 3 and 5 days, but not 1 day post-infection, the maximal amounts of fluorescent Tf internalized by infected cells were significantly greater than uninfected cells. The rates of Tf uptake and recycling were the same for infected and uninfected cells; however, residual Tf persisted in EEA. 1 positive compartments adjacent to large PV after 30 min of recycling in the absence of labeled Tf. On average, C. burnetii-infected cells contained significantlymore CD63-positive endosomes than uninfected cells. In contrast, cells containing large vacuoles generated by Chlamydia trachomatis exhibited increased rates of Tf internalization without increased CD63 expression. Our results suggest that C. burnetii infection expands the endosomal system to increase capacity for endocytic material. Furthermore, this study demonstrates the power of high-content imaging for measurement of cellular responses to infection by intracellular pathogens.
C1 [Larson, Charles L.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA.
RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA.
EM rheinzen@niaid.nih.gov
FU Intramural Research Program of the National Institute of Allergy and
Infectious Diseases, National Institutes of Health [ZAI AI000931]
FX This work was supported by the Intramural Research Program of the
National Institute of Allergy and Infectious Diseases, National
Institutes of Health #ZAI AI000931 to RH.
NR 39
TC 0
Z9 0
U1 1
U2 1
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 2235-2988
J9 FRONT CELL INFECT MI
JI Front. Cell. Infect. Microbiol.
PD FEB 28
PY 2017
VL 7
AR 48
DI 10.3389/fcimb.2017.00048
PG 10
WC Immunology; Microbiology
SC Immunology; Microbiology
GA EL8UX
UT WOS:000394896900001
PM 28293541
ER
PT J
AU Truzzi, A
Bornstein, MH
Senese, VP
Shinohara, K
Setoh, P
Esposito, G
AF Truzzi, Anna
Bornstein, Marc H.
Senese, Vincenzo P.
Shinohara, Kazuyuki
Setoh, Peipei
Esposito, Gianluca
TI Serotonin Transporter Gene Polymorphisms and Early Parent-Infant
Interactions Are Related to Adult Male Heart Rate Response to Female
Crying
SO FRONTIERS IN PHYSIOLOGY
LA English
DT Article
DE parent-infant interaction; serotonin transporter gene; opposite-sex
conspecific interaction; gene* environment; physiological responses;
social distress
ID ENVIRONMENT INTERACTION; ROMANTIC RELATIONSHIPS; ATTACHMENT STYLES;
SOCIAL-SKILLS; LIFE EVENTS; 5-HTTLPR; DEPRESSION
AB Adults' adaptive interactions with intimate partners enhance well-being. Here we hypothesized that adult males' physiological responses to opposite-sex conspecifics' distress result from an interaction between an environmental factor (early social interaction with caregivers) and a genetic factor (a polymorphism within the promoter region of the serotonin transporter gene, 5-HTTLPR). We assessed heart rate changes in 42 non-married male adults to distress vocalizations (female, infant, and bonobo cries). Males' early interaction with parents was assessed using the Parental Bonding Instrument. Buccal mucosa cell samples were collected to assess their 5-HTTLPR genotype. A significant interaction emerged between early experience and genetic predisposition. Males with a genetic predisposition for higher sensitivity to environmental factors showed atypical physiological responses to adult female cries according to their experienced early maternal parenting. Environmental experiences and genetic characteristics are associated with adult males' physiological responses to socially meaningfully stimuli. Understanding the mechanisms that modulate responses to opposite-sex conspecifics may improve personal well-being and social adaptiveness.
C1 [Truzzi, Anna; Esposito, Gianluca] Univ Trento, Dept Psychol & Cognit Sci, Rovereto, Italy.
[Truzzi, Anna] RIKEN, Brain Sci Inst, Lab Affiliat Social Behav, Saitama, Japan.
[Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Bethesda, MD USA.
[Senese, Vincenzo P.] Univ Naples 2, Dept Psychol, Psychometr Lab, Naples, Italy.
[Shinohara, Kazuyuki] Nagasaki Univ, Dept Neurobiol & Behav, Unit Basic Med Sci, Nagasaki, Japan.
[Setoh, Peipei; Esposito, Gianluca] Nanyang Technol Univ, Sch Humanities & Social Sci, Div Psychol, Singapore, Singapore.
RP Esposito, G (reprint author), Univ Trento, Dept Psychol & Cognit Sci, Rovereto, Italy.; Esposito, G (reprint author), Nanyang Technol Univ, Sch Humanities & Social Sci, Div Psychol, Singapore, Singapore.
EM gianluca.esposito@unitn.it
FU Intramural Research Program of the NIH; NICHD; NAP-SUG program of the
Nanyang Technological University
FX All participants in this study are gratefully acknowledged. This
research was partially supported by the Intramural Research Program of
the NIH, NICHD as well as the NAP-SUG program of the Nanyang
Technological University.
NR 29
TC 0
Z9 0
U1 0
U2 0
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 1664-042X
J9 FRONT PHYSIOL
JI Front. Physiol.
PD FEB 28
PY 2017
VL 8
AR 111
DI 10.3389/fphys.2017.00111
PG 6
WC Physiology
SC Physiology
GA EL7PH
UT WOS:000394812500001
PM 28293197
ER
PT J
AU Chan, WV
Pearson, TA
Bennett, GC
Cushman, WC
Gaziano, TA
Gorman, PN
Handler, J
Krumholz, HM
Kushner, RF
MacKenzie, TD
Sacco, RL
Smith, SC
Stevens, VJ
Wells, BL
AF Chan, Wiley V.
Pearson, Thomas A.
Bennett, Glen C.
Cushman, William C.
Gaziano, Thomas A.
Gorman, Paul N.
Handler, Joel
Krumholz, Harlan M.
Kushner, Robert F.
MacKenzie, Thomas D.
Sacco, Ralph L.
Smith, Sidney C., Jr.
Stevens, Victor J.
Wells, Barbara L.
TI ACC/AHA Special Report: Clinical Practice Guideline Implementation
Strategies: A Summary of Systematic Reviews by the NHLBI Implementation
Science Work Group
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Article
DE ACC/AHA Clinical Practice Guideline; evidence-based; effectiveness;
interventions; detailing; incentives; reminders; cost; systematic review
ID DECISION-SUPPORT-SYSTEMS; HEALTH-CARE; VENOUS THROMBOEMBOLISM; IMPROVE
PROPHYLAXIS; DISEASE MANAGEMENT; PATIENT OUTCOMES; MEDICATION USE;
INTERVENTIONS; METAANALYSIS; QUALITY
AB BACKGROUND In 2008, the National Heart, Lung, and Blood Institute convened an Implementation Science Work Group to assess evidence-based strategies for effectively implementing clinical practice guidelines. This was part of a larger effort to update existing clinical practice guidelines on cholesterol, blood pressure, and overweight/obesity.
OBJECTIVES Review evidence from the published implementation science literature and identify effective or promising strategies to enhance the adoption and implementation of clinical practice guidelines. METHODS This systematic review was conducted on 4 critical questions, each focusing on the adoption and effectiveness of 4 intervention strategies: (1) reminders, (2) educational outreach visits, (3) audit and feedback, and (4) provider incentives. A scoping review of the Rx for Change database of systematic reviews was used to identify promising guideline implementation interventions aimed at providers. Inclusion and exclusion criteria were developed a priori for each question, and the published literature was initially searched up to 2012, and then updated with a supplemental search to 2015. Two independent reviewers screened the returned citations to identify relevant reviews and rated the quality of each included review.
RESULTS Audit and feedback and educational outreach visits were generally effective in improving both process of care (15 of 21 reviews and 12 of 13 reviews, respectively) and clinical outcomes (7 of 12 reviews and 3 of 5 reviews, respectively). Provider incentives showed mixed effectiveness for improving both process of care (3 of 4 reviews) and clinical outcomes (3 reviews equally distributed between generally effective, mixed, and generally ineffective). Reminders showed mixed effectiveness for improving process of care outcomes (27 reviews with 11 mixed and 3 generally ineffective results) and were generally ineffective for clinical outcomes (18 reviews with 6 mixed and 9 generally ineffective results). Educational outreach visits (2 of 2 reviews), reminders (3 of 4 reviews), and provider incentives (1 of 1 review) were generally effective for cost reduction. Educational outreach visits (1 of 1 review) and provider incentives (1 of 1 review) were also generally effective for cost-effectiveness outcomes. Barriers to clinician adoption or adherence to guidelines included time constraints (8 reviews/overviews); limited staffing resources (2 overviews); timing (5 reviews/overviews); clinician skepticism (5 reviews/overviews); clinician knowledge of guidelines (4 reviews/overviews); and higher age of the clinician (1 overview). Facilitating factors included guideline characteristics such as format, resources, and end-user involvement (6 reviews/overviews); involving stakeholders (5 reviews/overviews); leadership support (5 reviews/overviews); scope of implementation (5 reviews/overviews); organizational culture such as multidisciplinary teams and low-baseline adherence (9 reviews/overviews); and electronic guidelines systems (3 reviews).
CONCLUSION The strategies of audit and feedback and educational outreach visits were generally effective in improving both process of care and clinical outcomes. Reminders and provider incentives showed mixed effectiveness, or were generally ineffective. No general conclusion could be reached about cost effectiveness, because of limitations in the evidence. Important gaps exist in the evidence on effectiveness of implementation interventions, especially regarding clinical outcomes, cost effectiveness and contextual issues affecting successful implementation.
C1 [Chan, Wiley V.; Cushman, William C.; Gaziano, Thomas A.; Gorman, Paul N.; Handler, Joel; Krumholz, Harlan M.; Kushner, Robert F.; MacKenzie, Thomas D.; Sacco, Ralph L.; Smith, Sidney C., Jr.; Stevens, Victor J.; Wells, Barbara L.] NHLBI, Implementat Sci Work Grp, Bldg 10, Bethesda, MD 20892 USA.
[Bennett, Glen C.] NHLBI, Ctr Translat Res & Implementat Sci, Bldg 10, Bethesda, MD 20892 USA.
[Cushman, William C.] Vet Affairs Med Ctr, Memphis, TN USA.
[Wells, Barbara L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA.
RP Chan, WV (reprint author), NHLBI, Implementat Sci Work Grp, Bldg 10, Bethesda, MD 20892 USA.
FU National Heart, Lung, and Blood Institute, National Institutes of
Health, U.S. Department of Health and Human Services under GSA
[GS-10F-0112J, HHSN2268201100098U]
FX This project was funded in whole or in part with federal funds from the
National Heart, Lung, and Blood Institute, National Institutes of
Health, U.S. Department of Health and Human Services, under GSA contract
No. GS-10F-0112J, Order No. HHSN2268201100098U.
NR 54
TC 0
Z9 0
U1 2
U2 2
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 FEB 28
PY 2017
VL 69
IS 8
BP 1076
EP 1092
DI 10.1016/j.jacc.2016.11.004
PG 17
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EN9YY
UT WOS:000396356700013
PM 28132746
ER
PT J
AU Schneller, JL
Lee, CM
Bao, G
Venditti, CP
AF Schneller, Jessica L.
Lee, Ciaran M.
Bao, Gang
Venditti, Charles P.
TI Genome editing for inborn errors of metabolism: advancing towards the
clinic
SO BMC MEDICINE
LA English
DT Review
DE Inborn errors of metabolism; Genome editing; CRISPR/Cas9; Zinc-finger
nucleases; Liver metabolic disorders
ID ADENOASSOCIATED VIRUS VECTORS; STAPHYLOCOCCUS-AUREUS CAS9; ZINC-FINGER
NUCLEASES; UREA CYCLE DISORDERS; IN-VIVO; MOUSE MODEL; GENE-THERAPY;
MUSCULAR-DYSTROPHY; MESSENGER-RNA; OFF-TARGET
AB Inborn errors of metabolism (IEM) include many disorders for which current treatments aim to ameliorate disease manifestations, but are not curative. Advances in the field of genome editing have recently resulted in the in vivo correction of murine models of IEM. Site-specific endonucleases, such as zinc-finger nucleases and the CRISPR/Cas9 system, in combination with delivery vectors engineered to target disease tissue, have enabled correction of mutations in disease models of hemophilia B, hereditary tyrosinemia type I, ornithine transcarbamylase deficiency, and lysosomal storage disorders. These in vivo gene correction studies, as well as an overview of genome editing and future directions for the field, are reviewed and discussed herein.
C1 [Schneller, Jessica L.] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY USA.
[Schneller, Jessica L.; Venditti, Charles P.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bldg 10,Room,7N248A, Bethesda, MD 20892 USA.
[Lee, Ciaran M.; Bao, Gang] Rice Univ, Dept Bioengn, 6500 Main St, Houston, TX 77030 USA.
RP Venditti, CP (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bldg 10,Room,7N248A, Bethesda, MD 20892 USA.
EM venditti@mail.nih.gov
OI Lee, Ciaran/0000-0002-0789-9149
FU National Institutes of Health; Cancer Prevention and Research Institute
of Texas [RR140081]
FX JLS and CPV were supported by the intramural research program of the
National Human Genome Research Institute in the National Institutes of
Health. This work was supported in part by the Cancer Prevention and
Research Institute of Texas (RR140081 to GB).
NR 81
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Z9 0
U1 1
U2 1
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1741-7015
J9 BMC MED
JI BMC Med.
PD FEB 27
PY 2017
VL 15
AR 43
DI 10.1186/s12916-017-0798-4
PG 12
WC Medicine, General & Internal
SC General & Internal Medicine
GA EN5UD
UT WOS:000396070300001
PM 28238287
ER
PT J
AU Jackson, LH
Vlachodimitropoulou, E
Shangaris, P
Roberts, TA
Ryan, TM
Campbell-Washburn, AE
David, AL
Porter, JB
Lythgoe, MF
Stuckey, DJ
AF Jackson, Laurence H.
Vlachodimitropoulou, Evangelia
Shangaris, Panicos
Roberts, Thomas A.
Ryan, Thomas M.
Campbell-Washburn, Adrienne E.
David, Anna L.
Porter, John B.
Lythgoe, Mark F.
Stuckey, Daniel J.
TI Non-invasive MRI biomarkers for the early assessment of iron overload in
a humanized mouse model of beta-thalassemia
SO SCIENTIFIC REPORTS
LA English
DT Article
ID SICKLE-CELL-DISEASE; MAGNETIC-RESONANCE; GLOBIN GENE; T2 MEASUREMENT;
MYOCARDIAL T2; CARDIAC IRON; STEM-CELLS; SURVIVAL; BETA(0)-THALASSEMIA;
CARDIOMYOPATHY
AB beta-thalassemia (beta T) is a genetic blood disorder causing profound and life threatening anemia. Current clinical management of beta T is a lifelong dependence on regular blood transfusions, a consequence of which is systemic iron overload leading to acute heart failure. Recent developments in gene and chelation therapy give hope of better prognosis for patients, but successful translation to clinical practice is hindered by the lack of thorough preclinical testing using representative animal models and clinically relevant quantitative biomarkers. Here we demonstrate a quantitative and non-invasive preclinical Magnetic Resonance Imaging (MRI) platform for the assessment of beta T in the.gamma beta(0)/gamma beta(A) humanized mouse model of beta T. Changes in the quantitative MRI relaxation times as well as severe splenomegaly were observed in the heart, liver and spleen in beta T. These data showed high sensitivity to iron overload and a strong relationship between quantitative MRI relaxation times and hepatic iron content. Importantly these changes preceded the onset of iron overload cardiomyopathy, providing an early biomarker of disease progression. This work demonstrates that multiparametric MRI is a powerful tool for the assessment of preclinical beta T, providing sensitive and quantitative monitoring of tissue iron sequestration and cardiac dysfunction-parameters essential for the preclinical development of new therapeutics.
C1 [Jackson, Laurence H.; Roberts, Thomas A.; Lythgoe, Mark F.; Stuckey, Daniel J.] UCL, Div Med, Ctr Adv Biomed Imaging, London, England.
[Vlachodimitropoulou, Evangelia; Porter, John B.] UCL, Dept Haematol, London, England.
[Shangaris, Panicos; David, Anna L.] UCL, Inst Womens Hlth, London, England.
[Ryan, Thomas M.] Univ Alabama Birmingham, Dept Biochem & Mol Genet, Birmingham, AL USA.
[Campbell-Washburn, Adrienne E.] NHLBI, Lab Imaging Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Stuckey, DJ (reprint author), UCL, Div Med, Ctr Adv Biomed Imaging, London, England.
EM d.stuckey@ucl.ac.uk
FU Medical Research Council, UK [MR/K50077X/1]; Medical Research Council
[MR/J013110/1]; King's College London; UCL Comprehensive Cancer Imaging
Centre CR-UK; EPSRC; MRC (England); DoH (England); National Centre for
the Replacement, Reduction and Refinement of Animal in Research (NC3Rs);
UK Regenerative Medicine Platform Safety Hub [MRC: MR/K026739/1]; Eli
Lilly and Company; Wellcome Trust Sparks Research Training Fellowship
FX DJS is a BHF Intermediate Basic Science Research Fellow
(FS/15/33/31608). LHJ is supported by the Medical Research Council, UK
(MR/K50077X/1). ML receives funding from Medical Research Council
(MR/J013110/1); the King's College London and UCL Comprehensive Cancer
Imaging Centre CR-UK & EPSRC, in association with the MRC and DoH
(England); the National Centre for the Replacement, Reduction and
Refinement of Animal in Research (NC3Rs); UK Regenerative Medicine
Platform Safety Hub (MRC: MR/K026739/1); Eli Lilly and Company. EVK is
an Onassis Scholar (Athens, Greece). This study was supported by
researchers at the National Institute for Health Research University
College London Hospitals Biomedical Research Centre (ALD). PS is funded
by a Wellcome Trust Sparks Research Training Fellowship.
NR 47
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U1 2
U2 2
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 27
PY 2017
VL 7
AR 43439
DI 10.1038/srep43439
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL8NZ
UT WOS:000394878300001
PM 28240317
ER
PT J
AU Sowrirajan, B
Saito, Y
Poudyal, D
Chen, Q
Sui, HY
DeRavin, SS
Imamichi, H
Sato, T
Kuhns, DB
Noguchi, N
Malech, HL
Lane, HC
Imamichi, T
AF Sowrirajan, Bharatwaj
Saito, Yoshiro
Poudyal, Deepak
Chen, Qian
Sui, Hongyan
DeRavin, Suk See
Imamichi, Hiromi
Sato, Toyotaka
Kuhns, Douglas B.
Noguchi, Noriko
Malech, Harry L.
Lane, H. Clifford
Imamichi, Tomozumi
TI Interleukin-27 Enhances the Potential of Reactive Oxygen Species
Generation from Monocyte-derived Macrophages and Dendritic cells by
Induction of p47(phox)
SO SCIENTIFIC REPORTS
LA English
DT Article
ID EXTRACELLULAR-SUPEROXIDE DISMUTASE; FAMILY NADPH OXIDASES; CD4(+)
T-CELLS; HIV-1 INFECTION; COMPLETE REGRESSION; IL-27; EXPRESSION;
ACTIVATION; CARCINOMA; ANTITUMOR
AB Interleukin (IL)-27, a member of the IL-12 cytokine family, plays an important and diverse role in the function of the immune system. We have previously demonstrated that IL-27 is an anti-viral cytokine which inhibits HIV-1, HIV-2, Influenza virus and herpes simplex virus infection, and enhances the potential of reactive oxygen species (ROS) generating activity during differentiation of monocytes to macrophages. In this study, we further investigated the mechanism of the enhanced potential for ROS generation by IL-27. Real time PCR, western blot and knock down assays demonstrate that IL-27 is able to enhance the potential of superoxide production not only during differentiation but also in terminally differentiated-macrophages and immature dendritic cells (iDC) in association with the induction of p47(phox), a cytosolic component of the ROS producing enzyme, NADPH oxidase, and the increase in amounts of phosphorylated p47phox upon stimulation. We also demonstrate that IL-27 is able to induce extracellular superoxide dismutase during differentiation of monocytes but not in terminal differentiated macrophages. Since ROS plays an important role in a variety of inflammation, our data demonstrate that IL-27 is a potent regulator of ROS induction and may be a novel therapeutic target.
C1 [Sowrirajan, Bharatwaj; Poudyal, Deepak; Chen, Qian; Sui, Hongyan; Sato, Toyotaka; Imamichi, Tomozumi] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Human Retrovirol & Immunoinformat, Frederick, MD 21702 USA.
[Saito, Yoshiro; Noguchi, Noriko] Doshisha Univ, Fac Life & Med Sci, Dept Med Life Syst, Syst Life Sci Lab, Kyoto 6100394, Japan.
[DeRavin, Suk See; Malech, Harry L.] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20802 USA.
[Imamichi, Hiromi; Lane, H. Clifford] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA.
[Kuhns, Douglas B.] Leidos Biomed Res Inc, Neutrophil Monitoring Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.
RP Imamichi, T (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Human Retrovirol & Immunoinformat, Frederick, MD 21702 USA.
EM timamichi@mail.nih.gov
OI Saito, Yoshiro/0000-0002-0559-5889
FU National Cancer Institute, National Institutes of Health
[HHSN261200800001E]; National Institute of Allergy and Infectious
Diseases
FX Authors thank Dr. T. Kamata for discussion and B. Sherman for critical
reading. This project has been funded in whole or in part with federal
funds from the National Cancer Institute, National Institutes of Health,
under Contract No. HHSN261200800001E. The content of this publication
does not necessarily reflect the views or policies of the Department of
Health and Human Services, nor does mention of trade names, commercial
products, or organizations imply endorsement by the U.S. Government.
This research was supported [in part] by the National Institute of
Allergy and Infectious Diseases.
NR 53
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U1 1
U2 1
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 27
PY 2017
VL 7
AR 43441
DI 10.1038/srep43441
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL8OI
UT WOS:000394879200001
PM 28240310
ER
PT J
AU Chan, M
Elias, C
Fauci, A
Lake, A
Berkley, S
AF Chan, Margaret
Elias, Chris
Fauci, Anthony
Lake, Anthony
Berkley, Seth
TI Reaching everyone, everywhere with life-saving vaccines
SO LANCET
LA English
DT Editorial Material
C1 [Chan, Margaret] WHO, Geneva, Switzerland.
[Elias, Chris] Bill & Melinda Gates Fdn, Seattle, WA 98109 USA.
[Fauci, Anthony] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Lake, Anthony] United Nations Childrens Fund, New York, NY USA.
[Berkley, Seth] Gavi, Geneva, Switzerland.
RP Elias, C (reprint author), Bill & Melinda Gates Fdn, Seattle, WA 98109 USA.
NR 8
TC 0
Z9 0
U1 0
U2 0
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0140-6736
EI 1474-547X
J9 LANCET
JI Lancet
PD FEB 25
PY 2017
VL 389
IS 10071
BP 777
EP 779
PG 3
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL9UU
UT WOS:000394966400011
PM 28248159
ER
PT J
AU Ginsburg, O
Badwe, R
Boyle, P
Derricks, G
Dare, A
Evans, T
Eniu, A
Jimenez, J
Kutluk, T
Lopes, G
Mohammed, SI
Qiao, YL
Rashid, SF
Summers, D
Sarfati, D
Temmerman, M
Trimble, EL
Padela, AI
Aggarwal, A
Sullivan, R
AF Ginsburg, Ophira
Badwe, Rajan
Boyle, Peter
Derricks, Gemma
Dare, Anna
Evans, Tim
Eniu, Alexandru
Jimenez, Jorge
Kutluk, Tezer
Lopes, Gilberto
Mohammed, Sulma I.
Qiao, You-Lin
Rashid, Sabina Faiz
Summers, Diane
Sarfati, Diana
Temmerman, Marleen
Trimble, Edward L.
Padela, Aasim I.
Aggarwal, Ajay
Sullivan, Richard
TI Changing global policy to deliver safe, equitable, and affordable care
for women's cancers
SO LANCET
LA English
DT Article
ID UNIVERSAL HEALTH COVERAGE; HIGH-INCOME COUNTRIES; BREAST-CANCER;
SCREENING PRACTICES; AMERICAN MUSLIMS; DISEASE BURDEN; MORTALITY;
MIDDLE; INDIA; AFRICA
AB Breast and cervical cancer are major threats to the health of women globally, particularly in low-income and middle-income countries. Radical progress to close the global cancer divide for women requires not only evidence-based policy making, but also broad multisectoral collaboration that capitalises on recent progress in the associated domains of women's health and innovative public health approaches to cancer care and control. Such multisectoral collaboration can serve to build health systems for cancer, and more broadly for primary care, surgery, and pathology. This Series paper explores the global health and public policy landscapes that intersect with women's health and global cancer control, with new approaches to bringing policy to action. Cancer is a major global social and political priority, and women's cancers are not only a tractable socioeconomic policy target in themselves, but also an important Trojan horse to drive improved cancer control and care.
C1 [Ginsburg, Ophira] Univ Toronto, Dalla Lana Sch Publ Hlth, Fac Med, Womens Coll Res Inst, Toronto, ON, Canada.
[Ginsburg, Ophira; Temmerman, Marleen] WHO, Geneva, Switzerland.
[Badwe, Rajan] Tata Mem Hosp, Bombay, Maharashtra, India.
[Boyle, Peter] Int Prevent Res Inst, Lyon, France.
[Boyle, Peter] Univ Strathclyde, Inst Global Publ Hlth iPRI, Glasgow, Lanark, Scotland.
[Derricks, Gemma] Brunel Univ, London, England.
[Dare, Anna] Univ Toronto, Ctr Global Hlth Res, Toronto, ON, Canada.
[Dare, Anna] Univ Toronto, Dept Surg, Toronto, ON, Canada.
[Evans, Tim] World Bank Grp, Hlth Nutr & Populat Global Practice, Washington, DC USA.
[Eniu, Alexandru] Canc Inst Ion Chiricuta, Cluj Napoca, Romania.
[Jimenez, Jorge] Pontificia Univ Catolica Chile, Santiago, Chile.
[Kutluk, Tezer] Hacettepe Univ, Dept Pediat Oncol, Ankara, Turkey.
[Lopes, Gilberto] Oncoclin Grp, Sao Paulo, Brazil.
[Lopes, Gilberto] Univ Miami, Miller Sch Med, Coral Gables, FL 33124 USA.
[Mohammed, Sulma I.] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA.
[Mohammed, Sulma I.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA.
[Qiao, You-Lin] Chinese Acad Med Sci, Natl Canc Ctr, Dept Canc Epidemiol, Beijing, Peoples R China.
[Qiao, You-Lin] Peking Union Med Coll, Beijing, Peoples R China.
[Rashid, Sabina Faiz] BRAC Univ, James P Grant Sch Publ Hlth, Dhaka, Bangladesh.
[Summers, Diane] UNICEF, South Asia Reg Off, Kathmandu, Nepal.
[Sarfati, Diana] Univ Otago, Dept Publ Hlth, Wellington, New Zealand.
[Temmerman, Marleen] Univ Ghent, Ghent, Belgium.
[Temmerman, Marleen] Aga Khan Univ, Nairobi, Kenya.
[Trimble, Edward L.] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA.
[Padela, Aasim I.] Univ Chicago, Initiat Islam & Med, Chicago, IL 60637 USA.
[Padela, Aasim I.] Univ Chicago, Dept Med, Chicago, IL 60637 USA.
[Aggarwal, Ajay] London Sch Hyg & Trop, London, England.
[Aggarwal, Ajay; Sullivan, Richard] Kings Hlth Partners, Kings Ctr Global Hlth, Kings Hlth Partners Comprehens Canc Ctr, Inst Canc Policy, London, England.
[Aggarwal, Ajay; Sullivan, Richard] Kings Coll London, London, England.
Univ Toronto, Womens Coll Hosp, Toronto, ON M5S 1B2, Canada.
RP Ginsburg, O (reprint author), Univ Toronto, Womens Coll Hosp, 75 Grenville St, Toronto, ON M5S 1B2, Canada.
EM ophira.ginsburg@wchospital.ca
OI Sullivan, Richard/0000-0002-6435-1825
FU Canadian Institutes for Health Research; Dalla Lana School of Public
Health, University of Toronto; EU Commission [602536]; American Cancer
Society [MRSG-14-032-01-CPPB]
FX This work was part funded by Canadian Institutes for Health Research and
the Dalla Lana School of Public Health, University of Toronto, and the
EU Commission Grant Mapping NCD (no: 602536). OG thanks Ms Sabiha
Merchant (Women's College Research Institute, Toronto, ON, Canada) for
administrative support. RS thanks the NCI Centre for Global Health for
their core support and Dr G Lewison and Miss M Begum for research
analysis (Institue of Cancer Policy, King's College London, London, UK).
AIP was supported by a Mentored Research Scholar Grant in Applied and
Clinical Research (MRSG-14-032-01-CPPB), from the American Cancer
Society. The opinions expressed here are those of the authors and do not
necessarily represent an official position of the organisations with
which they are affiliated.
NR 71
TC 0
Z9 0
U1 2
U2 2
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 FEB 25
PY 2017
VL 389
IS 10071
BP 871
EP 880
DI 10.1016/S0140-6736(16)31393-9
PG 10
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL9UU
UT WOS:000394966400039
PM 27814964
ER
PT J
AU Chawla, B
Hedman, AC
Sayedyahossein, S
Erdemir, HH
Li, ZG
Sacks, DB
AF Chawla, Bhavna
Hedman, Andrew C.
Sayedyahossein, Samar
Erdemir, Huseyin H.
Li, Zhigang
Sacks, David B.
TI Absence of IQGAP1 Protein Leads to Insulin Resistance
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
DE Akt PKB; insulin; insulin receptor; insulin receptor substrate 1
(IRS-1); insulin resistance; mitogen-activated protein kinase (MAPK);
phosphatidylinositide 3-kinase (PI 3-kinase); IQGAP1
ID PLECKSTRIN-HOMOLOGY DOMAIN; HEPATOCELLULAR-CARCINOMA; MICE LACKING; PTB
DOMAIN; IQ MOTIFS; RECEPTOR; IRS-1; SCAFFOLD; BINDING; ACTIVATION
AB Insulin binds to the insulin receptor (IR) and induces tyrosine phosphorylation of the receptor and insulin receptor substrate-1 (IRS-1), leading to activation of the PKB/Akt and MAPK/ERK pathways. IQGAP1 is a scaffold protein that interacts with multiple binding partners and integrates diverse signaling cascades. Here we show that IQGAP1 associates with both IR and IRS-1 and influences insulin action. In vitro analysis with pure proteins revealed that the IQ region of IQGAP1 binds directly to the intracellular domain of IR. Similarly, the phosphotyrosine-binding domain of IRS-1 mediates a direct interaction with the C-terminal tail of IQGAP1. Consistent with these observations, both IR and IRS-1 co-immunoprecipitated with IQGAP1 from cells. Investigation of the functional effects of the interactions revealed that in the absence of IQGAP1, insulin-stimulated phosphorylation of Akt and ERK, as well as the association of phosphatidylinositol 3-kinase with IRS-1, were significantly decreased. Importantly, loss of IQGAP1 results in impaired insulin signaling and glucose homeostasis in vivo. Collectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling.
C1 [Chawla, Bhavna; Hedman, Andrew C.; Sayedyahossein, Samar; Erdemir, Huseyin H.; Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, 10 Ctr Dr,10-2C306, Bethesda, MD 20892 USA.
[Chawla, Bhavna] US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Silver Spring, MD 20993 USA.
[Erdemir, Huseyin H.] Cleveland Clin, Dept Pediat Hematol Oncol, Cleveland, OH 44195 USA.
[Erdemir, Huseyin H.] Cleveland Clin, BMT, Cleveland, OH 44195 USA.
RP Sacks, DB (reprint author), NIH, Dept Lab Med, 10 Ctr Dr,10-2C306, Bethesda, MD 20892 USA.
EM david.sacks2@nih.gov
OI Sacks, David/0000-0003-3100-0735
FU National Institutes of Health Intramural Research Program
FX This work was supported by the National Institutes of Health Intramural
Research Program. The authors declare that they have no conflicts of
interest with the contents of this article. The content is solely the
responsibility of the authors and does not necessarily represent the
official views of the National Institutes of Health.
NR 53
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U1 0
U2 0
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD FEB 24
PY 2017
VL 292
IS 8
BP 3273
EP 3289
DI 10.1074/jbc.M116.752642
PG 17
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EM8CM
UT WOS:000395538800019
PM 28082684
ER
PT J
AU Carrer, A
Parris, JLD
Trefely, S
Henry, RA
Montgomery, DC
Torres, A
Viola, JM
Kuo, YM
Blair, IA
Meier, JL
Andrews, AJ
Snyder, NW
Wellen, KE
AF Carrer, Alessandro
Parris, Joshua L. D.
Trefely, Sophie
Henry, Ryan A.
Montgomery, David C.
Torres, AnnMarie
Viola, John M.
Kuo, Yin-Ming
Blair, Ian A.
Meier, Jordan L.
Andrews, Andrew J.
Snyder, Nathaniel W.
Wellen, Kathryn E.
TI Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation
Levels
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
DE Acetyl-CoA; adipose tissue; diet; histone acetylation; liver
ID ATP-CITRATE-LYASE; ONE-CARBON METABOLISM; CELLULAR-METABOLISM; DNA
METHYLATION; DYNAMICS; TRANSCRIPTION; EPIGENETICS; MECHANISMS; COENZYME;
CANCER
AB Cellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood but could alter gene expression and influence metabolic health. ATP citrate-lyase produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high-fat diet (HFD) results in suppression of ATP citrate-lyase levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a HFD despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. Butyryl-CoA and isobutyryl-CoA interacted with the acetyltransferase P300/CBP-associated factor (PCAF) in liver lysates and inhibited its activity in vitro. This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in the liver.
C1 [Carrer, Alessandro; Parris, Joshua L. D.; Trefely, Sophie; Torres, AnnMarie; Viola, John M.; Wellen, Kathryn E.] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Dept Canc Biol, Philadelphia, PA 19104 USA.
[Blair, Ian A.] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA.
[Trefely, Sophie; Snyder, Nathaniel W.] Drexel Univ, AJ Drexel Autism Inst, Philadelphia, PA 19104 USA.
[Henry, Ryan A.; Kuo, Yin-Ming; Andrews, Andrew J.] Fox Chase Canc Ctr, Dept Canc Biol, 7701 Burholme Ave, Philadelphia, PA 19111 USA.
[Montgomery, David C.; Meier, Jordan L.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Ft Detrick, MD 21702 USA.
RP Wellen, KE (reprint author), Univ Penn, Perelman Sch Med, Dept Canc Biol, 421 Curie Blvd,BRB 2-2 Rm 653, Philadelphia, PA 19104 USA.
EM wellenk@exchange.upenn.edu
OI Carrer, Alessandro/0000-0002-9300-6879
FU American Diabetes Association [7-12-JF-59]; Pancreatic Cancer Action
Network-American Association; Abramson Cancer Center Basic Science
Center; NCI, National Institutes of Health [R01CA174761, ZIABC011488];
National Institutes of Health [R21HD087866, K22ES26235]; Penn-PREP
post-baccalaureate program; Penn-PORT IRACDA postdoctoral fellowship
[K12 GM081259]
FX This work was supported by American Diabetes Association Grant
7-12-JF-59, NCI, National Institutes of Health Grant R01CA174761, by a
Pancreatic Cancer Action Network-American Association for Cancer
Research career development award (to K. E. W.), by the Abramson Cancer
Center Basic Science Center for Excellence in Cancer Metabolism (to K.
E. W. and I. A. B.), by National Institutes of Health Grants R21HD087866
and K22ES26235 (to N. W. S.), and by NCI, National Institutes of Health
Grant ZIABC011488-04 (to J. L. M.). The authors declare that they have
no conflicts of interest with the contents of this article. The content
is solely the responsibility of the authors and does not necessarily
represent the official views of the National Institutes of Health.;
Supported by the Penn-PREP post-baccalaureate program.; Supported by
Penn-PORT IRACDA postdoctoral fellowship K12 GM081259.
NR 43
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U1 1
U2 1
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD FEB 24
PY 2017
VL 292
IS 8
BP 3312
EP 3322
DI 10.1074/jbc.M116.750620
PG 11
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EM8CM
UT WOS:000395538800022
PM 28077572
ER
PT J
AU Yadav, H
Devalaraja, S
Chung, ST
Rane, SG
AF Yadav, Hariom
Devalaraja, Samir
Chung, Stephanie T.
Rane, Sushil G.
TI TGF-1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate
Hepatic Gluconeogenesis
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
DE AMP-activated kinase (AMPK); diabetes; FOXO; gluconeogenesis; liver;
obesity; phosphoprotein phosphatase; SMAD transcription factor;
transforming growth factor (TGF-)
ID ACTIVATED PROTEIN-KINASE; TGF-BETA; GENE-EXPRESSION; C-ELEGANS;
PHOSPHOENOLPYRUVATE CARBOXYKINASE; INSULIN SENSITIVITY; DIETARY
RESTRICTION; TRANSGENIC MICE; DB/DB MICE; GROWTH
AB Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-1/Smad3 signals suppressed endogenous glucose production. TGF-1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.
C1 [Yadav, Hariom; Devalaraja, Samir; Chung, Stephanie T.; Rane, Sushil G.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20854 USA.
RP Rane, SG (reprint author), NIDDK, Clin Res Ctr, Diabet Endocrinol & Obes Branch, NIH, Bldg 10,9000 Rockville Pike, Bethesda, MD 20814 USA.
EM ranes@mail.nih.gov
FU National Institutes of Health Intramural Research Program
FX This work was supported by a grant from the National Institutes of
Health Intramural Research Program. The authors declare that they have
no conflicts of interest with the contents of this article. The content
is solely the responsibility of the authors and does not necessarily
represent the official views of the National Institutes of Health.
NR 43
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U1 1
U2 1
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD FEB 24
PY 2017
VL 292
IS 8
BP 3420
EP 3432
DI 10.1074/jbc.M116.764910
PG 13
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EM8CM
UT WOS:000395538800031
PM 28069811
ER
PT J
AU Gonzalez, M
DeVico, AL
Spouge, JL
AF Gonzalez, Mileidy
DeVico, Anthony L.
Spouge, John L.
TI Conserved signatures indicate HIV-1 transmission is under strong
selection and thus is not a "stochastic" process
SO RETROVIROLOGY
LA English
DT Letter
DE Transmitted/founder virus; T/F; Transmission signatures; Selection
during HIV transmission; Phenotypic versus genotypic selection
ID RHESUS MACAQUES; INFECTION; TRIAL; BREAKTHROUGH; VACCINATION; SEQUENCES;
SIVSME660; TYPE-1; GP120; STEP
AB Recently, Oberle et al. published a paper in Retrovirology evaluating the question of whether selection plays a role in HIV transmission. The Oberle study found no obvious genotypic or phenotypic differences between donors and recipients of epidemiologically linked pairs from the Swiss cohort. Thus, Oberle et al. characterized HIV-1 B transmission as largely "stochastic", an imprecise and potentially misleading term. Here, we re-analyzed their data and placed them in the context of transmission data for over 20 other human and animal trials. The present study finds that the transmitted/founder (T/F) viruses from the Swiss cohort show the same non-random genetic signatures conserved in 118 HIV-1, 40 SHIV, and 12 SIV T/F viruses previously published by two independent groups. We provide alternative interpretations of the Swiss cohort data and conclude that the sequences of their donor viruses lacked variability at the specific sites where other studies were able to demonstrate genotypic selection. Oberle et al. observed no phenotypic selection in vitro, so the problem of determining the in vivo phenotypic mechanisms that cause genotypic selection in HIV remains open.
C1 [Gonzalez, Mileidy; Spouge, John L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Stat Computat Biol Grp, Bethesda, MD USA.
[DeVico, Anthony L.] Univ Maryland Sch Med, Inst Human Virol, Div Basic Sci & Vaccine Res, Baltimore, MD USA.
RP Gonzalez, M (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Stat Computat Biol Grp, Bethesda, MD USA.
EM mileidy.gonzalez@nih.gov
FU Intramural Research Program of the NIH; National Library of Medicine;
The Bill and Melinda Gates Foundation; NIAID; NIH
FX MG and JLS were supported by the Intramural Research Program of the NIH,
National Library of Medicine. ALD was funded by grants from The Bill and
Melinda Gates Foundation and NIAID,NIH.
NR 17
TC 2
Z9 2
U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1742-4690
J9 RETROVIROLOGY
JI Retrovirology
PD FEB 24
PY 2017
VL 14
AR 13
DI 10.1186/s12977-016-0326-1
PG 4
WC Virology
SC Virology
GA EN5QY
UT WOS:000396061800001
PM 28231858
ER
PT J
AU Cherry, JL
AF Cherry, Joshua L.
TI A practical exact maximum compatibility algorithm for reconstruction of
recent evolutionary history
SO BMC BIOINFORMATICS
LA English
DT Article
DE Phylogeny; Maximum compatibility; Homoplasy; Bacterial genomes
ID CHARACTERS; PARSIMONY
AB Background: Maximum compatibility is a method of phylogenetic reconstruction that is seldom applied to molecular sequences. It may be ideal for certain applications, such as reconstructing phylogenies of closely-related bacteria on the basis of whole-genome sequencing.
Results: Here I present an algorithm that rapidly computes phylogenies according to a compatibility criterion. Although based on solutions to the maximum clique problem, this algorithm deals properly with ambiguities in the data. The algorithm is applied to bacterial data sets containing up to nearly 2000 genomes with several thousand variable nucleotide sites. Run times are several seconds or less. Computational experiments show that maximum compatibility is less sensitive than maximum parsimony to the inclusion of nucleotide data that, though derived from actual sequence reads, has been identified as likely to be misleading.
Conclusions: Maximum compatibility is a useful tool for certain phylogenetic problems, such as inferring the relationships among closely-related bacteria from whole-genome sequence data. The algorithm presented here rapidly solves fairly large problems of this type, and provides robustness against misleading characters than can pollute large-scale sequencing data.
C1 [Cherry, Joshua L.] Natl Ctr Biotechnol Informat, Natl Inst Hlth, Natl Lib Med, Bethesda, MD 20894 USA.
RP Cherry, JL (reprint author), Natl Ctr Biotechnol Informat, Natl Inst Hlth, Natl Lib Med, Bethesda, MD 20894 USA.
EM jcherry@ncbi.nlm.nih.gov
FU Intramural Research Program of the NIH,; National Library of Medicine
FX This research was supported by the Intramural Research Program of the
NIH, National Library of Medicine.
NR 18
TC 0
Z9 0
U1 1
U2 1
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2105
J9 BMC BIOINFORMATICS
JI BMC Bioinformatics
PD FEB 23
PY 2017
VL 18
AR 127
DI 10.1186/s12859-017-1520-4
PG 12
WC Biochemical Research Methods; Biotechnology & Applied Microbiology;
Mathematical & Computational Biology
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
Mathematical & Computational Biology
GA EP6RM
UT WOS:000397506600004
PM 28231758
ER
PT J
AU DiNapoli, SR
Ortiz, AM
Wu, F
Matsuda, K
Twigg, HL
Hirsch, VM
Knox, K
Brenchley, JM
AF DiNapoli, Sarah R.
Ortiz, Alexandra M.
Wu, Fan
Matsuda, Kenta
Twigg, Homer L., III
Hirsch, Vanessa M.
Knox, Kenneth
Brenchley, Jason M.
TI Tissue-resident macrophages can contain replication-competent virus in
antiretroviral-naive, SIV-infected Asian macaques
SO JCI INSIGHT
LA English
DT Article
ID SIMIAN IMMUNODEFICIENCY VIRUS; CD4(+) T-CELLS; CENTRAL-NERVOUS-SYSTEM;
LINKED GLYCOSYLATION SITE; NEUROCOGNITIVE DISORDERS; RHESUS MACAQUES;
PERIVASCULAR MACROPHAGES; BRONCHOALVEOLAR LAVAGE; LATENT RESERVOIR;
HIV-1 INFECTION
AB SIV DNA can be detected in lymphoid tissue-resident macrophages of chronically SIV-infected Asian macaques. These macrophages also contain evidence of recently phagocytosed SIV-infected CD4(+) T cells. Here, we examine whether these macrophages contain replication-competent virus, whether viral DNA can be detected in tissue-resident macrophages from antiretroviral (ARV) therapy-treated animals and humans, and how the viral sequences amplified from macrophages and contemporaneous CD4(+) T cells compare. In ARV-naive animals, we find that lymphoid tissue-resident macrophages contain replication-competent virus if they also contain viral DNA in ARV-naive Asian macaques. The genetic sequence of the virus within these macrophages is similar to those within CD4(+) T cells from the same anatomic sites. In ARV-treated animals, we find that viral DNA can be amplified from lymphoid tissue-resident macrophages of SIV-infected Asian macaques that were treated with ARVs for at least 5 months, but we could not detect replicationcompetent virus from macrophages of animals treated with ARVs. Finally, we could not detect viral DNA in alveolar macrophages from HIV-infected individuals who received ARVs for 3 years and had undetectable viral loads. These data demonstrate that macrophages can contain replicationcompetent virus, but may not represent a significant reservoir for HIV in vivo.
C1 [DiNapoli, Sarah R.; Ortiz, Alexandra M.; Brenchley, Jason M.] NIAID, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Wu, Fan; Matsuda, Kenta; Hirsch, Vanessa M.] NIAID, Lab Mol Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Twigg, Homer L., III] Indiana Univ, Dept Med, Indianapolis, IN USA.
[Knox, Kenneth] Univ Arizona, Dept Med, Tucson, AZ USA.
RP Brenchley, JM (reprint author), 4 Ctr Dr Room 201,9000 Rockville Pike, Bethesda, MD 20892 USA.
EM jbrenchl@mail.nih.gov
FU Division of Intramural Research/NIAID/NIH
FX We would like to acknowledge Heather Cronise, JoAnne Swerczek, Richard
Herbert, and all the veterinary staff at the NIH animal center. We would
like to thank CLIC/BBC for advice and helpful discussions. We would like
to thank Brandon Keele and Bernard Lafont for assistance in analyzing
SIV Env sequencing data. Funding for this study was provided in part by
the Division of Intramural Research/NIAID/NIH. 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 71
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U1 1
U2 1
PU AMER SOC CLINICAL INVESTIGATION INC
PI ANN ARBOR
PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA
SN 2379-3708
J9 JCI INSIGHT
JI JCI Insight
PD FEB 23
PY 2017
VL 2
IS 4
AR e91214
DI 10.1172/jci.insight.91214
PG 15
WC Medicine, Research & Experimental
SC Research & Experimental Medicine
GA EN5ET
UT WOS:000396029100014
PM 28239657
ER
PT J
AU Li, QX
Bu, W
Gabriel, E
Aguilar, F
Hoshino, Y
Miyadera, H
Hess, C
Hornung, RL
Roy, A
Cohen, JI
AF Li, Qingxue
Bu, Wei
Gabriel, Erin
Aguilar, Fiona
Hoshino, Yo
Miyadera, Hiroko
Hess, Christoph
Hornung, Ronald L.
Roy, Amitava
Cohen, Jeffrey I.
TI HLA-DQ beta 1 alleles associated with Epstein-Barr virus (EBV)
infectivity and EBV gp42 binding to cells
SO JCI INSIGHT
LA English
DT Article
ID AGE-SPECIFIC PREVALENCE; CLASS-II; B-LYMPHOCYTES; SOLUBLE GP42;
RECEPTOR; ACQUISITION; CORECEPTOR; ANTIGENS; REVEALS; HLA-DR1
AB Epstein-Barr virus (EBV) infects B cells and similar to 95% of adults are infected. EBV glycoprotein gp42 is essential for entry of virus into B cells. EBV gp42 binds to the beta 1 chain of HLA-DQ, -DR, and -DP on B cells, and uses these molecules for infection. To investigate if certain HLA-DQ alleles are associated with EBV seronegativity, we recruited similar to 3,300 healthy adult blood donors, identified 106 EBV-seronegative individuals, and randomly selected a control group of EBV-seropositive donors from the donor pool. A larger than expected proportion of EBV-seronegative subjects were HLA-DQ beta 1 *04/*05 and *06/*06, and to a lesser extent, *02/*03, compared with the control group, while a larger than expected portion of EBV-seropositive persons were HLA-DQ beta 1 *02/*02. We examined the ability of EBV gp42 to bind to different HLA-DQ molecules using human and mouse cells stably expressing these alleles. EBV gp42 bound less effectively to cells expressing HLA-DQ beta 1 *04/*05, *06/*06, or *03/*03 than to cells expressing HLA-DQ beta 1 *02/*02. These data are consistent with our observations of increased EBV seronegativity with DQ beta 1 *04/*05 or *06/*06 alleles. These findings emphasize the importance of a single genetic locus (HLA-DQ beta 1) to influence infectivity with EBV.
C1 [Li, Qingxue; Bu, Wei; Aguilar, Fiona; Hoshino, Yo; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Gabriel, Erin] NIAID, Div Clin Res, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Miyadera, Hiroko] Univ Tokyo, Grad Sch Med, Dept Human Genet, Tokyo, Japan.
[Miyadera, Hiroko] Natl Ctr Global Hlth & Med, Res Ctr Hepatitis & Immunol, Chiba, Japan.
[Hess, Christoph] Univ Basel Hosp, Dept Biomed & Med Outpatient Div, Immunobiol Lab, Basel, Switzerland.
[Hornung, Ronald L.] Leidos Biomed Res Inc, Clin Serv Program, Frederick Natl Lab Canc Res, Frederick, MD USA.
[Roy, Amitava] NIH, Bioinformat & Computat Biosci Branch, Rocky Mt Labs, Hamilton, MT USA.
RP Cohen, JI (reprint author), NIH, Bldg 50,Room 6134,50 South Dr,MSC8007, Bethesda, MD 20892 USA.
EM jcohen@niaid.nih.gov
FU intramural research program of the National Institute of Allergy and
Infectious Diseases; National Cancer Institute, NIH [HHSN261200800001E]
FX We thank Melanie Spriggs for plasmid pDC409-BZLF2 and Sharon Adams for
assistance with HLA typing. We thank Toshio Kitamura for providing pMXs
plasmids and Henri-Jacques Delecluse and Bill Sugden for the cell line
expressing 293-EBV. This work was supported by the intramural research
program of the National Institute of Allergy and Infectious Diseases.
This project has been funded in whole or in part with federal funds from
the National Cancer Institute, NIH, under contract HHSN261200800001E.
The content of this publication does not necessarily reflect the views
or policies of the Department of Health and Human Services, nor does
mention of trade names, commercial products, or organizations imply
endorsement by the U.S. Government.
NR 46
TC 0
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U1 0
U2 0
PU AMER SOC CLINICAL INVESTIGATION INC
PI ANN ARBOR
PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA
SN 2379-3708
J9 JCI INSIGHT
JI JCI Insight
PD FEB 23
PY 2017
VL 2
IS 4
AR e85687
DI 10.1172/jci.insight.85687
PG 17
WC Medicine, Research & Experimental
SC Research & Experimental Medicine
GA EN5ET
UT WOS:000396029100001
PM 28239644
ER
PT J
AU Musich, T
Jones, JC
Keele, BF
Jenkins, LMM
Demberg, T
Uldrick, TS
Yarchoan, R
Robert-Guroff, M
AF Musich, Thomas
Jones, Jennifer C.
Keele, Brandon F.
Jenkins, Lisa M. Miller
Demberg, Thorsten
Uldrick, Thomas S.
Yarchoan, Robert
Robert-Guroff, Marjorie
TI Flow virometric sorting and analysis of HIV quasispecies from plasma
SO JCI INSIGHT
LA English
DT Article
ID IMMUNODEFICIENCY-VIRUS TYPE-1; SIMIAN IMMUNODEFICIENCY; PARTICLES;
CYTOMETRY; INFECTION; PROTEINS; GP120; ANTIBODIES; RESPONSES; KINETICS
AB Flow cytometry is utilized extensively for cellular analysis, but technical limitations have prevented its routine application for characterizing virus. The recent introduction of nanoscale fluorescence-activated cytometric cell sorting now allows analysis of individual virions. Here, we demonstrate staining and sorting of infectious HIV. Fluorescent antibodies specific for cellular molecules found on budding virions were used to label CCR5-tropic Bal HIV and CXCR4-tropic NL4.3 HIV Env-expressing pseudovirions made in THP-1 cells (monocyte/macrophage) and H9 cells (T cells), respectively. Using a flow cytometer, we resolved the stained virus beyond isotype staining and demonstrated purity and infectivity of sorted virus populations on cells with the appropriate coreceptors. We subsequently sorted infectious simian/human immunodeficiency virus from archived plasma. Recovery was approximately 0.5%, but virus present in plasma was already bound to viral-specific IgG generated in vivo, likely contributing to the low yield. Importantly, using two broadly neutralizing HIV antibodies, PG9 and VRC01, we also sorted virus from archived human plasma and analyzed the sorted populations genetically and by proteomics, identifying the quasispecies present. The ability to sort infectious HIV from clinically relevant samples provides material for detailed molecular, genetic, and proteomic analyses applicable to future design of vaccine antigens and potential development of personalized treatment regimens.
C1 [Musich, Thomas; Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, Immune Biol Retroviral Infect Sect, Bethesda, MD USA.
[Jones, Jennifer C.] NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, Bethesda, MD 20892 USA.
[Keele, Brandon F.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA.
[Jenkins, Lisa M. Miller] NCI, Collaborat Prot Technol Resource, Cell Biol Lab, Bethesda, MD 20892 USA.
[Uldrick, Thomas S.; Yarchoan, Robert] NCI, Retroviral Dis Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA.
[Demberg, Thorsten] Immat US Inc, Houston, TX USA.
RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA.
EM guroffm@mail.nih.gov
RI Jones, Jennifer/C-8691-2015
OI Jones, Jennifer/0000-0002-9488-7719
FU Intramural Research Program of the NIH, National Cancer Institute
[HHSN261200800001E]
FX We would like to thank Karen Aleman for her help with the clinical
samples used in this study and Stefanie Musich for her graphical help in
preparing this manuscript. The following reagents were obtained through
the NIH AIDS Research and Reference Reagent Program, Division of AIDS,
National Institute of Allergy and Infectious Diseases: anti-HIV-1 gp120
monoclonal PG9; anti-HIV-1 gp120 monoclonal VRC01 from John Mascola;
HIV-1 gp120 mAb 7B2-AAA from Barton F. Haynes and HuaXin Liao; and
U373-MAGI-CCR5E and U373-MAGI-CXCR4 CEM cells from Michael Emerman. This
work was supported by the Intramural Research Program of the NIH,
National Cancer Institute, and 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 33
TC 0
Z9 0
U1 0
U2 0
PU AMER SOC CLINICAL INVESTIGATION INC
PI ANN ARBOR
PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA
SN 2379-3708
J9 JCI INSIGHT
JI JCI Insight
PD FEB 23
PY 2017
VL 2
IS 4
AR e90626
DI 10.1172/jci.insight.90626
PG 13
WC Medicine, Research & Experimental
SC Research & Experimental Medicine
GA EN5ET
UT WOS:000396029100011
PM 28239654
ER
PT J
AU Lack, J
Gillard, M
Cam, M
Paner, GP
VanderWeele, DJ
AF Lack, Justin
Gillard, Marc
Cam, Maggie
Paner, Gladell P.
VanderWeele, David J.
TI Circulating tumor cells capture disease evolution in advanced prostate
cancer
SO JOURNAL OF TRANSLATIONAL MEDICINE
LA English
DT Article
DE Circulating tumor cells; Castrate resistant prostate cancer; Tumor
evolution; Neuroendocrine prostate cancer
ID SEQUENCING DATA; SAMPLES; EXPRESSION; MUTATIONS; FRAMEWORK; GENOMICS;
TISSUE; AR-V7
AB Background: Genetic analysis of advanced cancer is limited by availability of representative tissue. Biopsies of prostate cancer metastasized to bone are invasive with low quantity of tumor tissue. The prostate cancer genome is dynamic, however, with temporal heterogeneity requiring repeated evaluation as the disease evolves. Circulating tumor cells (CTCs) offer an alternative, "liquid biopsy", though single CTC sequencing efforts are laborious with high failure rates.
Methods: We performed exome sequencing of matched treatment-naive tumor tissue, castrate resistant tumor tissue, and pooled CTC samples, and compared mutations identified in each.
Results: Thirty-seven percent of CTC mutations were private to CTCs, one mutation was shared with treatment-naive disease alone, and 62% of mutations were shared with castrate-resistant disease, either alone or with treatment-naive disease. An acquired nonsense mutation in the Retinoblastoma gene, which is associated with progression to small cell cancer, was identified in castrate resistant and CTC samples, but not treatment-naive disease. This timecourse correlated with the tumor acquiring neuroendocrine features and a change to neuroendocrine-specific therapy.
Conclusions: These data support the use of pooled CTCs to facilitate the genetic analysis of late stage prostate cancer.
C1 [Lack, Justin; Cam, Maggie] NCI, Ctr Canc Res Collaborat Bioinformat Resource, Ctr Canc Res, Bethesda, MD 20892 USA.
[Gillard, Marc] Univ Chicago, Dept Surg, Chicago, IL 60615 USA.
[Paner, Gladell P.] Univ Chicago, Dept Pathol, Chicago, IL 60615 USA.
[VanderWeele, David J.] NCI, Lab Genitourinary Pathogenesis, Ctr Canc Res, 37 Convent Dr,Rm 1066A, Bethesda, MD 20892 USA.
[VanderWeele, David J.] Univ Chicago, Dept Med, Chicago, IL 60615 USA.
RP VanderWeele, DJ (reprint author), NCI, Lab Genitourinary Pathogenesis, Ctr Canc Res, 37 Convent Dr,Rm 1066A, Bethesda, MD 20892 USA.
EM david.vanderweele@nih.gov
FU Office of the Assistant Secretary of Defense for Health Affairs, through
the Prostate Cancer Research Program [W81XWH-13-1-0451]; University of
Chicago Cancer Center Support Grant [P30 CA014599]; Intramural Research
Program of the NIH, National Cancer Institute, Center for Cancer
Research
FX This work was supported by the Office of the Assistant Secretary of
Defense for Health Affairs, through the Prostate Cancer Research Program
under Award No. W81XWH-13-1-0451 (DVW). Opinions, interpretations,
conclusions and recommendations are those of the author and are not
necessarily endorsed by the Department of Defense. The U.S. Army Medical
Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD
21702-5014 is the awarding and administering acquisition office. This
work was also supported by the University of Chicago Cancer Center
Support Grant P30 CA014599 (DVW), and the Intramural Research Program of
the NIH, National Cancer Institute, Center for Cancer Research (DVW).
This work utilized the computational resources of the NIH HPC Biowulf
cluster (http://hpc.nih.gov).
NR 28
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U1 3
U2 3
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 FEB 23
PY 2017
VL 15
AR 44
DI 10.1186/s12967-017-1138-3
PG 8
WC Medicine, Research & Experimental
SC Research & Experimental Medicine
GA EM8MT
UT WOS:000395566200001
PM 28228136
ER
PT J
AU White, SH
McDermott, MM
Sufit, RL
Kosmac, K
Bugg, AW
Gonzalez-Freire, M
Ferrucci, L
Tian, L
Zhao, LH
Gao, Y
Kibbe, MR
Criqui, MH
Leeuwenburgh, C
Peterson, CA
AF White, Sarah H.
McDermott, Mary M.
Sufit, Robert L.
Kosmac, Kate
Bugg, Alex W.
Gonzalez-Freire, Marta
Ferrucci, Luigi
Tian, Lu
Zhao, Lihui
Gao, Ying
Kibbe, Melina R.
Criqui, Michael H.
Leeuwenburgh, Christiaan
Peterson, Charlotte A.
TI Walking performance is positively correlated to calf muscle fiber size
in peripheral artery disease subjects, but fibers show aberrant
mitophagy: an observational study (vol 14, 284, 2016)
SO JOURNAL OF TRANSLATIONAL MEDICINE
LA English
DT Correction
C1 [White, Sarah H.; Kosmac, Kate; Bugg, Alex W.; Peterson, Charlotte A.] Univ Kentucky, Coll Hlth Sci, 900 S Limestone CTW105, Lexington, KY 40536 USA.
[White, Sarah H.; Kosmac, Kate; Bugg, Alex W.; Peterson, Charlotte A.] Univ Kentucky, Ctr Muscle Biol, 900 S Limestone CTW105, Lexington, KY 40536 USA.
[McDermott, Mary M.] Northwestern Univ, Div Gen Internal Med, Dept Med, Feinberg Sch Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA.
[McDermott, Mary M.; Zhao, Lihui; Gao, Ying] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
[Sufit, Robert L.] Northwestern Univ, Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA.
[Gonzalez-Freire, Marta; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA.
[Tian, Lu] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA.
[Kibbe, Melina R.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA.
[Kibbe, Melina R.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA.
[Criqui, Michael H.] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
[Leeuwenburgh, Christiaan] Univ Florida, Dept Aging & Geriatr Res, Inst Aging, Gainesville, FL USA.
RP Peterson, CA (reprint author), Univ Kentucky, Coll Hlth Sci, 900 S Limestone CTW105, Lexington, KY 40536 USA.; Peterson, CA (reprint author), Univ Kentucky, Ctr Muscle Biol, 900 S Limestone CTW105, Lexington, KY 40536 USA.; McDermott, MM (reprint author), Northwestern Univ, Div Gen Internal Med, Dept Med, Feinberg Sch Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA.
EM mdm608@northwestern.edu; cpete4@uky.edu
NR 1
TC 0
Z9 0
U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1479-5876
J9 J TRANSL MED
JI J. Transl. Med.
PD FEB 23
PY 2017
VL 15
AR 45
DI 10.1186/s12967-017-1127-6
PG 1
WC Medicine, Research & Experimental
SC Research & Experimental Medicine
GA EM8MT
UT WOS:000395566200002
PM 28241774
ER
PT J
AU Lewandowski, LB
Watt, MH
Schanberg, LE
Thielman, NM
Scott, C
AF Lewandowski, Laura B.
Watt, Melissa H.
Schanberg, Laura E.
Thielman, Nathan M.
Scott, Christiaan
TI Missed opportunities for timely diagnosis of pediatric lupus in South
Africa: a qualitative study
SO PEDIATRIC RHEUMATOLOGY
LA English
DT Article
DE Lupus; Pediatric SLE; Africa; Access to care; Chronic illness;
Qualitative
ID HEALTH-CARE; ERYTHEMATOSUS; MORTALITY; RHEUMATOLOGY; ACCESS; CHALLENGES;
NEPHRITIS; CHILDREN; SLE; DISPARITIES
AB Background: Systemic Lupus Erythematosus (SLE) is a serious multisystem autoimmune disease, which is more aggressive in children and people of African descent. In South Africa, pediatric SLE (pSLE) patients are at high risk for severe disease. Similar to pSLE worldwide, South African children and adolescents with SLE require subspecialized medical care. The aim of this study is to describe the care-seeking experiences of families and examine factors that contribute to delays in the diagnosis of pSLE. Specifically, we sought to identify factors to inform interventions that support the timely referral and diagnosis of pediatric SLE patients in South Africa.
Methods: In-depth, semi-structured interviews were conducted with 22 caregivers of pSLE patients recruited from two government hospitals in Cape Town, South Africa in 2014. Interviews were audio-recorded, transcribed, and analyzed for themes related to barriers to diagnosis.
Results: Six themes were identified and classified as either caregiver or health system barriers to diagnosis. Caregiver barriers included lack of knowledge regarding SLE, financial difficulties, and the social stigma of SLE. Health system barriers were lack of trained staff, a complex medical system, and misdiagnosis.
Conclusion: Caregivers reported missed opportunities for diagnosing pSLE in their children. Raising public awareness may improve caregiver awareness and reduce stigma of pSLE. Improving family education at diagnosis holds potential to increase patient-physician trust and mitigate fear. Education modules for primary care providers at initial point of contact with the health care system may improve recognition of early pSLE and facilitate expedited referral to a specialist.
C1 [Lewandowski, Laura B.] NIH DHHS, Natl Inst Arthritis Musculoskeletal & Skin Dis, 9000 Rockville Pike,Bldg 10,12 N248 Room 28, Bethesda, MD USA.
[Lewandowski, Laura B.; Watt, Melissa H.; Thielman, Nathan M.] Duke Univ, Duke Global Hlth Inst, 310 Trent Dr, Durham, NC 27710 USA.
[Schanberg, Laura E.] Duke Univ Med Ctr, Pediat Rheumatol, 2301 Erwin Rd, Durham, NC USA.
[Scott, Christiaan] Univ Cape Town, Red Cross War Mem Childrens Hosp, Klipfontein Rd,Rondebosch, Cape Town, South Africa.
RP Lewandowski, LB (reprint author), NIH DHHS, Natl Inst Arthritis Musculoskeletal & Skin Dis, 9000 Rockville Pike,Bldg 10,12 N248 Room 28, Bethesda, MD USA.; Lewandowski, LB (reprint author), Duke Univ, Duke Global Hlth Inst, 310 Trent Dr, Durham, NC 27710 USA.
EM laura.lewandowski@nih.gov
FU Lupus Foundation of America Early Career Award; training grant at Duke
University [T32 AI0007217]; Duke Global Health Institute Fieldwork;
Fogarty International Center (NIH) [R25TW009337]
FX LBL was funded by the Lupus Foundation of America Early Career Award, a
training grant at Duke University (T32 AI0007217), a Duke Global Health
Institute Fieldwork grant, and the Fogarty International Center (NIH
R25TW009337).
NR 55
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U1 2
U2 2
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1546-0096
J9 PEDIATR RHEUMATOL
JI Pediatr. Rheumatol.
PD FEB 23
PY 2017
VL 15
AR 14
DI 10.1186/s12969-017-0144-6
PG 9
WC Pediatrics; Rheumatology
SC Pediatrics; Rheumatology
GA EP4AF
UT WOS:000397322100001
PM 28231857
ER
PT J
AU Mork, J
Aronson, A
Demner-Fushman, D
AF Mork, James
Aronson, Alan
Demner-Fushman, Dina
TI 12 years on - Is the NLM medical text indexer still useful and relevant?
SO JOURNAL OF BIOMEDICAL SEMANTICS
LA English
DT Article
DE Indexing methods; Text categorization; MeSH; MEDLINE; Machine learning;
BioASQ
AB Background: Facing a growing workload and dwindling resources, the US National Library of Medicine (NLM) created the Indexing Initiative project in 1996. This cross-library team's mission is to explore indexing methodologies for ensuring quality and currency of NLM document collections. The NLM Medical Text Indexer (MTI) is the main product of this project and has been providing automated indexing recommendations since 2002. After all of this time, the questions arise whether MTI is still useful and relevant.
Methods: To answer the question about MTI usefulness, we track a wide variety of statistics related to how frequently MEDLINE indexers refer to MTI recommendations, how well MTI performs against human indexing, and how often MTI is used. To answer the question of MTI relevancy compared to other available tools, we have participated in the 2013 and 2014 BioASQ Challenges. The BioASQ Challenges have provided us with an unbiased comparison between the MTI system and other systems performing the same task.
Results: Indexers have continually increased their use of MTI recommendations over the years from 15.75% of the articles they index in 2002 to 62.44% in 2014 showing that the indexers find MTI to be increasingly useful. The MTI performance statistics show significant improvement in Precision (+0.2992) and F-1 (+0.1997) with modest gains in Recall (+0.0454) over the years. MTI consistency is comparable to the available indexer consistency studies. MTI performed well in both of the BioASQ Challenges ranking within the top tier teams.
Conclusions: Based on our findings, yes, MTI is still relevant and useful, and needs to be improved and expanded. The BioASQ Challenge results have shown that we need to incorporate more machine learning into MTI while still retaining the indexing rules that have earned MTI the indexers' trust over the years. We also need to expand MTI through the use of full text, when and where it is available, to provide coverage of indexing terms that are typically only found in the full text. The role of MTI at NLM is also expanding into new areas, further reinforcing the idea that MTI is increasingly useful and relevant.
C1 [Mork, James; Aronson, Alan; Demner-Fushman, Dina] US Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA.
RP Mork, J (reprint author), US Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA.
EM jmork@mail.nlm.nih.gov
FU Intramural Research Program of the National Institutes of Health;
National Library of Medicine
FX This work was supported by the Intramural Research Program of the
National Institutes of Health and the National Library of Medicine. We
would like to thank our colleagues Francois Lang and Willie Rogers for
providing direct and indirect support of MTI. We would also like to
extend special acknowledgment to Hua Florence Chang who was the original
creator of MTI. Florence's foresight has provided us with a robust and
tunable program. We would also like to take this opportunity to thank
George Paliouras and the entire BioASQ Team for organizing the BioASQ
Challenges and providing the opportunity to evaluate MTI. Finally, we
would like to thank the NLM indexers and Indexing staff for their
continued support and collaboration they have provided over the last
twelve years teaching the MTI team how they index and ensuring that MTI
succeeds.
NR 24
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U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 2041-1480
J9 J BIOMED SEMANT
JI J. Biomed. Semant.
PD FEB 23
PY 2017
VL 8
AR 8
DI 10.1186/s13326-017-0113-5
PG 10
WC Mathematical & Computational Biology
SC Mathematical & Computational Biology
GA EP5NJ
UT WOS:000397425300001
PM 28231809
ER
PT J
AU Makarova, KS
Zhang, F
Koonin, EV
AF Makarova, Kira S.
Zhang, Feng
Koonin, Eugene V.
TI SnapShot: Class 1 CRISPR-Cas Systems
SO CELL
LA English
DT Editorial Material
ID IMMUNITY
C1 [Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA.
[Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
[Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
RP Makarova, KS (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA.
NR 9
TC 0
Z9 0
U1 7
U2 7
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 0092-8674
EI 1097-4172
J9 CELL
JI Cell
PD FEB 23
PY 2017
VL 168
IS 5
BP 946
EP +
PG 2
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA EN8YB
UT WOS:000396284800023
PM 28235204
ER
PT J
AU Kidder, BL
Hu, GQ
Cui, KR
Zhao, KJ
AF Kidder, Benjamin L.
Hu, Gangqing
Cui, Kairong
Zhao, Keji
TI SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell
self-renewal and prevent spurious differentiation
SO EPIGENETICS & CHROMATIN
LA English
DT Article
DE Embryonic stem cells; SMYD5; H4K20me3; Repetitive DNA; LTR; LINE;
Pluripotent; Epigenetics; Chromatin; Heterochromatin; Genomics; RNA-Seq;
ChIP-Seq; Self-renewal; Gene expression; Embryoid body; Differentiation;
Histone methyltransferase
ID EMBRYONIC STEM-CELLS; CORE TRANSCRIPTIONAL NETWORK; GENE-EXPRESSION;
MOUSE DEVELOPMENT; METHYLTRANSFERASE ESET; LYSINE-9 METHYLATION; LTR
RETROTRANSPOSONS; ENRICHMENT ANALYSIS; GENOME INTEGRITY; STRUCTURAL
BASIS
AB Background: Epigenetic regulation of chromatin states is thought to control the self-renewal and differentiation of embryonic stem (ES) cells. However, the roles of repressive histone modifications such as trimethylated histone 4 lysine 20 (H4K20me3) in pluripotency and development are largely unknown.
Results: Here, we show that the histone lysine methyltransferase SMYD5 mediates H4K20me3 at heterochromatin regions. Depletion of SMYD5 leads to compromised self-renewal, including dysregulated expression of OCT4 targets, and perturbed differentiation. SMYD5-bound regions are enriched with repetitive DNA elements. Knockdown of SMYD5 results in a global decrease of H4K20me3 levels, a redistribution of heterochromatin constituents including H3K9me3/2, G9a, and HP1a, and de-repression of endogenous retroelements. A loss of SMYD5-dependent silencing of heterochromatin nearby genic regions leads to upregulated expression of lineage-specific genes, thus contributing to the decreased self-renewal and perturbed differentiation of SMYD5-depleted ES cells.
Conclusions: Altogether, these findings implicate a role for SMYD5 in regulating ES cell self-renewal and H4K20me3-marked heterochromatin.
C1 [Kidder, Benjamin L.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48202 USA.
[Kidder, Benjamin L.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48202 USA.
[Kidder, Benjamin L.; Hu, Gangqing; Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA.
RP Kidder, BL (reprint author), Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48202 USA.; Kidder, BL (reprint author), Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48202 USA.; Kidder, BL; Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA.
EM Benjamin.kidder@wayne.edu; keji.zhao@nih.gov
FU Division of Intramural Research of the National Heart, Lung and Blood
Institute; Karmanos Cancer Institute, Wayne State University; National
Heart, Lung and Blood Institute [1K22HL126842-01A1]
FX This work was supported by the Division of Intramural Research of the
National Heart, Lung and Blood Institute, Karmanos Cancer Institute,
Wayne State University, and a grant from the National Heart, Lung and
Blood Institute (1K22HL126842-01A1) awarded to BLK.
NR 69
TC 0
Z9 0
U1 1
U2 1
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1756-8935
J9 EPIGENET CHROMATIN
JI Epigenetics Chromatin
PD FEB 23
PY 2017
VL 10
AR 8
DI 10.1186/s13072-017-0115-7
PG 20
WC Genetics & Heredity
SC Genetics & Heredity
GA EM7IP
UT WOS:000395485000001
PM 28250819
ER
PT J
AU Kumar, V
Moritz, AE
Keck, TM
Bonifazi, A
Ellenberger, MP
Sibley, CD
Free, RB
Shi, L
Lane, JR
Sibley, DR
Newman, AH
AF Kumar, Vivek
Moritz, Amy E.
Keck, Thomas M.
Bonifazi, Alessandro
Ellenberger, Michael P.
Sibley, Christopher D.
Free, R. Benjamin
Shi, Lei
Lane, J. Robert
Sibley, David R.
Newman, Amy Hauck
TI Synthesis and Pharmacological Characterization of Novel
trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity
and Allosteric Pharmacology at the Dopamine D-3 Receptor (D3R)
SO JOURNAL OF MEDICINAL CHEMISTRY
LA English
DT Article
ID PROTEIN-COUPLED RECEPTORS; MEDICINAL CHEMISTRY PERSPECTIVE;
ANTIPSYCHOTIC-DRUGS; BITOPIC LIGAND; ANTAGONISTS; DISCOVERY; ANALOGS;
DESIGN; POTENT; HYPOTHESIS
AB The development of bitopic ligands directed toward D-2-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D-3 receptor (D3R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmaco-phores were derived from the D3R-selective antagonists SB269,652 (1) and SB277011A (2) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a trans-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D3R-selective antagonists, 18a and 25a, which further delineates SAR associated with allosterism at D3R and provides leads toward novel drug development.
C1 [Kumar, Vivek; Keck, Thomas M.; Bonifazi, Alessandro; Ellenberger, Michael P.; Sibley, Christopher D.; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA.
[Shi, Lei] NINDS, Computat Chem & Mol Biophys Unit, Mol Targets & Medicat Discovery Branch, NIH, 35 Convent Dr, Baltimore, MD 21224 USA.
[Moritz, Amy E.; Free, R. Benjamin; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, 35 Convent Dr,MSC-3723, Bethesda, MD 20892 USA.
[Lane, J. Robert] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, 399 Royal Parade, Parkville, Vic 3052, Australia.
[Keck, Thomas M.] Rowan Univ, Coll Sci & Math, Dept Biomed & Translat Sci, Dept Chem & Biochem, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA.
RP Newman, AH (reprint author), NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA.
EM anewman@intra.nida.nih.gov
FU Intramural Research Programs of the National Institute on Drug Abuse;
National Institute of Neurological Disorders and Stroke
FX Support for this research was provided by the Intramural Research
Programs of the National Institute on Drug Abuse (V.K, T.M.K, A.B.,
M.P.E., and A.H.N.) and the National Institute of Neurological Disorders
and Stroke (A.E.M., C.D.S., R.B.F., and D.R.S.). J.R.L. is a RD Wright
Biomedical Career Development Fellow (NHMRC).
NR 54
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Z9 0
U1 0
U2 0
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 FEB 23
PY 2017
VL 60
IS 4
BP 1478
EP 1494
DI 10.1021/acs.jmedchem.6b01688
PG 17
WC Chemistry, Medicinal
SC Pharmacology & Pharmacy
GA EL9FH
UT WOS:000394924900017
PM 28186762
ER
PT J
AU Mordmuller, B
Surat, G
Lagler, H
Chakravarty, S
Ishizuka, AS
Lalremruata, A
Gmeiner, M
Campo, JJ
Esen, M
Ruben, AJ
Held, J
Calle, CL
Mengue, JB
Gebru, T
Ibanez, J
Sulyok, M
James, ER
Billingsley, PF
Kc, N
Manoj, A
Murshedkar, T
Gunasekera, A
Appen, AGE
Li, T
Stafford, RE
Li, ML
Felgner, PL
Seder, RA
Richie, TL
Sim, BKL
Hoffman, SL
Kremsner, PG
AF Mordmueller, Benjamin
Surat, Guezin
Lagler, Heimo
Chakravarty, Sumana
Ishizuka, Andrew S.
Lalremruata, Albert
Gmeiner, Markus
Campo, Joseph J.
Esen, Meral
Ruben, Adam J.
Held, Jana
Calle, Carlos Lamsfus
Mengue, Juliana B.
Gebru, Tamirat
Ibanez, Javier
Sulyok, Mihaly
James, Eric R.
Billingsley, Peter F.
Kc, Natasha
Manoj, Anita
Murshedkar, Tooba
Gunasekera, Anusha
Appen, Abraham G. E.
Li, Tao
Stafford, Richard E.
Li, Minglin
Felgner, Phil L.
Seder, Robert A.
Richie, Thomas L.
Sim, B. Kim Lee
Hoffman, Stephen L.
Kremsner, Peter G.
TI Sterile protection against human malaria by chemoattenuated PfSPZ
vaccine
SO NATURE
LA English
DT Article
ID PLASMODIUM-FALCIPARUM SPOROZOITES; DIRECT VENOUS INOCULATION; T-CELL
IMMUNITY; LIVER-STAGE; CHLOROQUINE PROPHYLAXIS; HUMAN VOLUNTEERS;
IMMUNIZATION; INFECTION; ANTIGEN; ANTIBODIES
AB A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites(1). A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes(2-4); by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine')(5,6); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine(7-10) or mefloquine(11) (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ ('PfSPZ Challenge'(12,13)) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac)(14). Three doses of 5.12 x 10(4) PfSPZ of PfSPZ Challenge(12,13) at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 x 10(3) (group I) or 1.28 x 10(4) (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 x 10(4) PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.
C1 [Mordmueller, Benjamin; Surat, Guezin; Lagler, Heimo; Lalremruata, Albert] Univ Tubingen, Inst Trop Med, Partner Site, D-72074 Tubingen, Germany.
[Gmeiner, Markus; Held, Jana; Gebru, Tamirat; James, Eric R.] German Ctr Infect Res, Partner Site, D-72074 Tubingen, Germany.
[Chakravarty, Sumana; Billingsley, Peter F.; Murshedkar, Tooba; Hoffman, Stephen L.] Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med, A-1090 Vienna, Austria.
[Seder, Robert A.] Sanaria Inc, Rockville, MD 20850 USA.
[Gmeiner, Markus; Ibanez, Javier; James, Eric R.; Kc, Natasha] NIAID, NIH, Vaccine Res Ctr VRC, Bethesda, MD 20892 USA.
[Billingsley, Peter F.; Kc, Natasha] Antigen Discovery Inc, Irvine, CA 92618 USA.
[Campo, Joseph J.; Mengue, Juliana B.; James, Eric R.; Manoj, Anita] Protein Potential LLC, Rockville, MD 20850 USA.
[Ishizuka, Andrew S.; Calle, Carlos Lamsfus; Appen, Abraham G. E.; Li, Tao] Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA.
RP Hoffman, SL (reprint author), Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med, A-1090 Vienna, Austria.
EM slhoffman@sanaria.com
OI Sulyok, Mihaly/0000-0002-6960-5126; Lagler, Heimo/0000-0003-3240-7385
FU German Federal Ministry of Education and Research (BMBF) through the
German Center for Infection Research (DZIF); National Institute of
Allergy and Infectious Diseases of the National Institutes of Health
under SBIR [5R44AI058375, 5R44AI055229]; intramural research program of
the VRC, NIAID, NIH; NIAID SBIR [5R44AI066791]; Bill & Melinda Gates
Foundation
FX The authors thank the vaccine trial participants for their contribution
and commitment to vaccine research. We thank F. Adomat, S. Adukpo, M.
Aldejohann, S. Bolte, S. Borrmann, A. Bouyoukou Hounkpatin, S. Bruckner,
E. Bruske, J. Fernandes, P. Granados Bayon, J. Hass, S. Jeyaraj, J.
Keim, A. Knoblich, R. Kollner, A. Kreidenweiss, D. N. Ndungu, R. Ritter,
J. A. Selvaraj, Z. Sulyok, S. Theil, N. Theurer, and I. Westermann for
support in conducting the trial, and P. Darrah and M. Roederer for
assistance with the interpretation of the T-cell data. We thank the
Sanaria and Protein Potential teams for manufacture and shipping of
investigational products, PfSPZ Challenge and diluents, regulatory,
quality, and clinical site activities, and legal and administrative
support, including especially D. Cheney (nee Padilla), Y. Abebe, E.
Saverino, Y. Wu, E. Fomumbod, A. Awe, M. King, M. Orozco, A. Patil, Y.
Wen, K. Nelson, J. Overby, S. Matheny, V. Pitch, B. Jiang, L. Gao, R.
Xu, T. T. Wai, S. Monsheimer, P. De La Vega, M. Laskowski, H. Huang, M.
Marquette, J. Jackson, F. Beams, R. Douglas, R. C. Thompson, D. Dolberg
and A. Hoffman. We thank J. Inglese and P. Dranchak of the National
Center for Advancing Translational Sciences (NCATS), NIH for support
with the automated immunofluorescence assay and inhibition of sporozoite
invasion assays. We appreciate the expert reviews of the Safety
Monitoring Committee (W. Chen, P. Coyne and P. Zanger). The clinical
trial was funded by the German Federal Ministry of Education and
Research (BMBF) through the German Center for Infection Research (DZIF).
Manufacture of investigational product by Sanaria was supported in part
by the National Institute of Allergy and Infectious Diseases of the
National Institutes of Health under SBIR award numbers 5R44AI058375 and
5R44AI055229. T cell studies were supported by the intramural research
program of the VRC, NIAID, NIH. Proteome microarray studies were
supported by NIAID SBIR grant 5R44AI066791 and funding from the Bill &
Melinda Gates Foundation.
NR 45
TC 0
Z9 0
U1 5
U2 5
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 FEB 23
PY 2017
VL 542
IS 7642
BP 445
EP +
DI 10.1038/nature21060
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100029
PM 28199305
ER
PT J
AU Thomou, T
Mori, MA
Dreyfuss, JM
Konishi, M
Sakaguchi, M
Wolfrum, C
Rao, TN
Winnay, JN
Garcia-Martin, R
Grinspoon, SK
Gorden, P
Kahn, CR
AF Thomou, Thomas
Mori, Marcelo A.
Dreyfuss, Jonathan M.
Konishi, Masahiro
Sakaguchi, Masaji
Wolfrum, Christian
Rao, Tata Nageswara
Winnay, Jonathon N.
Garcia-Martin, Ruben
Grinspoon, Steven K.
Gorden, Phillip
Kahn, C. Ronald
TI Adipose-derived circulating miRNAs regulate gene expression in other
tissues
SO NATURE
LA English
DT Article
ID EXTRACELLULAR VESICLES; MICRORNA BIOGENESIS; MEMBRANE-VESICLES; HUMAN
OBESITY; EXOSOMES; CELLS; RNA; DIFFERENTIATION; MICROVESICLES;
METABOLISM
AB Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3'UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.
C1 [Thomou, Thomas; Konishi, Masahiro; Sakaguchi, Masaji; Rao, Tata Nageswara; Winnay, Jonathon N.; Garcia-Martin, Ruben; Kahn, C. Ronald] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA.
[Thomou, Thomas; Dreyfuss, Jonathan M.; Konishi, Masahiro; Sakaguchi, Masaji; Rao, Tata Nageswara; Winnay, Jonathon N.; Garcia-Martin, Ruben; Grinspoon, Steven K.; Kahn, C. Ronald] Harvard Med Sch, Boston, MA 02115 USA.
[Mori, Marcelo A.] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Campinas, SP, Brazil.
[Dreyfuss, Jonathan M.] Joslin Diabet Ctr, Bioinformat Core, Boston, MA 02215 USA.
[Dreyfuss, Jonathan M.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA.
[Wolfrum, Christian] ETHZ, Dept Hlth Sci & Metab, Zurich, Switzerland.
[Rao, Tata Nageswara] Univ Basel Hosp, Dept Biomed, Expt Hematol, Basel, Switzerland.
[Grinspoon, Steven K.] Massachusetts Gen Hosp, MGH Program Nutr Metab, Boston, MA 02114 USA.
[Gorden, Phillip] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.
RP Kahn, CR (reprint author), Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA.; Kahn, CR (reprint author), Harvard Med Sch, Boston, MA 02115 USA.
EM c.ronald.kahn@joslin.harvard.edu
OI Dreyfuss, Jonathan/0000-0001-7242-3991
FU NIH [R01 DK082659, R01 DK033201, P30 DK040561]; Mary K. Iacocca
Professorship; Joslin Diabetes Center DRC [P30DK036836]; FAPESP
[2010/52557-0, 2015/01316-7]
FX We thank M. Torriani and K. V. Fitch for assistance with HIV
lipodystrophy samples; M. Lynnes, S. Kasif, and A. M. Cypess for help
with reagents and discussions; and the Joslin Histology, Media and
Physiology Core Facilities for help with experiments. This study was
supported by grants from the NIH R01 DK082659 and R01 DK033201, the Mary
K. Iacocca Professorship, and the Joslin Diabetes Center DRC Grant
P30DK036836. S.K.G. was funded by grants from the NIH (P30 DK040561).
M.A.M. was funded by grants from FAPESP (2010/52557-0 and 2015/01316-7).
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PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 450
EP +
DI 10.1038/nature21365
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100030
PM 28199304
ER
PT J
AU Compagno, M
Wang, Q
Pighi, C
Cheong, TC
Meng, FL
Poggio, T
Yeap, LS
Karaca, E
Blasco, RB
Langellotto, F
Ambrogio, C
Voena, C
Wiestner, A
Kasar, SN
Brown, JR
Sun, J
Wu, CJ
Gostissa, M
Alt, FW
Chiarle, R
AF Compagno, Mara
Wang, Qi
Pighi, Chiara
Cheong, Taek-Chin
Meng, Fei-Long
Poggio, Teresa
Yeap, Leng-Siew
Karaca, Elif
Blasco, Rafael B.
Langellotto, Fernanda
Ambrogio, Chiara
Voena, Claudia
Wiestner, Adrian
Kasar, Siddha N.
Brown, Jennifer R. .
Sun, Jing
Wu, Catherine J.
Gostissa, Monica
Alt, Frederick W.
Chiarle, Roberto
TI Phosphatidylinositol 3-kinase delta blockade increases genomic
instability in B cells
SO NATURE
LA English
DT Article
ID CHRONIC LYMPHOCYTIC-LEUKEMIA; INDUCED CYTIDINE DEAMINASE; CLASS-SWITCH
RECOMBINATION; SEQUENCING REVEALS; CHROMOSOMAL TRANSLOCATIONS;
SUPER-ENHANCERS; TARGETING BTK; AID; DNA; HYPERMUTATION
AB Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation(1). In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma(2). AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase delta (PI3K delta) pathway regulates AID by suppressing its expression in B cells4. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3K delta activity directly or indirectly(5-8), potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3K delta inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3K delta inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3K delta or Bruton's tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.
C1 [Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Voena, Claudia; Chiarle, Roberto] Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA.
[Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Voena, Claudia; Chiarle, Roberto] Harvard Med Sch, Boston, MA 02115 USA.
[Meng, Fei-Long; Yeap, Leng-Siew; Gostissa, Monica; Alt, Frederick W.] Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA.
[Meng, Fei-Long; Yeap, Leng-Siew; Gostissa, Monica; Alt, Frederick W.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
[Poggio, Teresa; Voena, Claudia; Chiarle, Roberto] Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy.
[Kasar, Siddha N.; Brown, Jennifer R. .; Sun, Jing] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
[Wiestner, Adrian] Natl Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD USA.
[Meng, Fei-Long] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China.
[Yeap, Leng-Siew] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Immunol, Shanghai 200025, Peoples R China.
[Langellotto, Fernanda; Gostissa, Monica] Agenus Inc, 3 Forbes Rd, Lexington, MA 02421 USA.
RP Chiarle, R (reprint author), Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA.; Chiarle, R (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Chiarle, R (reprint author), Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy.
EM roberto.chiarle@childrens.harvard.edu
FU NIH [R01 CA196703-01, 1U10CA180861-01, R01AI077595]; Associazione
Italiana per la Ricerca sul Cancro [IG-12023, MFAG 10708]; Worldwide
Cancer Research grant [12-0216]; Compagnia di San Paolo-Comitato Gigi
Ghirotti; American Cancer Society [RSG-13-002-01-CCE]; National Research
Foundation of Korea(NRF); PhRMA Foundation; NHLBI, NIH
FX We thank K. Okkenhaug and F. Garcon for providing wild-type and mutated
PI3K delta constructs, F. Zhang for providing CRISPR/Cas9 plasmids. We
thank M. Fleming and M. M. Awad for critically reading the manuscript.
This work was supported by NIH grants R01 CA196703-01 to R.C.;
1U10CA180861-01 to C.J.W., R01AI077595 to F.W.A; Associazione Italiana
per la Ricerca sul Cancro grant IG-12023 to R.C. and MFAG 10708 to M.C.;
Worldwide Cancer Research grant 12-0216 to R.C.; Compagnia di San
Paolo-Comitato Gigi Ghirotti to M.C.; American Cancer Society Grant
RSG-13-002-01-CCE to J.R.B.; T.C.C. is supported by a National Research
Foundation of Korea(NRF) fellowship; L.S.Y. was a Cancer Research
Institute postdoctoral fellow; F.M. was a Lymphoma Research Foundation
postdoctoral fellow; J.S. is a recipient of a PhRMA Foundation Research
Fellowship; C.J.W. is Scholar of the Leukemia and Lymphoma Society;
F.W.A. is an investigator of the Howard Hughes Medical Institute. A.W.
is supported by the intramural program of NHLBI, NIH.
NR 43
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PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0028-0836
EI 1476-4687
J9 NATURE
JI Nature
PD FEB 23
PY 2017
VL 542
IS 7642
BP 489
EP +
DI 10.1038/nature21406
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1RG
UT WOS:000395094100039
PM 28199309
ER
PT J
AU Schlusser, KE
Pilcher, C
Kallas, EG
Santos, BR
Deeks, SG
Facente, S
Keating, SM
Busch, MP
Murphy, G
Welte, A
Quinn, T
Eshleman, SH
Laeyendecker, O
AF Schlusser, Katherine E.
Pilcher, Christopher
Kallas, Esper G.
Santos, Breno R.
Deeks, Steven G.
Facente, Shelley
Keating, Sheila M.
Busch, Michael P.
Murphy, Gary
Welte, Alex
Quinn, Thomas
Eshleman, Susan H.
Laeyendecker, Oliver
TI Comparison of cross-sectional HIV incidence assay results from dried
blood spots and plasma
SO PLOS ONE
LA English
DT Article
ID BED-ENZYME-IMMUNOASSAY; TYPE-1 SEROCONVERSION; CHALLENGES
AB Background
Assays have been developed for cross-sectional HIV incidence estimation using plasma samples. Large scale surveillance programs are planned using dried blood spot (DBS) specimens for incidence assessment. However, limited information exists on the performance of HIV cross-sectional incidence assays using DBS.
Methods
The assays evaluated were: Maxim HIV-1 Limiting Antigen Avidity EIA (LAg-Avidity), Sedia HIV-1 BED-Capture EIA (BED-CEIA), and CDC modified BioRad HIV-1/2 Plus O Aviditybased Assay (CDC-BioRad Avidity) using pre-determined cutoff values. 100 matched HIV-1 positive plasma and DBS samples, with known duration of infection, from the Consortium for the Evaluation and Performance of HIV Incidence Assays repository were tested. All assays were run in duplicate. To examine the degree of variability within and between results for each sample type, both categorical and continuous results were analyzed. Associations were assessed with Bland Altman, R-2 values and Cohen's kappa coefficient (kappa).
Results
Intra-assay variability using the same sample type was similar for all assays (R-2 0.96 to 1.00). The R-2 values comparing DBS and plasma results for LAg-Avidity, BED-CEIA, and CDC-BioRad Avidity were 0.96, 0.94, and 0.84, respectively. The concordance and. values between DBS and plasma for all three assays were > 87% and > 0.64, respectively. The Bland-Altman analysis showed significant differences between plasma and DBS samples. For all three assays, a higher number of samples were classified as recent infections using DBS samples.
Conclusions
DBS and plasma sample results were highly correlated. However, when compared to plasma, each assay performed somewhat differently in DBS at the lower and higher ends of the dynamic range. DBS samples were more likely to be classified as recently infected by all three assays, which may lead to overestimation of incidence in surveys using performance criteria derived for plasma samples.
C1 [Schlusser, Katherine E.; Quinn, Thomas; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA.
[Pilcher, Christopher; Deeks, Steven G.; Facente, Shelley; Keating, Sheila M.; Busch, Michael P.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA USA.
[Kallas, Esper G.] Univ Sao Paulo, Sao Paulo, Brazil.
[Kallas, Esper G.] Grp Hosp Conceicao, Porto Alegre, RS, Brazil.
[Keating, Sheila M.; Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA.
[Murphy, Gary] Publ Hlth England, London, England.
[Welte, Alex] Univ Stellenbosch, South African DST NRF Ctr Excellence Epidemiol Mo, Stellenbosch, South Africa.
[Quinn, Thomas; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA.
[Eshleman, Susan H.] Johns Hopkins Univ Sch Med, Dept Pathol, Baltimore, MD USA.
RP Laeyendecker, O (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA.; Laeyendecker, O (reprint author), NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA.
EM olaeyen1@jhmi.edu
FU Division of Intramural Research, National Institute of Allergy and
Infectious Diseases (NIAID), NIH; HIV Prevention Trials Network (HPTN) -
NIAID, National Institutes of Child Health and Human Development
(NICH/HD), National Institute on Drug Abuse, National Institute of
Mental Health; Office of AIDS Research; Office of NIH, DHHS [UM1
AI1068613, R01 AI095068, R34MH096606]; Bill and Melinda Gates Foundation
[OPP1017716]; NIH [P01 AI071713, R01 HD074511, P30 AI027763, R24
AI067039]; Brazilian Ministry of Health, Brazilian Program
[914/BRA/3014-UNESCO]; Sao Paulo City Health Department
[2004-0.168.922-7]
FX This study was supported in part by the Division of Intramural Research,
National Institute of Allergy and Infectious Diseases (NIAID), NIH.
Other support was provided by the HIV Prevention Trials Network (HPTN)
sponsored by the NIAID, National Institutes of Child Health and Human
Development (NICH/HD), National Institute on Drug Abuse, National
Institute of Mental Health, and Office of AIDS Research, of the NIH,
DHHS, UM1 AI1068613 (Eshleman), R01 AI095068 (Eshleman) and R34MH096606
(Pilcher). Funding for this project was also provided by the Bill and
Melinda Gates Foundation (grant OPP1017716). The AM PLIAR and Options
Cohorts received funding from the NIH (grants P01 AI071713 and R01
HD074511). The SCOPE study also received funding from the NIH (grants
P30 AI027763 and R24 AI067039). The Sao Paulo Cohort acknowledges
funding by the Brazilian Ministry of Health, Brazilian Program for STD
and AIDS (grant 914/BRA/3014-UNESCO) and the Sao Paulo City Health
Department (grant 2004-0.168.922-7). The funders had no role in study
design, data collection and analysis, decision to publish, or
preparation of the manuscript.
NR 19
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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 FEB 23
PY 2017
VL 12
IS 2
AR e0172283
DI 10.1371/journal.pone.0172283
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL5SX
UT WOS:000394682400033
ER
PT J
AU Jorissen, W
Wouters, E
Bogie, JF
Vanmierlo, T
Noben, JP
Sviridov, D
Hellings, N
Somers, V
Valcke, R
Vanwijmeersch, B
Stinissen, P
Mulder, MT
Remaley, AT
Hendriks, JJA
AF Jorissen, Winde
Wouters, Elien
Bogie, Jeroen F.
Vanmierlo, Tim
Noben, Jean-Paul
Sviridov, Denis
Hellings, Niels
Somers, Veerle
Valcke, Roland
Vanwijmeersch, Bart
Stinissen, Piet
Mulder, Monique T.
Remaley, Alan T.
Hendriks, Jerome J. A.
TI Relapsing-remitting multiple sclerosis patients display an altered
lipoprotein profile with dysfunctional HDL
SO SCIENTIFIC REPORTS
LA English
DT Article
ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; TUMOR-NECROSIS-FACTOR;
ACUTE-PHASE RESPONSE; REVERSE CHOLESTEROL TRANSPORT;
CORONARY-ARTERY-DISEASE; CENTRAL-NERVOUS-SYSTEM; INSULIN-RESISTANCE;
FACTOR-ALPHA; CARDIOVASCULAR-DISEASE
AB Lipoproteins modulate innate and adaptive immune responses. In the chronic inflammatory disease multiple sclerosis (MS), reports on lipoprotein level alterations are inconsistent and it is unclear whether lipoprotein function is affected. Using nuclear magnetic resonance (NMR) spectroscopy, we analysed the lipoprotein profile of relapsing-remitting (RR) MS patients, progressive MS patients and healthy controls (HC). We observed smaller LDL in RRMS patients compared to healthy controls and to progressive MS patients. Furthermore, low-BMI (BMI <= 23 kg/m(2)) RRMS patients show increased levels of small HDL (sHDL), accompanied by larger, triglyceride (TG)-rich VLDL, and a higher lipoprotein insulin resistance (LP-IR) index. These alterations coincide with a reduced serum capacity to accept cholesterol via ATP-binding cassette (ABC) transporter G1, an impaired ability of HDL3 to suppress inflammatory activity of human monocytes, and modifications of HDL3's main protein component ApoA-I. In summary, lipoprotein levels and function are altered in RRMS patients, especially in low-BMI patients, which may contribute to disease progression in these patients.
C1 [Jorissen, Winde; Wouters, Elien; Bogie, Jeroen F.; Vanmierlo, Tim; Noben, Jean-Paul; Hellings, Niels; Somers, Veerle; Stinissen, Piet; Hendriks, Jerome J. A.] Hasselt Univ, Dept Immunol & Biochem, Biomed, Diepenbeek, Belgium.
[Sviridov, Denis; Remaley, Alan T.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA.
[Valcke, Roland] Hasselt Univ, Fac Sci Mol & Phys Plant Physiol, Diepenbeek, Belgium.
[Vanwijmeersch, Bart] Revalidat & MS Ctr, Overpelt, Belgium.
[Mulder, Monique T.] Erasmus MC, Dept Vasc & Met Dis, Rotterdam, Netherlands.
RP Hendriks, JJA (reprint author), Hasselt Univ, Dept Immunol & Biochem, Biomed, Diepenbeek, Belgium.
EM jerome.hendriks@uhasselt.be
RI Vanmierlo, Tim/C-7773-2013;
OI Vanmierlo, Tim/0000-0003-2912-0578; Noben, Jean-Paul/0000-0003-3368-5686
FU European Molecular Biology Organization (EMBO); Agentschap Innovatie
door Wetenschap en Technologie (IWT); Fonds Wetenschappelijk Onderzoek
(FWO); NHLBI; Hercules Foundation
FX The authors thank Dr. Maureen Sampson, Dr. Francesca Solmi and Dr.
Michele Ampe for the statistical support, Erik Royackers for the
excellent technical assistance, and Dr. Anatol Kontush and Virginie Bito
for critically reading the manuscript. This work was supported by grants
from the European Molecular Biology Organization (EMBO), the Agentschap
Innovatie door Wetenschap en Technologie (IWT), and the Fonds
Wetenschappelijk Onderzoek (FWO). Research by ATR was supported by
intramural DIR research funds from NHLBI. Funding of the LTQ-Orbitrap
mass spectrometer was obtained through Hercules Foundation.
NR 108
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U1 2
U2 2
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 23
PY 2017
VL 7
AR 43410
DI 10.1038/srep43410
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL6TG
UT WOS:000394754500001
PM 28230201
ER
PT J
AU Amar, MJA
Kaler, M
Courville, AB
Shamburek, R
Sampson, M
Wolska, A
Remaley, AT
AF Amar, Marcelo J. A.
Kaler, Maryann
Courville, Amber B.
Shamburek, Robert
Sampson, Maureen
Wolska, Anna
Remaley, Alan T.
TI Randomized double blind clinical trial on the effect of oral
alpha-cyclodextrin on serum lipids (vol 15, pg 115, 2016)
SO LIPIDS IN HEALTH AND DISEASE
LA English
DT Correction
C1 [Amar, Marcelo J. A.; Kaler, Maryann; Courville, Amber B.; Shamburek, Robert; Sampson, Maureen; Wolska, Anna; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bldg 10,Room 8 N-228,10 Ctr Dr,MSC 1666, Bethesda, MD 20892 USA.
RP Amar, MJA (reprint author), NHLBI, Lipoprot Metab Sect, NIH, Bldg 10,Room 8 N-228,10 Ctr Dr,MSC 1666, Bethesda, MD 20892 USA.
EM ma90x@nih.gov
NR 1
TC 0
Z9 0
U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1476-511X
J9 LIPIDS HEALTH DIS
JI Lipids Health Dis.
PD FEB 22
PY 2017
VL 16
DI 10.1186/s12944-017-0435-4
PG 1
WC Biochemistry & Molecular Biology; Nutrition & Dietetics
SC Biochemistry & Molecular Biology; Nutrition & Dietetics
GA EO6EU
UT WOS:000396785500002
PM 28228137
ER
PT J
AU Wang, RH
Bai, J
Deng, J
Fang, CJ
Chen, XY
AF Wang, Rui-Hui
Bai, Jie
Deng, Jun
Fang, Chen-Jie
Chen, Xiaoyuan
TI TAT-Modified Gold Nanoparticle Carrier with Enhanced Anticancer Activity
and Size Effect on Overcoming Multidrug Resistance
SO ACS APPLIED MATERIALS & INTERFACES
LA English
DT Article
DE AuNPs; TAT; anthracene derivatives; antiproliferation; size effect on
MDR
ID P-GLYCOPROTEIN; CELLULAR UPTAKE; CANCER-CELLS; DRUG-DELIVERY; BINDING;
COMPLEXES; TRANSACTIVATOR; TRANSCRIPTION; ENDOCYTOSIS; DOXORUBICIN
AB Highly efficient targeted delivery is crucial for successful anticancer chemotherapy. In this study, we developed a drug delivery system ANS-TAT-AuNP that loads anticancer molecule 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) via conjugation with cell penetrating peptide TAT modified AuNPs. The in vitro study showed that the IC50 value of ANS-TAT-AuNPs(3.8 nm), reduced by 11.28- (24 h) and 12.64-fold (48 h) after incubation with liver hepatocellular carcinoma HepG(2) cells compared to that of free ANS, suggesting that TAT modified AuNPs could enhance the antiproliferative activity of ANS. Also, ANS-TAT-AuNPs showed a size effect on overcoming multidrug resistance (MDR). The potential of ANS-TAT-AuNPs in overcoming MDR was assessed with MCF-7/ADR drug-resistant cell line, the drug resistance index (DRI) of which was extremely high (>190). The DRI of ANS-TAT-AuNPs(22.1 nm) decreased dramatically to 1.48 (24 h) and 2.20 (48 h), while that of ANS-TAT-AuNPs3.8. decreased to 7.64 (24 h) and 7.77 (48 h), indicating that ANS-TAT-AuNPs(22.2 nm) could treat extremely resistant MCF-7/ADR cancer cells as drug sensitive ones. The data suggest that the larger AuNPs had more profound effect on overcoming MDR, which could effectively prevent drug efflux due to their size being much larger than that of the p-glycoprotein channel (9-25 angstrom).
C1 [Wang, Rui-Hui; Bai, Jie; Fang, Chen-Jie] Capital Med Univ, Sch Pharmaceut Sci, Beijing 100069, Peoples R China.
[Deng, Jun] Capital Med Univ, Core Facil Ctr, Beijing 100069, Peoples R China.
[Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA.
RP Fang, CJ (reprint author), Capital Med Univ, Sch Pharmaceut Sci, Beijing 100069, Peoples R China.; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA.
EM cjfang@ccmu.edu.cn; shawn.chen@nih.gov
FU NSFC [21571133, 21171120]; Natural Science Foundation of Beijing
Municipality [7132020]; Intramural Research Program, National Institute
of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of
Health (NIH)
FX The authors thank the NSFC (21571133, 21171120), Natural Science
Foundation of Beijing Municipality (7132020), and the Intramural
Research Program, National Institute of Biomedical Imaging and
Bioengineering (NIBIB), National Institutes of Health (NIH) for
financial support. The authors also thank Dr. Yilin Lu for his nice
support in the Raman spectroscopy.
NR 53
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U1 3
U2 3
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 1944-8244
J9 ACS APPL MATER INTER
JI ACS Appl. Mater. Interfaces
PD FEB 22
PY 2017
VL 9
IS 7
BP 5828
EP 5837
DI 10.1021/acsami.6b15200
PG 10
WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary
SC Science & Technology - Other Topics; Materials Science
GA EL7VQ
UT WOS:000394829800019
PM 28124900
ER
PT J
AU Rudebeck, PH
Ripple, JA
Mitz, AR
Averbeck, BB
Murray, EA
AF Rudebeck, Peter H.
Ripple, Joshua A.
Mitz, Andrew R.
Averbeck, Bruno B.
Murray, Elisabeth A.
TI Amygdala Contributions to Stimulus-Reward Encoding in the Macaque Medial
and Orbital Frontal Cortex during Learning
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
DE amygdala; learning; macaque; prefrontal; reward
ID PRIMATE ORBITOFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; PREFRONTAL
CORTEX; BASOLATERAL AMYGDALA; RHESUS-MONKEYS; NEURONAL-ACTIVITY;
DECISION-MAKING; LESIONS; MECHANISMS; CHOICES
AB Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus-reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus-reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus-reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus-reward associations rapidly by shaping encoding within OFC and MFC.
C1 [Rudebeck, Peter H.] Friedman Brain Inst, Icahn Sch Med, New York, NY 10029 USA.
[Rudebeck, Peter H.; Ripple, Joshua A.; Mitz, Andrew R.; Averbeck, Bruno B.; Murray, Elisabeth A.] Natl Inst Hlth, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bethesda, MD 20892 USA.
RP Rudebeck, PH (reprint author), Friedman Brain Inst, Icahn Sch Med, New York, NY 10029 USA.; Rudebeck, PH (reprint author), Natl Inst Hlth, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bethesda, MD 20892 USA.
EM peter.rudebeck@mssm.edu
FU National Institute of Mental Health [ZI-AMH002886, R01MH110822]; NARSAD
FX This work was supported by the National Institute of Mental Health
(Intramural Research Program Grant ZI-AMH002886 to E.A.M.; BRAINS Award
R01MH110822 to P.H.R.) and NARSAD (Young Investigator Award to P.H.R.).
Wethank Kevin Blomstrom, Kevin Fomalont and Ravi Chacko for assistance
with data collection; James Fellows, Ping Yu Chen, and David Yu for help
with surgery and histology; and Steven Wise for discussion and comments.
NR 48
TC 0
Z9 0
U1 0
U2 0
PU SOC NEUROSCIENCE
PI WASHINGTON
PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA
SN 0270-6474
J9 J NEUROSCI
JI J. Neurosci.
PD FEB 22
PY 2017
VL 37
IS 8
BP 2186
EP 2202
DI 10.1523/JNEUROSCI.0933-16.2017
PG 17
WC Neurosciences
SC Neurosciences & Neurology
GA EP2BV
UT WOS:000397188900020
PM 28123082
ER
PT J
AU Aflaki, E
Westbroek, W
Sidransky, E
AF Aflaki, Elma
Westbroek, Wendy
Sidransky, Ellen
TI The Complicated Relationship between Gaucher Disease and Parkinsonism:
Insights from a Rare Disease
SO NEURON
LA English
DT Review
ID ALPHA-SYNUCLEIN CLEARANCE; CHAPERONE-MEDIATED AUTOPHAGY;
GLUCOCEREBROSIDASE MUTATIONS; DOPAMINE NEURONS; ASHKENAZI JEWS;
PHARMACOLOGICAL CHAPERONE; LYSOSOMAL BIOGENESIS; SUBSTRATE REDUCTION;
BETA-GLUCOSIDASE; GBA MUTATIONS
AB The discovery of a link between mutations in GBA1, encoding the lysosomal enzyme glucocerebrosidase, and the synucleinopathies directly resulted from the clinical recognition of patients with Gaucher disease with parkinsonism. Mutations in GBA1 are now the most common known genetic risk factor for several Lewy body disorders, and an inverse relationship exists between levels of glucocerebrosidase and oligomeric alpha-synuclein. While the underlying mechanisms are still debated, this complicated association is shedding light on the role of lysosomes in neurodegenerative disorders, demonstrating how insights from a rare disorder can direct research into the pathogenesis and therapy of seemingly unrelated common diseases.
C1 [Aflaki, Elma; Westbroek, Wendy; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA.
RP Sidransky, E (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA.
EM sidranse@mail.nih.gov
FU Intramural NIH HHS [Z99 HG999999]
NR 97
TC 0
Z9 0
U1 0
U2 0
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 0896-6273
EI 1097-4199
J9 NEURON
JI Neuron
PD FEB 22
PY 2017
VL 93
IS 4
BP 737
EP 746
DI 10.1016/j.neuron.2017.01.018
PG 10
WC Neurosciences
SC Neurosciences & Neurology
GA EO1AE
UT WOS:000396429100007
PM 28231462
ER
PT J
AU Cho, YE
Im, EJ
Moon, PG
Mezey, E
Song, BJ
Baek, MC
AF Cho, Young-Eun
Im, Eun-Ju
Moon, Pyong-Gon
Mezey, Esteban
Song, Byoung-Joon
Baek, Moon-Chang
TI Increased liver-specific proteins in circulating extracellular vesicles
as potential biomarkers for drug- and alcohol-induced liver injury
SO PLOS ONE
LA English
DT Article
ID ACETAMINOPHEN HEPATOTOXICITY; NONALCOHOLIC STEATOHEPATITIS;
MESSENGER-RNAS; TOXICITY; EXOSOMES; IDENTIFICATION; DISEASES; MOUSE;
HEPATOCYTES; MICRORNAS
AB Drug- and alcohol-induced liver injury are a leading cause of liver failure and transplantation. Emerging evidence suggests that extracellular vesicles (EVs) are a source of biomarkers because they contain unique proteins reflecting the identity and tissue-specific origin of the EV proteins. This study aimed to determine whether potentially hepatotoxic agents, such as acetaminophen (APAP) and binge alcohol, can increase the amounts of circulating EVs and evaluate liver-specific EV proteins as potential biomarkers for liver injury. The circulating EVs, isolated from plasma of APAP-exposed, ethanol-fed mice, or alcoholic hepatitis patients versus normal control counterparts, were characterized by proteomics and biochemical methods. Liver specific EV proteins were analyzed by immunoblots and ELISA. The amounts of total and liver-specific proteins in circulating EVs from APAP-treated mice significantly increased in a dose-and time-dependent manner. Proteomic analysis of EVs from APAP-exposed mice revealed that the amounts of liver-specific and/or hepatotoxic proteins were increased compared to those of controls. Additionally, the increased protein amounts in EVs following APAP exposure returned to basal levels when mice were treated with N-acetylcysteine or glutathione. Similar results of increased amounts and liver-specific proteins in circulating EVs were also observed in mice exposed to hepatotoxic doses of thioacetamide or D-galactosamine but not by non-hepatotoxic penicillin or myotoxic bupivacaine. Additionally, binge ethanol exposure significantly elevated liver-specific proteins in circulating EVs from mice and alcoholics with alcoholic hepatitis, compared to control counterparts. These results indicate that circulating EVs in drug-and alcohol-mediated hepatic injury contain liver-specific proteins that could serve as specific biomarkers for hepatotoxicity.
C1 [Cho, Young-Eun; Im, Eun-Ju; Moon, Pyong-Gon; Baek, Moon-Chang] Kyungpook Natl Univ, Cell & Matrix Res Inst, Sch Med, Dept Mol Med, Daegu, South Korea.
[Cho, Young-Eun; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA.
[Mezey, Esteban] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA.
RP Baek, MC (reprint author), Kyungpook Natl Univ, Cell & Matrix Res Inst, Sch Med, Dept Mol Med, Daegu, South Korea.
EM mcbaek@knu.ac.kr
FU National Research Foundation of Korea (NRF) - Korea government
[2014R1A5A2009242]; Intramural Fund of the National Institute on
Alcoholism and Alcohol Abuse, NIH, U.S.A; Korean Research Institute of
Bioscience and Biotechnology
FX This work was supported by a National Research Foundation of Korea (NRF)
grant funded by the Korea government (2014R1A5A2009242) and by the
Intramural Fund of the National Institute on Alcoholism and Alcohol
Abuse, NIH, U.S.A. In addition, this research was partially supported by
the Korean Biomedical Scientist Fellowship Program Award (to YEC) by the
Korean Research Institute of Bioscience and Biotechnology.
NR 55
TC 0
Z9 0
U1 1
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 FEB 22
PY 2017
VL 12
IS 2
AR e0172463
DI 10.1371/journal.pone.0172463
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL5SK
UT WOS:000394680900044
PM 28225807
ER
PT J
AU Nasser, HM
Calu, DJ
Schoenbaum, G
Sharpe, MJ
AF Nasser, Helen M.
Calu, Donna J.
Schoenbaum, Geoffrey
Sharpe, Melissa J.
TI The Dopamine Prediction Error: Contributions to Associative Models of
Reward Learning
SO FRONTIERS IN PSYCHOLOGY
LA English
DT Review
DE prediction error; attention; associative learning; dopamine; model-based
learning
ID VENTRAL TEGMENTAL AREA; RAT PREFRONTAL CORTEX; VISUAL-ATTENTION;
NUCLEUS-ACCUMBENS; BASOLATERAL AMYGDALA; AVERSIVE STIMULI; NEURONS
ENCODE; CONDITIONED INHIBITION; ORBITOFRONTAL CORTEX; COMPLEX
ENVIRONMENTS
AB Phasic activity of midbrain dopamine neurons is currently thought to encapsulate the prediction-error signal described in Sutton and Barto's (1981) model-free reinforcement learning algorithm. This phasic signal is thought to contain information about the quantitative value of reward, which transfers to the reward-predictive cue after learning. This is argued to endow the reward-predictive cue with the value inherent in the reward, motivating behavior toward cues signaling the presence of reward. Yet theoretical and empirical research has implicated prediction-error signaling in learning that extends far beyond a transfer of quantitative value to a reward-predictive cue. Here, we review the research which demonstrates the complexity of how dopaminergic prediction errors facilitate learning. After briefly discussing the literature demonstrating that phasic dopaminergic signals can act in the manner described by Sutton and Barto (1981), we consider how these signals may also influence attentional processing across multiple attentional systems in distinct brain circuits. Then, we discuss how prediction errors encode and promote the development of context-specific associations between cues and rewards. Finally, we consider recent evidence that shows dopaminergic activity contains information about causal relationships between cues and rewards that reflect information garnered from rich associative models of the world that can be adapted in the absence of direct experience. In discussing this research we hope to support the expansion of how dopaminergic prediction errors are thought to contribute to the learning process beyond the traditional concept of transferring quantitative value.
C1 [Nasser, Helen M.; Calu, Donna J.; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA.
[Schoenbaum, Geoffrey; Sharpe, Melissa J.] NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA.
[Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD USA.
[Sharpe, Melissa J.] Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA.
RP Nasser, HM (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA.; Sharpe, MJ (reprint author), NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA.; Sharpe, MJ (reprint author), Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA.
EM helennasser2200@gmail.com; melissa.sharpe@nih.gov
OI Calu, Donna/0000-0003-2377-9494
FU Intramural Research Program of the National Institute on Drug Abuse
FX The work was supported by the Intramural Research Program of the
National Institute on Drug Abuse.
NR 140
TC 0
Z9 0
U1 7
U2 7
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 1664-1078
J9 FRONT PSYCHOL
JI Front. Psychol.
PD FEB 22
PY 2017
VL 8
AR 244
DI 10.3389/fpsyg.2017.00244
PG 17
WC Psychology, Multidisciplinary
SC Psychology
GA EL3WP
UT WOS:000394550300001
PM 28275359
ER
PT J
AU Qiu, ZJ
Zhang, ZH
Roschke, A
Varga, T
Aplan, PD
AF Qiu, Zhijun
Zhang, Zhenhua
Roschke, Anna
Varga, Tamas
Aplan, Peter D.
TI Generation of Gross Chromosomal Rearrangements by a Single Engineered
DNA Double Strand Break
SO SCIENTIFIC REPORTS
LA English
DT Article
ID CHRONIC MYELOID-LEUKEMIA; END-JOINING PATHWAY; HOMOLOGOUS RECOMBINATION;
GENOMIC INSTABILITY; SEQUENCING REVEALS; TOPOISOMERASE-II; HISTONE H2AX;
STEM-CELLS; REPAIR; TRANSLOCATIONS
AB Gross chromosomal rearrangements (GCRs), including translocations, inversions amplifications, and deletions, can be causal events leading to malignant transformation. GCRs are thought to be triggered by DNA double strand breaks (DSBs), which in turn can be spontaneous or induced by external agents (eg. cytotoxic chemotherapy, ionizing radiation). It has been shown that induction of DNA DSBs at two defined loci can produce stable balanced chromosomal translocations, however, a single engineered DNA DSB could not. Herein, we report that although a single engineered DNA DSB in H2AX "knockdown" cells did not generate GCRs, repair of a single engineered DNA DSB in fibroblasts that had ablated H2ax did produce clonal, stable GCRs, including balanced translocations and megabase-pair inversions. Upon correction of the H2ax deficiency, cells no longer generated GCRs following a single engineered DNA DSB. These findings demonstrate that clonal, stable GCRs can be produced by a single engineered DNA DSB in H2ax knockout cells, and that the production of these GCRs is ameliorated by H2ax expression.
C1 [Qiu, Zhijun; Zhang, Zhenhua; Roschke, Anna; Varga, Tamas; Aplan, Peter D.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA.
RP Aplan, PD (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA.
EM aplanp@mail.nih.gov
FU National Cancer Institute, NIH
FX This work was supported by the intramural program of the National Cancer
Institute, NIH. The authors would like to thank Andre Nussenzweig and
Hua Tang Chen for the kind gift of H2ax knockout fibroblasts.
NR 48
TC 0
Z9 0
U1 3
U2 3
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 22
PY 2017
VL 7
AR 43156
DI 10.1038/srep43156
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL3QP
UT WOS:000394534200001
PM 28225067
ER
PT J
AU Hu, LS
Hu, SQ
Guo, LY
Shen, CC
Yang, MH
Rasooly, A
AF Hu, Lanshuang
Hu, Shengqiang
Guo, Linyan
Shen, Congcong
Yang, Minghui
Rasooly, Avraham
TI DNA Generated Electric Current Biosensor
SO ANALYTICAL CHEMISTRY
LA English
DT Article
ID BREAST-CANCER PATIENTS; ELECTROCHEMICAL DETECTION; ENZYME-IMMUNOASSAY;
GOLD NANOPARTICLES; SERUM; HER2; AMPLIFICATION; HER-2/NEU; CELLS
AB In addition to its primary function as a genetic material, deoxyribonucleic acid (DNA) is also a potential biologic energy source for molecular electronics. For the first time, we demonstrate that DNA can generate a redox electric current. As an example of this new functionality, DNA generated redox current was used for electrochemical detection of human epidermal growth factor receptor 2 (HER2), a clinically important breast cancer biomarker. To induce redox current, the phosphate of the single stranded DNA aptamer backbone was reacted with molybdate to form redox molybdophosphate precipitate and generate an electrochemical current of similar to 16.8 mu A/ mu M cm(2). This detection of HER2 was performed using a sandwich detection assay. A HER2 specific peptide was immobilized onto a gold electrode surface for capturing HER2 in buffer and serum. The HER2 specific aptamer was used as both ligand to bind the captured HER2 and to generate a redox current signal. When tested for HER2 detection, the electrochemical current generated by the aptasensor was proportional to HER2 concentration in the range of 0.01 to 5 ng/mL, with a current generated in the range of similar to 6.37 to 31.8 mu A/cm(2) in both buffer and serum. This detection level is within the clinically relevant range of HER2 concentrations. This method of electrochemical signal amplification greatly simplifies the signal transduction of aptasensors, broadening their use for HER2 analysis. This novel approach of using the same aptamer as biosensor ligand and as transducer can be universally extended to other aptasensors for a wide array of biodetection applications. Moreover, electric currents generated by DNA or other nucleic acids can be used in molecular electronics or implanted devices for both power generation and measurement of output.
C1 [Hu, Lanshuang; Hu, Shengqiang; Guo, Linyan; Shen, Congcong; Yang, Minghui] Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China.
[Rasooly, Avraham] NCI, NIH, Rockville, MD 20850 USA.
RP Yang, MH (reprint author), Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China.; Rasooly, A (reprint author), NCI, NIH, Rockville, MD 20850 USA.
EM yangminghui@csu.edu.cn; rasoolya@mail.nih.gov
FU National Key Basic Research Program of China [2014CB744502]; National
Natural Science Foundation of China [21575165]; Natural Science
Foundation of Hunan Province [2015JJ1019]
FX The authors thank the support of this work by the National Key Basic
Research Program of China (Grant 2014CB744502), the National Natural
Science Foundation of China (Grant No. 21575165), and the Natural
Science Foundation of Hunan Province (Grant No. 2015JJ1019).
NR 44
TC 0
Z9 0
U1 10
U2 10
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 0003-2700
EI 1520-6882
J9 ANAL CHEM
JI Anal. Chem.
PD FEB 21
PY 2017
VL 89
IS 4
BP 2547
EP 2552
DI 10.1021/acs.analchem.6b04756
PG 6
WC Chemistry, Analytical
SC Chemistry
GA EL6IG
UT WOS:000394724700052
PM 28219246
ER
PT J
AU Libich, DS
Tugarinov, V
Ghirlando, R
Clore, GM
AF Libich, David S.
Tugarinov, Vitali
Ghirlando, Rodolfo
Clore, G. Marius
TI Confinement and Stabilization of Fyn SH3 Folding Intermediate Mimetics
within the Cavity of the Chaperonin GroEL Demonstrated by
Relaxation-Based NMR
SO BIOCHEMISTRY
LA English
DT Article
ID MOLECULAR CHAPERONES; CONFORMATIONAL STATES; PROTEINS; EXCHANGE; SECB
AB The interaction of two folding intermediate mimetics of the model protein substrate Fyn SH3 with the chaperonin GroEL, a supramolecular foldase/unfoldase machine, has been investigated by N-15 relaxation-based nuclear magnetic resonance spectroscopy (lifetime line broadening, dark state exchange saturation transfer, and relaxation dispersion). The two mimetics comprise C-terminal truncations of wild-type and triple-mutant (A39V/N53P/V55L) Fyn SH3 in which the C-terminal strand of the SH3 domain is unfolded, while preserving the remaining domain structure. Quantitative analysis of the data reveals that a mobile state of the SH3 domain confined and tethered within the cavity of GroEL, possibly through interactions with the disordered, methionine-rich C-terminal tail(s), can be detected, and that the native state of the folding intermediate mimetics is stabilized by both confinement within and binding to apo GroEL. These data provide a basis for understanding the passive activity of GroEL as a foldase/unfoldase: the unfolded state, in the absence of hydrophobic GroEL-binding consensus sequences, is destabilized within the cavity because of its larger radius of gyration compared to that of the folding intermediate, while the folding intermediate is stabilized relative to the native state because of exposure of a hydrophobic patch that favors GroEL binding.
C1 [Libich, David S.; Tugarinov, Vitali; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.
[Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA.
RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.
EM mariusc@mail.nih.gov
FU Intramural Program of NIDDK, NIH; AIDS Targeted Antiviral program of the
Office of the Director of the NIH
FX This work was supported by the Intramural Program of NIDDK, NIH, and by
the AIDS Targeted Antiviral program of the Office of the Director of the
NIH (to G.M.C.).
NR 23
TC 0
Z9 0
U1 0
U2 0
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 0006-2960
J9 BIOCHEMISTRY-US
JI Biochemistry
PD FEB 21
PY 2017
VL 56
IS 7
BP 903
EP 906
DI 10.1021/acs.biochem.6b01237
PG 4
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EL6IL
UT WOS:000394725300001
PM 28156097
ER
PT J
AU Donahue, RN
Lepone, LM
Grenga, I
Jochems, C
Fantini, M
Madan, RA
Heery, CR
Gulley, JL
Schlom, J
AF Donahue, Renee N.
Lepone, Lauren M.
Grenga, Italia
Jochems, Caroline
Fantini, Massimo
Madan, Ravi A.
Heery, Christopher R.
Gulley, James L.
Schlom, Jeffrey
TI Analyses of the peripheral immunome following multiple administrations
of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody
SO JOURNAL FOR IMMUNOTHERAPY OF CANCER
LA English
DT Article
DE Avelumab; Anti-PD-L1; Checkpoint inhibitor; Immunotherapy; Peripheral
immunome; Immune subsets; ADCC; Antibody-dependent cell-mediated
cytotoxicity
ID DEPENDENT CELLULAR CYTOTOXICITY; NATURAL-KILLER-CELLS; T-CELLS;
TUMOR-CELLS; OPEN-LABEL; CANCER; RECEPTORS; THERAPY; TRIAL; NK
AB Background: Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers. This study was designed to investigate the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab.
Methods: One hundred twenty-three distinct immune cell subsets in the peripheral blood of cancer patients (n = 28) in a phase I trial were analyzed by flow cytometry prior to and following one, three, and nine cycles of avelumab. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC.
Results: No statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27: sCD40L were observed, suggesting potential immune activation. Controlled in vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from five donors.
Conclusions: These studies demonstrate the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These results complement prior studies showing anti-tumor effects of avelumab and comparable levels of adverse events with avelumab versus other anti-PD-1/PD-L1 MAbs. These studies provide the rationale to further exploit the potential ADCC mechanismof action of avelumab as well as other human IgG1 checkpoint inhibitors.
C1 [Donahue, Renee N.; Lepone, Lauren M.; Grenga, Italia; Jochems, Caroline; Fantini, Massimo; Heery, Christopher R.; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA.
[Madan, Ravi A.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.
RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA.
EM js141c@nih.gov
FU Intramural Research Program of the Center for Cancer Research, National
Cancer Institute (NCI), National Institutes of Health; EMD Serono; NCI
FX This research was supported by the Intramural Research Program of the
Center for Cancer Research, National Cancer Institute (NCI), National
Institutes of Health, and via a Cooperative Research and Development
Agreement (CRADA) between EMD Serono and the NCI.
NR 35
TC 0
Z9 0
U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 2051-1426
J9 J IMMUNOTHER CANCER
JI J. Immunother. Cancer
PD FEB 21
PY 2017
VL 5
AR 20
DI 10.1186/s40425-017-0220-y
PG 16
WC Oncology
SC Oncology
GA EO8CH
UT WOS:000396916000001
PM 28239472
ER
PT J
AU Ito, D
Schureck, MA
Desai, SA
AF Ito, Daisuke
Schureck, Marc A.
Desai, Sanjay A.
TI An essential dual-function complex mediates erythrocyte invasion and
channel-mediated nutrient uptake in malaria parasites
SO ELIFE
LA English
DT Article
ID SURFACE ANION CHANNEL; FALCIPARUM-INFECTED ERYTHROCYTES; CLAG MULTIGENE
FAMILY; RED-BLOOD-CELLS; PLASMODIUM-FALCIPARUM; RHOPTRY PROTEIN; PTEX
COMPONENT; RESISTANCE; REVEALS; TRAFFICKING
AB Malaria parasites evade immune detection by growth and replication within erythrocytes. After erythrocyte invasion, the intracellular pathogen must increase host cell uptake of nutrients from plasma. Here, we report that the parasite-encoded RhopH complex contributes to both invasion and channel-mediated nutrient uptake. As rhoph2 and rhoph3 gene knockouts were not viable in the human P. falciparum pathogen, we used conditional knockdowns to determine that the encoded proteins are essential and to identify their stage-specific functions. We exclude presumed roles for RhopH2 and CLAG3 in erythrocyte invasion but implicate a RhopH3 contribution either through ligand-receptor interactions or subsequent parasite internalization. These proteins then traffic via an export translocon to the host membrane, where they form a nutrient channel. Knockdown of either RhopH2 or RhopH3 disrupts the entire complex, interfering with organellar targeting and subsequent trafficking. Therapies targeting this complex should attack the pathogen at two critical points in its cycle.
C1 [Ito, Daisuke; Schureck, Marc A.; Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA.
RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA.
EM sdesai@niaid.nih.gov
FU Intramural Research Program of the National Institutes of Health;
National Institute of Allergy and Infectious Diseases
FX We thank Josh Beck, Daniel Goldberg, Thomas Wellems, Jose-Juan
Lopez-Rubio, Philip Shaw, and Takafumi Tsuboi for providing plasmids,
antibodies, and/or parasite clones; Josh Beck and Daniel Goldberg for
helpful discussions and sharing their unpublished results on PTEX
activity; Nicole Potchen and Meera Garriga for critical reading of the
manuscript; and Ryan Kissinger and Anita Mora for artwork. DSM1
(MRA-1161) was obtained through MR4 as part of the BEI Resources
Repository, NIAID, NIH. SAD is a named inventor on US and international
patent applications and on an issued US patent on the drug targets
presented in this manuscript ('INHIBITORS OF THE PLASMODIAL SURFACE
ANION CHANNEL AS ANTIMALARIALS', International Patent Application
Publication WO/2010/011537; Chinese Patent Application 200980137435;
European Patent Application EP2313100A1; Indian Patent Application
470/CHENP/2011; US Patent Application Publication US2014/0088082A1; and
issued US Patent U58,618,090). The other authors have no conflicts of
interest. This research was supported by the Intramural Research Program
of the National Institutes of Health, National Institute of Allergy and
Infectious Diseases.
NR 54
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Z9 2
U1 1
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 FEB 21
PY 2017
VL 6
DI 10.7554/eLife.23485
PG 24
WC Biology
SC Life Sciences & Biomedicine - Other Topics
GA EP8KC
UT WOS:000397623300001
ER
PT J
AU Dumitrescu, L
Ritchie, MD
Denny, JC
El Rouby, NM
McDonough, CW
Bradford, Y
Ramirez, AH
Bielinski, SJ
Basford, MA
Chai, HS
Peissig, P
Carrell, D
Pathak, J
Rasmussen, LV
Wang, XM
Pacheco, JA
Kho, AN
Hayes, MG
Matsumoto, M
Smith, ME
Li, RL
Cooper-DeHoff, RM
Kullo, IJ
Chute, CG
Chisholm, RL
Jarvik, GP
Larson, EB
Carey, D
McCarty, CA
Williams, MS
Roden, DM
Bottinger, E
Johnson, JA
de Andrade, M
Crawford, DC
AF Dumitrescu, Logan
Ritchie, Marylyn D.
Denny, Joshua C.
El Rouby, Nihal M.
McDonough, Caitrin W.
Bradford, Yuki
Ramirez, Andrea H.
Bielinski, Suzette J.
Basford, Melissa A.
Chai, High Seng
Peissig, Peggy
Carrell, David
Pathak, Jyotishman
Rasmussen, Luke V.
Wang, Xiaoming
Pacheco, Jennifer A.
Kho, Abel N.
Hayes, M. Geoffrey
Matsumoto, Martha
Smith, Maureen E.
Li, Rongling
Cooper-DeHoff, Rhonda M.
Kullo, Iftikhar J.
Chute, Christopher G.
Chisholm, Rex L.
Jarvik, Gail P.
Larson, Eric B.
Carey, David
McCarty, Catherine A.
Williams, Marc S.
Roden, Dan M.
Bottinger, Erwin
Johnson, Julie A.
de Andrade, Mariza
Crawford, Dana C.
TI Genome-wide study of resistant hypertension identified from electronic
health records
SO PLOS ONE
LA English
DT Article
ID GENETIC EPIDEMIOLOGY RESEARCH; AMERICAN-HEART-ASSOCIATION;
CORONARY-ARTERY-DISEASE; BLOOD-PRESSURE RESPONSE; AGING GERA COHORT;
MEDICAL-RECORDS; EMERGE NETWORK; CONTROL RATES; QUALITY-CONTROL; PULSE
PRESSURE
AB Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among > 47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was CLNK rs13144136 at p = 1.00x10(-6) (odds ratio = 0.68; 95% CI = 0.58-0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension.
C1 [Dumitrescu, Logan] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA.
[Ritchie, Marylyn D.; Bradford, Yuki] Geisinger Hlth Syst, Biomed & Translat Informat, Danville, PA USA.
[Denny, Joshua C.; Wang, Xiaoming] Vanderbilt Univ, Dept Biomed Informat, 221 Kirkland Hall, Nashville, TN 37235 USA.
[Denny, Joshua C.; Ramirez, Andrea H.; Roden, Dan M.] Vanderbilt Univ, Dept Med, Nashville, TN USA.
[El Rouby, Nihal M.; McDonough, Caitrin W.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA.
[El Rouby, Nihal M.; McDonough, Caitrin W.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.] Univ Florida, Coll Pharm, Ctr Pharmacogen, Gainesville, FL USA.
[Bielinski, Suzette J.] Mayo Clin, Div Epidemiol, Rochester, MN USA.
[Basford, Melissa A.] Vanderbilt Univ, Res Off, 221 Kirkland Hall, Nashville, TN 37235 USA.
[Chai, High Seng; Pathak, Jyotishman; Matsumoto, Martha; de Andrade, Mariza] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA.
[Peissig, Peggy] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA.
[Carrell, David; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA.
[Rasmussen, Luke V.] Northwestern Univ, Dept Prevent Med, Div Hlth & Biomed Informat, Chicago, IL 60611 USA.
[Pacheco, Jennifer A.; Smith, Maureen E.; Chisholm, Rex L.] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA.
[Kho, Abel N.; Hayes, M. Geoffrey] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA.
[Li, Rongling] NHGRI, Div Genom Med, Bethesda, MD 20892 USA.
[Cooper-DeHoff, Rhonda M.; Crawford, Dana C.] Case Western Reserve Univ, Inst Computat Biol, Epidemiol & Biostat, Cleveland, OH 44106 USA.
[Kullo, Iftikhar J.] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN USA.
[Chute, Christopher G.] Johns Hopkins Univ, Div Gen Internal Med, Baltimore, MD USA.
[Jarvik, Gail P.] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA.
[Carey, David] Geisinger Hlth Syst, Weis Ctr Res, Danville, PA USA.
[McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA.
[Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA.
[Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA.
[Bottinger, Erwin] Mt Sinai, Charles R Bronfman Inst Personalized Med, New York, NY USA.
[Johnson, Julie A.] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA.
RP Crawford, DC (reprint author), Case Western Reserve Univ, Inst Computat Biol, Epidemiol & Biostat, Cleveland, OH 44106 USA.
EM dana.crawford@case.edu
FU NHGRI; NIGMS [U01HG04599, U01HG006379, U01HG004610, U01HG006375,
U01HG004608, U01HG004609, U01HG006388, U01HG04603, U01HG006378,
U01HG006385, U01HG006382, U01HG006380, U01HG006830, U01HG006828];
Vanderbilt CTSA grant from NCATS/NIH [UL1 TR000445]; Mayo Clinic Biobank
- Mayo Clinic Center for Individualized Medicine; NIH [R01 HL074730, U01
GM074492, U01 NS038529, R01 NS073346]; [KL2 TR001429]
FX The eMERGE Network is funded by NHGRI, with additional funding from
NIGMS through the following grants: U01HG04599 and U01HG006379 to Mayo
Clinic; U01HG004610 and U01HG006375 to Group Health Cooperative and
University of Washington, Seattle; U01HG004608 to Marshfield Clinic;
U01HG006389 to Essentia Institute of Rural Health; U01HG004609 and
U01HG006388 to Northwestern University; U01HG04603 and U01HG006378 to
Vanderbilt University; U01HG006385 to the Coordinating Center;
U01HG006382 to Geisinger Clinic; U01HG006380 to Mount Sinai School of
Medicine; U01HG006830 to The Children's Hospital of Philadelphia; and
U01HG006828 to Cincinnati Children's Hospital and Boston Children's
Hospital. A portion of the dataset(s) used for the analyses described
were obtained from Vanderbilt University Medical Centers BioVU,
supported by institutional funding and by the Vanderbilt CTSA grant UL1
TR000445 from NCATS/NIH, and the Mayo Clinic Biobank supported by the
Mayo Clinic Center for Individualized Medicine. INVEST-GENES was funded
by NIH grants R01 HL074730 and U01 GM074492. SPS3 and SPS3-GENES were
funded by NIH grants U01 NS038529, U01 GM074492, and R01 NS073346. CWM
was also supported by KL2 TR001429. The funders had no role in study
design, data collection and analysis, decision to publish, or
preparation of the manuscript.
NR 93
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U2 0
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 FEB 21
PY 2017
VL 12
IS 2
AR e0171745
DI 10.1371/journal.pone.0171745
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL5QV
UT WOS:000394676800017
PM 28222112
ER
PT J
AU Ulmer, B
Tingler, M
Kurz, S
Maerker, M
Andre, P
Monch, D
Campione, M
Deissler, K
Lewandoski, M
Thumberger, T
Schweickert, A
Fainsod, A
Steinbeisser, H
Blum, M
AF Ulmer, Baerbel
Tingler, Melanie
Kurz, Sabrina
Maerker, Markus
Andre, Philipp
Moench, Dina
Campione, Marina
Deissler, Kirsten
Lewandoski, Mark
Thumberger, Thomas
Schweickert, Axel
Fainsod, Abraham
Steinbeisser, Herbert
Blum, Martin
TI A novel role of the organizer gene Goosecoid as an inhibitor of
Wnt/PCP-mediated convergent extension in Xenopus and mouse
SO SCIENTIFIC REPORTS
LA English
DT Article
ID PLANAR-CELL-POLARITY; NEURAL-TUBE CLOSURE; HOMEOBOX GENE; SIGNALING
PATHWAYS; MARGINAL ZONE; SUBCELLULAR-LOCALIZATION; VERTEBRATE EMBRYOS;
SPEMANNS ORGANIZER; AMPHIOXUS GENOME; GASTRULATION
AB Goosecoid (Gsc) expression marks the primary embryonic organizer in vertebrates and beyond. While functions have been assigned during later embryogenesis, the role of Gsc in the organizer has remained enigmatic. Using conditional gain-of-function approaches in Xenopus and mouse to maintain Gsc expression in the organizer and along the axial midline, neural tube closure defects (NTDs) arose and dorsal extension was compromised. Both phenotypes represent convergent extension (CE) defects, arising from impaired Wnt/planar cell polarity (PCP) signaling. Dvl2 recruitment to the cell membrane was inhibited by Gsc in Xenopus animal cap assays and key Wnt/PCP factors (RhoA, Vangl2, Prickle, Wnt11) rescued Gsc-mediated NTDs. Re-evaluation of endogenous Gsc functions in MO-mediated gene knockdown frog and knockout mouse embryos unearthed PCP/CE-related phenotypes as well, including cartilage defects in Xenopus and misalignment of inner ear hair cells in mouse. Our results assign a novel function to Gsc as an inhibitor of Wnt/PCP-mediated CE. We propose that in the organizer Gsc represses CE as well: Gsc-expressing prechordal cells, which leave the organizer first, migrate and do not undergo CE like the Gsc-negative notochordal cells, which subsequently emerge from the organizer. In this model, Gsc provides a switch between cell migration and CE, i.e. cell intercalation.
C1 [Ulmer, Baerbel; Tingler, Melanie; Kurz, Sabrina; Maerker, Markus; Andre, Philipp; Moench, Dina; Campione, Marina; Deissler, Kirsten; Thumberger, Thomas; Schweickert, Axel; Blum, Martin] Univ Hohenheim, Garbenstr 30, D-70599 Stuttgart, Germany.
[Lewandoski, Mark] NCI, Canc & Dev Biol Lab, Genet Vertebrate Dev Sect, NIH, Frederick, MD 21702 USA.
[Fainsod, Abraham] Hebrew Univ Jerusalem, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-9112102 Jerusalem, Israel.
[Steinbeisser, Herbert] Univ Heidelberg Hosp, Inst Human Genet, Neuenheimer Feld 366, D-69120 Heidelberg, Germany.
[Ulmer, Baerbel] Univ Med Ctr Hamburg Eppendorf, Cardiovasc Res Ctr, Dept Expt Pharmacol & Toxicol, D-20246 Hamburg, Germany.
[Campione, Marina] Univ Padua, CNR, Inst Neurosci, Dept Biomed Sci, I-35100 Padua, Italy.
[Thumberger, Thomas] Heidelberg Univ, Ctr Organismal Studies COS Heidelberg, Neuenheimer Feld 230, D-69120 Heidelberg, Germany.
RP Blum, M (reprint author), Univ Hohenheim, Garbenstr 30, D-70599 Stuttgart, Germany.
EM martin.blum@uni-hohenheim.de
FU Volkswagen Foundation; Landesgraduiertenforderung Baden-Wurttemberg
FX This paper is dedicated to the memory of the late Herbert Steinbeiber,
who passed away in 2014. He was involved in this project from its
beginning in the 1990 s; the Dvl2 membrane recruitment experiments in
animal caps were performed in his laboratory. We thank all members of
the Blum lab for continuous support and suggestions. Verena Andre,
Andreas Faissler, Simone Kienle, Anna Schafer and Susanne Seitz helped
with some of the experiments. This work was supported by a grant from
the Volkswagen Foundation to MB and a fellowship from the
Landesgraduiertenforderung Baden-Wurttemberg to BU.
NR 92
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U1 3
U2 3
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 21
PY 2017
VL 7
AR 43010
DI 10.1038/srep43010
PG 17
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL5ZA
UT WOS:000394699000001
PM 28220837
ER
PT J
AU Kwon, EM
Connelly, JP
Hansen, NF
Donovan, FX
Winkler, T
Davis, BW
Alkadi, H
Chandrasekharappa, SC
Dunbar, CE
Mullikin, JC
Liu, P
AF Kwon, Erika M.
Connelly, John P.
Hansen, Nancy F.
Donovan, Frank X.
Winkler, Thomas
Davis, Brian W.
Alkadi, Halah
Chandrasekharappa, Settara C.
Dunbar, Cynthia E.
Mullikin, James C.
Liu, Paul
TI iPSCs and fibroblast subclones from the same fibroblast population
contain comparable levels of sequence variations
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE iPSCs; fibroblasts; reprogramming; genomic variation; exome sequencing
ID PLURIPOTENT STEM-CELLS; COPY NUMBER VARIATION; HUMAN GENOME; SOMATIC
MOSAICISM; CODING MUTATIONS; EXPRESSION
AB Genome integrity of induced pluripotent stem cells (iPSCs) has been extensively studied in recent years, but it is still unclear whether iPSCs contain more genomic variations than cultured somatic cells. One important question is the origin of genomic variations detected in iPSCs-whether iPSC reprogramming induces such variations. Here, we undertook a unique approach by deriving fibroblast subclones and clonal iPSC lines from the same fibroblast population and applied next-generation sequencing to compare genomic variations in these lines. Targeted deep sequencing of parental fibroblasts revealed that most variants detected in clonal iPSCs and fibroblast subclones were rare variants inherited from the parental fibroblasts. Only a small number of variants remained undetectable in the parental fibroblasts, which were thus likely to be de novo. Importantly, the clonal iPSCs and fibroblast subclones contained comparable numbers of de novo variants. Collectively, our data suggest that iPSC reprogramming is not mutagenic.
C1 [Kwon, Erika M.; Connelly, John P.; Alkadi, Halah; Liu, Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA.
[Hansen, Nancy F.; Mullikin, James C.] NHGRI, Comparat Genom Unit, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA.
[Donovan, Frank X.; Chandrasekharappa, Settara C.] NHGRI, Genom Core, NIH, Bethesda, MD 20892 USA.
[Winkler, Thomas; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA.
[Davis, Brian W.] NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA.
[Connelly, John P.] Washington Univ, Genome Engn & iPSC Ctr, St Louis, MO 63110 USA.
RP Liu, P (reprint author), NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA.
EM pliu@mail.nih.gov
FU Intramural Research Programs of National Human Genome Research
Institute; National Heart, Lung, and Blood Institute, NIH
FX We thank Dionyssia Clagett (Georgetown University) for establishing
fibroblast lines from patients with FPD, Ms. Ursula Harper for
performing short tandem repeat mapping for sample identify confirmation,
members of the NIH Intramural Sequencing Center for their support on WES
and targeted sequencing, and Julia Fekecs for expert design of Fig. 1.
The research was supported by the Intramural Research Programs of
National Human Genome Research Institute and National Heart, Lung, and
Blood Institute, NIH.
NR 32
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Z9 0
U1 2
U2 2
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 21
PY 2017
VL 114
IS 8
BP 1964
EP 1969
DI 10.1073/pnas.1616035114
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1TI
UT WOS:000395099500075
PM 28167771
ER
PT J
AU Kurth, EG
Peremyslov, VV
Turner, HL
Makarova, KS
Iranzo, J
Mekhedov, SL
Koonin, EV
Dolja, VV
AF Kurth, Elizabeth G.
Peremyslov, Valera V.
Turner, Hannah L.
Makarova, Kira S.
Iranzo, Jaime
Mekhedov, Sergei L.
Koonin, Eugene V.
Dolja, Valerian V.
TI Myosin-driven transport network in plants
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE myosins; receptors; adaptors; cytoplasmic streaming; nuclear transport
ID CLASS-XI MYOSINS; F-ACTIN ORGANIZATION; ROOT HAIR; CELL EXPANSION;
ARABIDOPSIS; PROTEIN; TRAFFICKING; MEMBRANE; MOTILITY; DOMAIN
AB We investigate the myosin XI-driven transport network in Arabidopsis using protein-protein interaction, subcellular localization, gene knockout, and bioinformatics analyses. The two major groups of nodes in this network are myosins XI and their membrane-anchored receptors (MyoB) that, together, drive endomembrane trafficking and cytoplasmic streaming in the plant cells. The network shows high node connectivity and is dominated by generalists, with a smaller fraction of more specialized myosins and receptors. We show that interaction with myosins and association with motile vesicles are common properties of the MyoB family receptors. We identify previously uncharacterized myosin-binding proteins, putative myosin adaptors that belong to two unrelated families, with four members each (MadA and MadB). Surprisingly, MadA1 localizes to the nucleus and is rapidly transported to the cytoplasm, suggesting the existence of myosin XI-driven nucleocytoplasmic trafficking. In contrast, MadA2 and MadA3, as well as MadB1, partition between the cytosolic pools of motile endomembrane vesicles that colocalize with myosin XI-K and diffuse material that does not. Gene knockout analysis shows that MadB1-4 contribute to polarized root hair growth, phenocopying myosins, whereas MadA1-4 are redundant for this process. Phylogenetic analysis reveals congruent evolutionary histories of the myosin XI, MyoB, MadA, and MadB families. All these gene families emerged in green algae and show concurrent expansions via serial duplication in flowering plants. Thus, the myosin XI transport network increased in complexity and robustness concomitantly with the land colonization by flowering plants and, by inference, could have been a major contributor to this process.
C1 [Kurth, Elizabeth G.; Peremyslov, Valera V.; Turner, Hannah L.; Dolja, Valerian V.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA.
[Makarova, Kira S.; Iranzo, Jaime; Mekhedov, Sergei L.; Koonin, Eugene V.; Dolja, Valerian V.] Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA.
[Dolja, Valerian V.] Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA.
RP Koonin, EV; Dolja, VV (reprint author), Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA.; Dolja, VV (reprint author), Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA.
EM koonin@ncbi.nlm.nih.gov; doljav@oregonstate.edu
FU US-Israel Binational Science Foundation [2013084]; US Department of
Health and Human Services
FX We thank Prof. Viktor Zarsky for critical reading of the manuscript and
helpful suggestions. V.V.D. is a Fellow, Scientific Visitors Program,
National Center for Biotechnology Information, NIH. The work in the
V.V.D. laboratory was supported, in part, by US-Israel Binational
Science Foundation Award 2013084. The research in group of E.V.K. is
supported by intramural funds of the US Department of Health and Human
Services (to the National Library of Medicine).
NR 53
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U1 2
U2 2
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 21
PY 2017
VL 114
IS 8
BP E1385
EP E1394
DI 10.1073/pnas.1620577114
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM1TI
UT WOS:000395099500011
PM 28096376
ER
PT J
AU DeFilippis, AP
Young, R
McEvoy, JW
Michos, ED
Sandfort, V
Kronmal, RA
McClelland, RL
Blaha, MJ
AF DeFilippis, Andrew Paul
Young, Rebekah
McEvoy, John W.
Michos, Erin D.
Sandfort, Veit
Kronmal, Richard A.
McClelland, Robyn L.
Blaha, Michael J.
TI Risk score overestimation: the impact of individual cardiovascular risk
factors and preventive therapies on the performance of the American
Heart Association-American College of Cardiology-Atherosclerotic
Cardiovascular Disease risk score in a modern multi-ethnic cohort
SO EUROPEAN HEART JOURNAL
LA English
DT Article
DE Cardiovascular risk prediction; Prevention; Risk factors
ID POPULATION; VALIDATION; GUIDELINES; STATINS; DESIGN
AB Aims To evaluate the 2013 American Heart Association (AHA)-American College of Cardiology (ACC)-Atherosclerotic Cardiovascular Disease (ASCVD) risk score among four different race/ethnic groups and to ascertain which factors are most associated with risk overestimation by the AHA-ACC-ASCVD score.
Methods and results The Multi-Ethnic Study of Atherosclerosis (MESA), a prospective community-based cohort, was used to examine calibration and discrimination of the AHA-ACC-ASCVD risk score in 6441 White, Black, Chinese, and Hispanic Americans (aged 45-79 years and free of known ASCVD at baseline). Using univariable and multivariable absolute risk regression, we modelled the impact of individual risk factors on the discordance between observed and predicted 10-year ASCVD risk. Overestimation was observed in all race/ethnic groups in MESA and was highest among Chinese (252% for women and 314% for men) and lowest in White women (72%) and Hispanic men (67%). Higher age, Chinese race/ethnicity (when compared with White), systolic blood pressure (treated and untreated), diabetes, alcohol use, exercise, lipid-lowering medication, and aspirin use were all associated with more risk overestimation, whereas family history was associated with less risk overestimation in a multivariable model (all P< 0.05).
Conclusion The AHA-ACC-ASCVD risk score overestimates ASCVD risk among men, women, and all four race/ethnic groups evaluated in a modern American primary prevention cohort. Clinicians treating patients similar to those in MESA, particularly older individuals and those with factors associated with more risk overestimation, may consider interpreting absolute ASCVD risk estimates with caution.
C1 [DeFilippis, Andrew Paul] Jewish Hosp, Louisville, KY 40202 USA.
[DeFilippis, Andrew Paul; McEvoy, John W.; Michos, Erin D.; Blaha, Michael J.] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA.
[DeFilippis, Andrew Paul] Univ Louisville, Div Cardiovasc Med, 550 South Jackson St, Louisville, KY 40202 USA.
[Young, Rebekah; Kronmal, Richard A.; McClelland, Robyn L.] Univ Washington, Seattle, WA 98195 USA.
[Sandfort, Veit] NIH, Bldg 10, Bethesda, MD 20892 USA.
RP DeFilippis, AP (reprint author), Jewish Hosp, Louisville, KY 40202 USA.; DeFilippis, AP (reprint author), Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA.; DeFilippis, AP (reprint author), Univ Louisville, Div Cardiovasc Med, 550 South Jackson St, Louisville, KY 40202 USA.
EM apdefi01@louisville.edu
FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160,
N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165,
N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NCRR
[UL1-TR-000040, UL1-TR-001079]
FX This research was supported by contracts N01-HC-95159, N01-HC-95160,
N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165,
N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the
National Heart, Lung, and Blood Institute and by grants UL1-TR-000040
and UL1-TR-001079 from NCRR.
NR 22
TC 1
Z9 1
U1 0
U2 0
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0195-668X
EI 1522-9645
J9 EUR HEART J
JI Eur. Heart J.
PD FEB 21
PY 2017
VL 38
IS 8
BP 598
EP 608
DI 10.1093/eurheartj/ehw301
PG 11
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EO6EL
UT WOS:000396784600007
PM 27436865
ER
PT J
AU Fradkin, JE
Rodgers, GP
AF Fradkin, Judith E.
Rodgers, Griffin P.
TI Glycemic Therapy for Type 2 Diabetes: Choices Expand, Data Lag Behind
SO ANNALS OF INTERNAL MEDICINE
LA English
DT Editorial Material
ID DRUGS
C1 [Fradkin, Judith E.; Rodgers, Griffin P.] NIH, Bldg 10, Bethesda, MD 20892 USA.
[Fradkin, Judith E.] MSC 2560,6707 Democracy Blvd, Bethesda, MD 20892 USA.
[Rodgers, Griffin P.] 31 Ctr Dr,Room 9A52, Bethesda, MD 20892 USA.
RP Fradkin, JE (reprint author), MSC 2560,6707 Democracy Blvd, Bethesda, MD 20892 USA.
EM judith.fradkin@nih.gov
NR 9
TC 0
Z9 0
U1 0
U2 0
PU AMER COLL PHYSICIANS
PI PHILADELPHIA
PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA
SN 0003-4819
EI 1539-3704
J9 ANN INTERN MED
JI Ann. Intern. Med.
PD FEB 21
PY 2017
VL 166
IS 4
BP 309
EP +
DI 10.7326/M16-2883
PG 3
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL7FO
UT WOS:000394786700026
PM 28055042
ER
PT J
AU McCullough, LE
Chen, J
Cho, YH
Khankari, NK
Bradshaw, PT
White, AJ
Teitelbaum, SL
Terry, MB
Neugut, AI
Hibshoosh, H
Santella, RM
Gammon, MD
AF McCullough, Lauren E.
Chen, Jia
Cho, Yoon Hee
Khankari, Nikhil K.
Bradshaw, Patrick T.
White, Alexandra J.
Teitelbaum, Susan L.
Terry, Mary Beth
Neugut, Alfred I.
Hibshoosh, Hanina
Santella, Regina M.
Gammon, Marilie D.
TI Modification of the association between recreational physical activity
and survival after breast cancer by promoter methylation in breast
cancer-related genes
SO BREAST CANCER RESEARCH
LA English
DT Article
DE Physical activity; Epigenetics; Methylation; Breast cancer; Survival
ID CPG ISLAND HYPERMETHYLATION; DNA METHYLATION; LONG-ISLAND; CELL; TUMOR;
TIME; EXPRESSION; SUBTYPES; CARCINOGENESIS; EPIGENETICS
AB Background: Mechanisms underlying the inverse association between physical activity and survival after breast cancer are unresolved, but DNA methylation may play a role. We hypothesized that promoter methylation of breast cancer-related genes, as well as global methylation, may modify the association between prediagnostic recreational physical activity (RPA) and breast cancer mortality.
Methods: Using a population-based sample of 1254 women diagnosed with first primary breast cancer, we examined modification of the RPA-mortality association by gene-specific promoter methylation and global methylation. Average lifetime RPA was assessed from menarche to diagnosis through structured in-home interviews. Promoter methylation of 13 breast cancer-related genes was evaluated in archived tumor by methylation-specific polymerase chain reaction and MethyLight assay. Global methylation in white blood cell DNA was determined at long interspersed nucleotide element 1 and by the luminometric methylation assay. After approximately 15 years of follow-up, 486 patients had died, and 186 of the deaths were breast cancer-related. We used Cox proportional hazards regression to estimate HRs and 95% CIs as well as likelihood ratio tests to assess multiplicative interactions.
Results: All-cause mortality was lower only among physically active women with methylated promoter of APC (HR 0.60, 95% CI 0.40-0.80), CCND2 (HR 0.56, 95% CI 0.32-0.99), HIN (HR 0.55, 95% CI 0.38-0.80), and TWIST1 (HR 0.28, 95% CI 0.14-0.56) in tumors, but not among those with unmethylated tumors (significant interaction p < 0.05). We found no interaction between RPA and global methylation.
Conclusions: The improved survival after breast cancer that is associated with RPA may be more pronounced in women with promoter tumor methylation in biologically plausible genes.
C1 [McCullough, Lauren E.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA.
[Chen, Jia; Teitelbaum, Susan L.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA.
[Chen, Jia] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA.
[Chen, Jia] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA.
[Cho, Yoon Hee] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA.
[Khankari, Nikhil K.] Vanderbilt Univ, Med Ctr, Div Epidemiol, Nashville, TN 37203 USA.
[Bradshaw, Patrick T.] Univ Calif Berkeley, Div Epidemiol, Berkeley, CA 94720 USA.
[White, Alexandra J.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA.
[Terry, Mary Beth; Neugut, Alfred I.] Columbia Univ, Dept Epidemiol, New York, NY 10032 USA.
[Neugut, Alfred I.] Columbia Univ, Dept Med, New York, NY 10032 USA.
[Hibshoosh, Hanina] Columbia Univ, Dept Pathol, New York, NY 10032 USA.
[Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA.
[Gammon, Marilie D.] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC 27599 USA.
RP McCullough, LE (reprint author), Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA.
EM lauren.mccullough@emory.edu
FU National Institutes of Health [R25CA057726, U01CA/ES66572, R01CA66572,
R01CA109753, 3R01CA109753-04S1, P30ES009089, P30ES10126]; U.S.
Department of Defense [BC972772]; Intramural Research Program of the
National Institutes of Health through the National Institute of
Environmental Health Sciences
FX This work was supported in part by grants from the National Institutes
of Health (R25CA057726, U01CA/ES66572, R01CA66572, R01CA109753,
3R01CA109753-04S1, P30ES009089, P30ES10126) and the U.S. Department of
Defense (BC972772). This research was also supported in part by the
Intramural Research Program of the National Institutes of Health through
the National Institute of Environmental Health Sciences.
NR 56
TC 0
Z9 0
U1 4
U2 4
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1465-542X
EI 1465-5411
J9 BREAST CANCER RES
JI Breast Cancer Res.
PD FEB 21
PY 2017
VL 19
AR 19
DI 10.1186/s13058-017-0811-z
PG 11
WC Oncology
SC Oncology
GA EL7UB
UT WOS:000394825000001
PM 28222775
ER
PT J
AU Mattapallil, MJ
Caspi, RR
AF Mattapallil, Mary J.
Caspi, Rachel R.
TI Compliments of Factor H: What's in it for AMD?
SO IMMUNITY
LA English
DT Editorial Material
ID MACULAR DEGENERATION
AB Genetic variations in complement factor H (CFH) confer greater risk for age-related macular degeneration (AMD). In this issue of Immunity, Calippe et al. (2017) uncover a non-canonical role for CFH in the inhibition of mononuclear phagocyte elimination from sub-retinal lesions, providing insight into the pathophysiology of AMD associated with CFH variants.
C1 [Mattapallil, Mary J.; Caspi, Rachel R.] NEI, Bethesda, MD 20892 USA.
RP Caspi, RR (reprint author), NEI, Bethesda, MD 20892 USA.
EM caspir@nei.nih.gov
FU NIH/NEI Intramural grant [ZIA EY000184-34]
FX NIH/NEI Intramural grant ZIA EY000184-34 (R.R.C.) provided funding for
this research.
NR 9
TC 0
Z9 0
U1 0
U2 0
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 FEB 21
PY 2017
VL 46
IS 2
BP 167
EP 169
DI 10.1016/j.immuni.2017.02.008
PG 4
WC Immunology
SC Immunology
GA EO0TM
UT WOS:000396410900003
PM 28228273
ER
PT J
AU Brewitz, A
Eickhoff, S
Dahling, S
Quast, T
Bedoui, S
Kroczek, RA
Kurts, C
Garbi, N
Barchet, W
Iannacone, M
Klauschen, F
Kolanus, W
Kaisho, T
Colonna, M
Germain, RN
Kastenmuller, W
AF Brewitz, Anna
Eickhoff, Sarah
Daehling, Sabrina
Quast, Thomas
Bedoui, Sammy
Kroczek, Richard A.
Kurts, Christian
Garbi, Natalio
Barchet, Winfried
Iannacone, Matteo
Klauschen, Frederick
Kolanus, Waldemar
Kaisho, Tsuneyasu
Colonna, Marco
Germain, Ronald N.
Kastenmueller, Wolfgang
TI CD8(+) T Cells Orchestrate pDC-XCR1(+) Dendritic Cell Spatial and
Functional Cooperativity to Optimize Priming
SO IMMUNITY
LA English
DT Article
ID LYMPH-NODES; ANTIVIRAL IMMUNITY; CROSS-PRESENTATION; VIRAL-INFECTION;
VIRUS-INFECTION; IFN-GAMMA; IN-VIVO; ACTIVATION; ANTIGEN; CD4(+)
AB Adaptive cellular immunity is initiated by antigenspecific interactions between T lymphocytes and dendritic cells (DCs). Plasmacytoid DCs (pDCs) support antiviral immunity by linking innate and adaptive immune responses. Here we examined pDC spatiotemporal dynamics during viral infection to uncover when, where, and how they exert their functions. We found that pDCs accumulated at sites of CD8(+) T cell antigen-driven activation in a CCR5-dependent fashion. Furthermore, activated CD8(+) T cells orchestrated the local recruitment of lymph node-resident XCR1 chemokine receptor-expressing DCs via secretion of the XCL1 chemokine. Functionally, this CD8+ T cell-mediated reorganization of the local DC network allowed for the interaction and cooperation of pDCs and XCR1(+) DCs, thereby optimizing XCR1(+) DC maturation and cross-presentation. These data support a model in which CD8(+) T cells upon activation create their own optimal priming microenvironment by recruiting additional DC subsets to the site of initial antigen recognition.
C1 [Brewitz, Anna; Eickhoff, Sarah; Daehling, Sabrina; Kurts, Christian; Garbi, Natalio; Kastenmueller, Wolfgang] Univ Bonn, Inst Expt Immunol, D-53127 Bonn, Germany.
[Quast, Thomas; Kolanus, Waldemar] Univ Bonn, Mol Immunol & Cell Biol Life & Med Sci Inst, D-53115 Bonn, Germany.
[Bedoui, Sammy] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia.
[Kroczek, Richard A.] Robert Koch Inst, Mol Immunol, D-13353 Berlin, Germany.
[Barchet, Winfried] Univ Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany.
[Iannacone, Matteo] Univ Vita Salute San Raffaele, Div Immunol Transplantat & Infect Dis, Via Olgettina 58, I-20132 Milan, Italy.
[Iannacone, Matteo] Univ Vita Salute San Raffaele, Expt Imaging Ctr, IRCCS San Raffaele Sci Inst, Via Olgettina 58, I-20132 Milan, Italy.
[Klauschen, Frederick] Charite, Inst Pathol, CharitePlatz 1, D-10117 Berlin, Germany.
[Klauschen, Frederick] Einstein Fdn Berlin, D-10117 Berlin, Germany.
[Kaisho, Tsuneyasu] Wakayama Med Univ, Inst Adv Med, Dept Immunol, Wakayama 6418509, Japan.
[Kaisho, Tsuneyasu] RIKEN Ctr Integrat Med Sci IMS RCAI, Lab Inflammatory Regulat, Yokohama, Kanagawa 2300045, Japan.
[Kaisho, Tsuneyasu] Osaka Univ, World Premier Int Res Ctr Initiat, Immunol Frontier Res Ctr, Lab Immune Regulat, Suita, Osaka 5650871, Japan.
[Colonna, Marco] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63108 USA.
[Germain, Ronald N.] Natl Inst Allergy & Infect Dis, Lab Syst Biol, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA.
[Brewitz, Anna; Eickhoff, Sarah; Daehling, Sabrina; Kurts, Christian; Garbi, Natalio; Kastenmueller, Wolfgang] Univ Hosp, Inst Expt Immunol, D-53127 Bonn, Germany.
[Barchet, Winfried; Kastenmueller, Wolfgang] Univ Hosp, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany.
RP Kastenmuller, W (reprint author), Univ Bonn, Inst Expt Immunol, D-53127 Bonn, Germany.; Kastenmuller, W (reprint author), Univ Hosp, Inst Expt Immunol, D-53127 Bonn, Germany.; Kastenmuller, W (reprint author), Univ Hosp, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany.
EM wkastenm@uni-bonn.de
FU NRW-Ruckkehrerprogramm of the German state of Northrhine-Westfalia;
Kishimoto Foundation; Japan Society for the Promotion of Science (JSPS)
[26293106]; Einstein Foundation Berlin; Intramural Research Program,
NIAID, NIH; DFG Graduate program [2168/1]; [SFB704]
FX We would like to thank S. Ebbinghaus and S. Rathmann for technical
assistance and D.H. Busch for kindly providing MHCI multimers. This
research was supported by the Intramural Research Program, NIAID, NIH.
W. Kastenmuller, N.G., C.K., and W. Kolanus are members of the DFG
Excellence Cluster ImmunoSensation in Bonn, Germany, and are supported
by grant SFB704. S.D., S.B., and W. Kastenmuller are supported by the
DFG Graduate program 2168/1 (Bo&MeRang). W. Kastenmuller is supported by
NRW-Ruckkehrerprogramm of the German state of Northrhine-Westfalia. T.K.
was supported by the Kishimoto Foundation and a Grant-in-Aid for
Scientific Research (B) from Japan Society for the Promotion of Science
(JSPS, 26293106). F.K. is supported by the Einstein Foundation Berlin
(JF-Klauschen-2014).
NR 47
TC 1
Z9 1
U1 4
U2 4
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 FEB 21
PY 2017
VL 46
IS 2
BP 205
EP 219
DI 10.1016/j.immuni.2017.01.003
PG 15
WC Immunology
SC Immunology
GA EO0TM
UT WOS:000396410900010
PM 28190711
ER
PT J
AU Paules, CI
Fauci, AS
AF Paules, Catharine I.
Fauci, Anthony S.
TI Emerging and Reemerging Infectious Diseases The Dichotomy Between Acute
Outbreaks and Chronic Endemicity
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Editorial Material
ID ZIKA VIRUS-INFECTION; WEST NILE VIRUS
C1 [Paules, Catharine I.; Fauci, Anthony S.] NIAID, Off Director, 9000 Rockville Pike, Bethesda, MD 20892 USA.
RP Fauci, AS (reprint author), NIAID, 31 Ctr Dr,MSC 2520,Bldg 31,Room 7A-03, Bethesda, MD 20892 USA.
EM afauci@niaid.nih.gov
NR 7
TC 0
Z9 0
U1 3
U2 3
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 FEB 21
PY 2017
VL 317
IS 7
BP 691
EP 692
DI 10.1001/jama.2016.21079
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL8WR
UT WOS:000394901600011
PM 28097318
ER
PT J
AU Resnick, SM
Matsumoto, AM
Stephens-Shields, AJ
Ellenberg, SS
Gill, TM
Shumaker, SA
Pleasants, DD
Barrett-Connor, E
Bhasin, S
Cauley, JA
Cella, D
Crandall, JP
Cunningham, GR
Ensrud, KE
Farrar, JT
Lewis, CE
Molitch, ME
Pahor, M
Swerdloff, RS
Cifelli, D
Anton, S
Basaria, S
Diem, SJ
Wang, C
Hou, XL
Snyder, PJ
AF Resnick, Susan M.
Matsumoto, Alvin M.
Stephens-Shields, Alisa J.
Ellenberg, Susan S.
Gill, Thomas M.
Shumaker, Sally A.
Pleasants, Debbie D.
Barrett-Connor, Elizabeth
Bhasin, Shalender
Cauley, Jane A.
Cella, David
Crandall, Jill P.
Cunningham, Glenn R.
Ensrud, Kristine E.
Farrar, John T.
Lewis, Cora E.
Molitch, Mark E.
Pahor, Marco
Swerdloff, Ronald S.
Cifelli, Denise
Anton, Stephen
Basaria, Shehzad
Diem, Susan J.
Wang, Christina
Hou, Xiaoling
Snyder, Peter J.
TI Testosterone Treatment and Cognitive Function in Older Men With Low
Testosterone and Age-Associated Memory Impairment
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Article
ID SERUM TESTOSTERONE; SEX-HORMONES; ALZHEIMER-DISEASE; VERBAL MEMORY;
ELDERLY-MEN; SUPPLEMENTATION; TRIAL; PERFORMANCE; DEPRESSION
AB IMPORTANCE Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions.
OBJECTIVE To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI).
DESIGN, SETTING, AND PARTICIPANTS The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014.
INTERVENTIONS Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year.
MAIN OUTCOMES AND MEASURES The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months.
RESULTS Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89).
CONCLUSIONS AND RELEVANCE Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions.
C1 [Snyder, Peter J.] Univ Penn, Div Endocrinol Diabet & Metab, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.
[Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA.
[Matsumoto, Alvin M.] Dept Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA.
[Matsumoto, Alvin M.] Univ Washington, Sch Med, Dept Internal Med, Div Gerontol & Geriatr Med, Seattle, WA USA.
[Stephens-Shields, Alisa J.; Ellenberg, Susan S.; Hou, Xiaoling] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA.
[Gill, Thomas M.] Yale Sch Med, Div Geriatr Med, New Haven, CT USA.
[Shumaker, Sally A.; Pleasants, Debbie D.; Basaria, Shehzad] Wake Forest Sch Med, Winston Salem, NC USA.
[Barrett-Connor, Elizabeth] Univ Calif San Diego, Sch Med, Dept Internal Med, La Jolla, CA 92093 USA.
[Barrett-Connor, Elizabeth] Univ Calif San Diego, Sch Med, Div Epidemiol, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
[Bhasin, Shalender] Harvard Med Sch, Brigham & Womens Hosp, Res Program Mens Hlth Aging & Metab, Boston, MA USA.
[Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA.
[Cella, David] Northwestern Univ, Dept Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA.
[Crandall, Jill P.] Albert Einstein Coll Med, Div Endocrinol, Bronx, NY 10467 USA.
[Crandall, Jill P.] Albert Einstein Coll Med, Div Geriatr, Bronx, NY 10467 USA.
[Cunningham, Glenn R.] Baylor Coll Med, Dept Med, Div Diabet Endocrinol & Metab, Houston, TX 77030 USA.
[Cunningham, Glenn R.] Baylor Coll Med, Dept Mol & Cellular Biol, Div Diabet Endocrinol & Metab, Houston, TX 77030 USA.
[Cunningham, Glenn R.] Baylor St Lukes Med Ctr, Houston, TX USA.
[Cunningham, Glenn R.; Ensrud, Kristine E.; Diem, Susan J.] Univ Minnesota, Dept Med, Div Epidemiol & Community Hlth, Box 736 UMHC, Minneapolis, MN 55455 USA.
[Ensrud, Kristine E.] Minneapolis Vet Affairs Hlth Care Syst, Minneapolis, MN USA.
[Farrar, John T.; Cifelli, Denise] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA.
[Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA.
[Molitch, Mark E.] Northwestern Univ, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL 60611 USA.
[Pahor, Marco; Anton, Stephen] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA.
[Swerdloff, Ronald S.; Wang, Christina] Harbor Univ Calif Los Angeles Med Ctr, Div Endocrinol, Torrance, CA USA.
[Swerdloff, Ronald S.; Wang, Christina] Los Angeles Biomed Res Inst, Torrance, CA USA.
RP Snyder, PJ (reprint author), Univ Penn, Div Endocrinol Diabet & Metab, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.
EM pjs@mail.med.upenn.edu
FU NIA/NIH [U01 AG030644, R01 AG37679]; National Heart, Lung, and Blood
Institute; National Institute of Neurological Disorders and Stroke;
National Institute of Child Health and Human Development; AndroGel;
placebo gel; Claude D. Pepper Older Americans Independence Center (OAIC)
[P30-AG013679]; Claude D. Pepper OAIC [P30AG021342]; Yale Clinical and
Translational Science Award [UL1TR000142]; Department of Veterans
Affairs Puget Sound Health Care System; NIA [K07AG043587]; Intramural
Research Program of NIA/NIH; National Institute for Diabetes and
Digestive and Kidney Diseases of NIH [DK079626]; Boston Claude D. Pepper
OAIC [5P30AG031679]
FX The Testosterone Trials were supported by grant U01 AG030644 from the
NIA/NIH, supplemented by funds from the National Heart, Lung, and Blood
Institute; National Institute of Neurological Disorders and Stroke; and
National Institute of Child Health and Human Development. AbbVie
provided funding, AndroGel, and placebo gel. The Boston site was
partially supported by grant P30-AG013679 from the Claude D. Pepper
Older Americans Independence Center (OAIC). The Yale Field Center was
partially supported by grant P30AG021342 from the Claude D. Pepper OAIC
and grant UL1TR000142 from the Yale Clinical and Translational Science
Award. Additional support was from the Department of Veterans Affairs
Puget Sound Health Care System (Dr Matsumoto); the Academic Leadership
Award (K07AG043587) from the NIA (Dr Gill); the Intramural Research
Program of NIA/NIH (Dr Resnick); grant DK079626 from the National
Institute for Diabetes and Digestive and Kidney Diseases of NIH to the
University of Alabama at Birmingham Diabetes Research and Training
Center (Dr Lewis); grant R01 AG37679 from NIA/NIH (Dr Cauley); and grant
5P30AG031679 from the Boston Claude D. Pepper OAIC (Dr Bhasin).
NR 37
TC 1
Z9 1
U1 1
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 FEB 21
PY 2017
VL 317
IS 7
BP 717
EP 727
DI 10.1001/jama.2016.21044
PG 11
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL8WR
UT WOS:000394901600019
PM 28241356
ER
PT J
AU Deedwania, P
Acharya, T
AF Deedwania, Prakash
Acharya, Tushar
TI Anticoagulation in Atrial Fibrillation Is the Paradigm Really Shifting?
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Editorial Material
DE atrial fibrillation; novel oral anticoagulant agents; registry data;
stroke prevention
ID ANTITHROMBOTIC THERAPY; ORAL ANTICOAGULANTS; AF; MANAGEMENT; REGISTRY
C1 [Deedwania, Prakash] Univ Calif San Francisco, Dept Internal Med, Div Cardiol, Fresno, CA USA.
[Acharya, Tushar] NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Deedwania, P (reprint author), Univ Calif San Francisco, Dept Internal Med, Div Cardiol, Acad Off, 2335 East Kashian Lane,Suite 460, Fresno, CA 93701 USA.
EM pdeedwania@fresno.ucsf.edu
NR 12
TC 0
Z9 0
U1 0
U2 0
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0735-1097
EI 1558-3597
J9 J AM COLL CARDIOL
JI J. Am. Coll. Cardiol.
PD FEB 21
PY 2017
VL 69
IS 7
BP 786
EP 788
DI 10.1016/j.jacc.2016.11.062
PG 3
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EN9SR
UT WOS:000396340400004
PM 28209219
ER
PT J
AU Webb, TR
Erdmann, J
Stirrups, KE
Stitziel, NO
Masca, NGD
Jansen, H
Kanoni, S
Nelson, CP
Ferrario, PG
Konig, IR
Eicher, JD
Johnson, AD
Hamby, SE
Betsholtz, C
Ruusalepp, A
Franzen, O
Schadt, EE
Bjorkegren, JLM
Weeke, PE
Auer, PL
Schick, UM
Lu, YC
Zhang, H
Dube, MP
Goel, A
Farrall, M
Peloso, GM
Won, HH
Do, R
van Iperen, E
Kruppa, J
Mahajan, A
Scott, RA
Willenborg, C
Braund, PS
van Capelleveen, JC
Doney, ASF
Donnelly, LA
Asselta, R
Merlini, PA
Duga, S
Marziliano, N
Denny, JC
Shaffer, C
El-Mokhtari, NE
Franke, A
Heilmann, S
Hengstenberg, C
Hoffmann, P
Holmen, OL
Hveem, K
Jansson, JH
Jockel, KH
Kessler, T
Kriebel, J
Laugwitz, KL
Marouli, E
Martinelli, N
McCarthy, MI
Van Zuydam, NR
Meisinger, C
Esko, T
Mihailov, E
Escher, SA
Alver, M
Moebus, S
Morris, AD
Virtamo, J
Nikpay, M
Olivieri, O
Provost, S
AlQarawi, A
Robertson, NR
Akinsansya, KO
Reilly, DF
Vogt, TF
Yin, W
Asselbergs, FW
Kooperberg, C
Jackson, RD
Stahl, E
Muller-Nurasyid, M
Strauch, K
Varga, TV
Waldenberger, M
Zeng, LY
Chowdhury, R
Salomaa, V
Ford, I
Jukema, JW
Amouyel, P
Kontto, J
Nordestgaard, BG
Ferrieres, J
Saleheen, D
Sattar, N
Surendran, P
Wagner, A
Young, R
Howson, JMM
Butterworth, AS
Danesh, J
Ardissino, D
Bottinger, EP
Erbel, R
Franks, PW
Girelli, D
Hall, AS
Hovingh, GK
Kastrati, A
Lieb, W
Meitinger, T
Kraus, WE
Shah, SH
McPherson, R
Orho-Melander, M
Melander, O
Metspalu, A
Palmer, CNA
Peters, A
Rader, DJ
Reilly, MP
Loos, RJF
Reiner, AP
Roden, DM
Tardif, JC
Thompson, JR
Wareham, NJ
Watkins, H
Willer, CJ
Samani, NJ
Schunkert, H
Deloukas, P
Kathiresan, S
AF Webb, Thomas R.
Erdmann, Jeanette
Stirrups, Kathleen E.
Stitziel, Nathan O.
Masca, Nicholas G. D.
Jansen, Henning
Kanoni, Stavroula
Nelson, Christopher P.
Ferrario, Paola G.
Koenig, Inke R.
Eicher, John D.
Johnson, Andrew D.
Hamby, Stephen E.
Betsholtz, Christer
Ruusalepp, Arno
Franzen, Oscar
Schadt, Eric E.
Bjoerkegren, Johan L. M.
Weeke, Peter E.
Auer, Paul L.
Schick, Ursula M.
Lu, Yingchang
Zhang, He
Dube, Marie-Pierre
Goel, Anuj
Farrall, Martin
Peloso, Gina M.
Won, Hong-Hee
Do, Ron
van Iperen, Erik
Kruppa, Jochen
Mahajan, Anubha
Scott, Robert A.
Willenborg, Christina
Braund, Peter S.
van Capelleveen, Julian C.
Doney, Alex S. F.
Donnelly, Louise A.
Asselta, Rosanna
Merlini, Pier A.
Duga, Stefano
Marziliano, Nicola
Denny, Josh C.
Shaffer, Christian
El-Mokhtari, Nour Eddine
Franke, Andre
Heilmann, Stefanie
Hengstenberg, Christian
Hoffmann, Per
Holmen, Oddgeir L.
Hveem, Kristian
Jansson, Jan-Hakan
Joeckel, Karl-Heinz
Kessler, Thorsten
Kriebel, Jennifer
Laugwitz, Karl L.
Marouli, Eirini
Martinelli, Nicola
McCarthy, Mark I.
Van Zuydam, Natalie R.
Meisinger, Christa
Esko, Tonu
Mihailov, Evelin
Escher, Stefan A.
Alver, Maris
Moebus, Susanne
Morris, Andrew D.
Virtamo, Jarma
Nikpay, Majid
Olivieri, Oliviero
Provost, Sylvie
AlQarawi, Alaa
Robertson, Neil R.
Akinsansya, Karen O.
Reilly, Dermot F.
Vogt, Thomas F.
Yin, Wu
Asselbergs, Folkert W.
Kooperberg, Charles
Jackson, Rebecca D.
Stahl, Eli
Mueller-Nurasyid, Martina
Strauch, Konstantin
Varga, Tibor V.
Waldenberger, Melanie
Zeng, Lingyao
Chowdhury, Rajiv
Salomaa, Veikko
Ford, Ian
Jukema, J. Wouter
Amouyel, Philippe
Kontto, Jukka
Nordestgaard, Borge G.
Ferrieres, Jean
Saleheen, Danish
Sattar, Naveed
Surendran, Praveen
Wagner, Aline
Young, Robin
Howson, Joanna M. M.
Butterworth, Adam S.
Danesh, John
Ardissino, Diego
Bottinger, Erwin P.
Erbel, Raimund
Franks, Paul W.
Girelli, Domenico
Hall, Alistair S.
Hovingh, G. Kees
Kastrati, Adnan
Lieb, Wolfgang
Meitinger, Thomas
Kraus, William E.
Shah, Svati H.
McPherson, Ruth
Orho-Melander, Marju
Melander, Olle
Metspalu, Andres
Palmer, Colin N. A.
Peters, Annette
Rader, Daniel J.
Reilly, Muredach P.
Loos, Ruth J. F.
Reiner, Alex P.
Roden, Dan M.
Tardif, Jean-Claude
Thompson, John R.
Wareham, Nicholas J.
Watkins, Hugh
Willer, Cristen J.
Samani, Nilesh J.
Schunkert, Heribert
Deloukas, Panos
Kathiresan, Sekar
CA Wellcome Trust Case Control
MORGAM Investigators
Myocardial Infarction Genetics
TI Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated
With Coronary Artery Disease
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Article
DE cholesteryl ester transfer protein; expression quantitative trait loci;
genetics; genome-wide association; single nucleotide polymorphism
ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN RECEPTOR; ABDOMINAL
AORTIC-ANEURYSM; HEART-DISEASE; SCAVENGER RECEPTOR; PHOSPHOLIPASE A(2);
COMMON VARIANTS; CETP MASS; SR-BI; RISK
AB BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.
OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.
METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.
RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.
CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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[Erdmann, Jeanette; Willenborg, Christina] Univ Lubeck, Inst Cardiogenet, Lubeck, Germany.
[Erdmann, Jeanette; Ferrario, Paola G.; Koenig, Inke R.] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany.
[Erdmann, Jeanette] Univ Heart Ctr Luebeck, Lubeck, Germany.
[Stirrups, Kathleen E.; Kanoni, Stavroula; Marouli, Eirini; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.
[Stirrups, Kathleen E.] Univ Cambridge, Dept Haematol, Cambridge, England.
[Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, Div Cardiovasc, St Louis, MO 63110 USA.
[Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA.
[Stitziel, Nathan O.; Hengstenberg, Christian] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA.
[Jansen, Henning; Hengstenberg, Christian; Kessler, Thorsten; Zeng, Lingyao; Kastrati, Adnan; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.
[Jansen, Henning; Kessler, Thorsten; Laugwitz, Karl L.; Mueller-Nurasyid, Martina; Zeng, Lingyao; Meitinger, Thomas; Peters, Annette; Schunkert, Heribert; Wellcome Trust Case Control] DZHK, Munich, Germany.
[Ferrario, Paola G.; Koenig, Inke R.] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany.
[Eicher, John D.; Johnson, Andrew D.] NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA.
[Betsholtz, Christer] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden.
[Betsholtz, Christer; Bjoerkegren, Johan L. M.] Karolinska Inst, Vasc Biol Unit, Dept Med Biochem & Biophys, Stockholm, Sweden.
[Ruusalepp, Arno; Bjoerkegren, Johan L. M.] Univ Tartu, Inst Biomed & Translat Med, Dept Physiol, Tartu, Estonia.
[Ruusalepp, Arno] Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia.
[Ruusalepp, Arno; Franzen, Oscar; Bjoerkegren, Johan L. M.] Clin Gene Networks AB, Stockholm, Sweden.
[Franzen, Oscar; Schadt, Eric E.; Bjoerkegren, Johan L. M.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA.
[Weeke, Peter E.; Denny, Josh C.; Shaffer, Christian; Roden, Dan M.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
[Weeke, Peter E.] Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Lab Mol Cardiol, Copenhagen, Denmark.
[Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA.
[Schick, Ursula M.; Kooperberg, Charles; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
[Schick, Ursula M.; Lu, Yingchang; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.
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[Won, Hong-Hee] Sungkyunkwan Univ, Samsung Med Ctr, Samsung Adv Inst Hlth Sci & Technol, Seoul, South Korea.
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[van Iperen, Erik] Acad Med Ctr, Dept Biostat, Amsterdam, Netherlands.
[Kruppa, Jochen] Univ Vet Med Hannover, Inst Anim Breeding & Genet, Hannover, Germany.
[Scott, Robert A.; Wareham, Nicholas J.] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England.
[van Capelleveen, Julian C.; Hovingh, G. Kees] Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands.
[Doney, Alex S. F.; Donnelly, Louise A.; Palmer, Colin N. A.] Univ Dundee, Hosp & Med Sch, Med Res Inst, Dundee, Scotland.
[Asselta, Rosanna; Duga, Stefano] Humanitas Univ, Dept Biomed Sci, Milan, Italy.
[Asselta, Rosanna; Duga, Stefano] Humanitas Clin & Res Ctr, Milan, Italy.
[Merlini, Pier A.] Osped Niguarda Ca Granda, Milan, Italy.
[Marziliano, Nicola] Azienda Sanit Locale 3 San Francesco, Nuoro, Italy.
[Denny, Josh C.] Vanderbilt Univ, Med Ctr, Dept Biomed informat, Nashville, TN USA.
[El-Mokhtari, Nour Eddine] Imland Klin Rendsburg, Klin Kardiol Pneumol & Innere Med, Rendsburg, Germany.
[Franke, Andre] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany.
[Heilmann, Stefanie; Hoffmann, Per] Univ Bonn, Inst Human Genet, Bonn, Germany.
[Heilmann, Stefanie; Hoffmann, Per] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany.
[Hoffmann, Per] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland.
[Holmen, Oddgeir L.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway.
[Holmen, Oddgeir L.] Trondheim Reg & Univ Hosp, St Olav Hosp, Trondheim, Norway.
[Hveem, Kristian] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Med, Levanger, Norway.
[Jansson, Jan-Hakan] Umea Univ, Res Unit Skelleftea, Dept Publ Hlth & Clin Med, Umea, Sweden.
[Joeckel, Karl-Heinz; Moebus, Susanne; Erbel, Raimund] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany.
[Kriebel, Jennifer; Waldenberger, Melanie] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.
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[Kriebel, Jennifer] German Ctr Diabet Res, Neuherberg, Germany.
[Laugwitz, Karl L.] Tech Univ Munich, Klinikum Rechts Isar, Inst Med Klin & Poliklin, Munich, Germany.
[Martinelli, Nicola; Olivieri, Oliviero; Girelli, Domenico] Univ Verona, Sect Internal Med, Dept Med, Verona, Italy.
[McCarthy, Mark I.; Van Zuydam, Natalie R.; Robertson, Neil R.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
[McCarthy, Mark I.] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Old Rd Headington, Oxford, England.
[Esko, Tonu; Mihailov, Evelin; Alver, Maris; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
[Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.
[Esko, Tonu] Harvard Med Sch, Dept Genet, Boston, MA USA.
[Esko, Tonu] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA.
[Escher, Stefan A.; Varga, Tibor V.; Franks, Paul W.] Lund Univ, Dept Clin Sci, Ctr Diabet, Genet & Mol Epidemiol Unit, Malmo, Sweden.
[Alver, Maris; Metspalu, Andres] Inst Mol & Cell Biol, Tartu, Estonia.
[Morris, Andrew D.] Univ Edinburgh, Sch Med, Sch Mol Genet & Populat Hlth Sci, Teviot Pl, Edinburgh, Midlothian, Scotland.
[Virtamo, Jarma; Salomaa, Veikko] Natl Inst Hlth & Welf THL, Helsinki, Finland.
[Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada.
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[Akinsansya, Karen O.; Reilly, Dermot F.; Vogt, Thomas F.; Yin, Wu] Merck Sharp & Dohme Ltd, Rahway, NJ USA.
[Asselbergs, Folkert W.] UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.
[Asselbergs, Folkert W.] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
[Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England.
[Jackson, Rebecca D.] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA.
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[Mueller-Nurasyid, Martina] Ludwig Maximilians Univ Munchen, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany.
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[Amouyel, Philippe] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,RID AGE U1167, Lille, France.
[Nordestgaard, Borge G.] Copenhagen Univ Hosp & Med Sci, Copenhagen, Denmark.
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[Franks, Paul W.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.
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[Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England.
[Lieb, Wolfgang] Christian Albrechts Univ Kiel, Inst Epidemiol & Biobank Popgen, Kiel, Germany.
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[Kraus, William E.; Shah, Svati H.] Duke Univ, Duke Mol Physiol Inst, Durham, NC USA.
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[Rader, Daniel J.] Univ Penn, Dept Genet, Cardiovasc Inst, Philadelphia, PA 19104 USA.
[Rader, Daniel J.] Univ Penn, Inst Translat Med & Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA.
[Reilly, Muredach P.] Columbia Univ, Dept Med, Div Cardiol, New York, NY USA.
[Reilly, Muredach P.] Columbia Univ, Irving Inst Clin & Translat Res, New York, NY USA.
[Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.
[Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.
[Roden, Dan M.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA.
[Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England.
[Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
[Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.
[Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.
RP Samani, NJ (reprint author), Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.; Samani, NJ (reprint author), Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.; Deloukas, P (reprint author), King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence R, Jeddah, Saudi Arabia.
EM njs@le.ac.uk; p.deloukas@qmul.ac.uk
RI Webb, Tom/C-6237-2011;
OI Dube, Marie-Pierre/0000-0001-8442-4393; Kontto,
Jukka/0000-0003-3899-9852; Peters, Annette/0000-0001-6645-0985
FU Merck Sharp Dohme; Pfizer; Novo Nordisk; Eli Lilly; Servier;
Sanofi-Aventis; Janssen; Roche; Boehringer-Ingelheim; Takeda; Merck;
AstraZeneca; Amgen; Sanofi; Amarin; DalCor
FX Dr. Vogt was an employee of Merck when aspects of this research was
conducted, but is now retired from Merck. A cholesteryl ester transfer
protein inhibitor, Anacetrapib ( MK-0859), is currently undergoing
clinical investigation in the REVEAL outcome trial sponsored by Merck
Sharp & Dohme. Dr. Schick is an employee of Recombine. Dr. Dube has
equity in DalCor Pharmaceuticals. Dr. McCarthy is a member of advisory
boards for Pfizer and Novo Nordisk; has received honoraria from Pfizer,
Novo Nordisk, and Eli Lilly; and has received research funding provided
by Pfizer, Novo Nordisk, Eli Lilly, Servier, Sanofi-Aventis, Janssen,
Roche, Boehringer-Ingelheim, Takeda, Merck, and AstraZeneca. Dr.
Ferrieres has received grants from Merck Sharp & Dohme, Amgen, and
Sanofi. Dr. Sattar has served as a consultant for Amgen and Sanofi. Dr.
Butterworth has received grants from Pfizer and Merck. Dr. Danesh has
served as a consultant for Takeda; has served on the Novartis
Cardiovascular & Metabolic Advisory Board and International
Cardiovascular and Metabolism Research and Development Portfolio
Committee of Novartis; has served on the UK Atherosclerosis Advisory
Board of Merck Sharp & Dohme; has served on the advisory board of
Sanofi; has served on the Pfizer Population Research Advisory Panel; and
has financial relationships with the British Heart Foundation, BUPA
Foundation, diaDexus, European Research Council, European Union, Evelyn
Trust, Fogarty International Centre, GlaxoSmithKline, Merck, National
Heart, Lung, and Blood Institute, National Health Service Blood and
Transplant, National Institute for Health Research, National Institute
of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi,
Takeda, The Wellcome Trust, UK Biobank, University of British Columbia,
and UK Medical Research Council. Dr. Tardif has received research grants
from Amarin, AstraZeneca, Merck, Pfizer, Eli Lilly, Sanofi, Servier, and
DalCor; has received honoraria from Pfizer (to his institution),
Servier, DalCor, and Sanofi (to his institution); and has received
modest equity interest from DalCor. Dr. Kathiresan has financial/ other
relationships with Regeneron, Bayer, Catabasis, Merck, Celera, Genomics
PLC, San Therapeutics, Novartis, Sanofi, AstraZeneca, Alnylam, Eli
Lilly, Leerink Partners, and Noble Insights. All other authors have
reported that they have no relationships relevant to the contents of
this paper to disclose. A full list of acknowledgments and funding
sources is included in the Online Appendix. Drs. Webb, Erdmann,
Strirrups, Stitziel, Samani, Schunkert, Deloukas, and Kathiresan
contributed equally to this work.
NR 44
TC 1
Z9 1
U1 0
U2 0
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0735-1097
EI 1558-3597
J9 J AM COLL CARDIOL
JI J. Am. Coll. Cardiol.
PD FEB 21
PY 2017
VL 69
IS 7
BP 823
EP 836
DI 10.1016/j.jacc.2016.11.056
PG 14
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EN9SR
UT WOS:000396340400009
PM 28209224
ER
PT J
AU Lucanic, M
Plummer, WT
Chen, E
Harke, J
Foulger, AC
Onken, B
Coleman-Hulbert, AL
Dumas, KJ
Guo, SZ
Johnson, E
Bhaumik, D
Xue, J
Crist, AB
Presley, MP
Harinath, G
Sedore, CA
Chamoli, M
Kamat, S
Chen, MK
Angeli, S
Chang, C
Willis, JH
Edgar, D
Royal, MA
Chao, EA
Patel, S
Garrett, T
Ibanez-Ventoso, C
Hope, J
Kish, JL
Guo, M
Lithgow, GJ
Driscoll, M
Phillips, PC
AF Lucanic, Mark
Plummer, W. Todd
Chen, Esteban
Harke, Jailynn
Foulger, Anna C.
Onken, Brian
Coleman-Hulbert, Anna L.
Dumas, Kathleen J.
Guo, Suzhen
Johnson, Erik
Bhaumik, Dipa
Xue, Jian
Crist, Anna B.
Presley, Michael P.
Harinath, Girish
Sedore, Christine A.
Chamoli, Manish
Kamat, Shaunak
Chen, Michelle K.
Angeli, Suzanne
Chang, Christina
Willis, John H.
Edgar, Daniel
Royal, Mary Anne
Chao, Elizabeth A.
Patel, Shobhna
Garrett, Theo
Ibanez-Ventoso, Carolina
Hope, June
Kish, Jason L.
Guo, Max
Lithgow, Gordon J.
Driscoll, Monica
Phillips, Patrick C.
TI Impact of genetic background and experimental reproducibility on
identifying chemical compounds with robust longevity effects
SO NATURE COMMUNICATIONS
LA English
DT Article
ID ADULT CAENORHABDITIS-ELEGANS; EXTENDS LIFE-SPAN; DIETARY RESTRICTION;
STRESS RESISTANCE; C. ELEGANS; INCREASE; RESVERATROL; POPULATIONS;
DROSOPHILA; ORGANISMS
AB Limiting the debilitating consequences of ageing is a major medical challenge of our time. Robust pharmacological interventions that promote healthy ageing across diverse genetic backgrounds may engage conserved longevity pathways. Here we report results from the Caenorhabditis Intervention Testing Program in assessing longevity variation across 22 Caenorhabditis strains spanning 3 species, using multiple replicates collected across three independent laboratories. Reproducibility between test sites is high, whereas individual trial reproducibility is relatively low. Of ten pro-longevity chemicals tested, six significantly extend lifespan in at least one strain. Three reported dietary restriction mimetics are mainly effective across C. elegans strains, indicating species and strain-specific responses. In contrast, the amyloid dye ThioflavinT is both potent and robust across the strains. Our results highlight promising pharmacological leads and demonstrate the importance of assessing lifespans of discrete cohorts across repeat studies to capture biological variation in the search for reproducible ageing interventions.
C1 [Lucanic, Mark; Plummer, W. Todd; Foulger, Anna C.; Dumas, Kathleen J.; Bhaumik, Dipa; Presley, Michael P.; Chamoli, Manish; Angeli, Suzanne; Edgar, Daniel; Chao, Elizabeth A.; Garrett, Theo; Hope, June; Kish, Jason L.; Lithgow, Gordon J.] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA.
[Chen, Esteban; Onken, Brian; Guo, Suzhen; Xue, Jian; Harinath, Girish; Kamat, Shaunak; Chang, Christina; Royal, Mary Anne; Patel, Shobhna; Ibanez-Ventoso, Carolina; Driscoll, Monica] Rutgers State Univ, Dept Mol Biol & Biochem, Nelson Biol Labs, Piscataway, NJ 08854 USA.
[Harke, Jailynn; Coleman-Hulbert, Anna L.; Johnson, Erik; Crist, Anna B.; Sedore, Christine A.; Chen, Michelle K.; Willis, John H.; Phillips, Patrick C.] Univ Oregon, Inst Ecol & Evolut, Eugene, OR 97403 USA.
[Guo, Max] NIA, Div Aging Biol, 7201 Wisconsin Ave, Bethesda, MD 20892 USA.
[Harke, Jailynn] NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA.
RP Lithgow, GJ (reprint author), Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA.; Driscoll, M (reprint author), Rutgers State Univ, Dept Mol Biol & Biochem, Nelson Biol Labs, Piscataway, NJ 08854 USA.; Phillips, PC (reprint author), Univ Oregon, Inst Ecol & Evolut, Eugene, OR 97403 USA.
EM glithgow@buckinstitute.org; driscoll@dls.rutgers.edu; pphil@uoregon.edu
FU NIH Office of Research Infrastructure Programs [P40 OD010440]; Larry L.
Hillblom Foundation; Glenn Foundation for Medical Research; NIH grants
[UL1024917, 1R01AG029631, R21AG048528, UO1AG045844, U01AG045864]
FX We acknowledge all the members of the Lithgow, Driscoll and Phillips
labs for helpful discussions particularly focused on detailed protocols.
We also thank the CITP Advisory Committee and Ronald Kohanski (National
Institute on Aging). We thank Asher Cutter, Marie-Anne Felix and
Christian Braendle for providing strains that they had directly
collected. Additional strains were provided by the CGC, which is funded
by NIH Office of Research Infrastructure Programs (P40 OD010440). This
work was supported by funding from the Larry L. Hillblom Foundation, the
Glenn Foundation for Medical Research and NIH grants (UL1024917,
supporting the Interdisciplinary Research Consortium on Geroscience,
1R01AG029631, R21AG048528, UO1AG045844 and U01AG045864).
NR 60
TC 0
Z9 0
U1 2
U2 2
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD FEB 21
PY 2017
VL 8
AR 14256
DI 10.1038/ncomms14256
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL3CY
UT WOS:000394498400001
PM 28220799
ER
PT J
AU Ren, NSX
Ji, M
Tokar, EJ
Busch, EL
Xu, XJ
Lewis, D
Li, XC
Jin, AW
Zhang, YP
Wu, WKK
Huang, WC
Li, LP
Fargo, DC
Keku, TO
Sandler, RS
Li, XL
AF Ren, Natalie S. X.
Ji, Ming
Tokar, Erik J.
Busch, Evan L.
Xu, Xiaojiang
Lewis, DeAsia
Li, Xiangchun
Jin, Aiwen
Zhang, Yanping
Wu, William K. K.
Huang, Weichun
Li, Leping
Fargo, David C.
Keku, Temitope O.
Sandler, Robert S.
Li, Xiaoling
TI Haploinsufficiency of SIRT1 Enhances Glutamine Metabolism and Promotes
Cancer Development
SO CURRENT BIOLOGY
LA English
DT Article
ID CARE OUTCOMES RESEARCH; COLORECTAL-CANCER; CELL-SURVIVAL; P53;
TUMORIGENESIS; MICE; DAMAGE; HOMEOSTASIS; ACTIVATION; EXPRESSION
AB SIRT1, the most conserved mammalian NAID(+)-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and may be dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here, we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development. Heterozygous deletion of Sirt1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance, and cancer formation. In contrast, homozygous deletion of Sirt1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose dependence in cells, intestine-specific Sirt1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific Sirt1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction, but not deletion, is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contribute to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1-small-molecule-activator/inhibitor-based therapeutic strategies for cancers.
C1 [Ren, Natalie S. X.; Ji, Ming; Lewis, DeAsia; Li, Xiaoling] NIEHS, Signal Transduct Lab, POB 12233, Res Triangle Pk, NC 27709 USA.
[Tokar, Erik J.] Natl Toxicol Program, Stem Cell Toxicol Grp, Res Triangle Pk, NC 27709 USA.
[Busch, Evan L.] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC 27599 USA.
[Xu, Xiaojiang; Fargo, David C.] NIEHS, Integrat Bioinformat Branch, POB 12233, Res Triangle Pk, NC 27709 USA.
[Huang, Weichun; Li, Leping] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA.
[Li, Xiangchun; Wu, William K. K.] Chinese Univ Hong Kong, Inst Digest Dis, Dept Anaesthesia & Intens Care, Hong Kong, Hong Kong, Peoples R China.
[Li, Xiangchun; Wu, William K. K.] Chinese Univ Hong Kong, State Key Lab Digest Dis, Hong Kong, Hong Kong, Peoples R China.
[Jin, Aiwen; Zhang, Yanping] Univ North Carolina Chapel Hill, Dept Radiat Oncol, Chapel Hill, NC 27599 USA.
[Jin, Aiwen; Zhang, Yanping] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.
[Keku, Temitope O.; Sandler, Robert S.] Univ North Carolina Chapel Hill, Dept Med, Chapel Hill, NC 27599 USA.
[Busch, Evan L.] Harvard Med Sch, Channing Div Network Med, Dept Med, Boston, MA 02115 USA.
[Busch, Evan L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
[Busch, Evan L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
RP Li, XL (reprint author), NIEHS, Signal Transduct Lab, POB 12233, Res Triangle Pk, NC 27709 USA.
EM lix3@niehs.nih.gov
FU Intramural Research Program of National Institute of Environmental
Health Sciences [Z01 ES102205]; NIH [P30DK034987, U01CA93326]; National
Cancer Institute [5T32CA009001, 3P30CA016086]
FX We thank Drs. Anton Jetten and Dmitry Gordenin and members of the
Xiaoling Li laboratory for critical reading of the manuscript. We also
thank Dr. Yi Fang and Ms. Qing Xu for technical support, Dr. E. Terence
Adams from Integrated Laboratory Systems for histopathologic evaluation
of colon tumors developed in mice, and Stephanie Cohen (image analysis)
and Yongjuan Xia and Gabriela De la Cruz (staining) in the UNC
Translational Pathology Laboratory (TPL) for expert technical
assistance. This research was supported by the Intramural Research
Program of National Institute of Environmental Health Sciences to
Xiaoling Li (Z01 ES102205) and was also supported, in part, by
extramural grants from the NIH (P30DK034987 and U01CA93326). E.L.B. was
supported in part by a grant from the National Cancer Institute
(5T32CA009001). The UNC TPL is supported in part by grants from the
National Cancer Institute (3P30CA016086).
NR 45
TC 0
Z9 0
U1 0
U2 0
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 FEB 20
PY 2017
VL 27
IS 4
BP 483
EP 494
DI 10.1016/j.cub.2016.12.047
PG 12
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA EL6IF
UT WOS:000394724600018
PM 28162896
ER
PT J
AU Ferreira, MP
Coghill, AE
Chaves, CB
Bergmann, A
Thuler, LC
Soares, EA
Pfeiffer, RM
Engels, EA
Soares, MA
AF Ferreira, Mariana P.
Coghill, Anna E.
Chaves, Claudia B.
Bergmann, Anke
Thuler, Luiz C.
Soares, Esmeralda A.
Pfeiffer, Ruth M.
Engels, Eric A.
Soares, Marcelo A.
TI Outcomes of cervical cancer among HIV-infected and HIV-uninfected women
treated at the Brazilian National Institute of Cancer
SO AIDS
LA English
DT Article
DE AIDS; cervical cancer; HIV infection; relapse; survival; treatment
response
ID HUMAN-IMMUNODEFICIENCY-VIRUS; UNITED-STATES; TRANSPLANT RECIPIENTS;
MORTALITY; RISK; AIDS; PEOPLE
AB Objective: We assessed mortality, treatment response, and relapse among HIV-infected and HIV-uninfected women with cervical cancer in Rio de Janeiro, Brazil. Design: Cohort study of 87 HIV-infected and 336 HIV-uninfected women with cervical cancer.
Methods: Patients at the Brazilian National Institute of Cancer (2001-2013) were matched on age, calendar year of diagnosis, clinical stage, and tumor histology. Staging and treatment with surgery, radiotherapy, and/or chemotherapy followed international guidelines. We used a Markov model to assess responses to initial therapy, and Cox models for mortality and relapse after complete response (CR).
Results: Among 234 deaths, most were from cancer (82% in HIV-infected vs. 93% in HIV-uninfected women); only 9% of HIV-infected women died from AIDS. HIV was not associated withmortality during initial follow-up but was associated more than 1-2 years after diagnosis [ overall mortality: stage-adjusted hazard ratio 2.02, 95% confidence interval (CI) 1.27-3.22; cancer-specific mortality: 4.35, 1.86-10.2]. Among 222 patients treated with radiotherapy, HIV-infected had similar response rates to initial cancer therapy as HIV-uninfected women (hazard ratio 0.98, 95% CI 0.58-1.66). However, among women who were treated and had a CR, HIV was associated with elevated risk of subsequent relapse (hazard ratio 3.60, 95% CI 1.86-6.98, adjusted for clinical stage).
Conclusion: Among women with cervical cancer, HIV infection was not associated with initial treatment response or early mortality, but relapse after attaining a CR and late mortality were increased in those with HIV. These results point to a role for an intact immune system in control of residual tumor burden among treated cervical cancer patients. (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
C1 [Ferreira, Mariana P.; Soares, Esmeralda A.; Soares, Marcelo A.] Inst Nacl Canc, Programa Oncovirol, Rua Andre Cavalcanti 37-40, BR-20231050 Rio De Janeiro, RJ, Brazil.
[Coghill, Anna E.; Pfeiffer, Ruth M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
[Chaves, Claudia B.] Inst Nacl Canc, Secao Ginecol Oncol, Rio De Janeiro, RJ, Brazil.
[Chaves, Claudia B.; Bergmann, Anke] Inst Nacl Canc, Programa Carcinogenese Mol, Rio De Janeiro, RJ, Brazil.
[Bergmann, Anke; Thuler, Luiz C.] Inst Nacl Canc, Programa Pesquisa Clin, Rio De Janeiro, RJ, Brazil.
RP Soares, MA (reprint author), Inst Nacl Canc, Programa Oncovirol, Rua Andre Cavalcanti 37-40, BR-20231050 Rio De Janeiro, RJ, Brazil.
EM masoares@inca.gov.br
FU US-Brazil Collaborative Research Program of the US National Institutes
of Health; Brazilian Ministry of Health [467874/2014-0]; Brazilian
Ministry of Science and Technology [467874/2014-0]; Intramural Research
Program of the US National Cancer Institute
FX The study was supported by a grant under the US-Brazil Collaborative
Research Program of the US National Institutes of Health and the
Brazilian Ministries of Health and of Science and Technology (no.
467874/2014-0). MPF was supported through an MSc fellowship by the
Brazilian Ministry of Health. C.B.C., A.B., L.C.T., E.A.S., and M.A.S.
were supported by intramural resources of the Brazilian Ministry of
Health. A.E.C., R.M.P., and E.A.E. were supported by the Intramural
Research Program of the US National Cancer Institute.
NR 23
TC 0
Z9 0
U1 1
U2 1
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0269-9370
EI 1473-5571
J9 AIDS
JI Aids
PD FEB 20
PY 2017
VL 31
IS 4
BP 523
EP 531
DI 10.1097/QAD.0000000000001367
PG 9
WC Immunology; Infectious Diseases; Virology
SC Immunology; Infectious Diseases; Virology
GA EK2JW
UT WOS:000393754600011
PM 28060014
ER
PT J
AU Moukambi, F
Rodrigues, V
Fortier, Y
Rabezanahary, H
Borde, C
Krust, B
Andreani, G
Silvestre, R
Petrovas, C
Laforge, M
Estaquier, J
AF Moukambi, Felicien
Rodrigues, Vasco
Fortier, Yasmina
Rabezanahary, Henintsoa
Borde, Chloe
Krust, Bernard
Andreani, Guadalupe
Silvestre, Ricardo
Petrovas, Constantinos
Laforge, Mireille
Estaquier, Jerome
TI CD4 T Follicular Helper Cells and HIV Infection: Friends or Enemies?
SO FRONTIERS IN IMMUNOLOGY
LA English
DT Review
DE AIDS; Tfh; CD4; B cell; vaccine; pathogen; SIV; reservoir
ID SIMIAN IMMUNODEFICIENCY VIRUS; CHRONIC VIRAL-INFECTION; CENTER B-CELL;
AFRICAN-GREEN MONKEYS; TRANSCRIPTION FACTOR; SIV INFECTION; LYMPH-NODES;
TFH CELLS; LENTIVIRAL INFECTIONS; DISEASE PROGRESSION
AB Follicular T helper (Tfh) cells, a subset of CD4 T lymphocytes, are essential for memory B cell activation, survival, and differentiation and assist B cells in the production of antigen-specific antibodies. Work performed in recent years pointed out the importance of Tfh cells in the context of HIV and SIV infections. The importance of tissue distribution of Tfh is also an important point since their frequency differs between peripheral blood and lymph nodes compared to the spleen, the primary organ for B cell activation, and differentiation. Our recent observations indicated an early and profound loss of splenic Tfh cells. The role of transcriptional activator and repressor factors that control Tfh differentiation is also discussed in the context of HIV/SIV infection. Because Tfh cells are important for B cell differentiation and antibody production, accelerating the Tfh responses early during HIV/SIV infection could be promising as novel immunotherapeutic approach or alternative vaccine strategies. However, because Tfh cells are infected during the HIV/SIV infection and represent a reservoir, this may interfere with HIV vaccine strategy. Thus, Tfh represent the good and bad guys during HIV infection.
C1 [Moukambi, Felicien; Rabezanahary, Henintsoa; Andreani, Guadalupe; Estaquier, Jerome] Univ Laval, Fac Med, Res Ctr, Ctr Hosp Univ CHU Quebec, Quebec City, PQ, Canada.
[Rodrigues, Vasco; Fortier, Yasmina; Borde, Chloe; Krust, Bernard; Laforge, Mireille; Estaquier, Jerome] Paris Descartes Univ, Fac Med St Peres, CNRS, FR3636, Paris, France.
[Silvestre, Ricardo] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal.
[Silvestre, Ricardo] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal.
[Petrovas, Constantinos] NIAID, Tissue Anal Core, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
RP Estaquier, J (reprint author), Univ Laval, Fac Med, Res Ctr, Ctr Hosp Univ CHU Quebec, Quebec City, PQ, Canada.; Estaquier, J (reprint author), Paris Descartes Univ, Fac Med St Peres, CNRS, FR3636, Paris, France.
EM estaquier@yahoo.fr
FU Agence Nationale de Recherches sur le Sida et les Hepatites Virales
(ANRS); Canadian HIV Cure Enterprise Team Grant from the Canadian
Institutes of Health Research (CIHR) [HIG-13305]; CANFAR; IAS; Fondation
du CHU de Quebec; ANRS; Canada Research Chair; FCT-Fundacao para a
Ciencia e a Tecnologia/MEC-Ministerio da Educacao e Ciencia atraves de
fundos nacionais; Fundacao para a Ciencia e a Tecnologia (FCT)
[IF/00021/2014]; FEDER [4293]
FX This work was supported by grants to JE from the Agence Nationale de
Recherches sur le Sida et les Hepatites Virales (ANRS) and from The
Canadian HIV Cure Enterprise Team Grant HIG-13305 from the Canadian
Institutes of Health Research (CIHR) in partnership with CANFAR and IAS.
FM is supported by a fellowship from Fondation du CHU de Quebec. CB and
YF are supported by fellowships from ANRS. JE acknowledges the support
of the Canada Research Chair program. RS is supported by FCT-Fundacao
para a Ciencia e a Tecnologia/MEC-Ministerio da Educacao e Ciencia
atraves de fundos nacionais e quando aplicavel cofinanciado pelo FEDER,
no ambito do Acordo de Parceria PT2020 referente a unidade de
investigacao no 4293. RS is supported by the Fundacao para a Ciencia e a
Tecnologia (FCT) (IF/00021/2014).
NR 108
TC 0
Z9 0
U1 3
U2 3
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 1664-3224
J9 FRONT IMMUNOL
JI Front. Immunol.
PD FEB 20
PY 2017
VL 8
AR 135
DI 10.3389/fimmu.2017.00135
PG 8
WC Immunology
SC Immunology
GA EL0HN
UT WOS:000394303600001
PM 28265271
ER
PT J
AU Nair, SG
Patel, DP
Sanyal, M
Singhal, P
Shrivastav, PS
AF Nair, Sneha G.
Patel, Daxesh P.
Sanyal, Mallika
Singhal, Puran
Shrivastav, Pranav S.
TI Simultaneous analysis of glucocorticosteroid fluticasone propionate and
its metabolite fluticasone propionate 17 beta-carboxylic acid in human
plasma by UPLC-MS/MS at sub pg/mL level
SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
LA English
DT Article
DE Fluticasone propionate; Fluticasone propionate 17/beta-carboxylic acid;
UPLC-MS/MS; Sub pg/mL; Human plasma; Nasal spray
ID TANDEM MASS-SPECTROMETRY; NASAL SPRAY FORMULATIONS; LC-MS/MS; SAMPLES
AB A highly sensitive and rapid ultra performance liquid chromatography-tandem mass spectrometry method has been developed for the simultaneous determination of fluticasone propionate (FP) and its major metabolite, fluticasone propionate-17beta-carboxylic acid (FP 17 beta-CA) in human plasma. The analytes and their deuterated internal standards, FP-d3 and FP 17 beta-CA-d3 were extracted from 500 mu L plasma samples by solid phase extraction on Oasis MAX cartridges. The chromatographic analysis was performed on ACQUITY UPLC BEH C18 (50mm x 2.1 mm, 1.7 mu m) column using methanol-acetonitrile (50:50, v/v) and 2.0 mM ammonium trifluroacetate (ATFA) (85:15, v/v) as the mobile phase. Following separation of the analytes, protonated precursor production transitions (FP: m/z 501.1 -> 293.2, FP17 beta-CA: m/z 453.3 -> 293.2, FP-d3: m/z 504.2 -> 293.2, FP 17 beta-CA-d3: m/z 456.3 -> 293.2) were monitored on FP 17 beta-CA a triple quadrupole mass spectrometer, operating in multiple reaction monitoring (MRM) and positive ionization mode. The calibration curves were established in the range of 0.5-100pg/mL with a correlation coefficient (r(2))>= 0.9992 for both the analytes. The intra-batch and inter-batch accuracy and precision varied from 95.5-103.4% and 0.74-5.06% across quality controls for both the analytes. The mean assay recoveries for FP and FP 17 beta-CA were 84.2% and 93.5% respectively. The validated method was successfully applied to support a bioequivalence study of 200 mu g FP, administered using nasal spray formulation in 18 healthy Indian subjects. Reproducibility of the method was assessed by reanalysis of 98 incurred study samples. (C) 2016 Elsevier B.V. All rights reserved.
C1 [Nair, Sneha G.; Shrivastav, Pranav S.] Gujarat Univ, Sch Sci, Dept Chem, Ahmadabad 380009, Gujarat, India.
[Patel, Daxesh P.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA.
[Sanyal, Mallika] St Xaviers Coll, Dept Chem, Ahmadabad 380009, Gujarat, India.
[Singhal, Puran] Alkem Labs Ltd, Bioanalyt Dept, Mumbai 400013, Maharashtra, India.
RP Shrivastav, PS (reprint author), Gujarat Univ, Sch Sci, Dept Chem, Ahmadabad 380009, Gujarat, India.
EM pranav_shrivastav@yahoo.com
NR 21
TC 0
Z9 0
U1 8
U2 8
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0731-7085
EI 1873-264X
J9 J PHARMACEUT BIOMED
JI J. Pharm. Biomed. Anal.
PD FEB 20
PY 2017
VL 135
BP 1
EP 7
DI 10.1016/j.jpba.2016.12.008
PG 7
WC Chemistry, Analytical; Pharmacology & Pharmacy
SC Chemistry; Pharmacology & Pharmacy
GA EJ0NB
UT WOS:000392905200001
PM 27987390
ER
PT J
AU Groen, IIA
Silson, EH
Baker, CI
AF Groen, Iris I. A.
Silson, Edward H.
Baker, Chris I.
TI Contributions of low- and high-level properties to neural processing of
visual scenes in the human brain
SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
LA English
DT Article
DE natural scenes; functional magnetic resonance imaging;
electro-encephalography; category-selectivity; retinotopy; image
statistics
ID PARAHIPPOCAMPAL PLACE AREA; HUMAN OCCIPITOTEMPORAL CORTEX; SELECTIVE
CORTICAL REGIONS; LATERAL OCCIPITAL CORTEX; REAL-WORLD SCENES; OBJECT
RECOGNITION; TIME-COURSE; IMAGE STATISTICS; DECISION-MAKING; NATURAL
SCENES
AB Visual scene analysis in humans has been characterized by the presence of regions in extrastriate cortex that are selectively responsive to scenes compared with objects or faces. While these regions have often been interpreted as representing high-level properties of scenes (e.g. category), they also exhibit substantial sensitivity to low-level (e.g. spatial frequency) and mid-level (e.g. spatial layout) properties, and it is unclear how these disparate findings can be united in a single framework. In this opinion piece, we suggest that this problem can be resolved by questioning the utility of the classical low- to high-level framework of visual perception for scene processing, and discuss why low-and mid-level properties may be particularly diagnostic for the behavioural goals specific to scene perception as compared to object recognition. In particular, we highlight the contributions of low-level vision to scene representation by reviewing (i) retinotopic biases and receptive field properties of scene-selective regions and (ii) the temporal dynamics of scene perception that demonstrate overlap of low-and mid-level feature representations with those of scene category. We discuss the relevance of these findings for scene perception and suggest a more expansive framework for visual scene analysis.
This article is part of the themed issue 'Auditory and visual scene analysis'.
C1 [Groen, Iris I. A.; Silson, Edward H.; Baker, Chris I.] NIH, Lab Brain & Cognit, 10 Ctr Dr 10-3N228, Bethesda, MD 20892 USA.
RP Groen, IIA (reprint author), NIH, Lab Brain & Cognit, 10 Ctr Dr 10-3N228, Bethesda, MD 20892 USA.
EM iris.groen@nih.gov
OI Groen, Iris/0000-0002-5536-6128; Baker, Chris/0000-0001-6861-8964
FU National Institutes of Health [ZIA-MH-002909]; Rubicon Fellowship from
Netherlands Organization for Scientific Research (NWO)
FX I.I.A.G., E.H.S. and C.I.B. are supported by the Intramural Program of
the National Institutes of Health (ZIA-MH-002909). I.I.A.G. is also
supported by a Rubicon Fellowship from the Netherlands Organization for
Scientific Research (NWO).
NR 122
TC 1
Z9 1
U1 13
U2 13
PU ROYAL SOC
PI LONDON
PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND
SN 0962-8436
EI 1471-2970
J9 PHILOS T R SOC B
JI Philos. Trans. R. Soc. B-Biol. Sci.
PD FEB 19
PY 2017
VL 372
IS 1714
AR 20160102
DI 10.1098/rstb.2016.0102
PG 11
WC Biology
SC Life Sciences & Biomedicine - Other Topics
GA EI1AD
UT WOS:000392206300003
ER
PT J
AU Gostic, KM
Ambrose, M
Worobey, M
Lloyd-Smith, JO
AF Gostic, Katelyn M.
Ambrose, Monique
Worobey, Michael
Lloyd-Smith, James O.
TI Maternal antibodies' role in immunity Response
SO SCIENCE
LA English
DT Letter
ID ORIGINAL ANTIGENIC SIN; INFLUENZA-VIRUSES
C1 [Gostic, Katelyn M.; Ambrose, Monique; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA.
[Worobey, Michael] Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA.
[Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA.
RP Worobey, M; Lloyd-Smith, JO (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA.; Worobey, M (reprint author), Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA.; Lloyd-Smith, JO (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA.
EM worobey@email.arizona.edu; jlloydsmith@ucla.edu
NR 8
TC 0
Z9 0
U1 3
U2 3
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 FEB 17
PY 2017
VL 355
IS 6326
BP 705
EP 705
DI 10.1126/science.aam7389
PG 1
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EM2AC
UT WOS:000395117700031
PM 28209868
ER
PT J
AU Dotsey, E
Ushach, I
Pone, E
Nakajima, R
Jasinskas, A
Argueta, DA
Dillon, A
DiPatrizio, N
Davies, H
Zlotnik, A
Crompton, PD
Felgner, PL
AF Dotsey, Emmanuel
Ushach, Irina
Pone, Egest
Nakajima, Rie
Jasinskas, Algis
Argueta, Donovan A.
Dillon, Andrea
DiPatrizio, Nicholas
Davies, Huw
Zlotnik, Albert
Crompton, Peter D.
Felgner, Philip L.
TI Transient Cannabinoid Receptor 2 Blockade during Immunization Heightens
Intensity and Breadth of Antigen-specific Antibody Responses in Young
and Aged mice
SO SCIENTIFIC REPORTS
LA English
DT Article
ID ENDOCANNABINOID SYSTEM; T-CELLS; B-CELLS; PROTEOME MICROARRAYS;
IMMUNE-RESPONSES; LYMPHOID ORGANS; DENDRITIC CELLS; MARGINAL ZONE; CB2
RECEPTOR; DIFFERENTIATION
AB The hallmark of vaccines is their ability to prevent the spread of infectious pathogens and thereby serve as invaluable public health tool. Despite their medical relevance, there is a gap in our understanding of the physiological factors that mediate innate and adaptive immune response to vaccines. The endocannabinoid (eCB) system is a critical modulator of homeostasis in vertebrates. Our results indicate that macrophages and dendritic cells produce the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG) upon antigen activation. We have also established that 2-AG levels are upregulated in the serum and in the lymph node of mice during vaccination. We hypothesized that the intrinsic release of eCBs from immune cells during activation by pathogenic antigens mitigate inflammation, but also suppress overall innate and adaptive immune response. Here we demonstrate, for the first time, that transient administration of the cannabinoid receptor 2 antagonist AM630 (10 mg/kg) or inverse agonist JTE907 (3 mg/kg) during immunization heightens the intensity and breadth of antigen-specific immune responses in young and aged mice through the upregulation of immunomodulatory genes in secondary lymphoid tissues.
C1 [Dotsey, Emmanuel; Ushach, Irina; Nakajima, Rie; Jasinskas, Algis; Davies, Huw; Felgner, Philip L.] Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA.
[Pone, Egest] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA USA.
[Argueta, Donovan A.; Dillon, Andrea; DiPatrizio, Nicholas] Univ Calif Riverside, Div Biomed Sci, Sch Med, Riverside, CA 92521 USA.
[Zlotnik, Albert] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92717 USA.
[Crompton, Peter D.] NIAID, Malaria Infect Biol & Immun Unit, Immunogenet Lab, NIH, Rockville, MD USA.
RP Dotsey, E (reprint author), Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA.
EM edotsey@uci.edu
OI Argueta, Donovan/0000-0002-8234-141X
FU NIH [R01 AI095916-01A1, R01 AI095916-02S1]; Division of Intramural
Research, National Institute of Allergy and Infectious Diseases, NIH
FX This study was supported by NIH grants R01 AI095916-01A1 and R01
AI095916-02S1. PDC is supported by the Division of Intramural Research,
National Institute of Allergy and Infectious Diseases, NIH.
NR 74
TC 0
Z9 0
U1 2
U2 2
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 17
PY 2017
VL 7
AR 42584
DI 10.1038/srep42584
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL0MU
UT WOS:000394317300001
PM 28209996
ER
PT J
AU Ishikawa, K
Medina, SH
Schneider, JP
Klar, AJS
AF Ishikawa, Ken
Medina, Scott H.
Schneider, Joel P.
Klar, Amar J. S.
TI Glycan Alteration Imparts Cellular Resistance to a Membrane-Lytic
Anticancer Peptide
SO CELL CHEMICAL BIOLOGY
LA English
DT Article
ID SCHIZOSACCHAROMYCES-POMBE; FISSION-YEAST; REVERSE-TRANSCRIPTASE;
FILAMENTOUS GROWTH; DRUG-RESISTANCE; PROTEIN-KINASE; CANCER; GALACTOSE;
IDENTIFICATION; FLOCCULATION
AB Although resistance toward small-molecule chemotherapeutics has been well studied, the potential of tumor cells to avoid destruction by membrane-lytic compounds remains unexplored. Anticancer peptides (ACPs) are a class of such agents that disrupt tumor cell membranes through rapid and non-stereospecific mechanisms, encouraging the perception that cellular resistance toward ACPs is unlikely to occur. We demonstrate that eukaryotic cells can, indeed, develop resistance to the model oncolytic peptide SVS-1, which preferentially disrupts the membranes of cancer cells. Utilizing fission yeast as a model organism, we show that ACP resistance is largely controlled through the loss of cell-surface anionic saccharides. A similar mechanism was discovered in mammalian cancer cells where removal of negatively charged sialic acid residues directly transformed SVS-1-sensitive cell lines into resistant phenotypes. These results demonstrate that changes in cell-surface glycosylation play a major role in tumor cell resistance toward oncolytic peptides.
C1 [Ishikawa, Ken; Klar, Amar J. S.] NCI, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA.
[Ishikawa, Ken; Medina, Scott H.; Schneider, Joel P.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA.
RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA.; Schneider, JP (reprint author), NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA.
EM joel.schneider@nih.gov; klara@mail.nih.gov
FU Intramural Research Program of the National Cancer Institute, NIH
FX This work was supported by the Intramural Research Program of the
National Cancer Institute, NIH. We thank Mike Bonaduce, Shuo Gu, Lisheng
Dai, Kimberley Peifley, and Stephen Lockett for technical assistance
and/ or for the use of their facilities, as well as Henry Levin for
providing reagents for the yeast transposon mutagenesis procedure. Bulk
quantities of the sialyltransferase inhibitor 3Fax- Peracetyl Neu5Ac was
synthesized and provided by Gary Pauly. We thank Sherimay Ablan and Eric
Freed for providing Jurkat cell line. We thank our colleagues Yuji
Yamada, Stephen Hughes, and Jeffrey Strathern for valuable discussions.
NR 30
TC 1
Z9 1
U1 0
U2 0
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 2451-9448
J9 CELL CHEM BIOL
JI Cell Chem. Biol.
PD FEB 16
PY 2017
VL 24
IS 2
BP 149
EP 158
DI 10.1016/j.chembiol.2016.12.009
PG 10
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EP5NB
UT WOS:000397424400009
PM 28089756
ER
PT J
AU Kulkarni, RA
Worth, AJ
Zengeya, TT
Shrimp, JH
Garlick, JM
Roberts, AM
Montgomery, DC
Sourbier, C
Gibbs, BK
Mesaros, C
Tsai, YC
Das, S
Chan, KC
Zhou, M
Andresson, T
Weissman, AM
Linehan, WM
Blair, IA
Snyder, NW
Meier, JL
AF Kulkarni, Rhushikesh A.
Worth, Andrew J.
Zengeya, Thomas T.
Shrimp, Jonathan H.
Garlick, Julie M.
Roberts, Allison M.
Montgomery, David C.
Sourbier, Carole
Gibbs, Benjamin K.
Mesaros, Clementina
Tsai, Yien Che
Das, Sudipto
Chan, King C.
Zhou, Ming
Andresson, Thorkell
Weissman, Allan M.
Linehan, W. Marston
Blair, Ian A.
Snyder, Nathaniel W.
Meier, Jordan L.
TI Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity
Profiling
SO CELL CHEMICAL BIOLOGY
LA English
DT Article
ID ACID SYNTHASE INHIBITION; COENZYME-A; HISTONE ACETYLATION; CANCER-CELLS;
PROTEIN ACETYLATION; LYSINE ACETYLTRANSFERASES; CRYSTAL-STRUCTURE;
CITRATE LYASE; METABOLISM; COA
AB Non-enzymatic protein modification driven by thioester reactivity is thought to play a major role in the establishment of cellular lysine acylation. However, the specific protein targets of this process are largely unknown. Here we report an experimental strategy to investigate non-enzymatic acylation in cells. Specifically, we develop a chemoproteomic method that separates thioester reactivity from enzymatic utilization, allowing selective enrichment of non-enzymatic acylation targets. Applying this method to cancer cell lines identifies numerous candidate targets of nonenzymatic acylation, including several enzymes in lower glycolysis. Functional studies highlight malonyl-CoA as a reactive thioester metabolite that can modify and inhibit glycolytic enzyme activity. Finally, we show that synthetic thioesters can be used as novel reagents to probe non-enzymatic acylation in living cells. Our studies provide new insights into the targets and drivers of non-enzymatic acylation, and demonstrate the utility of reactivity-based methods to experimentally investigate this phenomenon in biology and disease.
C1 [Kulkarni, Rhushikesh A.; Zengeya, Thomas T.; Shrimp, Jonathan H.; Garlick, Julie M.; Roberts, Allison M.; Montgomery, David C.; Meier, Jordan L.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA.
[Worth, Andrew J.; Mesaros, Clementina; Blair, Ian A.] Univ Penn, Penn SRP Ctr, Ctr Excellence Environm Toxicol, Philadelphia, PA 19104 USA.
[Sourbier, Carole; Gibbs, Benjamin K.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20817 USA.
[Tsai, Yien Che; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA.
[Das, Sudipto; Chan, King C.; Zhou, Ming; Andresson, Thorkell] Leidos Biomed Res Inc, Prot Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.
[Snyder, Nathaniel W.] Drexel Univ, AJ Drexel Autism Inst, 3020 Market St, Philadelphia, PA 19104 USA.
RP Meier, JL (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA.
EM jordan.meier@nih.gov
OI Tsai, Yien Che/0000-0001-9624-1092
FU Pennsylvania Department of Health CURE; NIH [K22ES26235, P30ES013508,
ZIA BC011488-02]; Intramural Research Program of the NIH, National
Cancer Institute, Center for Cancer Research [ZIA BC011488-02]
FX The authors thank Dr. Carissa Grose (Protein Expression Laboratory) for
assisting with cloning and preparation of plasmid DNA, Dr. David Evans
and Lori Bowles (Developmental Therapeutics Program) for NCI-60 cell
lines, and Dr. Daniel McVicar (Cancer Inflammation Program) and Dr.
Martin Schnermann (Chemical Biology Laboratory) for helpful discussions.
This work was supported by a Pennsylvania Department of Health CURE
grant, the NIH (K22ES26235 and P30ES013508), and the Intramural Research
Program of the NIH, National Cancer Institute, Center for Cancer
Research (ZIA BC011488-02).
NR 59
TC 1
Z9 1
U1 0
U2 0
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 2451-9448
J9 CELL CHEM BIOL
JI Cell Chem. Biol.
PD FEB 16
PY 2017
VL 24
IS 2
BP 231
EP 242
DI 10.1016/j.chembiol.2017.01.002
PG 12
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EP5NB
UT WOS:000397424400016
PM 28163016
ER
PT J
AU Battistelli, C
Cicchini, C
Santangelo, L
Tramontano, A
Grassi, L
Gonzalez, FJ
de Nonno, V
Grassi, G
Amicone, L
Tripodi, M
AF Battistelli, C.
Cicchini, C.
Santangelo, L.
Tramontano, A.
Grassi, L.
Gonzalez, F. J.
de Nonno, V.
Grassi, G.
Amicone, L.
Tripodi, M.
TI The Snail repressor recruits EZH2 to specific genomic sites through the
enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition
SO ONCOGENE
LA English
DT Article
ID LONG NONCODING RNA; NUCLEAR FACTOR 4-ALPHA; E-CADHERIN EXPRESSION;
TRANSCRIPTION FACTORS; COMPLEX 2; CHROMATIN MODIFICATION; CARCINOMA
PROGRESSION; MOLECULAR-MECHANISMS; EMT/MET DYNAMICS; GENE-EXPRESSION
AB The transcription factor Snail is a master regulator of cellular identity and epithelial-to-mesenchymal transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail-specific binding sites is unclear. Here we report that the long non-coding RNA (lncRNA) HOTAIR (for HOX Transcript Antisense Intergenic RNA) mediates a physical interaction between Snail and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2 and the main writer of chromatin-repressive marks. The Snail-repressive activity, here monitored on genes with a pivotal function in epithelial and hepatic morphogenesis, differentiation and cell-type identity, depends on the formation of a tripartite Snail/HOTAIR/EZH2 complex. These results demonstrate an lncRNA-mediated mechanism by which a transcriptional factor conveys a general chromatin modifier to specific genes, thereby allowing the execution of hepatocyte transdifferentiation; moreover, they highlight HOTAIR as a crucial player in the Snail-mediated EMT.
C1 [Battistelli, C.; Cicchini, C.; Santangelo, L.; de Nonno, V.; Amicone, L.; Tripodi, M.] Sapienza Univ Rome, Ist Pasteur Italia Fdn Cenci Bolognetti, Dept Cellular Biotechnol & Haematol, Sez Genet Mol, Rome, Italy.
[Tramontano, A.] Sapienza Univ Rome, Ist Pasteur Italia Fdn Cenci Bolognetti, Dept Phys, Rome, Italy.
[Grassi, L.] Sapienza Univ Rome, Dept Phys, Rome, Italy.
[Gonzalez, F. J.] NCI, Ctr Canc Res, Lab Metab, NIH, Bethesda, MD 20892 USA.
[Grassi, G.; Tripodi, M.] IRCCS, Natl Inst Infect Dis L Spallanzani, Rome, Italy.
RP Cicchini, C; Tripodi, M (reprint author), Sapienza Univ Rome, Fdn Cenci Bolognetti, Ist Pasteur Italia, Dipartimento Biotecnol Cellulari & Ematol,Sez Gen, Viale Regina Elena 324, I-00161 Rome, Italy.
EM cicchini@bce.uniroma1.it; tripodi@bce.uniroma1.it
FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG 14114];
Ministero della Salute; Ministero Universita e Ricerca Scientifica [PRIN
20108XYHJS]; Epigenomics Flagship Project-EPIGEN
FX We thank I Bozzoni and SA Ciafre for suggestions and critical revision
of the manuscript. This was supported by Associazione Italiana per la
Ricerca sul Cancro (AIRC) IG 14114; Ministero della Salute; Ministero
Universita e Ricerca Scientifica PRIN 20108XYHJS; Epigenomics Flagship
Project-EPIGEN.
NR 57
TC 1
Z9 1
U1 0
U2 0
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD FEB 16
PY 2017
VL 36
IS 7
BP 942
EP 955
DI 10.1038/onc.2016.260
PG 14
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
Heredity
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
Heredity
GA EK8JG
UT WOS:000394169100007
PM 27452518
ER
PT J
AU Uldrick, TS
AF Uldrick, Thomas S.
TI iNKT cell defects in HHV-8-associated MCD
SO BLOOD
LA English
DT Editorial Material
ID MULTICENTRIC CASTLEMAN-DISEASE; KAPOSI-SARCOMA; T-CELLS; INFECTION; AIDS
AB In this issue of Blood, Sbihi et al provide the first evidence of invariant natural killer T (iNKT) cell abnormalities in patients with human herpesvirus 8 (HHV-8) -associated multicentric Castleman disease (MCD).
C1 [Uldrick, Thomas S.] NCI, Bethesda, MD USA.
RP Uldrick, TS (reprint author), NCI, Bethesda, MD USA.
NR 9
TC 0
Z9 0
U1 0
U2 0
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 FEB 16
PY 2017
VL 129
IS 7
BP 806
EP 807
DI 10.1182/blood-2016-11-751875
PG 4
WC Hematology
SC Hematology
GA EO9OW
UT WOS:000397019000003
PM 28209751
ER
PT J
AU Arfelt, KN
Barington, L
Benned-Jensen, T
Kubale, V
Kovalchuk, AL
Daugvilaite, V
Christensen, JP
Thomsen, AR
Egerod, KL
Bassi, MR
Spiess, K
Schwartz, TW
Wang, HS
Morse, HC
Holst, PJ
Rosenkilde, MM
AF Arfelt, Kristine Niss
Barington, Line
Benned-Jensen, Tau
Kubale, Valentina
Kovalchuk, Alexander L.
Daugvilaite, Viktorija
Christensen, Jan Pravsgaard
Thomsen, Allan Randrup
Egerod, Kristoffer L.
Bassi, Maria R.
Spiess, Katja
Schwartz, Thue W.
Wang, Hongsheng
Morse, Herbert C., III
Holst, Peter J.
Rosenkilde, Mette M.
TI EBI2 overexpression in mice leads to B1 B-cell expansion and chronic
lymphocytic leukemia-like B-cell malignancies
SO BLOOD
LA English
DT Article
ID 7-TRANSMEMBRANE RECEPTOR; CONSTITUTIVE ACTIVITY; LIGAND MODULATION;
IL-10 PRODUCTION; MARGINAL ZONE; B-1 CELLS; EXPRESSION; IDENTIFICATION;
MIGRATION; MOUSE
AB Human and mouse chronic lymphocytic leukemia (CLL) develops from CD5(+) B cells that in mice and macaques are known to define the distinct B1a B-cell lineage. B1a cells are characterized by lack of germinal center (GC) development, and the B1a cell population is increased in mice with reduced GC formation. As a major mediator of follicular B-cell migration, the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2 or GPR183) directs B-cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells toward the extrafollicular area, whereas downregulation is essential for GC formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to CLL. Here, we demonstrate that B-cell-targeted expression of human EBI2 (hEBI2) in mice reduces GC-dependent immune responses, reduces total immunoglobulin M (igM) and igG levels, and leads to increased proliferation and upregulation of cellular oncogenes. Furthermore, hEBI2 overexpression leads to an abnormally expanded CD5(+) B1a B-cell subset (present as early as 4 days after birth), late-onset lymphoid cancer development, and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B-cell malignancies.
C1 [Arfelt, Kristine Niss; Barington, Line; Benned-Jensen, Tau; Kubale, Valentina; Daugvilaite, Viktorija; Egerod, Kristoffer L.; Spiess, Katja; Schwartz, Thue W.; Rosenkilde, Mette M.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Copenhagen, Denmark.
[Kovalchuk, Alexander L.; Wang, Hongsheng; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA.
[Christensen, Jan Pravsgaard; Thomsen, Allan Randrup; Bassi, Maria R.; Holst, Peter J.] Univ Copenhagen, Dept Immunol & Microbiol, Copenhagen, Denmark.
[Egerod, Kristoffer L.; Schwartz, Thue W.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.
RP Holst, PJ (reprint author), CSS, Ctr Med Parasitol, Bldg 22&23,Oster Farigmagsgade 5, DK-1014 Copenhagen, Denmark.; Rosenkilde, MM (reprint author), Univ Copenhagen, Dept Neurosci & Pharmacol, Blegdamsvej 3b,Bldg 18-5, DK-2200 Copenhagen, Denmark.
EM pholst@sund.ku.dk; rosenkilde@sund.ku.dk
OI Daugvilaite, Viktorija /0000-0001-8786-348X
FU NovoNordisk Foundation; Danish Council for Independent Research [Medical
Sciences]; Lundbeck Foundation; University of Copenhagen; Aase and Einar
Danielsen Foundation; A.P. Moller Foundation for Advancement of Medical
Science; National Institutes of Health; National Institute of Allergy
and Infectious Diseases; Slovenian Research Agency [P4-0053]
FX This work was supported in part by the NovoNordisk Foundation, the
Danish Council for Independent Research [Medical Sciences], the Lundbeck
Foundation, the University of Copenhagen, the Aase and Einar Danielsen
Foundation, the A.P. Moller Foundation for the Advancement of Medical
Science (K.N.A., L.B., T.B.-J., V.K., V.D., K.S., P.J.H., and M.M.R.),
and the Intramural Research Program of the National Institutes of
Health, National Institute of Allergy and Infectious Diseases (A.L.K.
and H.C.M.). V.K. was further supported by the Slovenian Research Agency
(P4-0053).
NR 48
TC 0
Z9 0
U1 0
U2 0
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 FEB 16
PY 2017
VL 129
IS 7
BP 866
EP 878
DI 10.1182/blood-2016-02-697185
PG 13
WC Hematology
SC Hematology
GA EO9OW
UT WOS:000397019000011
ER
PT J
AU Nelson, KB
Sartwelle, TP
Rouse, DJ
AF Nelson, Karin B.
Sartwelle, Thomas P.
Rouse, Dwight J.
TI Most cases of cerebral palsy are associated with antenatal events Reply
SO BMJ-BRITISH MEDICAL JOURNAL
LA English
DT Letter
C1 [Nelson, Karin B.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
[Sartwelle, Thomas P.] Deans & Lyons, Houston, TX USA.
[Rouse, Dwight J.] Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA.
[Rouse, Dwight J.] Brown Univ, Providence, RI 02912 USA.
RP Nelson, KB (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
EM nelsonk@ninds.nih.gov
NR 6
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 1756-1833
J9 BMJ-BRIT MED J
JI BMJ-British Medical Journal
PD FEB 16
PY 2017
VL 356
AR j835
DI 10.1136/bmj.j835
PG 1
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL4GN
UT WOS:000394579800008
PM 28209563
ER
PT J
AU Smargon, AA
Cox, DBT
Pyzocha, NK
Zheng, KJ
Slaymaker, IM
Gootenberg, JS
Abudayyeh, OA
Essletzbichler, P
Shmakov, S
Makarova, KS
Koonin, EV
Zhang, F
AF Smargon, Aaron A.
Cox, David B. T.
Pyzocha, Neena K.
Zheng, Kaijie
Slaymaker, Ian M.
Gootenberg, Jonathan S.
Abudayyeh, Omar A.
Essletzbichler, Patrick
Shmakov, Sergey
Makarova, Kira S.
Koonin, Eugene V.
Zhang, Feng
TI Cas13b Is a Type VI-B CRISPR-Associated RNA-Guided RNase Differentially
Regulated by Accessory Proteins Csx27 and Csx28
SO MOLECULAR CELL
LA English
DT Article
ID BINDING PROTEINS; THERMUS-THERMOPHILUS; PYROCOCCUS-FURIOSUS; COMPLEX;
SYSTEMS; PREDICTION; IDENTIFICATION; TRANSCRIPTOME; ALIGNMENT; IMMUNITY
AB CRISPR-Cas adaptive immune systems defend microbes against foreign nucleic acids via RNA-guided endonucleases. Using a computational sequence database mining approach, we identify two class 2 CRISPR-Cas systems (subtype VI-B) that lack Cas1 and Cas2 and encompass a single large effector protein, Cas13b, along with one of two previously uncharacterized associated proteins, Csx27 and Csx28. We establish that these CRISPR-Cas systems can achieve RNA interference when heterologously expressed. Through a combination of biochemical and genetic experiments, we show that Cas13b processes its own CRISPR array with short and long direct repeats, cleaves target RNA, and exhibits collateral RNase activity. Using an E. coli essential gene screen, we demonstrate that Cas13b has a double-sided protospacer-flanking sequence and elucidate RNA secondary structure requirements for targeting. We also find that Csx27 represses, whereas Csx28 enhances, Cas13b-mediated RNA interference. Characterization of these CRISPR systems creates opportunities to develop tools to manipulate and monitor cellular transcripts.
C1 [Smargon, Aaron A.; Cox, David B. T.; Pyzocha, Neena K.; Zheng, Kaijie; Slaymaker, Ian M.; Gootenberg, Jonathan S.; Abudayyeh, Omar A.; Essletzbichler, Patrick; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
[Smargon, Aaron A.; Cox, David B. T.; Pyzocha, Neena K.; Zheng, Kaijie; Slaymaker, Ian M.; Gootenberg, Jonathan S.; Abudayyeh, Omar A.; Essletzbichler, Patrick; Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
[Smargon, Aaron A.; Cox, David B. T.; Pyzocha, Neena K.; Zheng, Kaijie; Slaymaker, Ian M.; Gootenberg, Jonathan S.; Abudayyeh, Omar A.; Essletzbichler, Patrick; Zhang, Feng] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.
[Smargon, Aaron A.; Cox, David B. T.; Pyzocha, Neena K.; Zheng, Kaijie; Slaymaker, Ian M.; Gootenberg, Jonathan S.; Abudayyeh, Omar A.; Essletzbichler, Patrick; Zhang, Feng] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
[Smargon, Aaron A.; Zhang, Feng] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA.
[Cox, David B. T.; Abudayyeh, Omar A.] Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA.
[Cox, David B. T.; Pyzocha, Neena K.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
[Gootenberg, Jonathan S.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.
[Shmakov, Sergey] Skolkovo Inst Sci & Technol, Skolkovo 143025, Russia.
[Shmakov, Sergey; Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA.
RP Zhang, F (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Zhang, F (reprint author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Zhang, F (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.; Zhang, F (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Zhang, F (reprint author), MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA.
EM zhang@broadinstitute.org
OI Essletzbichler, Patrick/0000-0003-2237-0005
FU National Institute of General Medical Sciences [T32GM007753]; Simons
Center for the Social Brain; D.O.E. Computational Science Graduate
Fellowship; Paul and Daisy Soros Fellowship; Friends of the McGovern
Institute Fellowship; Poitras Center for Affective Disorders; U.S.
Department of Health and Human services; Skoltech-MIT Next Generation
Program grant; NIH through NIMH [5DP1-MH100706, 1R01-MH110049]; NSF; New
York Stem Cell Foundation; Allen Distinguished Investigator Program,
through The Paul G. Allen Frontiers Group; Simons Foundation; Vallee
Foundation; Howard Hughes Medical Institute; Skoltech-MIT Next
Generation Program; James and Patricia Poitras and the Poitras Center
for Affective Disorders; Robert Metcalfe
FX We would like to thank R. Belliveau for overall research support, R.
Macrae for critical reading of the manuscript, and the entire Zhang
laboratory for support and advice. D.B.T.C. is supported by award number
T32GM007753 from the National Institute of General Medical Sciences. The
content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institute of
General Medical Sciences or the NIH. I.M.S. is supported by the Simons
Center for the Social Brain. J.S.G. is supported by a D.O.E.
Computational Science Graduate Fellowship. O.A.A. is supported by a Paul
and Daisy Soros Fellowship, a Friends of the McGovern Institute
Fellowship, and the Poitras Center for Affective Disorders. K.S.M.,
E.V.K., and S.S. are supported by the intramural program of the U.S.
Department of Health and Human services (to the National Library of
Medicine). S.S. is also supported by a Skoltech-MIT Next Generation
Program grant (to K. Severinov and F.Z.). F.Z. is supported by the NIH
through NIMH (5DP1-MH100706 and 1R01-MH110049); NSF; the New York Stem
Cell Foundation; the Allen Distinguished Investigator Program, through
The Paul G. Allen Frontiers Group; the Simons and Vallee Foundations;
the Howard Hughes Medical Institute; the Skoltech-MIT Next Generation
Program; James and Patricia Poitras and the Poitras Center for Affective
Disorders; Robert Metcalfe; and David Cheng. F.Z. is a New York Stem
Cell Foundation-Robertson Investigator. A patent application has been
filed related to this work, and the authors plan to make the reagents
widely available to the academic community through Addgene and to
provide protocols and software tools via the Zhang lab website
(http://www.genome-engineering.org) and GitHub
(https://www.github.com/fengzhanglab).
NR 40
TC 1
Z9 1
U1 5
U2 5
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 1097-2765
EI 1097-4164
J9 MOL CELL
JI Mol. Cell
PD FEB 16
PY 2017
VL 65
IS 4
BP 618
EP +
DI 10.1016/j.molcel.2016.12.023
PG 20
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA EO1BB
UT WOS:000396431500006
PM 28065598
ER
PT J
AU Younge, N
Goldstein, RF
Bann, CM
Hintz, SR
Patel, RM
Smith, PB
Bell, EF
Rysavy, MA
Duncan, AF
Vohr, BR
Das, A
Goldberg, RN
Higgins, RD
Cotten, CM
AF Younge, Noelle
Goldstein, Ricki F.
Bann, Carla M.
Hintz, Susan R.
Patel, Ravi M.
Smith, P. Brian
Bell, Edward F.
Rysavy, Matthew A.
Duncan, Andrea F.
Vohr, Betty R.
Das, Abhik
Goldberg, Ronald N.
Higgins, Rosemary D.
Cotten, C. Michael
CA Eunice Kennedy Shriver Natl Inst C
Human Dev Neonatal Res Network
TI Survival and Neurodevelopmental Outcomes among Periviable Infants
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Article
ID BIRTH-WEIGHT INFANTS; EXTREMELY PRETERM INFANTS; ACTIVE PERINATAL-CARE;
WEEKS GESTATIONAL-AGE; BAYLEY-III; NATIONAL INSTITUTE; CHILDREN BORN;
SCHOOL-AGE; MORTALITY; MORBIDITY
AB BACKGROUND Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes. METHODS We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs ( 2000-2003 [ epoch 1], 2004-2007 [ epoch 2], and 20082011 [ epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death. RESULTS Data on the primary outcome were available for 4274 of 4458 infants ( 96%) born at the 11 centers. The percentage of infants who survived increased from 30% ( 424 of 1391 infants) in epoch 1 to 36% ( 487 of 1348 infants) in epoch 3 ( P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% ( 217 of 1391) in epoch 1 to 20% ( 276 of 1348) in epoch 3 (P = 0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly ( 15% [ 207 of 1391] in epoch 1 and 16% [ 211 of 1348] in epoch 3, P = 0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment as compared with death) and the rate of survival without neurodevelopmental impairment ( as compared with death) increased over time ( adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [ 95% CI, 1.28 to 1.99], respectively). CONCLUSIONS The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. ( Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633.)
C1 [Younge, Noelle; Goldstein, Ricki F.; Smith, P. Brian; Goldberg, Ronald N.; Cotten, C. Michael] Duke Univ, Dept Pediat, DUMC Box 2739, Durham, NC 27710 USA.
[Bann, Carla M.; Das, Abhik] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA.
[Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA.
[Hintz, Susan R.] Lucile Packard Childrens Hosp, Palo Alto, CA USA.
[Patel, Ravi M.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA.
[Patel, Ravi M.] Childrens Healthcare Atlanta, Atlanta, GA USA.
[Bell, Edward F.; Rysavy, Matthew A.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA.
[Rysavy, Matthew A.] Univ Wisconsin, Dept Pediat, Madison, WI USA.
[Duncan, Andrea F.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA.
[Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA.
[Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA.
RP Younge, N (reprint author), Duke Univ, Dept Pediat, DUMC Box 2739, Durham, NC 27710 USA.
EM noelle.younge@duke.edu
FU National Institutes of Health [5T32HD043728-10, HD060558-05,
4K12HD043494-14]; Eunice Kennedy Shriver National Institute of Child
Health and Human Development; National Center for Research Resources;
National Center for Advancing Translational Sciences for the Neonatal
Research Network's Generic Database and Follow-up Studies [U10 HD27904,
U10 HD21364, M01 RR80, U10 HD68284, U10 HD27853, M01 RR8084, U10
HD40492, M01 RR30, U10 HD27851, M01 RR39, U10 HD27856, M01 RR750, U10
HD68278, U10 HD36790, U10 HD27880, M01 RR70, UL1 TR93, U10 HD53119, M01
RR54]; [U10 HD68244]; [U10 HD68263]; [U10 HD40521]; [UL1 RR24160];
[M01 RR44]; [UL1 TR42]; [U10 HD21415]; [U10 HD21373]; [U10 HD40689];
[M01 RR633]; [U10 HD53124]; [M01 RR64]; [UL1 TR105]; [U10 HD40498];
[M01 RR7122]; [U10 HD21385]; [U10 HD27871]; [UL1 RR24139]; [M01
RR125]; [UL1 TR142]; [M01 RR59]; [U10 HD21397]; [M01 RR16587]; [U10
HD27881]; [U10 HD53089]; [M01 RR997]; [U10 HD34216]; [M01 RR32];
[U10 HD68270]; [U10 HD40461]; [U10 HD53109]
FX Supported by grants from the National Institutes of Health ( including
grants 5T32HD043728-10, HD060558-05, and 4K12HD043494-14 to Dr. Younge)
and from the Eunice Kennedy Shriver National Institute of Child Health
and Human Development, grants from the National Center for Research
Resources, and cooperative agreements from the National Center for
Advancing Translational Sciences for the Neonatal Research Network's
Generic Database and Follow-up Studies (U10 HD27904, U10 HD21364, M01
RR80, U10 HD68284, U10 HD27853, M01 RR8084, U10 HD40492, M01 RR30, U10
HD27851, M01 RR39, U10 HD27856, M01 RR750, U10 HD68278, U10 HD36790, U10
HD27880, M01 RR70, UL1 TR93, U10 HD53119, M01 RR54, U10 HD34216, M01
RR32, U10 HD68270, U10 HD40461, U10 HD53109, M01 RR59, U10 HD21397, M01
RR16587, U10 HD27881, U10 HD53089, M01 RR997, U10 HD68244, U10 HD68263,
U10 HD40521, UL1 RR24160, M01 RR44, UL1 TR42, U10 HD21415, U10 HD21373,
U10 HD40689, M01 RR633, U10 HD53124, M01 RR64, UL1 TR105, U10 HD40498,
M01 RR7122, U10 HD21385, U10 HD27871, UL1 RR24139, M01 RR125, and UL1
TR142).
NR 39
TC 1
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U1 3
U2 3
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 FEB 16
PY 2017
VL 376
IS 7
BP 617
EP 628
DI 10.1056/NEJMoa1605566
PG 12
WC Medicine, General & Internal
SC General & Internal Medicine
GA EO0QJ
UT WOS:000396402700013
PM 28199816
ER
PT J
AU Davey, RT
Nordwall, J
Proschan, MA
AF Davey, Richard T., Jr.
Nordwall, Jacquie
Proschan, Michael A.
CA Prevail II Study Team
TI Trial of ZMapp for Ebola Virus Infection REPLY
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Letter
C1 [Davey, Richard T., Jr.; Proschan, Michael A.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA.
[Nordwall, Jacquie] Univ Minnesota, Minneapolis, MN USA.
RP Davey, RT (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA.
EM rdavey@niaid.nih.gov
NR 3
TC 0
Z9 0
U1 0
U2 0
PU MASSACHUSETTS MEDICAL SOC
PI WALTHAM
PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA
SN 0028-4793
EI 1533-4406
J9 NEW ENGL J MED
JI N. Engl. J. Med.
PD FEB 16
PY 2017
VL 376
IS 7
BP 700
EP 701
PG 3
WC Medicine, General & Internal
SC General & Internal Medicine
GA EO0QJ
UT WOS:000396402700026
PM 28199801
ER
PT J
AU Rosenberg, SA
Tran, E
Robbins, PF
AF Rosenberg, Steven A.
Tran, Eric
Robbins, Paul F.
TI T-Cell Transfer Therapy Targeting Mutant KRAS REPLY
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Letter
C1 [Rosenberg, Steven A.; Tran, Eric; Robbins, Paul F.] NCI, Bethesda, MD 20892 USA.
RP Rosenberg, SA (reprint author), NCI, Bethesda, MD 20892 USA.
EM sar@nih.gov
NR 5
TC 0
Z9 0
U1 0
U2 0
PU MASSACHUSETTS MEDICAL SOC
PI WALTHAM
PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA
SN 0028-4793
EI 1533-4406
J9 NEW ENGL J MED
JI N. Engl. J. Med.
PD FEB 16
PY 2017
VL 376
IS 7
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA EO0QJ
UT WOS:000396402700004
ER
PT J
AU Gaksch, M
Jorde, R
Grimnes, G
Joakimsen, R
Schirmer, H
Wilsgaard, T
Mathiesen, EB
Njolstad, I
Lochen, ML
Marz, W
Kleber, ME
Tomaschitz, A
Grubler, M
Eiriksdottir, G
Gudmundsson, EF
Harris, TB
Cotch, MF
Aspelund, T
Gudnason, V
Rutters, F
Beulens, JWJ
van't Riet, E
Nijpels, G
Dekker, JM
Grove-Laugesen, D
Rejnmark, L
Busch, MA
Mensink, GBM
Scheidt-Nave, C
Thamm, M
Swart, KMA
Brouwer, IA
Lips, P
van Schoor, NM
Sempos, CT
Durazo-Arvizu, RA
Skrabakova, Z
Dowling, KG
Cashman, KD
Kiely, M
Pilz, S
AF Gaksch, Martin
Jorde, Rolf
Grimnes, Guri
Joakimsen, Ragnar
Schirmer, Henrik
Wilsgaard, Tom
Mathiesen, Ellisiv B.
Njolstad, Inger
Lochen, Maja-Lisa
Maerz, Winfried
Kleber, Marcus E.
Tomaschitz, Andreas
Gruebler, Martin
Eiriksdottir, Gudny
Gudmundsson, Elias F.
Harris, Tamara B.
Cotch, Mary F.
Aspelund, Thor
Gudnason, Vilmundur
Rutters, Femke
Beulens, Joline W. J.
van't Riet, Esther
Nijpels, Giel
Dekker, Jacqueline M.
Grove-Laugesen, Diana
Rejnmark, Lars
Busch, Markus A.
Mensink, Gert B. M.
Scheidt-Nave, Christa
Thamm, Michael
Swart, Karin M. A.
Brouwer, Ingeborg A.
Lips, Paul
van Schoor, Natasja M.
Sempos, Christopher T.
Durazo-Arvizu, Ramon A.
Skrabakova, Zuzana
Dowling, Kirsten G.
Cashman, Kevin D.
Kiely, Mairead
Pilz, Stefan
TI Vitamin D and mortality: Individual participant data meta-analysis of
standardized 25-hydroxyvitamin D in 26916 individuals from a European
consortium
SO PLOS ONE
LA English
DT Article
ID ALL-CAUSE MORTALITY; DOSE-RESPONSE DATA; D DEFICIENCY; D TRIALS; HEALTH;
OUTCOMES; CANCER; PREVENTION; DISEASE; COHORT
AB Background
Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality.
Methods
In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488.
Findings
We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH) D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00 +/- 1.29), 1.33 (1.16 +/- 1.51), and 1.67 (1.44 +/- 1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L.
Interpretation
In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.
C1 [Gaksch, Martin; Gruebler, Martin; Pilz, Stefan] Med Univ Graz, Div Endocrinol & Diabetol, Dept Internal Med, Graz, Austria.
[Jorde, Rolf; Grimnes, Guri; Joakimsen, Ragnar; Mathiesen, Ellisiv B.] Univ Tromso, Dept Clin Med, Tromso Endocrine Res Grp, Tromso, Norway.
[Schirmer, Henrik] UiT Arctic Univ Norway, Dept Clin Med, Tromso Cardiovasc Res Grp UNN, Tromso, Norway.
[Wilsgaard, Tom; Njolstad, Inger; Lochen, Maja-Lisa] UiT Arctic Univ Norway, Dept Community Med, Tromso, Norway.
[Maerz, Winfried; Kleber, Marcus E.] Heidelberg Univ, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim Med Fac, Mannheim, Germany.
[Maerz, Winfried] Synlab Acad, Mannheim, Germany.
[Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria.
[Kleber, Marcus E.] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany.
[Tomaschitz, Andreas; Gruebler, Martin] Med Univ Graz, Dept Cardiol, Graz, Austria.
[Tomaschitz, Andreas] Specialist Clin Rehabil Bad Aussee, Bad Aussee, Austria.
[Tomaschitz, Andreas] Charite, Campus Virchow Klinikum, Dept Internal Med Cardiol, Berlin, Germany.
[Gruebler, Martin] Univ Hosp Bern, Dept Cardiol, Swiss Cardiovasc Ctr Bern, Bern, Switzerland.
[Eiriksdottir, Gudny; Gudmundsson, Elias F.; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland.
[Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA.
[Cotch, Mary F.] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA.
[Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, Sch Hlth Sci, Reykjavik, Iceland.
[Rutters, Femke; Beulens, Joline W. J.; van't Riet, Esther; Nijpels, Giel; Dekker, Jacqueline M.; Swart, Karin M. A.; van Schoor, Natasja M.; Pilz, Stefan] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands.
[Rutters, Femke; Beulens, Joline W. J.; van't Riet, Esther; Nijpels, Giel; Dekker, Jacqueline M.; Swart, Karin M. A.; van Schoor, Natasja M.; Pilz, Stefan] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.
[Beulens, Joline W. J.; Pilz, Stefan] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
[Grove-Laugesen, Diana; Rejnmark, Lars] Aarhus Univ Hosp, Dept Endocrinol & Internal Med, Aarhus, Denmark.
[Busch, Markus A.; Mensink, Gert B. M.; Scheidt-Nave, Christa; Thamm, Michael] Robert Koch Inst, Dept Epidemiol & Hlth Monitoring, Berlin, Germany.
[Brouwer, Ingeborg A.] Vrije Univ Amsterdam, Dept Hlth Sci, Amsterdam, Netherlands.
[Brouwer, Ingeborg A.] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Fac Earth & Life Sci, Amsterdam, Netherlands.
[Lips, Paul] Vrije Univ Amsterdam Med Ctr, Dept Internal Med, Endocrine Sect, Amsterdam, Netherlands.
[Sempos, Christopher T.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA.
[Durazo-Arvizu, Ramon A.] Loyola Univ, Med Ctr, Dept Prevent Med & Epidemiol, 2160 S 1st Ave, Maywood, IL 60153 USA.
[Skrabakova, Zuzana; Dowling, Kirsten G.; Cashman, Kevin D.; Kiely, Mairead] Univ Coll Cork, Cork Ctr Vitamin D & Nutr Res, Sch Food & Nutr Sci, Cork, Ireland.
[Cashman, Kevin D.] Univ Coll Cork, Dept Med, Cork, Ireland.
[Kiely, Mairead] Univ Coll Cork, Irish Ctr Fetal & Neonatal Translat Res INFANT, Cork, Ireland.
RP Pilz, S (reprint author), Med Univ Graz, Div Endocrinol & Diabetol, Dept Internal Med, Graz, Austria.; Pilz, S (reprint author), Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.; Pilz, S (reprint author), Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
EM stefan.pilz@chello.at
FU European Community [613977]
FX This project has received funding from the European Community's Seventh
Framework Programme (FP7/2007-2013) under Grant Agreement 613977 for the
ODIN Integrated Project [Food-based solutions for optimal vitamin D
nutrition and health through the life cycle http://www.odin-vitd.eu/].
Funding for the individual studies contributing data to this effort can
be found in Appendix (S1File), section 11.
NR 40
TC 0
Z9 0
U1 2
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 FEB 16
PY 2017
VL 12
IS 2
AR e0170791
DI 10.1371/journal.pone.0170791
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2BG
UT WOS:000394424500013
PM 28207791
ER
PT J
AU Luo, ZP
Dauter, Z
AF Luo, Zhipu
Dauter, Zbigniew
TI Embarras de richesses - It is not good to be too anomalous: Accurate
structure of selenourea, a chiral crystal of planar molecules
SO PLOS ONE
LA English
DT Article
ID DIFFRACTION
AB Selenourea, SeC(NH2)(2), recently found an application as a derivatization reagent providing a significant anomalous diffraction signal used for phasing macromolecular crystal structures. The crystal structure of selenourea itself was solved about 50 years ago, from data recorded on films and evaluated by eye and refined to R= 0.15 with errors of bond lengths and angles about 0.1 angstrom and 6 degrees. In the current work this structure is re-evaluated on the basis of synchrotron data and refined to R1 = 0.021 with bond and angle errors about 0.007 angstrom and 0.5. The nine planar molecules of selenourea pack either in the P3(1) or in the P3(2) unit cell. All unique molecules are connected by a complex network of Se center dot center dot center dot H-N hydrogen bonds and Se center dot center dot center dot Se contacts. The packing of selenourea molecules is highly pseudosymmetric, approximating either of the P3(1(2))12, R3, and R32 space groups. Because the overwhelming majority of diffracted X-ray intensity originates form the anomalously scattering selenium atoms, the measurable anomalous Bijvoet differences are diminished and it was not possible to solve this crystal structure based on the anomalous signal alone.
C1 [Luo, Zhipu; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Argonne Natl Lab, Argonne, IL 60439 USA.
RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, Argonne Natl Lab, Argonne, IL 60439 USA.
EM dauter@anl.gov
FU Intramural Research Program of the National Cancer Institute
FX This work was supported by the Intramural Research Program of the
National Cancer Institute. The funder had no role in study design, data
collection and analysis, decision to publish, or preparation of the
manuscript.
NR 18
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U1 0
U2 0
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 FEB 16
PY 2017
VL 12
IS 2
AR e0171740
DI 10.1371/journal.pone.0171740
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EL2BG
UT WOS:000394424500049
PM 28207770
ER
PT J
AU Deziel, NC
Nuckols, JR
Jones, RR
Graubard, BI
De Roos, AJ
Pronk, A
Gourley, C
Colt, JS
Ward, MH
AF Deziel, Nicole C.
Nuckols, John R.
Jones, Rena R.
Graubard, Barry I.
De Roos, Anneclaire J.
Pronk, Anjoeka
Gourley, Chris
Colt, Joanne S.
Ward, Mary H.
TI Comparison of industrial emissions and carpet dust concentrations of
polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in a
multi-center US study
SO SCIENCE OF THE TOTAL ENVIRONMENT
LA English
DT Article
DE Dioxins; Furans; Geographic information systems; Dust; Air pollution;
Environmental exposure; Non-Hodgkin lymphoma (NHL)
ID SOLID-WASTE INCINERATOR; IN-HOUSE DUST; NON-HODGKINS-LYMPHOMA;
PERSISTENT ORGANIC POLLUTANTS; HUMAN EXPOSURE; ATTIC DUST;
UNITED-STATES; TREATMENT-PLANT; SERUM-LEVELS; PCBS
AB Proximity to facilities emitting polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) has been associated with increased risk of non-Hodgkin lymphoma (NHL). There is limited information about whether proximity to industrial sources leads to indoor PCDD/F contamination of homes. We measured carpet dust concentrations (pg/g) of 17 toxic PCDD/F congeners and calculated their toxic equivalence (TEQ) in 100 homes in a population-based case-control study of NHL in Detroit, Los Angeles, Seattle, and Iowa (1998-2000). We took global positioning system readings at residences and obtained coordinates and PCDD/F emissions (ng TEQ/yr) from an Environmental Protection Agency database for 6 facility types: coal-fired electricity generating plants, cement kilns burning non-hazardous waste, hazardous waste incinerators, medical waste incinerators, municipal solid waste incinerators, and sewage sludge incinerators. For each residence, we computed an inverse distance-squared weighted average emission index (AEI [pg TEQ/km(2)/yr]) for all facilities within 5 km from 1983 to 2000. We also computed AEIs for each of the 6 facility types. We evaluated relationships between PCDD/F dust concentrations and the all-facility AEI or categories of facility-type AEIs using multivariable linear regression, adjusting for study center, demographics, and home characteristics. A doubling of the all-facility AEI was associated with a 4-8% increase in PCDD/F dust concentrations of 7 of 17 PCDD/F congeners and the TEQ (p-value < 0.1). We also observed positive associations between PCDD/F dust concentrations and facility-type AEIs (highest vs. lowest exposure category) for municipal solid Waste incinerators (9 PCDD/F, TEQ), and medical waste incinerators (7 PCDD/F, TEQ) (p < 0.1). Our results from diverse geographical areas suggest that industrial PCDD/F emission sources contribute to residential PCDD/F dust concentrations. Our emissions index could be improved by incorporating local meteorological data and terrain characteristics. Future research is needed to better understand the links between nearby emission sources, human exposure pathways, and health risks. (C) 2016 Elsevier B.V. All rights reserved.
C1 [Deziel, Nicole C.] Yale Sch Publ Hlth, Dept Environm Hlth Sci, 60 Coll St, New Haven, CT 06510 USA.
[Deziel, Nicole C.; Jones, Rena R.; Graubard, Barry I.; Colt, Joanne S.; Ward, Mary H.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 9609 Med Ctr Dr, Rockville, MD 20850 USA.
[Nuckols, John R.] Colorado State Univ, Dept Environm Hlth Sci, 1681 Campus Delivery, Ft Collins, CO 80523 USA.
[Nuckols, John R.] JRN Environm Hlth Sci Ltd, 10916 Wickshire Way, North Bethesda, MD 20852 USA.
[De Roos, Anneclaire J.] Drexel Univ, Dornsife Sch Publ Hlth, Dept Environm & Occupat Hlth, 3215 Market S1, Philadelphia, PA 19104 USA.
[Pronk, Anjoeka] TNO, Zeist, Netherlands.
[Gourley, Chris] Southwest Res Inst, 6220 Culebra Rd, San Antonio, TX 78238 USA.
RP Deziel, NC (reprint author), Yale Sch Publ Hlth, Dept Environm Hlth Sci, 60 Coll St, New Haven, CT 06510 USA.
EM nicole.deziel@yale.edu
FU Intramural Research Program of the Division of Cancer Epidemiology and
Genetics, National Cancer Institute (NCI), National Institutes of
Health; NCI-Iowa SEER [N01-CN-67008]; NCI-Los Angeles County SEER
[N01-CN-67010]; NCI-Seattle SEER [N01-PC-67009]; NCI-Detroit SEER
[N01-PC-65064]; Colorado State University
FX This study was supported by the Intramural Research Program of the
Division of Cancer Epidemiology and Genetics, National Cancer Institute
(NCI), National Institutes of Health; NCI-Iowa SEER contract
N01-CN-67008; NCI-Los Angeles County SEER contract N01-CN-67010;
NCI-Seattle SEER contract N01-PC-67009; and NCI-Detroit SEER contract
N01-PC-65064. John Nuckols was supported, in part, through an
intergovernmental personnel and Colorado State University.
NR 76
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PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0048-9697
EI 1879-1026
J9 SCI TOTAL ENVIRON
JI Sci. Total Environ.
PD FEB 15
PY 2017
VL 580
BP 1276
EP 1286
DI 10.1016/j.scitotenv.2016.12.090
PG 11
WC Environmental Sciences
SC Environmental Sciences & Ecology
GA EM5LS
UT WOS:000395353600125
PM 28017415
ER
PT J
AU Shiels, MS
Althoff, KN
Pfeiffer, RM
Achenbach, CJ
Abraham, AG
Castilho, J
Cescon, A
D'Souza, G
Dubrow, R
Eron, JJ
Gebo, K
Gill, MJ
Goedert, JJ
Grover, S
Hessol, NA
Justice, A
Kitahata, M
Mayor, A
Moore, RD
Napravnik, S
Novak, RM
Thorne, JE
Silverberg, MJ
Engels, EA
AF Shiels, Meredith S.
Althoff, Keri N.
Pfeiffer, Ruth M.
Achenbach, Chad J.
Abraham, Alison G.
Castilho, Jessica
Cescon, Angela
D'Souza, Gypsyamber
Dubrow, Robert
Eron, Joseph J.
Gebo, Kelly
Gill, M. John
Goedert, James J.
Grover, Surbhi
Hessol, Nancy A.
Justice, Amy
Kitahata, Mari
Mayor, Angel
Moore, Richard D.
Napravnik, Sonia
Novak, Richard M.
Thorne, Jennifer E.
Silverberg, Michael J.
Engels, Eric A.
CA North American AIDS Cohort Collabo
TI HIV Infection, Immunosuppression, and Age at Diagnosis of
Non-AIDS-Defining Cancers
SO CLINICAL INFECTIOUS DISEASES
LA English
DT Article
DE HIV; cancer; immunosuppression; AIDS; aging
ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSPLANT RECIPIENTS; UNITED-STATES;
LUNG-CANCER; RISK-FACTORS; INDIVIDUALS; CARCINOMA; COHORT; METAANALYSIS;
POPULATION
AB Background. It is unclear whether immunosuppression leads to younger ages at cancer diagnosis among people living with human immunodeficiency virus (PLWH). A previous study found that most cancers are not diagnosed at a younger age in people with AIDS, with the exception of anal and lung cancers. This study extends prior work to include all PLWH and examines associations between AIDS, CD4 count, and age at cancer diagnosis.
Methods. We compared the median age at cancer diagnosis between PLWH in the North American AIDS Cohort Collaboration on Research and Design and the general population using data from the Surveillance, Epidemiology and End Results Program. We used statistical weights to adjust for population differences. We also compared median age at cancer diagnosis by AIDS status and CD4 count.
Results. After adjusting for population differences, younger ages at diagnosis (P <.05) were observed for PLWH compared with the general population for lung (difference in medians = 4 years), anal (difference = 4), oral cavity/ pharynx (difference = 2), and kidney cancers (difference = 2) and myeloma (difference = 4). Among PLWH, having an AIDS- defining event was associated with a younger age at myeloma diagnosis (difference = 4; P =.01), and CD4 count < 200 cells/mu L (vs >= 500) was associated with a younger age at lung cancer diagnosis (difference = 4; P =.006).
Conclusions. Among PLWH, most cancers are not diagnosed at younger ages. However, this study strengthens evidence that lung cancer, anal cancer, and myeloma are diagnosed at modestly younger ages, and also shows younger ages at diagnosis of oral cavity/ pharynx and kidney cancers, possibly reflecting accelerated cancer progression, etiologic heterogeneity, or risk factor exposure in PLWH.
C1 [Shiels, Meredith S.; Pfeiffer, Ruth M.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA.
[Althoff, Keri N.; Abraham, Alison G.; D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.
[Achenbach, Chad J.] Northwestern Univ, Feinberg Sch Med, Ctr Global hlth, Dept Med Div Infectious Dis, Chicago, IL 60208 USA.
[Abraham, Alison G.] Johns Hopkins Sch Med, Dept Ophthalmol, Baltimore, MD USA.
[Castilho, Jessica] Vanderbilt Univ Sch Med, Div Infectious Dis, Nashville, TN USA.
[Cescon, Angela] Northern Ontario Sch Med, Sudbury, ON, Canada.
[Dubrow, Robert] Yale Sch Publ Hlth, Dept Epidemiol, New Haven, CT USA.
[Eron, Joseph J.] Univ N Carolina, Dept Med, Chapel Hill, NC USA.
[Gebo, Kelly] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA.
[Gill, M. John] Univ Calgary, Dept Med, Calgary, AB T2N 1N4, Canada.
[Grover, Surbhi] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA.
[Hessol, Nancy A.] Univ Calif San Francisco, Sch Pharm, San Francisco, CA 94143 USA.
[Justice, Amy] Yale Sch Med, Dept Med, New Haven, CT USA.
[Kitahata, Mari] Univ Washington, Ctr AIDS Res, Seattle, WA 98195 USA.
[Mayor, Angel] Univ Cent Caribe, Sch Med, Bayamon, PR USA.
[Novak, Richard M.] Univ Illinois, Coll Med, Div Infectious Dis, Chicago, IL 60680 USA.
[Silverberg, Michael J.] Kaiser Permanente Northern California, Div Res, Oakland, CA USA.
RP Shiels, MS (reprint author), NCI, NIH, 9609 Med Ctr Dr,Rm 6F-218 MSC 9767, Bethesda, MD 20892 USA.
EM shielsms@mail.nih.gov
FU ICMJE
FX All authors certify no potential conflicts of interest. The authors have
submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest. Conflicts that the editors consider relevant to the content of
the manuscript have been disclosed.
NR 31
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PU OXFORD UNIV PRESS INC
PI CARY
PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA
SN 1058-4838
EI 1537-6591
J9 CLIN INFECT DIS
JI Clin. Infect. Dis.
PD FEB 15
PY 2017
VL 64
IS 4
BP 468
EP 475
DI 10.1093/cid/ciw764
PG 8
WC Immunology; Infectious Diseases; Microbiology
SC Immunology; Infectious Diseases; Microbiology
GA EP3SB
UT WOS:000397300900019
ER
PT J
AU Kadri, SS
O'Grady, NP
AF Kadri, Sameer S.
O'Grady, Naomi P.
TI How Will We Pay for the New Infectious Diseases/Critical Care Medicine
Subspecialty? Reply
SO CLINICAL INFECTIOUS DISEASES
LA English
DT Letter
C1 [Kadri, Sameer S.; O'Grady, Naomi P.] NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Bldg 10,2C-145, Bethesda, MD 20892 USA.
RP Kadri, SS (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Bldg 10,2C-145, Bethesda, MD 20892 USA.
EM sameer.kadri@nih.gov
NR 2
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Z9 0
U1 0
U2 0
PU OXFORD UNIV PRESS INC
PI CARY
PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA
SN 1058-4838
EI 1537-6591
J9 CLIN INFECT DIS
JI Clin. Infect. Dis.
PD FEB 15
PY 2017
VL 64
IS 4
BP 531
EP 531
DI 10.1093/cid/ciw790
PG 1
WC Immunology; Infectious Diseases; Microbiology
SC Immunology; Infectious Diseases; Microbiology
GA EP3SB
UT WOS:000397300900035
ER
PT J
AU Holt, MP
Punkosdy, GA
Glass, DD
Shevach, EM
AF Holt, Michael P.
Punkosdy, George A.
Glass, Deborah D.
Shevach, Ethan M.
TI TCR Signaling and CD28/CTLA-4 Signaling Cooperatively Modulate T
Regulatory Cell Homeostasis
SO JOURNAL OF IMMUNOLOGY
LA English
DT Article
ID MULTIORGAN TISSUE DESTRUCTION; IN-VIVO; STEADY-STATE; CTLA-4;
ACTIVATION; SELF; MICE; CD28; IL-2; CD4
AB Foxp3(+) T regulatory cells (Tregs), conventional CD4(+)Foxp3(-) T cells, and CD8(+) T cells represent heterogeneous populations composed of naive phenotype (NP, CD44(low)) and memory phenotype (MP, CD44(high)) subpopulations. NP and MP subsets differ in their activation state, contribution to immune function, and capacity to proliferate in vivo. To further understand the factors that contribute to the differential homeostasis of NP/MP subsets, we examined the differential effects of CD28 and CTLA-4 interaction with CD80/CD86, as well as MHC class II-TCR interaction within mouse Treg pools and CD4(+) and CD8(+) T cell pools. Blockade of CD80/CD86 with CTLA-4-Ig markedly reduced the cycling and absolute numbers of MP Tregs and MP CD4(+) T cells, with minimal effect on the NP T cell subpopulations. Blockade of MHC class II-TCR interaction led to selective expansion of MP Tregs and MP CD4(+) and CD8(+) T cells that was reversed upon cotreatment with CTLA-4-Ig. Treatment with anti-CTLA-4 mAb altered MP Treg and MP CD4(+) and CD8(+) T cell homeostasis in a manner similar to that observed with anti-MHC class II. We postulate a complex pathway in which CD28 is the primary driver of Treg proliferation and CTLA-4 functions as the main brake but is likely dependent on TCR signals and CD80/CD86. These findings have important implications for the use of biologic agents targeting such pathways to modulate autoimmune and neoplastic disease.
C1 [Holt, Michael P.; Glass, Deborah D.; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA.
[Punkosdy, George A.] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA.
[Punkosdy, George A.] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA.
RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA.
EM eshevach@niaid.nih.gov
FU Intramural Research Program of the National Institute of Allergy and
Infectious Diseases, National Institutes of Health
FX This work was supported by funds from the Intramural Research Program of
the National Institute of Allergy and Infectious Diseases, National
Institutes of Health.
NR 53
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U1 1
U2 1
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 FEB 15
PY 2017
VL 198
IS 4
BP 1503
EP 1511
DI 10.4049/jimmunol.1601670
PG 9
WC Immunology
SC Immunology
GA EN3HC
UT WOS:000395898600014
PM 28053234
ER
PT J
AU Del Brutto, OH
Nash, TE
White, AC
Rajshekhar, V
Wilkins, PP
Singh, G
Vasquez, CM
Salgado, P
Gilman, RH
Garcia, HH
AF Del Brutto, O. H.
Nash, T. E.
White, A. C., Jr.
Rajshekhar, V.
Wilkins, P. P.
Singh, G.
Vasquez, C. M.
Salgado, P.
Gilman, R. H.
Garcia, H. H.
TI Revised set of diagnostic criteria for neurocysticercosis (in reply to
Garg and Malhotra)
SO JOURNAL OF THE NEUROLOGICAL SCIENCES
LA English
DT Letter
DE Cysticercosis; Neurocysticercosis; Diagnostic criteria
C1 [Del Brutto, O. H.] Univ Espiritu Santo Ecuador, Sch Med, Guayaquil, Ecuador.
[Nash, T. E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA.
[White, A. C., Jr.] Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, Galveston, TX 77555 USA.
[Rajshekhar, V.] Christian Med Coll & Hosp, Dept Neurol Sci, Vellore, Tamil Nadu, India.
[Wilkins, P. P.] Parasitol Serv, Marathon, FL USA.
[Singh, G.] Dayanand Med Coll, Dept Neurol, Ludhiana, Punjab, India.
[Vasquez, C. M.] Inst Nacl Ciencias Neurol, Dept Neurosurg, Lima, Peru.
[Salgado, P.] Natl Inst Neurol & Neurosurg, Neuroimaging Unit, Mexico City, DF, Mexico.
[Gilman, R. H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA.
[Garcia, H. H.] Univ Peruana Cayetano Heredia, Sch Sci, Ctr Global Hlth Tumbes, Lima, Peru.
[Garcia, H. H.] Univ Peruana Cayetano Heredia, Sch Sci, Dept Microbiol, Lima, Peru.
RP Del Brutto, OH (reprint author), Air Ctr 3542,POB 522970, Miami, FL 33152 USA.
EM oscardelbrutto@hotmail.com
NR 9
TC 0
Z9 0
U1 0
U2 0
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0022-510X
EI 1878-5883
J9 J NEUROL SCI
JI J. Neurol. Sci.
PD FEB 15
PY 2017
VL 373
BP 350
EP 351
DI 10.1016/j.jns.2016.12.018
PG 2
WC Clinical Neurology; Neurosciences
SC Neurosciences & Neurology
GA EK8US
UT WOS:000394200700081
PM 28011076
ER
PT J
AU Ha, S
Mendola, P
AF Ha, Sandie
Mendola, Pauline
TI Invited Commentary: Ambient Environment and the Risk of Preterm Birth
SO AMERICAN JOURNAL OF EPIDEMIOLOGY
LA English
DT Editorial Material
DE air pollution; meteorology; preterm birth; temperature
ID AIR-POLLUTION; RESIDENTIAL-MOBILITY; PREGNANCY OUTCOMES; EVENTS
AB Preterm birth is a common adverse birth outcome known to be associated with increased infant mortality, and it often results in a higher burden of offspring morbidity in both the short and long terms. The potential for environmental factors, particularly air pollution and meteorological parameters, to increase preterm birth risk has received significant attention worldwide, but the findings are generally inconsistent, with variations in study designs and methods across populations and geographic locations. In the current issue of the Journal, GiorgisAllemand et al. (Am J Epidemiol. 2017; 185(4):247-258) take the field a step further than most prior investigations of the ambient environment. They examined the associations of ambient air pollution and meteorological factors with preterm risk among 13 cohorts across 11 European countries. No association with air pollution was observed, but associations with increased preterm birth risk were found for both increased atmospheric pressure and ambient temperature exposures during the first trimester. The study is notable in attempting to address several important issues that challenge the field, including exposure misclassification and defining critical windows of exposure. Their comprehensive evaluation of ambient exposures is to be commended.
C1 [Ha, Sandie; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6710B Rockledge Dr Room 3119, Bethesda, MD 20817 USA.
RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6710B Rockledge Dr Room 3119, Bethesda, MD 20817 USA.
EM pauline.mendola@nih.gov
FU Intramural Research Program of the Eunice Kennedy Shriver National
Institute of Child Health and Human Development
FX This work was supported in part by the Intramural Research Program of
the Eunice Kennedy Shriver National Institute of Child Health and Human
Development.
NR 16
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U1 0
U2 0
PU OXFORD UNIV PRESS INC
PI CARY
PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA
SN 0002-9262
EI 1476-6256
J9 AM J EPIDEMIOL
JI Am. J. Epidemiol.
PD FEB 15
PY 2017
VL 185
IS 4
BP 259
EP 261
DI 10.1093/aje/kww138
PG 3
WC Public, Environmental & Occupational Health
SC Public, Environmental & Occupational Health
GA EP2WU
UT WOS:000397245100002
ER
PT J
AU Power, RA
Tansey, KE
Buttenschon, HN
Cohen-Woods, S
Bigdeli, T
Hall, LS
Kutalik, Z
Lee, SH
Ripke, S
Steinberg, S
Teumer, A
Viktorin, A
Wray, NR
Arolt, V
Baune, BT
Boomsma, DI
Borglum, AD
Byrne, EM
Castelao, E
Craddock, N
Craig, IW
Dannlowski, U
Deary, IJ
Degenhardt, F
Forstner, AJ
Gordon, SD
Grabe, HJ
Grove, J
Hamilton, SP
Hayward, C
Heath, AC
Hocking, LJ
Homuth, G
Hottenga, JJ
Kloiber, S
Krogh, J
Landen, M
Lang, MR
Levinson, DF
Lichtenstein, P
Lucae, S
MacIntyre, DJ
Madden, P
Magnusson, PKE
Martin, NG
McIntosh, AM
Middeldorp, CM
Milaneschi, Y
Montgomery, GW
Mors, O
Muller-Myhsok, B
Nyholt, DR
Oskarsson, H
Owen, MJ
Padmanabhan, S
Penninx, BWJH
Pergadia, ML
Porteous, DJ
Potash, JB
Preisig, M
Rivera, M
Shi, JX
Shyn, SI
Sigurdsson, E
Smit, JH
Smith, BH
Stefansson, H
Stefansson, K
Strohmaier, J
Sullivan, PF
Thomson, P
Thorgeirsson, TE
Van der Auwera, S
Weissman, MM
Breen, G
Lewis, CM
AF Power, Robert A.
Tansey, Katherine E.
Buttenschon, Henriette Normolle
Cohen-Woods, Sarah
Bigdeli, Tim
Hall, Lynsey S.
Kutalik, Zoltn
Lee, S. Hong
Ripke, Stephan
Steinberg, Stacy
Teumer, Alexander
Viktorin, Alexander
Wray, Naomi R.
Arolt, Volker
Baune, Bernard T.
Boomsma, Dorret I.
Borglum, Anders D.
Byrne, Enda M.
Castelao, Enrique
Craddock, Nick
Craig, Ian W.
Dannlowski, Udo
Deary, Ian J.
Degenhardt, Franziska
Forstner, Andreas J.
Gordon, Scott D.
Grabe, Hans J.
Grove, Jakob
Hamilton, Steven P.
Hayward, Caroline
Heath, Andrew C.
Hocking, Lynne J.
Homuth, Georg
Hottenga, Jouke J.
Kloiber, Stefan
Krogh, Jesper
Landen, Mikael
Lang, Maren
Levinson, Douglas F.
Lichtenstein, Paul
Lucae, Susanne
MacIntyre, Donald J.
Madden, Pamela
Magnusson, Patrik K. E.
Martin, Nicholas G.
McIntosh, Andrew M.
Middeldorp, Christel M.
Milaneschi, Yuri
Montgomery, Grant W.
Mors, Ole
Muller-Myhsok, Bertram
Nyholt, Dale R.
Oskarsson, Hogni
Owen, Michael J.
Padmanabhan, Sandosh
Penninx, Brenda W. J. H.
Pergadia, Michele L.
Porteous, David J.
Potash, James B.
Preisig, Martin
Rivera, Margarita
Shi, Jianxin
Shyn, Stanley I.
Sigurdsson, Engilbert
Smit, Johannes H.
Smith, Blair H.
Stefansson, Hreinn
Stefansson, Kari
Strohmaier, Jana
Sullivan, Patrick F.
Thomson, Pippa
Thorgeirsson, Thorgeir E.
Van der Auwera, Sandra
Weissman, Myrna M.
Breen, Gerome
Lewis, Cathryn M.
CA CONVERGE Consortium
CARDIoGRAM Consortium
GERAD1 Consortium
TI Genome-wide Association for Major Depression Through Age at Onset
Stratification: Major Depressive Disorder Working Group of the
Psychiatric Genomics Consortium
SO BIOLOGICAL PSYCHIATRY
LA English
DT Article
DE Age at onset; GWAS; Heterogeneity; Major depressive disorder; Polygenic
scoring; Stratification
ID HAN CHINESE WOMEN; FAMILY-HISTORY; RECURRENT DEPRESSION;
ALZHEIMERS-DISEASE; FOLLOW-UP; TWIN; METAANALYSIS; POPULATION;
MORTALITY; RISK
AB BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset.
METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease.
RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 x 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD.
CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult-and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.
C1 [Power, Robert A.; Craig, Ian W.; Rivera, Margarita; Breen, Gerome; Lewis, Cathryn M.] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England.
[Tansey, Katherine E.; Craddock, Nick; Owen, Michael J.] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, Med Res Council,Ctr Neuropsychiatr Genet & Genom, Cardiff, S Glam, Wales.
[Buttenschon, Henriette Normolle; Grove, Jakob; Mors, Ole] Aarhus Univ, Dept Clin Med, Translat Neuropsychiatry Unit HNB, Initiat Integrat Psychiat Res,iPSYCH, Aarhus, Denmark.
[Cohen-Woods, Sarah; Baune, Bernard T.] Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia.
[Bigdeli, Tim] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA.
[Kutalik, Zoltn] Univ Vaudois, Ctr Hosp, Inst Social & Prevent Med, Lausanne, Switzerland.
[Lee, S. Hong; Wray, Naomi R.; Byrne, Enda M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.
[Lee, S. Hong] Univ New England, Sch Environm & Rural Sci, Armidale, NSW, Australia.
[Ripke, Stephan] Massachusetts Inst Technol & Harvard, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA.
[Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translational Genet Unit, Boston, MA 02114 USA.
[Ripke, Stephan] Harvard Med Sch, Boston, MA 02114 USA.
[Ripke, Stephan] Charite, Dept Psychiat & Psychotherapy, Berlin, Germany.
[Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari; Thorgeirsson, Thorgeir E.] deCODE Genet, Reykjavik, Iceland.
[Teumer, Alexander] Univ Med Greifswald, Inst Community Med, Greifswald, Germany.
[Viktorin, Alexander; Landen, Mikael; Lichtenstein, Paul; Magnusson, Patrik K. E.; Sullivan, Patrick F.] Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden.
[Arolt, Volker; Dannlowski, Udo] Univ Munster, Dept Psychiat & Psychotherapy, Munster, Germany.
[Boomsma, Dorret I.; Hottenga, Jouke J.; Middeldorp, Christel M.] Vrije Univ, Inst Hlth & Care Res & Neurosci Campus Amsterdam, EMGO, Amsterdam, Netherlands.
[Hottenga, Jouke J.; Middeldorp, Christel M.] Aarhus Univ, ISEQ, Dept Biomed, Aarhus, Denmark.
[Grove, Jakob] Aarhus Univ, ISEQ, Ctr Integrat Sequencing, Aarhus, Denmark.
[Dannlowski, Udo] Univ Lausanne Hosp, Lausanne, Switzerland.
[Dannlowski, Udo] Univ Marburg, Dept Psychiat, Marburg, Germany.
[Deary, Ian J.; McIntosh, Andrew M.; Thomson, Pippa] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.
[Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland.
[Degenhardt, Franziska; Forstner, Andreas J.] Univ Bonn, Life & Brain Ctr, Dept Genom, Inst Human Genet, Bonn, Germany.
[Gordon, Scott D.; Martin, Nicholas G.; Montgomery, Grant W.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.
[Grabe, Hans J.; Van der Auwera, Sandra] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany.
[Hamilton, Steven P.] Univ Edinburgh, Kaiser Permanente San Francisco Med Ctr, Dept Psychiat, San Francisco, CA USA.
[Hayward, Caroline; MacIntyre, Donald J.; Thomson, Pippa] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh, Midlothian, Scotland.
[Heath, Andrew C.; Madden, Pamela] Washington Univ St Louis, Dept Psychiat, St Louis, MO USA.
[Hocking, Lynne J.] Univ Aberdeen, Div Appl Hlth Sci, Aberdeen, Scotland.
[Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, Interfaculty Inst Genet & Funct Genom, Greifswald, Germany.
[Kloiber, Stefan; Lucae, Susanne; Muller-Myhsok, Bertram] Max Planck Inst Psychiat, Munich, Germany.
[Krogh, Jesper] Univ Copenhagen, Mental Hlth Serv Capital Reg, Mental Hlth Ctr Copenhagen, Copenhagen, Denmark.
[Lang, Maren] Univ Gothenburg, Inst Neuroscience & Physiol, Gothenburg, Sweden.
[Lang, Maren; Shi, Jianxin] Heidelberg Univ, Fac Med, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany.
[Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA USA.
[Milaneschi, Yuri; Penninx, Brenda W. J. H.; Smit, Johannes H.] Vrije Univ Med Ctr, EMGO Inst Hlth & Care Res & Neuro Sci Campus Amst, Dept Psychiat, Amsterdam, Netherlands.
[Mors, Ole] Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark.
[Muller-Myhsok, Bertram] Munich Cluster Syst Neurol, Munich, Germany.
[Muller-Myhsok, Bertram] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England.
[Nyholt, Dale R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia.
[Oskarsson, Hogni] Therapeia, Reykjavik, Iceland.
[Padmanabhan, Sandosh] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
[Pergadia, Michele L.] Florida Atlant Univ, Charles E Schmidt Coll Med, Boca Raton, FL USA.
[Potash, James B.] Univ Iowa, Dept Psychiat, Coll Med, Iowa City, IA USA.
[Rivera, Margarita] Univ Granada, Ctr Invest Biomed Red Salud Mental, Granada, Spain.
[Rivera, Margarita] Univ Granada, Hospit Univ Granada, Inst Invest Biosanitaria ibs, Granada, Spain.
[Shi, Jianxin] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA.
[Shyn, Stanley I.] Grp Hlth, Dept Psychiat, Seattle, WA USA.
[Sigurdsson, Engilbert] Univ Iceland, Fac Med, Reykjavik, Iceland.
[Sigurdsson, Engilbert] Landspitali Univ Hosp, Dept Psychiat, Reykjavik, Iceland.
[Smith, Blair H.] Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland.
[Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA.
[Weissman, Myrna M.] Columbia Univ, Coll Physicians & Surg, New York, NY USA.
[Weissman, Myrna M.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA.
[Weissman, Myrna M.] New York State Psychiat Inst & Hosp, New York, NY USA.
RP Lewis, CM (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England.
EM cathryn.lewis@kcl.ac.uk
OI Thorgeirsson, Thorgeir/0000-0002-5149-7040; McIntosh,
Andrew/0000-0002-0198-4588
FU National Institute of Mental Health (NIMH) [MH085520, MH080403];
SURFsara; Netherlands Scientific Organization [NWO 480-05-003];
department of Psychology; Dutch Brain Foundation; German Federal
Ministry of Education and Research (BMBF) through the Integrated Genome
Research Network Systematic Investigation of the Molecular Causes of
Major Mood Disorders and Schizophrenia [01GS08144, 01GS08147]; National
Genome Research Network plus, and through the Integrated Network
Integrated Understanding of Causes and Mechanisms in Mental Disorders;
e:Med Programme [01ZX1314A, 01ZX1314G]; German Research Foundation (DFG)
[FOR2107, RI908/11-1, NO246/10-1]; NIMH R01 [MH061686, MH059542,
MH075131, MH059552, MH059541, MH060912]; BMBF Program Molecular
Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major
Depression [01ES0811]; Bavarian Ministry of Commerce; BMBF in the
framework of the National Genome Research [NGFN2, NGFN-Plus, FKZ
01GS0481, 01GS08145]; Netherlands Organization for Scientific Research
(MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04004, 400-05-717,
912-100-20]; Spinozapremie [56-464-14192]; Geestkracht program
[10-000-1002]; Center for Medical Systems Biology (NWO Genomics);
Biobanking and Biomolecular Resources Research Infrastructure; Vrije
Universiteit's Institutes for Health and Care Research and Neuroscience
Campus Amsterdam; BIC/BioAssist/RK [2008.024]; European Science
Foundation [EU/QLRT-200101254]; European Community's Seventh Framework
Program [FP7/2007-2013]; ENGAGE [HEALTH-F4-2007-201413]; European
Science Council [ERC 230374]; GAIN of the Foundation for the US National
Institutes of Health; GAIN; NIMH [MH081802, MH072802, N01MH90003];
Australian National Health and Medical Research Council [241944, 339462,
389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739,
552485, 552498, 613602, 613608, 613674, 619667]; Australian Research
Council [FT0991360, FT0991022]; FP-5 GenomEUtwin Project
[QLG2-CT-2002-01254]; US National Institutes of Health [AA07535,
AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951,
U01 DK066134]; Center for Inherited Disease Research (Baltimore, MD); UK
Medical Research Council and GlaxoSmithKline [G0701420]; National
Institute for Health Research Specialist Biomedical Research Centre for
Mental Health at the South London; Maudsley National Health Service
Foundation Trust; Institute of Psychiatry, King's College London; UK
Medical Research Council [G0000647]; Marie Curie Industry-Academia
Partnership and Pathways [286213]; European Commission Framework 6 grant
(EC) [LSHB-CT2003- 503428]; GlaxoSmithKline; Faculty of Biology and
Medicine of Lausanne; Swiss National Science Foundation [3200B0-105993,
3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401];
GlaxoSmithKline Clinical Genetics; Federal Ministry of Education and
Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural
Affairs; Social Ministry of the Federal State of Mecklenburg-West
Pomerania; Siemens Healthcare, Erlangen, Germany; DFG [GR 1912/5-1, FOR
2107, DA1151/5-1]; Swedish Ministry for Higher Education; Swedish
Research Council [M-2005-1112]; GenomEUtwin [QLG2-CT-2002-01254,
EU/QLRT2001-01254]; Swedish Foundation for Strategic Research; Danish
Strategic Research Council; Stanley Research Foundation; European Union
[N Health-F2-2008-222963]; Innovative Medizinische Forschung of the
Medical Faculty of Munster [DA120903, DA111107, DA211012]; Wellcome
Trust Strategic Award "Stratifying Resilience and Depression
Longitudinally" [104036/Z/14/Z]; Chief Scientist Office of the Scottish
Government Health Directorates [CZD/16/6]; Scottish Funding Council
[HR03006]; Broad Institute Center for Genotyping and Analysis [U54
RR020278]; NIMH; National Alliance for Research on Schizophrenia and
Depression; BBSRC; MRC; German Federal Ministry of Education and
Research; European Union (FP 7); Interdisciplinary Center for Clinical
Research Munster; National Health and Medical Research Council
Australia; MRC-BBSRC, Centre for Cognitive Ageing and Cognitive
Epidemiology, part of the cross council Lifelong Health and Wellbeing
Initiative [MR/K026992/1]; German Research Foundation; Federal Ministry
of Education; Research Germany and speakers honoraria from Eli Lilly and
Servier; Medical Research Council (MRC); Biotechnology and Biological
Sciences Research Council (BBSRC); NRS Career Fellowship - Chief
Scientist Office; Scottish Funding Council Senior Clinical Fellowship;
Dame Theresa and Mortimer Sackler Foundation; Netherlands Organization
for Scientific Research [NOW VENI 916-76-125]
FX The PGC was funded by National Institute of Mental Health (NIMH) Grant
Nos. MH085520 (to PFS) and MH080403. Statistical analyses were carried
out on the Genetic Cluster Computer (http://www. geneticcluster.org)
hosted by SURFsara and financially supported by the Netherlands
Scientific Organization Grant No. NWO 480-05-003 (to D. Posthuma) and
the department of Psychology, Vrije Universiteit Amsterdam along with a
supplement from the Dutch Brain Foundation. The Bonn/Mannheim GWAS was
supported by the German Federal Ministry of Education and Research
(BMBF) through the Integrated Genome Research Network Systematic
Investigation of the Molecular Causes of Major Mood Disorders and
Schizophrenia Grant Nos. 01GS08144 and 01GS08147, under the auspices of
the National Genome Research Network plus, and through the Integrated
Network Integrated Understanding of Causes and Mechanisms in Mental
Disorders, under the auspices of the e:Med Programme Grant Nos.
01ZX1314A and 01ZX1314G. The Bonn/Mannheim GWAS was also supported by
the German Research Foundation (DFG) Grant Nos. FOR2107, RI908/11-1, and
NO246/10-1. The GenRED GWAS project was supported by NIMH R01 Grant Nos.
MH061686 (to DFL), MH059542 (to W.H. Coryell), MH075131 (W.B. Lawson),
MH059552 (JBP), MH059541 (W.A. Scheftner), and MH060912 (MMW). Max
Planck Institute of Psychiatry MARS study was supported by the BMBF
Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis
and Outcome in Major Depression by Grant No. 01ES0811. Genotyping was
supported by the Bavarian Ministry of Commerce, and the BMBF in the
framework of the National Genome Research Network by Grant Nos. NGFN2
and NGFN-Plus, FKZ 01GS0481 and 01GS08145. The Netherlands Study of
Depression and Anxiety and the Netherlands Twin Register contributed to
Genetic Association Information Network (GAIN)-MDD and to MDD2000.
Funding for NTR/NESDA was from the following: the Netherlands
Organization for Scientific Research (MagW/ZonMW Grant Nos. 904-61-090,
985-10-002, 904-61-193, 480-04004, 400-05-717, 912-100-20; Spinozapremie
Grant No. 56-464-14192; Geestkracht program Grant No. 10-000-1002); the
Center for Medical Systems Biology (NWO Genomics), Biobanking and
Biomolecular Resources Research Infrastructure, Vrije Universiteit's
Institutes for Health and Care Research and Neuroscience Campus
Amsterdam, BIC/BioAssist/RK (Grant No. 2008.024); the European Science
Foundation (Grant No. EU/QLRT-200101254); the European Community's
Seventh Framework Program (Grant No. FP7/2007-2013); ENGAGE (Grant No.
HEALTH-F4-2007-201413); and the European Science Council (Grant No. ERC
230374). Genotyping was funded in part by the GAIN of the Foundation for
the US National Institutes of Health, and analysis was supported by
grants from GAIN and the NIMH (Grant No. MH081802). Funding for the QIMR
samples was provided by the Australian National Health and Medical
Research Council (Grant Nos. 241944, 339462, 389927, 389875, 389891,
389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602,
613608, 613674, 619667), the Australian Research Council (Grant Nos.
FT0991360, FT0991022), the FP-5 GenomEUtwin Project (Grant No.
QLG2-CT-2002-01254), and the US National Institutes of Health (Grant
Nos. AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206,
DA12854, DA019951), and the Center for Inherited Disease Research
(Baltimore, MD). RADIANT was funded by the following: a joint grant from
the UK Medical Research Council and GlaxoSmithKline (Grant No.;
G0701420); the National Institute for Health Research Specialist
Biomedical Research Centre for Mental Health at the South London and
Maudsley National Health Service Foundation Trust and the Institute of
Psychiatry, King's College London; the UK Medical Research Council
(Grant No. G0000647), and the Marie Curie Industry-Academia Partnership
and Pathways (Grant No. 286213). The GENDEP study was funded by a
European Commission Framework 6 grant (EC Contract Ref.: LSHB-CT2003-
503428). Genotyping of STAR* D was supported by NIMH Grant No. MH072802
(to SPH). STAR* D was funded by NIMH Grant No. N01MH90003 to the
University of Texas Southwestern Medical Center at Dallas (to A.J.
Rush). The CoLaus/PsyCoLaus study was supported by research grants from
GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and
the Swiss National Science Foundation (Grant Nos. 3200B0-105993,
3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401) and two
grants from GlaxoSmithKline Clinical Genetics. SHIP is part of the
Community Medicine Research net of the University of Greifswald,
Germany, which is funded by the Federal Ministry of Education and
Research (Grant Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of
Cultural Affairs, and the Social Ministry of the Federal State of
Mecklenburg-West Pomerania. Genome-wide data have been supported by the
Federal Ministry of Education and Research (Grant No. 03ZIK012) and a
joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal
State of Mecklenburg-West Pomerania. SHIP-LEGEND is funded by the DFG
(Grant No. GR 1912/5-1). The TwinGene study was supported by the Swedish
Ministry for Higher Education, the Swedish Research Council (Grant No.
M-2005-1112), GenomEUtwin (Grant Nos.
EU/QLRT2001-01254,QLG2-CT-2002-01254), the Swedish Foundation for
Strategic Research and the US National Institutes of Health (Grant No.
U01 DK066134). The collection of PRISME control subjects and genotyping
of the 883 Danish control subjects was supported by grants from The
Danish Strategic Research Council, The Stanley Research Foundation, and
H. Lundbeck A/S. The Muenster Depression cohorts were supported by the
European Union (Grant No. N Health-F2-2008-222963) and by grants from
the DFG (Grant Nos. FOR 2107 and DA1151/5-1 [ to UD]), Innovative
Medizinische Forschung of the Medical Faculty of Munster (Grant Nos.
DA120903, DA111107, and DA211012 [ all to UD]). Generation Scotland is
supported by a Wellcome Trust Strategic Award "Stratifying Resilience
and Depression Longitudinally" (Reference No.: 104036/Z/14/Z) and core
support from the Chief Scientist Office of the Scottish Government
Health Directorates (Grant No. CZD/16/6) and the Scottish Funding
Council (Grant No. HR03006).; The NIMH Cell Repository at Rutgers
University and the NIMH Center for Collaborative Genetic Studies on
Mental Disorders made essential contributions to this project.
Genotyping was carried out by the Broad Institute Center for Genotyping
and Analysis with support from Grant No. U54 RR020278 (which partially
subsidized the genotyping of the GenRED cases). Collection and quality
control analyses of the control dataset were supported by grants from
NIMH and the National Alliance for Research on Schizophrenia and
Depression.; We acknowledge the contributions of Dr. George S Zubenko
and Dr. Wendy N Zubenko, Department of Psychiatry, University of
Pittsburgh School of Medicine, to the GenRED I project. We are grateful
to Knowledge Networks (Menlo Park, CA) for assistance in collecting the
control dataset. We express our profound appreciation to the families
who participated in this project, and to the many clinicians who
facilitated the referral of participants to the study. We thank the
twins and their families registered at the Australian Twin Registry for
their participation in the many studies that have contributed to this
research. We thank V. Mooser, G. Weaber, and P. Vollenweider who
initiated the CoLaus project. We express our gratitude to the Lausanne
inhabitants who volunteered to participate in the PsyCoLaus study. We
would like to acknowledge the PRISME-study group, Denmark, for
collection of the PRISME samples. We thank David M. Hougaard, Section of
Neonatal Screening and Hormones, Statens Serum Institute, Copenhagen,
Denmark; Preben Bo Mortensen, National Centre for Register-based
Research, Aarhus University, Denmark; Merete Nordentoft, Mental Health
Centre, Copenhagen, Denmark; and The Lundbeck Foundation Initiative for
Integrative Psychiatric Research, iPSYCH, Denmark. Funding from the
BBSRC and MRC is gratefully acknowledged.; Data used in the preparation
of this article were obtained from the Genetic and Environmental Risk
for Alzheimer's disease (GERAD1) Consortium. As such, the investigators
within the GERAD1 consortia contributed to the design and implementation
of GERAD1 and/or provided data but did not participate in analysis or
writing of this report.; SS, HS, KS, and TET are employees of deCODE
Genetics/Amgen. VA received funds from the German Federal Ministry of
Education and Research, from the European Union (FP 7), and from the
Interdisciplinary Center for Clinical Research Munster, and he has
served on the advisory boards of, or has given presentations on behalf
of the following companies: Astra-Zeneca, Janssen-Organon, Lilly,
Lundbeck, Servier, Pfizer, Otsuka, and Trommsdorff. BTB has received
funding from the National Health and Medical Research Council Australia
and honoraria from Lundbeck, BristolMeyers Squibb, Sanofi, Servier,
Astra-Zeneca, Pfizer. IJD is supported by the MRC-BBSRC, Centre for
Cognitive Ageing and Cognitive Epidemiology, part of the cross council
Lifelong Health and Wellbeing Initiative (Grant No. MR/K026992/1). HJG
has received funding from German Research Foundation and Federal
Ministry of Education and Research Germany and speakers honoraria from
Eli Lilly and Servier. CH acknowledges support from the Medical Research
Council (MRC) and the Biotechnology and Biological Sciences Research
Council (BBSRC). DJM is supported by an , funded by the Chief Scientist
Office. AMM is supported by a Scottish Funding Council Senior Clinical
Fellowship and by the Dame Theresa and Mortimer Sackler Foundation and
has received research support from Pfizer, Janssen, and Lilly. CMM was
supported by the Netherlands Organization for Scientific Research (Grant
No. NOW VENI 916-76-125). BM- M has consulted for Affectis
Pharmaceuticals. MP has served on the advisory boards of Lundbeck and
Eli Lilly
NR 56
TC 2
Z9 2
U1 2
U2 2
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 FEB 15
PY 2017
VL 81
IS 4
BP 325
EP 335
DI 10.1016/j.biopsych.2016.05.010
PG 11
WC Neurosciences; Psychiatry
SC Neurosciences & Neurology; Psychiatry
GA EO9MT
UT WOS:000397013500012
PM 27519822
ER
PT J
AU Pinsky, PF
Prorok, PC
Yu, K
Kramer, BS
Black, A
Gohagan, JK
Crawford, ED
Grubb, RL
Andriole, GL
AF Pinsky, Paul F.
Prorok, Philip C.
Yu, Kelly
Kramer, Barnett S.
Black, Amanda
Gohagan, John K.
Crawford, E. David
Grubb, Robert L.
Andriole, Gerald L.
TI Extended Mortality Results for Prostate Cancer Screening in the PLCO
Trial With Median Follow-Up of 15 Years
SO CANCER
LA English
DT Article
DE digital rectal examination (DRE); prostate cancer; prostate-specific
antigen (PSA); randomized trial; screening
ID SERVICES TASK-FORCE; PSA TESTING RATES
AB BACKGROUND: Two large-scale prostate cancer screening trials using prostate-specific antigen (PSA) have given conflicting results in terms of the efficacy of such screening. One of those trials, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, previously reported outcomes with 13 years of follow-up. This study presents updated findings from the PLCO trial. METHODS: The PLCO trial randomized subjects from 1993 to 2001 to an intervention or control arm. Intervention-arm men received annual PSA tests for 6 years and digital rectal examinations for 4 years. This study used a linkage with the National Death Index to extend mortality follow-up to a maximum of 19 years after randomization. RESULTS: Men were randomized to the intervention arm (n=38,340) or the control arm (n=38,343). The median follow-up time was 14.8 years (25th/75th, 12.7/16.5 years) in the intervention arm and 14.7 years (25th/75th, 12.6/16.4 years) in the control arm. There were 255 deaths from prostate cancer in the intervention arm and 244 deaths from prostate cancer in the control arm; this meant a rate ratio (RR) of 1.04 (95% confidence interval [ CI], 0.87-1.24). The RR for all-cause mortality was 0.977 (95% CI, 0.950-1.004). It was estimated that 86% of the men in the control arm and 99% of the men in the intervention arm received any PSA testing during the trial, and the estimated yearly screening-phase PSA testing rates were 46% and 84%, respectively. CONCLUSIONS: Extended follow-up of the PLCO trial over a median of 15 years continues to indicate no reduction in prostate cancer mortality for the intervention arm versus the control arm. Because of the high rate of control-arm PSA testing, this finding can be viewed as showing no benefit of organized screening versus opportunistic screening. (C) 2016 American Cancer Society.
C1 [Pinsky, Paul F.; Prorok, Philip C.; Kramer, Barnett S.] NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr,Room 5E108, Bethesda, MD 20892 USA.
[Yu, Kelly; Black, Amanda] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
[Gohagan, John K.] NIH, Off Dis Prevent, Bldg 10, Bethesda, MD 20892 USA.
[Crawford, E. David] Univ Colorado, Sch Med, Dept Surg, Aurora, CO USA.
[Grubb, Robert L.; Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol, St Louis, MO USA.
RP Pinsky, PF (reprint author), NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr,Room 5E108, Bethesda, MD 20892 USA.
EM pp4f@nih.gov
FU National Cancer Institute [HHSN261201100008C]
FX This study was funded in part by National Cancer Institute contract
HHSN261201100008C to E. David Crawford, Robert Grubb, and Gerald
Andriole; the other authors are employees of the National Institutes of
Health.
NR 16
TC 2
Z9 2
U1 1
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0008-543X
EI 1097-0142
J9 CANCER-AM CANCER SOC
JI Cancer
PD FEB 15
PY 2017
VL 123
IS 4
BP 592
EP 599
DI 10.1002/cncr.30474
PG 8
WC Oncology
SC Oncology
GA EO6ZP
UT WOS:000396841300010
PM 27911486
ER
PT J
AU Drahos, J
Ricker, W
Pfeiffer, RM
Cook, MB
AF Drahos, Jennifer
Ricker, Winnie
Pfeiffer, Ruth M.
Cook, Michael B.
TI Metabolic Syndrome and Risk of Esophageal Adenocarcinoma in Elderly
Patients in the United States: An Analysis of SEER-Medicare Data
SO CANCER
LA English
DT Article
DE Barrett esophagus; esophageal cancer; gastroesophageal reflux; obesity;
risk factors
ID GASTROESOPHAGEAL-REFLUX DISEASE; BARRETTS-ESOPHAGUS; SYNDROME INCREASES;
CANCER-RISK; OBESITY; ASSOCIATION; SEX; EPIDEMIOLOGY; METAANALYSIS;
POPULATION
AB BACKGROUND: Metabolic syndrome (MetS) is associated with cancer risk and increases the risk of Barrett esophagus, which is the precursor lesion of esophageal adenocarcinoma (EA), primarily in the absence of gastroesophageal reflux disease (GERD). However, to the authors' knowledge, little is known regarding whether MetS is associated with the risk of EA. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, the authors evaluated whether MetS was associated with EA. A total of 3167 cases of EA were compared with individually matched population controls (5: 1); a subset of 575 EA cases were able to be individually matched with 575 Barrett esophagus controls. MetS was defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in the period 1 to 3 years before the diagnosis of EA or control selection. Unconditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. Potential effect modification by GERD symptoms and sex was examined in stratified models. RESULTS: EA was found to be significantly associated with MetS (odds ratio, 1.16; 95% confidence interval, 1.06-1.26) compared with population controls. In males, the association was restricted to those individuals without prior GERD; however, in females, MetS was found to be associated with EA regardless of GERD status. Effect modification by sex was observed (P for interaction=.01). MetS was not found to be associated with EA risk when compared with Barrett esophagus controls. CONCLUSIONS: In this older population, MetS was found to be associated with an increased risk of EA in males without GERD and females regardless of GERD status. Given the lack of an association when compared with Barrett esophagus controls, MetS may impact EA risk by primarily increasing the risk of the precursor lesion, Barrett esophagus. (C) 2016 American Cancer Society.
C1 [Drahos, Jennifer; Pfeiffer, Ruth M.; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA.
[Ricker, Winnie] Informat Management Serv Inc, Rockville, MD USA.
RP Drahos, J (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 9609 Med Ctr Dr,MSC 9774, Bethesda, MD 20892 USA.
EM jdrahos@gmail.com
FU National Cancer Institute at the National Institutes of Health;
Department of Health and Human Services
FX Supported by the Intramural Program of the National Cancer Institute at
the National Institutes of Health and the Department of Health and Human
Services. The findings and conclusions in this report are those of the
authors and do not necessarily represent the official position of the
National Institutes of Health.
NR 41
TC 0
Z9 0
U1 0
U2 0
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0008-543X
EI 1097-0142
J9 CANCER-AM CANCER SOC
JI Cancer
PD FEB 15
PY 2017
VL 123
IS 4
BP 657
EP 665
DI 10.1002/cncr.30365
PG 9
WC Oncology
SC Oncology
GA EO6ZP
UT WOS:000396841300017
PM 27861759
ER
PT J
AU Adamo, M
Boten, JA
Coyle, LM
Cronin, KA
Lam, CJK
Negoita, S
Penberthy, L
Stevens, JL
Ward, KC
AF Adamo, Margaret (Peggy)
Boten, Jessica A.
Coyle, Linda M.
Cronin, Kathleen A.
Lam, Clara J. K.
Negoita, Serban
Penberthy, Lynne
Stevens, Jennifer L.
Ward, Kevin C.
CA Natl Canc Inst Surveillance
TI Validation of Prostate-Specific Antigen Laboratory Values Recorded in
Surveillance, Epidemiology, and End Results Registries
SO CANCER
LA English
DT Article
DE data quality; implied decimal; laboratory value; prostate cancer;
prostate-specific antigen (PSA); staging; Surveillance; Epidemiology;
and End Results (SEER) program
ID BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; CANCER; RECOMMENDATION;
RECURRENCE; NOMOGRAM; PREDICT; UPDATE; MARKER; MEN
AB BACKGROUND: Researchers have used prostate-specific antigen (PSA) values collected by central cancer registries to evaluate tumors for potential aggressive clinical disease. An independent study collecting PSA values suggested a high error rate (18%) related to implied decimal points. To evaluate the error rate in the Surveillance, Epidemiology, and End Results (SEER) program, a comprehensive review of PSA values recorded across all SEER registries was performed. METHODS: Consolidated PSA values for eligible prostate cancer cases in SEER registries were reviewed and compared with text documentation from abstracted records. Four types of classification errors were identified: implied decimal point errors, abstraction or coding implementation errors, nonsignificant errors, and changes related to "unknown" values. RESULTS: A total of 50,277 prostate cancer cases diagnosed in 2012 were reviewed. Approximately 94.15% of cases did not have meaningful changes (85.85% correct, 5.58% with a nonsignificant change of <1 ng/mL, and 2.80% with no clinical change). Approximately 5.70% of cases had meaningful changes (1.93% due to implied decimal point errors, 1.54% due to abstract or coding errors, and 2.23% due to errors related to unknown categories). Only 419 of the original 50,277 cases (0.83%) resulted in a change in disease stage due to a corrected PSA value. CONCLUSIONS: The implied decimal error rate was only 1.93% of all cases in the current validation study, with a meaningful error rate of 5.81%. The reasons for the lower error rate in SEER are likely due to ongoing and rigorous quality control and visual editing processes by the central registries. The SEER program currently is reviewing and correcting PSA values back to 2004 and will re-release these data in the public use research file. (C) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
C1 [Adamo, Margaret (Peggy); Boten, Jessica A.; Cronin, Kathleen A.; Lam, Clara J. K.; Penberthy, Lynne] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Rm 4E454, Rockville, MD 20850 USA.
[Coyle, Linda M.; Stevens, Jennifer L.] Informat Management Serv Inc, Calverton, MD USA.
[Negoita, Serban] Westat Corp, Rockville, MD USA.
[Ward, Kevin C.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA.
RP Cronin, KA (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Rm 4E454, Rockville, MD 20850 USA.
EM Kathy.cronin@nih.gov
FU Surveillance Research Program of the Division of Cancer Control and
Population Sciences at the National Cancer Institute/National Institutes
of Health contracts
FX Supported by Surveillance Research Program of the Division of Cancer
Control and Population Sciences at the National Cancer
Institute/National Institutes of Health contracts with the Surveillance,
Epidemiology, and End Results registries. The authors gratefully
acknowledge the contributions of the state and regional cancer registry
staffs for their work in collecting the data used for this study.
NR 21
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U1 1
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0008-543X
EI 1097-0142
J9 CANCER-AM CANCER SOC
JI Cancer
PD FEB 15
PY 2017
VL 123
IS 4
BP 697
EP 703
DI 10.1002/cncr.30401
PG 7
WC Oncology
SC Oncology
GA EO6ZP
UT WOS:000396841300022
ER
PT J
AU Carta, D
Bortolozzi, R
Sturlese, M
Salmaso, V
Hamel, E
Basso, G
Calderan, L
Quintieri, L
Moro, S
Viola, G
Ferlin, MG
AF Carta, Davide
Bortolozzi, Roberta
Sturlese, Mattia
Salmaso, Veronica
Hamel, Ernest
Basso, Giuseppe
Calderan, Laura
Quintieri, Luigi
Moro, Stefano
Viola, Giampietro
Ferlin, Maria Grazia
TI Synthesis, structure-activity relationships and biological evaluation of
7-phenyl-pyrroloquinolinone 3-amide derivatives as potent antimitotic
agents
SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
LA English
DT Article
DE Microtubules; Phenylpyrroloquinolinone; Tubulin; Apoptosis; Molecular
docking; Structure-activity relationships
ID SHOW POTENT; IN-VITRO; TUBULIN; CANCER; POLYMERIZATION; GENERATION;
APOPTOSIS; MITOCHONDRIA; INHIBITORS; CELLS
AB A small library of 7-pyrrolo[3,2-f]quinolinones was obtained by introducing benzoyl, sulfonyl and carbamoyl side chains at the 3-N position, and their cytotoxicity against a panel of leukemic and solid tumor cell lines was evaluated. Most of them showed high antiproliferative activity with GI(50)s ranging from micro-to sub-nanomolar values, and these values correlated well with the inhibitory activities of the compounds against tubulin polymerization. Based on a recently proposed colchicine bind site inhibitors (CBSIs) pharmacophore, the interactions of the novel 7-PPyQs at the colchicine domain were rationalized. The most active compounds (4a and 4b) did not induce significant cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. In particular, 4a was a potent inducer of apoptosis in both the HeLa and Jurkat cell lines. On the other hand, the sulfonyl derivative 4b exhibited a lower potency in comparison with 4a. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, suggesting that cells treated with the compounds followed the intrinsic pathway of apoptosis. (C) 2016 Elsevier Masson SAS.
C1 [Carta, Davide; Sturlese, Mattia; Salmaso, Veronica; Calderan, Laura; Quintieri, Luigi; Moro, Stefano; Ferlin, Maria Grazia] Univ Padua, Dept Pharmaceut & Pharmacol Sci, I-35131 Padua, Italy.
[Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dept Womans & Childs Hlth, Lab Oncohematol, I-35128 Padua, Italy.
[Hamel, Ernest] Natl Inst Hlth, Screening Technol Branch, Dev Therapeut Program,Div Canc Treatment & Diag, Fredrick Natl Lab Canc Res,Natl Canc Inst, Frederick, MD 21702 USA.
RP Ferlin, MG (reprint author), Univ Padua, Dept Pharmaceut & Pharmacol Sci, I-35131 Padua, Italy.
EM mariagrazia.ferlin@unipd.it
RI Viola, Giampietro/I-4095-2012
OI Viola, Giampietro/0000-0001-9329-165X
FU University of Padova, Italy; University of Padova, Italy (UNIPD,
Progetto Giovani Studiosi) [79122]; European COST Action (GLISTEN)
[CM1207]
FX The computational work coordinated by S.M. has been supported with
financial support from the University of Padova, Italy. MMS lab is also
very grateful to Chemical Computing Group and OpenEye Scientific for the
scientific and technical partnership. S.M. participates in the European
COST Action CM1207 (GLISTEN). The work of M.S. has been supported by
University of Padova, Italy (UNIPD, Progetto Giovani Studiosi 2013:
Protocol number 79122). The content of this paper is solely the
responsibility of the authors and does not necessarily reflect the
official views of the Italian Ministry of Health.
NR 30
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U1 6
U2 6
PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
PI PARIS
PA 23 RUE LINOIS, 75724 PARIS, FRANCE
SN 0223-5234
EI 1768-3254
J9 EUR J MED CHEM
JI Eur. J. Med. Chem.
PD FEB 15
PY 2017
VL 127
BP 643
EP 660
DI 10.1016/j.ejmech.2016.10.026
PG 18
WC Chemistry, Medicinal
SC Pharmacology & Pharmacy
GA EP1VQ
UT WOS:000397172800052
PM 27823884
ER
PT J
AU Bouhrara, M
Spencer, RG
AF Bouhrara, Mustapha
Spencer, Richard G.
TI Rapid simultaneous high-resolution mapping of myelin water fraction and
relaxation times in human brain using BMC-mcDESPOT
SO NEUROIMAGE
LA English
DT Article
DE Brain; MRI; High-resolution mapping; Myelin water fraction; Relaxation
times
ID STATE FREE PRECESSION; MRI T-2 RELAXATION; PROGRESSIVE
MULTIPLE-SCLEROSIS; STOCHASTIC REGION CONTRACTION; APPEARING
WHITE-MATTER; TEMPORAL-LOBE EPILEPSY; MAGNETIC-RESONANCE; IN-VIVO; T2
RELAXATION; OFF-RESONANCE
AB A number of central nervous system (CNS) diseases exhibit changes in myelin content and magnetic resonance longitudinal, T-1, and transverse, T-2, relaxation times, which therefore represent important biomarkers of CNS pathology. Among the methods applied for measurement of myelin water fraction (MWF) and relaxation times, the multicomponent driven equilibrium single pulse observation of T-1 and T-2 (mcDESPOT) approach is of particular interest. mcDESPOT permits whole brain mapping of multicomponent T-1 and T-2, with data acquisition accomplished within a clinically realistic acquisition time. Unfortunately, previous studies have indicated the limited performance of mcDESPOT in the setting of the modest signal-to-noise range of high-resolution mapping, required for the depiction of small structures and to reduce partial volume effects. Recently, we showed that a new Bayesian Monte Carlo (BMC) analysis substantially improved determination of MWF from mcDESPOT imaging data. However, our previous study was limited in that it did not discuss determination of relaxation times. Here, we extend the BMC analysis to the simultaneous determination of whole-brain MWF and relaxation times using the two-component mcDESPOT signal model. Simulation analyses and in-vivo human brain studies indicate the overall greater performance of this approach compared to the stochastic region contraction (SRC) algorithm, conventionally used to derive parameter estimates from mcDESPOT data. SRC estimates of the transverse relaxation time of the long T-2 fraction, T-2,T-l, and the longitudinal relaxation time of the short T-1 fraction, T-1,T-s , clustered towards the lower and upper parameter search space limits, respectively, indicating failure of the fitting procedure. We demonstrate that this effect is absent in the BMC analysis. Our results also showed improved parameter estimation for BMC as compared to SRC for high-resolution mapping. Overall we find that the combination of BMC analysis and mcDESPOT, BMC-mcDESPOT, shows excellent performance for accurate high-resolution whole-brain mapping of MWF and bi-component transverse and longitudinal relaxation times within a clinically realistic acquisition time.
C1 [Bouhrara, Mustapha; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, Clin Invest Lab, NIH,Intramural Res Program, BRC 04B-116,251 Bayview Blvd, Baltimore, MD 21224 USA.
RP Bouhrara, M; Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, Clin Invest Lab, NIH,Intramural Res Program, BRC 04B-116,251 Bayview Blvd, Baltimore, MD 21224 USA.
EM bouhraram@mail.nih.gov; spencer@helix.nih.gov
FU Intramural Research Program of the NIH, National Institute on Aging
FX This work was supported by the Intramural Research Program of the NIH,
National Institute on Aging. We thank David A. Reiter and Christopher M.
Bergeron for assistance with data acquisition.
NR 103
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PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 1053-8119
EI 1095-9572
J9 NEUROIMAGE
JI Neuroimage
PD FEB 15
PY 2017
VL 147
BP 800
EP 811
DI 10.1016/j.neuroimage.2016.09.064
PG 12
WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical
Imaging
SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging
GA EL3ZW
UT WOS:000394560600068
PM 27729276
ER
PT J
AU Chen, G
Taylor, PA
Shin, YW
Reynolds, RC
Cox, RW
AF Chen, Gang
Taylor, Paul A.
Shin, Yong-Wook
Reynolds, Richard C.
Cox, Robert W.
TI Untangling the relatedness among correlations, Part II: Inter-subject
correlation group analysis through linear mixed-effects modeling
SO NEUROIMAGE
LA English
DT Article
ID FMRI GROUP-ANALYSIS; STATISTICAL-ANALYSIS; SOFTWARE; DISTANCE
AB It has been argued that naturalistic conditions in FMRI studies provide a useful paradigm for investigating perception and cognition through a synchronization measure, inter-subject correlation (ISC). However, one analytical stumbling block has been the fact that the ISC values associated with each single subject are not independent, and our previous paper (Chen et al., 2016) used simulations and analyses of real data to show that the methodologies adopted in the literature do not have the proper control for false positives. In the same paper, we proposed nonparametric subject-wise bootstrapping and permutation testing techniques for one and two groups, respectively, which account for the correlation structure, and these greatly outperformed the prior methods in controlling the false positive rate (FPR); that is, subject-wise bootstrapping (SWB) worked relatively well for both cases with one and two groups, and subject-wise permutation (SWP) testing was virtually ideal for group comparisons. Here we seek to explicate and adopt a parametric approach through linear mixed-effects (LME) modeling for studying the ISC values, building on the previous correlation framework, with the benefit that the LME platform offers wider adaptability, more powerful interpretations, and quality control checking capability than nonparametric methods. We describe both theoretical and practical issues involved in the modeling and the manner in which LME with crossed random effects (CRE) modeling is applied. A data-doubling step further allows us to conveniently track the subject index, and achieve easy implementations. We pit the LME approach against the best nonparametric methods, and find that the LME framework achieves proper control for false positives. The new LME methodologies are shown to be both efficient and robust, and they will be publicly available in AFNI (http://afni.nimh.nih.gov).
C1 [Chen, Gang; Taylor, Paul A.; Reynolds, Richard C.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
[Shin, Yong-Wook] Univ Ulsan, Coll Med, Dept Psychiat, Asan Med Ctr, Ulsan, South Korea.
RP Chen, G (reprint author), NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
EM gangchen@mail.nih.gov
FU NTMH; NINDS Intramural Research Programs of the NIH/HHS, USA
[ZICMH002888]; Asan Institute for Life Sciences, Asan Medical Center,
Seoul, Korea [2012-0230]
FX Our work benefited significantly from the statistical computational
language and environment R, the LME package lme4 with the capability to
modeling crossed random effects, and the great support of the R
community. The research and writing of the paper were supported by the
NTMH and NINDS Intramural Research Programs (ZICMH002888) of the
NIH/HHS, USA, and by a grant (2012-0230) from the Asan Institute for
Life Sciences, Asan Medical Center, Seoul, Korea.
NR 23
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U1 1
U2 1
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 1053-8119
EI 1095-9572
J9 NEUROIMAGE
JI Neuroimage
PD FEB 15
PY 2017
VL 147
BP 825
EP 840
DI 10.1016/j.neuroimage.2016.08.029
PG 16
WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical
Imaging
SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging
GA EL3ZW
UT WOS:000394560600070
PM 27751943
ER
PT J
AU Torrisi, S
Nord, CL
Balderston, NL
Roiser, JP
Grillon, C
Ernst, M
AF Torrisi, Salvatore
Nord, Camilla L.
Balderston, Nicholas L.
Roiser, Jonathan P.
Grillon, Christian
Ernst, Monique
TI Resting state connectivity of the human habenula at ultra-high field
SO NEUROIMAGE
LA English
DT Article
DE 7 T; Anxiety; Depression; Seed-based functional connectivity
ID LATERAL HABENULA; HUMAN BRAIN; FUNCTIONAL CONNECTIVITY; 7 T; NUCLEI;
FMRI; DEPRESSION; FLUCTUATIONS; STIMULI; SYSTEM
AB The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7 T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra-high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network.
C1 [Torrisi, Salvatore; Balderston, Nicholas L.; Grillon, Christian; Ernst, Monique] NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA.
[Nord, Camilla L.; Roiser, Jonathan P.] UCL, Neurosci & Cognit Neuropsychiat Grp, London, England.
RP Torrisi, S (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA.
FU Intramural Research Program of the National Institutes of Mental Health
[ZIAMH002798, 02-M-0321, NCT00047853]
FX Special thanks to Rick Reynolds and Daniel Glen for analysis help,
Katherine O'Connell, Andrew Davis, Gaby Alvarez and Joseph Leshin for
data collection help, Bari Fuchs for generating the anatomical underlay,
Erika Raven for iron deposition insight, and Okihide Hikosaka for
valuable feedback. This work utilized the computational resources of the
NIH HPC Biowulf cluster (http://hpc.nih.gov). This work was supported by
the Intramural Research Program of the National Institutes of Mental
Health, project number ZIAMH002798 (clinical protocol 02-M-0321,
NCT00047853) to CG. JPR is a consultant for Cambridge Cognition, though
this is not relevant to the current work. The authors report no
competing interest. The author(s) declare that, except for income
received from the primary employer, no financial support or compensation
has been received from any individual or corporate entity over the past
3 years for research or professional service and there are no personal
financial holdings that could be perceived as constituting a potential
conflict of interest.
NR 62
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PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 1053-8119
EI 1095-9572
J9 NEUROIMAGE
JI Neuroimage
PD FEB 15
PY 2017
VL 147
BP 872
EP 879
DI 10.1016/j.neuroimage.2016.10.034
PG 8
WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical
Imaging
SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging
GA EL3ZW
UT WOS:000394560600074
PM 27780778
ER
PT J
AU Chen, G
Taylor, PA
Cox, RW
AF Chen, Gang
Taylor, Paul A.
Cox, Robert W.
TI Is the statistic value all we should care about in neuroimaging?
SO NEUROIMAGE
LA English
DT Article
ID RESTING STATE FMRI; METAANALYSIS; ACTIVATION; GUIDELINES; RESPONSES;
MODEL; POWER
AB Here we address an important issue that has been embedded within the neuroimaging community for a long time: the absence of effect estimates in results reporting in the literature. The statistic value itself, as a dimensionless measure, does not provide information on the biophysical interpretation of a study, and it certainly does not represent the whole picture of a study. Unfortunately, in contrast to standard practice in most scientific fields, effect (or amplitude) estimates are usually not provided in most results reporting in the current neuroimaging publications and presentations. Possible reasons underlying this general trend include (1) lack of general awareness, (2) software limitations, (3) inaccurate estimation of the BOLD response, and (4) poor modeling due to our relatively limited understanding of FMRI signal components. However, as we discuss here, such reporting damages the reliability and interpretability of the scientific findings themselves, and there is in fact no overwhelming reason for such a practice to persist. In order to promote meaningful interpretation, cross validation, reproducibility, meta and power analyses in neuroimaging, we strongly suggest that, as part of good scientific practice, effect estimates should be reported together with their corresponding statistic values. We provide several easily adaptable recommendations for facilitating this process.
C1 [Chen, Gang; Taylor, Paul A.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
RP Chen, G (reprint author), NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
EM gangchen@mail.nih.gov
FU NIME; NINDS Intramural Research Programs of the NIH/HHS, USA
[ZICMH002888]
FX We thank Laurentius Huber for useful discussions on the physical
dependence of BOLD on MR acquisition. The research and writing of the
paper were supported by the NIME and NINDS Intramural Research Programs
(ZICMH002888) of the NIH/HHS, USA.
NR 51
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PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 1053-8119
EI 1095-9572
J9 NEUROIMAGE
JI Neuroimage
PD FEB 15
PY 2017
VL 147
BP 952
EP 959
DI 10.1016/j.neuroimage.2016.09.066
PG 8
WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical
Imaging
SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging
GA EL3ZW
UT WOS:000394560600081
PM 27729277
ER
PT J
AU Sclafani, JA
Constantin, A
Ho, PS
Akuthota, V
Chan, L
AF Sclafani, Joseph A.
Constantin, Alexandra
Ho, Pei-Shu
Akuthota, Venu
Chan, Leighton
TI y Descriptive Analysis of Spinal Neuroaxial Injections, Surgical
Interventions, and Physical Therapy Utilization for Degenerative Lumbar
Spondylolisthesis Within Medicare Beneficiaries from 2000 to 2011
SO SPINE
LA English
DT Article
DE degenerative spondylolisthesis; epidural steroid injection;
interventional pain management; low back pain; Medicare; physical
therapy; prevalence; spinal interventional techniques; treatment
utilization
ID LOW-BACK-PAIN; SPONDYLOLYSIS; DISPLACEMENT; ASSOCIATION; POPULATION;
PREVALENCE; DIAGNOSIS; EXERCISE; WOMEN
AB Study Design. A retrospective, observational study.
Objective. The aim of this study was to determine the utilization of various treatment modalities in the management of degenerative spondylolisthesis within Medicare beneficiaries.
Summary of Background Data. Degenerative lumbar spondylolisthesis is a condition often identified in symptomatic low back pain. A variety of treatment algorithms including physical therapy and interventional techniques can be used to manage clinically significant degenerative spondylolisthesis.
Methods. This study utilized the 5% national sample of Medicare carrier claims from 2000 through 2011. A cohort of beneficiaries with a new International Classification of Diseases 9th edition (ICD-9) diagnosis code for degenerative lumbar spondylolisthesis was identified. Current procedural terminology codes were used to identify the number of procedures performed each year by specialty on this cohort.
Results. A total of 95,647 individuals were included in the analysis. Average age at the time of initial diagnosis was 72.8 +/- 9.8 years. Within this study cohort, spondylolisthesis was more prevalent in females (69%) than males and in Caucasians (88%) than other racial demographics. Over 50% of beneficiaries underwent at least one injection, approximately one-third (37%) participated in physical therapy, one in five (21%) underwent spinal surgery, and one-third (36%) did not utilize any of these interventions. Greater than half of all procedures (124,280/216,088) occurred within 2 years of diagnosis. The ratio of focal interventions (transforaminal and facet interventions) to less selective (interlaminar) procedures was greater for the specialty of Physical Medicine and Rehabilitation than for the specialties of Anesthesiology, Interventional Radiology, Neurosurgery, and Orthopedic Surgery. The majority of physical therapy was dedicated to passive treatment modalities and range of motion exercises rather than active strengthening modalities within this cohort.
Conclusion. Interventional techniques and physical therapy are frequently used treatment modalities for symptomatic degenerative spondylolisthesis. Understanding utilization of these techniques is important to determine relative clinical efficacies and to optimize future health care expenditures.
C1 [Sclafani, Joseph A.] Medstar Georgetown Univ, Natl Rehabil Hosp, Washington, DC USA.
[Akuthota, Venu] Univ Colorado, Denver, CO 80202 USA.
[Sclafani, Joseph A.; Constantin, Alexandra; Ho, Pei-Shu; Chan, Leighton] NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Sclafani, JA (reprint author), 102 Irving St NW, Washington, DC 20010 USA.
EM sclafani@ucla.edu
FU National Institutes of Health
FX The Intramural Research Program of the National Institutes of Health
funds were received in support of this work.
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U2 0
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0362-2436
EI 1528-1159
J9 SPINE
JI SPINE
PD FEB 15
PY 2017
VL 42
IS 4
BP 240
EP 246
DI 10.1097/BRS.0000000000001724
PG 7
WC Clinical Neurology; Orthopedics
SC Neurosciences & Neurology; Orthopedics
GA EM9OS
UT WOS:000395641600013
PM 28207664
ER
PT J
AU Thomas, A
Tanaka, M
Trepel, J
Reinhold, WC
Rajapakse, VN
Pommier, Y
AF Thomas, Anish
Tanaka, Mamoru
Trepel, Jane
Reinhold, William C.
Rajapakse, Vinodh N.
Pommier, Yves
TI Temozolomide in the Era of Precision Medicine
SO CANCER RESEARCH
LA English
DT Review
ID O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; PROMOTER HYPERMETHYLATION;
COLORECTAL-CANCER; GLIOBLASTOMA; METHYLATION; INACTIVATION; INHIBITION
AB In the January 1, 2017, issue of Cancer Research, Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to temozolomide. Using a fluorescence-based multiplex flow cyto-metric host cell reactivation assay that provides simultaneous readout of DNA repair capacity across multiple pathways, they show that the multivariate drug response models derived from cell line data were applicable to patient-derived xenograft models of glioblastoma. In this commentary, we first outline the mechanism of activity and current clinical application of temozolomide, which, until now, has been largely limited to glioblastoma. Given the challenges of clinical application of functional assays, we argue that functional readouts be approximated by genomic signatures. In this context, a combination of MGMT activity and mismatch repair (MMR) status of the tumor are important parameters that determine sensitivity to temozolomide. More reliable methods are needed to determine MGMT activity as DNA methylation, the current standard, does not accurately reflect the expression of MGMT. Also, genomics for MMR are warranted. Furthermore, based on patterns of MGMT expression across different solid tumors, we make a case for revisiting temozolomide use in a broader spectrum of cancers based on our current understanding of its molecular basis of activity. (C) 2017 AACR.
C1 NCI, Ctr Canc Res, Dev Therapeut Branch, Bethesda, MD 20892 USA.
NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA.
RP Thomas, A (reprint author), NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA.
EM anish.thomas@nih.gov; pommier@nih.gov
FU Center for Cancer Research, the Intramural Program of the NCI [Z01 BC
006150]
FX This work was supported by the Center for Cancer Research, the
Intramural Program of the NCI (Z01 BC 006150).
NR 21
TC 1
Z9 1
U1 3
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 FEB 15
PY 2017
VL 77
IS 4
BP 823
EP 826
DI 10.1158/0008-5472.CAN-16-2983
PG 4
WC Oncology
SC Oncology
GA EK4HN
UT WOS:000393887800003
PM 28159862
ER
PT J
AU Xie, GQ
Chen, HQ
Jia, DY
Shu, ZQ
Palmer, WH
Huang, YC
Zeng, XK
Hou, SX
Jiao, RJ
Deng, WM
AF Xie, Gengqiang
Chen, Hanqing
Jia, Dongyu
Shu, Zhiqiang
Palmer, William Hunt
Huang, Yi-Chun
Zeng, Xiankun
Hou, Steven X.
Jiao, Renjie
Deng, Wu-Min
TI The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila
Imaginal Tissues
SO CANCER RESEARCH
LA English
DT Article
ID NOTCH; PROLIFERATION; MUTATIONS; GENOME; CANCER; GROWTH; GENES; CELLS;
ENDOCYTOSIS; TRAFFICKING
AB Components of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in various human cancers, yet only SMARCB1/hSNF5, a core member of the SWI/SNF complex, is mutated in malignant rhabdoid tumors (MRT). HowSMARCB1/hSNF5 functions differently from other members of the SWI/SNF complex remains unclear. Here, we use Drosophila imaginal epithelial tissues to demonstrate that Snr1, the conserved homolog of human SMARCB1/hSNF5, prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling cascades. Removal of Snr1 resulted in neoplastic tumorigenic overgrowth in imaginal epithelial tissues, whereas deple-tion of any other members of the SWI/SNF complex did not induce similar phenotypes. Unlike other components of the SWI/SNF complex that were detected only in the nucleus, Snr1 was observed in both the nucleus and the cytoplasm. Aberrant regulation of multiple signaling pathways, including Notch, JNK, and JAK/STAT, was responsible for tumor progression upon snr1-depletion. Our results suggest that the cytoplasmic Snr1 may play a tumor suppressive role in Drosophila imaginal tissues, offering a foundation for understanding the pivotal role of SMARCB1/hSNF5 in suppressing MRT during early childhood. (C) 2017 AACR.
C1 [Xie, Gengqiang; Jia, Dongyu; Shu, Zhiqiang; Palmer, William Hunt; Huang, Yi-Chun; Deng, Wu-Min] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA.
[Chen, Hanqing; Jiao, Renjie] Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing, Peoples R China.
[Zeng, Xiankun; Hou, Steven X.] NCI, Basic Res Lab, NIH, Frederick, MD 21701 USA.
[Jiao, Renjie] Guangzhou Med Univ, Sino French Hoffmann Inst, Guangzhou, Guangdong, Peoples R China.
RP Deng, WM (reprint author), Florida State Univ, 319 Stadium Dr,King Life Sci Bldg, Tallahassee, FL 32306 USA.; Jiao, RJ (reprint author), Chinese Acad Sci, Beijing 100101, Peoples R China.
EM rjiao@sun5.ibp.ac.cn; wumin@bio.fsu.edu
OI Xie, Gengqiang/0000-0002-2064-4757
FU NIH [R01GM072562]; National Science Foundation [IOS-1052333]; National
Natural Science Foundation of China [81470846, 31271573, 31529004];
Chinese Academy of Sciences [XDA04020413-02]
FX W.-M. Deng is supported by the NIH (grant number R01GM072562) and the
National Science Foundation (grant number IOS-1052333). R. Jiao is
supported by grants from the National Natural Science Foundation of
China (81470846, 31271573, and 31529004) and the Chinese Academy of
Sciences (XDA04020413-02).
NR 48
TC 0
Z9 0
U1 2
U2 2
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD FEB 15
PY 2017
VL 77
IS 4
BP 862
EP 873
DI 10.1158/0008-5472.CAN-16-0963
PG 12
WC Oncology
SC Oncology
GA EK4HN
UT WOS:000393887800007
PM 27923836
ER
PT J
AU Dzinic, SH
Bernardo, MM
Li, XH
Fernandez-Valdivia, R
Ho, YS
Mi, QS
Bandyopadhyay, S
Lonardo, F
Vranic, S
Oliveira, DSM
Bonfil, RD
Dyson, G
Chen, K
Omerovic, A
Sheng, XJ
Han, X
Wu, DH
Bi, XL
Cabaravdic, D
Jakupovic, U
Wahba, M
Pang, AR
Harajli, D
Sakr, WA
Sheng, SJ
AF Dzinic, Sijana H.
Bernardo, M. Margarida
Li, Xiaohua
Fernandez-Valdivia, Rodrigo
Ho, Ye-Shih
Mi, Qing-Sheng
Bandyopadhyay, Sudeshna
Lonardo, Fulvio
Vranic, Semir
Oliveira, Daniel S. M.
Bonfil, R. Daniel
Dyson, Gregory
Chen, Kang
Omerovic, Almasa
Sheng, Xiujie
Han, Xiang
Wu, Dinghong
Bi, Xinling
Cabaravdic, Dzenana
Jakupovic, Una
Wahba, Marian
Pang, Aaron
Harajli, Deanna
Sakr, Wael A.
Sheng, Shijie
TI An Essential Role of Maspin in Embryogenesis and Tumor Suppression
SO CANCER RESEARCH
LA English
DT Article
ID LUNG-CANCER; PULMONARY ADENOCARCINOMA; EXPRESSION PATTERNS;
CRYSTAL-STRUCTURE; STEM-CELLS; PROSTATE; GENE; PROGRESSION; MODEL; MICE
AB Maspin (SerpinB5) is an epithelial-specific tumor suppressor gene product that displays context-dependent cellular functions. Maspin-deficient mouse models created to date have not definitively established maspin functions critical for cancer suppression. In this study, we generated a mouse strain in which exon 4 of the Maspin gene was deleted, confirming its essential role in development but also enabling a breeding scheme to bypass embryonic lethality. Phenotypic characterization of this viable strain established that maspin deficiency was associated with a reduction in maximum body weight and a variety of context-dependent epithelial abnor-malities. Specifically, maspin-deficient mice exhibited pulmonary adenocarcinoma, myoepithelial hyperplasia of the mammary gland, hyperplasia of luminal cells of dorsolateral and anterior prostate, and atrophy of luminal cells of ventral prostate and stratum spinosum of epidermis. These cancer phenotypes were accompanied by increased inflammatory stroma. These mice also displayed the autoimmune disorder alopecia aerate. Overall, our findings defined context-specific tumor suppressor roles for maspin in a clinically relevant model to study maspin functions in cancer and other pathologies. (C) 2017 AACR.
C1 [Dzinic, Sijana H.; Bernardo, M. Margarida; Li, Xiaohua; Fernandez-Valdivia, Rodrigo; Bandyopadhyay, Sudeshna; Lonardo, Fulvio; Oliveira, Daniel S. M.; Bonfil, R. Daniel; Omerovic, Almasa; Cabaravdic, Dzenana; Jakupovic, Una; Pang, Aaron; Harajli, Deanna; Sakr, Wael A.; Sheng, Shijie] Wayne State Univ, Sch Med, Dept Pathol, 540 East Canfield St, Detroit, MI 48201 USA.
[Dzinic, Sijana H.; Bernardo, M. Margarida; Li, Xiaohua; Fernandez-Valdivia, Rodrigo; Mi, Qing-Sheng; Bandyopadhyay, Sudeshna; Lonardo, Fulvio; Oliveira, Daniel S. M.; Bonfil, R. Daniel; Dyson, Gregory; Chen, Kang; Omerovic, Almasa; Cabaravdic, Dzenana; Jakupovic, Una; Pang, Aaron; Harajli, Deanna; Sakr, Wael A.; Sheng, Shijie] Barbara Ann Karmanos Canc Inst, Tumor Biol & Microenvironm Program, Detroit, MI USA.
[Ho, Ye-Shih] Wayne State Univ, Sch Med, Inst Environm Hlth Sci, Detroit, MI USA.
[Mi, Qing-Sheng; Chen, Kang; Wu, Dinghong; Bi, Xinling] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA.
[Mi, Qing-Sheng; Wu, Dinghong; Bi, Xinling] Henry Ford Hlth Syst, Dept Dermatol, Detroit, MI USA.
[Vranic, Semir] Univ Clin Ctr, Dept Pathol, Div Expt Pathol, Sarajevo, Bosnia & Herceg.
[Oliveira, Daniel S. M.; Bonfil, R. Daniel; Chen, Kang] Wayne State Univ, Sch Med, Dept Urol, Detroit, MI USA.
[Bonfil, R. Daniel; Dyson, Gregory; Chen, Kang; Sheng, Shijie] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA.
[Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA.
[Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, Bethesda, MD 20892 USA.
[Sheng, Xiujie] Guangzhou Med Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Guangzhou, Guangdong, Peoples R China.
[Han, Xiang] Peking Univ, Affiliated Hosp 3, Hlth Sci Ctr, Beijing, Peoples R China.
[Wahba, Marian] Sinai Grace Hosp, Detroit Med Ctr, Dept Internal Med, Detroit, MI USA.
RP Sheng, SJ (reprint author), Wayne State Univ, Sch Med, Dept Pathol, 540 East Canfield St, Detroit, MI 48201 USA.
EM ssheng@med.wayne.edu
OI Vranic, Semir/0000-0001-9743-7265
FU NIH [CA127735, CA084176, P30 CA022453]; Fund for Cancer Research; Ruth
Sager Memorial Fund; Wayne State University Vice President Office for
Research; Wayne State University; Karmanos Cancer Institute Applied
Genomics Technology Center
FX This work was supported by NIH grants (CA127735 and CA084176 to S.
Sheng), Fund for Cancer Research (S. Sheng and E. Heath), and the Ruth
Sager Memorial Fund (S. Sheng), the Wayne State University Vice
President Office for Research (S. Sheng), and NIH grant P30 CA022453 (to
Karmanos Cancer Institute with S. Sheng as a program leader). The NIH
grant P30 CA022453 also supports the Wayne State University and Karmanos
Cancer Institute Applied Genomics Technology Center.
NR 55
TC 0
Z9 0
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 FEB 15
PY 2017
VL 77
IS 4
BP 886
EP 896
DI 10.1158/0008-5472.CAN-16-2219
PG 11
WC Oncology
SC Oncology
GA EK4HN
UT WOS:000393887800009
PM 27923833
ER
PT J
AU Sampson, JN
Falk, RT
Schairer, C
Moore, SC
Fuhrman, BJ
Dallal, CM
Bauer, DC
Dorgan, JF
Shu, XO
Zheng, W
Brinton, LA
Gail, MH
Ziegler, RG
Xu, X
Hoover, RN
Gierach, GL
AF Sampson, Joshua N.
Falk, Roni T.
Schairer, Catherine
Moore, Steven C.
Fuhrman, Barbara J.
Dallal, Cher M.
Bauer, Douglas C.
Dorgan, Joanne F.
Shu, Xiao-Ou
Zheng, Wei
Brinton, Louise A.
Gail, Mitchell H.
Ziegler, Regina G.
Xu, Xia
Hoover, Robert N.
Gierach, Gretchen L.
TI Association of Estrogen Metabolism with Breast Cancer Risk in Different
Cohorts of Postmenopausal Women
SO CANCER RESEARCH
LA English
DT Article
ID CHROMATOGRAPHY-MASS SPECTROMETRY; ASSAY REPRODUCIBILITY; ENDOGENOUS
ESTROGENS; URINARY ESTROGENS; SERUM ESTROGENS; RECEPTOR; ESTRADIOL;
CARCINOGENESIS; MECHANISMS
AB Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation: 16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. (C)2017 AACR.
C1 [Sampson, Joshua N.; Falk, Roni T.; Schairer, Catherine; Moore, Steven C.; Brinton, Louise A.; Gail, Mitchell H.; Ziegler, Regina G.; Hoover, Robert N.; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
[Fuhrman, Barbara J.] Univ Arkansas Med Sci, Fay W Boozman Coll Publ Hlth, Little Rock, AR 72205 USA.
[Dallal, Cher M.] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA.
[Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA.
[Dorgan, Joanne F.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA.
[Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA.
[Xu, Xia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA.
[Sampson, Joshua N.] 9609 Med Ctr Dr,Room 7-E594, Bethesda, MD 20892 USA.
RP Gierach, GL (reprint author), NCI, 9609 Med Ctr Dr,Room 7-E108, Bethesda, MD 20892 USA.; Sampson, JN (reprint author), 9609 Med Ctr Dr,Room 7-E594, Bethesda, MD 20892 USA.
EM sampsonjn@mail.nih.gov; gierachg@mail.nih.gov
RI Gierach, Gretchen/E-1817-2016
OI Gierach, Gretchen/0000-0002-0165-5522
FU Intramural Research Program of the Division of Cancer Epidemiology and
Genetics of the National Cancer Institute and National Cancer Institute
federal funds [HHSN261200800001E]; [R37CA70867]; [UM1CA182910]
FX This study was supported by the Intramural Research Program of the
Division of Cancer Epidemiology and Genetics of the National Cancer
Institute and National Cancer Institute federal funds awarded under
Contract No. HHSN261200800001E to SAIC-Frederick, Inc. The Shanghai
Women's Health Study is supported by R37CA70867 (W. Zheng) and
UM1CA182910 (W. Zheng).
NR 27
TC 0
Z9 0
U1 1
U2 1
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD FEB 15
PY 2017
VL 77
IS 4
BP 918
EP 925
DI 10.1158/0008-5472.CAN-16-1717
PG 8
WC Oncology
SC Oncology
GA EK4HN
UT WOS:000393887800012
PM 28011624
ER
PT J
AU Attali, I
Tobelaim, WS
Persaud, A
Motamedchaboki, K
Simpson-Lavy, KJ
Mashahreh, B
Levin-Kravets, O
Keren-Kaplan, T
Pilzer, I
Kupiec, M
Wiener, R
Wolf, DA
Rotin, D
Prag, G
AF Attali, Ilan
Tobelaim, William Sam
Persaud, Avinash
Motamedchaboki, Khatereh
Simpson-Lavy, Kobi J.
Mashahreh, Bayan
Levin-Kravets, Olga
Keren-Kaplan, Tal
Pilzer, Inbar
Kupiec, Martin
Wiener, Reuven
Wolf, Dieter A.
Rotin, Daniela
Prag, Gali
TI Ubiquitylation-dependent oligomerization regulates activity of Nedd4
ligases
SO EMBO JOURNAL
LA English
DT Article
DE inactivation; Nedd4; oligomerization; Rsp5; ubiquitylation
ID E3 UBIQUITIN LIGASES; EPITHELIAL NA+ CHANNEL; POTASSIUM CHANNEL; PROTEIN
LIGASES; BINDING SITE; HECT DOMAIN; C2 DOMAIN; DEGRADATION;
MONOUBIQUITINATION; FAMILY
AB Ubiquitylation controls protein function and degradation. Therefore, ubiquitin ligases need to be tightly controlled. We discovered an evolutionarily conserved allosteric restraint mechanism for Nedd4 ligases and demonstrated its function with diverse substrates: the yeast soluble proteins Rpn10 and Rvs167, and the human receptor tyrosine kinase FGFR1 and cardiac I-KS potassium channel. We found that a potential trimerization interface is structurally blocked by the HECT domain alpha 1-helix, which further undergoes ubiquitylation on a conserved lysine residue. Genetic, bioinformatics, biochemical and biophysical data show that attraction between this alpha 1-conjugated ubiquitin and the HECT ubiquitin-binding patch pulls the alpha 1-helix out of the interface, thereby promoting trimerization. Strikingly, trimerization renders the ligase inactive. Arginine substitution of the ubiquitylated lysine impairs this inactivation mechanism and results in unrestrained FGFR1 ubiquitylation in cells. Similarly, electrophysiological data and TIRF microscopy show that NEDD4 unrestrained mutant constitutively downregulates the I-KS channel, thus confirming the functional importance of E3-ligase autoinhibition.
C1 [Attali, Ilan; Levin-Kravets, Olga; Keren-Kaplan, Tal; Pilzer, Inbar; Prag, Gali] Tel Aviv Univ, Dept Biochem & Mol Biol, George S Wise Fac Life Sci, Tel Aviv, Israel.
[Tobelaim, William Sam] Sackler Tel Aviv Univ, Dept Physiol & Pharmacol, Tel Aviv, Israel.
[Persaud, Avinash; Rotin, Daniela] Univ Toronto, Hosp Sick Children, Cell Biol Program, Toronto, ON, Canada.
[Persaud, Avinash; Rotin, Daniela] Univ Toronto, Dept Biochem, Toronto, ON, Canada.
[Motamedchaboki, Khatereh; Wolf, Dieter A.] Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, La Jolla, CA USA.
[Motamedchaboki, Khatereh; Wolf, Dieter A.] NCI, Ctr Canc, Prote Facil, Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA.
[Simpson-Lavy, Kobi J.] Tel Aviv Univ, Dept Mol Microbiol & Biotechnol, George S Wise Fac Life Sci, Tel Aviv, Israel.
[Mashahreh, Bayan; Wiener, Reuven] Hebrew Univ Jerusalem, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, Hadassah Med Sch, Jerusalem, Israel.
[Wolf, Dieter A.] Xiamen Univ, Sch Pharmaceut Sci, Xiamen, Peoples R China.
[Prag, Gali] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel.
RP Prag, G (reprint author), Tel Aviv Univ, Dept Biochem & Mol Biol, George S Wise Fac Life Sci, Tel Aviv, Israel.; Prag, G (reprint author), Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel.
EM prag@post.tau.ac.il
NR 69
TC 2
Z9 2
U1 0
U2 0
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 FEB 15
PY 2017
VL 36
IS 4
BP 425
EP 440
DI 10.15252/embj.201694314
PG 16
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA EL2JU
UT WOS:000394446700006
PM 28069708
ER
PT J
AU Stolz, A
Putyrski, M
Kutle, I
Huber, J
Wang, CX
Major, V
Sidhu, SS
Youle, RJ
Rogov, VV
Dotsch, V
Ernst, A
Dikic, I
AF Stolz, Alexandra
Putyrski, Mateusz
Kutle, Ivana
Huber, Jessica
Wang, Chunxin
Major, Viktoria
Sidhu, Sachdev S.
Youle, Richard J.
Rogov, Vladimir V.
Doetsch, Volker
Ernst, Andreas
Dikic, Ivan
TI Fluorescence-based ATG8 sensors monitor localization and function of
LC3/GABARAP proteins
SO EMBO JOURNAL
LA English
DT Article
DE ATG8; immunofluorescence; LC3; phage display; selective autophagy
ID AUTOPHAGOSOME-LYSOSOME FUSION; UBIQUITIN-LIKE PROTEINS; SELECTIVE
AUTOPHAGY; LIR MOTIF; PROTEASOMAL DEGRADATION; STRUCTURAL BASIS;
PHOSPHORYLATION; RECEPTORS; MITOPHAGY; COMPLEX
AB Autophagy is a cellular surveillance pathway that balances metabolic and energy resources and transports specific cargos, including damaged mitochondria, other broken organelles, or pathogens for degradation to the lysosome. Central components of autophagosomal biogenesis are six members of the LC3 and GABARAP family of ubiquitin-like proteins (mATG8s). We used phage display to isolate peptides that possess bona fide LIR (LC3-interacting region) properties and are selective for individual mATG8 isoforms. Sensitivity of the developed sensors was optimized by multiplication, charge distribution, and fusion with a membrane recruitment (FYVE) or an oligomerization (PB1) domain. We demonstrate the use of the engineered peptides as intracellular sensors that recognize specifically GABARAP, GABL1, GABL2, and LC3C, as well as a bispecific sensor for LC3A and LC3B. By using an LC3C-specific sensor, we were able to monitor recruitment of endogenous LC3C to Salmonella during xenophagy, as well as to mitochondria during mitophagy. The sensors are general tools to monitor the fate of mATG8s and will be valuable in decoding the biological functions of the individual LC3/GABARAPs.
C1 [Stolz, Alexandra; Putyrski, Mateusz; Major, Viktoria; Ernst, Andreas; Dikic, Ivan] Goethe Univ, Inst Biochem 2, Frankfurt, Germany.
[Putyrski, Mateusz; Ernst, Andreas] Project Grp Translat Med & Pharmacol TMP, Fraunhofer Inst Mol Biol & Appl Ecol IME, Frankfurt, Germany.
[Kutle, Ivana; Dikic, Ivan] Buchmann Inst Mol Life Sci, Frankfurt, Germany.
[Huber, Jessica; Rogov, Vladimir V.; Doetsch, Volker] Goethe Univ, Inst Biophys Chem, Frankfurt, Germany.
[Wang, Chunxin; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
[Sidhu, Sachdev S.] Univ Toronto, Donnelly Ctr, Banting & Best Dept Med Res, Toronto, ON, Canada.
[Sidhu, Sachdev S.] Univ Toronto, Donnelly Ctr, Dept Mol Genet, Toronto, ON, Canada.
RP Ernst, A; Dikic, I (reprint author), Goethe Univ, Inst Biochem 2, Frankfurt, Germany.; Ernst, A (reprint author), Project Grp Translat Med & Pharmacol TMP, Fraunhofer Inst Mol Biol & Appl Ecol IME, Frankfurt, Germany.; Dikic, I (reprint author), Buchmann Inst Mol Life Sci, Frankfurt, Germany.
EM ernst@biochem2.de; dikic@biochem2.uni-frankfurt.de
NR 61
TC 0
Z9 0
U1 3
U2 3
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 FEB 15
PY 2017
VL 36
IS 4
BP 549
EP 564
DI 10.15252/embj.201695063
PG 16
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA EL2JU
UT WOS:000394446700014
PM 28028054
ER
PT J
AU Livingston, WS
Gill, JM
Cota, MR
Olivera, A
O'Keefe, JL
Martin, C
Latour, LL
AF Livingston, Whitney S.
Gill, Jessica M.
Cota, Martin R.
Olivera, Anlys
O'Keefe, Jessica L.
Martin, Christiana
Latour, Lawrence L.
TI Differential Gene Expression Associated with Meningeal Injury in Acute
Mild Traumatic Brain Injury
SO JOURNAL OF NEUROTRAUMA
LA English
DT Article
DE brain trauma; concussion; gene expression; MRI
ID GLASGOW COMA SCALE; BARRIER DISRUPTION; APACHE-II; INFLAMMATION; STROKE;
MENINGITIS; PREDICTION; OUTCOMES; HUMANS; SCORES
AB Injury to the meninges is not uncommon after traumatic brain injury (TBI), yet minimal research has been directed toward understanding the relevant biology. After a concussive event, the meninges are observed to abnormally enhance on post-contrast magnetic resonance imaging (MRI) in some patients, but not all. The aim of this work is to identify genes differentially expressed in patients with meningeal injury. Patients presenting to the emergency room with suspected TBI received a standard research MRI and blood draw within 48 h of injury. Two groups of patients were included: those with and without abnormal enhancement of the meninges on post-contrast MRI, both without other imaging findings. Groups were compared on microarray gene expression in peripheral blood samples using Affymetrix (Santa Clara, CA) and Partek Genomics Suite (Partek, Inc., St. Louis, MO) software (false discovery rate, <0.05). Forty patients were enrolled with a time from injury to MRI/blood draw of 16.8 h (interquartile range, 7.5-24.1). We observed 76 genes to be differentially expressed in patients with meningeal injury compared to those without, such as receptor for Fc fragment of IgA, multiple C2 domains, transmembrane 2, and G-protein-coupled receptor 27, which have been previously associated with initiating inflammatory mediators, phagocytosis, and other regulatory mechanisms. Post-contrast MRI is able to detect meningeal injury and has a unique biological signature observed through gene expression. These findings suggest that an acute inflammatory response occurs in response to injury to the meninges following a concussion.
C1 [Livingston, Whitney S.; Gill, Jessica M.; Olivera, Anlys; Martin, Christiana] NINR, NIH, Bethesda, MD 20892 USA.
[Gill, Jessica M.; Latour, Lawrence L.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA.
[Cota, Martin R.; O'Keefe, Jessica L.; Latour, Lawrence L.] NINDS, NIH, 10 Ctr Dr,Bldg 10,B1D733, Bethesda, MD 20892 USA.
RP Latour, LL (reprint author), NINDS, NIH, 10 Ctr Dr,Bldg 10,B1D733, Bethesda, MD 20892 USA.
EM latourl@ninds.nih.gov
FU Department of Defense in the Center for Neuroscience and Regenerative
Medicine (CNRM); NINDS; National Institute of Nursing Research (NINR)
FX The authors are grateful to the patients and their families, for without
them this research would not be possible. The authors acknowledge the
staff at Johns Hopkins Suburban Hospital, MedStar Washington Hospital
Center, and the National Institute of Neurological Disorders and Stroke
(NINDS) Acute Stroke Team for their assistance during this study.
Support for this work included Department of Defense in the Center for
Neuroscience and Regenerative Medicine (CNRM), the NINDS, and the
National Institute of Nursing Research (NINR).
NR 28
TC 0
Z9 0
U1 1
U2 1
PU MARY ANN LIEBERT, INC
PI NEW ROCHELLE
PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA
SN 0897-7151
EI 1557-9042
J9 J NEUROTRAUM
JI J. Neurotrauma
PD FEB 15
PY 2017
VL 34
IS 4
BP 853
EP 860
DI 10.1089/neu.2016.4479
PG 8
WC Critical Care Medicine; Clinical Neurology; Neurosciences
SC General & Internal Medicine; Neurosciences & Neurology
GA EL0XD
UT WOS:000394344200012
PM 27430610
ER
PT J
AU Johnson, TP
Tyagi, R
Lee, PR
Lee, MH
Johnson, KR
Kowalak, J
Elkahloun, A
Medynets, M
Hategan, A
Kubofcik, J
Sejvar, J
Ratto, J
Bunga, S
Makumbi, I
Aceng, JR
Nutman, TB
Dowell, SF
Nath, A
AF Johnson, Tory P.
Tyagi, Richa
Lee, Paul R.
Lee, Myoung-Hwa
Johnson, Kory R.
Kowalak, Jeffrey
Elkahloun, Abdel
Medynets, Marie
Hategan, Alina
Kubofcik, Joseph
Sejvar, James
Ratto, Jeffrey
Bunga, Sudhir
Makumbi, Issa
Aceng, Jane R.
Nutman, Thomas B.
Dowell, Scott F.
Nath, Avindra
TI Nodding syndrome may be an autoimmune reaction to the parasitic worm
Onchocerca volvulus
SO SCIENCE TRANSLATIONAL MEDICINE
LA English
DT Article
ID MUSCLE-CELLS; MUNDRI COUNTY; CASE SERIES; EPILEPSY; TANZANIA; UGANDA;
ENCEPHALITIS; EXPRESSION; ANTIBODIES; RECEPTOR
AB Nodding syndrome is an epileptic disorder of unknown etiology that occurs in children in East Africa. There is an epidemiological association with Onchocerca volvulus, the parasitic worm that causes onchocerciasis (river blindness), but there is limited evidence that the parasite itself is neuroinvasive. We hypothesized that nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, we detected autoantibodies to leiomodin-1 more abundantly in patients with nodding syndrome compared to unaffected controls from the same village. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with nodding syndrome. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive with O. volvulus antigens. This study provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry with O. volvulus antigens and suggests that patients may benefit from immunomodulatory therapies.
C1 [Johnson, Tory P.; Tyagi, Richa; Lee, Paul R.; Lee, Myoung-Hwa; Hategan, Alina; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA.
[Johnson, Kory R.] NINCDS, Bioinformat Sect, NIH, Bethesda, MD 20892 USA.
[Kowalak, Jeffrey] NINCDS, Clin Prote Unit, NIH, Bethesda, MD 20892 USA.
[Elkahloun, Abdel] NINCDS, Microarray Core Facil, NIH, Bethesda, MD 20892 USA.
[Medynets, Marie] NINCDS, Neural Differentiat Unit, NIH, Bethesda, MD 20892 USA.
[Kubofcik, Joseph; Nutman, Thomas B.] NINCDS, Helminth Immunol Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA.
[Sejvar, James] Ctr Dis Control & Prevent, Div High Consequence Pathogens & Pathol, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA.
[Ratto, Jeffrey; Bunga, Sudhir] Ctr Dis Control & Prevent, Div Global Hlth Protect, Ctr Global Hlth, Atlanta, GA 30333 USA.
[Makumbi, Issa; Aceng, Jane R.] Minist Hlth, Kampala, Uganda.
[Dowell, Scott F.] Bill & Melinda Gates Fdn, Seattle, WA 98109 USA.
RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA.
EM natha@ninds.nih.gov
FU NIH; CDC
FX This research was supported by the Intramural Research Programs of the
NIH and CDC. The findings and conclusions of this report are those of
the authors and do not necessarily represent the official position of
the CDC.
NR 35
TC 1
Z9 1
U1 1
U2 1
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 FEB 15
PY 2017
VL 9
IS 377
AR eaaf6953
DI 10.1126/scitranslmed.aaf6953
PG 10
WC Cell Biology; Medicine, Research & Experimental
SC Cell Biology; Research & Experimental Medicine
GA EL2LL
UT WOS:000394451100002
ER
PT J
AU Correa-De-Araujo, R
Harris-Love, MO
Miljkovic, I
Fragala, MS
Anthony, BW
Manini, TM
AF Correa-de-Araujo, Rosaly
Harris-Love, Michael O.
Miljkovic, Iva
Fragala, Maren S.
Anthony, Brian W.
Manini, Todd M.
TI The Need for Standardized Assessment of Muscle Quality in Skeletal
Muscle Function Deficit and Other Aging-Related Muscle Dysfunctions: A
Symposium Report
SO FRONTIERS IN PHYSIOLOGY
LA English
DT Review
DE muscle quality; sarcopenia; muscle strength; muscle power; skeletal
muscle function deficit; myosteatosis; imaging
ID INTERMUSCULAR ADIPOSE-TISSUE; MAGNETIC-RESONANCE-SPECTROSCOPY;
CLINICALLY RELEVANT WEAKNESS; DUCHENNE MUSCULAR-DYSTROPHY; FNIH
SARCOPENIA PROJECT; DIFFERENT FIBER TYPES; LOW LEAN MASS; OLDER-ADULTS;
INSULIN-RESISTANCE; BODY-COMPOSITION
AB A growing body of scientific literature suggests that not only changes in skeletal muscle mass, but also other factors underpinning muscle quality, play a role in the decline in skeletal muscle function and impaired mobility associated with aging. A symposium on muscle quality and the need for standardized assessment was held on April 28, 2016 at the International Conference on Frailty and Sarcopenia Research in Philadelphia, Pennsylvania. The purpose of this symposium was to provide a venue for basic science and clinical researchers and expert clinicians to discuss muscle quality in the context of skeletal muscle function deficit and other aging-related muscle dysfunctions. The present article provides an expanded introduction concerning the emerging definitions of muscle quality and a potential framework for scientific inquiry within the field. Changes in muscle tissue composition, based on excessive levels of inter-and intra-muscular adipose tissue and intramyocellular lipids, have been found to adversely impact metabolism and peak force generation. However, methods to easily and rapidly assess muscle tissue composition in multiple clinical settings and with minimal patient burden are needed. Diagnostic ultrasound and other assessment methods continue to be developed for characterizing muscle pathology, and enhanced sonography using sensors to provide user feedback and improve reliability is currently the subject of ongoing investigation and development. In addition, measures of relative muscle force such as specific force or grip strength adjusted for body size have been proposed as methods to assess changes in muscle quality. Furthermore, performance-based assessments of muscle power via timed tests of function and body size estimates, are associated with lower extremity muscle strength may be responsive to age-related changes in muscle quality. Future aims include reaching consensus on the definition and standardized assessments of muscle quality, and providing recommendations to address critical clinical and technology research gaps within the field.
C1 [Correa-de-Araujo, Rosaly] NIA, Div Geriatr & Clin Gerontol, NIH, US Dept HHS, Bethesda, MD 20892 USA.
[Harris-Love, Michael O.] Vet Affairs Med Ctr, Clin Res Ctr, Muscle Morphol Mech & Performance Lab, Human Performance Res Unit, Washington, DC 20422 USA.
[Harris-Love, Michael O.] Vet Affairs Med Ctr, Geriatr & Extended Care Serv Res Serv, Washington, DC 20422 USA.
[Harris-Love, Michael O.] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutrit Sci, Washington, DC 20052 USA.
[Miljkovic, Iva] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA.
[Fragala, Maren S.] Quest Diagnost, Madison, NJ USA.
[Anthony, Brian W.] MIT, Lab Mfg & Prod, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
[Anthony, Brian W.] MIT, Med lect Device Realizat Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
[Manini, Todd M.] Univ Florida, Coll Med, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL USA.
RP Correa-De-Araujo, R (reprint author), NIA, Div Geriatr & Clin Gerontol, NIH, US Dept HHS, Bethesda, MD 20892 USA.; Harris-Love, MO (reprint author), Vet Affairs Med Ctr, Clin Res Ctr, Muscle Morphol Mech & Performance Lab, Human Performance Res Unit, Washington, DC 20422 USA.; Harris-Love, MO (reprint author), Vet Affairs Med Ctr, Geriatr & Extended Care Serv Res Serv, Washington, DC 20422 USA.; Harris-Love, MO (reprint author), George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutrit Sci, Washington, DC 20052 USA.
EM rosaly.correa-de-araujo@nih.gov; michael.harris-love@va.gov
FU VA Office of Research and Development-Rehabilitation RD Service
[1IK2RX001854-01]
FX This publication was partially supported by the VA Office of Research
and Development-Rehabilitation R&D Service (1IK2RX001854-01). The
funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
NR 166
TC 0
Z9 0
U1 2
U2 2
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 1664-042X
J9 FRONT PHYSIOL
JI Front. Physiol.
PD FEB 15
PY 2017
VL 8
AR 87
DI 10.3389/fphys.2017.00087
PG 19
WC Physiology
SC Physiology
GA EK6TV
UT WOS:000394057900001
PM 28261109
ER
PT J
AU Adler-Wailes, DC
Kramer, JA
DePamphilis, ML
AF Adler-Wailes, Diane C.
Kramer, Joshua A.
DePamphilis, Melvin L.
TI Geminin Is Essential for Pluripotent Cell Viability During Teratoma
Formation, but Not for Differentiated Cell Viability During Teratoma
Expansion
SO STEM CELLS AND DEVELOPMENT
LA English
DT Article
DE DNA rereplication; embryonal carcinoma cells; embryonic stem cells;
geminin; germ cell neoplasia; teratocarcinoma
ID EMBRYONIC STEM-CELLS; PRIMORDIAL GERM-CELLS; MOUSE EMBRYOS;
BREAST-CANCER; TUMORS; PROLIFERATION; EXPRESSION; REPLICATION;
DERIVATION; CULTURE
AB Pluripotent embryonic stem cells (ESCs) are unusual in that geminin has been reported to be essential either to prevent differentiation by maintaining expression of pluripotency genes or to prevent DNA rereplication-dependent apoptosis. To distinguish between these two incompatible hypotheses, immune-compromised mice were inoculated subcutaneously with ESCs harboring conditional Gmnn alleles alone or together with a tamoxifen-dependent Cre recombinase gene. Mice were then injected with tamoxifen at various times during which the ESCs proliferated and differentiated into a teratoma. For comparison, the same ESCs were cultured in vitro in the presence of monohydroxytamoxifen. The results revealed that geminin is a haplosufficient gene that is essential for ESC viability before they differentiate into a teratoma, but once a teratoma is established, the differentiated cells can continue to proliferate in the absence of Gmnn alleles, geminin protein, and pluripotent stem cells. Thus, differentiated cells did not require geminin for efficient proliferation within the context of a solid tissue, although they did when teratoma cells were cultured in vitro. These results provide proof-of-principle that preventing geminin function could prevent malignancy in tumors derived from pluripotent cells by selectively eliminating the progenitor cells with little harm to normal cells.
C1 [Adler-Wailes, Diane C.; DePamphilis, Melvin L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 6A,Room 3A15,6 Ctr Dr, Bethesda, MD 20892 USA.
[Kramer, Joshua A.] Leidos Biomed Res Inc, Lab Anim Sci Program, Bethesda, MD USA.
RP DePamphilis, ML (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 6A,Room 3A15,6 Ctr Dr, Bethesda, MD 20892 USA.
EM depamphm@mail.nih.gov
FU national institute for Child Health and Human Development; National
Cancer Institute, National Institutes of Health [HHSN261200800001E]
FX this project was supported in part by the national institute for Child
Health and Human Development and, in part, by the National Cancer
Institute, National Institutes of Health, under contract no.
HHSN261200800001E. The content of this publication does not necessarily
reflect the views or policies of the Department of Health and Human
Services, nor does mention of trade names, commercial products, or
organizations imply endorsement by the U.S. Government. The Scientific
Director, NICHD/NIH, approved this research for publication
(BMGR/SEDR-MD/ MD-16-07729-R).
NR 67
TC 0
Z9 0
U1 0
U2 0
PU MARY ANN LIEBERT, INC
PI NEW ROCHELLE
PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA
SN 1547-3287
EI 1557-8534
J9 STEM CELLS DEV
JI Stem Cells Dev.
PD FEB 15
PY 2017
VL 26
IS 4
BP 285
EP 302
DI 10.1089/scd.2016.0260
PG 18
WC Cell & Tissue Engineering; Hematology; Medicine, Research &
Experimental; Transplantation
SC Cell Biology; Hematology; Research & Experimental Medicine;
Transplantation
GA EK0XJ
UT WOS:000393650100007
PM 27821018
ER
PT J
AU Bodelon, C
Oh, H
Chatterjee, N
Garcia-Closas, M
Palakal, M
Sherman, ME
Pfeiffer, RM
Geller, BM
Vacek, PM
Weaver, DL
Chicoine, RE
Papathomas, D
Xiang, J
Patel, DA
Khodr, ZG
Linville, L
Clare, SE
Visscher, DW
Mies, C
Hewitt, SM
Brinton, LA
Storniolo, AM
He, CY
Chanock, SJ
Gierach, GL
Figueroa, JD
AF Bodelon, Clara
Oh, Hannah
Chatterjee, Nilanjan
Garcia-Closas, Montserrat
Palakal, Maya
Sherman, Mark E.
Pfeiffer, Ruth M.
Geller, Berta M.
Vacek, Pamela M.
Weaver, Donald L.
Chicoine, Rachael E.
Papathomas, Daphne
Xiang, Jackie
Patel, Deesha A.
Khodr, Zeina G.
Linville, Laura
Clare, Susan E.
Visscher, Daniel W.
Mies, Carolyn
Hewitt, Stephen M.
Brinton, Louise A.
Storniolo, Anna Maria
He, Chunyan
Chanock, Stephen J.
Gierach, Gretchen L.
Figueroa, Jonine D.
TI Association between breast cancer genetic susceptibility variants and
terminal duct lobular unit involution of the breast
SO INTERNATIONAL JOURNAL OF CANCER
LA English
DT Article
DE genetic susceptibility; terminal duct lobular unit; involution; breast
cancer
ID GENOME-WIDE ASSOCIATION; MAMMOGRAPHIC DENSITY; COMMON VARIANTS; CONFER
SUSCEPTIBILITY; 14Q24.1 RAD51L1; RISK-FACTORS; IDENTIFIES 2; LOCI;
TISSUE; MUTATION
AB Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted perallele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.
C1 [Bodelon, Clara; Oh, Hannah; Chatterjee, Nilanjan; Garcia-Closas, Montserrat; Palakal, Maya; Sherman, Mark E.; Pfeiffer, Ruth M.; Papathomas, Daphne; Xiang, Jackie; Patel, Deesha A.; Khodr, Zeina G.; Linville, Laura; Brinton, Louise A.; Chanock, Stephen J.; Gierach, Gretchen L.; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
[Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA.
[Geller, Berta M.; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael E.] Univ Vermont, Coll Med, Dept Biostat, Burlington, VT USA.
[Geller, Berta M.; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael E.] Vermont Canc Ctr, Burlington, VT USA.
[Clare, Susan E.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA.
[Visscher, Daniel W.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
[Mies, Carolyn] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA.
[Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA.
[Storniolo, Anna Maria] Indiana Univ, Simon Canc Ctr, Susan G Komen Tissue Bank, Indianapolis, IN 46204 USA.
[He, Chunyan] Indiana Univ, Dept Epidemiol, Richard M Fairbanks Sch Publ Hlth, Indianapolis, IN 46204 USA.
[Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9YL, Midlothian, Scotland.
[Figueroa, Jonine D.] Univ Edinburgh, Edinburgh Canc Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland.
RP Bodelon, C (reprint author), Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 7-E236, Bethesda, MD 20892 USA.
EM clara.bodelon@nih.gov
RI Gierach, Gretchen/E-1817-2016
OI Gierach, Gretchen/0000-0002-0165-5522
FU National Cancer Institute
FX Grant sponsor: Intramural Research Program of the National Cancer
Institute
NR 44
TC 0
Z9 0
U1 8
U2 8
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0020-7136
EI 1097-0215
J9 INT J CANCER
JI Int. J. Cancer
PD FEB 15
PY 2017
VL 140
IS 4
BP 825
EP 832
DI 10.1002/ijc.30512
PG 8
WC Oncology
SC Oncology
GA EG0FA
UT WOS:000390705400009
PM 27859137
ER
PT J
AU Moran, LJ
Fraser, LM
Sundernathan, T
Deussen, AR
Louise, J
Yelland, LN
Grivell, RM
Macpherson, A
Gillman, MW
Robinson, JS
Owens, JA
Dodd, JM
AF Moran, Lisa J.
Fraser, Louise M.
Sundernathan, Tulika
Deussen, Andrea R.
Louise, Jennie
Yelland, Lisa N.
Grivell, Rosalie M.
Macpherson, Anne
Gillman, Matthew W.
Robinson, Jeffrey S.
Owens, Julie A.
Dodd, Jodie M.
TI The effect of an antenatal lifestyle intervention in overweight and
obese women on circulating cardiometabolic and inflammatory biomarkers:
secondary analyses from the LIMIT randomised trial
SO BMC MEDICINE
LA English
DT Article
DE Pregnancy; Overweight and obesity; Dietary and lifestyle intervention;
Randomised trial; Cardiometabolic markers; Inflammatory markers
ID GESTATIONAL DIABETES-MELLITUS; C-REACTIVE PROTEIN; BODY-MASS INDEX;
NECROSIS-FACTOR-ALPHA; WEIGHT-GAIN; PREGNANT-WOMEN; INSULIN-RESISTANCE;
HEALTH OUTCOMES; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME
AB Background: Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers.
Methods: We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-alpha, and interleukins 1 beta, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point.
Results: One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by mate
Conclusions: Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity.
C1 [Moran, Lisa J.; Fraser, Louise M.; Sundernathan, Tulika; Deussen, Andrea R.; Louise, Jennie; Yelland, Lisa N.; Grivell, Rosalie M.; Macpherson, Anne; Robinson, Jeffrey S.; Owens, Julie A.; Dodd, Jodie M.] Univ Adelaide, Robinson Res Inst & Discipline Obstet & Gynaecol, Adelaide, SA 5005, Australia.
[Moran, Lisa J.] Monash Univ, Monash Ctr Hlth Res Implementat, Clayton, Vic, Australia.
[Louise, Jennie; Yelland, Lisa N.] Univ Adelaide, Sch Populat Hlth, Adelaide, SA, Australia.
[Yelland, Lisa N.] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
[Grivell, Rosalie M.] Flinders Univ S Australia, Dept Obstet & Gynaecol, Bedford Pk, SA, Australia.
[Gillman, Matthew W.] Harvard Med Sch, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Obes Prevent Program, Boston, MA USA.
[Gillman, Matthew W.] NIH, Environm Influences Child Hlth Outcomes ECHO, Rockville, MD USA.
[Dodd, Jodie M.] Womens & Childrens Hosp, Dept Perinatal Med, Womens & Babies Div, Adelaide, SA, Australia.
RP Dodd, JM (reprint author), Univ Adelaide, Robinson Res Inst & Discipline Obstet & Gynaecol, Adelaide, SA 5005, Australia.; Dodd, JM (reprint author), Womens & Childrens Hosp, Dept Perinatal Med, Womens & Babies Div, Adelaide, SA, Australia.
EM jodie.dodd@adelaide.edu.au
FU National Health and Medical Research Council (NHMRC), Australia
[519240]; Diabetes Australia Research Trust; US National Institute of
Health (NIH) [R01 HL094235-01]; NHMRC Practitioner Fellowship [627005];
NHMRC Early Career Fellowship [1052388, 1073514]; South Australian
Cardiovascular Research Development Program (SACVRDP) Fellowship
[AC11S374]; National Heart Foundation of Australia; South Australian
Department of Health; South Australian Health and Medical Research
Institute
FX This project was funded by a 4-year project grant from the National
Health and Medical Research Council (NHMRC), Australia (ID 519240);
Diabetes Australia Research Trust; and US National Institute of Health
(NIH) (R01 HL094235-01). JM Dodd is supported through a NHMRC
Practitioner Fellowship (ID 627005). LN Yelland is supported through a
NHMRC Early Career Fellowship (ID 1052388). RM Grivell is supported
through a NHMRC Early Career Fellowship (ID 1073514). LJ Moran is
supported through a South Australian Cardiovascular Research Development
Program (SACVRDP) Fellowship (AC11S374); a program collaboratively
funded by the National Heart Foundation of Australia, the South
Australian Department of Health, and the South Australian Health and
Medical Research Institute. Infrastructure support was provided by The
University of Adelaide, the Women's and Children's Hospital, Flinders
Medical Centre, and the Lyell McEwin Hospital, Adelaide.
NR 51
TC 0
Z9 0
U1 1
U2 1
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1741-7015
J9 BMC MED
JI BMC Med.
PD FEB 14
PY 2017
VL 15
AR 32
DI 10.1186/s12916-017-0790-z
PG 12
WC Medicine, General & Internal
SC General & Internal Medicine
GA EN3UD
UT WOS:000395932500001
PM 28193219
ER
PT J
AU Lacuey, N
Zonjy, B
Londono, L
Lhatoo, SD
AF Lacuey, Nuria
Zonjy, Bilal
Londono, Luisa
Lhatoo, Samden D.
TI Amygdala and hippocampus are symptomatogenic zones for central apneic
seizures
SO NEUROLOGY
LA English
DT Article
ID EPILEPSY; STIMULATION; ONSET; DEATH
AB Objective: To identify limbic sites of respiratory control in the human brain, and by extension, the symptomatogenic zone for central apnea.
Methods: We used direct stimulation of anatomically, precisely placed stereotactic EEG electrodes to analyze breathing responses. We prospectively studied 3 patients who were explored with stereotactically implanted depth electrodes. The amygdala and hippocampus, as well as extralimbic sites (orbitofrontal, temporal tip, and temporal neocortex), were investigated.
Results: Individual stimulation of the amygdala and hippocampal head consistently elicited central apnea in the expiratory phase, as did exquisitely focal hippocampal seizures.
Conclusions: These findings confirm that hippocampus and amygdala are limbic breathing control sites in humans, as well as the symptomatogenic zone for central apneic seizures.
C1 [Lacuey, Nuria; Zonjy, Bilal; Londono, Luisa; Lhatoo, Samden D.] UH Cleveland Med Ctr, Epilepsy Ctr, Cleveland, OH 44106 USA.
[Lacuey, Nuria] Vall dHebron Univ Hosp, Dept Neurol, Barcelona, Spain.
[Lacuey, Nuria] Univ Autonoma Barcelona, Dept Med, E-08193 Barcelona, Spain.
[Lhatoo, Samden D.] NINDS, Ctr SUDEP Res CSR, Cleveland, OH USA.
RP Lacuey, N (reprint author), UH Cleveland Med Ctr, Epilepsy Ctr, Cleveland, OH 44106 USA.; Lacuey, N (reprint author), Vall dHebron Univ Hosp, Dept Neurol, Barcelona, Spain.; Lacuey, N (reprint author), Univ Autonoma Barcelona, Dept Med, E-08193 Barcelona, Spain.
EM nuria.lacuey@uhhospitals.org
FU Universitat Autonoma de Barcelona, Doctorate thesis in Medicine
FX This work was supported in part by the Universitat Autonoma de Barcelona
as part of a Doctorate thesis in Medicine.
NR 10
TC 0
Z9 0
U1 0
U2 0
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0028-3878
EI 1526-632X
J9 NEUROLOGY
JI Neurology
PD FEB 14
PY 2017
VL 88
IS 7
BP 701
EP 705
DI 10.1212/WNL.0000000000003613
PG 5
WC Clinical Neurology
SC Neurosciences & Neurology
GA EP4IP
UT WOS:000397344500018
PM 28087822
ER
PT J
AU Introne, WJ
Westbroek, W
Groden, CA
Bhambhani, V
Golas, GA
Baker, EH
Lehky, TJ
Snow, J
Ziegler, SG
Malicdan, MCV
Adams, DR
Dorward, HM
Hess, RA
Huizing, M
Gahl, WA
Toro, C
AF Introne, Wendy J.
Westbroek, Wendy
Groden, Catherine A.
Bhambhani, Vikas
Golas, Gretchen A.
Baker, Eva H.
Lehky, Tanya J.
Snow, Joseph
Ziegler, Shira G.
Malicdan, May Christine V.
Adams, David R.
Dorward, Heidi M.
Hess, Richard A.
Huizing, Marjan
Gahl, William A.
Toro, Camilo
TI Neurologic involvement in patients with atypical Chediak-Higashi disease
SO NEUROLOGY
LA English
DT Article
ID PARKINSONIAN-SYNDROME; CLINICAL PHENOTYPE; LYST; IDENTIFICATION;
LYSOSOMES; MUTATIONS; GENOTYPE; DOMAIN; CELLS; BEIGE
AB Objective: To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study.
Methods: Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation.
Results: In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism.
Conclusions: Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders.
C1 [Introne, Wendy J.; Groden, Catherine A.; Bhambhani, Vikas; Golas, Gretchen A.; Gahl, William A.; Toro, Camilo] Childrens Hosp & Clin Minnesota, Dept Med Genet, Clin Director, Minneapolis, MN USA.
[Westbroek, Wendy; Ziegler, Shira G.; Malicdan, May Christine V.; Adams, David R.; Dorward, Heidi M.; Hess, Richard A.; Huizing, Marjan; Gahl, William A.] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Med Genet Branch, Dept Med Genet, Minneapolis, MN USA.
[Baker, Eva H.] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Ctr Clin, Natl Human Genome Res Inst,Dept Radiol & Imaging, Minneapolis, MN USA.
[Lehky, Tanya J.] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Elect Sect Off Clin Director, Natl Inst Neurol Disorders & Stroke, Minneapolis, MN USA.
[Snow, Joseph] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Clin Director, Natl Inst Mental Hlth, Minneapolis, MN USA.
[Bhambhani, Vikas] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Natl Inst Hlth, Metab & Clin Geneticist, Minneapolis, MN USA.
RP Introne, WJ (reprint author), Childrens Hosp & Clin Minnesota, Dept Med Genet, Clin Director, Minneapolis, MN USA.
EM wintrone@mail.nih.gov
FU Intramural Research Programs of the National Human Genome Research
Institute; National Institute of Neurological Disorders and Stroke; the
Hatfield Clinical Center, NIH, Bethesda, MD
FX Supported by the Intramural Research Programs of the National Human
Genome Research Institute, the National Institute of Neurological
Disorders and Stroke, and the Hatfield Clinical Center, NIH, Bethesda,
MD.
NR 32
TC 2
Z9 2
U1 0
U2 0
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0028-3878
EI 1526-632X
J9 NEUROLOGY
JI Neurology
PD FEB 14
PY 2017
VL 88
IS 7
BP E57
EP E65
DI 10.1212/WNL.0000000000003622
PG 9
WC Clinical Neurology
SC Neurosciences & Neurology
GA EP4IP
UT WOS:000397344500004
PM 28193763
ER
PT J
AU Dall, GV
Vieusseux, JL
Korach, KS
Arao, Y
Hewitt, SC
Hamilton, KJ
Dzierzak, E
Boon, WC
Simpson, ER
Ramsay, RG
Stein, T
Morris, JS
Anderson, RL
Risbridger, GP
Britt, KL
AF Dall, Genevieve V.
Vieusseux, Jessica L.
Korach, Kenneth S.
Arao, Yukitomo
Hewitt, Sylvia C.
Hamilton, Katherine J.
Dzierzak, Elaine
Boon, Wah Chin
Simpson, Evan R.
Ramsay, Robert G.
Stein, Torsten
Morris, Joanne S.
Anderson, Robin L.
Risbridger, Gail P.
Britt, Kara L.
TI SCA-1 Labels a Subset of Estrogen-Responsive Bipotential Repopulating
Cells within the CD24(+) CD49f(hi) Mammary Stem Cell-Enriched
Compartment
SO STEM CELL REPORTS
LA English
DT Article
ID IN-VIVO; BREAST-CANCER; SELF-RENEWAL; GLAND; MOUSE; SUSCEPTIBILITY;
DIFFERENTIATION; CARCINOGENESIS; EXPRESSION; PREGNANCY
AB Estrogen stimulates breast development during puberty and mammary tumors in adulthood through estrogen receptor-alpha (ER alpha). These effects are proposed to occur via ER alpha(+) luminal cells and not the mammary stem cells (MaSCs) that are ER alpha(neg). Since ER alpha(+) luminal cells express stem cell antigen-1 (SCA-1), we sought to determine if SCA-1 could define an ER alpha(+) subset of EpCAM(+)/CD24(+)/CD49f(hi) MaSCs. We show that the MaSC population has a distinct SCA-1(+) population that is abundant in pre-pubertal mammary glands. The SCA-1(+) MaSCs have less stem cell markers and less in vivo repopulating activity than their SCA-1(neg) counterparts. However, they express ERa and specifically enter the cell cycle at puberty. Using estrogen-deficient aromatase knockouts (ArKO), we showed that the SCA-1(+) MaSC could be directly modulated by estrogen supplementation. Thus, SCA-1 enriches for an ER alpha(+), estrogen-sensitive subpopulation within the CD24(+)/CD49f(hi) MaSC population that may be responsible for the hormonal sensitivity of the developing mammary gland.
C1 [Dall, Genevieve V.; Vieusseux, Jessica L.; Britt, Kara L.] Peter MacCallum Canc Ctr, Canc Genet Lab, 305 Grattan St, Melbourne, Vic 3000, Australia.
[Dall, Genevieve V.; Risbridger, Gail P.; Britt, Kara L.] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia.
[Korach, Kenneth S.; Arao, Yukitomo; Hewitt, Sylvia C.; Hamilton, Katherine J.] NIEHS, Reprod & Dev Biol Lab, NIH, Res Triangle Pk, NC 27709 USA.
[Dzierzak, Elaine] Univ Edinburgh, MRC, Ctr Inflammat Res, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland.
[Boon, Wah Chin] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3010, Australia.
[Simpson, Evan R.] Hudson Inst Med Res, Clayton, Vic 3168, Australia.
[Ramsay, Robert G.] Peter MacCallum Canc Ctr, Differentiat & Transcript Lab, 305 Grattan St, Melbourne, Vic 3000, Australia.
[Stein, Torsten] Univ Glasgow, Inst Canc Sci, Coll MVLS, Glasgow G12 8QQ, Lanark, Scotland.
[Morris, Joanne S.] Univ Glasgow, Sch Vet Med, Coll MVLS, Glasgow G61 1QH, Lanark, Scotland.
[Anderson, Robin L.; Britt, Kara L.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia.
[Anderson, Robin L.] La Trobe Univ, Bundoora, Vic 3083, Australia.
RP Britt, KL (reprint author), Peter MacCallum Canc Ctr, Canc Genet Lab, 305 Grattan St, Melbourne, Vic 3000, Australia.; Britt, KL (reprint author), Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia.; Britt, KL (reprint author), Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia.
EM kara.britt@petermac.org
RI Risbridger, Gail/B-8655-2008
OI Risbridger, Gail/0000-0003-3089-4028
FU Australian Postgradutate Scholarship; NBCF ECR Fellowship [ECF 11-01];
NHMRC New Investigator grant [APP1044661]; VCA ECR fellowship
[ECSG08_07]; NBCF Senior Fellowship; Division of Intramural
Research/NIEHS [1ZIAESO70065]; NHMRC fellowship
FX G.D., Australian Postgradutate Scholarship; K.B., NBCF ECR Fellowship
(ECF 11-01), NHMRC New Investigator grant (APP1044661), and VCA ECR
fellowship (ECSG08_07); R.L.A., NBCF Senior Fellowship; K.S. K.,
Division of Intramural Research/NIEHS [1ZIAESO70065]; G.P.R., NHMRC
fellowship. We thank Dr. Carl Walkey (St Vincents Institute) and A/Prof
Steve Lane (QIMR Berghofer) for their helpful discussions about
cell-cycle-specific staining, the flow core facility at Monash
University, and the FACS facility at Peter Mac as well as Monash Micro
Imaging Facility and Peter Mac microscopy groups for provision of
instrumentation, training, and general support.
NR 49
TC 0
Z9 0
U1 0
U2 0
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 2213-6711
J9 STEM CELL REP
JI Stem Cell Rep.
PD FEB 14
PY 2017
VL 8
IS 2
BP 417
EP 431
DI 10.1016/j.stemcr.2016.12.022
PG 15
WC Cell & Tissue Engineering; Cell Biology
SC Cell Biology
GA EP0TH
UT WOS:000397099100021
PM 28132885
ER
PT J
AU Brait, M
Izumchenko, E
Kagohara, LT
Long, S
Wysocki, PT
Faherty, B
Fertig, EJ
Khor, TO
Bruckheimer, E
Baia, G
Ciznadija, D
Sloma, I
Ben-Zvi, I
Paz, K
Sidransky, D
AF Brait, Mariana
Izumchenko, Evgeny
Kagohara, Luciane T.
Long, Samuel
Wysocki, Piotr T.
Faherty, Brian
Fertig, Elana J.
Khor, Tin Oo
Bruckheimer, Elizabeth
Baia, Gilson
Ciznadija, Daniel
Sloma, Ido
Ben-Zvi, Ido
Paz, Keren
Sidransky, David
TI Comparative mutational landscape analysis of patient-derived tumour
xenografts
SO BRITISH JOURNAL OF CANCER
LA English
DT Article
DE mutation; ddPCR; NGS; PDX; WES; mutation detection techniques; qPCR
ID REAL-TIME PCR; PANCREATIC-CANCER; COLORECTAL-CANCER; SOMATIC MUTATIONS;
DIAGNOSTIC-TOOL; KRAS; EGFR; BRAF; IDENTIFICATION; GENOME
AB Background: Screening of patients for cancer-driving mutations is now used for cancer prognosis, remission scoring and treatment selection. Although recently emerged targeted next-generation sequencing-based approaches offer promising diagnostic capabilities, there are still limitations. There is a pressing clinical need for a well-validated, rapid, cost-effective mutation profiling system in patient specimens. Given their speed and cost-effectiveness, quantitative PCR mutation detection techniques are well suited for the clinical environment. The qBiomarker mutation PCR array has high sensitivity and shorter turnaround times compared with other methods. However, a direct comparison with existing viable alternatives are required to assess its true potential and limitations.
Methods: In this study, we evaluated a panel of 117 patient-derived tumour xenografts by the qBiomarker array and compared with other methods for mutation detection, including Ion AmpliSeq sequencing, whole-exome sequencing and droplet digital PCR.
Results: Our broad analysis demonstrates that the qBiomarker's performance is on par with that of other labour-intensive and expensive methods of cancer mutation detection of frequently altered cancer-associated genes, and provides a foundation for supporting its consideration as an option for molecular diagnostics.
Conclusions: This large-scale direct comparison and validation of currently available mutation detection approaches is extremely relevant for the current scenario of precision medicine and will lead to informed choice of screening methodologies, especially in lower budget conditions or time frame limitations.
C1 [Brait, Mariana; Izumchenko, Evgeny; Kagohara, Luciane T.; Wysocki, Piotr T.; Faherty, Brian; Sidransky, David] Johns Hopkins Univ, Dept Otolaryngol & Head & Neck Surg, Sch Med, Baltimore, MD 21231 USA.
[Long, Samuel] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA.
[Fertig, Elana J.; Sidransky, David] Johns Hopkins Univ, Dept Oncol, Sch Med, Dept Oncol, Baltimore, MD 21231 USA.
[Khor, Tin Oo; Bruckheimer, Elizabeth; Baia, Gilson; Ciznadija, Daniel; Sloma, Ido; Ben-Zvi, Ido; Paz, Keren] Champ Oncol, Baltimore, MD 21205 USA.
RP Sidransky, D (reprint author), Johns Hopkins Univ, Dept Otolaryngol & Head & Neck Surg, Sch Med, Baltimore, MD 21231 USA.; Sidransky, D (reprint author), Johns Hopkins Univ, Dept Oncol, Sch Med, Dept Oncol, Baltimore, MD 21231 USA.
EM dsidrans@jhmi.edu
FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E]
NR 49
TC 0
Z9 0
U1 1
U2 1
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0007-0920
EI 1532-1827
J9 BRIT J CANCER
JI Br. J. Cancer
PD FEB 14
PY 2017
VL 116
IS 4
BP 515
EP 523
DI 10.1038/bjc.2016.450
PG 9
WC Oncology
SC Oncology
GA EL2JT
UT WOS:000394446600013
PM 28118322
ER
PT J
AU Kar, SP
Adler, E
Tyrer, J
Hazelett, D
Anton-Culver, H
Bandera, EV
Beckmann, MW
Berchuck, A
Bogdanova, N
Brinton, L
Butzow, R
Campbell, I
Carty, K
Chang-Claude, J
Cook, LS
Cramer, DW
Cunningham, JM
Dansonka-Mieszkowska, A
Doherty, JA
Dork, T
Durst, M
Eccles, D
Fasching, PA
Flanagan, J
Gentry-Maharaj, A
Glasspool, R
Goode, EL
Goodman, MT
Gronwald, J
Heitz, F
Hildebrandt, MAT
Hogdall, E
Hogdall, CK
Huntsman, DG
Jensen, A
Karlan, BY
Kelemen, LE
Kiemeney, LA
Kjaer, SK
Kupryjanczyk, J
Lambrechts, D
Levine, DA
Li, QY
Lissowska, J
Lu, KRH
Lubinski, J
Massuger, LFAG
McGuire, V
McNeish, I
Menon, U
Modugno, F
Monteiro, AN
Moysich, KB
Ness, RB
Nevanlinna, H
Paul, J
Pearce, CL
Pejovic, T
Permuth, JB
Phelan, C
Pike, MC
Poole, EM
Ramus, SJ
Risch, HA
Rossing, MA
Salvesen, HB
Schildkraut, JM
Sellers, TA
Sherman, M
Siddiqui, N
Sieh, W
Song, HL
Southey, M
Terry, KL
Tworoger, SS
Walsh, C
Wentzensen, N
Whittemore, AS
Wu, ANH
Yang, H
Zheng, W
Ziogas, A
Freedman, ML
Gayther, SA
Pharoah, PDP
Lawrenson, K
AF Kar, Siddhartha P.
Adler, Emily
Tyrer, Jonathan
Hazelett, Dennis
Anton-Culver, Hoda
Bandera, Elisa V.
Beckmann, Matthias W.
Berchuck, Andrew
Bogdanova, Natalia
Brinton, Louise
Butzow, Ralf
Campbell, Ian
Carty, Karen
Chang-Claude, Jenny
Cook, Linda S.
Cramer, Daniel W.
Cunningham, Julie M.
Dansonka-Mieszkowska, Agnieszka
Doherty, Jennifer Anne
Doerk, Thilo
Duerst, Matthias
Eccles, Diana
Fasching, Peter A.
Flanagan, James
Gentry-Maharaj, Aleksandra
Glasspool, Rosalind
Goode, Ellen L.
Goodman, Marc T.
Gronwald, Jacek
Heitz, Florian
Hildebrandt, Michelle A. T.
Hogdall, Estrid
Hogdall, Claus K.
Huntsman, David G.
Jensen, Allan
Karlan, Beth Y.
Kelemen, Linda E.
Kiemeney, Lambertus A.
Kjaer, Susanne K.
Kupryjanczyk, Jolanta
Lambrechts, Diether
Levine, Douglas A.
Li, Qiyuan
Lissowska, Jolanta
Lu, Karen H.
Lubinski, Jan
Massuger, Leon F. A. G.
McGuire, Valerie
McNeish, Iain
Menon, Usha
Modugno, Francesmary
Monteiro, Alvaro N.
Moysich, Kirsten B.
Ness, Roberta B.
Nevanlinna, Heli
Paul, James
Pearce, Celeste L.
Pejovic, Tanja
Permuth, Jennifer B.
Phelan, Catherine
Pike, Malcolm C.
Poole, Elizabeth M.
Ramus, Susan J.
Risch, Harvey A.
Rossing, Mary Anne
Salvesen, Helga B.
Schildkraut, Joellen M.
Sellers, Thomas A.
Sherman, Mark
Siddiqui, Nadeem
Sieh, Weiva
Song, Honglin
Southey, Melissa
Terry, Kathryn L.
Tworoger, Shelley S.
Walsh, Christine
Wentzensen, Nicolas
Whittemore, Alice S.
Wu, Anna H.
Yang, Hannah
Zheng, Wei
Ziogas, Argyrios
Freedman, Matthew L.
Gayther, Simon A.
Pharoah, Paul D. P.
Lawrenson, Kate
TI Enrichment of putative PAX8 target genes at serous epithelial ovarian
cancer susceptibility loci
SO BRITISH JOURNAL OF CANCER
LA English
DT Article
DE serous ovarian cancer; transcription factor; PAX8; genome-wide
association study; gene set enrichment analysis
ID GENOME-WIDE ASSOCIATION; FUNCTIONAL-CHARACTERIZATION; RISK LOCI;
EXPRESSION; GWAS; IDENTIFICATION; PROSTATE; BREAST; CELLS; VARIANTS
AB Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis.
Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals).
Results: The PAX8-target gene set was ranked 1/615 in the discovery (P-GSEA<0.001; FDR = 0.21), 7/615 in the replication (P-GSEA = 0.004; FDR = 0.37), and 1/615 in the combined (P-GSEA<0.001; FDR = 0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P = 0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10(-5) (including six with P<5 x 10(-8)). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (P-GSEA = 0.025) and IGROV1 (P-GSEA = 0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation.
Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
C1 [Kar, Siddhartha P.; Tyrer, Jonathan; Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England.
[Adler, Emily; Pearce, Celeste L.; Pike, Malcolm C.; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA.
[Tyrer, Jonathan; Song, Honglin; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge CB1 8RN, England.
[Hazelett, Dennis] Cedars Sinai Med Ctr, Dept Biomed Sci, Bioinformat & Computat Biol Res Ctr, Los Angeles, CA 90048 USA.
[Hazelett, Dennis; Gayther, Simon A.; Lawrenson, Kate] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA.
[Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, UCI Ctr Canc Genet Res & Prevent, Genet Epidemiol Res Inst,Sch Med, Irvine, CA 92697 USA.
[Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ 08903 USA.
[Beckmann, Matthias W.; Fasching, Peter A.] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg, Univ Str 21-23, D-91054 Erlangen, Germany.
[Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA.
[Bogdanova, Natalia] Hannover Med Sch, Radiat Oncol Res Unit, D-30625 Hannover, Germany.
[Brinton, Louise; Sherman, Mark; Wentzensen, Nicolas; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
[Butzow, Ralf] Univ Helsinki, Dept Pathol, Helsinki 00100, Finland.
[Butzow, Ralf; Nevanlinna, Heli] Helsinki Univ Hosp, Helsinki 00100, Finland.
[Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, St Andrews Pl, East Melbourne, Vic 3002, Australia.
[Campbell, Ian] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia.
[Carty, Karen; Glasspool, Rosalind; Paul, James] Beatson West Scotland Canc Ctr, Glasgow G12 0YN, Lanark, Scotland.
[Chang-Claude, Jenny] Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany.
[Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, D-20246 Hamburg, Germany.
[Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA.
[Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA.
[Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA.
[Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol, PL-02781 Warsaw, Poland.
[Doherty, Jennifer Anne] Geisel Sch Med Dartmouth, Dept Pathol, Hanover, NH 03756 USA.
[Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, D-30625 Hannover, Germany.
[Duerst, Matthias] Jena Univ Hosp Friedrich Schiller Univ, Dept Gynecol, D-07737 Jena, Germany.
[Eccles, Diana] Univ Southampton, Fac Med, Southampton SO16 5YA, Hants, England.
[Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA.
[Flanagan, James] Imperial Coll London, Dept Surg & Canc, London SW7 2AZ, England.
[Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Dept Womens Canc, London W1T 7DN, England.
[Glasspool, Rosalind] Beatson West Scotland Canc Ctr, Glasgow G12 0YN, Lanark, Scotland.
[Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MI 55905 USA.
[Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA.
[Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Commun & Populat Hlth Res Inst, Los Angeles, CA 90048 USA.
[Gronwald, Jacek; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, PL-70001 Szczecin, Poland.
[Heitz, Florian] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, D-45136 Essen, Germany.
[Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, D-65199 Wiesbaden, Germany.
[Hildebrandt, Michelle A. T.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA.
[Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, DK-2100 Copenhagen, Denmark.
[Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, DK-1165 Copenhagen, Denmark.
[Hogdall, Claus K.] Univ Copenhagen, Dept Gynecol, Juliane Marie Ctr, Rigshosp, DK-2100 Copenhagen, Denmark.
[Huntsman, David G.] BC Canc Agcy, Vancouver Gen Hosp BC Canc Agcy, British Columbias Ovarian Canc Res OVCARE Program, Vancouver, BC V5Z 1L3, Canada.
[Huntsman, David G.] Univ British Columbia, Vancouver, BC V5Z 1L3, Canada.
[Huntsman, David G.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1L3, Canada.
[Huntsman, David G.] Univ British Columbia, Dept Obstet & Gynaecol, Vancouver, BC V5Z 1L3, Canada.
[Huntsman, David G.] BC Canc Agcy, Dept Mol Oncol, Res Ctr, Vancouver, BC V5Z 1L3, Canada.
[Karlan, Beth Y.; Walsh, Christine] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA.
[Kelemen, Linda E.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC 29435 USA.
[Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6500 HB Nijmegen, Netherlands.
[Kjaer, Susanne K.] Univ Copenhagen, Dept Gynaecol, Rigshosp, DK-2100 Copenhagen, Denmark.
[Lambrechts, Diether] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium.
[Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Louvain, Belgium.
[Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10065 USA.
[Li, Qiyuan] Dana Farber Canc Inst, Dept Med Oncol, Ctr Funct Canc Epigenet, Boston, MA 02215 USA.
[Li, Qiyuan] Xiamen Univ, Coll Med, Xiamen 361102, Peoples R China.
[Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland.
[Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA.
[Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, NL-6500 HB Nijmegen, Netherlands.
[McGuire, Valerie; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA.
[McNeish, Iain] Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Inst Canc Res, Glasgow G12 0YN, Lanark, Scotland.
[Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA 15213 USA.
[Modugno, Francesmary] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA.
[Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Ovarian Canc Ctr Excellence, Pittsburgh, PA 15213 USA.
[Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA.
[Monteiro, Alvaro N.; Permuth, Jennifer B.; Phelan, Catherine; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA.
[Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA.
[Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki 00100, Finland.
[Nevanlinna, Heli] Univ Texas Houston, Sch Publ Hlth, Houston, TX 77030 USA.
[Pearce, Celeste L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
[Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97239 USA.
[Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA.
[Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA.
[Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02215 USA.
[Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Med Sch, Boston, MA 02215 USA.
[Ramus, Susan J.] Univ New South Wales, Fac Med, Sydney, NSW 2052, Australia.
[Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06510 USA.
[Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98109 USA.
[Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98109 USA.
[Salvesen, Helga B.] Haukeland Univ Horpital, Dept Gynecol & Obstet, N-5058 Bergen, Norway.
[Salvesen, Helga B.] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, N-5058 Bergen, Norway.
[Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA.
[Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC 27710 USA.
[Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland.
[Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3002, Australia.
[Terry, Kathryn L.; Tworoger, Shelley S.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA.
[Zheng, Wei] Vanderbilt Univ, Div Epidemiol, Vanderbilt Ingram Canc Ctr, Med Ctr Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37232 USA.
[Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA.
[Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
[Freedman, Matthew L.] Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA.
[Gayther, Simon A.] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA.
[Lawrenson, Kate] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Los Angeles, CA 90048 USA.
RP Kar, SP (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England.
EM sk718@medschl.cam.ac.uk
RI Dork, Thilo/J-8620-2012
FU Medical Research Council [G0501974]; NCI NIH HHS [R01 CA136924, K07
CA080668, K07 CA092044, K07 CA095666, K07 CA143047, K22 CA138563, N01
CN025403, N01 PC067010, N01PC35137, P01 CA017054, P01 CA087969, P30
CA014089, P30 CA015083, P30 CA016056, P50 CA105009, P50 CA136393, P50
CA159981, R00 CA184415, R01 CA049449, R01 CA050385, R01 CA054419, R01
CA058598, R01 CA058860, R01 CA063678, R01 CA063682, R01 CA064277, R01
CA067262, R01 CA074850, R01 CA076016, R01 CA080742, R01 CA083918, R01
CA087538, R01 CA087696, R01 CA095023, R01 CA106414, R01 CA112523, R01
CA114343, R01 CA122443, R01 CA126841, R01 CA149429, R03 CA113148, R03
CA115195, R37 CA070867, U01 CA069417, U19 CA148112, UM1 CA176726, UM1
CA182910, UM1 CA186107]; NCRR NIH HHS [M01 RR000056]
NR 48
TC 0
Z9 0
U1 3
U2 3
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0007-0920
EI 1532-1827
J9 BRIT J CANCER
JI Br. J. Cancer
PD FEB 14
PY 2017
VL 116
IS 4
BP 524
EP 535
DI 10.1038/bjc.2016.426
PG 12
WC Oncology
SC Oncology
GA EL2JT
UT WOS:000394446600014
PM 28103614
ER
PT J
AU Scadding, GW
Calderon, MA
Shamji, MH
Eifan, AO
Penagos, M
Dumitru, F
Sever, ML
Bahnson, HT
Lawson, K
Harris, KM
Plough, AG
Panza, JL
Qin, TL
Lim, N
Tchao, NK
Togias, A
Durham, SR
AF Scadding, Guy W.
Calderon, Moises A.
Shamji, Mohamed H.
Eifan, Aarif O.
Penagos, Martin
Dumitru, Florentina
Sever, Michelle L.
Bahnson, Henry T.
Lawson, Kaitie
Harris, Kristina M.
Plough, Audrey G.
Panza, Joy Laurienzo
Qin, Tielin
Lim, Noha
Tchao, Nadia K.
Togias, Alkis
Durham, Stephen R.
CA Immune Tolerance Network GRASS Stu
TI Effect of 2 Years of Treatment With Sublingual Grass Pollen
Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among
Patients With Moderate to Severe Seasonal Allergic Rhinitis The GRASS
Randomized Clinical Trial
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Article
ID RESPIRATORY ALLERGY; EFFICACY; RHINOCONJUNCTIVITIS; CESSATION; OUTCOMES;
ASTHMA; SAFETY; TABLET; SCORE
AB Importance Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.
Objective To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.
Design, Setting, and Participants A randomized double-blind, placebo-controlled, 3-parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015.
Interventions Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 mu g of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 mu g of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation).
Main Outcomes and Measures Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy.
Results Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was -0.18 (95% CI, -1.25 to 0.90; [P = .75]).
Conclusions and Relevance Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.
C1 [Scadding, Guy W.; Calderon, Moises A.; Shamji, Mohamed H.; Eifan, Aarif O.; Penagos, Martin; Dumitru, Florentina; Durham, Stephen R.] Imperial Coll, London, England.
[Scadding, Guy W.; Calderon, Moises A.; Shamji, Mohamed H.; Eifan, Aarif O.; Penagos, Martin; Dumitru, Florentina; Durham, Stephen R.] Royal Brompton & Harefield Hosp NHS Fdn Trust, London, England.
[Sever, Michelle L.; Bahnson, Henry T.; Lawson, Kaitie] Rho Fed Syst Div, Chapel Hill, NC USA.
[Bahnson, Henry T.] Benaroya Res Inst, Immune Tolerance Network, Seattle, WA USA.
[Harris, Kristina M.; Qin, Tielin; Lim, Noha] Immune Tolerance Network, Bethesda, MD USA.
[Plough, Audrey G.; Tchao, Nadia K.] Immune Tolerance Network, San Francisco, CA USA.
[Panza, Joy Laurienzo; Togias, Alkis] NIAID, Rockville, MD USA.
[Tchao, Nadia K.] Amgen Inc, Dept Early Dev Hematol Oncol, San Francisco, CA USA.
RP Durham, SR (reprint author), Imperial Coll London, Natl Heart & Lung Inst, Allergy & Clin Immunol, Sect Inflammat Repair & Dev, Dovehouse St, London SW3 6LY, England.
EM s.durham@imperial.ac.uk
OI Eifan, Aarif/0000-0003-4098-4211
FU DAIT-NIAID, National Institutes of Health (NIH) [NO1-AI-15416,
UM1AI109565, UM2AI117870]; DAIT-NIAID [UM2AI117870, HHSN272200800029C,
HHSN272201200004C, HHSN272201200002C]
FX The trial was conducted by the ITN with financial support from the
DAIT-NIAID, National Institutes of Health (NIH) under award numbers
NO1-AI-15416, UM1AI109565, and UM2AI117870; the following
DAIT-NIAID-funded groups: Statistical and Clinical Coordinating Centers
(contract HHSN272200800029C and grant UM2AI117870), Clinical Site
Monitoring Center (contract HHSN272201200004C), and Regulatory
Management Center (contract HHSN272201200002C); ALK-Abello A/S Horsholm,
Denmark supplied Alutard SQ Grass Pollen, and Grazax, and matching
placebos used for the GRASS clinical trial to DAIT-NIAID without charge.
Dr Durham served as the sponsor of the Medicines and Healthcare Products
Regulatory Agency Clinical Trial Application.
NR 34
TC 1
Z9 1
U1 1
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 FEB 14
PY 2017
VL 317
IS 6
BP 615
EP 625
DI 10.1001/jama.2016.21040
PG 11
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL8LI
UT WOS:000394870900016
PM 28196255
ER
PT J
AU Nielles-Vallespin, S
Khalique, Z
Ferreira, PF
de Silva, R
Scott, AD
Kilner, P
McGill, LA
Giannakidis, A
Gatehouse, PD
Ennis, D
Aliotta, E
Al-Khalil, M
Kellman, P
Mazilu, D
Balaban, RS
Firmin, DN
Arai, AE
Pennell, DJ
AF Nielles-Vallespin, Sonia
Khalique, Zohya
Ferreira, Pedro F.
de Silva, Ranil
Scott, Andrew D.
Kilner, Philip
McGill, Laura-Ann
Giannakidis, Archontis
Gatehouse, Peter D.
Ennis, Daniel
Aliotta, Eric
Al-Khalil, Majid
Kellman, Peter
Mazilu, Dumitru
Balaban, Robert S.
Firmin, David N.
Arai, Andrew E.
Pennell, Dudley J.
TI Assessment of Myocardial Microstructural Dynamics by In Vivo Diffusion
Tensor Cardiac Magnetic Resonance
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Article
DE dilated cardiomyopathy; helical structure; hypertrophic cardiomyopathy;
laminar structure; left ventricle; sheetlet structure
ID HYPERTROPHIC CARDIOMYOPATHY; FIBER ORIENTATION; LEFT-VENTRICLE;
HISTOLOGICAL VALIDATION; LAMINAR ARCHITECTURE; EUROPEAN-SOCIETY; WATER
DIFFUSION; TASK-FORCE; MRI; STRAIN
AB BACKGROUND Cardiomyocytes are organized in microstructures termed sheetlets that reorientate during left ventricular thickening. Diffusion tensor cardiac magnetic resonance (DT-CMR) may enable noninvasive interrogation of in vivo cardiac microstructural dynamics. Dilated cardiomyopathy (DCM) is a condition of abnormal myocardium with unknown sheetlet function.
OBJECTIVES This study sought to validate in vivo DT-CMR measures of cardiac microstructure against histology, characterize microstructural dynamics during left ventricular wall thickening, and apply the technique in hypertrophic cardiomyopathy (HCM) and DCM.
METHODS In vivo DT-CMR was acquired throughout the cardiac cycle in healthy swine, followed by in situ and ex vivo DT-CMR, then validated against histology. In vivo DT-CMR was performed in 19 control subjects, 19 DCM, and 13 HCM patients.
RESULTS In swine, a DT-CMR index of sheetlet reorientation (E2A) changed substantially (E2A mobility similar to 46 degrees). E2A changes correlated with wall thickness changes (in vivo r(2) = 0.75; in situ r(2) = 0.89), were consistently observed under all experimental conditions, and accorded closely with histological analyses in both relaxed and contracted states. The potential contribution of cyclical strain effects to in vivo E2A was similar to 17%. In healthy human control subjects, E2A increased from diastole (18 degrees) to systole (65 degrees; p < 0.001; E2A mobility = 45 degrees). HCM patients showed significantly greater E2A in diastole than control subjects did (48 degrees; p < 0.001) with impaired E2A mobility (23 degrees; p < 0.001). In DCM, E2A was similar to control subjects in diastole, but systolic values were markedly lower (40 degrees; p < 0.001) with impaired E2A mobility (20 degrees; p < 0.001).
CONCLUSIONS Myocardial microstructure dynamics can be characterized by in vivo DT-CMR. Sheetlet function was abnormal in DCM with altered systolic conformation and reduced mobility, contrasting with HCM, which showed reduced mobility with altered diastolic conformation. These novel insights significantly improve understanding of contractile dysfunction at a level of noninvasive interrogation not previously available in humans.
C1 [Nielles-Vallespin, Sonia; Kellman, Peter; Mazilu, Dumitru; Balaban, Robert S.; Arai, Andrew E.] NHLBI, NIH, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA.
[Nielles-Vallespin, Sonia; Khalique, Zohya; Ferreira, Pedro F.; de Silva, Ranil; Scott, Andrew D.; Kilner, Philip; McGill, Laura-Ann; Giannakidis, Archontis; Gatehouse, Peter D.; Al-Khalil, Majid; Firmin, David N.; Pennell, Dudley J.] Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, Cardiovasc Magnet Resonance Unit, London, England.
[Nielles-Vallespin, Sonia; Khalique, Zohya; Ferreira, Pedro F.; de Silva, Ranil; Scott, Andrew D.; Kilner, Philip; McGill, Laura-Ann; Giannakidis, Archontis; Gatehouse, Peter D.; Firmin, David N.; Pennell, Dudley J.] Imperial Coll London, Natl Heart & Lung Inst, London, England.
[Khalique, Zohya; Ferreira, Pedro F.; de Silva, Ranil; Scott, Andrew D.; Kilner, Philip; Firmin, David N.; Pennell, Dudley J.] Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, Natl Inst Hlth Res, Cardiovasc Biomed Res Unit, London, England.
[Khalique, Zohya; Ferreira, Pedro F.; de Silva, Ranil; Scott, Andrew D.; Kilner, Philip; Firmin, David N.; Pennell, Dudley J.] Imperial Coll London, London, England.
[Ennis, Daniel; Aliotta, Eric] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90095 USA.
RP Nielles-Vallespin, S (reprint author), NHLBI, NIH, Bldg 10,Room B1D401,10 Ctr Dr, Bethesda, MD 20892 USA.
EM sonia.nielles-vallespin@nih.gov
FU National Heart, Lung, and Blood Institute, National Institutes of
Health, Division of Intramural Research, Department of Health and Human
Services [HL004607-14CPB]; British Heart Foundation; National Institute
of Health Research Cardiovascular Biomedical Research Unit at the Royal
Brompton Hospital and Imperial College, London; Siemens Medical
Solutions; Siemens
FX This work was supported by the National Heart, Lung, and Blood
Institute, National Institutes of Health, Division of Intramural
Research, Department of Health and Human Services (HL004607-14CPB); the
British Heart Foundation; and the National Institute of Health Research
Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital
and Imperial College, London. Dr. Gatehouse has a departmental research
agreement and collaborates on other work with Siemens. Dr. Ennis has
received research support from Siemens Medical Solutions. Dr. Arai is a
principal investigator on a U.S. government Cooperative Research and
Development Agreement with Siemens Medical Solutions (HL-CR-05-004); and
has a research agreement with Bayer. Dr. Pennell is a shareholder and
Director of Cardiovascular Imaging Solutions; and has received research
support from Siemens. Royal Brompton Hospital has research collaboration
agreements with Siemens AG Medical Solutions. All other authors have
reported that they have no relationships relevant to the contents of
this paper to disclose. Drs. Nielles-Vallespin, Khalique, and Ferreira
contributed equally to this work and are joint first authors. Drs.
Firmin, Arai, and Pennell contributed equally to this work and are joint
senior authors.
NR 49
TC 1
Z9 1
U1 0
U2 0
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0735-1097
EI 1558-3597
J9 J AM COLL CARDIOL
JI J. Am. Coll. Cardiol.
PD FEB 14
PY 2017
VL 69
IS 6
BP 661
EP 676
DI 10.1016/j.jacc.2016.11.051
PG 16
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EN9SC
UT WOS:000396338900009
PM 28183509
ER
PT J
AU Lansky, AJ
Messe, SR
Brickman, AM
Dwyer, M
van der Worp, HB
Lazar, RM
Pietras, CG
Abrams, KJ
McFadden, E
Petersen, NH
Browndyke, J
Prendergast, B
Ng, VG
Cutlip, DE
Kapadia, S
Krucoff, MW
Linke, A
Moy, CS
Schofer, J
van Es, GA
Virmani, R
Popma, J
Parides, MK
Kodali, S
Bilello, M
Zivadinov, R
Akar, J
Furie, KL
Gress, D
Voros, S
Moses, J
Greer, D
Forrest, JK
Holmes, D
Kappetein, AP
Mack, M
Baumbach, A
AF Lansky, Alexandra J.
Messe, Steven R.
Brickman, Adam M.
Dwyer, Michael
van der Worp, H. Bart
Lazar, Ronald M.
Pietras, Cody G.
Abrams, Kevin J.
McFadden, Eugene
Petersen, Nils H.
Browndyke, Jeffrey
Prendergast, Bernard
Ng, Vivian G.
Cutlip, Donald E.
Kapadia, Samir
Krucoff, Mitchell W.
Linke, Axel
Moy, Claudia Scala
Schofer, Joachim
van Es, Gerrit-Anne
Virmani, Renu
Popma, Jeffrey
Parides, Michael K.
Kodali, Susheel
Bilello, Michel
Zivadinov, Robert
Akar, Joseph
Furie, Karen L.
Gress, Daryl
Voros, Szilard
Moses, Jeffrey
Greer, David
Forrest, John K.
Holmes, David
Kappetein, Arie P.
Mack, Michael
Baumbach, Andreas
TI Proposed Standardized Neurological Endpoints for Cardiovascular Clinical
Trials An Academic Research Consortium Initiative
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Review
DE cardiovascular; methodology; neurological definitions; outcomes; stroke
trials
ID AORTIC-VALVE IMPLANTATION; ASSOCIATION/AMERICAN STROKE ASSOCIATION;
TRANSIENT ISCHEMIC ATTACK; HEALTH-CARE PROFESSIONALS; CEREBRAL-ISCHEMIA;
COGNITIVE IMPAIRMENT; CONSENSUS DOCUMENT; CARDIAC-SURGERY; DIFFUSION;
METAANALYSIS
AB Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies. (C) 2017 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. All rights reserved.
C1 [Lansky, Alexandra J.; Pietras, Cody G.; Ng, Vivian G.; Akar, Joseph; Forrest, John K.] Yale Sch Med, Dept Internal Med, Div Cardiovasc Med, 135 Coll St,Suite 101, New Haven, CT 06510 USA.
[Lansky, Alexandra J.; Pietras, Cody G.; Ng, Vivian G.] Yale Cardiovasc Res Grp, New Haven, CT USA.
[Lansky, Alexandra J.; Baumbach, Andreas] St Bartholomews Hosp, William Harvey Res Inst, Dept Cardiol, London, England.
[Lansky, Alexandra J.; Baumbach, Andreas] Queen Mary Univ London, London, England.
[Messe, Steven R.] Hosp Univ Penn, Dept Neurol, 3400 Spruce St, Philadelphia, PA 19104 USA.
[Brickman, Adam M.; Lazar, Ronald M.] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY USA.
[Dwyer, Michael; Zivadinov, Robert] SUNY Buffalo, Buffalo Neuroimaging Anal, Buffalo, NY USA.
[van der Worp, H. Bart] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands.
[Abrams, Kevin J.] Baptist Hosp Miami, Baptist Cardiac & Vasc Inst, Miami, FL USA.
[McFadden, Eugene] Cork Univ Hosp, Dept Cardiol, Cork, Ireland.
[Petersen, Nils H.; Greer, David] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA.
[Browndyke, Jeffrey] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Div Geriatr Behav Hlth, Durham, NC USA.
[Prendergast, Bernard] St Thomas Hosp, Dept Cardiol, London, England.
[Cutlip, Donald E.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc Med, Boston, MA 02215 USA.
[Kapadia, Samir] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA.
[Krucoff, Mitchell W.] Duke Univ, Med Ctr, Dept Cardiol, Durham, NC USA.
[Linke, Axel] Univ Leipzig, Dept Internal Med Cardiol, Leipzig, Germany.
[Moy, Claudia Scala] NINDS, Off Clin Res, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
[Schofer, Joachim] Albertine Heart Ctr, Medicare Ctr, Hamburg, Germany.
[Schofer, Joachim] Albertine Heart Ctr, Dept Percutaneous Intervent Struct Heart Dis, Hamburg, Germany.
[van Es, Gerrit-Anne] Cardialysis, Rotterdam, Netherlands.
[Virmani, Renu] CVpath Inst, Gaithersburg, MD USA.
[Popma, Jeffrey; Parides, Michael K.] Mt Sinai Grp, Icahn Sch Med, New York, NY USA.
[Kodali, Susheel; Moses, Jeffrey] Columbia Univ, Med Ctr, Dept Internal Med, Div Cardiol, New York, NY USA.
[Bilello, Michel] Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA.
[Furie, Karen L.] Rhode Isl Hosp, Dept Neurol, Providence, RI USA.
[Gress, Daryl] Univ Nebraska Med Ctr, Dept Neurol Sci, Omaha, NE USA.
[Voros, Szilard] Global Inst Res & Global Genom Grp, Richmond, VA USA.
[Holmes, David] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN USA.
[Kappetein, Arie P.] Erasmus Univ, Med Ctr, Dept Cardiothorac Surg, Rotterdam, Netherlands.
[Mack, Michael] Heart Hosp, Baylor Plano Res Ctr, Dept Cardiovasc Surg, Plano, TX USA.
RP Lansky, AJ (reprint author), Yale Sch Med, Dept Internal Med, Div Cardiovasc Med, 135 Coll St,Suite 101, New Haven, CT 06510 USA.
EM alexandra.lansky@yale.edu
FU Boston Scientific; Edwards Lifesciences; Medtronic Corporation; St. Jude
Medical; NeuroSave Inc.; Keystone Heart Ltd.; Keystone Heart;
GlaxoSmithKline; Bayer; Direct Flow Medical; Novartis; Claret Medical;
Dutch Heart Foundation [2010T075]; Medtronic; Abbott Vascular; 480
Biomedical; Abbott Vascular Japan; Atrium; Biosensors International;
Biotronik; Cordis Johnson Johnson; Kona; Microport Medical; OrbusNeich
Medical; ReCore; SINO Medical Technology; Terumo Corporation; W.L. Gore;
Abbott; Teva Pharmaceuticals; Biogen Idec; EMD Serono; Genzyme-Sanofi;
IMS Health; Intekrin
FX Grants to support travel costs, meeting rooms, and lodging for academic
attendees at the San Francisco and New York meetings were provided by
Boston Scientific, Edwards Lifesciences, Medtronic Corporation, St. Jude
Medical, NeuroSave Inc., and Keystone Heart Ltd. The NeuroARC meetings
involved members of the U.S. Center for Devices and Radiological Health,
U.S. Food and Drug Association (FDA). The opinions or assertions herein
are the views of the authors, and are not to be construed as reflecting
the views of the FDA. Dr. Lansky has received research grant support
from Keystone Heart, NeuroSave Inc., and Boston Scientific; and has
received speaker/consultant fees from Keystone Heart. Dr. Messe has
received research support from GlaxoSmithKline and Bayer; and is
participating on the Clinical Events Committee for the SALUS trial,
sponsored by Direct Flow Medical. Dr. Brickman has served as a
consultant for Keystone Heart, ERT, and ProPhase LLC. Dr. Dwyer has
received research grant support and is on the advisory board for
Novartis; has received research grant support and consulting fees from
Claret Medical; and is on the advisory board for EMD Serono. Dr. van der
Worp is supported by a grant from the Dutch Heart Foundation (2010T075).
Dr. Lazar has received grant support and consulting fees from Claret
Medical. Dr. Abrams has received consultant fees and equity for Keystone
Heart. Dr. Prendergast has received lecture fees from Edwards
Lifesciences and Boston Scientific. Dr. Cutlip has received research
contract funding from Medtronic and Boston Scientific to his
institution. Dr. Kapadia has served as the coprincipal investigator for
the Sentinel study sponsored by Claret Medical (unpaid). Dr. Krucoff has
received research grants from and served as a consultant for Abbott
Vascular, Medtronic, Boston Scientific, and St. Jude Medical. Dr. Linke
has received research grant support from Medtronic and Claret Medical;
has served as a consultant for Medtronic, Bard, and St. Jude Medical;
has received speaker honoraria from Medtronic, St. Jude Medical,
Symetis, Edwards Lifesciences, and Boston Scientific; and has stock
options in Claret Medical. Dr. Virmani has received research support
from 480 Biomedical, Abbott Vascular Japan, Atrium, Biosensors
International, Biotronik, Boston Scientific, Cordis Johnson & Johnson,
GlaxoSmithKline, Kona, Medtronic, Microport Medical, OrbusNeich Medical,
ReCore, SINO Medical Technology, Terumo Corporation, and W.L. Gore. Dr.
Popma has received institutional grants from Medtronic, Boston
Scientific, Abbott, and Direct Flow Medical; has served on the medical
advisory board of Boston Scientific; and has received consultant fees
from and has equity in Direct Flow Medical. Dr. Kodali has served on the
Steering Committee of the PARTNER III Trial, sponsored by Edwards
Lifesciences; has served as a consultant to Medtronic; is the principal
investigator of the Sentinel Trial sponsored by Claret Medical; has
served on the scientific advisory boards of Thubrikar Aortic Valve Inc.
and Dura Biotech; has received research support and travel reimbursement
from Edwards Lifesciences, Claret Medical, and Medtronic; and has equity
in Thubrikar Aortic Valve (minimal) and Dura Biotech. Dr. Zivadinov has
received speaker/consultant fees from Teva Pharmaceuticals, Biogen Idec,
EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health, and Novartis;
and has received research grants from Teva Pharmaceuticals,
Genzyme-Sanofi, Novartis, Claret Medical, Intekrin, and IMS Health. Dr.;
Gress has served as a consultant to Medtronic; and has served on the
scientific advisory board of Ornim, Keystone Heart, and Silk Road
Medical. Dr. Voros is a founder, shareholder, and executive of Global
Institute for Research; and is a minority shareholder in Keystone Heart.
Dr. Moses has equity in Claret. Dr. Forrest has received grant support
and consulting fees from Edwards Lifesciences and Medtronic. Dr.
Baumbach has received research grants and speakers fees for Keystone
Heart. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose.
NR 68
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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 FEB 14
PY 2017
VL 69
IS 6
BP 679
EP 691
DI 10.1016/j.jacc.2016.11.045
PG 13
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EN9SC
UT WOS:000396338900011
PM 28183511
ER
PT J
AU Yang, L
Pratt, C
Valencia, E
Conover, S
Fernandez, R
Burrone, MS
Cavalcanti, MT
Lovisi, G
Rojas, G
Alvarado, R
Galea, S
Price, LN
Susser, E
AF Yang, L.
Pratt, C.
Valencia, E.
Conover, S.
Fernandez, R.
Burrone, M. S.
Cavalcanti, M. T.
Lovisi, G.
Rojas, G.
Alvarado, R.
Galea, S.
Price, L. N.
Susser, E.
TI RedeAmericas: building research capacity in young leaders for
sustainable growth in community mental health services in Latin America
SO GLOBAL MENTAL HEALTH
LA English
DT Article
DE Capacity building; career development; global mental health; Latin
America; mentorship program; other
ID MIDDLE-INCOME COUNTRIES; IMPLEMENTATION; ILLNESS; STIGMA
AB The purpose of this paper is to describe the development and initial accomplishments of a training program of young leaders in community mental health research as part of a Latin American initiative known as RedeAmericas. RedeAmericas was one of five regional 'Hubs' funded by the National Institute of Mental Health (NIMH) to improve community mental health care and build mental health research capacity in low-and middle-income countries. It included investigators in six Latin American cities - Santiago, Chile; Medellin, Colombia; Rio de Janeiro, Brazil; and Cordoba, Neuquen, and Buenos Aires in Argentina - working together with a team affiliated with the Global Mental Health program at Columbia University in New York City. One component of RedeAmericas was a capacity-building effort that included an Awardee program for early career researchers in the mental health field. We review the aims of this component, how it developed, and what was learned that would be useful for future capacity-building efforts, and also comment on future prospects for maintaining this type of effort.
C1 [Yang, L.] NYU, Coll Global Publ Hlth, New York, NY USA.
[Yang, L.; Pratt, C.; Valencia, E.; Susser, E.] Columbia Univ, Mailman Sch Publ Hlth, 722 West 168th St 1030, New York, NY 10032 USA.
[Valencia, E.; Alvarado, R.] Univ Chile, Sch Publ Hlth, Fac Med, Santiago, Chile.
[Conover, S.] CUNY, Hunter Coll, Silberman Sch Social Work, New York, NY 10021 USA.
[Fernandez, R.; Burrone, M. S.] Natl Univ Cordoba, Sch Publ Hlth, Cordoba, Argentina.
[Cavalcanti, M. T.] Univ Fed Rio de Janeiro, Inst Psychiat, Rio De Janeiro, Brazil.
[Lovisi, G.] Univ Fed Rio de Janeiro, Sch Publ Hlth, Rio De Janeiro, Brazil.
[Rojas, G.] Univ Chile, Fac Med, Clin Hosp, Santiago, Chile.
[Galea, S.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA.
[Price, L. N.] NIMH, NIH, Bethesda, MD USA.
[Susser, E.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA.
RP Susser, E (reprint author), Columbia Univ, Mailman Sch Publ Hlth, 722 West 168th St 1030, New York, NY 10032 USA.; Susser, E (reprint author), New York State Psychiat Inst & Hosp, New York, NY 10032 USA.
EM ess8@cumc.columbia.edu
FU US National Institute of Mental Health of the National Institutes of
Health [U19MH095718]
FX The research reported in this article was supported by the US National
Institute of Mental Health of the National Institutes of Health under
award number U19MH095718. The views expressed are those of the authors
and do not necessarily represent those of the National Institute of
Mental Health, the National Institutes of Health, the Department of
Health and Human Services, or the US Government.
NR 21
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U2 1
PU CAMBRIDGE UNIV PRESS
PI CAMBRIDGE
PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND
SN 2054-4251
J9 GLOB MENT HEALTH
JI Glob. Ment. Health
PD FEB 14
PY 2017
VL 4
AR e3
DI 10.1017/gmh.2017.2
PG 9
WC Psychiatry
SC Psychiatry
GA EL0IF
UT WOS:000394305400001
ER
PT J
AU Hoglinger, D
Nadler, A
Haberkant, P
Kirkpatrick, J
Schifferer, M
Stein, F
Hauke, S
Porter, FD
Schultz, C
AF Hoeglinger, Doris
Nadler, Andre
Haberkant, Per
Kirkpatrick, Joanna
Schifferer, Martina
Stein, Frank
Hauke, Sebastian
Porter, Forbes D.
Schultz, Carsten
TI Trifunctional lipid probes for comprehensive studies of single lipid
species in living cells
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE lipid-protein interaction; sphingosine; diacylglycerol; caged lipids;
Niemann-Pick disease type C
ID NIEMANN-PICK-DISEASE; SACCHAROMYCES-CEREVISIAE; CORRELATED FLUORESCENCE;
ELECTRON-MICROSCOPY; PHOSPHATIDIC-ACID; PLASMA-MEMBRANE; SPHINGOSINE;
METABOLISM; PROTEINS; VISUALIZATION
AB Lipid-mediated signaling events regulate many cellular processes. Investigations of the complex underlying mechanisms are difficult because several different methods need to be used under varying conditions. Here we introduce multifunctional lipid derivatives to study lipid metabolism, lipid-protein interactions, and intracellular lipid localization with a single tool per target lipid. The probes are equipped with two photoreactive groups to allow photoliberation (uncaging) and photo-cross-linking in a sequential manner, as well as a click-handle for subsequent functionalization. We demonstrate the versatility of the design for the signaling lipids sphingosine and diacylglycerol; uncaging of the probe for these two species triggered calcium signaling and intracellular protein translocation events, respectively. We performed proteomic screens to map the lipid-interacting proteome for both lipids. Finally, we visualized a sphingosine transport deficiency in patient-derived Niemann-Pick disease type C fibroblasts by fluorescence as well as correlative light and electron microscopy, pointing toward the diagnostic potential of such tools. We envision that this type of probe will become important for analyzing and ultimately understanding lipid signaling events in a comprehensive manner.
C1 [Hoeglinger, Doris; Nadler, Andre; Haberkant, Per; Kirkpatrick, Joanna; Schifferer, Martina; Stein, Frank; Hauke, Sebastian; Schultz, Carsten] European Mol Biol Lab, Cell Biol & Biophys Unit, D-69117 Heidelberg, Germany.
[Hoeglinger, Doris] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England.
[Nadler, Andre] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany.
[Kirkpatrick, Joanna] Leibniz Inst, Aging Fritz Lipmann Inst, D-07745 Jena, Germany.
[Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Divis Translat Med, Bethesda, MD 20892 USA.
RP Schultz, C (reprint author), European Mol Biol Lab, Cell Biol & Biophys Unit, D-69117 Heidelberg, Germany.
EM schultz@embl.de
OI Hoeglinger, Doris/0000-0002-6862-0076
FU European Union Seventh Framework Programme [289278]; Deutsche
Forschungsgemeinschaft [Transregio 83]; intramural research program of
the National Institute of Child Health and Human Development; European
Union
FX We thank the Advanced Light Microscopy Facility and the Proteomic Core
Facility of the European Molecular Biology Laboratory (EMBL). This
research has received funding from the European Union Seventh Framework
Programme under Grant Agreement 289278-"Sphingonet"- as well as
Transregio 83 funded by the Deutsche Forschungsgemeinschaft. This work
was partially supported by the intramural research program of the
National Institute of Child Health and Human Development. M.S. is a
fellow of the EMBL Interdisciplinary Postdoc Program, cofunded by the
European Union.
NR 46
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U1 4
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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 FEB 14
PY 2017
VL 114
IS 7
BP 1566
EP 1571
DI 10.1073/pnas.1611096114
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK5TR
UT WOS:000393989300058
PM 28154130
ER
PT J
AU Sripathy, S
Leko, V
Adrianse, RL
Loe, T
Foss, EJ
Dalrymple, E
Lao, U
Gatbonton-Schwager, T
Carter, KT
Payer, B
Paddison, PJ
Grady, WM
Lee, JT
Bartolomei, MS
Bedalov, A
AF Sripathy, Smitha
Leko, Vid
Adrianse, Robin L.
Loe, Taylor
Foss, Eric J.
Dalrymple, Emily
Lao, Uyen
Gatbonton-Schwager, Tonibelle
Carter, Kelly T.
Payer, Bernhard
Paddison, Patrick J.
Grady, William M.
Lee, Jeannie T.
Bartolomei, Marisa S.
Bedalov, Antonio
TI Screen for reactivation of MeCP2 on the inactive X chromosome identifies
the BMP/TGF-beta superfamily as a regulator of XIST expression
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE XIST; X inactivation; MeCP2; Rett syndrome; BMP/TGF-beta
ID DE-LANGE-SYNDROME; RETT-SYNDROME; SACCHAROMYCES-CEREVISIAE; INTELLECTUAL
DISABILITY; HISTONE ACETYLATION; DOSAGE COMPENSATION; DNA DEMETHYLATION;
MUTATIONS; RNF12; TRANSCRIPTION
AB Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG-binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups. More than half encoded proteins with known enzymatic activity, and six were members of the bone morphogenetic protein (BMP)/TGF-beta pathway. shRNAs directed against each of these six genes down-regulated X-inactive specific transcript (XIST), a key player in X-chromosome inactivation that encodes an RNA that coats the silent X chromosome, and modulation of regulators of this pathway both in cell culture and in mice demonstrated robust regulation of XIST. Moreover, we show that Rnf12, an X-encoded ubiquitin ligase important for initiation of X-chromosome inactivation and XIST transcription in ES cells, also plays a role in maintenance of the inactive state through regulation of BMP/TGF-beta signaling. Our results identify pharmacologically suitable targets for reactivation of MeCP2 on the Xi and a genetic circuitry that maintains XIST expression and X-chromosome inactivation in differentiated cells.
C1 [Sripathy, Smitha; Leko, Vid; Adrianse, Robin L.; Loe, Taylor; Foss, Eric J.; Dalrymple, Emily; Lao, Uyen; Gatbonton-Schwager, Tonibelle; Carter, Kelly T.; Grady, William M.; Bedalov, Antonio] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA.
[Payer, Bernhard; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.
[Payer, Bernhard; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.
[Payer, Bernhard; Lee, Jeannie T.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
[Paddison, Patrick J.] Fred Hutchinson Canc Res Ctr, Human Biol Div, Seattle, WA 98109 USA.
[Grady, William M.] Univ Washington, Sch Med, Div Gastroenterol, Seattle, WA 98195 USA.
[Bartolomei, Marisa S.] Univ Penn, Dept Cell & Dev Biol, Perelman Sch Med, Epigenet Program, Philadelphia, PA 19104 USA.
[Bedalov, Antonio] Univ Washington, Sch Med, Dept Biochem & Med, Seattle, WA 98195 USA.
[Leko, Vid] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Bedalov, A (reprint author), Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA.; Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Lee, JT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Lee, JT (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Bedalov, A (reprint author), Univ Washington, Sch Med, Dept Biochem & Med, Seattle, WA 98195 USA.
EM lee@molbio.mgh.harvard.edu; abedalov@fhcrc.org
FU Rett Syndrome Research Trust
FX We thank Kathrin Plath for providing us with CMVluciferase/.XIST mouse
embryonic fibroblasts, Joost Gribnau for the Rnf12 expression plasmids,
Ross Dickins for shRNA library, and Christine Disteche for Patski cells.
This work was supported by grants from the Rett Syndrome Research Trust
(to A.B., M.S.B., and J.T.L.).
NR 52
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U1 1
U2 1
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 14
PY 2017
VL 114
IS 7
BP 1619
EP 1624
DI 10.1073/pnas.1621356114
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK5TR
UT WOS:000393989300067
PM 28143937
ER
PT J
AU Taniguchi, K
Moroishi, T
de Jong, PR
Krawczyk, M
Grebbin, BM
Luo, HY
Xu, RH
Golob-Schwarzl, N
Schweiger, C
Wang, KP
Di Caroa, G
Feng, Y
Fearon, ER
Raz, E
Kenner, L
Farin, HF
Guan, KL
Haybaeck, J
Datz, C
Zhang, K
Karin, M
AF Taniguchi, Koji
Moroishi, Toshiro
de Jong, Petrus R.
Krawczyk, Michal
Grebbin, Britta Moyo
Luo, Huiyan
Xu, Rui-hua
Golob-Schwarzl, Nicole
Schweiger, Caroline
Wang, Kepeng
Di Caroa, Giuseppe
Feng, Ying
Fearon, Eric R.
Raz, Eyal
Kenner, Lukas
Farin, Henner F.
Guan, Kun-Liang
Haybaeck, Johannes
Datz, Christian
Zhang, Kang
Karin, Michael
TI YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic
tumorigenesis
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE colorectal cancer; adenomatous polyposis coli; IL-6ST/gp130; YAP; STAT3
ID COLORECTAL-CANCER; IL-6 FAMILY; STEM-CELLS; IN-VITRO; INFLAMMATION;
YAP/TAZ; INACTIVATION; REGENERATION; HOMEOSTASIS; METASTASIS
AB Loss of tumor suppressor adenomatous polyposis coli (APC) activates beta-catenin to initiate colorectal tumorigenesis. However, beta-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.
C1 [Taniguchi, Koji; Wang, Kepeng; Di Caroa, Giuseppe; Karin, Michael] Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA.
[Taniguchi, Koji; Wang, Kepeng; Di Caroa, Giuseppe; Karin, Michael] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.
[Taniguchi, Koji; Wang, Kepeng; Di Caroa, Giuseppe; Karin, Michael] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA.
[Taniguchi, Koji] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka 8128582, Japan.
[Taniguchi, Koji] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan.
[Moroishi, Toshiro; Guan, Kun-Liang] Univ Calif San Diego, Moores Canc Ctr, Dept Pharmacol, La Jolla, CA 92093 USA.
[de Jong, Petrus R.; Raz, Eyal] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA.
[de Jong, Petrus R.] NCI, Sanford Burnham Prebys Med Discovery Inst, Designated Canc Ctr, La Jolla, CA 92037 USA.
[Krawczyk, Michal; Grebbin, Britta Moyo; Luo, Huiyan; Zhang, Kang] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA.
[Grebbin, Britta Moyo; Farin, Henner F.] German Canc Consortium, D-69120 Heidelberg, Germany.
[Grebbin, Britta Moyo; Farin, Henner F.] Georg Speyer Haus, Inst Tumor Biol & Expt Therapy, D-60596 Frankfurt, Germany.
[Farin, Henner F.] German Canc Res Ctr, D-69120 Heidelberg, Germany.
[Luo, Huiyan; Xu, Rui-hua] Sun Yat Sen Univ, Ctr Canc, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol, Guangzhou 510060, Guangdong, Peoples R China.
[Golob-Schwarzl, Nicole; Schweiger, Caroline; Haybaeck, Johannes] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria.
[Wang, Kepeng] Univ Connecticut, Ctr Hlth, Sch Med, Dept Immunol, Farmington, CT USA.
[Feng, Ying; Fearon, Eric R.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA.
[Fearon, Eric R.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA.
[Fearon, Eric R.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA.
[Kenner, Lukas] Med Univ Vienna, Clin Inst Pathol, A-1090 Vienna, Austria.
[Kenner, Lukas] Med Univ Vienna, Ludwig Boltzmann Inst Canc Res, A-1090 Vienna, Austria.
[Kenner, Lukas] Univ Vet Med Vienna, Dept Pathol Lab Anim, A-1210 Vienna, Austria.
[Haybaeck, Johannes] Otto von Guericke Univ, Dept Pathol, D-39120 Magdeburg, Germany.
[Datz, Christian] Paracelsus Private Univ Salzburg, Teaching Hosp, Hosp Oberndorf, Dept Internal Med, A-5110 Oberndorf, Austria.
[Karin, Michael] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
RP Karin, M (reprint author), Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA.; Karin, M (reprint author), Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.; Karin, M (reprint author), Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA.; Karin, M (reprint author), Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
EM karinoffice@ucsd.edu
OI Kenner, Lukas/0000-0003-2184-1338; de Jong, Petrus/0000-0003-2321-1153
FU Japan Society for the Promotion of Science; Uehara Memorial Foundation
Fellowship; Mochida Memorial Foundation for Medical and Pharmaceutical
Research; Kanae Foundation for the Promotion of Medical Science; KAKENHI
[15K21775]; "Kibou" Projects; Italian Association for Cancer Research;
Marie Curie Actions European Union-People-COFUND; Crohn's and Colitis
Foundation of America SRA [330251]; European Commission Marie Curie
program; Austrian Science Funds FWF; Innovative Medicines Initiative
Joint Undertaking [115234]; European Union's Seventh Framework Programme
(FP7); European Federation of Pharmaceutical Industries and Associations
companies; SPAR Austria; NIH [AI043477]; Incyte Inc; Ben and Wanda
Hildyard Chair for Mitochondrial and Metabolic Diseases; [P26011];
[P29251]
FX We thank Drs. D. Pan (Johns Hopkins University) and S. Akira (Osaka
University) for YapF/F and Stat3F/F mice,
respectively; Drs. D. L. Gumucio (University of Michigan) for the 12.4-
kb Villin promoter; C. A. O'Brien (University of Arkansas for Medical
Sciences) for the gp130-luciferase plasmid; T. Sato (Keio University),
H. Clevers (Hubrecht Institute), and Y. Hippo (National Cancer Center
Research Institute) for protocols describing intestinal organoid
culture; C. Kuo (Stanford University) for R-spondin1-producing cells; J.
Zhao [University of California, San Diego (UCSD) Transgenic Mouse and
Gene Targeting Core], L. Gapuz, R. Ly, and N. Varki (UCSD Histology
Core), N. Hiramatsu, S. Yamachika, S. I. Grivennikov, A. Chang, and T.
Lee for technical advice and assistance; and Cell Signaling, Santa Cruz
Biotechnology, GeneTex, and Incyte for antibodies and reagents. This
work was supported by Postdoctoral Fellowship for Research Abroad and
Research Fellowship for Young Scientists from the Japan Society for the
Promotion of Science, a Uehara Memorial Foundation Fellowship, the
Mochida Memorial Foundation for Medical and Pharmaceutical Research, the
Kanae Foundation for the Promotion of Medical Science, KAKENHI
(15K21775), and the "Kibou" Projects (all to K.T.); FIRC for Abroad and
iCare fellowship funded from the Italian Association for Cancer Research
and Marie Curie Actions European Union-People-COFUND (G.D.C.); and
Crohn's and Colitis Foundation of America SRA#330251 (to E.R.). L.K. is
supported by the European Commission Marie Curie 2020 program as a
Co-Coordinator within the "ALKATRAS' project as well as by the Austrian
Science Funds FWF; and Grants P26011 and P29251. TMA generation was
supported by the Innovative Medicines Initiative Joint Undertaking under
Grant 115234 (OncoTrack), resources of which are composed of financial
contributions from the European Union's Seventh Framework Programme
(FP7/2007-2013) and European Federation of Pharmaceutical Industries and
Associations companies' in-kind contribution (www.imi.europa.eu) (to
J.H.). C.D. was supported by SPAR Austria. Research at UCSD was
supported by the NIH (AI043477) and Incyte Inc. M. Karin is an American
Cancer Society Research Professor and holder of the Ben and Wanda
Hildyard Chair for Mitochondrial and Metabolic Diseases.
NR 47
TC 0
Z9 0
U1 4
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 FEB 14
PY 2017
VL 114
IS 7
BP 1643
EP 1648
DI 10.1073/pnas.1620290114
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK5TR
UT WOS:000393989300071
PM 28130546
ER
PT J
AU Tomasi, DG
Shokri-Kojori, E
Volkow, ND
AF Tomasi, Dardo G.
Shokri-Kojori, Ehsan
Volkow, Nora D.
TI Brain Network Dynamics Adhere to a Power Law
SO FRONTIERS IN NEUROSCIENCE
LA English
DT Article
DE FCDM; ALFF; lFCD; functional connectivity (FC); graph theory analysis;
brain networks; Taylor's law; numerical simulations
ID HUMAN CONNECTOME PROJECT; FUNCTIONAL CONNECTIVITY; RESTING-STATE;
BINOCULAR-RIVALRY; DECISION-MAKING; FMRI; MRI; PATTERNS; TRACKING;
CORTEX
AB The temporal dynamics of complex networks such as the Internet is characterized by a power scaling between the temporal mean and dispersion of signals at each network node. Here we tested the hypothesis that the temporal dynamics of the brain networks is characterized by a similar power law. This realization could be useful to assess the effects of randomness and external modulators on the brain network dynamics. Simulated data using a well-stablished random diffusion model allowed us to predict that the temporal dispersion of the amplitude of low frequency fluctuations (ALFF) and that of the local functional connectivity density (lFCD) scale with their temporal means. We tested this hypothesis in open-access resting-state functional magnetic resonance imaging datasets from 66 healthy subjects. A robust power law emerged from the temporal dynamics of ALFF and lFCD metrics, which was insensitive to the methods used for the computation of the metrics. The scaling exponents (ALFF: 0.8 +/- 0.1; lFCD: 1.1 +/- 0.1; mean +/- SD) decreased with age and varied significantly across brain regions; multimodal cortical areas exhibited lower scaling exponents, consistent with a stronger influence of external inputs, than limbic and subcortical regions, which exhibited higher scaling exponents, consistent with a stronger influence of internal randomness. Findings are consistent with the notion that external inputs govern neuronal communication in the brain and that their relative influence differs between brain regions. Further studies will assess the potential of this metric as biomarker to characterize neuropathology.
C1 [Tomasi, Dardo G.; Shokri-Kojori, Ehsan; Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA.
[Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD USA.
RP Tomasi, DG (reprint author), NIAAA, Bethesda, MD 20892 USA.
EM tomasidg@mail.nih.gov
FU 16 NIH Institutes and Centers [1U54MH091657]; McDonnell Center for
Systems Neuroscience at Washington University; National Institute on
Alcohol Abuse and Alcoholism [Y1AA-3009]
FX Data was provided by the Human Connectome Project (HCP), WU-Minn
Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil;
1U54MH091657) funded by the 16 NIH Institutes and Centers that support
the NIH Blueprint for Neuroscience Research and by the McDonnell Center
for Systems Neuroscience at Washington University. This work was
accomplished with support from the National Institute on Alcohol Abuse
and Alcoholism (Y1AA-3009).
NR 44
TC 0
Z9 0
U1 1
U2 1
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 1662-453X
J9 FRONT NEUROSCI-SWITZ
JI Front. Neurosci.
PD FEB 14
PY 2017
VL 11
AR 72
DI 10.3389/fnins.2017.00072
PG 9
WC Neurosciences
SC Neurosciences & Neurology
GA EK4RS
UT WOS:000393915100001
PM 28261049
ER
PT J
AU Woo, CW
Schmidt, L
Krishnan, A
Jepma, M
Roy, M
Lindquist, MA
Atlas, LY
Wager, TD
AF Woo, Choong-Wan
Schmidt, Liane
Krishnan, Anjali
Jepma, Marieke
Roy, Mathieu
Lindquist, Martin A.
Atlas, Lauren Y.
Wager, Tor D.
TI Quantifying cerebral contributions to pain beyond nociception
SO NATURE COMMUNICATIONS
LA English
DT Article
ID NUCLEUS-ACCUMBENS; NEUROPATHIC PAIN; FUNCTIONAL CONNECTIVITY; PHYSICAL
PAIN; BACK-PAIN; PREFRONTAL CORTEX; BRAIN MEDIATORS; BASAL GANGLIA;
FMRI; MECHANISMS
AB Cerebral processes contribute to pain beyond the level of nociceptive input and mediate psychological and behavioural influences. However, cerebral contributions beyond nociception are not yet well characterized, leading to a predominant focus on nociception when studying pain and developing interventions. Here we use functional magnetic resonance imaging combined with machine learning to develop a multivariate pattern signature-termed the stimulus intensity independent pain signature-1 (SIIPS1)-that predicts pain above and beyond nociceptive input in four training data sets (Studies 1-4, N = 137). The SIIPS1 includes patterns of activity in nucleus accumbens, lateral prefrontal and parahippocampal cortices, and other regions. In cross-validated analyses of Studies 1-4 and in two independent test data sets (Studies 5-6, N = 46), SIIPS1 responses explain variation in trial-by-trial pain ratings not captured by a previous fMRI-based marker for nociceptive pain. In addition, SIIPS1 responses mediate the pain-modulating effects of three psychological manipulations of expectations and perceived control. The SIIPS1 provides an extensible characterization of cerebral contributions to pain and specific brain targets for interventions.
C1 [Woo, Choong-Wan; Wager, Tor D.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA.
[Woo, Choong-Wan; Wager, Tor D.] Univ Colorado, Inst Cognit Sci, Boulder, CO 80309 USA.
[Schmidt, Liane] INSEAD, F-77300 Fontainebleau, France.
[Schmidt, Liane] Ecole Normale Super, INSERM U960, Dept Cognit Sci, Cognit Neurosci Lab, F-75005 Paris, France.
[Krishnan, Anjali] CUNY Brooklyn Coll, Dept Psychol, Brooklyn, NY 11210 USA.
[Jepma, Marieke] Leiden Univ, Inst Psychol, Cognit Psychol Unit, NL-2300 Leiden, Netherlands.
[Jepma, Marieke] Leiden Univ, Leiden Inst Brain & Cognit, NL-2300 Leiden, Netherlands.
[Roy, Mathieu] McGill Univ, Dept Psychol, Montreal, PQ H3A 0G4, Canada.
[Lindquist, Martin A.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21211 USA.
[Atlas, Lauren Y.] NIH, Natl Ctr Complementary & Integrat Hlth, Bethesda, MD 20892 USA.
[Atlas, Lauren Y.] NIDA, NIH, Rockville, MD 20852 USA.
[Woo, Choong-Wan] Inst Basic Sci, Ctr Neurosci Imaging Res, Suwon 16419, South Korea.
[Woo, Choong-Wan] Sungkyunkwan Univ, Dept Biomed Engn, Suwon 16419, South Korea.
RP Wager, TD (reprint author), Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA.; Wager, TD (reprint author), Univ Colorado, Inst Cognit Sci, Boulder, CO 80309 USA.
EM tor.wager@colorado.edu
OI Woo, Choong-Wan/0000-0002-7423-5422
FU NIH [R01DA035484, R01MH076136]; Intramural Research program of the NIH's
National Center for Complementary and Integrative Health; VENI grant of
the Netherlands Organization for Scientific Research
FX This work was funded by NIH R01DA035484 and R01MH076136 (T.D.W.), the
Intramural Research program of the NIH's National Center for
Complementary and Integrative Health (L.Y.A) and the VENI grant of the
Netherlands Organization for Scientific Research (M.J.).
NR 75
TC 0
Z9 0
U1 4
U2 4
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD FEB 14
PY 2017
VL 8
AR 14211
DI 10.1038/ncomms14211
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK3VV
UT WOS:000393857400001
PM 28195170
ER
PT J
AU Webster, DE
Suver, C
Doerr, M
Mounts, E
Domenico, L
Petrie, T
Leachman, SA
Trister, AD
Bot, BM
AF Webster, Dan E.
Suver, Christine
Doerr, Megan
Mounts, Erin
Domenico, Lisa
Petrie, Tracy
Leachman, Sancy A.
Trister, Andrew D.
Bot, Brian M.
TI Data Descriptor: The Mole Mapper Study, mobile phone skin imaging and
melanoma risk data collected using ResearchKit
SO SCIENTIFIC DATA
LA English
DT Article
AB Sensor-embedded phones are an emerging facilitator for participant-driven research studies. Skin cancer research is particularly amenable to this approach, as phone cameras enable self-examination and documentation of mole abnormalities that may signal a progression towards melanoma. Aggregation and open sharing of this participant-collected data can be foundational for research and the development of early cancer detection tools. Here we describe data from Mole Mapper, an iPhone-based observational study built using the Apple ResearchKit framework. The Mole Mapper app was designed to collect participant-provided images and measurements of moles, together with demographic and behavioral information relating to melanoma risk. The study cohort includes 2,069 participants who contributed 1,920 demographic surveys, 3,274 mole measurements, and 2,422 curated mole images. Survey data recapitulates associations between melanoma and known demographic risks, with red hair as the most significant factor in this cohort. Participant-provided mole measurements indicate an average mole size of 3.95 mm. These data have been made available to engage researchers in a collaborative, multidisciplinary effort to better understand and prevent melanoma.
C1 [Webster, Dan E.] NCI, Bethesda, MD 20892 USA.
[Suver, Christine; Doerr, Megan; Mounts, Erin; Trister, Andrew D.; Bot, Brian M.] Sage Bionetworks, Seattle, WA 98109 USA.
[Domenico, Lisa; Petrie, Tracy; Leachman, Sancy A.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA.
RP Bot, BM (reprint author), Sage Bionetworks, Seattle, WA 98109 USA.; Leachman, SA (reprint author), Oregon Hlth & Sci Univ, Portland, OR 97239 USA.
EM leachmas@ohsu.edu; brian.bot@sagebase.org
NR 9
TC 0
Z9 0
U1 3
U2 3
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2052-4463
J9 SCI DATA
JI Sci. Data
PD FEB 14
PY 2017
VL 4
DI 10.1038/sdata.2017.5
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK3VJ
UT WOS:000393856200001
ER
PT J
AU Khan, JM
Schenke, WH
Sonmez, M
Lederman, RJ
AF Khan, Jaffar M.
Schenke, William H.
Sonmez, Merdim
Lederman, Robert J.
TI Guidewire Electrosurgery Optimization For LAMPOON
SO JACC-CARDIOVASCULAR INTERVENTIONS
LA English
DT Meeting Abstract
C1 [Khan, Jaffar M.; Schenke, William H.; Sonmez, Merdim; Lederman, Robert J.] NIH, Bldg 10, Bethesda, MD 20892 USA.
NR 0
TC 0
Z9 0
U1 0
U2 0
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 1936-8798
EI 1876-7605
J9 JACC-CARDIOVASC INTE
JI JACC-Cardiovasc. Interv.
PD FEB 13
PY 2017
VL 10
IS 3
SU S
MA CRT-800.45
BP S76
EP S76
PG 1
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EP2MJ
UT WOS:000397217000207
ER
PT J
AU Le, MT
Kasprzak, WK
Kim, T
Gao, F
Young, MYL
Yuan, XF
Shapiro, BA
Seog, J
Simon, AE
AF Le, My-Tra
Kasprzak, Wojciech K.
kim, Taejin
Gao, Feng
Young, Megan Y. L.
Yuan, Xuefeng
Shapiro, Bruce A.
Seog, Joonil
Simon, Anne E.
TI Folding behavior of a T-shaped, ribosome-binding translation enhancer
implicated in a wide-spread conformational switch
SO ELIFE
LA English
DT Article
ID TURNIP-CRINKLE-VIRUS; PARTICLE MESH EWALD; OPTICAL TWEEZERS;
NUCLEIC-ACIDS; MOLECULAR-DYNAMICS; GENETIC-CONTROL; METAL-IONS;
VIRAL-RNA; RIBOSWITCHES; FORCE
AB Turnip crinkle virus contains a T-shaped, ribosome-binding, translation enhancer (TSS) in its 3'UTR that serves as a hub for interactions throughout the region. The viral RNA-dependent RNA polymerase (RdRp) causes the TSS/surrounding region to undergo a conformational shift postulated to inhibit translation. Using optical tweezers (OT) and steered molecular dynamic simulations (SMD), we found that the unusual stability of pseudoknotted element H4a/psi(3) required five upstream adenylates, and H4a/psi(3) was necessary for cooperative association of two other hairpins (H5/H4b) in Mg2+. SMD recapitulated the TSS unfolding order in the absence of Mg2+, showed dependence of the resistance to pulling on the 3D orientation and gave structural insights into the measured contour lengths of the TSS structure elements. Adenylate mutations eliminated one-site RdRp binding to the 3'UTR, suggesting that RdRp binding to the adenylates disrupts H4a/psi(3), leading to loss of H5/H4b interaction and promoting a conformational switch interrupting translation and promoting replication.
C1 [Le, My-Tra; Gao, Feng; Young, Megan Y. L.; Yuan, Xuefeng; Simon, Anne E.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA.
[Kasprzak, Wojciech K.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Bas Sci Program, Frederick, MD USA.
[kim, Taejin; Shapiro, Bruce A.] Natl Canc Inst, RNA Biol Lab, Ctr Canc Res, Frederick, MD USA.
[Seog, Joonil] Univ Maryland, Dept Mat Sci & Engn, College Pk, MD 20742 USA.
RP Le, MT; Simon, AE (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA.
EM my.letra@gmail.com; simona@umd.edu
FU National Science Foundation [MCB-1411836]; National Institutes of Health
[R21A1117882-01, 2T32A1051967-06A1]; National Cancer Institute
FX National Science Foundation MCB-1411836 My-Tra Le Feng Gao Megan Y L
Young Xuefeng Yuan Anne E Simon; National Institutes of Health
R21A1117882-01 My-Tra Le Feng Gao Anne E Simon; National Cancer
Institute Intramural Wojciech K Kasprzak Taejin Kim Bruce A Shapiro;
National Institutes of Health 2T32A1051967-06A1 Megan Y L Young Anne E
Simon
NR 64
TC 0
Z9 0
U1 4
U2 4
PU ELIFE SCIENCES PUBLICATIONS LTD
PI CAMBRIDGE
PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND
SN 2050-084X
J9 ELIFE
JI eLife
PD FEB 13
PY 2017
VL 6
AR e22883
DI 10.7554/eLife.22883
PG 24
WC Biology
SC Life Sciences & Biomedicine - Other Topics
GA EN5ZG
UT WOS:000396083700001
ER
PT J
AU Dewan, R
Pemov, A
Dutra, AS
Pak, ED
Edwards, NA
Ray-Chaudhury, A
Hansen, NF
Chandrasekharappa, SC
Mullikin, JC
Asthagiri, AR
Heiss, JD
Stewart, DR
Germanwala, AV
AF Dewan, Ramita
Pemov, Alexander
Dutra, Amalia S.
Pak, Evgenia D.
Edwards, Nancy A.
Ray-Chaudhury, Abhik
Hansen, Nancy F.
Chandrasekharappa, Settara C.
Mullikin, James C.
Asthagiri, Ashok R.
Heiss, John D.
Stewart, Douglas R.
Germanwala, Anand V.
CA NISC Comparative Sequencing Progra
TI First insight into the somatic mutation burden of neurofibromatosis type
2-associated grade I and grade II meningiomas: a case report
comprehensive genomic study of two cranial meningiomas with vastly
different clinical presentation
SO BMC CANCER
LA English
DT Article
DE Whole exome sequencing; Single nucleotide polymorphism; Spectral
karyotyping; NF2 gene; Somatic mutation; Case report
ID CANCER; TUMORS; VARIANTS; FEATURES; CELLS; AKT1; SMO; NF2
AB Background: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant nervous system tumor predisposition disorder caused by constitutive inactivation of one of the two copies of NF2. Meningiomas affect about one half of NF2 patients, and are associated with a higher disease burden. Currently, the somatic mutation landscape in NF2-associated meningiomas remains largely unexamined.
Case presentation: Here, we present an in-depth genomic study of benign and atypical meningiomas, both from a single NF2 patient. While the grade I tumor was asymptomatic, the grade II tumor exhibited an unusually high growth rate: expanding to 335 times its initial volume within one year. The genomes of both tumors were examined by whole-exome sequencing (WES) complemented with spectral karyotyping (SKY) and SNP-array copy-number analyses. To better understand the clonal composition of the atypical meningioma, the tumor was divided in four sections and each section was investigated independently. Both tumors had second copy inactivation of NF2, confirming the central role of the gene in meningioma formation. The genome of the benign tumor closely resembled that of a normal diploid cell and had only one other deleterious mutation (EPHB3). In contrast, the chromosomal architecture of the grade II tumor was highly re-arranged, yet uniform among all analyzed fragments, implying that this large and fast growing tumor was composed of relatively few clones. Besides multiple gains and losses, the grade II meningioma harbored numerous chromosomal translocations. WES analysis of the atypical tumor identified deleterious mutations in two genes: ADAMTSL3 and CAPN5 in all fragments, indicating that the mutations were present in the cell undergoing fast clonal expansion
Conclusions: This is the first WES study of NF2-associated meningiomas. Besides second NF2 copy inactivation, we found low somatic burden in both tumors and high level of genomic instability in the atypical meningioma. Genomic instability resulting in altered gene dosage and compromised structural integrity of multiple genes may be the primary reason of the high growth rate for the grade II tumor. Further study of ADAMTSL3 and CAPN5 may lead to elucidation of their molecular implications in meningioma pathogenesis.
C1 [Germanwala, Anand V.] Loyola Univ, Stritch Sch Med, Dept Neurol Surg, Maywood, IL 60153 USA.
[Germanwala, Anand V.] Edward Hines Jr VA Hosp, Dept Otolaryngol, 2160 South First Ave, Maywood, IL 60153 USA.
[Dewan, Ramita; Edwards, Nancy A.; Ray-Chaudhury, Abhik; Heiss, John D.] NINDS, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA.
[Pemov, Alexander; Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA.
[Dutra, Amalia S.; Pak, Evgenia D.] NHGRI, NIH, Genet Dis Res Branch, Bethesda, MD USA.
[Hansen, Nancy F.; Chandrasekharappa, Settara C.; Mullikin, James C.] NHGRI, NIH, Canc Genet & Comparat Genom Branch, Bethesda, MD USA.
[Mullikin, James C.] NHGRI, NIH, NIH Intramural Sequencing Ctr, Rockville, MD USA.
[Asthagiri, Ashok R.] Univ Virginia, Sch Med, Dept Neurol Surg, Charlottesville, VA 22908 USA.
RP Germanwala, AV (reprint author), Loyola Univ, Stritch Sch Med, Dept Neurol Surg, Maywood, IL 60153 USA.; Germanwala, AV (reprint author), Edward Hines Jr VA Hosp, Dept Otolaryngol, 2160 South First Ave, Maywood, IL 60153 USA.
EM agermanwala@gmail.com
FU Intramural Research Program of the National Institute of Neurologic
Disease and Stroke (NINDS); Division of Cancer Epidemiology and Genetics
of the National Cancer Institute (NCI); National Human Genome Research
Institute (NHGRI)
FX This study was supported by funding from the Intramural Research Program
of the National Institute of Neurologic Disease and Stroke (NINDS), the
Division of Cancer Epidemiology and Genetics of the National Cancer
Institute (NCI), and the National Human Genome Research Institute
(NHGRI). The roles of each funding body were as follows: NINDS for study
design, collection of data, and writing of the manuscript; NCI for study
design, collection, analysis, and interpretation of data, and writing of
the manuscript; and NHGRI for collection, analysis, and interpretation
of data.
NR 33
TC 0
Z9 0
U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2407
J9 BMC CANCER
JI BMC Cancer
PD FEB 13
PY 2017
VL 17
AR 127
DI 10.1186/s12885-017-3127-6
PG 10
WC Oncology
SC Oncology
GA EK3QX
UT WOS:000393842100004
PM 28193203
ER
PT J
AU Arca, B
Lombardo, F
Struchiner, CJ
Ribeiro, JMC
AF Arca, Bruno
Lombardo, Fabrizio
Struchiner, Claudio J.
Ribeiro, Jose M. C.
TI Anopheline salivary protein genes and gene families: an evolutionary
overview after the whole genome sequence of sixteen Anopheles species
SO BMC GENOMICS
LA English
DT Article
DE Salivary glands; Salivary proteins; Anophelines; Mosquito saliva; Vector
biology; Evolution; Salivary markers; Human exposure to malaria vectors;
Positive selection
ID ADULT FEMALE MOSQUITO; FLY LUTZOMYIA-LONGIPALPIS; RICH SECRETORY
PROTEINS; INDUCED PLATELET-AGGREGATION; IMMUNO-EPIDEMIOLOGIC TOOL;
EVALUATING HUMAN EXPOSURE; MALARIA VECTOR MOSQUITO;
VON-WILLEBRAND-FACTOR; AEDES-AEGYPTI; ANTIBODY-RESPONSE
AB Background: Mosquito saliva is a complex cocktail whose pharmacological properties play an essential role in blood feeding by counteracting host physiological response to tissue injury. Moreover, vector borne pathogens are transmitted to vertebrates and exposed to their immune system in the context of mosquito saliva which, in virtue of its immunomodulatory properties, can modify the local environment at the feeding site and eventually affect pathogen transmission. In addition, the host antibody response to salivary proteins may be used to assess human exposure to mosquito vectors. Even though the role of quite a few mosquito salivary proteins has been clarified in the last decade, we still completely ignore the physiological role of many of them as well as the extent of their involvement in the complex interactions taking place between the mosquito vectors, the pathogens they transmit and the vertebrate host. The recent release of the genomes of 16 Anopheles species offered the opportunity to get insights into function and evolution of salivary protein families in anopheline mosquitoes.
Results: Orthologues of fifty three Anopheles gambiae salivary proteins were retrieved and annotated from 18 additional anopheline species belonging to the three subgenera Cellia, Anopheles, and Nyssorhynchus. Our analysis included 824 full-length salivary proteins from 24 different families and allowed the identification of 79 novel salivary genes and re-annotation of 379 wrong predictions. The comparative, structural and phylogenetic analyses yielded an unprecedented view of the anopheline salivary repertoires and of their evolution over 100 million years of anopheline radiation shedding light on mechanisms and evolutionary forces that contributed shaping the anopheline sialomes.
Conclusions: We provide here a comprehensive description, classification and evolutionary overview of the main anopheline salivary protein families and identify two novel candidate markers of human exposure to malaria vectors worldwide. This anopheline sialome catalogue, which is easily accessible as hyperlinked spreadsheet, is expected to be useful to the vector biology community and to improve the capacity to gain a deeper understanding of mosquito salivary proteins facilitating their possible exploitation for epidemiological and/or pathogen-vector-host interaction studies.
C1 [Arca, Bruno; Lombardo, Fabrizio] Sapienza Univ, Dept Publ Hlth & Infect Dis, Div Parasitol, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
[Struchiner, Claudio J.] Fundacao Oswaldo Cruz, Ave Brasil, BR-4365 Rio De Janeiro, Brazil.
[Struchiner, Claudio J.] Univ Estado Rio de Janeiro, Inst Med Social, Rio De Janeiro, Brazil.
[Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA.
RP Arca, B (reprint author), Sapienza Univ, Dept Publ Hlth & Infect Dis, Div Parasitol, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
EM bruno.arca@uniroma1.it
FU European Union [228421]; Ministry of Education, University and Research
(MIUR) [2010C2LKKJ_004]; Brazilian Research Council (CNPq); FAPERJ;
Division of Intramural Research, National Institute of Allergy and
Infectious Diseases, National Institute of Health, USA
FX BA was supported by funds from the European Union grant INFRAVEC
(228421) and from the Ministry of Education, University and Research
(MIUR) grant SKINFLAM (2010C2LKKJ_004). JMCR by the Division of
Intramural Research, National Institute of Allergy and Infectious
Diseases, National Institute of Health, USA. CJS was supported by
Brazilian Research Council (CNPq) and FAPERJ.
NR 152
TC 0
Z9 0
U1 2
U2 2
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2164
J9 BMC GENOMICS
JI BMC Genomics
PD FEB 13
PY 2017
VL 18
AR 153
DI 10.1186/s12864-017-3579-8
PG 27
WC Biotechnology & Applied Microbiology; Genetics & Heredity
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA EL1MQ
UT WOS:000394384900002
PM 28193177
ER
PT J
AU Araya, RE
Goldszmid, RS
AF Araya, Romina E.
Goldszmid, Romina S.
TI IFNAR1 Degradation: A New Mechanism for Tumor Immune Evasion?
SO CANCER CELL
LA English
DT Editorial Material
ID I INTERFERON; DENDRITIC CELLS
AB Type I interferons have been shown to play a major role in anti-cancer immunity. In this issue of Cancer Cell, Katlinski et al. describe tumor-induced degradation of type I interferon receptor IFNAR1 chain as a new immune-evasion mechanism in colorectal cancers. Stabilizing IFNAR1 inhibits tumor growth and improves immunotherapy efficacy.
C1 [Araya, Romina E.; Goldszmid, Romina S.] NCI, Inflammatory Cell Dynam Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA.
RP Goldszmid, RS (reprint author), NCI, Inflammatory Cell Dynam Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA.
EM rgoldszmid@mail.nih.gov
FU intramural research program of the NCI
FX This work was supported by the intramural research program of the NCI.
We are grateful to Juan Pablo Borrelli for help with the illustration.
NR 10
TC 0
Z9 0
U1 0
U2 0
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 1535-6108
EI 1878-3686
J9 CANCER CELL
JI Cancer Cell
PD FEB 13
PY 2017
VL 31
IS 2
BP 161
EP 163
DI 10.1016/j.ccell.2017.01.012
PG 3
WC Oncology; Cell Biology
SC Oncology; Cell Biology
GA EL1WG
UT WOS:000394411500002
PM 28196588
ER
PT J
AU Fishbein, L
Leshchiner, I
Walter, V
Danilova, L
Robertson, AG
Johnson, AR
Lichtenberg, TM
Murray, BA
Ghayee, HK
Else, T
Ling, SY
Jefferys, SR
de Cubas, AA
Wenz, B
Korpershoek, E
Amelio, AL
Makowski, L
Rathmell, WK
Gimenez-Roqueplo, AP
Giordano, TJ
Asa, SL
Tischler, AS
Pacak, K
Nathanson, KL
Wilkerson, MD
AF Fishbein, Lauren
Leshchiner, Ignaty
Walter, Vonn
Danilova, Ludmila
Robertson, A. Gordon
Johnson, Amy R.
Lichtenberg, Tara M.
Murray, Bradley A.
Ghayee, Hans K.
Else, Tobias
Ling, Shiyun
Jefferys, Stuart R.
de Cubas, Aguirre A.
Wenz, Brandon
Korpershoek, Esther
Amelio, Antonio L.
Makowski, Liza
Rathmell, W. Kimryn
Gimenez-Roqueplo, Anne-Paule
Giordano, Thomas J.
Asa, Sylvia L.
Tischler, Arthur S.
Pacak, Karel
Nathanson, Katherine L.
Wilkerson, Matthew D.
CA Canc Genome Atlas Res Network
TI Comprehensive Molecular Characterization of Pheochromocytoma and
Paraganglioma
SO CANCER CELL
LA English
DT Article
ID RNA-BINDING PROTEIN; SPORADIC PHEOCHROMOCYTOMA; SOMATIC MUTATIONS;
GENE-EXPRESSION; STEM-CELLS; CANCER; TUMORS; CARCINOMA; RET;
DIFFERENTIATION
AB We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.
C1 [Fishbein, Lauren] Univ Penn, Perelman Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Philadelphia, PA 19104 USA.
[Leshchiner, Ignaty] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA.
[Leshchiner, Ignaty] Harvard Univ, Cambridge, MA 02142 USA.
[Walter, Vonn; Jefferys, Stuart R.; de Cubas, Aguirre A.; Amelio, Antonio L.; Makowski, Liza; Rathmell, W. Kimryn; Wilkerson, Matthew D.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.
[Danilova, Ludmila] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA.
[Robertson, A. Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada.
[Johnson, Amy R.] Univ North Carolina Chapel Hill, Dept Nutr, Chapel Hill, NC 27599 USA.
[Lichtenberg, Tara M.] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA.
[Ghayee, Hans K.] Univ Florida, Coll Med, Dept Med, Div Endocrinol & Metab, Gainesville, FL 32608 USA.
[Ghayee, Hans K.] Malcom Randall VA Med Ctr, Gainesville, FL 32608 USA.
[Else, Tobias] Univ Michigan Hlth Syst, Div Metab Endocrinol & Diabet, Dept Internal Med, Ann Arbor, MI 48109 USA.
[Ling, Shiyun] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
[de Cubas, Aguirre A.; Rathmell, W. Kimryn] Univ North Carolina Chapel Hill, Dept Med, Div Hematol & Oncol, Chapel Hill, NC 27599 USA.
[Wenz, Brandon; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA.
[Korpershoek, Esther] Erasmus MC Univ Med Ctr Rotterdam, Dept Pathol, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands.
[Gimenez-Roqueplo, Anne-Paule] INSERM, Paris Cardiovasc Res Ctr, UMR970, F-75015 Paris, France.
[Giordano, Thomas J.] Univ Michigan Hlth Syst, Dept Pathol, Ann Arbor, MI 48109 USA.
[Asa, Sylvia L.] Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2C4, Canada.
[Asa, Sylvia L.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 2C4, Canada.
[Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol & Lab Med, Boston, MA 02111 USA.
[Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Bethesda, MD 20892 USA.
[Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA.
[Wilkerson, Matthew D.] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA.
[Fishbein, Lauren] Univ Colorado, Sch Med, Dept Med, Div Endocrinol Metab & Diabet, Aurora, CO 80045 USA.
[Fishbein, Lauren; de Cubas, Aguirre A.; Rathmell, W. Kimryn] Vanderbilt Univ, Div Hematol & Oncol, Dept Med, Sch Med,Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA.
[Wilkerson, Matthew D.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Collaborat Hlth Initiat Res Program, Amer Genome Ctr, Bethesda, MD 20814 USA.
RP Wilkerson, MD (reprint author), Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.; Nathanson, KL (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA.; Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Bethesda, MD 20892 USA.; Nathanson, KL (reprint author), Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA.; Wilkerson, MD (reprint author), Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA.; Wilkerson, MD (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Collaborat Hlth Initiat Res Program, Amer Genome Ctr, Bethesda, MD 20814 USA.
EM karel@mail.nih.gov; knathans@exchange.upenn.edu; mdwilkerson@outlook.com
RI Marra, Marco/B-5987-2008; Holt, Robert/C-3303-2009;
OI Zelinka, Tomas/0000-0003-3395-8373; Gehlenborg, Nils/0000-0003-0327-8297
FU NIH [U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24
CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24
CA14385, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24
CA144025, P30 CA016672]; Bayer AG
FX We thank all of the patients and families who contributed to the study,
Ina Felau for project management, and Jill Dolinsky, MS, CGC, at Ambry
Genetics, Inc., for sharing mutation classification and frequency data.
This study was supported by NIH grants U54 HG003273, U54 HG003067, U54
HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24
CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24
CA143882, U24 CA143883, U24 CA144025, and P30 CA016672. S.L.A. is part
of the pathology imaging medical advisory board of Leica Biosystems.
Andrew D. Cherniack and Matthew Meyerson received research support from
Bayer AG.
NR 54
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U1 1
U2 1
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 1535-6108
EI 1878-3686
J9 CANCER CELL
JI Cancer Cell
PD FEB 13
PY 2017
VL 31
IS 2
BP 181
EP 193
DI 10.1016/j.ccell.2017.01.001
PG 13
WC Oncology; Cell Biology
SC Oncology; Cell Biology
GA EL1WG
UT WOS:000394411500008
PM 28162975
ER
PT J
AU Rossey, I
Gilman, MSA
Kabeche, SC
Sedeyn, K
Wrapp, D
Kanekiyo, M
Chen, M
Mas, V
Spitaels, J
Melero, JA
Graham, BS
Schepens, B
McLellan, JS
Saelens, X
AF Rossey, Iebe
Gilman, Morgan S. A.
Kabeche, Stephanie C.
Sedeyn, Koen
Wrapp, Daniel
Kanekiyo, Masaru
Chen, Man
Mas, Vicente
Spitaels, Jan
Melero, Jose A.
Graham, Barney S.
Schepens, Bert
McLellan, Jason S.
Saelens, Xavier
TI Potent single-domain antibodies that arrest respiratory syncytial virus
fusion protein in its prefusion state
SO NATURE COMMUNICATIONS
LA English
DT Article
ID HUMANIZED MONOCLONAL-ANTIBODY; PICHIA-PASTORIS; IN-VITRO; INFECTION;
GLYCOPROTEIN; MOTAVIZUMAB; SOFTWARE; RISK
AB Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in young children. The RSV fusion protein (F) is highly conserved and is the only viral membrane protein that is essential for infection. The prefusion conformation of RSV F is considered the most relevant target for antiviral strategies because it is the fusion-competent form of the protein and the primary target of neutralizing activity present in human serum. Here, we describe two llama-derived single-domain antibodies (VHHs) that have potent RSV-neutralizing activity and bind selectively to prefusion RSV F with picomolar affinity. Crystal structures of these VHHs in complex with prefusion F show that they recognize a conserved cavity formed by two F protomers. In addition, the VHHs prevent RSV replication and lung infiltration of inflammatory monocytes and T cells in RSV-challenged mice. These prefusion F-specific VHHs represent promising antiviral agents against RSV.
C1 [Rossey, Iebe; Sedeyn, Koen; Spitaels, Jan; Schepens, Bert; Saelens, Xavier] VIB, Ctr Med Biotechnol, Technol Pk 927, B-9052 Ghent, Belgium.
[Rossey, Iebe; Sedeyn, Koen; Spitaels, Jan; Schepens, Bert; Saelens, Xavier] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium.
[Gilman, Morgan S. A.; Kabeche, Stephanie C.; Wrapp, Daniel; McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem & Cell Biol, Hanover, NH 03755 USA.
[Kanekiyo, Masaru; Chen, Man; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA.
[Mas, Vicente; Melero, Jose A.] Inst Salud Carlos III, Ctr Nacl Microbiol, Madrid 28220, Spain.
[Mas, Vicente; Melero, Jose A.] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid 28220, Spain.
RP Schepens, B; Saelens, X (reprint author), VIB, Ctr Med Biotechnol, Technol Pk 927, B-9052 Ghent, Belgium.; Schepens, B; Saelens, X (reprint author), Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium.; McLellan, JS (reprint author), Geisel Sch Med Dartmouth, Dept Biochem & Cell Biol, Hanover, NH 03755 USA.
EM Bert.Schepens@vib-ugent.be; Jason.S.McLellan@dartmouth.edu;
xavier.saelens@vib-ugent.be
RI Mas, Vicente/M-4776-2015
OI Mas, Vicente/0000-0002-0887-0743
FU IWT-Vlaanderen; National Institute of General Medical Sciences of the
National Institutes of Health [T32GM008704, P20GM113132];
FWO-Vlaanderen; Ghent University [BOF12/GOA/014]; Interuniversity
Attraction Poles programme (IAP7, BELVIR); VIB; Mineco (Spain)
[SAF2015-67033-R]; U.S. Department of Energy, Office of Biological and
Environmental Research [DE-AC02-06CH11357]; National Cancer Institute
[ACB-12002]; National Institute of General Medical Sciences [AGM-12006]
FX We thank Amanda Goncalves and Eef Parthoens from VIB Bio Imaging Core,
Liesbeth Vande Ginste, Lien Van Hoecke, Soraya Van Cauwenberghe and
Emilie Shipman for excellent technical assistance and Dr Florencia
Linero for providing the control VHH. This study was supported by
IWT-Vlaanderen (Ph.D. student fellowship to I.R.), National Institute of
General Medical Sciences of the National Institutes of Health award
T32GM008704 (M.S.A.G.) and P20GM113132 (J.S.M.), FWO-Vlaanderen
(Postdoctoral fellowship to B.S.), Ghent University Special Research
Grant BOF12/GOA/014, Interuniversity Attraction Poles programme (IAP7,
BELVIR), VIB and Mineco (Spain) Grant SAF2015-67033-R (J.A.M.). Results
shown in this report are derived in part from work performed at Argonne
National Laboratory, Structural Biology Center at the Advanced Photon
Source. Argonne is operated by UChicago Argonne, LLC, for the U.S.
Department of Energy, Office of Biological and Environmental Research
under contract DE-AC02-06CH11357. Data in this report were also obtained
at GM/CA@APS, which has been funded in whole or in part with Federal
funds from the National Cancer Institute (ACB-12002) and the National
Institute of General Medical Sciences (AGM-12006).
NR 47
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U1 2
U2 2
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD FEB 13
PY 2017
VL 8
AR 14158
DI 10.1038/ncomms14158
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK8DE
UT WOS:000394153300001
PM 28194013
ER
PT J
AU Bulea, TC
Stanley, CJ
Damiano, DL
AF Bulea, Thomas C.
Stanley, Christopher J.
Damiano, Diane L.
TI Part 2: Adaptation of Gait Kinematics in Unilateral Cerebral Palsy
Demonstrates Preserved Independent Neural Control of Each Limb
SO FRONTIERS IN HUMAN NEUROSCIENCE
LA English
DT Article
DE neural circuits; after-effects; brain injury; knee angle; local dynamic
stability; neurorehabilitation
ID SPLIT-BELT; LOCOMOTOR ADAPTATION; HUMAN WALKING; DYNAMIC STABILITY;
PRISM ADAPTATION; INTERLIMB COORDINATION; TREADMILL WALKING; STROKE;
VARIABILITY; REHABILITATION
AB Motor adaptation, or alteration of neural control in response to a perturbation, is a potential mechanism to facilitate motor learning for rehabilitation. Central nervous system deficits are known to affect locomotor adaptation; yet we demonstrated that similar to adults following stroke, children with unilateral brain injuries can adapt step length in response to unilateral leg weighting. Here, we extend our analysis to explore kinematic strategies underlying step length adaptation and utilize dynamical systems approaches to elucidate how neural control may differ in those with hemiplegic CP across legs and compared to typically developing controls. Ten participants with hemiplegic CP and ten age-matched controls participated in this study. Knee and hip joint kinematics were analyzed during unilateral weighting of each leg in treadmill walking to assess adaptation and presence and persistence of after-effects. Peak joint angle displacement was used to represent changes in joint angles during walking. We examined baseline and task-specific variability and local dynamic stability to evaluate neuromuscular control across groups and legs. In contrast to controls, children with unilateral CP had asymmetries in joint angle variability and local dynamic stability at baseline, showing increased variability and reduced stability in the dominant limb. Kinematic variability increased and local stability decreased during weighting of ipsilateral and contralateral limbs in both groups compared to baseline. After weight removal both measures returned to baseline. Analogous to the temporal-spatial results, children with unilateral CP demonstrated similar capability as controls to adapt kinematics to unilateral leg weighting, however, the group with CP differed across sides after weight removal with dominant limb after-effects fading more quickly than in controls. The change in kinematics did not completely return to baseline in the non-dominant limb of the CP group, producing a transient improvement in joint angle symmetry. Recent studies demonstrate that neural control of gait is multi-layered with distinct circuits for different types of walking and for each leg. Remarkably, our results demonstrate that children with unilateral brain injury retain these separate circuits for each leg during walking and, importantly, that those networks can be adapted independently from one another to improve symmetry in the short term.
C1 [Bulea, Thomas C.; Stanley, Christopher J.; Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA.
RP Bulea, TC (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA.
EM thomas.bulea@nih.gov
FU NIH Clinical Center
FX This work was funded by the Intramural Research Program of the NIH
Clinical Center.
NR 48
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U1 1
U2 1
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 1662-5161
J9 FRONT HUM NEUROSCI
JI Front. Hum. Neurosci.
PD FEB 13
PY 2017
VL 11
AR 50
DI 10.3389/fnhum.2017.00050
PG 12
WC Neurosciences; Psychology
SC Neurosciences & Neurology; Psychology
GA EK1WK
UT WOS:000393716300001
PM 28243195
ER
PT J
AU Chinen, M
Lei, EP
AF Chinen, Madoka
Lei, Elissa P.
TI Drosophila Argonaute2 turnover is regulated by the ubiquitin proteasome
pathway
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Argonaute; RNAi; Protein stability; Ubiquitin; Proteasome
ID DISTINCT ROLES; HUMAN-CELLS; STABILITY; PROTEINS; GENE; COMPLEXES; RNAI
AB Argonaute (AGO) proteins play a central role in the RNA interference (RNAi) pathway, which is a cytoplasmic mechanism important for post-transcriptional regulation of gene expression. In Drosophila, AGO2 also functions in the nucleus to regulate chromatin insulator activity and transcription. Although there are a number of studies focused on AGO2 function, the regulation of AGO2 turnover is not well understood. We found that mutation of T1149 or R1158 in the conserved PIWI domain causes AGO2 protein instability, but only T1149 affects RNAi activity. Mass spec analysis shows that several proteasome components co-purify with both wildtype and mutant AGO2, and knockdown of two proteasome pathway components results in AGO2 protein accumulation. Finally, AGO2 protein levels increase after treatment with the proteasome inhibitor MG132. Our results indicate that the ubiquitin-proteasome pathway is involved in AGO2 protein turnover. Published by Elsevier Inc.
C1 [Chinen, Madoka; Lei, Elissa P.] NIDDK, Nucl Org & Gene Express Sect, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA.
RP Lei, EP (reprint author), NIDDK, Nucl Org & Gene Express Sect, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA.
EM leielissa@niddk.nih.gov
FU Intramural Research Program of the National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health [DK015602]
FX We thank M. Siomi, H. Siomi, and Q. Liu for anti-AG02; E.C. Lai and SW.
Shin for discussions; and A. Haase and members of the Lei laboratory for
comments on the manuscript. This work was funded by the Intramural
Research Program of the National Institute of Diabetes and Digestive and
Kidney Diseases DK015602, National Institutes of Health.
NR 22
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U1 1
U2 1
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD FEB 12
PY 2017
VL 483
IS 3
BP 951
EP 957
DI 10.1016/j.bbrc.2017.01.039
PG 7
WC Biochemistry & Molecular Biology; Biophysics
SC Biochemistry & Molecular Biology; Biophysics
GA EK1ZI
UT WOS:000393726400008
PM 28087276
ER
PT J
AU Hanley, DF
Lane, K
McBee, N
Ziai, W
Tuhrim, S
Lees, KR
Dawson, J
Gandhi, D
Ullman, N
Mould, WA
Mayo, SW
Mendelow, AD
Gregson, B
Butcher, K
Vespa, P
Wright, DW
Kase, CS
Carhuapoma, JR
Keyl, PM
Diener-West, M
Muschelli, J
Betz, JF
Thompson, CB
Sugar, EA
Yenokyan, G
Janis, S
John, S
Harnof, S
Lopez, GA
Aldrich, EF
Harrigan, MR
Ansari, S
Jallo, J
Caron, JL
LeDoux, D
Adeoye, O
Zuccarello, M
Adams, HP
Rosenblum, M
Thompson, RE
Awad, IA
AF Hanley, Daniel F.
Lane, Karen
McBee, Nichol
Ziai, Wendy
Tuhrim, Stanley
Lees, Kennedy R.
Dawson, Jesse
Gandhi, Dheeraj
Ullman, Natalie
Mould, W. Andrew
Mayo, Steven W.
Mendelow, A. David
Gregson, Barbara
Butcher, Kenneth
Vespa, Paul
Wright, David W.
Kase, Carlos S.
Carhuapoma, J. Ricardo
Keyl, Penelope M.
Diener-West, Marie
Muschelli, John
Betz, Joshua F.
Thompson, Carol B.
Sugar, Elizabeth A.
Yenokyan, Gayane
Janis, Scott
John, Sayona
Harnof, Sagi
Lopez, George A.
Aldrich, E. Francois
Harrigan, Mark R.
Ansari, Safdar
Jallo, Jack
Caron, Jean-Louis
LeDoux, David
Adeoye, Opeolu
Zuccarello, Mario
Adams, Harold P.
Rosenblum, Michael
Thompson, Richard E.
Awad, Issam A.
CA ClEAR III Investigators
TI Thrombolytic removal of intraventricular haemorrhage in treatment of
severe stroke: results of the randomised, multicentre, multiregion,
placebo-controlled CLEAR III trial
SO LANCET
LA English
DT Article
ID SPONTANEOUS INTRACEREBRAL HEMORRHAGE; PLASMINOGEN-ACTIVATOR;
CLINICAL-TRIAL; RESOLUTION; UPDATE; BLOOD
AB Background Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome.
Methods In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1: 1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0.9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov,NCT00784134.
Findings Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1.06 [95% CI 0.88-1.28; p=0.554]). A difference of 3.5% (RR 1.08 [95% CI 0.90-1.29], p= 0.420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0.60 [95% CI 0.41-0.86], p= 0.006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1.99 [95% CI 1.22-3.26], p= 0.007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0.55 [95% CI 0.31-0.97], p= 0.048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0.76 [95% CI 0.64-0.90], p= 0.002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1.21 [95% CI 0.37-3.91], p=0.771) was similar.
Interpretation In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocolbased use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status.
C1 [Hanley, Daniel F.; Lane, Karen; McBee, Nichol; Ziai, Wendy; Ullman, Natalie; Mould, W. Andrew; Carhuapoma, J. Ricardo; Keyl, Penelope M.] Johns Hopkins Univ, Sch Med, Brain Injury Outcomes Div, Baltimore, MD USA.
[Tuhrim, Stanley] Icahn Sch Med Mt Sinai, New York, NY 10029 USA.
[Lees, Kennedy R.; Dawson, Jesse] Univ Glasgow, Glasgow, Lanark, Scotland.
[Gandhi, Dheeraj; Aldrich, E. Francois] Univ Maryland, Baltimore, MD 21201 USA.
[Mayo, Steven W.] Emissary Int LLC, Austin, TX USA.
[Mendelow, A. David; Gregson, Barbara] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England.
[Butcher, Kenneth] Univ Alberta, Edmonton, AB, Canada.
[Vespa, Paul] Univ Calif Los Angeles, Los Angeles, CA USA.
[Wright, David W.] Emory Univ, Atlanta, GA 30322 USA.
[Kase, Carlos S.] Boston Univ, Boston, MA 02215 USA.
[Diener-West, Marie; Muschelli, John; Betz, Joshua F.; Thompson, Carol B.; Sugar, Elizabeth A.; Yenokyan, Gayane; Rosenblum, Michael; Thompson, Richard E.] Johns Hopkins Univ Bloomberg, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA.
[Janis, Scott] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
[John, Sayona] Rush Univ, Chicago, IL 60612 USA.
[Harnof, Sagi] Chaim Sheba Med Ctr, Ramat Gan, Israel.
[Lopez, George A.] Univ Texas Houston, Houston, TX USA.
[Harrigan, Mark R.] Univ Alabama Birmingham, Birmingham, AL USA.
[Ansari, Safdar] Univ Utah, Salt Lake City, UT USA.
[Jallo, Jack] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA.
[Caron, Jean-Louis] Univ Texas San Antonio, San Antonio, TX USA.
[LeDoux, David] North Shore Long Isl Jewish Med Ctr, Manhasset, NY USA.
[Adeoye, Opeolu; Zuccarello, Mario] Univ Cincinnati, Cincinnati, OH USA.
[Adams, Harold P.] Univ Iowa, Iowa City, IA USA.
[Awad, Issam A.] Univ Chicago, Chicago, IL 60637 USA.
RP Hanley, DF (reprint author), Johns Hopkins Univ, Acute Care Neurol, Div Brain Injury Outcomes, Baltimore, MD 21231 USA.
EM dhanley@jhmi.edu
FU National Institute of Neurological Disorders and Stroke
FX National Institute of Neurological Disorders and Stroke.
NR 25
TC 0
Z9 0
U1 3
U2 3
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 FEB 11
PY 2017
VL 389
IS 10069
BP 603
EP 611
DI 10.1016/S0140-6736(16)32410-2
PG 9
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL9AF
UT WOS:000394910800029
PM 28081952
ER
PT J
AU Lin, W
Zhang, PP
Chen, H
Chen, Y
Yang, HX
Zheng, WJ
Zhang, X
Zhang, FX
Zhang, W
Lipsky, PE
AF Lin, Wei
Zhang, Panpan
Chen, Hua
Chen, Yu
Yang, Hongxian
Zheng, Wenjie
Zhang, Xuan
Zhang, Fengxiao
Zhang, Wen
Lipsky, Peter E.
TI Circulating plasmablasts/plasma cells: a potential biomarker for
IgG4-related disease
SO ARTHRITIS RESEARCH & THERAPY
LA English
DT Article
DE IgG4-RD; Biomarker; Autoimmunity; CD19(+) CD24(-) CD38(hi)
plasmablast/plasma cell
ID IMMUNOGLOBULIN G4-RELATED DISEASE; PLASMA-CELLS; B-CELLS; RECEPTOR
STIMULATION; CD86; DIFFERENTIATION; EXPRESSION; TRANSCRIPTION; SUBSETS
AB Background: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multisystem fibroinflammatory disease. We previously reported that a circulating cell population expressing CD19(+) CD24(-)CD38(hi) was increased in patients with IgG4-RD. In this study, we aimed to document that this cell population represented circulating plasmablasts/plasma cells, to identify the detailed phenotype and gene expression profile of these IgG4-secreting plasmablasts/plasma cells, and to determine whether this B-cell lineage subset could be a biomarker in IgG4-related disease (IgG4-RD).
Methods: A total of 42 untreated patients with IgG4-RD were evaluated. Peripheral B-cell subsets, including CD19(+) CD24(-) CD38(hi) plasmablasts/plasma cells, CD19(+) CD24(+) CD38(-) memory B cells, CD19(+) CD24(int)CD38(int) naive B cells, and CD19(+) CD24(hi)CD38(hi) regulatory B cells, were assessed and sorted by flow cytometry. Microarray analysis was used to measure gene expression of circulating B-cell lineage subsets. Further characterization of CD19(+) CD24 (-)CD38(hi) plasmablasts/plasma cells was carried out by evaluating additional surface markers, including CD27, CD95, and human leukocyte antigen (HLA)-DR, by flow cytometric assay. In addition, various B-cell lineage subsets were cultured in vitro and IgG4 concentrations were measured by cytometric bead array.
Results: In untreated patients with IgG4-RD, the peripheral CD19(+) CD24(-)CD38(hi) plasmablast/plasma cell subset was increased and positively correlated with serum IgG4 levels, the number of involved organs, and the IgG4-related Disease Responder Index. It decreased after treatment with glucocorticoids. Characterization of the plasmablast/ plasma cell population by gene expression profiling documented a typical plasmablast/plasma cell signature with higher expression of X-box binding protein 1 and IFN regulatory factor 4, but lower expression of paired box gene 5 and B-cell lymphoma 6 protein. In addition, CD27, CD95, and HLA-DR were highly expressed on CD19(+) CD24(-)CD38(hi) plasmablasts/plasma cells from patients with IgG4-RD. Furthermore, CD19(+) CD24(-)CD38(hi) plasmablasts/ plasma cells secreted more IgG4 than other B-cell populations.
Conclusions: Circulating CD19(+) CD24(-)CD38(hi) plasmablasts/plasma cells are elevated in active IgG4-RD and decreased after glucocorticoid treatment. This IgG4-secreting plasmablast/plasma cell population might be a potentially useful biomarker for diagnosis and assessing response to treatment.
C1 [Lin, Wei; Zhang, Panpan; Chen, Hua; Chen, Yu; Yang, Hongxian; Zheng, Wenjie; Zhang, Xuan; Zhang, Wen] Chinese Acad Med Sci, Key Lab Rheumatol & Clin Immunol, Peking Union Med Coll Hosp, Dept Rheumatol,Minist Educ, Beijing 100730, Peoples R China.
[Lin, Wei; Zhang, Fengxiao] Hebei Gen Hosp, Dept Rheumatol, Shijiazhuang, Peoples R China.
[Lipsky, Peter E.] NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Zhang, W (reprint author), Chinese Acad Med Sci, Key Lab Rheumatol & Clin Immunol, Peking Union Med Coll Hosp, Dept Rheumatol,Minist Educ, Beijing 100730, Peoples R China.; Lipsky, PE (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA.
EM zhangwen91@sina.com; peterlipsky@comcast.net
OI zhang, xuan/0000-0001-8775-1699
FU National Natural Science Foundation of China [81373190, 81571587]
FX This work was supported by grants from the National Natural Science
Foundation of China (grant numbers 81373190, 81571587).
NR 39
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Z9 0
U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1478-6354
EI 1478-6362
J9 ARTHRITIS RES THER
JI Arthritis Res. Ther.
PD FEB 10
PY 2017
VL 19
AR 25
DI 10.1186/s13075-017-1231-2
PG 14
WC Rheumatology
SC Rheumatology
GA EN8UC
UT WOS:000396274300002
PM 28183334
ER
PT J
AU Erikson, JM
Valente, AJ
Mummidi, S
Kandikattu, HK
DeMarco, VG
Bender, SB
Fay, WP
Siebenlist, U
Chandrasekar, B
AF Erikson, John M.
Valente, Anthony J.
Mummidi, Srinivas
Kandikattu, Hemanth Kumar
DeMarco, Vincent G.
Bender, Shawn B.
Fay, William P.
Siebenlist, Ulrich
Chandrasekar, Bysani
TI Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits
Ischemia/Reperfusion- induced Myocardial Injury and Adverse Remodeling
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID ISCHEMIA-REPERFUSION INJURY; NF-KAPPA-B; IMPROVES CARDIAC-FUNCTION;
ACTIVATED PROTEIN-KINASE; MICROBUBBLE DESTRUCTION; NITRIC-OXIDE;
IN-VIVO; ENDOTHELIAL DYSFUNCTION; CARDIOMYOCYTE APOPTOSIS; ALBUMIN
MICROBUBBLES
AB Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both I kappa B kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-kappa B and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore, Traf3ip2 gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destruction-mediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-kappa B and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.
C1 [Erikson, John M.; Valente, Anthony J.; Mummidi, Srinivas] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.
[Kandikattu, Hemanth Kumar; DeMarco, Vincent G.; Fay, William P.; Chandrasekar, Bysani] Univ Missouri, Dept Med, Sch Med, Columbia, MO 65211 USA.
[Kandikattu, Hemanth Kumar; DeMarco, Vincent G.; Fay, William P.; Chandrasekar, Bysani] Harry S Truman Mem Vet Hosp, Res Serv, Columbia, MO 65201 USA.
[DeMarco, Vincent G.; Bender, Shawn B.; Fay, William P.; Chandrasekar, Bysani] Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO 65211 USA.
[Bender, Shawn B.; Siebenlist, Ulrich] Univ Missouri, Sch Med, Dept Biomed Sci, Columbia, MO 65211 USA.
[Bender, Shawn B.; Chandrasekar, Bysani] Dalton Cardiovasc Res Ctr, Columbia, MO 65201 USA.
[Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA.
RP Chandrasekar, B (reprint author), Univ Missouri, Sch Med, Med Cardiol, 1 Hosp Dr, Columbia, MO 65212 USA.
EM chandrasekarb@health.missouri.edu
FU United States Department of Veterans Affairs, Office of Research and
Development-Biomedical Laboratory Research and Development
[I01-BX002255]
FX The work was supported in part by United States Department of Veterans
Affairs, Office of Research and Development-Biomedical Laboratory
Research and Development (ORD-BLRD) Service Award I01-BX002255. The
authors declare that they have no conflicts of interest with the
contents of this article. The contents of this report do not represent
the views of the Department of Veterans Affairs or the United States
government. The content is solely the responsibility of the authors and
does not necessarily represent the official views of the National
Institutes of Health.
NR 61
TC 0
Z9 0
U1 1
U2 1
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD FEB 10
PY 2017
VL 292
IS 6
BP 2345
EP 2358
DI 10.1074/jbc.M116.764522
PG 14
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EM7ZG
UT WOS:000395530300025
PM 28053087
ER
PT J
AU Zhai, XH
Gao, YG
Mishra, SK
Simanshu, DK
Boldyrev, IA
Benson, LM
Bergen, HR
Malinina, L
Mundy, J
Molotkovsky, JG
Patel, DJ
Brown, RE
AF Zhai, Xiuhong
Gao, Yong-Guang
Mishra, Shrawan K.
Simanshu, Dhirendra K.
Boldyrev, Ivan A.
Benson, Linda M.
Bergen, H. Robert, III
Malinina, Lucy
Mundy, John
Molotkovsky, Julian G.
Patel, Dinshaw J.
Brown, Rhoderick E.
TI Phosphatidylserine Stimulates Ceramide 1-Phosphate (C1P) Intermembrane
Transfer by C1P Transfer Proteins
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID GLYCOLIPID TRANSFER PROTEIN; OXYSTEROL-BINDING PROTEINS; PROGRAMMED
CELL-DEATH; AMPHITROPIC PROTEINS; MEMBRANE INTERACTION;
GLYCOSPHINGOLIPID SYNTHESIS; TRANSBILAYER DISTRIBUTION; TRYPTOPHAN
FLUORESCENCE; PHOSPHOLIPID-BINDING; MEDIATED TRANSFER
AB Genetic models for studying localized cell suicide that halt the spread of pathogen infection and immune response activation in plants include Arabidopsis accelerated-cell-death 11 mutant (acd11). In this mutant, sphingolipid homeostasis is disrupted via depletion of ACD11, a lipid transfer protein that is specific for ceramide 1-phosphate (C1P) and phyto-C1P. The C1P binding site in ACD11 and in human ceramide-1-phosphate transfer protein (CPTP) is surrounded by cationic residues. Here, we investigated the functional regulation of ACD11 and CPTP by anionic phosphoglycerides and found that 1-palmitoyl-2-oleoyl-phosphatidic acid or 1-palmitoyl-2-oleoyl-phosphatidylglycerol (<= 15 mol %) in C1P source vesicles depressed C1P intermembrane transfer. Bycontrast, replacement with 1-palmitoyl-2-oleoyl-phosphatidylserine stimulated C1P transfer by ACD11 and CPTP. Notably, "soluble" phosphatidylserine (dihexanoyl-phosphatidylserine) failed to stimulate C1P transfer. Also, none of the anionic phosphoglycerides affected transfer action by human glycolipid lipid transfer protein (GLTP), which is glycolipid-specific and has few cationic residues near its glycolipid binding site. These findings provide the first evidence for a potential phosphoglyceride headgroup-specific regulatory interaction site(s) existing on the surface of any GLTP-fold and delineate new differences between GLTP superfamily members that are specific for C1P versus glycolipid.
C1 [Zhai, Xiuhong; Gao, Yong-Guang; Mishra, Shrawan K.; Malinina, Lucy; Brown, Rhoderick E.] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA.
[Simanshu, Dhirendra K.; Patel, Dinshaw J.] Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10065 USA.
[Boldyrev, Ivan A.; Molotkovsky, Julian G.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia.
[Benson, Linda M.; Bergen, H. Robert, III] Mayo Fdn, Med Genom Facil, Prote Core, Rochester, MN 55905 USA.
[Mundy, John] Univ Copenhagen, BioCtr, Dept Biol, DK-2200 Copenhagen N, Denmark.
[Simanshu, Dhirendra K.] NCI Frederick, Frederick Natl Lab Canc Res, NIH, 8560 Progress Dr,C1012, Frederick, MD 21702 USA.
RP Zhai, XH; Brown, RE (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA.
EM zhai@hi.umn.edu; reb@umn.edu
FU NIGMS, National Institutes of Health (NIH) [GM45928]; NHLBI, NIH
[HL125353, NCI CA121493]; Russian Foundation for Basic Research
[015-04-07415]; Danish Strategic Research Council [09-067148]; Abby
Rockefeller Mauze Trust; Maloris and Hormel Foundations
FX This work was supported in whole or part by NIGMS, National Institutes
of Health (NIH), Grant GM45928 and NHLBI, NIH, Grants HL125353 and NCI
CA121493; Russian Foundation for Basic Research Grant 015-04-07415;
Danish Strategic Research Council Grant 09-067148; the Abby Rockefeller
Mauze Trust; and the Maloris and Hormel Foundations. Portions of this
work were presented at the 2015 American Chemical Society and 2015
American Society for Biochemistry and Molecular Biology Annual Meetings.
The authors declare that they have no conflicts of interest with the
contents of this article. The content is solely the responsibility of
the authors and does not necessarily represent the official views of the
National Institutes of Health.
NR 73
TC 0
Z9 0
U1 1
U2 1
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD FEB 10
PY 2017
VL 292
IS 6
BP 2531
EP 2541
DI 10.1074/jbc.M116.760256
PG 11
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA EM7ZG
UT WOS:000395530300039
PM 28011644
ER
PT J
AU Carroll, YI
Eichwald, J
Scinicariello, F
Hoffman, HJ
Deitchman, S
Radke, MS
Themann, CL
Breysse, P
AF Carroll, Yulia I.
Eichwald, John
Scinicariello, Franco
Hoffman, Howard J.
Deitchman, Scott
Radke, Marilyn S.
Themann, Christa L.
Breysse, Patrick
TI Vital Signs: Noise-Induced Hearing Loss Among Adults - United States
2011-2012
SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT
LA English
DT Article
ID HEALTH
AB Introduction: The 2016 National Academies of Sciences report "Hearing Health Care for Adults: Priorities for Improving Access and Affordability" included a call to action for government agencies to strengthen efforts to collect, analyze, and disseminate population-based data on hearing loss in adults.
Methods: CDC analyzed the most recent available data collected both by questionnaire and audiometric tests of adult participants aged 20-69 years in the 2011-2012 National Health. and Nutrition Examination Survey (NHANES) to determine the presence of audiometric notches indicative of noise-induced hearing loss. Prevalence of both unilateral and,bilateral audiometric notches and their association with sociodemographics and self-reported exposure to loud noise were calculated.
Results: Nearly one in four adults (24%) had audiometric notches, suggesting a high prevalence of noise-induced hearing loss. The prevalence of notches was higher among males. Almost one in four U.S. adults who reported excellent or good hearing had audiometric notches (5.5% bilateral and 18.0% unilateral). Among participants who reported exposure to loud noise at work, almost one third had a notch.
Conclusions and Implications for Public Health Practice: Noise-induced hearing loss is a significant, often unrecognized health problem among U.S. adults. Discussions between patients and personal health care providers about hearing loss symptoms, tests, and ways to protect hearing might help with early diagnosis of hearing loss and provide opportunities to prevent harmful noise expoSures. Avoiding prolonged exposure to loud environments and using personal hearing protection devices can prevent noise-induced hearing loss.
C1 [Carroll, Yulia I.; Eichwald, John] CDC, Off Sci, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA.
[Scinicariello, Franco] Agcy Toxic Subst & Dis Registry, Div Toxicol & Human Hlth Serv, Atlanta, GA USA.
[Hoffman, Howard J.] NIDCD, NIH, Bethesda, MD USA.
[Deitchman, Scott; Breysse, Patrick] CDC, Off Director, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA.
[Radke, Marilyn S.] CDC, Div Emergency & Environm Hlth Serv, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA.
[Themann, Christa L.] CDC, NIOSH, Atlanta, GA 30333 USA.
RP Carroll, YI (reprint author), CDC, Off Sci, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA.
EM YCarroll@cdc.gov
NR 16
TC 0
Z9 0
U1 1
U2 1
PU CENTERS DISEASE CONTROL
PI ATLANTA
PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA
SN 0149-2195
EI 1545-861X
J9 MMWR-MORBID MORTAL W
JI MMWR-Morb. Mortal. Wkly. Rep.
PD FEB 10
PY 2017
VL 66
IS 5
BP 139
EP 144
PG 6
WC Public, Environmental & Occupational Health
SC Public, Environmental & Occupational Health
GA EL1US
UT WOS:000394407400005
PM 28182600
ER
PT J
AU Koonin, EV
AF Koonin, Eugene V.
TI Evolution of RNA- and DNA-guided antivirus defense systems in
prokaryotes and eukaryotes: common ancestry vs convergence
SO BIOLOGY DIRECT
LA English
DT Review
ID CRISPR-CAS SYSTEMS; ADAPTIVE IMMUNITY; ARGONAUTE PROTEINS;
CRYSTAL-STRUCTURE; STRUCTURAL INSIGHTS; BACTERIAL ARGONAUTE; GENOME
EVOLUTION; NONCODING RNA; CENTRAL DOGMA; FOREIGN DNA
AB Complementarity between nucleic acid molecules is central to biological information transfer processes. Apart from the basal processes of replication, transcription and translation, complementarity is also employed by multiple defense and regulatory systems. All cellular life forms possess defense systems against viruses and mobile genetic elements, and in most of them some of the defense mechanisms involve small guide RNAs or DNAs that recognize parasite genomes and trigger their inactivation. The nucleic acid-guided defense systems include prokaryotic Argonaute (pAgo)-centered innate immunity and CRISPR-Cas adaptive immunity as well as diverse branches of RNA interference (RNAi) in eukaryotes. The archaeal pAgo machinery is the direct ancestor of eukaryotic RNAi that, however, acquired additional components, such as Dicer, and enormously diversified through multiple duplications. In contrast, eukaryotes lack any heritage of the CRISPR-Cas systems, conceivably, due to the cellular toxicity of some Cas proteins that would get activated as a result of operon disruption in eukaryotes. The adaptive immunity function in eukaryotes is taken over partly by the PIWI RNA branch of RNAi and partly by protein-based immunity. In this review, I briefly discuss the interplay between homology and analogy in the evolution of RNA-and DNA-guided immunity, and attempt to formulate some general evolutionary principles for this ancient class of defense systems.
C1 [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA.
RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA.
EM koonin@ncbi.nlm.nih.gov
FU US Department of Health and Human Services
FX The author's research is supported by intramural funds of the US
Department of Health and Human Services (to the National Library of
Medicine).
NR 137
TC 0
Z9 0
U1 6
U2 6
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1745-6150
J9 BIOL DIRECT
JI Biol. Direct
PD FEB 10
PY 2017
VL 12
AR 5
DI 10.1186/s13062-017-0177-2
PG 14
WC Biology
SC Life Sciences & Biomedicine - Other Topics
GA EM8YB
UT WOS:000395595900001
PM 28187792
ER
PT J
AU Xu, C
Yang, XY
Fu, X
Tian, R
Jacobson, O
Wang, ZT
Lu, N
Liu, YJ
Fan, WP
Zhang, FW
Niu, G
Hu, S
Ali, IU
Chen, XY
AF Xu, Can
Yang, Xiangyu
Fu, Xiao
Tian, Rui
Jacobson, Orit
Wang, Zhantong
Lu, Nan
Liu, Yijing
Fan, Wenpei
Zhang, Fuwu
Niu, Gang
Hu, Shuo
Ali, Iqbal Unnisa
Chen, Xiaoyuan
TI Converting Red Blood Cells to Efficient Microreactors for Blood
Detoxification
SO ADVANCED MATERIALS
LA English
DT Article
ID ATOMIC-FORCE MICROSCOPY; URIC-ACID; MOUSE ERYTHROCYTES; HYPOTONIC
HEMOLYSIS; DRUG-DELIVERY; DEGRADATION; PEROXIDASE; CARRIERS; ENZYME;
MICROPARTICLES
AB A simple method to convert red blood cells (RBCs) into efficient microreactors is reported. Triton X-100 is employed at finely tuned concentrations to render RBCs highly permeable to substrates, while low concentrations of glutaraldehyde are used to stabilize cells. The ability for blood detoxification of these micro-reactors is demonstrated.
C1 [Xu, Can; Hu, Shuo] Cent S Univ, Xiangya Hosp, Dept PET Ctr, Changsha 410008, Hunan, Peoples R China.
[Xu, Can; Yang, Xiangyu; Fu, Xiao; Tian, Rui; Jacobson, Orit; Wang, Zhantong; Lu, Nan; Liu, Yijing; Fan, Wenpei; Zhang, Fuwu; Niu, Gang; Ali, Iqbal Unnisa; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA.
RP Hu, S (reprint author), Cent S Univ, Xiangya Hosp, Dept PET Ctr, Changsha 410008, Hunan, Peoples R China.; Ali, IU; Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA.
EM iqbal.ali@nih.gov; shawn.chen@nih.gov
FU National Institute of Biomedical Imaging and Bioengineering, National
Institutes of Health; National Science Foundation of China [NSFC
81471689]
FX This research was supported in part by the Intramural Research Program,
National Institute of Biomedical Imaging and Bioengineering, National
Institutes of Health, and the National Science Foundation of China (NSFC
81471689). All experiments with live animals were conducted in
accordance with a protocol approved by the National Institutes of Health
Clinical Center Animal Care and Use Committee (NIH CC/ACUC).
NR 59
TC 0
Z9 0
U1 7
U2 7
PU WILEY-V C H VERLAG GMBH
PI WEINHEIM
PA POSTFACH 101161, 69451 WEINHEIM, GERMANY
SN 0935-9648
EI 1521-4095
J9 ADV MATER
JI Adv. Mater.
PD FEB 10
PY 2017
VL 29
IS 6
AR UNSP 1603673
DI 10.1002/adma.201603673
PG 12
WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience &
Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied;
Physics, Condensed Matter
SC Chemistry; Science & Technology - Other Topics; Materials Science;
Physics
GA EN6WB
UT WOS:000396143000009
ER
PT J
AU Zhou, WC
Marinelli, F
Nief, C
Faraldo-Gomez, JD
AF Zhou, Wenchang
Marinelli, Fabrizio
Nief, Corrine
Faraldo-Gomez, Jose D.
TI Atomistic simulations indicate the c-subunit ring of the F1Fo ATP
synthase is not the mitochondrial permeability transition pore
SO ELIFE
LA English
DT Article
ID HIGH-RESOLUTION STRUCTURE; ROTOR RING; ILYOBACTER-TARTARICUS;
FORCE-FIELD; MECHANISM; OPTIMIZATION; DYNAMICS; CHANNEL; BINDING
AB Pathological metabolic conditions such as ischemia induce the rupture of the mitochondrial envelope and the release of pro-apoptotic proteins, leading to cell death. At the onset of this process, the inner mitochondrial membrane becomes depolarized and permeable to osmolytes, proposedly due to the opening of a non-selective protein channel of unknown molecular identity. A recent study purports that this channel, referred to as Mitochondrial Permeability Transition Pore (MPTP), is formed within the c-subunit ring of the ATP synthase, upon its dissociation from the catalytic domain of the enzyme. Here, we examine this claim for two c-rings of different lumen width, through calculations of their ion conductance and selectivity based on all-atom molecular dynamics simulations. We also quantify the likelihood that the lumen of these c-rings is in a hydrated, potentially conducting state rather than empty or blocked by lipid molecules. These calculations demonstrate that the structure and biophysical properties of a correctly assembled c-ring are inconsistent with those attributed to the MPTP.
C1 [Zhou, Wenchang; Marinelli, Fabrizio; Nief, Corrine; Faraldo-Gomez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Marinelli, F; Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA.
EM marinelli@nih.gov; jose.faraldo@nih.gov
FU National Heart, Lung, and Blood Institute
FX National Heart, Lung, and Blood Institute Wenchang Zhou Fabrizio
Marinelli Jose D Faraldo-Gomez.; The funders had no role in study
design, data collection and interpretation, or the decision to submit
the work for publication.
NR 39
TC 0
Z9 0
U1 0
U2 0
PU ELIFE SCIENCES PUBLICATIONS LTD
PI CAMBRIDGE
PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND
SN 2050-084X
J9 ELIFE
JI eLife
PD FEB 10
PY 2017
VL 6
AR e23781
DI 10.7554/eLife.23781
PG 11
WC Biology
SC Life Sciences & Biomedicine - Other Topics
GA EM3WA
UT WOS:000395244100001
ER
PT J
AU Weldon, CB
Madenci, AL
Boikos, SA
Janeway, KA
George, S
von Mehren, M
Pappo, AS
Schiffman, JD
Wright, J
Trent, JC
Pacak, K
Stratakis, CA
Helman, LJ
La Quaglia, MP
AF Weldon, Christopher B.
Madenci, Arin L.
Boikos, Sosipatros A.
Janeway, Katherine A.
George, Suzanne
von Mehren, Margaret
Pappo, Alberto S.
Schiffman, Joshua D.
Wright, Jennifer
Trent, Jonathan C.
Pacak, Karel
Stratakis, Constantine A.
Helman, Lee J.
La Quaglia, Michael P.
TI Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A
Report From the National Institutes of Health Pediatric and Wildtype
GIST Clinic
SO JOURNAL OF CLINICAL ONCOLOGY
LA English
DT Article
ID KINASE INHIBITOR THERAPY; TERM-FOLLOW-UP; PROGNOSTIC-FACTORS;
THE-LITERATURE; YOUNG-ADULTS; MUTATIONS; RECURRENCE; RESECTION; KIT;
DIAGNOSIS
AB Purpose
Wild-type gastrointestinal stromal tumors (WT-GISTs) that lack KIT or PDGFRA mutations represent a unique subtype of GIST that predominantly affects children. We sought to determine the effect on event-free survival (EFS) of staging variables, extent of resection, and repeat resection of tumors.
Methods
In 2008, a WT-GIST clinic was established at the National Cancer Institute, allowing the development of a large clinical database. We included participants who underwent resection of WT-GIST. Associations with EFS (ie, freedom from disease progression or recurrence) were evaluated using the Kaplan-Meier method and Cox proportional hazards modeling.
Results
Among 76 participants with WT-GISTs, the median follow-up was 4.1 years. Overall EFS (6 SE) was 72.6 +/- 5.4% at 1 year, 57.6 +/- 6.2% at 2 years, 23.7 +/- 6.0% at 5 years, and 16.3 +/- 6 5.5% at 10 years postoperatively. Hazard of disease progression or recurrence was significantly increased for patients with metastatic disease (adjusted hazard ratio [AHR], 2.3; 95% CI, 1.0 to 5.1; P 5.04) and. 5 mitoses per 50 high-power fields (AHR, 2.5; 95% CI, 1.1 to 6.0; P = .03), whereas there was no significant effect of negative microscopic resection margins (AHR, 0.9; 95% CI, 0.4 to 2.2; P = 0.86). There was no association between type of gastric resection (ie, anatomic v partial/wedge) and EFS (P = .67). Repeated resection after the initial resection was significantly associated with decreasing postoperative EFS (P < .01). Five patients (6%) died after initial enrollment in 2008.
Conclusion
WT-GIST is an indolent disease, and most patients survive with disease progression. We found no improvement in EFS with more extensive or serial resections. Disease progression or recurrence may be more closely related to tumor biology than surgical management. These data suggest that resections for WT-GISTs be restricted to the initial procedure and that subsequent resections be performed only to address symptoms such as obstruction or bleeding. (C) 2016 by American Society of Clinical Oncology
C1 [Weldon, Christopher B.; Madenci, Arin L.] Boston Childrens Hosp, Boston, MA USA.
[Weldon, Christopher B.; Madenci, Arin L.; Janeway, Katherine A.; George, Suzanne] Harvard Med Sch, Boston, MA USA.
[Weldon, Christopher B.; Janeway, Katherine A.; George, Suzanne] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA.
[Madenci, Arin L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
[Boikos, Sosipatros A.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA.
[von Mehren, Margaret] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA.
[Pappo, Alberto S.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA.
[Schiffman, Joshua D.; Wright, Jennifer] Huntsman Canc Inst, Salt Lake City, UT USA.
[Trent, Jonathan C.] Sylvester Comprehens Canc Ctr, Miami, FL USA.
[Pacak, Karel; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA.
[Helman, Lee J.] NCI, Bethesda, MD 20892 USA.
[La Quaglia, Michael P.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA.
[La Quaglia, Michael P.] Weill Cornell Med Coll, New York, NY USA.
RP Weldon, CB (reprint author), Dept Surg, 300 Longwood Ave,Fegan 3, Boston, MA 02115 USA.
EM christopher.weldon@childrens.harvard.edu
FU ArQule; Janssen; Morphotek
FX ArQule; ArQule; Janssen, Morphotek
NR 28
TC 0
Z9 0
U1 0
U2 0
PU AMER SOC CLINICAL ONCOLOGY
PI ALEXANDRIA
PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA
SN 0732-183X
EI 1527-7755
J9 J CLIN ONCOL
JI J. Clin. Oncol.
PD FEB 10
PY 2017
VL 35
IS 5
BP 523
EP +
DI 10.1200/JCO.2016.68.6733
PG 8
WC Oncology
SC Oncology
GA EL2KB
UT WOS:000394447400001
ER
PT J
AU Bradley, CJ
Yabroff, KR
Mariotto, AB
Zeruto, C
Tran, Q
Warren, JL
AF Bradley, Cathy J.
Yabroff, K. Robin
Mariotto, Angela B.
Zeruto, Christopher
Tran, Quyen
Warren, Joan L.
TI Antineoplastic Treatment of Advanced-Stage Non-Small-Cell Lung Cancer:
Treatment, Survival, and Spending (2000 to 2011)
SO JOURNAL OF CLINICAL ONCOLOGY
LA English
DT Article
ID PHASE-III TRIAL; CHEMOTHERAPY USE; THERAPY; BEVACIZUMAB; ERLOTINIB;
MEDICARE; COST; ONCOLOGY; UTILITY; CARE
AB Purpose
Multiple agents for advanced non-small-cell lung cancer (NSCLC) have been approved in the past decade, but little is known about their use and associated spending and survival.
Methods
We used SEER-Medicare data for elderly patients with a new diagnosis of advanced-stage NSCLC and were treated with antineoplastic agents between 2000 and 2011 (N = 22,163). We estimated the adjusted percentage of patients who received each agent, days while on treatment, survival, and spending in the 12 months after diagnosis.
Results
During the 12-year study period, a marked shift in treatment occurred along with a rapid adoption of pemetrexed (39.2%), erlotinib (20.3%), and bevacizumab (18.9%) and a decline in paclitaxel (38.7%), gemcitabine (17.0%), and vinorelbine (5.7%; all P < .05). The average total days on therapy increased by 5 days (from 103 to 108 days). Patients who received bevacizumab, erlotinib, or pemetrexed had the longest treatment durations on average (approximately 146 days v 75 days for those who did not receive these agents). Approximately 44% of patients received antineoplastic agents in the last 30 days of life throughout the study period. Acute inpatient spending declined (from $29,376 to $23,731), whereas outpatient spending increased 23% (from $37,931 to $46,642). Median survival gains of 1.5 months were observed.
Conclusion
Considerable shifts in the treatment of advanced-stage NSCLC occurred along with modest gains in survival and total Medicare spending. More precise outcome information is needed to inform value-based treatment decisions for advanced-stage NSCLC. (C) 2017 by American Society of Clinical Oncology
C1 [Bradley, Cathy J.] Univ Colorado, Aurora, CO USA.
[Yabroff, K. Robin] US Dept HHS, Washington, DC 20201 USA.
[Mariotto, Angela B.; Tran, Quyen; Warren, Joan L.] NCI, Bethesda, MD 20892 USA.
[Zeruto, Christopher] Informat Management Serv Inc, Beltsville, MD USA.
RP Bradley, CJ (reprint author), Univ Colorado, Ctr Canc, Dept Hlth Syst Management & Policy, 13001 E 17th Pl,B119,Bldg 500,Room N6203L, Aurora, CO 80045 USA.
EM cathy.bradley@ucdenver.edu
NR 24
TC 0
Z9 0
U1 0
U2 0
PU AMER SOC CLINICAL ONCOLOGY
PI ALEXANDRIA
PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA
SN 0732-183X
EI 1527-7755
J9 J CLIN ONCOL
JI J. Clin. Oncol.
PD FEB 10
PY 2017
VL 35
IS 5
BP 529
EP +
DI 10.1200/JCO.2016.69.4166
PG 8
WC Oncology
SC Oncology
GA EL2KB
UT WOS:000394447400002
ER
PT J
AU Shea, AA
Bernhards, RC
Cote, CK
Chase, CJ
Koehler, JW
Klimko, CP
Ladner, JT
Rozak, DA
Wolcott, MJ
Fetterer, DP
Kern, SJ
Koroleva, GI
Lovett, SP
Palacios, GF
Toothman, RG
Bozue, JA
Worsham, PL
Welkos, SL
AF Shea, A. A.
Bernhards, R. C.
Cote, C. K.
Chase, C. J.
Koehler, J. W.
Klimko, C. P.
Ladner, J. T.
Rozak, D. A.
Wolcott, M. J.
Fetterer, D. P.
Kern, S. J.
Koroleva, G. I.
Lovett, S. P.
Palacios, G. F.
Toothman, R. G.
Bozue, J. A.
Worsham, P. L.
Welkos, S. L.
TI Two stable variants of Burkholderia pseudomallei strain MSHR5848 express
broadly divergent in vitro phenotypes associated with their virulence
differences
SO PLOS ONE
LA English
DT Article
ID COLONY MORPHOLOGY VARIATION; ANTIGENIC VARIATION;
PSEUDOMONAS-PSEUDOMALLEI; CAPSULAR POLYSACCHARIDE; OXIDATIVE STRESS;
ANTIMICROBIAL PEPTIDES; CYSTIC-FIBROSIS; MICROARRAY DATA; D-SERINE;
MELIOIDOSIS
AB Burkholderia pseudomallei (Bp), the agent of melioidosis, causes disease ranging from acute and rapidly fatal to protracted and chronic. Bp is highly infectious by aerosol, can cause severe disease with nonspecific symptoms, and is naturally resistant to multiple antibiotics. However, no vaccine exists. Unlike many Bp strains, which exhibit random variability in traits such as colony morphology, Bp strain MSHR5848 exhibited two distinct and relatively stable colony morphologies on sheep blood agar plates: a smooth, glossy, pale yellow colony and a flat, rough, white colony. Passage of the two variants, designated "Smooth" and "Rough", under standard laboratory conditions produced cultures composed of > 99.9% of the single corresponding type; however, both could switch to the other type at different frequencies when incubated in certain nutritionally stringent or stressful growth conditions. These MSHR5848 derivatives were extensively characterized to identify variant-associated differences. Microscopic and colony morphology differences on six differential media were observed and only the Rough variant metabolized sugars in selective agar. Antimicrobial susceptibilities and lipopolysaccharide (LPS) features were characterized and phenotype microarray profiles revealed distinct metabolic and susceptibility disparities between the variants. Results using the phenotype microarray system narrowed the 1,920 substrates to a subset which differentiated the two variants. Smooth grew more rapidly in vitro than Rough, yet the latter exhibited a nearly 10-fold lower lethal dose for mice than Smooth. Finally, the Smooth variant was phagocytosed and replicated to a greater extent and was more cytotoxic than Rough in macrophages. In contrast, multiple locus sequence type (MLST) analysis, ribotyping, and whole genome sequence analysis demonstrated the variants' genetic conservation; only a single consistent genetic difference between the two was identified for further study. These distinct differences shown by two variants of a Bp strain will be leveraged to better understand the mechanism of Bp phenotypic variability and to possibly identify in vitro markers of infection.
C1 [Shea, A. A.; Chase, C. J.; Koehler, J. W.; Rozak, D. A.; Wolcott, M. J.] USAMRIID, Diagnost Syst Div, Frederick, MD USA.
[Bernhards, R. C.; Cote, C. K.; Klimko, C. P.; Toothman, R. G.; Bozue, J. A.; Worsham, P. L.; Welkos, S. L.] USAMRIID, Bacteriol Div, Frederick, MD 21702 USA.
[Ladner, J. T.; Koroleva, G. I.; Lovett, S. P.; Palacios, G. F.] USAMRIID, Ctr Genome Sci, Frederick, MD USA.
[Fetterer, D. P.; Kern, S. J.] USAMRIID, Biostat Serv Div, Frederick, MD USA.
[Bernhards, R. C.] Edgewood Chem Biol Ctr, Aberdeen Proving Ground, MD USA.
[Kern, S. J.] NIH, Bldg 10, Bethesda, MD 20892 USA.
RP Welkos, SL (reprint author), USAMRIID, Bacteriol Div, Frederick, MD 21702 USA.
EM susan.l.welkos.civ@mail.mil
OI Palacios, Gustavo/0000-0001-5062-1938
FU Joint Science & Technology Office for Chemical & Biological Defense
(JSTO-CBD), Defense Threat Reduction Agency (DTRA) [CB3846PPE-1,
CB10246]
FX This research was funded by the Joint Science & Technology Office for
Chemical & Biological Defense (JSTO-CBD), Defense Threat Reduction
Agency (DTRA) - (1) Project CCAR# CB3846PPE-1 Burkholderia
(PatriciaWorsham). (2) Project CB10246: High Speed Sequencing for Rapid
Response and Countermeasure Development (GustavoPalacios)
http://www.dtra. mil/Research/Chemical-Biological-TechnologyD
epartment/.
NR 98
TC 0
Z9 0
U1 1
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 FEB 10
PY 2017
VL 12
IS 2
AR e0171363
DI 10.1371/journal.pone.0171363
PG 32
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK9KV
UT WOS:000394244300022
ER
PT J
AU Shi, Y
Lai, XR
Ye, LY
Chen, KQ
Cao, Z
Gong, WH
Jin, LL
Wang, CY
Liu, MY
Liao, Y
Wang, JMM
Zhou, NM
AF Shi, Ying
Lai, Xiangru
Ye, Lingyan
Chen, Keqiang
Cao, Zheng
Gong, Wanghua
Jin, Lili
Wang, Chunyan
Liu, Mingyong
Liao, Yuan
Wang, Ji Ming
Zhou, Naiming
TI Activated niacin receptor HCA2 inhibits chemoattractant-mediated
macrophage migration via G beta gamma/PKC/ERK1/2 pathway and
heterologous receptor desensitization
SO SCIENTIFIC REPORTS
LA English
DT Article
ID NICOTINIC-ACID RECEPTOR; SUPPRESSES COLONIC INFLAMMATION; PUMA-G;
PROTEIN-KINASE; MOLECULAR-IDENTIFICATION; CROSS-DESENSITIZATION;
CHEMOKINE RECEPTORS; ARTERIAL BIOLOGY; PHOSPHOLIPASE-C; GAMMA-SUBUNITS
AB The niacin receptor HCA2 is implicated in controlling inflammatory host responses with yet poorly understood mechanistic basis. We previously reported that HCA2 in A431 epithelial cells transduced G beta gamma-protein kinase C-and G beta gamma-metalloproteinase/EGFR-dependent MAPK/ERK signaling cascades. Here, we investigated the role of HCA2 in macrophage-mediated inflammation and the underlying mechanisms. We found that proinflammatory stimulants LPS, IL-6 and IL-1 beta up-regulated the expression of HCA2 on macrophages. Niacin significantly inhibited macrophage chemotaxis in response to chemoattractants fMLF and CCL2 by disrupting polarized distribution of F-actin and G beta protein. Niacin showed a selected additive effect on chemoattractant-induced activation of ERK1/2, JNK and PI3K pathways, but only the MEK inhibitor UO126 reduced niacin-mediated inhibition of macrophage chemotaxis, while activation of ERK1/2 by EGF alone did not inhibit fMLF-mediated migration of HEK293T cells co-expressing HCA2 and fMLF receptor FPR1. In addition, niacin induced heterologous desensitization and internalization of FPR1. Furthermore, niacin rescued mice from septic shock by diminishing inflammatory symptoms and the effect was abrogated in HCA2(-/-)mice. These results suggest that G beta gamma/PKC-dependent ERK1/2 activation and heterologous desensitization of chemoattractant receptors are involved in the inhibition of chemoattractant-induced migration of macrophages by niacin. Thus, HCA2 plays a critical role in host protection against pro-inflammatory insults.
C1 [Shi, Ying; Lai, Xiangru; Ye, Lingyan; Cao, Zheng; Jin, Lili; Liao, Yuan; Zhou, Naiming] Zhejiang Univ, Coll Life Sci, Yu Hang Tang Load 388, Hangzhou, Zhejiang, Peoples R China.
[Chen, Keqiang; Gong, Wanghua; Wang, Chunyan; Liu, Mingyong; Wang, Ji Ming] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA.
[Wang, Chunyan] Xuzhou Yes Biotech Labs Ltd, Xuzhou, Jiangsu, Peoples R China.
[Liu, Mingyong] Third Mil Med Univ, Daping Hosp, Dept Spine Surg, Chongqing, Peoples R China.
RP Zhou, NM (reprint author), Zhejiang Univ, Coll Life Sci, Yu Hang Tang Load 388, Hangzhou, Zhejiang, Peoples R China.; Wang, JMM (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA.
EM wangji@mail.nih.gov; zhounaiming@zju.edu.cn
FU Ministry of Science and Technology of China [2012CB910402,
2012AA020303]; National Natural Science Foundation of China [81173106,
31200621]; Zhejiang Provincial Natural Science Foundation of China
[LY15C050001]; Siyuan Foundation; National Cancer Institute, National
Institutes of Health [HSN261200800001E]; Intramural Research Program of
the NCI,NIH
FX We thank Dr. Stefan Offermanns of Max-Planck-Institute for Heart and
Lung Research, Germany for providing Hca2 KO (C57BL) breeders, and We
also thank the staff of Immunohistochemistry Facility of College of
Pharmacological Science for preparation of frozen sections. This work
was supported by grants from the Ministry of Science and Technology of
China (2012CB910402 and 2012AA020303), the National Natural Science
Foundation of China (81173106 and 31200621), Zhejiang Provincial Natural
Science Foundation of China (LY15C050001) and Siyuan Foundation. This
project was also funded in part by federal funds from the National
Cancer Institute, National Institutes of Health, under Contract No.
HSN261200800001E and was supported in part by the Intramural Research
Program of the NCI, NIH.
NR 71
TC 0
Z9 0
U1 1
U2 1
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 10
PY 2017
VL 7
AR 42279
DI 10.1038/srep42279
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK7IM
UT WOS:000394099500001
PM 28186140
ER
PT J
AU Choi, YJ
Lin, CP
Risso, D
Chen, S
Kim, TA
Tan, MH
Li, JB
Wu, YL
Chen, CF
Xuan, ZY
Macfarlan, T
Peng, WQ
Lloyd, KCK
Kim, SY
Speed, TP
He, L
AF Choi, Yong Jin
Lin, Chao-Po
Risso, Davide
Chen, Sean
Kim, Thomas Aquinas
Tan, Meng How
Li, Jin Billy
Wu, Yalei
Chen, Caifu
Xuan, Zhenyu
Macfarlan, Todd
Peng, Weiqun
Lloyd, K. C. Kent
Kim, Sang Yong
Speed, Terence P.
He, Lin
TI Deficiency of microRNA miR-34a expands cell fate potential in
pluripotent stem cells
SO SCIENCE
LA English
DT Article
ID STAGE MOUSE BLASTOMERES; GENE-EXPRESSION; MUERV-L; EMBRYOS;
DIFFERENTIATION; P53; CONTRIBUTES; APOPTOSIS; ENDODERM; BIOLOGY
AB Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) efficiently generate all embryonic cell lineages but rarely generate extraembryonic cell types. We found that microRNA miR-34a deficiency expands the developmental potential of mouse pluripotent stem cells, yielding both embryonic and extraembryonic lineages and strongly inducing MuERV-L (MERVL) endogenous retroviruses, similar to what is seen with features of totipotent two-cell blastomeres. miR-34a restricts the acquisition of expanded cell fate potential in pluripotent stem cells, and it represses MERVL expression through transcriptional regulation, at least in part by targeting the transcription factor Gata2. Our studies reveal a complex molecular network that defines and restricts pluripotent developmental potential in cultured ESCs and iPSCs.
C1 [Choi, Yong Jin; Lin, Chao-Po; Chen, Sean; Kim, Thomas Aquinas; He, Lin] Univ Calif Berkeley, Div Cellular & Dev Biol, Dept Mol & Cell Biol, Berkeley, CA 94705 USA.
[Risso, Davide] Univ Calif Berkeley, Sch Publ Hlth, Div Biostat, Berkeley, CA 94720 USA.
[Tan, Meng How; Li, Jin Billy] Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
[Wu, Yalei] Thermo Fisher Sci, 180 Oyster Point Blvd, San Francisco, CA 94080 USA.
[Chen, Caifu] Integrated DNA Technol, 200 Chesapeake Dr, Redwood City, CA 94063 USA.
[Xuan, Zhenyu] Univ Texas Dallas, Dept Mol & Cell Biol, Richardson, TX 75080 USA.
[Macfarlan, Todd] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA.
[Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA.
[Lloyd, K. C. Kent] Univ Calif Davis, Mouse Biol Program, Davis, CA 95616 USA.
[Kim, Sang Yong] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA.
[Speed, Terence P.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA.
[Speed, Terence P.] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3010, Australia.
[Speed, Terence P.] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3052, Australia.
RP Lin, CP; He, L (reprint author), Univ Calif Berkeley, Div Cellular & Dev Biol, Dept Mol & Cell Biol, Berkeley, CA 94705 USA.
EM newcplin@gmail.com; lhe@berkeley.edu
OI Lin, Chao-Po/0000-0002-1457-1635; Kim, Sang Yong /0000-0001-7326-7505
FU NIH [S10RR029668, S10RR027303, U01MH105979]; California Institute for
Regenerative Medicine (CIRM) [RN2-00923-1]; National Cancer Institute
[R01 CA139067]; National Institute of General Medical Sciences
[R01GM114414]; Howard Hughes Medical Institute; CIRM predoctoral
fellowship; Cancer Research Coordinating Committee (CRCC) predoctoral
fellowship; Siebel postdoctoral fellowship; CIRM postdoctoral
fellowship; UT Dallas faculty startup fund
FX We thank V. Prideaux, W. Wang, R. Huang, K. N. Li, H. Aaron, J.-Y. Lee,
W. Xu, J. Ong, P. Cheung, B. Zaghi, M. Chung, J. Choi, A. Li, A. Perez,
W. Bao, S. Tindall, K. Zhao, K. Cui, B. Xue, O. Tam, K. Heydari, A.
Valeros, M. J. Bennett, C. Cattoglio, D. Young, N. Anchell, J. A. Wood,
A. Y.-F. Lee, and H. Noller for technical assistance; L. Xie, V. A.
Modzelewski, and R. Song for discussion and input; T. Heidmann, J.
Rossant, A. Li, V. Krizhanovsky, M. Stadtfeld, M. C. Lorincz, Y.
Shinkai, D. Trono, T. Chen, and R. Jaenisch for sharing valuable
reagents; P. Margolis for carefully reading the manuscript; and M. Rape
and N. Patel for sharing the use of an Olympus Revolution XD spinning
disk confocal microscope and a Zeiss LSM 700 confocal microscope. This
work used the Vincent J. Coates Genomics Sequencing Laboratory at UC
Berkeley (supported by NIH S10 instrumentation grants S10RR029668 and
S10RR027303) and the computing resource provided by the Center for
Systems Biology, UT Dallas. Supported by California Institute for
Regenerative Medicine (CIRM) new faculty award RN2-00923-1, National
Cancer Institute grant R01 CA139067, National Institute of General
Medical Sciences grant R01GM114414, and a Howard Hughes Medical
Institute faculty scholar award (L. H.); a CIRM predoctoral fellowship
and a Cancer Research Coordinating Committee (CRCC) predoctoral
fellowship (S. C.); a Siebel postdoctoral fellowship and a CIRM
postdoctoral fellowship (C-P. L.); NIH grant U01MH105979 (D. R.); and
the UT Dallas faculty startup fund (Z.X.). The RNA sequencing data are
publicly available at the NCBI Gene Expression Omnibus with accession
number GSE69484. The annotation of retrotransposons in GFF format is
available as supplementary data.
NR 53
TC 1
Z9 1
U1 12
U2 12
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 FEB 10
PY 2017
VL 355
IS 6325
BP 596
EP +
DI 10.1126/science.aag1927
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK0SF
UT WOS:000393636700040
ER
PT J
AU Solanki, S
Dube, PR
Birnbaumer, L
Vazquez, G
AF Solanki, Sumeet
Dube, Prabhatchandra R.
Birnbaumer, Lutz
Vazquez, Guillermo
TI Reduced Necrosis and Content of Apoptotic M1 Macrophages in Advanced
Atherosclerotic Plaques of Mice With Macrophage-Specific Loss of Trpc3
SO SCIENTIFIC REPORTS
LA English
DT Article
ID FOAM CELL-FORMATION; CARDIOVASCULAR-DISEASE; KNOCKOUT MOUSE; MURINE
MODELS; CHANNELS; LESIONS; RUPTURE; ROLES; EFFEROCYTOSIS; EXPRESSION
AB In previous work we reported that ApoeKO mice transplanted with bone marrow cells deficient in the Transient Receptor Potential Canonical 3 (TRPC3) channel have reduced necrosis and number of apoptotic macrophages in advanced atherosclerotic plaques. Also, in vitro studies with polarized macrophages derived from mice with macrophage-specific loss of TRPC3 showed that M1, but not M2 macrophages, deficient in Trpc3 are less susceptible to ER stress-induced apoptosis than Trpc3 expressing cells. The questions remained (a) whether the plaque phenotype in transplanted mice resulted from a genuine effect of Trpc3 on macrophages, and (b) whether the reduced necrosis and macrophage apoptosis in plaques of these mice was a manifestation of the selective effect of TRPC3 on apoptosis of M1 macrophages previously observed in vitro. Here, we addressed these questions using Ldlr knockout (Ldlr(-/-)) mice with macrophage-specific loss of Trpc3 (MacTrpc3(-/-)/Ldlr(-/-)-> Ldlr(-/-)). Compared to controls, we observed decreased plaque necrosis and number of apoptotic macrophages in MacTrpc3(-/-)/Ldlr(-/-)-> Ldlr(-/-) mice. Immunohistochemical analysis revealed a reduction in apoptotic M1, but not apoptotic M2 macrophages. These findings confirm an effect of TRPC3 on plaque necrosis and support the notion that this is likely a reflection of the reduced susceptibility of Trpc3-deficient M1 macrophages to apoptosis.
C1 [Solanki, Sumeet; Dube, Prabhatchandra R.; Vazquez, Guillermo] Univ Toledo, Coll Med & Life Sci, Dept Physiol & Pharmacol, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA.
[Solanki, Sumeet; Dube, Prabhatchandra R.; Vazquez, Guillermo] Univ Toledo, Coll Med & Life Sci, Ctr Hypertens & Personalized Med, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA.
[Birnbaumer, Lutz] NIEHS, Neurobiol Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA.
[Birnbaumer, Lutz] Fac Med Sci, BIOMED UCA CONICET, Inst Biomed Res, Av Alicia Moreau de Justo 1600,C1107AFF, Buenos Aires, Aires, Argentina.
RP Vazquez, G (reprint author), Univ Toledo, Coll Med & Life Sci, Dept Physiol & Pharmacol, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA.; Vazquez, G (reprint author), Univ Toledo, Coll Med & Life Sci, Ctr Hypertens & Personalized Med, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA.
EM Guillermo.Vazquez@utoledo.edu
FU NIH grant [R01HL111877-04]; University of Toledo College of Medicine and
Life Sciences; Intramural Research Program of the NIH Project
[Z01-ES-101864]; American Heart Association (Great Rivers Affiliate)
Pre-doctoral fellowship [15PRE24700002]
FX Work was supported by NIH grant R01HL111877-04 (to G.V.), the University
of Toledo College of Medicine and Life Sciences (G.V.), the Intramural
Research Program of the NIH Project Z01-ES-101864 (to L.B.) and American
Heart Association (Great Rivers Affiliate) Pre-doctoral fellowship
15PRE24700002 (to S.S.).
NR 47
TC 0
Z9 0
U1 0
U2 0
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 10
PY 2017
VL 7
AR 42526
DI 10.1038/srep42526
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2UY
UT WOS:000393783400001
PM 28186192
ER
PT J
AU Alsuliman, A
Muftuoglu, M
Khoder, A
Ahn, YO
Basar, R
Verneris, MR
Muranski, P
Barrett, AJ
Liu, E
Li, L
Stringaris, K
Armstrong-James, D
Shaim, H
Kondo, K
Imahashi, N
Andersson, B
Marin, D
Champlin, RE
Shpall, EJ
Rezvani, K
AF Alsuliman, Abdullah
Muftuoglu, Muharrem
Khoder, Ahmad
Ahn, Yong-Oon
Basar, Rafet
Verneris, Michael R.
Muranski, Pawel
Barrett, A. John
Liu, Enli
Li, Li
Stringaris, Kate
Armstrong-James, Darius
Shaim, Hila
Kondo, Kayo
Imahashi, Nobuhiko
Andersson, Borje
Marin, David
Champlin, Richard E.
Shpall, Elizabeth J.
Rezvani, Katayoun
TI A subset of virus-specific CD161(+) T cells selectively express the
multidrug transporter MDR1 and are resistant to chemotherapy in AML
SO BLOOD
LA English
DT Article
ID HEMATOPOIETIC STEM-CELLS; P-GLYCOPROTEIN; TH17 CELLS; MYELOID-LEUKEMIA;
MEMORY; LYMPHOCYTES; IMMUNITY; NAIVE; BET; DIFFERENTIATION
AB The establishment of long-lived pathogen-specific T cells is a fundamental property of the adaptive immune response. However, the mechanisms underlying long-term persistence of antigen-specific CD4(+) T cells are not well-defined. Here we identify a subset of memory CD4(+) T cells capable of effluxing cellular toxins, including rhodamine (Rho), through the multidrug efflux protein MDR1 (also known as P-glycoprotein and ABCB1). Drug-effluxing CD4(+) T cells were characterized as CD161(+)CD95(+)CD45RA(-)CD127(hi)CD28(+)CD25(int) cells with a distinct chemokine profile and a Th1-polarized pro-inflammatory phenotype. CD4(+) CD161(+) Rho-effluxing T cells proliferated vigorously in response to stimulation with antiCD3/CD28 beads and gave rise to CD161(-) progeny in vitro. These cells were also capable of self-renewal and maintained their phenotypic and functional characteristics when cultured with homeostatic cytokines. Multidrug-effluxing CD4(+) CD161(+) T cells were enriched within the viral-specific Th1 repertoire of healthy donors and patients with acute myeloid leukemia (AML) and survived exposure to daunorubicin chemotherapy in vitro. Multidrug-effluxing CD4(+) CD161(+) T cells also resisted chemotherapy-induced cytotoxicity in vivo and underwent significant expansion in AML patients rendered lymphopenic after chemotherapy, contributing to the repopulation of anti-CMV immunity. Finally, after influenza vaccination, the proportion of influenza-specific CD4(+) T cells coexpressing CD161 was significantly higher after 2 years compared with 4 weeks after immunization, suggesting CD161 is a marker for long-lived antigen-specific memory T cells. These findings suggest that CD4(+) CD161 1 T cells with rapid efflux capacity contribute to the maintenance of viral-specific memory T cells. These data provide novel insights into mechanisms that preserve antiviral immunity in patients undergoing chemotherapy and have implications for the development of novel immunotherapeutic approaches.
C1 [Alsuliman, Abdullah; Muftuoglu, Muharrem; Basar, Rafet; Liu, Enli; Li, Li; Shaim, Hila; Kondo, Kayo; Imahashi, Nobuhiko; Andersson, Borje; Marin, David; Champlin, Richard E.; Shpall, Elizabeth J.; Rezvani, Katayoun] MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, Houston, TX USA.
[Khoder, Ahmad; Stringaris, Kate] Imperial Coll London, Dept Hematol, London, England.
[Ahn, Yong-Oon; Verneris, Michael R.] Univ Minnesota, Dept Pediat, Div Hematol Oncol, Minneapolis, MN USA.
[Muranski, Pawel; Barrett, A. John] Natl Inst Hlth, Natl Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD USA.
[Armstrong-James, Darius] Imperial Coll London, Natl Heart & Lung Inst, Fac Med, London, England.
RP Rezvani, K (reprint author), MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, Houston, TX USA.
EM krezvani@mdanderson.org
FU National Institutes of Health, National Cancer Institute grants [P01
CA148600-02, RO1 CA061508-18]; National Institutes of Health through M.
D. Anderson's Cancer Center Support Grant [CA016672]
FX This work was funded in part by National Institutes of Health, National
Cancer Institute grants P01 CA148600-02 and RO1 CA061508-18. The flow
studies were performed in the Flow Cytometry & Cellular Imaging
Facility, which is supported in part by the National Institutes of
Health through M. D. Anderson's Cancer Center Support Grant CA016672.
NR 36
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U1 1
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 FEB 9
PY 2017
VL 129
IS 6
BP 740
EP 758
DI 10.1182/blood-2016-05-713347
PG 19
WC Hematology
SC Hematology
GA EO9OD
UT WOS:000397017100013
PM 27821506
ER
PT J
AU Tubbs, A
Nussenzweig, A
AF Tubbs, Anthony
Nussenzweig, Andre
TI Endogenous DNA Damage as a Source of Genomic Instability in Cancer
SO CELL
LA English
DT Review
ID DOUBLE-STRAND BREAKS; REGIONAL MUTATION-RATES; SOMATIC MUTATIONS;
PROSTATE-CANCER; CHROMOSOMAL REARRANGEMENTS; TRANSCRIPTION STRESS;
SEQUENCING REVEALS; SUPER-ENHANCERS; TOPOISOMERASE 1; STEM-CELLS
AB Genome instability, defined as higher than normal rates of mutation, is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. On the other hand, genomic instability can have catastrophic consequences for age-related diseases such as cancer. Mutations arise either from inactivation of DNA repair pathways or in a repair-competent background due to genotoxic stress from celluar processes such as transcription and replication that overwhelm high-fidelity DNA repair. Here, we review recent studies that shed light on endogenous sources of mutation and epigenomic features that promote genomic instability during cancer evolution.
C1 [Tubbs, Anthony; Nussenzweig, Andre] NIH, Lab Genome Integr, Bldg 10, Bethesda, MD 20892 USA.
RP Nussenzweig, A (reprint author), NIH, Lab Genome Integr, Bldg 10, Bethesda, MD 20892 USA.
EM andre_nussenzweig@nih.gov
FU NIH; National Cancer Institute; Center for Cancer Research; US
Department of Defense [BC133858, BC151331]; Ellison Foundation; Alex's
Lemonade Stand Foundation; American Cancer Society [PF-16-037-01-DMC]
FX We are especially grateful to Joshua Waterfall, Ferenc Livak, Avinash
Bhandoola, and Sam John for comments on the manuscript and to Jiri
Lukas, Keith Caldecott, and Yossi Shiloh for discussions. This work was
supported by the Intramural Research Program of the NIH, the National
Cancer Institute, and the Center for Cancer Research. A.N. was also
supported by the US Department of Defense (BCRP DOD Idea Expansion Award
BC133858 and BCRP Breakthrough Award BC151331), the Ellison Foundation
Award for Aging Research, and Alex's Lemonade Stand Foundation Reach
Award. A.T. has been supported by a fellowship from the American Cancer
Society (PF-16-037-01-DMC).
NR 92
TC 0
Z9 0
U1 8
U2 8
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 0092-8674
EI 1097-4172
J9 CELL
JI Cell
PD FEB 9
PY 2017
VL 168
IS 4
DI 10.1016/j.cell.2017.01.002
PG 13
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA EN8VJ
UT WOS:000396277600015
PM 28187286
ER
PT J
AU Haft, DR
Haft, DH
AF Haft, David Renfrew
Haft, Daniel H.
TI A comprehensive software suite for protein family construction and
functional site prediction
SO PLOS ONE
LA English
DT Article
ID COMPARATIVE GENOMICS; MICROBIOLOGY; ANNOTATION
AB In functionally diverse protein families, conservation in short signature regions may outperform full-length sequence comparisons for identifying proteins that belong to a subgroup within which one specific aspect of their function is conserved. The SIMBAL workflow (Sites Inferred by Metabolic Background Assertion Labeling) is a data-mining procedure for finding such signature regions. It begins by using clues from genomic context, such as co-occurrence or conserved gene neighborhoods, to build a useful training set from a large number of uncharacterized but mutually homologous proteins. When training set construction is successful, the YES partition is enriched in proteins that share function with the user's query sequence, while the NO partition is depleted. A selected query sequence is then mined for short signature regions whose closest matches overwhelmingly favor proteins from the YES partition. High-scoring signature regions typically contain key residues critical to functional specificity, so proteins with the highest sequence similarity across these regions tend to share the same function. The SIMBAL algorithm was described previously, but significant manual effort, expertise, and a supporting software infrastructure were required to prepare the requisite training sets. Here, we describe a new, distributable software suite that speeds up and simplifies the process for using SIMBAL, most notably by providing tools that automate training set construction. These tools have broad utility for comparative genomics, allowing for flexible collection of proteins or protein domains based on genomic context as well as homology, a capability that can greatly assist in protein family construction. Armed with this new software suite, SIMBAL can serve as a fast and powerful in silico alternative to direct experimentation for characterizing proteins and their functional interactions.
C1 [Haft, David Renfrew] J Craig Venter Inst, Rockville, MD USA.
[Haft, Daniel H.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA.
RP Haft, DH (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA.
EM daniel.haft@nih.gov
FU National Science Foundationunder [1458808]
FX This work was supported by the National Science Foundationunder Grant
No.1458808 to the J.Craig Venter Institute and by the Intramural
Research Program of the NIH, National Library of Medicine. The funders
had no role in study design data collection and analysis, decision to
publish, or preparation of the manuscript.
NR 22
TC 0
Z9 0
U1 0
U2 0
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 FEB 9
PY 2017
VL 12
IS 2
AR e0171758
DI 10.1371/journal.pone.0171758
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK9GJ
UT WOS:000394231800102
PM 28182651
ER
PT J
AU Kugelman, JR
Wiley, MR
Nagle, ER
Reyes, D
Pfeffer, BP
Kuhn, JH
Sanchez-Lockhart, M
Palacios, GF
AF Kugelman, Jeffrey R.
Wiley, Michael R.
Nagle, Elyse R.
Reyes, Daniel
Pfeffer, Brad P.
Kuhn, Jens H.
Sanchez-Lockhart, Mariano
Palacios, Gustavo F.
TI Error baseline rates of five sample preparation methods used to
characterize RNA virus populations
SO PLOS ONE
LA English
DT Article
ID LIBRARY PREPARATION; SEQUENCING DATA; QUALITY-CONTROL; EBOLA-VIRUS;
GENOMES; REPLICATION; VARIANTS; COLI
AB Individual RNA viruses typically occur as populations of genomes that differ slightly from each other due to mutations introduced by the error-prone viral polymerase. Understanding the variability of RNA virus genome populations is critical for understanding virus evolution because individual mutant genomes may gain evolutionary selective advantages and give rise to dominant sub populations, possibly even leading to the emergence of viruses resistant to medical countermeasures. Reverse transcription of virus genome populations followed by next-generation sequencing is the only available method to characterize variation for RNA viruses. However, both steps may lead to the introduction of artificial mutations, thereby skewing the data. To better understand how such errors are introduced during sample preparation, we determined and compared error baseline rates of five different sample preparation methods by analyzing in vitro transcribed Ebola virus RNA from an artificial plasmid-based system. These methods included: shotgun sequencing from plasmid DNA or in vitro transcribed RNA as a basic "no amplification" method, amplicon sequencing from the plasmid DNA or in vitro transcribed RNA as a "targeted" amplification method, sequenceindependent single-primer amplification (SISPA) as a "random" amplification method, rolling circle reverse transcription sequencing (CirSeq) as an advanced "no amplification" method, and Illumina TruSeq RNA Access as a "targeted" enrichment method. The measured error frequencies indicate that RNA Access offers the best tradeoff between sensitivity and sample preparation error (1.4(-5)) of all compared methods.
C1 [Kugelman, Jeffrey R.; Wiley, Michael R.; Nagle, Elyse R.; Reyes, Daniel; Pfeffer, Brad P.; Sanchez-Lockhart, Mariano; Palacios, Gustavo F.] US Army, Med Res Inst Infect Dis, Ctr Genome Sci, Frederick, MD 21702 USA.
[Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, NIH, Frederick, MD USA.
RP Palacios, GF (reprint author), US Army, Med Res Inst Infect Dis, Ctr Genome Sci, Frederick, MD 21702 USA.
EM gustavo.f.palacios.ctr@mail.mil
OI Palacios, Gustavo/0000-0001-5062-1938
FU Defense Threat Reduction Agency; Battelle Memorial Institute's prime; US
National Institute of Allergy and Infectious Diseases (NIAID)
[HHSN272200700016I]; Tunnell Government Services, Inc.
FX This work was supported by Defense Threat Reduction Agency and Battelle
Memorial Institute's prime contract with the US National Institute of
Allergy and Infectious Diseases (NIAID)under Contract No.
HHSN272200700016I (J.H.K.). A subcontractor to Battelle Memorial
Institute who performed this work is : J.H.K., an employee of Tunnell
Government Services, Inc.
NR 34
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U1 0
U2 0
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 FEB 9
PY 2017
VL 12
IS 2
AR e0171333
DI 10.1371/journal.pone.0171333
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK9GJ
UT WOS:000394231800055
PM 28182717
ER
PT J
AU Taye, M
Kim, J
Yoon, SH
Lee, W
Hanotte, O
Dessie, T
Kemp, S
Mwai, OA
Caetano-Anolles, K
Cho, S
Oh, SJ
Lee, HK
Kim, H
AF Taye, Mengistie
Kim, Jaemin
Yoon, Sook Hee
Lee, Wonseok
Hanotte, Olivier
Dessie, Tadelle
Kemp, Stephen
Mwai, Okeyo Ally
Caetano-Anolles, Kelsey
Cho, Seoae
Oh, Sung Jong
Lee, Hak-Kyo
Kim, Heebal
TI Whole genome scan reveals the genetic signature of African Ankole cattle
breed and potential for higher quality beef
SO BMC GENETICS
LA English
DT Article
DE African cattle; Ankole cattle; Meat quality; Sanga cattle; XP-CLR;
XP-EHH
ID RESIDUAL FEED-INTAKE; DIFFERENTIALLY EXPRESSED GENES; INTRAMUSCULAR
FAT-CONTENT; PORCINE SKELETAL-MUSCLE; LARGE WHITE-PIGS; MEAT QUALITY;
CANDIDATE GENES; FUNCTIONAL-ANALYSIS; POSITIVE SELECTION; WIDE
ASSOCIATION
AB Background: Africa is home to numerous cattle breeds whose diversity has been shaped by subtle combinations of human and natural selection. African Sanga cattle are an intermediate type of cattle resulting from interbreeding between Bos taurus and Bos indicus subspecies. Recently, research has asserted the potential of Sanga breeds for commercial beef production with better meat quality as compared to Bos indicus breeds. Here, we identified meat quality related gene regions that are positively selected in Ankole (Sanga) cattle breeds as compared to indicus (Boran, Ogaden, and Kenana) breeds using cross-population (XP-EHH and XP-CLR) statistical methods.
Results: We identified 238 (XP-EHH) and 213 (XP-CLR) positively selected genes, of which 97 were detected from both statistics. Among the genes obtained, we primarily reported those involved in different biological process and pathways associated with meat quality traits. Genes (CAPZB, COL9A2, PDGFRA, MAP3K5, ZNF410, and PKM2) involved in muscle structure and metabolism affect meat tenderness. Genes (PLA2G2A, PARK2, ZNF410, MAP2K3, PLCD3, PLCD1, and ROCK1) related to intramuscular fat (IMF) are involved in adipose metabolism and adipogenesis. MB and SLC48A1 affect meat color. In addition, we identified genes (TIMP2, PKM2, PRKG1, MAP3K5, and ATP8A1) related to feeding efficiency. Among the enriched Gene Ontology Biological Process (GO BP) terms, actin cytoskeleton organization, actin filament-based process, and protein ubiquitination are associated with meat tenderness whereas cellular component organization, negative regulation of actin filament depolymerization and negative regulation of protein complex disassembly are involved in adipocyte regulation. The MAPK pathway is responsible for cell proliferation and plays an important role in hyperplastic growth, which has a positive effect on meat tenderness.
Conclusion: Results revealed several candidate genes positively selected in Ankole cattle in relation to meat quality characteristics. The genes identified are involved in muscle structure and metabolism, and adipose metabolism and adipogenesis. These genes help in the understanding of the biological mechanisms controlling beef quality characteristics in African Ankole cattle. These results provide a basis for further research on the genomic characteristics of Ankole and other Sanga cattle breeds for quality beef.
C1 [Taye, Mengistie; Yoon, Sook Hee; Lee, Wonseok; Kim, Heebal] Seoul Natl Univ, Dept Agr Biotechnol, Anim Biotechnol & Res Inst Agr & Life Sci, Seoul 151921, South Korea.
[Taye, Mengistie] Bahir Dar Univ, Coll Agr & Environm Sci, POB 79, Bahir Dar, Ethiopia.
[Kim, Jaemin] NHGRI, NIH, 50 South Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA.
[Hanotte, Olivier] Univ Nottingham, Sch Life Sci, Nottingham NG7 2RD, England.
[Hanotte, Olivier; Dessie, Tadelle] ILRI, POB 5689, Addis Ababa, Ethiopia.
[Kemp, Stephen; Mwai, Okeyo Ally] ILRI, POB 30709-00100, Nairobi, Kenya.
[Kemp, Stephen] Univ Edinburgh, Roslin Inst, Ctr Trop Livestock Genet & Hlth, Easter Bush Campus, Roslin EH25 9RG, Midlothian, Scotland.
[Caetano-Anolles, Kelsey] Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA.
[Cho, Seoae; Kim, Heebal] C&K Genom, Main Bldg 514,SNU Res Pk, Seoul 151919, South Korea.
[Oh, Sung Jong] RDA, Natl Inst Anim Sci, Wonju, South Korea.
[Lee, Hak-Kyo] Chonbuk Natl Univ, Dept Anim Biotechnol, Anim Mol Genet & Breeding Ctr, Jeonju 561756, South Korea.
[Kim, Heebal] Shinshu Univ, Inst Biomed Sci, Nagano, Japan.
RP Kim, H (reprint author), Seoul Natl Univ, Dept Agr Biotechnol, Anim Biotechnol & Res Inst Agr & Life Sci, Seoul 151921, South Korea.; Kim, H (reprint author), C&K Genom, Main Bldg 514,SNU Res Pk, Seoul 151919, South Korea.
EM heebal@snu.ac.kr
FU Next-Generation BioGreen 21 Program, Rural Development Administration
(RDA), Republic of Korea [PJ01134905]
FX This work was supported by a grant from the Next-Generation BioGreen 21
Program (Project No. PJ01134905), Rural Development Administration
(RDA), Republic of Korea.
NR 96
TC 0
Z9 0
U1 2
U2 2
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2156
J9 BMC GENET
JI BMC Genet.
PD FEB 9
PY 2017
VL 18
AR 11
DI 10.1186/s12863-016-0467-1
PG 14
WC Genetics & Heredity
SC Genetics & Heredity
GA EK7UW
UT WOS:000394131700001
PM 28183280
ER
PT J
AU Carmona-Rivera, C
Purmalek, MM
Moore, E
Waldman, M
Walter, PJ
Garraffo, HM
Phillips, KA
Preston, KL
Graf, J
Kaplan, MJ
Grayson, PC
AF Carmona-Rivera, Carmelo
Purmalek, Monica M.
Moore, Erica
Waldman, Meryl
Walter, Peter J.
Garraffo, H. Martin
Phillips, Karran A.
Preston, Kenzie L.
Graf, Jonathan
Kaplan, Mariana J.
Grayson, Peter C.
TI A role for muscarinic receptors in neutrophil extracellular trap
formation and levamisole-induced autoimmunity
SO JCI INSIGHT
LA English
DT Article
ID ACETYLCHOLINE-RECEPTORS; NETTING NEUTROPHILS; RHEUMATIC-DISEASES; VAGUS
NERVE; MICE; COCAINE; CONTRACTION; ANTIBODIES; VASCULITIS; AORTA
AB Levamisole, an anthelmintic drug with cholinergic properties, has been implicated in cases of drug-induced vasculitis when added to cocaine for profit purposes. Neutrophil extracellular trap (NET) formation is a cell death mechanism characterized by extrusion of chromatin decorated with granule proteins. Aberrant NET formation and degradation have been implicated in idiopathic autoimmune diseases that share features with levamisole-induced autoimmunity as well as in drug-induced autoimmunity. This study's objective was to determine how levamisole modulates neutrophil biology and its putative effects on the vasculature. Murine and human neutrophils exposed to levamisole demonstrated enhanced NET formation through engagement of muscarinic subtype 3 receptor. Levamisole-induced NETosis required activation of Akt and the RAF/MEK/ERK pathway, ROS induction through the nicotinamide adenine dinucleotide phosphate oxidase, and peptidylarginine deiminase activation. Sera from two cohorts of patients actively using levamisole-adulterated cocaine displayed autoantibodies against NET components. Cutaneous biopsy material obtained from individuals exposed to levamisole suggests that neutrophils produce NETs in areas of vasculitic inflammation and thrombosis. NETs generated by levamisole were toxic to endothelial cells and impaired endothelium-dependent vasorelaxation. Stimulation of muscarinic receptors on neutrophils by cholinergic agonists may contribute to the pathophysiology observed in drug-induced autoimmunity through the induction of inflammatory responses and neutrophil-induced vascular damage.
C1 [Carmona-Rivera, Carmelo; Purmalek, Monica M.; Moore, Erica; Kaplan, Mariana J.; Grayson, Peter C.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Syst Autoimmun Branch, Bethesda, MD USA.
[Waldman, Meryl; Walter, Peter J.; Garraffo, H. Martin] NIDDK, NIH, Bethesda, MD USA.
[Phillips, Karran A.; Preston, Kenzie L.] NIDA, NIH, Baltimore, MD USA.
[Graf, Jonathan] UCSF, Div Rheumatol, San Francisco, CA USA.
RP Kaplan, MJ (reprint author), NIAMSD, Syst Autoimmun Branch, NIH, 10 Ctr Dr,6D-47C, Bethesda, MD 20892 USA.
EM mariana.kaplan@nih.gov
FU Intramural Research Program at the NIAMS [NIH ZIA AR041199]
FX This research was supported by the Intramural Research Program at the
NIAMS (NIH ZIA AR041199). Cl-amidine was provided by Paul Thompson and
Venkataraman Subramaniam. Ann Biehl performed calculations to determine
physiologic concentrations of levamisole. We also thank Jorge
Irizarry-Caro for technical support.
NR 58
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Z9 0
U1 3
U2 3
PU AMER SOC CLINICAL INVESTIGATION INC
PI ANN ARBOR
PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA
SN 2379-3708
J9 JCI INSIGHT
JI JCI Insight
PD FEB 9
PY 2017
VL 2
IS 3
AR e89780
DI 10.1172/jci.insight.89780
PG 15
WC Medicine, Research & Experimental
SC Research & Experimental Medicine
GA EK1TN
UT WOS:000393708800008
PM 28194438
ER
PT J
AU Iyer, MR
Cinar, R
Katz, A
Gao, M
Erdelyi, K
Jourdan, T
Coffey, NJ
Pacher, P
Kunos, G
AF Iyer, Malliga R.
Cinar, Resat
Katz, Alexis
Gao, Michael
Erdelyi, Katalin
Jourdan, Tony
Coffey, Nathan J.
Pacher, Pal
Kunos, George
TI Design, Synthesis, and Biological Evaluation of Novel,
Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible
Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver
Fibrosis
SO JOURNAL OF MEDICINAL CHEMISTRY
LA English
DT Article
ID RECEPTOR ANTAGONISTS; DRUG DISCOVERY; RIMONABANT; OBESITY; FUTURE;
POTENT; DERIVATIVES; RESISTANCE; BLOCKERS; SYSTEM
AB We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CB1R) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB1 receptor (CB1R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB1R antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CB1R binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CB(1)Rs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CB1R antagonism.
C1 [Iyer, Malliga R.; Cinar, Resat; Katz, Alexis; Gao, Michael; Jourdan, Tony; Coffey, Nathan J.; Kunos, George] NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA.
[Erdelyi, Katalin; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA.
RP Iyer, MR; Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA.
EM Malliga.Iyer@nih.gov; George.Kunos@nih.gov
OI CINAR, RESAT/0000-0002-8597-7253
FU National Institute on Alcohol Abuse and Alcoholism (NIAAA)
FX This work was supported by intramural funds from the National Institute
on Alcohol Abuse and Alcoholism (NIAAA) to M.R.I, RC, P.P., and G.K.
Resources from National Institute on Drug Abuse (NIDA) is gratefully
acknowledged. Helpful advice and suggestions from Dr. Kenner C. Rice are
acknowledged. John Lloyd, Noel Whittaker, and Bill Leister are
acknowledged for supplying MS data and providing help with LC/MS data.
NR 38
TC 0
Z9 0
U1 3
U2 3
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 FEB 9
PY 2017
VL 60
IS 3
BP 1126
EP 1141
DI 10.1021/acs.jmedchem.6b01504
PG 16
WC Chemistry, Medicinal
SC Pharmacology & Pharmacy
GA EK4WM
UT WOS:000393928300018
PM 28085283
ER
PT J
AU Marouli, E
Graff, M
Medina-Gomez, C
Lo, KS
Wood, AR
Kjaer, TR
Fine, RS
Lu, YC
Schurmann, C
Highland, HM
Rueger, S
Thorleifsson, G
Justice, AE
Lamparter, D
Stirrups, KE
Turcot, V
Young, KL
Winkler, TW
Esko, T
Karaderi, T
Locke, AE
Masca, NGD
Ng, MCY
Mudgal, P
Rivas, MA
Vedantam, S
Mahajan, A
Guo, XQ
Abecasis, G
Aben, KK
Adair, LS
Alam, DS
Albrecht, E
Allin, KH
Allison, M
Amouyel, P
Appel, EV
Arveiler, D
Asselbergs, FW
Auer, PL
Balkau, B
Banas, B
Bang, LE
Benn, M
Bergmann, S
Bielak, LF
Bluher, M
Boeing, H
Boerwinkle, E
Boger, CA
Bonnycastle, LL
Bork-Jensen, J
Bots, ML
Bottinger, EP
Bowden, DW
Brandslund, I
Breen, G
Brilliant, MH
Broer, L
Burt, AA
Butterworth, AS
Carey, DJ
Caulfield, MJ
Chambers, JC
Chasman, DI
Chen, YDI
Chowdhury, R
Christensen, C
Chu, AY
Cocca, M
Collins, FS
Cook, JP
Corley, J
Galbany, JC
Cox, AJ
Cuellar-Partida, G
Danesh, J
Davies, G
de Bakker, PIW
de Borst, GJ
de Denus, S
de Groot, MCH
de Mutsert, R
Deary, IJ
Dedoussis, G
Demerath, EW
den Hollander, AI
Dennis, JG
Di Angelantonio, E
Drenos, F
Du, MM
Dunning, AM
Easton, DF
Ebeling, T
Edwards, TL
Ellinor, PT
Elliott, P
Evangelou, E
Farmaki, AE
Faul, JD
Feitosa, MF
Feng, S
Ferrannini, E
Ferrario, MM
Ferrieres, J
Florez, JC
Ford, I
Fornage, M
Franks, PW
Frikke-Schmidt, R
Galesloot, TE
Gan, W
Gandin, I
Gasparini, P
Giedraitis, V
Giri, A
Girotto, G
Gordon, SD
Gordon-Larsen, P
Gorski, M
Grarup, N
Grove, ML
Gudnason, V
Gustafsson, S
Hansen, T
Harris, KM
Harris, TB
Hattersley, AT
Hayward, C
He, L
Heid, IM
Heikkila, K
Helgeland, O
Hernesniemi, J
Hewitt, AW
Hocking, LJ
Hollensted, M
Holmen, OL
Hovingh, GK
Howson, JMM
Hoyng, CB
Huang, PL
Hveem, K
Ikram, MA
Ingelsson, E
Jackson, AU
Jansson, JH
Jarvik, GP
Jensen, GB
Jhun, MA
Jia, YC
Jiang, XJ
Johansson, S
Jorgensen, ME
Jorgensen, T
Jousilahti, P
Jukema, JW
Kahali, B
Kahn, RS
Kahonen, M
Kamstrup, PR
Kanoni, S
Kaprio, J
Karaleftheri, M
Kardia, SLR
Karpe, F
Kee, F
Keeman, R
Kiemeney, LA
Kitajima, H
Kluivers, KB
Kocher, T
Komulainen, P
Kontto, J
Kooner, JS
Kooperberg, C
Kovacs, P
Kriebel, J
Kuivaniemi, H
Kury, S
Kuusisto, J
La Bianca, M
Laakso, M
Lakka, TA
Lange, EM
Lange, LA
Langefeld, CD
Langenberg, C
Larson, EB
Lee, IT
Lehtimaki, T
Lewis, CE
Li, HX
Li, J
Li-Gao, R
Lin, HH
Lin, LA
Lin, X
Lind, L
Lindstrom, J
Linneberg, A
Liu, YH
Liu, YM
Lophatananon, A
Luan, J
Lubitz, SA
Lyytikainen, LP
Mackey, DA
Madden, PAF
Manning, AK
Mannisto, S
Marenne, G
Marten, J
Martin, NG
Mazul, AL
Meidtner, K
Metspalu, A
Mitchell, P
Mohlke, KL
Mook-Kanamori, DO
Morgan, A
Morris, AD
Morris, AP
Muller-Nurasyid, M
Munroe, PB
Nalls, MA
Nauck, M
Nelson, CP
Nelson, CP
Neville, M
Nielsen, SF
Nikus, K
Njolstad, PR
Nordestgaard, BG
Ntalla, I
O'Connel, JR
Oksa, H
Loohuis, LMO
Ophoff, RA
Owen, KR
Packard, CJ
Padmanabhan, S
Palmer, CNA
Pasterkamp, G
Patel, AP
Pattie, A
Pedersen, O
Peissig, PL
Peloso, GM
Pennell, CE
Perola, M
Perry, JA
Perry, JRB
Person, TN
Pirie, A
Polasek, O
Posthuma, D
Raitakari, OT
Rasheed, A
Rauramaa, R
Reilly, DF
Reiner, AP
Renstrom, F
Ridker, PM
Rioux, JD
Robertson, N
Robino, A
Rolandsson, O
Rudan, I
Ruth, KS
Saleheen, D
Salomaa, V
Samani, NJ
Sandow, K
Sapkota, Y
Sattar, N
Schmidt, MK
Schreiner, PJ
Schulze, MB
Scott, RA
Segura-Lepe, MP
Shah, S
Sim, XL
Sivapalaratnam, S
Small, KS
Smith, AV
Smith, JA
Southam, L
Spector, TD
Speliotes, EK
Starr, JM
Steinthorsdottir, V
Stringham, HM
Stumvoll, M
Surendran, P
't Hart, LM
Tansey, KE
Tardif, JC
Taylor, KD
Teumer, A
Thompson, DJ
Thorsteinsdottir, U
Thuesen, BH
Tonjes, A
Tromp, G
Trompet, S
Tsafantakis, E
Tuomilehto, J
Tybjaerg-Hansen, A
Tyrer, JP
Uher, R
Uitterlinden, AG
Ulivi, S
van der Laan, SW
Van Der Leij, AR
van Duijn, CM
van Schoor, NM
van Setten, J
Varbo, A
Varga, TV
Varma, R
Edwards, DRV
Vermeulen, SH
Vestergaard, H
Vitart, V
Vogt, TF
Vozzi, D
Walker, M
Wang, FJ
Wang, CA
Wang, S
Wang, YQ
Wareham, NJ
Warren, HR
Wessel, J
Willems, SM
Wilson, JG
Witte, DR
Woods, MO
Wu, Y
Yaghootkar, H
Yao, J
Yao, P
Yerges-Armstrong, LM
Young, R
Zeggini, E
Zhan, XW
Zhang, WH
Zhao, JH
Zhao, W
Zhao, W
Zheng, H
Zhou, W
Rotter, JI
Boehnke, M
Kathiresan, S
McCarthy, MI
Willer, CJ
Stefansson, K
Borecki, IB
Liu, DJ
North, KE
Heard-Costa, NL
Pers, TH
Lindgren, CM
Oxvig, C
Kutalik, Z
Rivadeneira, F
Loos, RJF
Frayling, TM
Hirschhorn, JN
Deloukas, P
Lettre, G
AF Marouli, Eirini
Graff, Mariaelisa
Medina-Gomez, Carolina
Lo, Ken Sin
Wood, Andrew R.
Kjaer, Troels R.
Fine, Rebecca S.
Lu, Yingchang
Schurmann, Claudia
Highland, Heather M.
Rueger, Sina
Thorleifsson, Gudmar
Justice, Anne E.
Lamparter, David
Stirrups, Kathleen E.
Turcot, Valerie
Young, Kristin L.
Winkler, Thomas W.
Esko, Tonu
Karaderi, Tugce
Locke, Adam E.
Masca, Nicholas G. D.
Ng, Maggie C. Y.
Mudgal, Poorva
Rivas, Manuel A.
Vedantam, Sailaja
Mahajan, Anubha
Guo, Xiuqing
Abecasis, Goncalo
Aben, Katja K.
Adair, Linda S.
Alam, Dewan S.
Albrecht, Eva
Allin, Kristine H.
Allison, Matthew
Amouyel, Philippe
Appel, Emil V.
Arveiler, Dominique
Asselbergs, Folkert W.
Auer, Paul L.
Balkau, Beverley
Banas, Bernhard
Bang, Lia E.
Benn, Marianne
Bergmann, Sven
Bielak, Lawrence F.
Blueher, Matthias
Boeing, Heiner
Boerwinkle, Eric
Boeger, Carsten A.
Bonnycastle, Lori L.
Bork-Jensen, Jette
Bots, Michiel L.
Bottinger, Erwin P.
Bowden, Donald W.
Brandslund, Ivan
Breen, Gerome
Brilliant, Murray H.
Broer, Linda
Burt, Amber A.
Butterworth, Adam S.
Carey, David J.
Caulfield, Mark J.
Chambers, John C.
Chasman, Daniel I.
Chen, Yii-Der Ida
Chowdhury, Rajiv
Christensen, Cramer
Chu, Audrey Y.
Cocca, Massimiliano
Collins, Francis S.
Cook, James P.
Corley, Janie
Galbany, Jordi Corominas
Cox, Amanda J.
Cuellar-Partida, Gabriel
Danesh, John
Davies, Gail
de Bakker, Paul I. W.
de Borst, Gert J.
de Denus, Simon
de Groot, Mark C. H.
de Mutsert, Renee
Deary, Ian J.
Dedoussis, George
Demerath, Ellen W.
den Hollander, Anneke I.
Dennis, Joe G.
Di Angelantonio, Emanuele
Drenos, Fotios
Du, Mengmeng
Dunning, Alison M.
Easton, Douglas F.
Ebeling, Tapani
Edwards, Todd L.
Ellinor, Patrick T.
Elliott, Paul
Evangelou, Evangelos
Farmaki, Aliki-Eleni
Faul, Jessica D.
Feitosa, Mary F.
Feng, Shuang
Ferrannini, Ele
Ferrario, Marco M.
Ferrieres, Jean
Florez, Jose C.
Ford, Ian
Fornage, Myriam
Franks, Paul W.
Frikke-Schmidt, Ruth
Galesloot, Tessel E.
Gan, Wei
Gandin, Ilaria
Gasparini, Paolo
Giedraitis, Vilmantas
Giri, Ayush
Girotto, Giorgia
Gordon, Scott D.
Gordon-Larsen, Penny
Gorski, Mathias
Grarup, Niels
Grove, Megan L.
Gudnason, Vilmundur
Gustafsson, Stefan
Hansen, Torben
Harris, Kathleen Mullan
Harris, Tamara B.
Hattersley, Andrew T.
Hayward, Caroline
He, Liang
Heid, Iris M.
Heikkila, Kauko
Helgeland, Oyvind
Hernesniemi, Jussi
Hewitt, Alex W.
Hocking, Lynne J.
Hollensted, Mette
Holmen, Oddgeir L.
Hovingh, G. Kees
Howson, Joanna M. M.
Hoyng, Carel B.
Huang, Paul L.
Hveem, Kristian
Ikram, M. Arfan
Ingelsson, Erik
Jackson, Anne U.
Jansson, Jan-Hakan
Jarvik, Gail P.
Jensen, Gorm B.
Jhun, Min A.
Jia, Yucheng
Jiang, Xuejuan
Johansson, Stefan
Jorgensen, Marit E.
Jorgensen, Torben
Jousilahti, Pekka
Jukema, J. Wouter
Kahali, Bratati
Kahn, Rene S.
Kahonen, Mika
Kamstrup, Pia R.
Kanoni, Stavroula
Kaprio, Jaakko
Karaleftheri, Maria
Kardia, Sharon L. R.
Karpe, Fredrik
Kee, Frank
Keeman, Renske
Kiemeney, Lambertus A.
Kitajima, Hidetoshi
Kluivers, Kirsten B.
Kocher, Thomas
Komulainen, Pirjo
Kontto, Jukka
Kooner, Jaspal S.
Kooperberg, Charles
Kovacs, Peter
Kriebel, Jennifer
Kuivaniemi, Helena
Kury, Sebastien
Kuusisto, Johanna
La Bianca, Martina
Laakso, Markku
Lakka, Timo A.
Lange, Ethan M.
Lange, Leslie A.
Langefeld, Carl D.
Langenberg, Claudia
Larson, Eric B.
Lee, I-Te
Lehtimaki, Terho
Lewis, Cora E.
Li, Huaixing
Li, Jin
Li-Gao, Ruifang
Lin, Honghuang
Lin, Li-An
Lin, Xu
Lind, Lars
Lindstrom, Jaana
Linneberg, Allan
Liu, Yeheng
Liu, Yongmei
Lophatananon, Artitaya
Luan, Jian'an
Lubitz, Steven A.
Lyytikainen, Leo-Pekka
Mackey, David A.
Madden, Pamela A. F.
Manning, Alisa K.
Mannisto, Satu
Marenne, Gaelle
Marten, Jonathan
Martin, Nicholas G.
Mazul, Angela L.
Meidtner, Karina
Metspalu, Andres
Mitchell, Paul
Mohlke, Karen L.
Mook-Kanamori, Dennis O.
Morgan, Anna
Morris, Andrew D.
Morris, Andrew P.
Mueller-Nurasyid, Martina
Munroe, Patricia B.
Nalls, Mike A.
Nauck, Matthias
Nelson, Christopher P.
Nelson, Christopher P.
Neville, Matt
Nielsen, Sune F.
Nikus, Kjell
Njolstad, Pal R.
Nordestgaard, Borge G.
Ntalla, Ioanna
O'Connel, Jeffrey R.
Oksa, Heikki
Loohuis, Loes M. Olde
Ophoff, Roel A.
Owen, Katharine R.
Packard, Chris J.
Padmanabhan, Sandosh
Palmer, Colin N. A.
Pasterkamp, Gerard
Patel, Aniruddh P.
Pattie, Alison
Pedersen, Oluf
Peissig, Peggy L.
Peloso, Gina M.
Pennell, Craig E.
Perola, Markus
Perry, James A.
Perry, John R. B.
Person, Thomas N.
Pirie, Ailith
Polasek, Ozren
Posthuma, Danielle
Raitakari, Olli T.
Rasheed, Asif
Rauramaa, Rainer
Reilly, Dermot F.
Reiner, Alex P.
Renstrom, Frida
Ridker, Paul M.
Rioux, John D.
Robertson, Neil
Robino, Antonietta
Rolandsson, Olov
Rudan, Igor
Ruth, Katherine S.
Saleheen, Danish
Salomaa, Veikko
Samani, Nilesh J.
Sandow, Kevin
Sapkota, Yadav
Sattar, Naveed
Schmidt, Marjanka K.
Schreiner, Pamela J.
Schulze, Matthias B.
Scott, Robert A.
Segura-Lepe, Marcelo P.
Shah, Svati
Sim, Xueling
Sivapalaratnam, Suthesh
Small, Kerrin S.
Smith, Albert Vernon
Smith, Jennifer A.
Southam, Lorraine
Spector, Timothy D.
Speliotes, Elizabeth K.
Starr, John M.
Steinthorsdottir, Valgerdur
Stringham, Heather M.
Stumvoll, Michael
Surendran, Praveen
't Hart, Leen M.
Tansey, Katherine E.
Tardif, Jean-Claude
Taylor, Kent D.
Teumer, Alexander
Thompson, Deborah J.
Thorsteinsdottir, Unnur
Thuesen, Betina H.
Toenjes, Anke
Tromp, Gerard
Trompet, Stella
Tsafantakis, Emmanouil
Tuomilehto, Jaakko
Tybjaerg-Hansen, Anne
Tyrer, Jonathan P.
Uher, Rudolf
Uitterlinden, Andre G.
Ulivi, Sheila
van der Laan, Sander W.
Van Der Leij, Andries R.
van Duijn, Cornelia M.
van Schoor, Natasja M.
van Setten, Jessica
Varbo, Anette
Varga, Tibor V.
Varma, Rohit
Edwards, Digna R. Velez
Vermeulen, Sita H.
Vestergaard, Henrik
Vitart, Veronique
Vogt, Thomas F.
Vozzi, Diego
Walker, Mark
Wang, Feijie
Wang, Carol A.
Wang, Shuai
Wang, Yiqin
Wareham, Nicholas J.
Warren, Helen R.
Wessel, Jennifer
Willems, Sara M.
Wilson, James G.
Witte, Daniel R.
Woods, Michael O.
Wu, Ying
Yaghootkar, Hanieh
Yao, Jie
Yao, Pang
Yerges-Armstrong, Laura M.
Young, Robin
Zeggini, Eleftheria
Zhan, Xiaowei
Zhang, Weihua
Zhao, Jing Hua
Zhao, Wei
Zhao, Wei
Zheng, He
Zhou, Wei
Rotter, Jerome I.
Boehnke, Michael
Kathiresan, Sekar
McCarthy, Mark I.
Willer, Cristen J.
Stefansson, Kari
Borecki, Ingrid B.
Liu, Dajiang J.
North, Kari E.
Heard-Costa, Nancy L.
Pers, Tune H.
Lindgren, Cecilia M.
Oxvig, Claus
Kutalik, Zoltan
Rivadeneira, Fernando
Loos, Ruth J. F.
Frayling, Timothy M.
Hirschhorn, Joel N.
Deloukas, Panos
Lettre, Guillaume
CA EPIC-InterAct Consortium
EPIC-CVD Consortium
CHD Exome Consortium
ExomeBP Consortium
T2D-Genes Consortium
GoT2D Genes Consortium
Global Lipids Genetics Consortium
ReproGen Consortium
MAGIC Investigators
TI Rare and low-frequency coding variants alter human adult height
SO NATURE
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; MISSING HERITABILITY; GENETIC ARCHITECTURE;
INTERLEUKIN-11; MUTATIONS; MICE
AB Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
C1 [Marouli, Eirini; Stirrups, Kathleen E.; Caulfield, Mark J.; Kanoni, Stavroula; Munroe, Patricia B.; Ntalla, Ioanna; Warren, Helen R.; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England.
[Graff, Mariaelisa; Highland, Heather M.; Justice, Anne E.; Young, Kristin L.; Mazul, Angela L.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA.
[Medina-Gomez, Carolina; Ikram, M. Arfan; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Rivadeneira, Fernando] Erasmus Sch Ctr, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.
[Medina-Gomez, Carolina; Broer, Linda; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus Sch Ctr, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.
[Lo, Ken Sin; Turcot, Valerie; de Denus, Simon; Rioux, John D.; Tardif, Jean-Claude; Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.
[Wood, Andrew R.; Ruth, Katherine S.; Yaghootkar, Hanieh; Frayling, Timothy M.] Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX2 5DW, Devon, England.
[Kjaer, Troels R.; Oxvig, Claus] Aarhus Univ, Dept Mol Biol & Genet, DK-8000 Aarhus, Denmark.
[Fine, Rebecca S.; Esko, Tonu; Rivas, Manuel A.; Vedantam, Sailaja; Chasman, Daniel I.; Patel, Aniruddh P.; Kathiresan, Sekar; Hirschhorn, Joel N.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
[Fine, Rebecca S.; Vedantam, Sailaja] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
[Fine, Rebecca S.; Esko, Tonu; Vedantam, Sailaja; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.
[Fine, Rebecca S.; Esko, Tonu; Vedantam, Sailaja; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.
[Lu, Yingchang] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA.
[Lu, Yingchang; Schurmann, Claudia; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.
[Lu, Yingchang; Schurmann, Claudia; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10069 USA.
[Highland, Heather M.] Univ Texas Hlth Sci Ctr Houston, Univ Texas Grad Sch Biomed Sci Houston, Univ Texas Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.
[Rueger, Sina; Kutalik, Zoltan] Univ Lausanne Hosp, Inst Social & Prevent Med, CH-1010 Lausanne, Switzerland.
[Rueger, Sina; Lamparter, David; Bergmann, Sven; Kutalik, Zoltan] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland.
[Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet Amgen Inc, IS-101 Reykjavik, Iceland.
[Lamparter, David; Bergmann, Sven] Univ Lausanne, Dept Comp Biol, CH-1011 Lausanne, Switzerland.
[Stirrups, Kathleen E.] Univ Cambridge, Dept Hematol, Cambridge CB2 0PT, England.
[Winkler, Thomas W.; Gorski, Mathias; Heid, Iris M.] Univ Regensburg, Dept Genet Epidemiol, D-93051 Regensburg, Germany.
[Esko, Tonu; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
[Karaderi, Tugce; Mahajan, Anubha; Gan, Wei; Kitajima, Hidetoshi; Morris, Andrew P.; Robertson, Neil; Southam, Lorraine; McCarthy, Mark I.; Lindgren, Cecilia M.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
[Locke, Adam E.; Abecasis, Goncalo; Jackson, Anne U.; Sim, Xueling; Stringham, Heather M.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.
[Locke, Adam E.; Abecasis, Goncalo; Feng, Shuang; Jackson, Anne U.; Sim, Xueling; Stringham, Heather M.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
[Locke, Adam E.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63108 USA.
[Masca, Nicholas G. D.; Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.
[Masca, Nicholas G. D.; Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England.
[Ng, Maggie C. Y.; Mudgal, Poorva; Bowden, Donald W.; Cox, Amanda J.] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC 27157 USA.
[Ng, Maggie C. Y.; Bowden, Donald W.; Cox, Amanda J.] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA.
[Rivas, Manuel A.] Nuffield Dept Clin Med, Oxford OX3 7BN, England.
[Guo, Xiuqing; Chen, Yii-Der Ida; Jia, Yucheng; Liu, Yeheng; Sandow, Kevin; Taylor, Kent D.; Yao, Jie; Rotter, Jerome I.] LABioMed Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.
[Aben, Katja K.] Netherland Comprehens Canc Org, NL-3501 DB Utrecht, Netherlands.
[Aben, Katja K.; Galesloot, Tessel E.; Kiemeney, Lambertus A.; Kluivers, Kirsten B.; Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, NL-6500 HB Nijmegen, Netherlands.
[Adair, Linda S.; Linneberg, Allan] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA.
[Alam, Dewan S.] Ctr Control Chron Dis, Dhaka 1212, Bangladesh.
[Albrecht, Eva; Heid, Iris M.; Mueller-Nurasyid, Martina] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.
[Allin, Kristine H.; Appel, Emil V.; Bork-Jensen, Jette; Grarup, Niels; Hansen, Torben; Hollensted, Mette; Pedersen, Oluf; Vestergaard, Henrik; Pers, Tune H.] Univ Copenhagen, Fac Med & Hlth Sci, Novo Nordisk Fdn Ctr Basic Metab Res, DK-2100 Copenhagen, Denmark.
[Allison, Matthew] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
[Amouyel, Philippe] INSERM, U1167, F-59019 Lille, France.
[Amouyel, Philippe] Inst Pasteur, U1167, F-59019 Lille, France.
[Amouyel, Philippe] Univ Lille, U1167, RID AGE Risk Factors & Mol Determinants Aging Rel, F-59019 Lille, France.
[Arveiler, Dominique] Univ Strasbourg, Dept Epidemiol & Publ Hlth, F-67085 Strasbourg, France.
[Arveiler, Dominique] Univ Hosp Strasbourg, Dept Publ Hlth, F-67081 Strasbourg, France.
[Asselbergs, Folkert W.; van Setten, Jessica] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
[Asselbergs, Folkert W.] ICIN Netherland Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
[Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England.
[Auer, Paul L.] Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA.
[Balkau, Beverley] INSERM, Ctr Rech Epidemiol & Sante Populat CESP, U1018, Villejuif, France.
[Banas, Bernhard; Boeger, Carsten A.; Gorski, Mathias] Univ Hosp Regensburg, Dept Nephrol, D-93042 Regensburg, Germany.
[Bang, Lia E.] Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, DK-2100 Copenhagen, Denmark.
[Benn, Marianne; Kamstrup, Pia R.; Nielsen, Sune F.; Nordestgaard, Borge G.; Varbo, Anette] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark.
[Benn, Marianne; Frikke-Schmidt, Ruth; Jorgensen, Torben; Linneberg, Allan; Nielsen, Sune F.; Nordestgaard, Borge G.; Tybjaerg-Hansen, Anne; Varbo, Anette] Univ Copenhagen, Fac Med & Hlth Sci, DK-2200 Copenhagen, Denmark.
[Bielak, Lawrence F.; Jhun, Min A.; Kardia, Sharon L. R.; Smith, Jennifer A.; Zhao, Wei] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
[Gorski, Mathias; Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, IFB Adipos Dis, D-04103 Leipzig, Germany.
[Blueher, Matthias; Stumvoll, Michael] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany.
[Boeing, Heiner] German Inst Human Nutr Potsdam Rehbruecke DIfE, Dept Epidemiol, D-14558 Nuthetal, Germany.
[Boerwinkle, Eric; Grove, Megan L.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.
[Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
[Bonnycastle, Lori L.; Collins, Francis S.] NHGRI, Med Genom & Metabol Genet Branch, NIH, Bethesda, MD 20892 USA.
[Bots, Michiel L.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
[Bowden, Donald W.] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC 27157 USA.
[Brandslund, Ivan] Lillebaelt Hosp, Dept Clin Biochem, DK-7100 Vejle, Denmark.
[Brandslund, Ivan] Univ Southern Denmark, Inst Reg Hlth Res, DK-5000 Odense, Denmark.
[Breen, Gerome] Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC Social Genet & Dev Psychiat Ctr, London SE5 8AF, England.
[Breen, Gerome] NIHR Biomed Res Ctr Mental Hlth Maudsley, London SE5 8AF, England.
[Brilliant, Murray H.; Peissig, Peggy L.; Person, Thomas N.] Marshfield Clin Res Fdn, Marshfield, WI 54449 USA.
[Burt, Amber A.; Jarvik, Gail P.; Larson, Eric B.] Univ Washington, Dept Med, Seattle, WA 98195 USA.
[Butterworth, Adam S.; Chowdhury, Rajiv; Danesh, John; Di Angelantonio, Emanuele; Howson, Joanna M. M.; Surendran, Praveen; Young, Robin] Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England.
[Butterworth, Adam S.; Danesh, John; Di Angelantonio, Emanuele] Univ Cambridge, NIHR Blood & Transplant Res Unit Donor Hlth Genom, Cambridge CB1 8RN, England.
[Carey, David J.; Kuivaniemi, Helena; Tromp, Gerard] Sigfried & Janet Weis Ctr Res, Danville, PA 17822 USA.
[Caulfield, Mark J.; Munroe, Patricia B.; Warren, Helen R.] Queen Mary Univ, Barts & London Sch Med & Dent, NIHR Barts Cardiovasc Res Unit, London EC1M 6BQ, England.
[Chambers, John C.; Kooner, Jaspal S.; Zhang, Weihua] London North West Healthcare NHS Trust, Ealing Hosp, Dept Cardiol, Middlesex UB1 3HW, England.
[Chambers, John C.; Evangelou, Evangelos; Segura-Lepe, Marcelo P.; Zhang, Weihua] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.
[Chambers, John C.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Healthcare NHS Trust, London W12 0HS, England.
[Chasman, Daniel I.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA.
[Chasman, Daniel I.; Patel, Aniruddh P.; Ridker, Paul M.; Kathiresan, Sekar] Harvard Med Sch, Boston, MA 02115 USA.
[Chasman, Daniel I.; Chu, Audrey Y.; Ridker, Paul M.] Brigham & Womens & Harvard Med Sch, Div Prevent Med, Boston, MA 02115 USA.
[Christensen, Cramer] Lillebaelt Hosp, Dept Med, DK-7100 Vejle, Denmark.
[Chu, Audrey Y.; Heard-Costa, Nancy L.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.
[Cocca, Massimiliano] Univ Trieste, Dept Med Surg & Hlth Sci, I-34100 Trieste, Italy.
[Cook, James P.; Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England.
[Corley, Janie; Davies, Gail; Deary, Ian J.; Starr, John M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.
[Corley, Janie; Davies, Gail; Deary, Ian J.; Pattie, Alison] Univ Edinburgh, Dept Psychol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland.
[Galbany, Jordi Corominas] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands.
[Cox, Amanda J.] Griffith Univ, Menzies Hlth Inst Queensland, Southport, Qld, Australia.
[Cuellar-Partida, Gabriel] Univ Queensland, Diamantina Inst, Brisbane, Qld 4072, Australia.
[Cuellar-Partida, Gabriel; Gordon, Scott D.; Martin, Nicholas G.; Sapkota, Yadav] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia.
[Danesh, John; Marenne, Gaelle; Southam, Lorraine; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England.
[Danesh, John] Univ Cambridge, Dept Med, Cambridge Escellence, British Heart Fdn, Cambridge CB2 0QQ, England.
[de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Genet, NL-3584 CX Utrecht, Netherlands.
[de Borst, Gert J.] Univ Med Ctr Utrecht, Dept Vasc Surg, Div Surg Specialties, NL-3584 CX Utrecht, Netherlands.
[de Denus, Simon] Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada.
[de Groot, Mark C. H.] Univ Med Ctr Utrecht, Div Lab & Pharm, Dept Clin Chem & Haematol, NL-3508 GA Utrecht, Netherlands.
[de Groot, Mark C. H.] Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht Inst Pharmaceut Sci, NL-3508 TB Utrecht, Netherlands.
[de Mutsert, Renee; Li-Gao, Ruifang; Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RC Leiden, Netherlands.
[Dedoussis, George; Farmaki, Aliki-Eleni] Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens 17671, Greece.
[Demerath, Ellen W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA.
[den Hollander, Anneke I.; Hoyng, Carel B.] Radbound Univ Med Ctr, Dept Ophthalmol, NL-6500 HB Nijmegen, Netherlands.
[Dennis, Joe G.; Easton, Douglas F.; Thompson, Deborah J.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England.
[Drenos, Fotios] UCL, Inst Cardiovasc Sci, London WC1E 6JF, England.
[Drenos, Fotios] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England.
[Du, Mengmeng] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.
[Du, Mengmeng] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10017 USA.
[Dunning, Alison M.; Easton, Douglas F.; Pirie, Ailith; Tyrer, Jonathan P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England.
[Ebeling, Tapani] Oulu Univ Hosp, Dept Med, Oulu 90029, Finland.
[Ebeling, Tapani] Univ Oulu, Res Unit Internal Med, FI-90014 Oulu, Finland.
[Edwards, Todd L.; Giri, Ayush] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Dept Med,Div Epidemiol, Nashville, TN 37203 USA.
[Ellinor, Patrick T.; Florez, Jose C.; Huang, Paul L.; Lubitz, Steven A.; Manning, Alisa K.; Patel, Aniruddh P.; Peloso, Gina M.; Sivapalaratnam, Suthesh; Kathiresan, Sekar] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Ellinor, Patrick T.; Florez, Jose C.; Lubitz, Steven A.; Manning, Alisa K.; Peloso, Gina M.] Broad Inst, Med & Populat Genet Program, Cambridge, MA 02141 USA.
[Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.
[Evangelou, Evangelos] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece.
[Faul, Jessica D.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48104 USA.
[Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA.
[Ferrannini, Ele] CNR Inst Clin Physiol, Pisa, Italy.
[Ferrannini, Ele] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy.
[Ferrario, Marco M.] Univ Insubria, Dept Clin & Expt Med, Res Ctr Epidemiol & Prevent Med, I-21100 Varese, Italy.
[Ferrieres, Jean] Toulouse Univ, Sch Med, F-31059 Toulouse, France.
[Florez, Jose C.; Manning, Alisa K.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
[Ford, Ian; Packard, Chris J.; Padmanabhan, Sandosh; Sattar, Naveed; Young, Robin] Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland.
[Fornage, Myriam; Lin, Li-An] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA.
[Franks, Paul W.; Renstrom, Frida; Varga, Tibor V.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden.
[Franks, Paul W.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
[Franks, Paul W.] Umea Univ, Med Unit, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden.
[Frikke-Schmidt, Ruth; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, DK-2100 Copenhagen, Denmark.
[Gandin, Ilaria; Gasparini, Paolo; Girotto, Giorgia; Morgan, Anna] Univ Trieste, Dept Med Sci, I-34137 Trieste, Italy.
[Gasparini, Paolo; Girotto, Giorgia; Vozzi, Diego] Sidra Med & Res Ctr, Div Expt Genet, Doha 26999, Qatar.
[Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth, Geriat, S-75185 Uppsala, Sweden.
[Gordon-Larsen, Penny; Harris, Kathleen Mullan] Univ N Carolina, Caroline Populat Ctr, Chapel Hill, NC 27514 USA.
[Gordon-Larsen, Penny] Univ N Carolina, Dept Nutr, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27514 USA.
[Gudnason, Vilmundur; Smith, Albert Vernon; Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.
[Gudnason, Vilmundur; Smith, Albert Vernon] Icelandic Heart Assoc, IS-201 Kopavogur, Iceland.
[Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, S-75141 Uppsala, Sweden.
[Harris, Kathleen Mullan] Univ N Carolina, Dept Sociol, Chapel Hill, NC 27514 USA.
[Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA.
[Hattersley, Andrew T.] Univ Exeter, Univ Exeter Med Sch, Exeter EX2 5DW, Devon, England.
[Hayward, Caroline; Marten, Jonathan; Vitart, Veronique] Univ Edinburgh, Inst Genet & Mol Med, MRCHGU, Edinburgh EH4 2XU, Midlothian, Scotland.
[He, Liang] Duke Univ, Social Sci Res Inst, Biodemog Aging Res Unit, Durham, NC 27708 USA.
[He, Liang; Heikkila, Kauko; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, FI-00014 Helsinki, Finland.
[Dunning, Alison M.; Heikkila, Kauko; Kaprio, Jaakko] Univ Helsinki, Inst Mol Med Finland FIMM, FI-00014 Helsinki, Finland.
[Helgeland, Oyvind; Njolstad, Pal R.] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway.
[Helgeland, Oyvind; Johansson, Stefan; Njolstad, Pal R.] Univ Bergen, Dept Clin Sci, KG Jebson Ctr Diabet Res, N-5020 Bergen, Norway.
[Hernesniemi, Jussi] Tampere Univ Hosp, Dept Cardiol, Ctr Heart, FI-33521 Tampere, Finland.
[Hernesniemi, Jussi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.
[Hernesniemi, Jussi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka] Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland.
[Hewitt, Alex W.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic 3002, Australia.
[Hewitt, Alex W.; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Vis Sci, Perth, WA 6009, Australia.
[Hewitt, Alex W.] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas 7000, Australia.
[Hocking, Lynne J.] Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh EH4 2XU, Midlothian, Scotland.
[Hocking, Lynne J.] Univ Aberdeen, Div Appl Med, Musculoskeletal Res Programme, Aberdeen AB25 2ZD, Scotland.
[Holmen, Oddgeir L.] Norwegian Univ Sci & Technol, NTNU, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7600 Trondheim, Norway.
[Hovingh, G. Kees] AMC, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands.
[Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.
[Ikram, M. Arfan] Erasmus Sch Ctr, Dept Neurol, NL-3015 GE Rotterdam, Netherlands.
[Ikram, M. Arfan] Erasmus Sch Ctr, Dept Radiol, NL-3015 GE Rotterdam, Netherlands.
[Ingelsson, Erik] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA.
[Jansson, Jan-Hakan; Rolandsson, Olov] Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden.
[Jansson, Jan-Hakan] Res Unit Skelleftea, SE-93141 Skelleftea, Sweden.
[Jarvik, Gail P.] Univ Washington, Dept Genom Sci, Seattle, WA 98195 USA.
[Jensen, Gorm B.] Frederiksberg Univ Hosp, Copenhagen City Heart Study, DK-2000 Frederiksberg, Denmark.
[Jiang, Xuejuan] Univ Calif Los Angeles, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA.
[Jiang, Xuejuan; Varma, Rohit] Univ Southern Calif, Keck Sch Med, Dept Ophthalmol, USC Roski Eye Inst, Los Angeles, CA 90089 USA.
[Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway.
[Jorgensen, Marit E.] Univ Southern Denmark, Natl Inst Publ Hlth, DK-1353 Copenhagen, Denmark.
[Jorgensen, Marit E.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark.
[Jorgensen, Torben] Aalborg Hosp, DK-9000 Aalborg, Denmark.
[Jorgensen, Torben; Linneberg, Allan; Thuesen, Betina H.] Capital Reg Denmark, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark.
[Jousilahti, Pekka; Kaprio, Jaakko; Kontto, Jukka; Lindstrom, Jaana; Mannisto, Satu; Perola, Markus; Salomaa, Veikko; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland.
[Jukema, J. Wouter; Trompet, Stella] Leiden Univ Med Ctr, Dept Cardiol, NL-2333 Leiden, Netherlands.
[Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, NL-2333 Utrecht, Netherlands.
[Kahali, Bratati; Speliotes, Elizabeth K.; Zhou, Wei; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
[Kahali, Bratati; Speliotes, Elizabeth K.; Zhou, Wei; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA.
[Kahali, Bratati; Speliotes, Elizabeth K.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA.
[Kahn, Rene S.; Ophoff, Roel A.] Ctr Med Univ Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CG Utrecht, Netherlands.
[Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland.
[Karaleftheri, Maria] Echinos Med Ctr, Echinos, Greece.
[Karpe, Fredrik; Neville, Matt; Owen, Katharine R.; Robertson, Neil; McCarthy, Mark I.] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabetes Endocrinol & Metab, Oxford OX3 7LE, England.
[Karpe, Fredrik; Neville, Matt; Owen, Katharine R.; McCarthy, Mark I.] Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LE, England.
[Kee, Frank] Queens Univ Belfast, UKCRC Ctr Excellence Publ Hlth Res, Belfast BT12 6BJ, Antrim, North Ireland.
[Keeman, Renske; Schmidt, Marjanka K.] Netherlands Canc Inst, Antoni van Leewenhoek Hosp, NL-1066 CX Amsterdam, Netherlands.
[Kocher, Thomas] Univ Med Greifswald, Dept Restorat Dent Periodontol & Endodontol, D-17475 Greifswald, Germany.
[Komulainen, Pirjo; Lakka, Timo A.; Manning, Alisa K.; Rauramaa, Rainer] Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio 70100, Finland.
[Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Hammersmith Hosp Campus, London W12 0NN, England.
[Kooperberg, Charles; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.
[Kriebel, Jennifer; Meidtner, Karina; Schulze, Matthias B.] German Ctr Diabet Res, D-85764 Munich, Germany.
[Kriebel, Jennifer] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, D-85764 Neuherberg, Germany.
[Kriebel, Jennifer] Helmholtz Zentrum Munchen German Res Ctr Environm, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.
[Kuivaniemi, Helena] Univ Stellenbosch, Fac Med & Hlth Sci, Dept Biomed Sci, Dept Psychiat, ZA-7505 Tygerberg, Western Cape, South Africa.
[Kuivaniemi, Helena] Univ Stellenbosch, Fac Med & Hlth Sci, Dept Biomed Sci, Div Mol Biol & Human Genet, ZA-7505 Tygerberg, Western Cape, South Africa.
[Kury, Sebastien] CHU Nantes, Serv Genet Med, F-44093 Nantes, France.
[Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio 70210, Finland.
[Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland.
[La Bianca, Martina; Robino, Antonietta; Ulivi, Sheila] Inst Maternal & Child Hlth IRCCS Burlo Garofolo, I-34137 Trieste, Italy.
[Lakka, Timo A.] Univ Eastern Finland, Inst Biomed & Physiol, Kuopio 70210, Finland.
[Lange, Ethan M.; Lange, Leslie A.; Mohlke, Karen L.; Wu, Ying] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA.
[Langefeld, Carl D.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA.
[Langefeld, Carl D.] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27157 USA.
[Langenberg, Claudia; Luan, Jian'an; Perry, John R. B.; Scott, Robert A.; Wareham, Nicholas J.; Willems, Sara M.; Zhao, Jing Hua] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England.
[Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA 98101 USA.
[Larson, Eric B.] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA.
[Lee, I-Te] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrinol & Metab, Taichung 407, Taiwan.
[Lee, I-Te] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan.
[Lee, I-Te] Chung Shan Med Univ, Sch Med, Taichung 402, Taiwan.
[Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL 35205 USA.
[Li, Huaixing; Lin, Xu; Wang, Feijie; Wang, Yiqin; Yao, Pang; Zheng, He] Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci,Key Lab Nutr & Metab, Shanghai 200031, Peoples R China.
[Li, Jin] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Palo Alto, CA 94305 USA.
[Lin, Honghuang; Teumer, Alexander] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA.
[Lind, Lars] Uppsala Univ, S-75185 Uppsala, Sweden.
[Linneberg, Allan] Rigshosp, Dept Expt Med, DK-2200 Copenhagen, Denmark.
[Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA.
[Lophatananon, Artitaya] Warsaw Acad Med & Hosp, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England.
[Madden, Pamela A. F.] Washington Univ, Dept Psychiat, St Louis, MO 63110 USA.
[Meidtner, Karina; Schulze, Matthias B.] German Inst Human Nutr Potsdam Rehbruecke DIfE, Dept Mol Epidemiol, D-14558 Nuthetal, Germany.
[Mitchell, Paul] Univ Sydney, Ctr Vis Res, Westmead Millennium Inst Med Res, Sydney, NSW 2022, Australia.
[Mitchell, Paul] Univ Sydney, Dept Ophthalmol, Sydney, NSW 2022, Australia.
[Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, NL-2300 RC Leiden, Netherlands.
[Morris, Andrew D.; Polasek, Ozren; Rudan, Igor] Univ Edinburgh, Ctr Global Hlth Res, Ushar Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
[Mueller-Nurasyid, Martina] Univ Munich, Dept Med 1, D-81377 Munich, Germany.
[Mueller-Nurasyid, Martina] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany.
[Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA.
[Nauck, Matthias] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany.
[Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem, D-17475 Greifswald, Germany.
[Nauck, Matthias] Univ Med Greifswald, Lab Med, D-17475 Greifswald, Germany.
[Nikus, Kjell] Univ Tampere, Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland.
[Nikus, Kjell] Univ Tampere, Sch Med, Tampere 33521, Finland.
[O'Connel, Jeffrey R.; Perry, James A.; Yerges-Armstrong, Laura M.] Univ Maryland, Sch Med, Dept Med, Program Personalized Med, Baltimore, MD 21201 USA.
[Oksa, Heikki] Tampere Univ Hosp, Dept Med, Tampere 33521, Finland.
[Loohuis, Loes M. Olde; Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA.
[Palmer, Colin N. A.] Ninewells Hosp & Med Sch, Med Res Inst, Pat Macpherson Ctr Pharmacogenet & Pharmacogenom, Dundee DD1 9SY, Scotland.
[Pasterkamp, Gerard] Univ Med Ctr Utrecht, Div Labs & Pharm, Lab Clin Chem & Hematol, NL-3584 CX Utrecht, Netherlands.
[van der Laan, Sander W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Lab Expt Cardiol, NL-3584 CX Utrecht, Netherlands.
[Pennell, Craig E.; Wang, Carol A.] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia.
[Perola, Markus] Univ Helsinki, Inst Mol Med FIMM, FI-00014 Helsinki, Finland.
[Perola, Markus] Univ Helsinki, Diabet & Obes Res Program, FI-00014 Helsinki, Finland.
[Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
[Polasek, Ozren] Univ Split, Sch Med, Split 21000, Croatia.
[Posthuma, Danielle] Vrije Univ Amsterdam, Dept Complex Trait Genet, Ctr Neurogenom & Cognit Res, NL-1081 HV Amsterdam, Netherlands.
[Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Neurosci Campus Amsterdam, NL-1081 HV Amsterdam, Netherlands.
[Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.
[Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland.
[Rasheed, Asif; Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan.
[Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland.
[Reilly, Dermot F.] MRL Merck & Co Inc, Genet & Pharmacogenom, Boston, MA 02115 USA.
[Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.
[Renstrom, Frida] Umea Univ, Dept Biobank Res, SE-90187 Umea, Sweden.
[Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA.
[Rioux, John D.; Tardif, Jean-Claude; Lettre, Guillaume] Univ Montreal, Fac Med, Dept Med, Montreal, PQ H3T 1J4, Canada.
[Rolandsson, Olov] Umea Univ, Unit Family Med, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden.
[Saleheen, Danish; Zhao, Wei] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.
[Schreiner, Pamela J.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA.
[Shah, Svati] Duke Univ, Durham, NC 27703 USA.
[Sim, Xueling] Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.
[Sivapalaratnam, Suthesh] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England.
[Sivapalaratnam, Suthesh] AMC, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands.
[Small, Kerrin S.; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.
[Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland.
['t Hart, Leen M.; van Schoor, Natasja M.] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands.
['t Hart, Leen M.] Leiden Univ, Med Ctr, Dept Mol & Cell Biol, NL-2333 ZC Leiden, Netherlands.
['t Hart, Leen M.] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2333 ZC Leiden, Netherlands.
[Tansey, Katherine E.] Cardiff Univ, Coll Biomed & Life Sci, Cardiff CF14 4EP, S Glam, Wales.
[Tansey, Katherine E.] Univ Bristol, Dept Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England.
[Teumer, Alexander] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany.
[Toenjes, Anke] Univ Leipzig, Dept Womens & Child Hlth, Ctr Pediat Res, D-04103 Leipzig, Germany.
[Tromp, Gerard] Univ Stellenbosch, Fac Med & Hlth Sci, Dept Biomed Sci, Div Human Genet & Mol Biol, ZA-7505 Tygerberg, Western Cape, South Africa.
[Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2333 Leiden, Netherlands.
[Tsafantakis, Emmanouil] Anogia Med Ctr, Anogia, Greece.
[Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria.
[Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman 15462, Kuwait.
[Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia.
[Uher, Rudolf] Dalhousie Univ, Dept Psychiat, Halifax, NS B3H 4R2, Canada.
[Van Der Leij, Andries R.] Univ Amsterdam, Dept Brain & Cognit, NL-1018 WS Amsterdam, Netherlands.
[Edwards, Digna R. Velez] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Dept Obstet & Gynecol, Nashville, TN 37203 USA.
[Vogt, Thomas F.] MRL Merck Co Inc, Cardiometab Dis, Kenilworth, NJ 07033 USA.
[Walker, Mark] Newcastle Univ, Sch Med, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
[Wang, Shuai] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.
[Wessel, Jennifer] Indiana Univ, Fairbanks Sch Publ Hlth, Diabet Translat Res Ctr, Dept Epidemiol & Med, Indianapolis, IN 46202 USA.
[Wessel, Jennifer] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA.
[Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA.
[Witte, Daniel R.] Danish Diabet Acad, DK-5000 Odense, Denmark.
[Witte, Daniel R.] Aarhus Univ, Dept Publ Hlth, DK-8000 Aarhus, Denmark.
[Woods, Michael O.] Mem Univ Newfoundland, Fac Med, Discipline Genet, St John, NF A1B 3V6, Canada.
[Yerges-Armstrong, Laura M.] GlaxoSmithKlein, King Of Prussia, PA 19406 USA.
[Zhan, Xiaowei] Univ Texas Southwestern Med Ctr Dallas, Quantitat Biomed Res Ctr, Ctr Genet Host Def, Dept Clin Sci, Dallas, TX 75390 USA.
[Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.
[Liu, Dajiang J.] Penn State Univ, Coll Med, Inst Personalized Med, Dept Publ Hlth Sci, Hershey, PA 17033 USA.
[North, Kari E.] Dept Epidemiol, Chapel Hill, NC 27514 USA.
[North, Kari E.] Carolina Ctr Genome Sci, Chapel Hill, NC 27514 USA.
[Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.
[Pers, Tune H.] Statens Serum Inst, Dept Epidemiol Res, DK-2200 Copenhagen, Denmark.
[Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7BN, England.
[Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10069 USA.
[Hirschhorn, Joel N.] Harvard Med Sch, Dept Pediat & Genet, Boston, MA 02115 USA.
[Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia.
RP Deloukas, P (reprint author), Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England.; Lettre, G (reprint author), Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.; Hirschhorn, JN (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Hirschhorn, JN (reprint author), Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.; Hirschhorn, JN (reprint author), Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.; Lettre, G (reprint author), Univ Montreal, Fac Med, Dept Med, Montreal, PQ H3T 1J4, Canada.; Hirschhorn, JN (reprint author), Harvard Med Sch, Dept Pediat & Genet, Boston, MA 02115 USA.; Deloukas, P (reprint author), King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia.
EM joelh@broadinstitute.org; p.deloukas@qmul.ac.uk;
guillaume.lettre@umontreal.ca
RI Polasek, Ozren/B-6002-2011; Feitosa, Mary/K-8044-2012; Mackey,
David/H-5340-2014; Rioux, John/A-9599-2015;
OI Ewing, Ailith/0000-0002-2272-1277; Bergmann, Sven/0000-0002-6785-9034;
Linneberg, Allan/0000-0002-0994-0184; Polasek,
Ozren/0000-0002-5765-1862; Feitosa, Mary/0000-0002-0933-2410; Mackey,
David/0000-0001-7914-4709; Smith, Jennifer/0000-0002-3575-5468; Rioux,
John/0000-0001-7560-8326; Jorgensen, Torben/0000-0001-9453-2830; Small,
Kerrin/0000-0003-4566-0005; Medina-Gomez, Carolina/0000-0001-7999-5538;
Varga, Tibor/0000-0002-2383-699X; Kaprio, Jaakko/0000-0002-3716-2455;
Evangelou, Evangelos/0000-0002-5488-2999; Kontto,
Jukka/0000-0003-3899-9852
FU Doris Duke Charitable Foundation [2014105]; Medical Research Council
[G0600237, MC_PC_15018, MR/K006584/1, MR/K026992/1, MR/L01341X/1,
MR/L01632X/1]; NCATS NIH HHS [UL1 TR000124, UL1 TR001881]; NCI NIH HHS
[P30 CA008748]; NHLBI NIH HHS [HHSN268201100046C, HHSN268201300046C, K23
HL114724, K99 HL130580, N01 HC095159]; NICHD NIH HHS [P2C HD050924];
NIDDK NIH HHS [P30 DK063491, R01 DK075787, R01 DK089256]
NR 29
TC 0
Z9 0
U1 11
U2 11
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 FEB 9
PY 2017
VL 542
IS 7640
BP 186
EP 190
DI 10.1038/nature21039
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK2DJ
UT WOS:000393737500031
PM 28146470
ER
PT J
AU Wang, YJ
Patel, BA
Anreddy, N
Zhang, YK
Zhang, GN
Alqahtani, S
Singh, S
Shukla, S
Kaddoumi, A
Ambudkar, SV
Talele, TT
Chen, ZS
AF Wang, Yi-Jun
Patel, Bhargav A.
Anreddy, Nagaraju
Zhang, Yun-Kai
Zhang, Guan-Nan
Alqahtani, Saeed
Singh, Satyakam
Shukla, Suneet
Kaddoumi, Amal
Ambudkar, Suresh V.
Talele, Tanaji T.
Chen, Zhe-Sheng
TI Thiazole-valine peptidomimetic (TTT-28) antagonizes multidrug resistance
in vitro and in vivo by selectively inhibiting the efflux activity of
ABCB1
SO SCIENTIFIC REPORTS
LA English
DT Article
ID DRUG-RESISTANCE; P-GLYCOPROTEIN; HEART-FAILURE; CANCER-CELLS;
TRANSPORTERS; PACLITAXEL; PROTEIN; ABCG2; POLYMORPHISMS; DOXORUBICIN
AB Multidrug resistance (MDR) attenuates the chemotherapy efficacy and increases the probability of cancer recurrence. The accelerated drug efflux mediated by ATP-binding cassette (ABC) transporters is one of the major MDR mechanisms. This study investigated if TTT-28, a newly synthesized thiazolevaline peptidomimetic, could reverse ABCB1-mediated MDR in vitro and in vivo. TTT-28 reversed the ABCB1-mediated MDR and increased the accumulation of [H-3]-paclitaxel in ABCB1 overexpressing cells by selectively blocking the efflux function of ABCB1, but not interfering with the expression level and localization of ABCB1. Animal study revealed that TTT-28 enhanced the intratumoral concentration of paclitaxel and promoted apoptosis, thereby potently inhibiting the growth of ABCB1 overexpressing tumors. But TTT-28 did not induce the toxicity (cardiotoxicity/myelosuppression) of paclitaxel in mice. In this study, we synthesized and evaluated a novel selective inhibitor of ABCB1 (TTT-28) with high efficacy and low toxicity. The identification and characterization of this new thiazole-valine peptidomimetic will facilitate design and synthesis of a new generation of ABCB1 inhibitors, leading to further research on multidrug resistance and combination chemotherapy. Furthermore, the strategy that co-administer MDR-ABCB1 inhibitor to overcome the resistance of one FDA approved, widely used chemotherapeutic paclitaxel, may be promising direction for the field of adjuvant chemotherapy.
C1 [Wang, Yi-Jun; Patel, Bhargav A.; Anreddy, Nagaraju; Zhang, Yun-Kai; Zhang, Guan-Nan; Singh, Satyakam; Talele, Tanaji T.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA.
[Alqahtani, Saeed; Kaddoumi, Amal] Univ Louisiana Monroe, Sch Pharm, Dept Basic Pharmaceut Sci, Monroe, LA 71201 USA.
[Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA.
RP Chen, ZS (reprint author), St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA.
EM chenz@stjohns.edu
FU NIH [1R15CA143701]; St. John's University Research Seed Grant
[579-1110-7002]; Intramural Research Program of the National Institutes
of Health, National Cancer Institute, Center for Cancer Research
FX This work was supported by funds from NIH (No. 1R15CA143701) and St.
John's University Research Seed Grant (No. 579-1110-7002) to Z.S. Chen.
SS and SVA were supported by the Intramural Research Program of the
National Institutes of Health, National Cancer Institute, Center for
Cancer Research. We thank Drs. Susan E. Bates and Robert W. Robey (NCI,
NIH, Bethesda, MD) for providing SW620 and SW620/Ad300 cell lines.
NR 36
TC 0
Z9 0
U1 6
U2 6
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 9
PY 2017
VL 7
AR 42106
DI 10.1038/srep42106
PG 12
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK3MY
UT WOS:000393831700001
PM 28181548
ER
PT J
AU McManus, DD
Rong, J
Huan, TX
Lacey, S
Tanriverdi, K
Munson, PJ
Larson, MG
Joehanes, R
Murthy, V
Shah, R
Freedman, JE
Levy, D
AF McManus, David D.
Rong, Jian
Huan, Tianxiao
Lacey, Sean
Tanriverdi, Kahraman
Munson, Peter J.
Larson, Martin G.
Joehanes, Roby
Murthy, Venkatesh
Shah, Ravi
Freedman, Jane E.
Levy, Daniel
TI Messenger RNA and MicroRNA transcriptomic signatures of cardiometabolic
risk factors
SO BMC GENOMICS
LA English
DT Article
DE Cardiovascular disease risk factors; Epidemiology; Circulation; mRNA;
microRNA
ID VASCULAR SMOOTH-MUSCLE; CORONARY-HEART-DISEASE; METABOLIC SYNDROME;
CARDIOVASCULAR-DISEASE; GENE-EXPRESSION; ASSOCIATION; HYPERTENSION;
CELLS; POLYMORPHISMS; VARIANTS
AB Background: Cardiometabolic (CM) risk factors are heritable and cluster in individuals. We hypothesized that CM risk factors are associated with multiple shared and unique mRNA and microRNA (miRNA) signatures. We examined associations of mRNA and miRNA levels with 6 CM traits: body mass index, HDL-cholesterol and triglycerides, fasting glucose, and systolic and diastolic blood pressures through cross-sectional analysis of 2812 Framingham Heart Study who had whole blood collection for RNA isolation for mRNA and miRNA expression studies and who consented to genetic research. We excluded participants taking medication for hypertension, dyslipidemia, or diabetes. We measured mRNA (n = 17,318; using the Affymetrix GeneChip Human Exon 1.0 ST Array) and miRNA (n = 315; using qRT-PCR) expression in whole blood. We used linear regression for mRNA analyses and a combination of linear and logistic regression for miRNA analyses. We conducted miRNA-mRNA coexpression and gene ontology enrichment analyses to explore relations between pleiotropic miRNAs, mRNA expression, and CM trait clustering.
Results: We identified hundreds of significant associations between mRNAs, miRNAs, and individual CM traits. Four mRNAs (FAM13A, CSF2RB, HIST1H2AC, WNK1) were associated with all 6 CM traits (FDR < 0.001) and four miRNAs (miR-197-3p, miR-328, miR-505-5p, miR-145-5p) were associated with four CM traits (FDR < 0.05). Twelve mRNAs, including WNK1, that were coexpressed with the four most pleiotropic miRNAs, were also miRNA targets. mRNAs coexpressed with pleiotropic miRNAs were enriched for RNA metabolism (miR-505-5p), ubiquitin-dependent protein catabolism (miR-197-3p, miR-328) and chromatin assembly (miR-328).
Conclusions: We identified mRNA and miRNA signatures of individual CM traits and their clustering. Implicated transcripts may play causal roles in CM risk or be downstream consequences of CM risk factors on the transcriptome. Studies are needed to establish whether or not pleiotropic circulating transcripts illuminate causal pathways for CM risk.
C1 [McManus, David D.; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA 01003 USA.
[McManus, David D.; Rong, Jian; Huan, Tianxiao; Lacey, Sean; Larson, Martin G.; Levy, Daniel] NHLBI, Framingham, MA 02215 USA.
[McManus, David D.; Rong, Jian; Huan, Tianxiao; Lacey, Sean; Larson, Martin G.; Levy, Daniel] Boston Univ Framingham Heart Study, Framingham, MA 20892 USA.
[McManus, David D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Epidemiol, Worcester, MA 01605 USA.
[Rong, Jian; Lacey, Sean; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.
[Rong, Jian; Levy, Daniel] Boston Univ, Sch Med, Dept Med, Div Neurol, Boston, MA 02215 USA.
[Huan, Tianxiao; Joehanes, Roby; Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.
[Huan, Tianxiao; Joehanes, Roby; Levy, Daniel] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
[Munson, Peter J.; Joehanes, Roby] NIH, Ctr Informat Technol, Mathemat & Stat Comp Lab, Bethesda, MD 20892 USA.
[Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA.
[Joehanes, Roby] Hebrew SeniorLife, Boston, MA USA.
[Joehanes, Roby] Harvard Med Sch, Boston, MA USA.
[Murthy, Venkatesh] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA.
[Shah, Ravi] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiol, Boston, MA USA.
[McManus, David D.] 1355 Lake Ave North, Worcester, MA 01655 USA.
RP McManus, DD (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA 01003 USA.; McManus, DD (reprint author), NHLBI, Framingham, MA 02215 USA.; McManus, DD (reprint author), Boston Univ Framingham Heart Study, Framingham, MA 20892 USA.; McManus, DD (reprint author), Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Epidemiol, Worcester, MA 01605 USA.; McManus, DD (reprint author), 1355 Lake Ave North, Worcester, MA 01655 USA.
EM mcmanusd@ummhc.org
FU National Institutes of Health [N01-HC-25195]; Division of Intramural
Research, National Heart, Lung, and Blood Institute, National Institutes
of Health, Bethesda, MD; NIH [N01-HC-25195]; Division of Intramural
Research, National Heart, Lung, and Blood Institute; Center for
Information Technology, National Institutes of Health, Bethesda, MD;
National Heart, Lung and Blood Institute of the National Institutes of
Health, Bethesda, MA [KL2RR031981, 1R01HL126911-01A1, 1R15HL121761-01A1,
1UH2TR000921-02]
FX The Framingham Heart Study is funded by National Institutes of Health
contract N01-HC-25195. The laboratory work for this investigation was
funded by the Division of Intramural Research, National Heart, Lung, and
Blood Institute, National Institutes of Health, Bethesda, MD and by NIH
contract N01-HC-25195. The analytical component of this project was
funded by the Division of Intramural Research, National Heart, Lung, and
Blood Institute, and the Center for Information Technology, National
Institutes of Health, Bethesda, MD. DDM's time was supported by
KL2RR031981, 1R01HL126911-01A1, 1R15HL121761-01A1, and 1UH2TR000921-02
from the National Heart, Lung and Blood Institute of the National
Institutes of Health, Bethesda, MA.
NR 43
TC 0
Z9 0
U1 1
U2 1
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2164
J9 BMC GENOMICS
JI BMC Genomics
PD FEB 8
PY 2017
VL 18
AR 139
DI 10.1186/s12864-017-3533-9
PG 13
WC Biotechnology & Applied Microbiology; Genetics & Heredity
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA EL1MG
UT WOS:000394383900002
PM 28178938
ER
PT J
AU Doulatov, S
Vo, LT
Macari, ER
Wahlster, L
Kinney, MA
Taylor, AM
Barragan, J
Gupta, M
McGrath, K
Lee, HY
Humphries, JM
DeVine, A
Narla, A
Alter, BP
Beggs, AH
Agarwal, S
Ebert, BL
Gazda, HT
Lodish, HF
Sieff, CA
Schlaeger, TM
Zon, LI
Daley, GQ
AF Doulatov, Sergei
Vo, Linda T.
Macari, Elizabeth R.
Wahlster, Lara
Kinney, Melissa A.
Taylor, Alison M.
Barragan, Jessica
Gupta, Manav
McGrath, Katherine
Lee, Hsiang-Ying
Humphries, Jessica M.
DeVine, Alex
Narla, Anupama
Alter, Blanche P.
Beggs, Alan H.
Agarwal, Suneet
Ebert, Benjamin L.
Gazda, Hanna T.
Lodish, Harvey F.
Sieff, Colin A.
Schlaeger, Thorsten M.
Zon, Leonard I.
Daley, George Q.
TI Drug discovery for Diamond-Blackfan anemia using reprogrammed
hematopoietic progenitors
SO SCIENCE TRANSLATIONAL MEDICINE
LA English
DT Article
ID PLURIPOTENT STEM-CELLS; RIBOSOMAL-PROTEIN S19; AUTOPHAGY; GENE;
ERYTHROPOIESIS; DYSFUNCTION; PRECURSORS; GENERATION; MUTATIONS;
REGULATOR
AB Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.
C1 [Doulatov, Sergei; Vo, Linda T.; Macari, Elizabeth R.; Wahlster, Lara; Kinney, Melissa A.; Taylor, Alison M.; Barragan, Jessica; Gupta, Manav; McGrath, Katherine; Humphries, Jessica M.; DeVine, Alex; Agarwal, Suneet; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA.
[Doulatov, Sergei; Vo, Linda T.; Macari, Elizabeth R.; Wahlster, Lara; Kinney, Melissa A.; Taylor, Alison M.; Barragan, Jessica; Gupta, Manav; McGrath, Katherine; Humphries, Jessica M.; DeVine, Alex; Agarwal, Suneet; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA.
[Doulatov, Sergei; Vo, Linda T.; Macari, Elizabeth R.; Wahlster, Lara; Kinney, Melissa A.; Taylor, Alison M.; Barragan, Jessica; Gupta, Manav; McGrath, Katherine; Humphries, Jessica M.; DeVine, Alex; Narla, Anupama; Agarwal, Suneet; Sieff, Colin A.; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA.
[Taylor, Alison M.; Beggs, Alan H.; Agarwal, Suneet; Ebert, Benjamin L.; Gazda, Hanna T.; Sieff, Colin A.; Zon, Leonard I.; Daley, George Q.] Harvard Med Sch, Boston, MA 02115 USA.
[Lee, Hsiang-Ying; Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA.
[Lee, Hsiang-Ying; Lodish, Harvey F.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA.
[Lee, Hsiang-Ying; Lodish, Harvey F.] MIT, Dept Biol Engn, Cambridge, MA 02142 USA.
[Narla, Anupama; Ebert, Benjamin L.] Brigham & Womens Hosp, Boston, MA 02115 USA.
[Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
[Beggs, Alan H.; Gazda, Hanna T.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.
[Beggs, Alan H.; Agarwal, Suneet; Gazda, Hanna T.; Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA.
[Doulatov, Sergei] Univ Washington, Dept Med, Seattle, WA 98195 USA.
RP Zon, LI; Daley, GQ (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA.; Zon, LI; Daley, GQ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Zon, LI; Daley, GQ (reprint author), Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA.; Zon, LI; Daley, GQ (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Daley, GQ (reprint author), Manton Ctr Orphan Dis Res, Boston, MA 02115 USA.
EM zon@enders.tch.harvard.edu; george.daley@childrens.harvard.edu
FU NIH National Institute of Diabetes and Digestive and Kidney Diseases
[R24-DK092760, R24-DK49216, U54DK110805]; National Heart, Lung, and
Blood Institute (NHLBI) Progenitor Cell Biology Consortium
[UO1-HL100001, U01HL134812]; NHLBI [R01HL04880, 1K99HL123484,
R00HL123484-03, R01HL107558]; NIH [R24OD017870-01, K02HL111156]; Alex's
Lemonade Stand Foundation; Taub Foundation Grants Program for MDS
Research; Doris Duke Medical Foundation; Division of Cancer Epidemiology
and Genetics, NCI, NIH; Helen Hay Whitney Foundation; NSF Graduate
Research Fellowship; NIH NHLBI [1F32HL124948-01]; University of
Heidelberg Medical School; Brigham and Women's Hospital; Charles H. Hood
Foundation
FX This work was supported by grants from the NIH National Institute of
Diabetes and Digestive and Kidney Diseases (R24-DK092760, R24-DK49216,
and U54DK110805) and National Heart, Lung, and Blood Institute (NHLBI)
Progenitor Cell Biology Consortium (UO1-HL100001 and U01HL134812) (NHLBI
R01HL04880 and NIH R24OD017870-01); Alex's Lemonade Stand Foundation;
The Taub Foundation Grants Program for MDS Research; and the Doris Duke
Medical Foundation. This study was funded in part by the intramural
research program of the Division of Cancer Epidemiology and Genetics,
NCI, NIH (B.P.A.). G.Q.D. is an associate member of the Broad Institute
and an investigator of the Howard Hughes Medical Institute and the
Manton Center for Orphan Disease Research. S.D. was supported by NHLBI
1K99HL123484, R00HL123484-03, and the Helen Hay Whitney Foundation.
H.T.G. was supported by NIH K02HL111156 and NHLBI R01HL107558. L.T.V.
was supported by an NSF Graduate Research Fellowship. E.R.M. was
supported by NIH NHLBI 1F32HL124948-01. L.W. was supported by a Career
Development Award from the University of Heidelberg Medical School.
M.A.K. was supported by a T32 hematology training grant from Brigham and
Women's Hospital. H.-Y.L. was supported by a postdoctoral fellowship
from the Charles H. Hood Foundation.
NR 44
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 FEB 8
PY 2017
VL 9
IS 376
AR eaah5645
DI 10.1126/scitranslmed.aah5645
PG 11
WC Cell Biology; Medicine, Research & Experimental
SC Cell Biology; Research & Experimental Medicine
GA EL2LE
UT WOS:000394450400002
ER
PT J
AU Rainwater-Lovett, K
Ziemniak, C
Watson, D
Luzuriaga, K
Siberry, G
Petru, A
Chen, YH
Uprety, P
McManus, M
Ho, YC
Lamers, SL
Persaud, D
AF Rainwater-Lovett, Kaitlin
Ziemniak, Carrie
Watson, Douglas
Luzuriaga, Katherine
Siberry, George
Petru, Ann
Chen, YaHui
Uprety, Priyanka
McManus, Margaret
Ho, Ya-Chi
Lamers, Susanna L.
Persaud, Deborah
TI Paucity of Intact Non-Induced Provirus with Early, Long-Term
Antiretroviral Therapy of Perinatal HIV Infection
SO PLOS ONE
LA English
DT Article
ID VIRUS TYPE-1 RECOMBINATION; CD4(+) T-CELLS; LATENT RESERVOIR;
HIV-1-INFECTED CHILDREN; VIROLOGICAL CONTROL; PERIPHERAL-BLOOD;
IMMUNE-RESPONSES; REPLICATION; SUPPRESSION; CURE
AB The latent reservoir is a major barrier to HIV eradication. Reservoir size is emerging as an important biomarker to assess the likelihood of HIV remission in the absence of antiretroviral therapy (ART) and may be reduced by earlier initiation of ART that restricts HIV spread into CD4+ T cells. Reservoir size is traditionally measured with a quantitative viral outgrowth assay (QVOA) that induces replication-competent HIV production through in vitro stimulation of resting CD4+ T cells. However, the recent identification of replication-intact, non-induced proviral genomes (NIPG) suggests the QVOA significantly underestimates (by 62-fold) latent reservoir size in chronically-infected adults. Whether formation and persistence of Intact, NIPG is thwarted by early ART initiation and long-term virologic suppression in perinatal infection is unclear. Here, we show that the latent reservoir in 11 early treated, long-term suppressed perinatally infected children and adolescents was not inducible by QVOA and dominated by defective, NIPG. Single genome analysis of 164 NIPG from 232 million cultured resting CD4+ T cells revealed no replication-intact, near-full length sequences. Forty-three (26%) NIPG contained APOBEC3G-mediated hypermutation, 115 (70%) NIPG contained large internal deletions, one NIPG contained nonsense mutations and indels, and 5 (3%) NIPG were assigned as "Not Evaluable" due to multiple failed sequencing attempts that precluded further classification. The lack of replication competent inducible provirus and intact NIPG in this cohort indicate early, long-term ART of perinatal infection leads to marked diminution of replication-competent HIV-1 reservoirs, creating a favorable state towards interventions aimed at virologic remission.
C1 [Rainwater-Lovett, Kaitlin; Ziemniak, Carrie; Chen, YaHui; Uprety, Priyanka; Persaud, Deborah] Johns Hopkins Univ, Sch Med, Dept Pediat Infect Dis, Baltimore, MD 21218 USA.
[Watson, Douglas] Univ Maryland, Dept Pediat, Baltimore, MD 21201 USA.
[Luzuriaga, Katherine; McManus, Margaret] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA.
[Siberry, George] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Rockville, MD USA.
[Petru, Ann] Childrens Hosp & Res Ctr Oakland, Dept Pediat Infect Dis, Oakland, CA USA.
[Ho, Ya-Chi] Johns Hopkins Univ, Sch Med, Dept Med Infect Dis, Baltimore, MD USA.
[Lamers, Susanna L.] Bioinfoexperts LLC, Thibodaux, LA USA.
RP Persaud, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat Infect Dis, Baltimore, MD 21218 USA.
EM dpers@jhmi.edu
FU NIAID; NICHD [R01 HD080474]; Johns Hopkins Center for AIDS Research [P30
A1094189]; International Maternal Pediatric Adolescent AIDS Clinical
Trials (IMPAACT) Network; NIAID [UM1 Al068632, UM1 Al068616, UM1
Al106716]; NICHD; NIMH
FX This study was supported by the NIAID and NICHD (R01 HD080474 to DP),
the Johns Hopkins Center for AIDS Research (P30 A1094189), and
subspecialty laboratory funding to DP from the International Maternal
Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network. Overall
support for IMPAACT was provided by NIAID (UM1 Al068632, UM1 Al068616,
and UM1 Al106716) with co-funding from NICHD and NIMH. The content is
solely the responsibility of the authors and does not necessarily
represent the official views of the NIH. The funder provided support in
the form of salaries for authors [SL], 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 45
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U1 0
U2 0
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 FEB 8
PY 2017
VL 12
IS 2
AR e0170548
DI 10.1371/journal.pone.0170548
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK1UY
UT WOS:000393712500008
PM 28178277
ER
PT J
AU Damiano, DL
Stanley, CJ
Bulea, TC
Park, HS
AF Damiano, Diane L.
Stanley, Christopher J.
Bulea, Thomas C.
Park, Hyung Soon
TI Motor Learning Abilities Are Similar in Hemiplegic Cerebral Palsy
Compared to Controls as Assessed by Adaptation to Unilateral
Leg-Weighting during Gait: Part I
SO FRONTIERS IN HUMAN NEUROSCIENCE
LA English
DT Article
DE asymmetry; aftereffects; cerebellar deficits; brain injury; children
ID SPLIT-BELT TREADMILL; LOCOMOTOR ADAPTATION; HUMAN WALKING;
REHABILITATION; STROKE; POSTSTROKE; CHILDREN; LIMB
AB Introduction: Individuals with cerebral palsy (CP) demonstrate high response variability to motor training insufficiently accounted for by age or severity. We propose here that differences in the inherent ability to learn new motor tasks may explain some of this variability. Damage to motor pathways involving the cerebellum, which may be a direct or indirect effect of the brain injury for many with CP, has been shown to adversely affect the ability to learn new motor tasks and may be a potential explanation. Classic adaptation paradigms that evaluate cerebellar integrity have been utilized to assess adaptation to gait perturbations in adults with stroke, traumatic brain injury and other neurological injuries but not in children with CP.
Materials and Methods: A case-control study of 10 participants with and 10 without hemiplegic CP within the age range of 5-20 years was conducted. Mean age of participants in the CP group was slightly but not significantly higher than controls. Step length and swing time adaptation, defined as gradual accommodation to a perturbation, and aftereffects, or maintenance of the accommodation upon removal of the perturbation, to unilateral leg weighing during treadmill gait were quantified to assess group differences in learning.
Results: Adaptation and aftereffects were demonstrated in step length across groups with no main effect for group. In CP, the dominant leg had a greater response when either leg was weighted. Swing time accommodated immediately (no adaptation) in the weighted leg only, with the non-dominant leg instead showing a more pronounced response in CP.
Discussion: This group of participants with unilateral CP did not demonstrate poorer learning or retention similar to reported results in adult stroke. Deficits, while not found here, may become evident in those with other etiologies or greater severity of CP. Our data further corroborate an observation from the stroke literature that repeated practice of exaggerating the asymmetry (error augmentation), in this case by weighting the more involved or shorter step leg, vs. minimizing it by weighting the less involved or longer step leg (error reduction) may be a useful training strategy to improve step symmetry in unilateral CP.
C1 [Damiano, Diane L.; Stanley, Christopher J.; Bulea, Thomas C.] NIH, Funct & Appl Biomech Sect, Bldg 10, Bethesda, MD 20892 USA.
[Park, Hyung Soon] Korea Adv Inst Sci & Technol, Dept Mech Engn, Daejeon, South Korea.
RP Damiano, DL (reprint author), NIH, Funct & Appl Biomech Sect, Bldg 10, Bethesda, MD 20892 USA.
EM damianod@cc.nih.gov
FU Intramural Research Program of the NIH Clinical Center
FX This work was funded by the Intramural Research Program of the NIH
Clinical Center.
NR 22
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U1 6
U2 6
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 1662-5161
J9 FRONT HUM NEUROSCI
JI Front. Hum. Neurosci.
PD FEB 8
PY 2017
VL 11
AR 49
DI 10.3389/fnhum.2017.00049
PG 9
WC Neurosciences; Psychology
SC Neurosciences & Neurology; Psychology
GA EJ9LF
UT WOS:000393546900001
PM 28228720
ER
PT J
AU Nguyen, TA
Cisse, OH
Wong, JY
Zheng, P
Hewitt, D
Nowrousian, M
Stajich, JE
Jedd, G
AF Tu Anh Nguyen
Cisse, Ousmane H.
Wong, Jie Yun
Zheng, Peng
Hewitt, David
Nowrousian, Minou
Stajich, Jason E.
Jedd, Gregory
TI Innovation and constraint leading to complex multicellularity in the
Ascomycota
SO NATURE COMMUNICATIONS
LA English
DT Article
ID GENOME REVEALS; ANIMAL DEVELOPMENT; SEXUAL DEVELOPMENT; HIGH-THROUGHPUT;
EVOLUTION; PROTEIN; PEROXISOMES; DYNEIN; DYNACTIN; DOMAIN
AB The advent of complex multicellularity (CM) was a pivotal event in the evolution of animals, plants and fungi. In the fungal Ascomycota, CM is based on hyphal filaments and arose in the Pezizomycotina. The genus Neolecta defines an enigma: phylogenetically placed in a related group containing mostly yeasts, Neolecta nevertheless possesses Pezizomycotina-like CM. Here we sequence the Neolecta irregularis genome and identify CM-associated functions by searching for genes conserved in Neolecta and the Pezizomycotina, which are absent or divergent in budding or fission yeasts. This group of 1,050 genes is enriched for functions related to diverse endomembrane systems and their organization. Remarkably, most show evidence for divergence in both yeasts. Using functional genomics, we identify new genes involved in fungal complexification. Together, these data show that rudimentary multicellularity is deeply rooted in the Ascomycota. Extensive parallel gene divergence during simplification and constraint leading to CM suggest a deterministic process where shared modes of cellular organization select for similarly configured organelle- and transport-related machineries.
C1 [Tu Anh Nguyen; Wong, Jie Yun; Zheng, Peng; Jedd, Gregory] Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore.
[Tu Anh Nguyen; Wong, Jie Yun; Zheng, Peng; Jedd, Gregory] Natl Univ Singapore, Dept Biol Sci, Singapore 117604, Singapore.
[Cisse, Ousmane H.; Stajich, Jason E.] Univ Calif Riverside, Inst Integrat Genome Biol, Dept Plant Pathol & Microbiol, Riverside, CA 92521 USA.
[Hewitt, David] Acad Nat Sci Philadelphia, Dept Bot, Philadelphia, PA 19103 USA.
[Nowrousian, Minou] Ruhr Univ Bochum, Lehrstuhl Allgemeine & Mol Bot, D-44780 Bochum, Germany.
[Cisse, Ousmane H.] Natl Inst Hlth, Dept Crit Care Med, Bethesda, MD 20814 USA.
RP Jedd, G (reprint author), Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore.; Jedd, G (reprint author), Natl Univ Singapore, Dept Biol Sci, Singapore 117604, Singapore.; Stajich, JE (reprint author), Univ Calif Riverside, Inst Integrat Genome Biol, Dept Plant Pathol & Microbiol, Riverside, CA 92521 USA.
EM jason.stajich@ucr.edu; gregory@tll.org.sg
OI Cisse, Ousmane/0000-0002-2990-2185; Stajich, Jason/0000-0002-7591-0020
FU Temasek Life Sciences Laboratory; Singapore Millennium Foundation; A.P.
Sloan Foundation; USDA Agriculture Experimental Station at the
University of California-Riverside; NIFA Hatch project
[CA-R-PPA-5062-H]; German Research Foundation [DFG NO407/5-1];
Department of General and Molecular Botany; Swiss National Science
Foundation [151780]; National Institutes of Health [P01 GM068087]
FX Research in the Jedd group is funded by the Temasek Life Sciences
Laboratory and Singapore Millennium Foundation. J.E.S. was supported by
the A.P. Sloan Foundation, USDA Agriculture Experimental Station at the
University of California-Riverside and NIFA Hatch project
CA-R-PPA-5062-H. M.N. was supported by the German Research Foundation
(DFG NO407/5-1) and thanks Ulrich Kuck for his support at the Department
of General and Molecular Botany. O.H.C was supported by the Swiss
National Science Foundation fellowship grant no. 151780. We thank Zhang
Louxin for insightful discussion, Dillon McDonald and Katherine
Borkovich for help with Saitoella experiments, Don Pfister, Pete and
Kitty Griffith for help with Neolecta fruiting bodies collection, and
gratefully acknowledge use of deletion mutants generated by National
Institutes of Health Grant P01 GM068087 'Functional Analysis of a Model
Filamentous Fungus'.
NR 88
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U1 11
U2 11
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD FEB 8
PY 2017
VL 8
AR 14444
DI 10.1038/ncomms14444
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EJ8EU
UT WOS:000393458800001
PM 28176784
ER
PT J
AU Jin, LL
Liu, Y
Sun, FY
Collins, MT
Blackwell, K
Woo, AS
Reichenberger, EJ
Hu, Y
AF Jin, Lingling
Liu, Yi
Sun, Fanyue
Collins, Michael T.
Blackwell, Keith
Woo, Albert S.
Reichenberger, Ernst J.
Hu, Ying
TI Three novel ANO5 missense mutations in Caucasian and Chinese families
and sporadic cases with gnathodiaphyseal dysplasia
SO SCIENTIFIC REPORTS
LA English
DT Article
ID FIBROOSSEOUS LESIONS; MUSCULAR-DYSTROPHY; BONE; GENE; PROTEIN;
DIFFERENTIATION; MINERALIZATION; EXPRESSION
AB Gnathodiaphyseal dysplasia (GDD; MIM#166260) is an autosomal dominant syndrome with characteristic cemento-osseous lesions of jawbones, bone fragility, and diaphyseal sclerosis of tubular bones. To date, only five mutations in the proposed calcium-activated chloride channel ANO5/TMEM16E gene have been identified. In this study, we describe two families and two singular patients with three new mutations. One Caucasian family with seven affected members exhibited frequent bone fractures and florid osseous dysplasia (p. Cys356Tyr), while one Chinese family with two affected members suffered from cementoma and purulent osteomyelitis (p. Cys360Tyr). In addition, two different novel mutations (p. Gly518Glu and p. Arg215Gly) were identified in sporadic patients without family history. In vitro studies overexpressing GDD mutations (p. Cys356Tyr and p. Cys360Tyr) showed significantly reduced ANO5 protein. It appears that all GDD mutations known so far locate in an extracellular domain following the first transmembrane domain or in the 4th putative transmembrane domain. Both wildtype and mutant ANO5 protein localize to the endoplasmic reticulum. After Ano5 gene knock-down with shRNA in MC3T3-E1 osteoblast precursors we saw elevated expression of osteoblast-related genes such as Col1a1, osteocalcin, osterix and Runx2 as well as increased mineral nodule formation in differentiating cells. Our data suggest that ANO5 plays a role in osteoblast differentiation.
C1 [Jin, Lingling; Hu, Ying] Capital Med Univ, Beijing Stomatol Hosp, Beijing Inst Dent Res, Beijing, Peoples R China.
[Liu, Yi] Capital Med Univ, Beijing Stomatol Hosp, Dept Maxillofacial Surg, Beijing, Peoples R China.
[Sun, Fanyue; Reichenberger, Ernst J.] Univ Connecticut Hlth, Ctr Regenerat Med & Skeletal Dev, Dept Reconstruct Sci, Farmington, CT 06030 USA.
[Collins, Michael T.] Natl Inst Dent & Craniofacial Res NIDCR, Bethesda, MD 20892 USA.
[Blackwell, Keith] Univ Calif Los Angeles, Dept Head & Neck Surg, Los Angeles, CA 90095 USA.
[Woo, Albert S.] Brown Univ, Warren Alpert Med Sch, Div Plast Craniofacial & Pediat Surg, Providence, RI 02903 USA.
RP Hu, Y (reprint author), Capital Med Univ, Beijing Stomatol Hosp, Beijing Inst Dent Res, Beijing, Peoples R China.; Reichenberger, EJ (reprint author), Univ Connecticut Hlth, Ctr Regenerat Med & Skeletal Dev, Dept Reconstruct Sci, Farmington, CT 06030 USA.
EM reichenberger@uchc.edu; hyshuai@ccmu.edu.cn
FU School of Stomatology, Capital Medical University; UCH; National Natural
Science Foundation of China [81570958]; High-level Talents of Beijing
Health System [2013-3-036]; Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry
[2015-1098]; DIR NIDCR; CRC (University of Connecticut Clinical Research
Center (NIH grant) [M01RR006192]
FX We thank all individuals for participating in this study and for
institutional support from the School of Stomatology, Capital Medical
University and UCH. We thank Drs P.G. Robey and S. Kuznetsov for
providing patient cells for genetic analysis. This work was supported by
the National Natural Science Foundation of China (Grant #81570958);
High-level Talents of Beijing Health System (grant # 2013-3-036);
Scientific Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry (grant # 2015-1098); the DIR NIDCR;
and the CRC (University of Connecticut Clinical Research Center, (NIH
grant # M01RR006192)).
NR 29
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U1 1
U2 1
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 8
PY 2017
VL 7
AR 40935
DI 10.1038/srep40935
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK0GE
UT WOS:000393604000001
PM 28176803
ER
PT J
AU Dai, JQ
Voloshin, O
Potapova, S
Camerini-Otero, RD
AF Dai, Jieqiong
Voloshin, Oleg
Potapova, Svetlana
Camerini-Otero, R. Daniel
TI Meiotic Knockdown and Complementation Reveals Essential Role of RAD51 in
Mouse Spermatogenesis
SO CELL REPORTS
LA English
DT Article
ID DOUBLE-STRAND BREAKS; RECA HOMOLOGS RAD51; CHROMOSOME SYNAPSIS;
SACCHAROMYCES-CEREVISIAE; PROPHASE ARREST; GENE-TRANSFER; IN-VIVO; DMC1;
RECOMBINATION; MEIOSIS
AB Meiotic homologous recombination (HR) is important for proper chromosomal segregation during gametogenesis and facilitates evolutionary adaptation via genomic reshuffling. In most eukaryotes, HR is mediated by two recombinases, the ubiquitous RAD51 and the meiosis- specific DMC1. The role of RAD51 in mammalian meiosis is unclear and study of its function is limited due to embryonic lethality of RAD51 knockouts. Here, we developed an in vivo meiotic knockdown and protein complementation system to study RAD51 during mouse spermatogenesis. We show that RAD51 is crucial during meiotic prophase and its loss leads to depletion of late prophase I spermatocytes through a p53- dependent apoptotic pathway. This phenotype is distinct from that observed in the DMC1 knockdown. Our meiotic knockdown and complementation system establishes an experimental platform for mechanistic studies of meiotic proteins with unknown functions or essential genes for which a testis- specific knockout is not possible.
C1 [Dai, Jieqiong; Voloshin, Oleg; Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA.
[Potapova, Svetlana] NIDDK, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA.
EM rdcamerini@mail.nih.gov
FU NIDDK Intramural Research Program
FX We are grateful to G. Petukhova (Uniformed Services University of Health
Sciences), P. Hsieh, F. Pratto, and K. Brick (National Institute of
Diabetes and Digestive and Kidney Diseases) for valuable comments and
discussion of the manuscript. We also thank M. A. Handel (The Jackson
Laboratory) for the H1t antibody. This work was supported by the NIDDK
Intramural Research Program (to R.D.C.-O.).
NR 45
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U2 0
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 FEB 7
PY 2017
VL 18
IS 6
BP 1383
EP 1394
DI 10.1016/j.celrep.2017.01.024
PG 12
WC Cell Biology
SC Cell Biology
GA EP4AR
UT WOS:000397323400005
PM 28178517
ER
PT J
AU Flici, H
Schnitzler, CE
Millane, RC
Govinden, G
Houlihan, A
Boomkamp, SD
Shen, SB
Baxevanis, AD
Frank, U
AF Flici, Hakima
Schnitzler, Christine E.
Millane, R. Cathriona
Govinden, Graham
Houlihan, Amy
Boomkamp, Stephanie D.
Shen, Sanbing
Baxevanis, Andreas D.
Frank, Uri
TI An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis
in a Cnidarian
SO CELL REPORTS
LA English
DT Article
ID CENTRAL-NERVOUS-SYSTEM; HISTONE DEACETYLASES 1; EMBRYONIC STEM-CELLS;
MULTIPLE SOX GENES; NEMATOSTELLA-VECTENSIS; TRANSCRIPTION FACTOR;
BRAIN-DEVELOPMENT; PROGENITOR CELLS; BETA-CATENIN; DIFFERENTIATION
AB SoxB transcription factors and histone deacetylases (HDACs) are each major players in the regulation of neurogenesis, but a functional link between them has not been previously demonstrated. Here, we show that SoxB2 and Hdac2 act together to regulate neurogenesis in the cnidarian Hydractinia echinata during tissue homeostasis and head regeneration. We find that misexpression of SoxB genes modifies the number of neural cells in all life stages and interferes with head regeneration. Hdac2 was coexpressed with SoxB2, and its downregulation phe-nocopied SoxB2 knockdown. We also show that SoxB2 and Hdac2 promote each other's transcript levels, but Hdac2 counteracts this amplification cycle by deacetylating and destabilizing SoxB2 protein. Finally, we present evidence for conservation of these interactions in human neural progenitors. We hypothesize that crosstalk between SoxB transcription factors and Hdac2 is an ancient feature of metazoan neurogenesis and functions to stabilize the correct levels of these multifunctional proteins.
C1 [Flici, Hakima; Millane, R. Cathriona; Govinden, Graham; Houlihan, Amy; Frank, Uri] Natl Univ Ireland, Sch Nat Sci, CCB, Galway H91 CF50, Ireland.
[Schnitzler, Christine E.] Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA.
[Schnitzler, Christine E.] Univ Florida, Dept Biol, Gainesville, FL 32611 USA.
[Schnitzler, Christine E.; Baxevanis, Andreas D.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA.
[Boomkamp, Stephanie D.; Shen, Sanbing] Natl Univ Ireland, Regenerat Med Inst REMEDI, Galway H91 CF50, Ireland.
RP Frank, U (reprint author), Natl Univ Ireland, Sch Nat Sci, CCB, Galway H91 CF50, Ireland.
EM uri.frank@nuigalway.ie
FU Science Foundation Ireland (SFI) [11/PI/1020]; Intramural Research
Program of the National Human Genome Research Institute,NIH
FX We thank members of the Frank lab for advice and assistance. HDAC2
inhibitors BRD4884 and BRD6688 were a kind gift from F.F. Wagner and
E.B. Holson, Broad Institute of Harvard and MIT. Class I Hdac inhibitor
RGFP966 was kindly provided by Bob Lahue, Centre for Chromosome Biology,
NUI Galway. Ncol3 antibody was a kind gift from SuatO " zbek, University
of Heidelberg.Katya McDonagh and Martin Madill, REMEDI, NUI Galway, are
kindly acknowledged for providing human neural progenitors. This work
was supported by Science Foundation Ireland (SFI) through grant number
11/PI/1020 to U.F. This work was also supported in part by the
Intramural Research Program of the National Human Genome Research
Institute,NIH
NR 56
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PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 2211-1247
J9 CELL REP
JI Cell Reports
PD FEB 7
PY 2017
VL 18
IS 6
BP 1395
EP 1409
DI 10.1016/j.celrep.2017.01.019
PG 15
WC Cell Biology
SC Cell Biology
GA EP4AR
UT WOS:000397323400006
PM 28178518
ER
PT J
AU Russell, RA
Chojnacki, J
Jones, DM
Johnson, E
Do, T
Eggeling, C
Padilla-Parra, S
Sattentau, QJ
AF Russell, Rebecca A.
Chojnacki, Jakub
Jones, Daniel M.
Johnson, Errin
Do, Thao
Eggeling, Christian
Padilla-Parra, Sergi
Sattentau, Quentin J.
TI Astrocytes Resist HIV-1 Fusion but Engulf Infected Macrophage Material
SO CELL REPORTS
LA English
DT Article
ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN FETAL ASTROCYTES;
CENTRAL-NERVOUS-SYSTEM; HUMAN GLIAL-CELLS; LASER CAPTURE
MICRODISSECTION; CHEMOKINE RECEPTORS; POTENTIAL ROLE; PRODUCTIVE
INFECTION; SITU HYBRIDIZATION; TYPE-1 INFECTION
AB HIV-1 disseminates to diverse tissues and establishes long-lived viral reservoirs. These reservoirs include the CNS, in which macrophage-lineage cells, and as suggested by many studies, astrocytes, may be infected. Here, we have investigated astrocyte infection by HIV-1. We confirm that astrocytes trap and internalize HIV-1 particles for subsequent release but find no evidence that these particles infect the cell. Astrocyte infection was not observed by cell-free or cell-to-cell routes using diverse approaches, including luciferase and GFP reporter viruses, fixed and live-cell fusion assays, multispectral flow cytometry, and super-resolution imaging. By contrast, we observed intimate interactions between HIV-1-infected macrophages and astrocytes leading to signals that might be mistaken for astrocyte infection using less stringent approaches. These results have implications for HIV-1 infection of the CNS, viral reservoir formation, and antiretroviral therapy.
C1 [Russell, Rebecca A.; Johnson, Errin; Sattentau, Quentin J.] Univ Oxford, Sir William Dunn Sch Pathol, South Parks Rd, Oxford OX1 3RE, England.
[Chojnacki, Jakub; Eggeling, Christian] Univ Oxford, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford OX3 9DS, England.
[Jones, Daniel M.; Padilla-Parra, Sergi] Univ Oxford, Henry Wellcome Bldg Genom Med, Div Struct Biol, Oxford OX3 7BN, England.
[Jones, Daniel M.; Padilla-Parra, Sergi] Univ Oxford, Wellcome Trust Ctr Human Genet, Cellular Imaging Core, Oxford OX3 7BN, England.
[Do, Thao] NIH, Natl Canc Inst, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA.
RP Sattentau, QJ (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, South Parks Rd, Oxford OX1 3RE, England.
EM quentin.sattentau@path.ox.ac.uk
FU Medical Research Council [MC_UU_12010, G0902418, MC_UU_12025]; Wolfson
Foundation [18272]; MRC/BBSRC/EPSRC [MR/K01577X/1]; Wellcome Trust
[104924/14/Z/14]; Deutsche Forschungsgemeinschaft [1905]; Nuffield
Department of Medicine Leadership Fellowship from Oxford University;
Wellcome Trust Centre for Human Genetics is supported by Wellcome Trust
[090532/Z/09/Z]; Cellular Imaging Core from the Wellcome Trust Centre
for Human Genetics; Wolfson Imaging Centre at the Weatherall Institute
of Molecular Medicine
FX J.C. and C.E. were supported by The Medical Research Council (grant
MC_UU_12010 and unit programs G0902418 and MC_UU_12025), the Wolfson
Foundation (grant 18272), MRC/BBSRC/EPSRC (grant MR/K01577X/1), Wellcome
Trust (grant 104924/14/Z/14), and the Deutsche Forschungsgemeinschaft
(grant 1905, Research unit 1905, "Structure and Function of the
Peroxisomal Translocon''). The S.P.-P. research group is funded by the
Nuffield Department of Medicine Leadership Fellowship from Oxford
University. The Wellcome Trust Centre for Human Genetics is supported by
Wellcome Trust (grant 090532/Z/09/Z). We thank the Cellular Imaging Core
from the Wellcome Trust Centre for Human Genetics and the Wolfson
Imaging Centre at the Weatherall Institute of Molecular Medicine for
their support and input. Q. J. S. is a Jenner investigator and a James
Martin senior fellow. Electron microscopy was performed at the Dunn
School EM Facility, and we are grateful to Anna Pielach for preparing
the EM samples.
NR 59
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PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 2211-1247
J9 CELL REP
JI Cell Reports
PD FEB 7
PY 2017
VL 18
IS 6
BP 1473
EP 1483
DI 10.1016/j.celrep.2017.01.027
PG 11
WC Cell Biology
SC Cell Biology
GA EP4AR
UT WOS:000397323400012
PM 28178524
ER
PT J
AU Gill, J
Merchant-Borna, K
Jeromin, A
Livingston, W
Bazarian, J
AF Gill, Jessica
Merchant-Borna, Kian
Jeromin, Andreas
Livingston, Whitney
Bazarian, Jeffrey
TI Acute plasma tau relates to prolonged return to play after concussion
SO NEUROLOGY
LA English
DT Article
ID TRAUMATIC BRAIN-INJURY; SPORTS-RELATED CONCUSSION; ICE HOCKEY PLAYERS;
CEREBROSPINAL-FLUID; NEUROTROPHIC FACTOR; EXERCISE; ENCEPHALOPATHY;
BIOMARKERS; MANAGEMENT; IMPACT
AB Objective: To determine whether tau changes after sport-related concussion (SRC) relate to return to play (RTP).
Methods: Collegiate athletes underwent preseason plasma sampling and cognitive testing and were followed. After a SRC (n = 46), athletes and controls (n 5 37) had sampling at 6 hours, and at 24 hours, 72 hours, and 7 days after SRC. A sample of 21 nonathlete controls were compared at baseline. SRC athletes were grouped by long (. 10 days, n = 23) and short (< 10 days, n = 18) RTP. Total tau was measured using an ultrasensitive immunoassay.
Results: Both SRC and athlete controls had significantly higher mean tau at baseline compared to nonathlete healthy controls (F-101,(3) = 19.644, p, < 0.01). Compared to SRC athletes with short RTP, those with long RTP had higher tau concentrations overall, after controlling for sex (F-39,1 = 3.59, p = 0.022), compared to long RTP athletes, at 6 (p, 0.01), 24 (p, 0.01), and 72 hours (p = 0.02). Receiver operator characteristic analyses showed that higher plasma tau 6 hours postSRC was a significant predictor of RTP.10 days (area under the curve 0.81; 95% confidence interval 0.62-0.97, p = 0.01).
Conclusions: Elevated plasma tau concentration within 6 hours following a SRC was related to having a prolonged RTP, suggesting that tau levels may help inform RTP.
C1 [Gill, Jessica; Livingston, Whitney] NINR, NIH, Bethesda, MD 20892 USA.
[Merchant-Borna, Kian; Bazarian, Jeffrey] Univ Rochester, Sch Med & Dent, Dept Emergency Med, Rochester, NY USA.
[Jeromin, Andreas] Quanterix Corp, Lexington, MA USA.
RP Gill, J (reprint author), NINR, NIH, Bethesda, MD 20892 USA.
EM gillj@mail.nih.gov
FU NIH/NICHD [K24HD064754]; NIH; National Institute of Nursing Research
Intramural Research Program
FX This work was supported by funds from the NIH/NICHD (award
no.K24HD064754) and the NIH, National Institute of Nursing Research
Intramural Research Program.
NR 35
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U2 0
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0028-3878
EI 1526-632X
J9 NEUROLOGY
JI Neurology
PD FEB 7
PY 2017
VL 88
IS 6
BP 595
EP 602
PG 8
WC Clinical Neurology
SC Neurosciences & Neurology
GA EP4HR
UT WOS:000397342100015
PM 28062722
ER
PT J
AU Thompson, PM
Ramachandran, S
Case, LB
Tolbert, CE
Tandon, A
Pershad, M
Dokholyan, NV
Waterman, CM
Campbell, SL
AF Thompson, Peter M.
Ramachandran, Srinivas
Case, Lindsay B.
Tolbert, Caitlin E.
Tandon, Arpit
Pershad, Mihir
Dokholyan, Nikolay V.
Waterman, Clare M.
Campbell, Sharon L.
TI A Structural Model for Vinculin Insertion into PIP2-Containing Membranes
and the Effect of Insertion on Vinculin Activation and Localization
SO STRUCTURE
LA English
DT Article
ID DISCRETE MOLECULAR-DYNAMICS; CELL MECHANICAL-PROPERTIES;
PROTEIN-KINASE-C; F-ACTIN-BINDING; FOCAL ADHESION; TAIL DOMAIN; I-GAMMA;
INTRAMOLECULAR ASSOCIATION; PTDINS(4,5)P-2 SYNTHESIS; NANOSCALE
ARCHITECTURE
AB Vinculin, a scaffolding protein that localizes to focal adhesions (FAs) and adherens junctions, links the actin cytoskeleton to the adhesive super-structure. While vinculin binds to a number of cytoskeletal proteins, it can also associate with phosphatidylinositol 4,5-bisphosphate (PIP2) to drive membrane association. To generate a structural model for PIP2-dependent interaction of vinculin with the lipid bilayer, we conducted lipid-association, nuclear magnetic resonance, and computational modeling experiments. We find that two basic patches on the vinculin tail drive membrane association: the basic collar specifically recognizes PIP2, while the basic ladder drives association with the lipid bilayer. Vinculin mutants with defects in PIP2-dependent liposome association were then expressed in vinculin knockout murine embryonic fibroblasts. Results from these analyses indicate that PIP2 binding is not required for localization of vinculin to FAs or FA strengthening, but is required for vinculin activation and turnover at FAs to promote its association with the force transduction FA nanodomain.
C1 [Thompson, Peter M.; Ramachandran, Srinivas; Tandon, Arpit; Dokholyan, Nikolay V.; Campbell, Sharon L.] Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA.
[Case, Lindsay B.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA.
[Tolbert, Caitlin E.] Univ North Carolina Chapel Hill, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA.
[Pershad, Mihir] Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC 27599 USA.
[Dokholyan, Nikolay V.; Campbell, Sharon L.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.
[Thompson, Peter M.] NIEHS, Lab Genome Integr & Struct Biol, POB 12233, Res Triangle Pk, NC 27709 USA.
[Ramachandran, Srinivas] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA.
[Case, Lindsay B.; Waterman, Clare M.] Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA.
[Tolbert, Caitlin E.] Francis Crick Inst, Cellular Signaling & Cytoskeletal Funct Lab, London NW1 1AT, England.
RP Campbell, SL (reprint author), Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA.; Campbell, SL (reprint author), Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.
EM campbesl@med.unc.edu
OI Ramachandran, Srinivas/0000-0003-2929-1377
FU American Heart Association [12PRE11820012]; NIH [1R01GM115597, GM029860]
FX P.M.T. was supported by the American Heart Association (12PRE11820012).
Funding to S.L.C. and N.V.D. was supported by the NIH (1R01GM115597).
Funding to C.E.T. was supported by the NIH (GM029860). The authors wish
to thank Evan Nelsen, Greg Young, and Paul Sapienza for their assistance
with methods as well as Keith Burridge for his feedback on the
manuscript.
NR 58
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U1 1
U2 1
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 0969-2126
EI 1878-4186
J9 STRUCTURE
JI Structure
PD FEB 7
PY 2017
VL 25
IS 2
BP 264
EP 275
DI 10.1016/j.str.2016.12.002
PG 12
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA EO4ZL
UT WOS:000396702700008
PM 28089450
ER
PT J
AU Markovic-Mueller, S
Stuttfeld, E
Asthana, M
Weinert, T
Bliven, S
Goldie, KN
Kisko, K
Capitani, G
Ballmer-Hofer, K
AF Markovic-Mueller, Sandra
Stuttfeld, Edward
Asthana, Mayanka
Weinert, Tobias
Bliven, Spencer
Goldie, Kenneth N.
Kisko, Kaisa
Capitani, Guido
Ballmer-Hofer, Kurt
TI Structure of the Full-length VEGFR-1 Extracellular Domain in Complex
with VEGF-A
SO STRUCTURE
LA English
DT Article
ID ENDOTHELIAL-GROWTH-FACTOR; RECEPTOR TYROSINE KINASE; STEM-CELL FACTOR;
LIGAND-BINDING; CRYSTAL-STRUCTURE; FLT-1 RECEPTOR; ACTIVATION;
ANGIOGENESIS; DIMERIZATION; CONTACTS
AB Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases: VEGFR-1, -2, and -3. Partial structures of VEGFR/VEGF complexes based on single-particle electron microscopy, small-angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and domain arrangement of individual receptor subdomains. Here, we describe the structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A at 4 angstrom resolution. We combined X-ray crystallography, single-particle electron microscopy, and molecular modeling for structure determination and validation. The structure reveals the molecular details of ligand-induced receptor dimerization, in particular of homotypic receptor interactions in immunoglobulin homology domains 4, 5, and 7. Functional analyses of ligand binding and receptor activation confirm the relevance of these homotypic contacts and identify them as potential therapeutic sites to allosterically inhibit VEGFR-1 activity.
C1 [Markovic-Mueller, Sandra; Asthana, Mayanka; Weinert, Tobias; Bliven, Spencer; Kisko, Kaisa; Capitani, Guido; Ballmer-Hofer, Kurt] Paul Scherrer Inst, Lab Biomol Res, CH-5232 Villigen, Switzerland.
[Stuttfeld, Edward] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland.
[Goldie, Kenneth N.] Univ Basel, Biozentrum, C CINA, CH-4056 Basel, Switzerland.
[Bliven, Spencer] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA.
[Markovic-Mueller, Sandra] LeadXpro AG, Pk Innovaare, CH-5234 Villigen, Switzerland.
RP Ballmer-Hofer, K (reprint author), Paul Scherrer Inst, Lab Biomol Res, CH-5232 Villigen, Switzerland.
EM kurt.ballmer-hofer@unibas.ch
FU Swiss National Science Foundation [31003A-130463]; Oncosuisse [OC2
01200-08-2007]; Intramural Research Program of the NCBI; National
Library of Medicine; NIH (United States)
FX K.B.-H. thanks the Swiss National Science Foundation (grant
31003A-130463) and Oncosuisse (grant OC2 01200-08-2007) for continuous
support of his research. S.B. was supported by the Intramural Research
Program of the NCBI, National Library of Medicine, and NIH (United
States). We are also grateful to Thomas Schleier, Kate Thieltges, and
Julia Kostin for technical assistance and the staff of the X06SA and
X06DA beamlines of the Swiss Light Source for their support during data
collection. We thank the Foldit players and Firas Khatib for modeling D1
and D6 (https://fold.it/portal/info/credits).
NR 58
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U1 2
U2 2
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 0969-2126
EI 1878-4186
J9 STRUCTURE
JI Structure
PD FEB 7
PY 2017
VL 25
IS 2
BP 341
EP 352
DI 10.1016/j.str.2016.12.012
PG 12
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA EO4ZL
UT WOS:000396702700015
PM 28111021
ER
PT J
AU Song, H
Fang, XY
Jin, L
Shaw, GX
Wang, YX
Ji, XH
AF Song, He
Fang, Xianyang
Jin, Lan
Shaw, Gary X.
Wang, Yun-Xing
Ji, Xinhua
TI The Functional Cycle of Rnt1p: Five Consecutive Steps of Double-Stranded
RNA Processing by a Eukaryotic RNase III
SO STRUCTURE
LA English
DT Article
ID SMALL-ANGLE SCATTERING; MOLECULAR-STRUCTURE DETERMINATION;
X-RAY-SCATTERING; RIBONUCLEASE-III; BIOLOGICAL MACROMOLECULES;
STRUCTURAL BASIS; XPLOR-NIH; MECHANISM; DICER; COMPLEX
AB Double-stranded RNA (dsRNA)-specific RNase III proteins are required for RNA maturation and gene regulation. The mechanism of prokaryotic RNase IIIs has been well characterized, but how eukaryotic RNase IIIs (exemplified by Rnt1p, Drosha, and Dicer) work is less clear. Recently, we reported the crystal structure of Rnt1p in complex with RNA, revealing a double-ruler mechanism for substrate selection. Here, we present more structures of Rnt1p, either RNA free or RNA bound, featuring two major conformations of the enzyme. Using these structures with existing data, we describe the functional cycle of Rnt1p in five steps, selecting, loading, locking, cleavage, and releasing. We also describe atomic details of the two-Mg2+-ion catalytic mechanism that is applicable to all eukaryotic RNase III enzymes. Overall, our results indicate that substrate selection is achieved independent of cleavage, allowing the recognition of substrates with different structures while preserving the basic mechanism of cleavage.
C1 [Song, He; Jin, Lan; Shaw, Gary X.; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA.
[Fang, Xianyang; Wang, Yun-Xing] NCI, Struct Biophys Lab, Frederick, MD 21702 USA.
[Fang, Xianyang] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China.
RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA.
EM jix@mail.nih.gov
FU Department of Energy, Office of Science, Office of Basic Energy Sciences
[DE-AC02-06CH11357, 22978]; Intramural Research Program of the NIH,
National Cancer Institute, Center for Cancer Research
FX We thank Dr. Xiaobing Zuo for assistance with the SAXS experiments and
Drs. Sherif Abou Elela, Donald Court, and Alexander Wlodawer for
critical reading of the manuscript and insightful discussions. X-ray
diffraction data were collected at the SER-CAT beamlines of the Advanced
Photon Source (APS), Argonne National Laboratory (ANL). SAXS data were
collected at the APS beamline 12-ID-B, ANL. Use of the APS was supported
by the U.S. Department of Energy, Office of Science, Office of Basic
Energy Sciences, under contract no. DE-AC02-06CH11357 and under the
Partner User Proposal PUP no. 22978. This research was supported by the
Intramural Research Program of the NIH, National Cancer Institute,
Center for Cancer Research.
NR 48
TC 0
Z9 0
U1 2
U2 2
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 0969-2126
EI 1878-4186
J9 STRUCTURE
JI Structure
PD FEB 7
PY 2017
VL 25
IS 2
BP 353
EP 363
DI 10.1016/j.str.2016.12.013
PG 11
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA EO4ZL
UT WOS:000396702700016
PM 28111020
ER
PT J
AU Dalgard, C
Eidelman, O
Jozwik, C
Olsen, CH
Srivastava, M
Biswas, R
Eudy, Y
Rothwell, SW
Mueller, GP
Yuan, P
Drevets, WC
Manji, HK
Vythlingam, M
Charney, DS
Neumeister, A
Ursano, RJ
Jacobowitz, DM
Pollard, HB
Bonne, O
AF Dalgard, C.
Eidelman, O.
Jozwik, C.
Olsen, C. H.
Srivastava, M.
Biswas, R.
Eudy, Y.
Rothwell, S. W.
Mueller, G. P.
Yuan, P.
Drevets, W. C.
Manji, H. K.
Vythlingam, M.
Charney, D. S.
Neumeister, A.
Ursano, R. J.
Jacobowitz, D. M.
Pollard, H. B.
Bonne, O.
TI The MCP-4/MCP-1 ratio in plasma is a candidate circadian biomarker for
chronic post-traumatic stress disorder
SO TRANSLATIONAL PSYCHIATRY
LA English
DT Article
ID CEREBROSPINAL-FLUID; MONOCYTES; SLEEP; INFLAMMATION; DEPRESSION;
CHEMOKINE; TRAUMA; RHYTHM; CLOCK
AB Post-traumatic stress disorder (PTSD) is psychiatric disease, which can occur following exposure to traumatic events. PTSD may be acute or chronic, and can have a waxing and waning course of symptoms. It has been hypothesized that proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) or plasma might be mediators of the psychophysiological mechanisms relating a history of trauma exposure to changes in behavior and mental health disorders, and medical morbidity. Here we test the cytokine/ chemokine hypothesis for PTSD by examining levels of 17 classical cytokines and chemokines in CSF, sampled at 0900 hours, and in plasma sampled hourly for 24 h. The PTSD and healthy control patients are from the NIMH Chronic PTSD and healthy control cohort, initially described by Bonne et al. (2011), in which the PTSD patients have relatively low comorbidity for major depressive disorder (MDD), drug or alcohol use. We find that in plasma, but not CSF, the bivariate MCP4 (CCL13)/MCP1(CCL2) ratio is ca. twofold elevated in PTSD patients compared with healthy controls. The MCP-4/MCP-1 ratio is invariant over circadian time, and is independent of gender, body mass index or the age at which the trauma was suffered. By contrast, MIP-1 alpha is a candidate biomarker for PTSD only in females, whereas TARC is a candidate biomarker for PTSD only in males. It remains to be discovered whether these disease-specific differences in circadian expression for these specific immune signaling molecules are biomarkers, surrogates, or drivers for PTSD, or whether any of these analytes could contribute to therapy.
C1 [Dalgard, C.; Eidelman, O.; Srivastava, M.; Biswas, R.; Eudy, Y.; Rothwell, S. W.; Mueller, G. P.; Jacobowitz, D. M.; Pollard, H. B.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA.
[Dalgard, C.; Jozwik, C.; Srivastava, M.; Biswas, R.; Mueller, G. P.; Jacobowitz, D. M.; Pollard, H. B.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, CHIRP, Bethesda, MD 20814 USA.
[Jozwik, C.] Henry M Jackson Fdn Mil Med, Bethesda, MD USA.
[Olsen, C. H.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA.
[Yuan, P.] NIMH, Mood & Anxiety Disorders Branch, Bethesda, MD 20892 USA.
[Rothwell, S. W.; Mueller, G. P.] LLC, Janssen Res & Dev, Johnson & Johnson, Titusville, NJ USA.
[Vythlingam, M.] United States Dept Def, Washington, DC USA.
[Vythlingam, M.; Charney, D. S.] Mt Sinai Sch Med, Office Dean, New York, NY USA.
[Neumeister, A.] Mitsubishi Tanabe Pharma Dev Amer, Jersey City, NJ USA.
[Ursano, R. J.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Psychiat, Bethesda, MD 20814 USA.
[Ursano, R. J.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Ctr Study Traumat Stress, Bethesda, MD 20814 USA.
[Bonne, O.] Hadassah Med Ctr, Dept Psychiat, Jerusalem, Israel.
RP Pollard, HB (reprint author), Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA.
EM Harvey.pollard@usuhs.edu; bonne@hadassah.org.il
FU CDMRP [W81WH-08-2-0201]; Center for Neurology and Regenerative Medicine
(CNRM); Center for Studies on Traumatic Stress (CSTS); Collaborative
Health Initiative Research Program (CHIRP)
FX We acknowledge support from CDMRP No. W81WH-08-2-0201, PI: HBP); the
Center for Neurology and Regenerative Medicine (CNRM; PI: HBP); and
Center for Studies on Traumatic Stress (CSTS, PI: RJU); and
Collaborative Health Initiative Research Program (CHIRP, PI: HBP). We
also acknowledge the National Institute of Mental Health (NIMH, NIH)
clinical study for which both NIH and USUHS Institutional
Investigational Review Board (IRB) approvals made samples of CSF and
plasma available for this study (Protocol 02-M-0317; PI: OB).
NR 32
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U1 0
U2 0
PU NATURE PUBLISHING GROUP
PI NEW YORK
PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA
SN 2158-3188
J9 TRANSL PSYCHIAT
JI Transl. Psychiatr.
PD FEB 7
PY 2017
VL 7
AR e1025
DI 10.1038/tp.2016.285
PG 11
WC Psychiatry
SC Psychiatry
GA EP2KY
UT WOS:000397213200003
PM 28170001
ER
PT J
AU Crowley, MJ
Diamantidis, CJ
McDuffie, JR
Cameron, CB
Stanifer, JW
Mock, CK
Wang, XW
Tang, S
Nagi, A
Kosinski, AS
Williams, JW
AF Crowley, Matthew J.
Diamantidis, Clarissa J.
McDuffie, Jennifer R.
Cameron, C. Blake
Stanifer, John W.
Mock, Clare K.
Wang, Xianwei
Tang, Shuang
Nagi, Avishek
Kosinski, Andrzej S.
Williams, John W., Jr.
TI Clinical Outcomes of Metformin Use in Populations With Chronic Kidney
Disease, Congestive Heart Failure, or Chronic Liver Disease A Systematic
Review
SO ANNALS OF INTERNAL MEDICINE
LA English
DT Review
ID CARDIOVASCULAR EVENTS; DIABETES-MELLITUS; SERUM CREATININE;
OLDER-ADULTS; MORTALITY; METAANALYSIS; TRIALS; COHORT; RISK; ASSOCIATION
AB Background: Recent changes to the U.S. Food and Drug Administration boxed warning for metformin will increase its use in persons with historical contraindications or precautions. Prescribers must understand the clinical outcomes of metformin use in these populations.
Purpose: To synthesize data addressing outcomes of metformin use in populations with type 2 diabetes and moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment.
Data Sources: MEDLINE (via PubMed) from January 1994 to September 2016, and Cochrane Library, EMBASE, and International Pharmaceutical Abstracts from January 1994 to November 2015.
Study Selection: English-language studies that: 1) examined adults with type 2 diabetes and CKD (with estimated glomerular filtration rate less than 60 mL/min/1.73 m(2)), CHF, or CLD with hepatic impairment; 2) compared diabetes regimens that included metformin with those that did not; and 3) reported all-cause mortality, major adverse cardiovascular events, and other outcomes of interest.
Data Extraction: 2 reviewers abstracted data and independently rated study quality and strength of evidence.
Data Synthesis: On the basis of quantitative and qualitative syntheses involving 17 observational studies, metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF.
Limitations: Strength of evidence was low, and data on multiple outcomes of interest were sparse. Available studies were observational and varied in follow-up duration.
Conclusion: Metformin use in patients with moderate CKD, CHF, or CLD with hepatic impairment is associated with improvements in key clinical outcomes. Our findings support the recent changes in metformin labeling.
C1 [Nagi, Avishek] Durham Vet Affairs Med Ctr, 508 Fulton St, Durham, NC 27705 USA.
Duke Univ, Sch Med, Durham, NC USA.
[Crowley, Matthew J.] Durham Vet Affairs Med Ctr, Hlth Serv Res & Dev 152, 508 Fulton St, Durham, NC 27705 USA.
[Diamantidis, Clarissa J.; Williams, John W., Jr.] 411 West Chapel Hill St,Suite 500, Durham, NC 27701 USA.
[McDuffie, Jennifer R.] 411 West Chapel Hill St,Suite 6, Durham, NC 27701 USA.
[Cameron, C. Blake] 2424 Erwin Rd,Suite 605, Durham, NC 27705 USA.
[Stanifer, John W.] Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA.
[Mock, Clare K.] Univ N Carolina, Hillsborough Hosp, 430 Waterstone Dr, Hillsborough, NC 27278 USA.
[Wang, Xianwei] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurol, 6 Tiantan Xili, Beijing 100050, Peoples R China.
[Tang, Shuang] NIEHS, Signal Transduct Lab, Res Triangle Pk, NC 27709 USA.
[Kosinski, Andrzej S.] Duke Clin Res Inst, Room 7058,POB 17969, Durham, NC 27715 USA.
RP Crowley, MJ (reprint author), Durham Vet Affairs Med Ctr, Hlth Serv Res & Dev 152, 508 Fulton St, Durham, NC 27705 USA.
EM matthew.crowley@dm.duke.edu
FU VHA Evidence-based Synthesis Program [09-009]; Career Development Award
from VHA Health Services Research and Development [CDA 13-261]; Mentored
Patient-Oriented Research Career Development Award from the National
Institute of Diabetes and Digestive and Kidney Diseases [K23-DK099385]
FX This project was supported by the VHA Evidence-based Synthesis Program
(project 09-009). Dr. Crowley is supported by a Career Development Award
from VHA Health Services Research and Development (CDA 13-261). Dr.
Diamantidis is supported by a Mentored Patient-Oriented Research Career
Development Award from the National Institute of Diabetes and Digestive
and Kidney Diseases (K23-DK099385).
NR 52
TC 1
Z9 1
U1 0
U2 0
PU AMER COLL PHYSICIANS
PI PHILADELPHIA
PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA
SN 0003-4819
EI 1539-3704
J9 ANN INTERN MED
JI Ann. Intern. Med.
PD FEB 7
PY 2017
VL 166
IS 3
BP 191
EP +
DI 10.7326/M16-1901
PG 21
WC Medicine, General & Internal
SC General & Internal Medicine
GA EL7DL
UT WOS:000394781200008
PM 28055049
ER
PT J
AU Friend, DM
Devarakonda, K
O'Neal, TJ
Skirzewski, M
Papazoglou, I
Kaplan, AR
Liow, JS
Guo, J
Rane, SG
Rubinstein, M
Alvarez, VA
Hall, KD
Kravitz, AV
AF Friend, Danielle M.
Devarakonda, Kavya
O'Neal, Timothy J.
Skirzewski, Miguel
Papazoglou, Ioannis
Kaplan, Alanna R.
Liow, Jeih-San
Guo, Juen
Rane, Sushil G.
Rubinstein, Marcelo
Alvarez, Veronica A.
Hall, Kevin D.
Kravitz, Alexxai V.
TI Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity
SO CELL METABOLISM
LA English
DT Article
ID DIET-INDUCED OBESITY; DOPAMINE-RECEPTOR GENE; HIGH-FAT DIET; LOW-ENERGY
INTAKE; Y GASTRIC BYPASS; SEDENTARY BEHAVIOR; OVERWEIGHT WOMEN; EATING
BEHAVIOR; D2 RECEPTORS; WEIGHT-LOSS
AB Obesity is associated with physical inactivity, which exacerbates the health consequences of weight gain. However, the mechanisms that mediate this association are unknown. We hypothesized that deficits in dopamine signaling contribute to physical inactivity in obesity. To investigate this, we quantified multiple aspects of dopamine signaling in lean and obese mice. We found that D2-type receptor (D2R) binding in the striatum, but not D1-type receptor binding or dopamine levels, was reduced in obese mice. Genetically removing D2Rs from striatal medium spiny neurons was sufficient to reduce motor activity in lean mice, whereas restoring G(i) signaling in these neurons increased activity in obese mice. Surprisingly, although mice with low D2Rs were less active, they were not more vulnerable to diet-induced weight gain than control mice. We conclude that deficits in striatal D2R signaling contribute to physical inactivity in obesity, but inactivity is more a consequence than a cause of obesity.
C1 [Friend, Danielle M.; Devarakonda, Kavya; O'Neal, Timothy J.; Papazoglou, Ioannis; Guo, Juen; Rane, Sushil G.; Hall, Kevin D.; Kravitz, Alexxai V.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA.
[Kaplan, Alanna R.; Alvarez, Veronica A.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIAID, NIH, Bethesda, MD 20892 USA.
[Kravitz, Alexxai V.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIDA, NIH, Bethesda, MD 20892 USA.
[Liow, Jeih-San] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIMH, NIH, Bethesda, MD 20892 USA.
[Skirzewski, Miguel] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Sect Mol Neurobiol, NIH, Bethesda, MD 20892 USA.
[Rubinstein, Marcelo] Consejo Nacl Invest Cient & Tecn, Inst Invest Ingn Genet & Biol Mol, C1428ADN, Buenos Aires, DF, Argentina.
[Rubinstein, Marcelo] Univ Buenos Aires, FCEN, Dept Physiol Mol & Cellular Biol, C1428EGA, Buenos Aires, DF, Argentina.
[Rubinstein, Marcelo] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA.
RP Kravitz, AV (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA.; Kravitz, AV (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIDA, NIH, Bethesda, MD 20892 USA.
EM lex.kravitz@nih.gov
FU Intramural Research Program of the 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). We would like to thank the Mouse Metabolism Core at the NIDDK
for assessing serum metabolites and hormones, Andres Buonanno with his
assistance in designing dopamine microdialysis experiments, and Dr.
Judith Walters, Dr. Kristin Dupre, and Dr. Claire Delaville for
assistance with HPLC dopamine tissue content analysis. We would also
like to thank Dr. Scott Young for the use of his laboratory equipment
and assistance with binding studies. Thanks also to the members of the
A.V.K. laboratory, Marc Reitman, and Nick Ryba for input on experimental
design and careful reading of the manuscript.
NR 71
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U2 0
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 1550-4131
EI 1932-7420
J9 CELL METAB
JI Cell Metab.
PD FEB 7
PY 2017
VL 25
IS 2
BP 312
EP 321
DI 10.1016/j.cmet.2016.12.001
PG 10
WC Cell Biology; Endocrinology & Metabolism
SC Cell Biology; Endocrinology & Metabolism
GA EN9YB
UT WOS:000396354400013
PM 28041956
ER
PT J
AU Visweswaraiah, J
Hinnebusch, AG
AF Visweswaraiah, Jyothsna
Hinnebusch, Alan G.
TI Interface between 40S exit channel protein uS7/Rps5 and eIF2 alpha
modulates start codon recognition in vivo
SO ELIFE
LA English
DT Article
ID EUKARYOTIC TRANSLATION INITIATION; FACTOR 1 EIF1;
SACCHAROMYCES-CEREVISIAE; PREINITIATION COMPLEX; SCANNING MECHANISM;
RIBOSOMAL-SUBUNIT; SELECTION; ELEMENTS; BINDING; ACCURACY
AB The eukaryotic pre-initiation complex (PIC) bearing the eIF2.GTP.Met-tRNA(i)(Met) ternary complex (TC) scans the mRNA for an AUG codon in favorable context. AUG recognition evokes rearrangement of the PIC from an open, scanning to a closed, arrested conformation. Cryo-EM reconstructions of yeast PICs suggest remodeling of the interface between 40S protein Rps5/uS7 and eIF2 alpha between open and closed states; however, its importance was unknown. uS7 substitutions disrupting eIF2 alpha contacts favored in the open complex increase initiation at suboptimal sites, and uS7-S223D stabilizes TC binding to PICs reconstituted with a UUG start codon, indicating inappropriate rearrangement to the closed state. Conversely, uS7-D215 substitutions, perturbing uS7-eIF2 alpha interaction in the closed state, confer the opposite phenotypes of hyperaccuracy and (for D215L) accelerated TC dissociation from reconstituted PICs. Thus, remodeling of the uS7/eIF2 alpha interface appears to stabilize first the open, and then the closed state of the PIC to promote accurate AUG selection in vivo.
C1 [Visweswaraiah, Jyothsna; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA.
RP Hinnebusch, AG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA.
EM ahinnebusch@nih.gov
FU National Institutes of Health Intramural Program [HD001004]
FX National Institutes of Health Intramural Program HD001004 Alan G
Hinnebusch; The funders had no role in study design, data collection and
interpretation, or the decision to submit the work for publication.
NR 32
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U1 0
U2 0
PU ELIFE SCIENCES PUBLICATIONS LTD
PI CAMBRIDGE
PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND
SN 2050-084X
J9 ELIFE
JI eLife
PD FEB 7
PY 2017
VL 6
AR e22572
DI 10.7554/eLife.22572
PG 22
WC Biology
SC Life Sciences & Biomedicine - Other Topics
GA EM3HC
UT WOS:000395204100001
ER
PT J
AU Greenbaum, AB
Babaliaros, VC
Chen, MY
Stine, AM
Rogers, T
O'Neill, WW
Paone, G
Thourani, VH
Muhammad, KI
Leonardi, RA
Ramee, S
Troendle, JF
Lederman, RJ
AF Greenbaum, Adam B.
Babaliaros, Vasilis C.
Chen, Marcus Y.
Stine, Annette M.
Rogers, Toby
O'Neill, William W.
Paone, Gaetano
Thourani, Vinod H.
Muhammad, Kamran I.
Leonardi, Robert A.
Ramee, Stephen
Troendle, James F.
Lederman, Robert J.
TI Transcaval Access and Closure for Transcatheter Aortic Valve Replacement
A Prospective Investigation
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Article
DE caval-aortic access; nontransfemoral access; structural heart disease;
transcatheter aortic valve replacement; transcaval; vascular access
ID INTERMEDIATE-RISK PATIENTS; IMPLANTATION; REGISTRY; STENOSIS;
BIOPROSTHESIS; EXPERIENCE; OUTCOMES; SURGERY
AB BACKGROUND Transcaval access may enable fully percutaneous transcatheter aortic valve replacement (TAVR) without the hazards and discomfort of transthoracic (transapical or transaortic) access.
OBJECTIVES The authors performed a prospective, independently adjudicated, multicenter, single-arm trial of transcaval access for TAVR in patients who were ineligible for femoral artery access and had high or prohibitive risk of complications from transthoracic access.
METHODS A total of 100 patients underwent attempted percutaneous transcaval access to the abdominal aorta by electrifying a caval guidewire and advancing it into a pre-positioned aortic snare. After exchanging for a rigid guidewire, conventional TAVR was performed through transcaval introducer sheaths. Transcaval access ports were closed with nitinol cardiac occluders. A core laboratory analyzed pre-discharge and 30-day abdominal computed tomograms. The Society of Thoracic Surgeons predicted risk of mortality was 9.6 +/- 6.3%.
RESULTS Transcaval access was successful in 99 of 100 patients. Device success (access and closure with a nitinol cardiac occluder without death or emergency surgical rescue) occurred 98 of 99 patients; 1 subject had closure with a covered stent. Inpatient survival was 96%, and 30-day survival was 92%. Second Valve Academic Research Consortium (VARC-2) life-threatening bleeding and modified VARC-2 major vascular complications possibly related to transcaval access were 7% and 13%, respectively. Median length of stay was 4 days (range 2 to 6 days). There were no vascular complications after discharge.
CONCLUSIONS Transcaval access enabled TAVR in patients who were not good candidates for transthoracic access. Bleeding and vascular complications, using permeable nitinol cardiac occluders to close the access ports, were common but acceptable in this high-risk cohort. Transcaval access should be investigated in patients who are eligible for transthoracic access. Purpose-built closure devices are in development that may simplify the procedure and reduce bleeding. (Transcaval Access for Transcatheter Aortic Valve Replacement in People With No Good Options for Aortic Access; NCT02280824) Published by Elsevier on behalf of the American College of Cardiology Foundation.
C1 [Greenbaum, Adam B.; O'Neill, William W.; Paone, Gaetano] Henry Ford Hosp, Detroit, MI 48202 USA.
[Babaliaros, Vasilis C.; Thourani, Vinod H.] Emory Univ, Atlanta, GA 30322 USA.
[Chen, Marcus Y.; Stine, Annette M.; Rogers, Toby; Troendle, James F.; Lederman, Robert J.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA.
[Muhammad, Kamran I.] Oklahoma Heart Inst, Tulsa, OK USA.
[Leonardi, Robert A.] Lexington Med Ctr, W Columbia, SC USA.
[Ramee, Stephen] Ochsner Med Ctr, New Orleans, LA USA.
RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC 1538, Bethesda, MD 20892 USA.
EM lederman@nih.gov
FU NHLBI Division of Intramural Research [Z01-HL006040]; St. Jude Medical;
Edwards Lifesciences; Abbott Vascular; Medtronic; Boston Scientific;
Abbott Medical
FX This study was supported by the NHLBI Division of Intramural Research
Z01-HL006040. Dr. Greenbaum is a proctor for Edwards Lifesciences and
St. Jude Medical; and his employer receives research support from St.
Jude Medical. Dr. Babaliaros is a researcher and consultant for Edwards
Lifesciences and Abbott Vascular; and his employer receives research
support from Edwards Lifesciences, Abbott Vascular, Medtronic, St. Jude
Medical, and Boston Scientific. Dr. O'Neill is a consultant for Edwards
Lifesciences, Medtronic, St. Jude Medical, and Boston Scientific. Dr.
Paone is a consultant and proctor for Edwards Lifesciences. Dr. Thourani
is a consultant for Edwards Lifesciences and Abbott Vascular; and his
employer receives research support from Edwards Lifesciences, Boston
Scientific, Medtronic, St. Jude Medical, and Abbott Medical. Dr.
Muhammad is a consultant for Edwards Lifesciences and Abiomed. Dr.
Leonardi is a consultant for St. Jude Medical; and a paid speaker for
Edwards Lifesciences. Dr. Ramee is an investigator for Edwards
Lifesciences and St. Jude Medical; and has received honoraria from
Edwards Lifesciences and Medtronic. Drs. Greenbaum, Rogers, and Lederman
are co-inventors of devices, not tested in this protocol, intended to
close transcaval access. The other authors have reported that they have
no relationships relevant to the contents of this paper to disclose.
NR 26
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U1 2
U2 2
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 FEB 7
PY 2017
VL 69
IS 5
BP 511
EP 521
DI 10.1016/j.jacc.2016.10.024
PG 11
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA EJ1UE
UT WOS:000392994900007
PM 27989885
ER
PT J
AU Lacy, ME
Wellenius, GA
Sumner, AE
Correa, A
Carnethon, MR
Liem, RI
Wilson, JG
Sacks, DB
Jacobs, DR
Carson, AP
Luo, X
Gjelsvik, A
Reiner, AP
Naik, RP
Liu, SM
Musani, SK
Eaton, CB
Wu, WC
AF Lacy, Mary E.
Wellenius, Gregory A.
Sumner, Anne E.
Correa, Adolfo
Carnethon, Mercedes R.
Liem, Robert I.
Wilson, James G.
Sacks, David B.
Jacobs, David R., Jr.
Carson, April P.
Luo, Xi
Gjelsvik, Annie
Reiner, Alexander P.
Naik, Rakhi P.
Liu, Simin
Musani, Solomon K.
Eaton, Charles B.
Wu, Wen-Chih
TI Association of Sickle Cell Trait With Hemoglobin A(1c) in African
Americans
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Article
ID UNITED-STATES; LIFE-SPAN; A1C; GLUCOSE; ADULTS; PREVALENCE; DISPARITIES;
HBA(1C)
AB IMPORTANCE Hemoglobin A(1c) (HbA(1c)) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it.
OBJECTIVE To evaluate the association between SCT and HbA(1c) for given levels of fasting or 2-hour glucose levels among African Americans.
DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA(1c) and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA(1c) levels, controlling for fasting or 2-hour glucose measures.
EXPOSURES Presence of SCT.
MAIN OUTCOMES AND MEASURES Hemoglobin A(1c) stratified by the presence or absence of SCT was the primary outcome measure.
RESULTS The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA(1c) levels. In unadjusted GEE analyses, for a given fasting glucose, HbA(1c) values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA(1c) difference, -0.29%; 95% CI, -0.35% to -0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA(1c) concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA(1c) difference of -0.30% (95% CI, -0.39% to -0.21%). The HbA(1c) difference by SCT was greater at higher fasting (P=.02 for interaction) and 2-hour (P=.03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA(1c) values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<. 001 for both comparisons).
CONCLUSIONS AND RELEVANCE Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA(1c) at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA(1c) may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.
C1 [Lacy, Mary E.; Wellenius, Gregory A.; Gjelsvik, Annie; Liu, Simin; Eaton, Charles B.; Wu, Wen-Chih] Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 S Main St,POB G, Providence, RI 02906 USA.
[Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.
[Sumner, Anne E.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA.
[Correa, Adolfo; Musani, Solomon K.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
[Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA.
[Liem, Robert I.] Ann & Robert H Lurie Childrens Hosp, Div Hematol Oncol & SCT, Chicago, IL USA.
[Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA.
[Sacks, David B.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA.
[Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA.
[Carson, April P.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA.
[Luo, Xi] Brown Univ, Sch Publ Hlth, Dept Biostat, Providence, RI 02912 USA.
[Reiner, Alexander P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA.
[Naik, Rakhi P.] Johns Hopkins Univ, Dept Med, Div Hematol, Baltimore, MD USA.
[Wu, Wen-Chih] Providence Vet Affairs Med Ctr, Ctr Innovat Long Term Serv & Support, Providence, RI USA.
[Wu, Wen-Chih] Providence Vet Affairs Med Ctr, Div Cardiol, Providence, RI USA.
[Liu, Simin; Wu, Wen-Chih] Brown Univ, Alpert Med Sch, Dept Med, Providence, RI 02912 USA.
RP Lacy, ME (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 S Main St,POB G, Providence, RI 02906 USA.
EM mary_lacy@brown.edu
FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C,
HHSN268201300026C, HHSN268201300027C, HHSN268201300028C,
HHSN268201300029C, HHSN26820090004]; Intramural Research Program of the
National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005,
HHSN268201300046C, HHSN268201300047C, HHSN268201300048C,
HHSN268201300049C, HHSN268201300050C, K08HL125100]; National Institute
on Minority Health and Health Disparities; Center of Innovation in
Long-Term Services and Support, Providence VA Medical Center; NIDDK;
NIMHD; NIH; [F31DK105791]; [K01DK095928]; [R01HL107816]
FX CARDIA is supported by contracts HHSN268201300025C, HHSN268201300026C,
HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and
HHSN26820090004 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). The JHS is supported by contracts HHSN268201300046C,
HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and
HHSN268201300050C from the NHLBI and the National Institute on Minority
Health and Health Disparities. Dr Lacy was supported by F31DK105791 (Drs
Wu and Wellenius are cosponsors of this grant). Dr Wu was supported by
the Center of Innovation in Long-Term Services and Support, Providence
VA Medical Center. Dr Carson was supported by K01DK095928. Dr Sumner is
supported by the intramural program of NIDDK and NIMHD. Dr Sacks is
supported by the Intramural Research Program of the NIH. Dr Naik was
supported by NHLBI grant K08HL125100. Joint calling of exome sequence
data in JHS was supported by R01HL107816 to S. Kathiresan, who was the
principal investigator of the ancillary study that obtained the SCT data
on JHS participants.
NR 35
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U1 1
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 FEB 7
PY 2017
VL 317
IS 5
BP 507
EP 515
DI 10.1001/jama.2016.21035
PG 9
WC Medicine, General & Internal
SC General & Internal Medicine
GA EJ9RN
UT WOS:000393564200019
PM 28170479
ER
PT J
AU Thomason, ME
Marusak, HA
AF Thomason, Moriah E.
Marusak, Hilary A.
TI TOWARD UNDERSTANDING THE IMPACT OF TRAUMA ON THE EARLY DEVELOPING HUMAN
BRAIN
SO NEUROSCIENCE
LA English
DT Review
DE adversity; maltreatment; abuse; neural; children; adolescents
ID POSTTRAUMATIC-STRESS-DISORDER; EARLY-LIFE STRESS; NEURAL DEVELOPMENT
DEPRIVATION; ADVERSE CHILDHOOD EXPERIENCES; DEFAULT NETWORK
CONNECTIVITY; HUMAN CEREBRAL-CORTEX; HIPPOCAMPAL VOLUME; HOUSEHOLD
DYSFUNCTION; MATERNAL-DEPRIVATION; FEAR CIRCUITRY
AB Traumatic experiences early in life predispose animals and humans to later cognitive-behavioral, emotional, and somatic problems. In humans, traumatic experiences are strong predictors of psychiatric illness. A growing body of research has emphasized alterations in neurological structure and function that underscore phenotypic changes following trauma. However, results are mixed and imprecise. We argue that future translation of neurological findings to clinical practice will require: (1) discovery of neurobehavioral associations within a longitudinal context, (2) dissociation of trauma types and of trauma versus chronic stress, and (3) better localization of neural sequelae considerate of the fine resolution of neural circuitry. We provide a brief overview of early brain development and highlight the role of longitudinal research in unearthing brain-behavior relations in youth. We relay an emergent framework in which dissociable trauma types are hypothesized to impact distinct, rationally informed neural systems. In line with this, we discuss the long-standing challenge of separating effects of chronic stress and trauma, as these are often intertwined. We bring to light inconsistencies in localization of neural correlates of trauma, emphasizing results in medial prefrontal regions. We assert that more precise spatial brain localization will help to advance prevailing models of trauma pathways and inform future research. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
C1 [Thomason, Moriah E.; Marusak, Hilary A.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI USA.
[Thomason, Moriah E.] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA.
[Thomason, Moriah E.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA.
[Marusak, Hilary A.] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI USA.
RP Thomason, ME (reprint author), Wayne State Univ, Merrill Palmer Skillman Inst, 71 E Ferry St, Detroit, MI 48009 USA.
EM moriah@wayne.edu
FU NIH National Institute of Environmental Health Sciences [P30 ES020957,
R21 ES026022]
FX This work was supported by the NIH National Institute of Environmental
Health Sciences awards P30 ES020957 and R21 ES026022 (MET).
NR 125
TC 1
Z9 1
U1 9
U2 9
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 FEB 7
PY 2017
VL 342
SI SI
BP 55
EP 67
DI 10.1016/j.neuroscience.2016.02.022
PG 13
WC Neurosciences
SC Neurosciences & Neurology
GA EJ0LC
UT WOS:000392899100005
PM 26892294
ER
PT J
AU Kelleher, AM
Peng, W
Pru, JK
Pru, CA
DeMayo, FJ
Spencer, TE
AF Kelleher, Andrew M.
Peng, Wang
Pru, James K.
Pru, Cindy A.
DeMayo, Francesco J.
Spencer, Thomas E.
TI Forkhead box a2 (FOXA2) is essential for uterine function and fertility
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE uterus; gland; FOXA2; pregnancy; LIF
ID LEUKEMIA INHIBITORY FACTOR; MOUSE UTERUS; EMBRYO IMPLANTATION;
BLASTOCYST IMPLANTATION; PROGESTERONE-RECEPTOR; TRANSCRIPTION FACTORS;
ENDOMETRIAL GLANDS; HYPERPLASIA FORMATION; BIOLOGICAL ROLES;
EARLY-PREGNANCY
AB Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy inmice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.
C1 [Kelleher, Andrew M.; Peng, Wang; Spencer, Thomas E.] Univ Missouri, Dept Anim Sci, Columbia, MO 65211 USA.
[Pru, James K.; Pru, Cindy A.] Washington State Univ, Dept Anim Sci, Pullman, WA 99164 USA.
[DeMayo, Francesco J.] NIEHS, Pregnancy & Female Reprod Grp, POB 12233, Res Triangle Pk, NC 27709 USA.
RP Spencer, TE (reprint author), Univ Missouri, Dept Anim Sci, Columbia, MO 65211 USA.
EM spencerte@missouri.edu
FU Eunice Kennedy Shriver National Institute of Child Health and
Development [R21 HD076347]
FX This work was supported by Grant R21 HD076347 from the Eunice Kennedy
Shriver National Institute of Child Health and Development (to T.E.S.).
NR 80
TC 1
Z9 1
U1 2
U2 2
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 7
PY 2017
VL 114
IS 6
BP E1018
EP E1026
DI 10.1073/pnas.1618433114
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EJ7SH
UT WOS:000393422200016
PM 28049832
ER
PT J
AU Perni, M
Galvagnion, C
Maltsev, A
Meisl, G
Muller, MBD
Challa, PK
Kirkegaard, JB
Flagmeier, P
Cohen, SIA
Cascella, R
Chen, SW
Limboker, R
Sormanni, P
Heller, GT
Aprile, FA
Cremades, N
Cecchi, C
Chiti, F
Nollen, EAA
Knowles, TPJ
Vendruscolo, M
Bax, A
Zasloff, M
Dobson, CM
AF Perni, Michele
Galvagnion, Celine
Maltsev, Alexander
Meisl, Georg
Mueller, Martin B. D.
Challa, Pavan K.
Kirkegaard, Julius B.
Flagmeier, Patrick
Cohen, Samuel I. A.
Cascella, Roberta
Chen, Serene W.
Limboker, Ryan
Sormanni, Pietro
Heller, Gabriella T.
Aprile, Francesco A.
Cremades, Nunilo
Cecchi, Cristina
Chiti, Fabrizio
Nollen, Ellen A. A.
Knowles, Tuomas P. J.
Vendruscolo, Michele
Bax, Adriaan
Zasloff, Michael
Dobson, Christopher M.
TI A natural product inhibits the initiation of alpha-synuclein aggregation
and suppresses its toxicity
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE Parkinson's disease; protein aggregation; amyloid formation; toxic
oligomers; drug development
ID PROTEIN MISFOLDING DISEASES; PARKINSONS-DISEASE; CAENORHABDITIS-ELEGANS;
AMPLIFICATION STEPS; NMR-SPECTROSCOPY; SURFACE-CHARGE; LEWY BODIES;
SQUALAMINE; BINDING; PHOSPHORYLATION
AB The self-assembly of alpha-synuclein is closely associated with Parkinson's disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects alpha-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces alpha-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of alpha-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing alpha-synuclein, observing a dramatic reduction of alpha-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions.
C1 [Perni, Michele; Galvagnion, Celine; Meisl, Georg; Mueller, Martin B. D.; Challa, Pavan K.; Flagmeier, Patrick; Cohen, Samuel I. A.; Chen, Serene W.; Limboker, Ryan; Sormanni, Pietro; Heller, Gabriella T.; Aprile, Francesco A.; Knowles, Tuomas P. J.; Vendruscolo, Michele; Dobson, Christopher M.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England.
[Perni, Michele; Mueller, Martin B. D.; Nollen, Ellen A. A.] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Aging, NL-9713 AV Groningen, Netherlands.
[Maltsev, Alexander; Bax, Adriaan] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.
[Kirkegaard, Julius B.] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 0WA, England.
[Cascella, Roberta; Cecchi, Cristina; Chiti, Fabrizio] Univ Florence, Dept Expt & Clin Biomed Sci, I-50134 Florence, Italy.
[Cremades, Nunilo] Univ Zaragoza, Biocomputat & Complex Syst Phys Inst BIFI Joint U, Zaragoza 50018, Spain.
[Zasloff, Michael] Georgetown Univ, MedStar Georgetown Transplant Inst, Sch Med, Washington, DC 20010 USA.
RP Vendruscolo, M; Dobson, CM (reprint author), Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England.; Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.; Zasloff, M (reprint author), Georgetown Univ, Sch Med, MedStar Georgetown Transplant Inst, Washington, DC 20010 USA.
EM mv245@cam.ac.uk; bax@nih.gov; maz5@georgetown.edu; cmd44@cam.ac.uk
FU Intramural Research Program of the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK), US National Institutes of Health;
Boehringer Ingelheim Fonds; European Research Council; Cambridge Centre
for Misfolding Diseases; Agency for Science, Technology, and Research,
Singapore
FX The authors thank Alfonso de Simone, Sam Casford, Mandy Koopman, and
Maarten C. Hardenberg for valuable advice and discussions. This work was
supported by the Intramural Research Program of the National Institute
of Diabetes and Digestive and Kidney Diseases (NIDDK), US National
Institutes of Health (A.M. and A.B.); by the Boehringer Ingelheim Fonds
(P.F.); by a European Research Council starting grant (to M.B.D.M. and
E.A.A.N.); and by The Cambridge Centre for Misfolding Diseases. N.C.
thanks the Spanish Ministry of Economy and Competitiveness
(RYC-2012-12068). S.W.C. thanks the Agency for Science, Technology, and
Research, Singapore for support.
NR 55
TC 2
Z9 2
U1 18
U2 18
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 FEB 7
PY 2017
VL 114
IS 6
BP E1009
EP E1017
DI 10.1073/pnas.1610586114
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EJ7SH
UT WOS:000393422200015
PM 28096355
ER
PT J
AU Tebebi, PA
Kim, SJ
Williams, RA
Milo, B
Frenkel, V
Burks, SR
Frank, JA
AF Tebebi, Pamela A.
Kim, Saejeong J.
Williams, Rashida A.
Milo, Blerta
Frenkel, Victor
Burks, Scott R.
Frank, Joseph A.
TI Improving the therapeutic efficacy of mesenchymal stromal cells to
restore perfusion in critical limb ischemia through pulsed focused
ultrasound
SO SCIENTIFIC REPORTS
LA English
DT Article
ID PERIPHERAL ARTERIAL-DISEASE; ENDOTHELIAL PROGENITOR CELLS; ACUTE
HINDLIMB ISCHEMIA; BONE-MARROW-CELLS; STEM-CELLS; SKELETAL-MUSCLE; MOUSE
MODEL; ANGIOGENESIS; TRANSPLANTATION; MICE
AB Mesenchymal stem cells (MSC) are promising therapeutics for critical limb ischemia (CLI). Mechanotransduction from pulsed focused ultrasound (pFUS) upregulates local chemoattractants to enhance homing of intravenously (IV)-infused MSC and improve outcomes. This study investigated whether pFUS exposures to skeletal muscle would improve local homing of iv-infused MSCs and their therapeutic efficacy compared to iv-infused MSCs alone. CLI was induced by external iliac arterial cauterization in 10-12-month-old mice. pFUS/MSC treatments were delayed 14 days, when surgical inflammation subsided. Mice were treated with iv-saline, pFUS alone, IV-MSC, or pFUS and IV-MSC. Proteomic analyses revealed pFUS upregulated local chemoattractants and increased MSC tropism to CLI muscle. By 7 weeks post-treatment, pFUS + MSC significantly increased perfusion and CD31 expression, while reducing fibrosis compared to saline. pFUS or MSC alone reduced fibrosis, but did not increase perfusion or CD31. Furthermore, MSCs homing to pFUS-treated CLI muscle expressed more vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) than MSCs homing to non-pFUS-treated muscle. pFUS + MSC improved perfusion and vascular density in this clinically-relevant CLI model. The molecular effects of pFUS increased both MSC homing and MSC production of VEGF and IL-10, suggesting microenvironmental changes from pFUS also increased potency of MSCs in situ to further enhance their efficacy.
C1 [Tebebi, Pamela A.; Kim, Saejeong J.; Williams, Rashida A.; Milo, Blerta; Burks, Scott R.; Frank, Joseph A.] NIH, Ctr Clin, Radiol & Imaging Sci Dept, Frank Lab, Bethesda, MD 20892 USA.
[Tebebi, Pamela A.] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA.
[Frenkel, Victor] Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, Baltimore, MD 21201 USA.
[Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA.
RP Frank, JA (reprint author), NIH, Ctr Clin, Radiol & Imaging Sci Dept, Frank Lab, Bethesda, MD 20892 USA.; Frank, JA (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA.
EM jfrank@helix.nih.gov
FU Intramural Research Program of the National Institutes of Health
Clinical Center; National Institute of Biomedical Imaging and
Bioengineering
FX This research was funded by the Intramural Research Program of the
National Institutes of Health Clinical Center and the National Institute
of Biomedical Imaging and Bioengineering.
NR 52
TC 0
Z9 0
U1 1
U2 1
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 7
PY 2017
VL 7
AR 41550
DI 10.1038/srep41550
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EJ8VR
UT WOS:000393505400001
PM 28169278
ER
PT J
AU Staunton, JR
Blehm, B
Devine, A
Tanner, K
AF Staunton, Jack R.
Blehm, Ben
Devine, Alexus
Tanner, Kandice
TI In situ calibration of position detection in an optical trap for active
microrheology in viscous materials
SO OPTICS EXPRESS
LA English
DT Article
ID FOCAL-PLANE INTERFEROMETRY; MECHANICAL-PROPERTIES; EX-VIVO; TWEEZERS;
FORCE; COLLAGEN; DISPLACEMENTS; SPECTROSCOPY; ELASTICITY; MICROSCOPY
AB In optical trapping, accurate determination of forces requires calibration of the position sensitivity relating displacements to the detector readout via the V-nm conversion factor (beta). Inaccuracies in measured trap stiffness (k) and dependent calculations of forces and material properties occur if beta is assumed to be constant in optically heterogeneous materials such as tissue, necessitating calibration at each probe. For solid-like samples in which probes are securely positioned, calibration can be achieved by moving the sample with a nanopositioning stage and stepping the probe through the detection beam. However, this method may be applied to samples only under select circumstances. Here, we introduce a simple method to find a in any material by steering the detection laser beam while the probe is trapped. We demonstrate the approach in the yolk of living Danio rerio (zebrafish) embryos and measure the viscoelastic properties over an order of magnitude of stress-strain amplitude. (C) 2017 Optical Society of America
C1 [Staunton, Jack R.; Blehm, Ben; Devine, Alexus; Tanner, Kandice] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.
RP Tanner, K (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.
EM kandice.tanner@nih.gov
FU Intramural Research Program of the National Institutes of Health, the
National Cancer Institute
FX This effort was supported by the Intramural Research Program of the
National Institutes of Health, the National Cancer Institute.
NR 54
TC 0
Z9 0
U1 0
U2 0
PU OPTICAL SOC AMER
PI WASHINGTON
PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA
SN 1094-4087
J9 OPT EXPRESS
JI Opt. Express
PD FEB 6
PY 2017
VL 25
IS 3
BP 1746
EP 1761
DI 10.1364/OE.25.001746
PG 16
WC Optics
SC Optics
GA EP3XI
UT WOS:000397314600013
ER
PT J
AU Cahan, A
Cimino, JJ
AF Cahan, Amos
Cimino, James J.
TI Improving precision medicine using individual patient data from trials
SO CANADIAN MEDICAL ASSOCIATION JOURNAL
LA English
DT Article
ID RANDOMIZED CONTROLLED-TRIALS; EXTERNAL VALIDITY; CLINICAL-PRACTICE;
SUBGROUP ANALYSIS; GUIDELINES; EXPERIENCE
AB Our first commitment as clinicians is to our patients as individuals. This understanding lies at the heart of the precision medicine initiative, which aims to customize treatments based not only on a patient's clinical picture but also on their genetic, demographic and environmental profile. (1) Clinical trials are rigid by design, typically assessing the effect of one intervention. In a reality of complex patients and polypharmacy, clinical trials cannot provide all the answers that clinicians are seeking. It is widely accepted that the uniquely complex health care environment requires the implementation at scale of informatics tools to help physicians navigate through the huge volume of medical data, and technology is being developed and refined to support this need. Whereas data from electronic health records are routinely reused in research to generate evidence-based recommendations for patient care, databases of clinical trial populations are not. The potential of individual-level data of participants in completed clinical trials to facilitate evidence-personalized treatment decisions has not yet been fully realized.
C1 [Cahan, Amos] IBM TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA.
[Cimino, James J.] NIH, Natl Lib Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA.
[Cimino, James J.] Univ Alabama Birmingham, Sch Med, Inst Informat, Birmingham, AL USA.
RP Cahan, A (reprint author), IBM TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA.
EM acahan@us.ibm.com
FU Research Participation Program for the Centers for Disease Control and
Prevention; National Center for Environmental Health; Division of
Laboratory Sciences (DLS); National Library of Medicine and the National
Institues of Health (NIH) Clinical Center; Informatics Institute at the
University of Alabama School of Medicine, Birmingham
FX Amos Cahan was supported by an appointment to the Research Participation
Program for the Centers for Disease Control and Prevention, National
Center for Environmental Health, Division of Laboratory Sciences
(DLS),administered by the Oak Ridge Institute for Science and Education
through an agreement between the US Department of Energy and DLS. Amos
Cahan is currently employed by IBM. James Cimino was supported in part
by research funds from the National Library of Medicine and the National
Institues of Health (NIH) Clinical Center, and is currently supported by
the Informatics Institute at the University of Alabama School of
Medicine, Birmingham.
NR 19
TC 0
Z9 0
U1 0
U2 0
PU CMA-CANADIAN MEDICAL ASSOC
PI OTTAWA
PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA
SN 0820-3946
EI 1488-2329
J9 CAN MED ASSOC J
JI Can. Med. Assoc. J.
PD FEB 6
PY 2017
VL 189
IS 5
BP E204
EP E207
DI 10.1503/cmaj.160267
PG 4
WC Medicine, General & Internal
SC General & Internal Medicine
GA EM7RF
UT WOS:000395509300005
PM 27573743
ER
PT J
AU Vijayakumar, P
Hoyer, A
Nelson, RG
Brinks, R
Pavkov, ME
AF Vijayakumar, Pavithra
Hoyer, Annika
Nelson, Robert G.
Brinks, Ralph
Pavkov, Meda E.
TI Estimation of chronic kidney disease incidence from prevalence and
mortality data in American Indians with type 2 diabetes
SO PLOS ONE
LA English
DT Article
ID PIMA-INDIANS; RISK-FACTORS; MELLITUS; ESRD; MICROALBUMINURIA;
ALBUMINURIA; POPULATION; ANTIBODIES; REMISSION; EQUATION
AB The objective was to estimate chronic kidney disease (CKD) incidence rates from prevalence and mortality data, and compare the estimates with observed (true) incidence rates in a well-characterized population with diabetes. Pima Indians aged 20 years and older with type 2 diabetes were followed from 1982 through 2007. CKD was defined by estimated GFR (eGFR) <60 ml/min/1.72 m(2) or albumin-to-creatinine ratio (ACR) >= 30 mg/g. True CKD incidence and mortality rates were computed for the whole study period, and prevalence for the intervals 1982-1994 and 1995-2007. Estimated age-sex stratified CKD incidence rates were computed using illness-death models of the observed prevalences, and of the whole period mortality rate ratio of CKD to non-CKD persons. Among 1201 participants, 616 incident events of CKD occurred during a median follow-up of 5.6 years. Observed CKD prevalence was 56.9% (95%X153.7-60.0) and 48.0% (95%X145.2-50.8) in women; 54.0% (95% CI 49.9-58.1) and 49.6% (95%C 46.0-53.3) in men, across the two periods. Mortality rate was 2.5 (95%CI 11.9-3.3) times as high in women with CKD and 1.6 (95%Cl 1.3-2.1) times as high in men with CKD, compared to women or men without CKD. In women, estimated CKD incidence increased linearly from 25.6 (95%CI14.2-53.0) to 128.6 (95%CI177.1-196.6) with each 5-year age group up to 69 years, and to 99.8 (95% CI 38.7-204.7) at age >= 70. In men, estimated CKD incidence increased form 28.5 (95% CI13.8-71.2) at age 20-24 years to 118.7 (95%CI123.6-336.7) at age >= 70. Age-sex-stratified estimated incidence reflected the magnitude and directional trend of the true incidence and were similar to the true incidence rates (p>0.05 for difference) except for age 20-24 in women (p = 0.008) and age 2529 in men (p = 0.002). In conclusion, the estimated and observed incidence rates of CKD agree well over 25 years of observation in this well characterized population with type 2 diabetes.
C1 [Vijayakumar, Pavithra; Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ USA.
[Hoyer, Annika; Brinks, Ralph] German Diabet Ctr Duesseldorf, Inst Epidemiol & Biometry, Dusseldorf, Germany.
[Pavkov, Meda E.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA 30333 USA.
[Pavkov, Meda E.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA.
RP Pavkov, ME (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA 30333 USA.; Pavkov, ME (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA.
EM mpavkov@cdc.gov
OI Pavkov, Meda/0000-0002-6203-1772
FU Intramural Research Program of the National Institute of Diabetes and
Digestive and Kidney Diseases
FX This work was supported in part by the Intramural Research Program of
the National Institute of Diabetes and Digestive and Kidney Diseases.
The authors received no specific funding for this work. There was no
additional external funding received for this study.
NR 27
TC 0
Z9 0
U1 1
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 FEB 6
PY 2017
VL 12
IS 2
AR e0171027
DI 10.1371/journal.pone.0171027
PG 11
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA EK1QH
UT WOS:000393700100020
PM 28166298
ER
PT J
AU O'Neal, TJ
Friend, DM
Guo, JE
Hall, KD
Kravitz, AV
AF O'Neal, Timothy J.
Friend, Danielle M.
Guo, Juen
Hall, Kevin D.
Kravitz, Alexxai V.
TI Increases in Physical Activity Result in Diminishing Increments in Daily
Energy Expenditure in Mice
SO CURRENT BIOLOGY
LA English
DT Article
ID WEIGHT-LOSS; COMPENSATORY RESPONSES; VOLUNTARY EXERCISE; SEDENTARY TIME;
OBESITY; DIET; INTERVENTIONS; TEMPERATURE; LOCOMOTION; BALANCE
AB Exercise is a common component of weight loss strategies, yet exercise programs are associated with surprisingly small changes in body weight [1-4]. This may be due in part to compensatory adaptations, in which calories expended during exercise are counteracted by decreases in other aspects of energy expenditure [1, 5-10]. Here we examined the relationship between a rodent model of voluntary exercise wheel running and total daily energy expenditure. Use of a running wheel for 3 to 7 days increased daily energy expenditure, resulting in a caloric deficit of similar to 1 kcal/day; however, total daily energy expenditure remained stable after the first week of wheel access, despite further increases in wheel use. We hypothesized that compensatory mechanisms accounted for the lack of increase in daily energy expenditure after the first week. Supporting this idea, we observed a decrease in off-wheel ambulation when mice were using the wheels, indicating behavioral compensation. Finally, we asked whether individual variation in wheel use within a group of mice would be associated with different levels of daily energy expenditure. Despite a large variation in wheel running, we did not observe a significant relationship between the amount of daily wheel running and total daily energy expenditure or energy intake across mice. Together, our experiments support a model in which the transition from sedentary to light activity is associated with an increase in daily energy expenditure, but further increases in physical activity produce diminishingly small increments in daily energy expenditure.
C1 [O'Neal, Timothy J.; Friend, Danielle M.; Kravitz, Alexxai V.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.
[O'Neal, Timothy J.; Guo, Juen; Hall, Kevin D.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA.
[Kravitz, Alexxai V.] NIDA, NIH, Baltimore, MD 21224 USA.
RP Kravitz, AV (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.; Kravitz, AV (reprint author), NIDA, NIH, Baltimore, MD 21224 USA.
EM lex.kravitz@nih.gov
FU Intramural Research Program of the NIH, The National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) [1ZIADK075096]
FX This research was supported by the Intramural Research Program of the
NIH, The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK; grant no. 1ZIADK075096). We would like to thank the
Mouse Metabolism Core at the National Institute of Diabetes and
Digestive and Kidney Diseases for assistance with indirect calorimetry
experiments. We thank members of the A.V.K. lab, Marc Reitman, and
Oksana Gavrilova for helpful discussions and insight on the manuscript.
NR 38
TC 0
Z9 0
U1 2
U2 2
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 FEB 6
PY 2017
VL 27
IS 3
BP 423
EP 430
DI 10.1016/j.cub.2016.12.009
PG 8
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA EK1ZH
UT WOS:000393726300029
PM 28111149
ER
PT J
AU Law, PJ
Berndt, SI
Speedy, HE
Camp, NJ
Sava, GP
Skibola, CF
Holroyd, A
Joseph, V
Sunter, NJ
Nieters, A
Bea, S
Monnereau, A
Martin-Garcia, D
Goldin, LR
Clot, G
Teras, LR
Quintela, I
Birmann, BM
Jayne, S
Cozen, W
Majid, A
Smedby, KE
Lan, Q
Dearden, C
Brooks-Wilson, AR
Hall, AG
Purdue, MP
Mainou-Fowler, T
Vajdic, CM
Jackson, GH
Cocco, P
Marr, H
Zhang, YW
Zheng, TZ
Giles, GG
Lawrence, C
Call, TG
Liebow, M
Melbye, M
Glimelius, B
Mansouri, L
Glenn, M
Curtin, K
Diver, WR
Link, BK
Conde, L
Bracci, PM
Holly, EA
Jackson, RD
Tinker, LF
Benavente, Y
Boffetta, P
Brennan, P
Maynadie, M
McKay, J
Albanes, D
Weinstein, S
Wang, ZM
Caporaso, NE
Morton, LM
Severson, RK
Riboli, E
Vineis, P
Vermeulen, RCH
Southey, MC
Milne, RL
Clavel, J
Topka, S
Spinelli, JJ
Kraft, P
Ennas, MG
Summerfield, G
Ferri, GM
Harris, RJ
Miligi, L
Pettitt, AR
North, KE
Allsup, DJ
Fraumeni, JF
Bailey, JR
Offit, K
Pratt, G
Hjalgrim, H
Pepper, C
Chanock, SJ
Fegan, C
Rosenquist, R
de Sanjose, S
Carracedo, A
Dyer, MJS
Catovsky, D
Campo, E
Cerhan, JR
Allan, JM
Rothman, N
Houlston, R
Slager, SL
AF Law, Phillip J.
Berndt, Sonja I.
Speedy, Helen E.
Camp, Nicola J.
Sava, Georgina P.
Skibola, Christine F.
Holroyd, Amy
Joseph, Vijai
Sunter, Nicola J.
Nieters, Alexandra
Bea, Silvia
Monnereau, Alain
Martin-Garcia, David
Goldin, Lynn R.
Clot, Guillem
Teras, Lauren R.
Quintela, Ines
Birmann, Brenda M.
Jayne, Sandrine
Cozen, Wendy
Majid, Aneela
Smedby, Karin E.
Lan, Qing
Dearden, Claire
Brooks-Wilson, Angela R.
Hall, Andrew G.
Purdue, Mark P.
Mainou-Fowler, Tryfonia
Vajdic, Claire M.
Jackson, Graham H.
Cocco, Pierluigi
Marr, Helen
Zhang, Yawei
Zheng, Tongzhang
Giles, Graham G.
Lawrence, Charles
Call, Timothy G.
Liebow, Mark
Melbye, Mads
Glimelius, Bengt
Mansouri, Larry
Glenn, Martha
Curtin, Karen
Diver, W. Ryan
Link, Brian K.
Conde, Lucia
Bracci, Paige M.
Holly, Elizabeth A.
Jackson, Rebecca D.
Tinker, Lesley F.
Benavente, Yolanda
Boffetta, Paolo
Brennan, Paul
Maynadie, Marc
McKay, James
Albanes, Demetrius
Weinstein, Stephanie
Wang, Zhaoming
Caporaso, Neil E.
Morton, Lindsay M.
Severson, Richard K.
Riboli, Elio
Vineis, Paolo
Vermeulen, Roel C. H.
Southey, Melissa C.
Milne, Roger L.
Clavel, Jacqueline
Topka, Sabine
Spinelli, John J.
Kraft, Peter
Ennas, Maria Grazia
Summerfield, Geoffrey
Ferri, Giovanni M.
Harris, Robert J.
Miligi, Lucia
Pettitt, Andrew R.
North, Kari E.
Allsup, David J.
Fraumeni, Joseph F., Jr.
Bailey, James R.
Offit, Kenneth
Pratt, Guy
Hjalgrim, Henrik
Pepper, Chris
Chanock, Stephen J.
Fegan, Chris
Rosenquist, Richard
de Sanjose, Silvia
Carracedo, Angel
Dyer, Martin J. S.
Catovsky, Daniel
Campo, Elias
Cerhan, James R.
Allan, James M.
Rothman, Nathanial
Houlston, Richard
Slager, Susan L.
TI Genome-wide association analysis implicates dysregulation of immunity
genes in chronic lymphocytic leukaemia
SO NATURE COMMUNICATIONS
LA English
DT Article
ID TRANSCRIPTION FACTORS; COMMON VARIATION; BREAST-CANCER; RISK; DISEASE;
METAANALYSIS; IMPUTATION; CHROMATIN; VARIANTS; LOCI
AB Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P = 5.04 X 10 (-) (13)), 1q42.13 (rs41271473, P = 1.06 X 10 (-) (10)), 4q24 (rs71597109, P = 1.37 X 10 (-) (10)), 4q35.1 (rs57214277, P = 3.69 X 10 (-) (8)), 6p21.31 (rs3800461, P = 1.97 X 10 (-) (8)), 11q23.2 (rs61904987, P = 2.64 X 10 (-) (11)), 18q21.1 (rs1036935, P = 3.27 X 10 (-) (8)), 19p13.3 (rs7254272, P = 4.67 X 10 (-) (8)) and 22q13.33 (rs140522, P = 2.70 X 10 (-) (9)). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.
C1 [Law, Phillip J.; Speedy, Helen E.; Sava, Georgina P.;