FN Thomson Reuters Web of Science™
VR 1.0
PT J
AU Zhou, GQ
Chan, P
Zheng, YP
AF Zhou, Guang-Quan
Chan, Phoebe
Zheng, Yong-Ping
TI Automatic measurement of pennation angle and fascicle length of
gastrocnemius muscles using real-time ultrasound imaging
SO ULTRASONICS
LA English
DT Article
DE Sonomyography; Ultrasound imaging; Pennation angle; Fascicle length;
Gabor wavelet
ID IN-VIVO; TEXTURE ANALYSIS; SKELETAL-MUSCLE; RECEPTIVE-FIELD;
RADON-TRANSFORM; TENDON BEHAVIOR; MOTION ANALYSIS; ANKLE PLANTAR;
ARCHITECTURE; IMAGES
AB Muscle imaging is a promising field of research to understand the biological and bioelectrical characteristics of muscles through the observation of muscle architectural change. Sonomyography (SMG) is a technique which can quantify the real-time architectural change of muscles under different contractions and motions with ultrasound imaging. The pennation angle and fascicle length are two crucial SMG parameters to understand the contraction mechanics at muscle level, but they have to be manually detected on ultrasound images frame by frame. In this study, we proposed an automatic method to quantitatively identify pennation angle and fascicle length of gastrocnemius (GM) muscle based on multi-resolution analysis and line feature extraction, which could overcome the limitations of tedious and time-consuming manual measurement. The method started with convolving Gabor wavelet specially designed for enhancing the line-like structure detection in GM ultrasound image. The resulting image was then used to detect the fascicles and aponeuroses for calculating the pennation angle and fascicle length with the consideration of their distribution in ultrasound image. The performance of this method was tested on computer simulated images and experimental images in vivo obtained from normal subjects. Tests on synthetic images showed that the method could identify the fascicle orientation with an average error less than 0.1 degrees. The result of in vivo experiment showed a good agreement between the results obtained by the automatic and the manual measurements (r = 0.94 +/- 0.03; p < 0.001, and r = 0.95 +/- 0.02, p < 0.001). Furthermore, a significant correlation between the ankle angle and pennation angle (r = 0.89 +/- 0.05; p < 0.001) and fascicle length (r = -0.90 +/- 0.04; p < 0.001) was found for the ankle plantar flexion. This study demonstrated that the proposed method was able to automatically measure the pennation angle and fascicle length of GM ultrasound images, which made it feasible to investigate muscle-level mechanics more comprehensively in vivo. (C) 2014 Elsevier B.V. All rights reserved.
C1 [Zhou, Guang-Quan; Zheng, Yong-Ping] Hong Kong Polytech Univ, Interdisciplinary Div Biomed Engn, Kowloon, Hong Kong, Peoples R China.
[Chan, Phoebe] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA.
RP Zheng, YP (reprint author), Hong Kong Polytech Univ, Interdisciplinary Div Biomed Engn, Kowloon, Hong Kong, Peoples R China.
EM ypzheng@ieee.org
RI Zhou, Guangquan/P-2153-2015;
OI Zhou, Guangquan/0000-0002-6467-3592; Zheng,
Yong-Ping/0000-0002-3407-9226
FU Hong Kong Polytechnic University [G-YL74]
FX This work was supported by the Hong Kong Polytechnic University
(G-YL74). We would like to thank the donation from Dr. HUI Kin Sang
(5-ZD6).
NR 63
TC 2
Z9 4
U1 3
U2 22
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0041-624X
EI 1874-9968
J9 ULTRASONICS
JI Ultrasonics
PD MAR
PY 2015
VL 57
BP 72
EP 83
DI 10.1016/j.ultras.2014.10.020
PG 12
WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging
SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging
GA AY6CH
UT WOS:000347654700010
PM 25465963
ER
PT J
AU Han, Y
Signorello, LB
Strom, SS
Kittles, RA
Rybicki, BA
Stanford, JL
Goodman, PJ
Berndt, SI
Carpten, J
Casey, G
Chu, LS
Conti, DV
Rand, KA
Diver, WR
Hennis, AJM
John, EM
Kibel, AS
Klein, EA
Kolb, S
Le Marchand, L
Leske, MC
Murphy, AB
Neslund-Dudas, C
Park, JY
Pettaway, C
Rebbeck, TR
Gapstur, SM
Zheng, SL
Wu, SY
Witte, JS
Xu, JF
Isaacs, W
Ingles, SA
Hsing, A
Easton, DF
Eeles, RA
Schumacher, FR
Chanock, S
Nemesure, B
Blot, WJ
Stram, DO
Henderson, BE
Haiman, CA
AF Han, Ying
Signorello, Lisa B.
Strom, Sara S.
Kittles, Rick A.
Rybicki, Benjamin A.
Stanford, Janet L.
Goodman, Phyllis J.
Berndt, Sonja I.
Carpten, John
Casey, Graham
Chu, Lisa
Conti, David V.
Rand, Kristin A.
Diver, W. Ryan
Hennis, Anselm J. M.
John, Esther M.
Kibel, Adam S.
Klein, Eric A.
Kolb, Suzanne
Le Marchand, Loic
Leske, M. Cristina
Murphy, Adam B.
Neslund-Dudas, Christine
Park, Jong Y.
Pettaway, Curtis
Rebbeck, Timothy R.
Gapstur, Susan M.
Zheng, S. Lilly
Wu, Suh-Yuh
Witte, John S.
Xu, Jianfeng
Isaacs, William
Ingles, Sue A.
Hsing, Ann
Easton, Douglas F.
Eeles, Rosalind A.
Schumacher, Fredrick R.
Chanock, Stephen
Nemesure, Barbara
Blot, William J.
Stram, Daniel O.
Henderson, Brian E.
Haiman, Christopher A.
CA PRACTICAL Consortium
ELLIPSE GAME-ON Consortium
TI Generalizability of established prostate cancer risk variants in men of
African ancestry
SO INTERNATIONAL JOURNAL OF CANCER
LA English
DT Article
DE prostate cancer; genetic risk variant; generalizability; African
ancestry
ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; SEQUENCE VARIANTS;
IDENTIFICATION; REPLICATION
AB Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p<0.05, with the most statistically significant variants being rs116041037 (p=3.7 x 10(-26)) and rs6983561 (p=1.1 x 10(-16)) at 8q24, as well as rs7210100 (p=5.4 x 10(-8)) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p<0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR)=1.12, p=7.3 x 10(-98)]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.
C1 [Han, Ying; Casey, Graham; Conti, David V.; Rand, Kristin A.; Ingles, Sue A.; Schumacher, Fredrick R.; Stram, Daniel O.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA.
[Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
[Signorello, Lisa B.] Dana Farber Harvard Canc Ctr, Boston, MA USA.
[Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Dept Epidemiol, Houston, TX 77030 USA.
[Kittles, Rick A.] Univ Illinois, Dept Med, Chicago, IL USA.
[Rybicki, Benjamin A.; Neslund-Dudas, Christine] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA.
[Stanford, Janet L.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA.
[Goodman, Phyllis J.] SWOG Stat Ctr, Seattle, WA USA.
[Berndt, Sonja I.; Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
[Carpten, John] Translat Genom Res Inst, Phoenix, AZ USA.
[Casey, Graham; Schumacher, Fredrick R.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA.
[Chu, Lisa; John, Esther M.; Hsing, Ann] Canc Prevent Inst Calif, Fremont, CA USA.
[Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA.
[Hennis, Anselm J. M.; Leske, M. Cristina; Wu, Suh-Yuh; Nemesure, Barbara] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA.
[Hennis, Anselm J. M.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados.
[Hennis, Anselm J. M.] Univ W Indies, Fac Med Sci, Bridgetown, Barbados.
[Hennis, Anselm J. M.] Minist Hlth, Bridgetown, Barbados.
[John, Esther M.; Hsing, Ann] Stanford Univ, Sch Med, Div Epidemiol, Dept Hlth Res & Policy, Stanford, CA 94305 USA.
[John, Esther M.; Hsing, Ann] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA.
[Kibel, Adam S.] Brigham & Womens Hosp, Div Urol Surg, Dana Farber Canc Inst, Boston, MA 02115 USA.
[Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA.
[Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA.
[Murphy, Adam B.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA.
[Park, Jong Y.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA.
[Pettaway, Curtis] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA.
[Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.
[Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA.
[Zheng, S. Lilly; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA.
[Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Inst Human Genet, San Francisco, CA 94143 USA.
[Witte, John S.] Univ Calif San Francisco, Dept Urol, Inst Human Genet, San Francisco, CA USA.
[Isaacs, William] Johns Hopkins Hosp & Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA.
[Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England.
[Eeles, Rosalind A.] Inst Canc Res, London SW3 6JB, England.
[Eeles, Rosalind A.] Inst Canc Res, Sutton, Surrey, England.
[Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv Fdn Trust, London, England.
[Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv Fdn Trust, Sutton, Surrey, England.
[Blot, William J.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA.
[Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA.
[Blot, William J.] Int Epidemiol Inst, Rockville, MD USA.
RP Haiman, CA (reprint author), Harlyne Norris Res Tower,1450 Biggy St,Room 1504, Los Angeles, CA 90033 USA.
EM haiman@usc.edu
OI Eeles, Rosalind/0000-0002-3698-6241
FU National Institutes of Health (NIH) [CA63464, CA54281, CA1326792,
CA148085, HG004726]
FX Grant sponsor: National Institutes of Health (NIH); Grant number:
CA63464, CA54281, CA1326792, CA148085, HG004726
NR 25
TC 20
Z9 20
U1 1
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 MAR 1
PY 2015
VL 136
IS 5
BP 1210
EP 1217
DI 10.1002/ijc.29066
PG 8
WC Oncology
SC Oncology
GA AW5ZY
UT WOS:000346350500046
PM 25044450
ER
PT J
AU Townsend, EL
Tamhane, H
Gross, KD
AF Townsend, Elise L.
Tamhane, Himani
Gross, K. Douglas
TI Effects of AFO Use on Walking in Boys With Duchenne Muscular Dystrophy:
A Pilot Study
SO PEDIATRIC PHYSICAL THERAPY
LA English
DT Article
DE child; Duchenne muscular dystrophy; foot orthoses; gait; male; physical
endurance; walking
ID CORTICOSTEROID TREATMENT; CONTROLLED-TRIAL; PREDNISONE; MULTICENTER;
THERAPY
AB Purpose: Although bracing in the late ambulatory stage of Duchenne muscular dystrophy (DMD) has been described, the effects of ankle-foot orthoses (AFOs) in earlier stages have not been evaluated. The aim of this pilot study was to describe the effects of dynamic response AFO (DR-AFO) use in boys with DMD who are ambulatory. Methods: Using a crossover design, 3 boys were randomly assigned to either a 2-week DR-AFO or a placebo intervention. Phases were separated by a 1-week washout period. Primary outcomes were time to walk 10 m and a 6-Minute Walk Test. Results: With DR-AFO use, declines in 10-m walk time (median decline = 0.8 s) and 6-Minute Walk Distance (median = 25.0 m) occurred. Parental report suggested that the use of DR-AFOs increased falls in 2 of 3 participants. Conclusion: This pilot study does not support the use of DR-AFOs by boys with DMD who are ambulatory.
C1 [Townsend, Elise L.; Gross, K. Douglas] MGH Inst Hlth Profess, Sch Hlth & Rehabilitat Sci, Dept Phys Therapy, Boston, MA 02129 USA.
[Townsend, Elise L.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Gross, K. Douglas] Boston Univ, Sch Med, Boston, MA 02118 USA.
[Tamhane, Himani] Hlth East Med Ctr, Englewood, NJ USA.
RP Townsend, EL (reprint author), MGH Inst Hlth Profess, Sch Hlth & Rehabilitat Sci, Dept Phys Therapy, 36 1st Ave, Boston, MA 02129 USA.
EM etownsend@mghihp.edu
FU MGH Institute of Health Professions
FX Grant Support: This study was supported by a Marjorie K. Ionta Grant
from the MGH Institute of Health Professions awarded to Himani Tamhane.
NR 32
TC 2
Z9 2
U1 1
U2 12
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0898-5669
EI 1538-005X
J9 PEDIATR PHYS THER
JI Pediatr. Phys. Ther.
PD SPR
PY 2015
VL 27
IS 1
BP 24
EP 29
DI 10.1097/PEP.0000000000000099
PG 6
WC Pediatrics; Rehabilitation
SC Pediatrics; Rehabilitation
GA AX1UJ
UT WOS:000346731100006
PM 25401456
ER
PT J
AU Abramovitch, A
Shaham, N
Levin, L
Bar-Hen, M
Schweiger, A
AF Abramovitch, Amitai
Shaham, Noa
Levin, Lior
Bar-Hen, Moran
Schweiger, Avraham
TI Response inhibition in a subclinical obsessive-compulsive sample
SO JOURNAL OF BEHAVIOR THERAPY AND EXPERIMENTAL PSYCHIATRY
LA English
DT Article
DE OCD; Obsessive-compulsive disorder; Executive function; Analogue sample;
Endophenotype; Neuropsychology
ID EXECUTIVE FUNCTION DEFICITS; NEUROPSYCHOLOGICAL PERFORMANCE;
DECISION-MAKING; DISORDER; SYMPTOMS; TASK; ENDOPHENOTYPES; IMPAIRMENTS;
DEPRESSION; INVENTORY
AB Background and objectives: Inconsistent findings across studies challenge the viability of response inhibition (RI) as an endophenotype of obsessive-compulsive disorder (OCD). Contemporary conceptualization of endophenotypes in psychiatric disorders suggests that these markers vary continuously in the general population, highlighting the importance of analogue sample research. Although neuropsychological functions have been studied in subclinical obsessive-compulsive (OC) samples, no study to date had examined RI in the context of the go/no-go paradigm.
Methods: A subclinical OC sample (HOC; n = 27) and a low OC symptoms control sample (LOC; n = 25), as determined by the Obsessive-Compulsive Inventory-Revised, completed a go/no-go task and clinical questionnaires.
Results: The groups did not differ on age, gender, or state anxiety. Controlling for depressive severity, the HOC group made significantly more commission errors and exhibited larger response time variability on the go/no-go task. However, standardized scores produced using population norms revealed that the HOC group performed within normative range.
Limitations: This study used a non-clinical sample and no structured clinical screening was performed.
Conclusions: Compared to LOC participants, a psychometrically-defined subclinical OC sample exhibited deficient RI and sustained attention. However, when raw scores were converted to age and education adjusted standardized scores according to the test's population norms, the HOC group task performance was in the normative range. These results, are in line with findings in OCD samples, suggesting that moderate degree of RI deficiencies is associated with the presence of OC symptomatology regardless of clinical status. However, the conceptualization of RI underperformance as an OCD disorder-specific impairment, remains controversial. (C) 2014 Elsevier Ltd. All rights reserved.
C1 [Abramovitch, Amitai] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.
[Abramovitch, Amitai] Harvard Univ, Sch Med, Boston, MA USA.
[Shaham, Noa; Levin, Lior; Bar-Hen, Moran; Schweiger, Avraham] Acad Coll Tel Aviv, Dept Psychol, Tel Aviv, Israel.
RP Abramovitch, A (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 185 Cambridge St,Suite 2000, Boston, MA 02114 USA.
EM aabramovitch@mgh.harvard.edu
OI Abramovitch, Amitai/0000-0001-9640-0970
NR 56
TC 3
Z9 4
U1 1
U2 22
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0005-7916
EI 1873-7943
J9 J BEHAV THER EXP PSY
JI J. Behav. Ther. Exp. Psychiatry
PD MAR
PY 2015
VL 46
BP 66
EP 71
DI 10.1016/j.jbtep.2014.09.001
PG 6
WC Psychology, Clinical; Psychiatry
SC Psychology; Psychiatry
GA AX0ED
UT WOS:000346625200010
PM 25244676
ER
PT J
AU Villani, TS
Reichert, W
Ferruzzi, MG
Pasinetti, GM
Simon, JE
Wu, QL
AF Villani, Tom S.
Reichert, William
Ferruzzi, Mario G.
Pasinetti, Giulio M.
Simon, James E.
Wu, Qingli
TI Chemical investigation of commercial grape seed derived products to
assess quality and detect adulteration
SO FOOD CHEMISTRY
LA English
DT Article
DE Grape seed extract; LC-MS; Polyphenol; Proanthocyanidins; Adulteration;
Quality control
ID ALZHEIMERS-DISEASE; ANTIOXIDANT CAPACITY; DIETARY-SUPPLEMENTS; PEANUT
SKINS; IN-VITRO; PROANTHOCYANIDINS; EXTRACT; BIOAVAILABILITY;
ANTIBACTERIAL; PROCYANIDINS
AB Fundamental concerns in quality control arise due to increasing use of grape seed extract (GSE) and the complex chemical composition of GSE. Proanthocyanidin monomers and oligomers are the major bioactive compounds in GSE. Given no standardized criteria for quality, large variation exists in the composition of commercial GSE supplements. Using HPLC/UV/MS, 21 commercial GSE containing products were purchased and chemically profiled, major compounds quantitated, and compared against authenticated grape seed extract, peanut skin extract, and pine bark extract. The antioxidant capacity and total polyphenol content for each sample was also determined and compared using standard techniques. Nine products were adulterated, found to contain peanut skin extract. A wide degree of variability in chemical composition was detected in commercial products, demonstrating the need for development of quality control standards for GSE. A TLC method was developed to allow for rapid and inexpensive detection of adulteration in GSE by peanut skin. (C) 2014 Elsevier Ltd. All rights reserved.
C1 [Villani, Tom S.; Reichert, William; Simon, James E.; Wu, Qingli] Rutgers State Univ, Dept Plant Biol & Pathol, New Use Agr & Nat Plant Prod Program, New Brunswick, NJ 08901 USA.
[Villani, Tom S.; Simon, James E.; Wu, Qingli] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Med Chem, Piscataway, NJ 08854 USA.
[Ferruzzi, Mario G.] Purdue Univ, Dept Food Sci, W Lafayette, IN 47907 USA.
[Pasinetti, Giulio M.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA.
[Pasinetti, Giulio M.] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY 10468 USA.
RP Simon, JE (reprint author), Rutgers State Univ, Dept Plant Biol & Pathol, New Use Agr & Nat Plant Prod Program, New Brunswick, NJ 08901 USA.
EM jimsimon@rci.rutgers.edu; qlwu@aesop.rutgers.edu
FU National Institute of Health [PO1AT004511]; Rutgers New Use Agriculture
and Natural Plant Products Program; New Jersey Agricultural Experiment
Station, Rutgers, The State University of New Jersey
FX This work was supported by the National Institute of Health grant
PO1AT004511. We also thank the Rutgers New Use Agriculture and Natural
Plant Products Program and the New Jersey Agricultural Experiment
Station, Rutgers, The State University of New Jersey for their partial
funding and support. We thank Xiaoyou Zhang in BannerBio Nutraceuticals
Inc. (Shenzhen, China) for providing the authenticated reference
materials. We thank Paul Coates, Joe Betz, Gordon Cragg and others at
the NIH ODS for their interest in this work. We thank Ray Facto, Wendy
Wang, and Grace Lin for their invaluable help in this work.
NR 48
TC 5
Z9 5
U1 2
U2 85
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0308-8146
EI 1873-7072
J9 FOOD CHEM
JI Food Chem.
PD MAR 1
PY 2015
VL 170
BP 271
EP 280
DI 10.1016/j.foodchem.2014.08.084
PG 10
WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics
SC Chemistry; Food Science & Technology; Nutrition & Dietetics
GA AR7SO
UT WOS:000343780400036
PM 25306345
ER
PT J
AU Luke, JJ
Ott, PA
AF Luke, Jason J.
Ott, Patrick A.
TI PD-1 pathway inhibitors: The next generation of immunotherapy for
advanced melanoma
SO ONCOTARGET
LA English
DT Article
DE immunotherapy; melanoma; programmed death 1 pathway; PD-1; adverse
events
ID MONOCLONAL-ANTIBODY MK-3475; ONCOLOGY-GROUP TRIALS; METASTATIC MELANOMA;
CANCER-IMMUNOTHERAPY; IMPROVED SURVIVAL; PATIENTS PTS; ANTI-CTLA-4
ANTIBODIES; ANTI-PD-1 ANTIBODY; ANTITUMOR-ACTIVITY; RESPONSE CRITERIA
AB Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumab-treated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novo stimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors, including discussion of their novel mechanism of action and clinical data to-date, with a focus on melanoma.
C1 [Luke, Jason J.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA.
[Ott, Patrick A.] Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02115 USA.
[Ott, Patrick A.] Harvard Univ, Sch Med, Boston, MA USA.
RP Luke, JJ (reprint author), Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA.
EM jluke@medicine.bsd.uchicago.edu
FU Bristol-Myers Squibb
FX The authors take full responsibility for the content of this publication
and confirm that it reflects their viewpoint and expertise. Professional
medical writing assistance was provided by Britt Anderson, PhD and
professional editing assistance was provided by Karin McGlynn at
StemScientific and was funded by Bristol-Myers Squibb. Bristol-Myers
Squibb generated the concept for this Review Article; however, the
authors developed the content. Bristol-Myers Squibb reviewed a draft for
medical accuracy only. Neither Bristol-Myers Squibb nor StemScientific
influenced the content of the manuscript, nor did the authors receive
financial compensation for authoring the manuscript.
NR 69
TC 35
Z9 38
U1 2
U2 12
PU IMPACT JOURNALS LLC
PI ALBANY
PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA
SN 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD FEB 28
PY 2015
VL 6
IS 6
BP 3479
EP 3492
PG 14
WC Oncology; Cell Biology
SC Oncology; Cell Biology
GA CF6WB
UT WOS:000352696200005
PM 25682878
ER
PT J
AU Chang, K
Karnad, A
Zhao, SJ
Freeman, JW
AF Chang, Katherine
Karnad, Anand
Zhao, Shujie
Freeman, James W.
TI Roles of c-Met and RON Kinases in tumor progression and their potential
as therapeutic targets
SO ONCOTARGET
LA English
DT Article
DE c-Met; RON kinase; Met inhibitors
ID RECEPTOR TYROSINE KINASE; HEPATOCYTE GROWTH-FACTOR; CELL LUNG-CANCER;
GLIOBLASTOMA STEM-CELLS; PANCREATIC-CANCER; BREAST-CANCER;
HEPATOCELLULAR-CARCINOMA; TUMORIGENIC ACTIVITIES; SIGNALING PATHWAY;
POINT MUTATIONS
AB c-Met and receptor originated from nantes (RON) are structurally related transmembrane phosphotyrosine kinase receptors. c-Met and RON show increased expression or activity in a variety of tumors leading to tumor progression and may play a role in acquired resistance to therapy. Although often co-expressed, the distinct functional roles of c-Met and RON are not fully understood. c-Met and RON form both activated homodimers and heterodimers with themselves and other families of phosphotyrosine kinase receptors. Inhibitors for c-Met and RON including small molecular weigh kinase inhibitors and neutralizing antibodies are in pre-clinical investigation and clinical trials. Several of the tyrosine kinase inhibitors have activity against both c-Met and RON kinases whereas the antibodies generally are target specific. As with many targeted agents used to treat solid tumors, it is likely that c-Met/RON inhibitors will have greater benefit when used in combination with chemotherapy or other targeted agents. A careful analysis of c-Met/RON expression or activity and a better elucidation of how they influence cell signaling will be useful in predicting which tumors respond best to these inhibitors as well as determining which agents can be used with these inhibitors for combined therapy.
C1 [Chang, Katherine; Karnad, Anand; Zhao, Shujie; Freeman, James W.] Univ Texas Hlth Sci Ctr San Antonio, Div Med Oncol, Dept Med, San Antonio, TX 78229 USA.
[Chang, Katherine; Karnad, Anand; Freeman, James W.] Canc Therapy & Res Ctr S Texas, Expt & Dev Therapeut Program, San Antonio, TX 78229 USA.
[Freeman, James W.] Audie L Murphy Mem Vet Adm Med Ctr, Res & Dev, San Antonio, TX USA.
RP Freeman, JW (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Med Oncol, Dept Med, Floyd Curl Dr, San Antonio, TX 78229 USA.
EM freemanjw@uthscsa.edu
FU VA merit award; CPRIT; [NIH-RO1CA069122]; [NIH-P30CA054174]
FX This work was supported by Grants to J.W.F., VA merit award, and
NIH-RO1CA069122 and NIH-P30CA054174. The authors would like to thank Mr.
David Baker for design of medical illustrations. The work was also
supported by CPRIT postdoctoral fellowship to Dr. Katherine Chang.
NR 91
TC 11
Z9 12
U1 0
U2 2
PU IMPACT JOURNALS LLC
PI ALBANY
PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA
SN 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD FEB 28
PY 2015
VL 6
IS 6
BP 3507
EP 3518
PG 12
WC Oncology; Cell Biology
SC Oncology; Cell Biology
GA CF6WB
UT WOS:000352696200007
PM 25784650
ER
PT J
AU Jackman, DM
Cioffredi, LA
Jacobs, L
Sharmeen, F
Morse, LK
Lucca, J
Plotkin, SR
Marcoux, PJ
Rabin, MS
Lynch, TJ
Johnson, BE
Kesari, S
AF Jackman, David M.
Cioffredi, Leigh A.
Jacobs, Lorraine
Sharmeen, Farhana
Morse, Linda K.
Lucca, Joan
Plotkin, Scott R.
Marcoux, Paul J.
Rabin, Michael S.
Lynch, Thomas J.
Johnson, Bruce E.
Kesari, Santosh
TI A Phase I trial of high dose gefitinib for patients with leptomeningeal
metastases from non-small cell lung cancer
SO ONCOTARGET
LA English
DT Article
DE non-small cell lung carcinoma; epidermal growth factor receptor;
meningeal carcinomatosis; kinase inhibitors
ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; SOLID TUMORS; ZD1839;
EGFR; MUTATIONS; IRESSA; CARCINOMATOSIS; CHEMOTHERAPY; RESISTANCE
AB Introduction: There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI.
Methods: This phase I open-label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR-TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF).
Results: Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3months (range 1.6-4.0 months); median OS was 3.5months (range 1.6-5.1months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF.
Conclusion: Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high-dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation.
C1 [Jackman, David M.; Sharmeen, Farhana; Morse, Linda K.; Lucca, Joan; Marcoux, Paul J.; Rabin, Michael S.; Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA.
[Jackman, David M.; Plotkin, Scott R.; Marcoux, Paul J.; Rabin, Michael S.; Johnson, Bruce E.] Harvard Univ, Sch Med, Boston, MA USA.
[Kesari, Santosh] Univ Calif San Diego, Dept Neurosci, Moores UCSD Canc Ctr, Translat Neurooncol Labs, La Jolla, CA 92093 USA.
[Cioffredi, Leigh A.] Georgetown Univ, Sch Med, Washington, DC USA.
[Jacobs, Lorraine] Eurofins Medinet BV, Breda, Netherlands.
[Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA USA.
[Lynch, Thomas J.] Smilow Canc Hosp Yale New Haven, Yale Canc Ctr, New Haven, CT USA.
[Lynch, Thomas J.] Yale Univ, New Haven, CT USA.
RP Jackman, DM (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA.
EM djackman@partners.org; skesari@ucsd.edu
FU AstraZeneca Pharmaceuticals; Dunkin Donuts Rising Stars Program;
American Society of Clinical Oncology (ASCO) Translational Research
Professorship; Alice and Steven D. Cutler Investigator Fund in Thoracic
Oncology; NIH [3P30CA023100-25S8]; James S. McDonnell Foundation
FX This trial was supported in part by AstraZeneca Pharmaceuticals, the
Dunkin Donuts Rising Stars Program (DMJ), the American Society of
Clinical Oncology (ASCO) Translational Research Professorship (BEJ,
DMJ), and the Alice and Steven D. Cutler Investigator Fund in Thoracic
Oncology (DMJ). This work was also supported in part by grants from NIH
3P30CA023100-25S8 (SK) and James S. McDonnell Foundation (SK).
NR 35
TC 11
Z9 12
U1 0
U2 0
PU IMPACT JOURNALS LLC
PI ALBANY
PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA
SN 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD FEB 28
PY 2015
VL 6
IS 6
BP 4527
EP 4536
PG 10
WC Oncology; Cell Biology
SC Oncology; Cell Biology
GA CF6WB
UT WOS:000352696200084
PM 25784657
ER
PT J
AU Yentes, JM
Schmid, KK
Blanke, D
Romberger, DJ
Rennard, SI
Stergiou, N
AF Yentes, Jennifer M.
Schmid, Kendra K.
Blanke, Daniel
Romberger, Debra J.
Rennard, Stephen I.
Stergiou, Nicholas
TI Gait mechanics in patients with chronic obstructive pulmonary disease
SO RESPIRATORY RESEARCH
LA English
DT Article
DE Pulmonary disease; Locomotion; Joint kinematics; Joint kinetics;
Biomechanics
ID VASTUS LATERALIS MUSCLE; RANDOMIZED CONTROLLED-TRIAL; TRAUMATIC
BRAIN-INJURY; STEP WIDTH VARIABILITY; CEREBRAL-PALSY; CARDIORESPIRATORY
DISORDERS; EXERCISE PERFORMANCE; SYMPTOM INTENSITY; PHYSICAL-ACTIVITY;
FUNCTIONAL STATUS
AB Background: Chronic obstructive pulmonary disease (COPD) is characterized by the frequent association of disease outside the lung. The objective of this study was to determine the presence of biomechanical gait abnormalities in COPD patients compared to healthy controls while well rested and without rest.
Methods: Patients with COPD (N = 17) and aged-matched, healthy controls (N = 21) walked at their self-selected pace down a 10-meter walkway while biomechanical gait variables were collected. A one-minute rest was given between each of the five collected trials to prevent tiredness (REST condition). Patients with COPD then walked at a self-selected pace on a treadmill until the onset of self-reported breathlessness or leg tiredness. Subjects immediately underwent gait analysis with no rest between each of the five collected trials (NO REST condition). Statistical models with and without covariates age, gender, and smoking history were used.
Results: After adjusting for covariates, COPD patients demonstrated more ankle power absorption in mid-stance (P = 0.006) than controls during both conditions. Both groups during NO REST demonstrated increased gait speed (P = 0.04), stride length (P = 0.03), and peak hip flexion (P = 0.04) with decreased plantarflexion moment (P = 0.04) and increased knee power absorption (P = 0.04) as compared to REST. A significant interaction revealed that peak ankle dorsiflexion moment was maintained from REST to NO REST for COPD but increased for controls (P < 0.01). Stratifying by disease severity did not alter these findings, except that step width decreased in NO REST as compared to REST (P = 0.01). Standardized effect sizes of significant effects varied from 0.5 to 0.98.
Conclusions: Patients with COPD appear to demonstrate biomechanical gait changes at the ankle as compared to healthy controls. This was seen not only in increased peak ankle power absorption during no rest but was also demonstrated by a lack of increase in peak ankle dorsiflexion moment from the REST to the NO REST condition as compared to the healthy controls. Furthermore, a wider step width has been associated with fall risk and this could account for the increased incidence of falls in patients with COPD.
C1 [Yentes, Jennifer M.; Blanke, Daniel; Stergiou, Nicholas] Univ Nebraska, Omaha, NE 68182 USA.
[Schmid, Kendra K.; Stergiou, Nicholas] Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE 68198 USA.
[Romberger, Debra J.] Nebraska Western Iowa Vet Hlth Care Syst, US Dept Vet Affairs, Omaha, NE 68105 USA.
[Romberger, Debra J.; Rennard, Stephen I.] Univ Nebraska Med Ctr, Dept Pulm & Crit Care Med, Omaha, NE 68198 USA.
RP Yentes, JM (reprint author), Univ Nebraska, Biomech Res Bldg,6001 Dodge St, Omaha, NE 68182 USA.
EM jyentes@unomaha.edu
OI Yentes, Jennifer/0000-0001-6550-7759
FU Nebraska Medical Center; University of Nebraska Medical Center; National
Institutes of Health [P20 GM109090]
FX The authors would like to thank Mary Carlson, NP for her assistance in
screening all of the subjects and Jeff Kaipust, MS for his assistance
with data collections. Funding provided by American Society of
Biomechanics Grant-in-Aid, American Alliance for Health, Physical
Education, Recreation and Dance Graduate Student Grant-in-Aid, NASA
Nebraska Space Grant Fellowship program and Research Support Fund from
the Nebraska Medical Center and the University of Nebraska Medical
Center. Additional funding provided by the National Institutes of Health
(P20 GM109090). Funding sources had no involvement in study design, data
interpretation, and/or manuscript preparation.
NR 82
TC 0
Z9 0
U1 1
U2 6
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1465-993X
EI 1465-9921
J9 RESP RES
JI Respir. Res.
PD FEB 28
PY 2015
VL 16
AR 31
DI 10.1186/s12931-015-0187-5
PG 13
WC Respiratory System
SC Respiratory System
GA CD0VD
UT WOS:000350791100001
PM 25849481
ER
PT J
AU Singh, JP
Holzmeister, J
AF Singh, Jagmeet P.
Holzmeister, Johannes
TI SIMPLEr not to test implantable cardioverter defibrillators?
SO LANCET
LA English
DT Editorial Material
ID EXPERIENCE
C1 [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA USA.
[Holzmeister, Johannes] Univ Zurich, Univ Heart Ctr Zurich, CH-8091 Zurich, Switzerland.
RP Holzmeister, J (reprint author), Univ Zurich, Univ Heart Ctr Zurich, CH-8091 Zurich, Switzerland.
EM johannes.holzmeister@gmail.com
NR 11
TC 1
Z9 2
U1 0
U2 2
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0140-6736
EI 1474-547X
J9 LANCET
JI Lancet
PD FEB 28
PY 2015
VL 385
IS 9970
BP 753
EP 755
DI 10.1016/S0140-6736(15)60242-2
PG 3
WC Medicine, General & Internal
SC General & Internal Medicine
GA CC0UD
UT WOS:000350051700011
PM 25715990
ER
PT J
AU Elmariah, S
Mauri, L
Doros, G
Galper, BZ
O'Neill, KE
Steg, PG
Kereiakes, DJ
Yeh, RW
AF Elmariah, Sammy
Mauri, Laura
Doros, Gheorghe
Galper, Benjamin Z.
O'Neill, Kelly E.
Steg, Philippe Gabriel
Kereiakes, Dean J.
Yeh, Robert W.
TI Extended duration dual antiplatelet therapy and mortality: a systematic
review and meta-analysis
SO LANCET
LA English
DT Article
ID PERCUTANEOUS CORONARY INTERVENTION; ELUTING STENT IMPLANTATION;
CONTROLLED-TRIAL; CLOPIDOGREL; ASPIRIN; DEATH; DISCONTINUATION;
MULTICENTER; EFFICACY; STROKE
AB Background Treatment with aspirin and a P2Y12 inhibitor is commonly used in patients with cardiovascular disorders. The overall effect of such treatment on all-cause mortality is unknown. In the Dual Antiplatelet Therapy (DAPT) Study, continuation of dual antiplatelet therapy beyond 12 months after coronary stenting was associated with an unexpected increase in non-cardiovascular death. In view of the potential public health importance of these findings, we aimed to assess the effect of extended duration dual antiplatelet therapy on mortality by doing a meta-analysis of all randomised, controlled trials of treatment duration in various cardiovascular disorders.
Methods We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomised controlled trials assessing the effect of extended duration versus no or short duration dual antiplatelet therapy, published before Oct 1, 2014. We did a meta-analysis to pool results with a hierarchical Bayesian random-effects model. The primary outcomes were hazard ratios comparing rates of all-cause, cardiovascular, and non-cardiovascular death.
Findings Including the DAPT Study, we identified 14 eligible trials that randomly assigned 69 644 participants to different durations of dual antiplatelet therapy. Compared with aspirin alone or short duration dual antiplatelet therapy (<= 6 months), continued treatment was not associated with a difference in all-cause mortality (hazard ratio [HR] 1.05, 95% credible interval [CrI] 0.96-1.19; p=0.33). Similarly, cardiovascular (1.01, 0.93-1.12; p=0.81) and non-cardiovascular mortality (1.04, 0.90-1.26; p=0.66) were no different with extended duration versus short duration dual antiplatelet therapy or aspirin alone.
Interpretation Extended duration dual antiplatelet therapy was not associated with a difference in the risk of all-cause, cardiovascular, or non-cardiovascular death compared with aspirin alone or short duration dual antiplatelet therapy.
C1 [Elmariah, Sammy; Yeh, Robert W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA 02114 USA.
[Mauri, Laura; Galper, Benjamin Z.; O'Neill, Kelly E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA 02114 USA.
[Elmariah, Sammy; Mauri, Laura; Doros, Gheorghe; Yeh, Robert W.] Harvard Clin Res Inst, Boston, MA USA.
[Doros, Gheorghe] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
[Steg, Philippe Gabriel] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France.
[Steg, Philippe Gabriel] Dept Hosp Univ FIRE Fibrosis Inflammat & Remodeli, INSERM, U1148, Paris, France.
[Steg, Philippe Gabriel] Hop Bichat Claude Bernard, AP HP, F-75877 Paris, France.
[Steg, Philippe Gabriel] Univ London Imperial Coll Sci Technol & Med, Natl Heart Lung Inst, Royal Brompton Hosp, London, England.
[Kereiakes, Dean J.] Christ Hosp Heart & Vasc Ctr, Lindner Res Ctr, Cincinnati, OH USA.
RP Yeh, RW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA 02114 USA.
EM ryeh@mgh.harvard.edu
FU American Heart Association; Siemens Medical Solutions; Abbott; Boston
Scientific; Cordis; Medtronic; Eli Lilly/Daiichi Sankyo;
Sanofi-Aventis/Bristol-Myers Squibb; Recor; St Jude Medical (St Paul,
MN, USA); Biotronik; Amarin; AstraZeneca; Bayer; Boehringer Ingelheim;
Bristol-Myers Squibb; Daiichi-Sankyo; GlaxoSmithKline; Eli Lilly;
Merck-Sharpe-Dohme; Novartis; Otsuka; Pfizer; Sanofi-Aventis; Servier;
Vivus; Janssen; Medicines Company; Orexigen; Abbott Vascular; Gilead
Sciences
FX SE reports institutional research grants from the American Heart
Association and Siemens Medical Solutions. LM reports institutional
research grants from Abbott, Boston Scientific, Cordis, Medtronic, Eli
Lilly/Daiichi Sankyo, and Sanofi-Aventis/Bristol-Myers Squibb; and
personal fees from Medtronic, Recor, St Jude Medical (St Paul, MN, USA),
and Biotronik. PGS reports personal fees from Amarin, AstraZeneca,
Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo,
GlaxoSmithKline, Eli Lilly, Merck-Sharpe-Dohme, Novartis, Otsuka,
Pfizer, Roche, Medtronic, Sanofi-Aventis, Servier, Vivus, Janssen, The
Medicines Company, and Orexigen; and grants from Sanofi-Aventis and
Servier. RWY reports personal fees from Abbott Vascular and Gilead
Sciences.
NR 25
TC 69
Z9 73
U1 2
U2 14
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 28
PY 2015
VL 385
IS 9970
BP 792
EP 798
DI 10.1016/S0140-6736(14)62052-3
PG 7
WC Medicine, General & Internal
SC General & Internal Medicine
GA CC0UD
UT WOS:000350051700033
PM 25467565
ER
PT J
AU Braunwald, E
AF Braunwald, Eugene
TI The war against heart failure: the Lancet lecture
SO LANCET
LA English
DT Review
ID VENTRICULAR ASSIST DEVICE; MECHANICAL CIRCULATORY SUPPORT; MESENCHYMAL
STEM-CELLS; ACUTE MYOCARDIAL-INFARCTION; CARDIOSPHERE-DERIVED CELLS;
CALCIUM UP-REGULATION; FAILING HUMAN HEARTS; BONE-MARROW-CELLS;
GENE-THERAPY; SARCOPLASMIC-RETICULUM
AB Heart failure is a global problem with an estimated prevalence of 38 million patients worldwide, a number that is increasing with the ageing of the population. It is the most common diagnosis in patients aged 65 years or older admitted to hospital and in high-income nations. Despite some progress, the prognosis of heart failure is worse than that of most cancers. Because of the seriousness of the condition, a declaration of war on five fronts has been proposed for heart failure. Efforts are underway to treat heart failure by enhancing myofilament sensitivity to Ca2+; transfer of the gene for SERCA2a, the protein that pumps calcium into the sarcoplasmic reticulum of the cardiomyocyte, seems promising in a phase 2 trial. Several other abnormal calcium-handling proteins in the failing heart are candidates for gene therapy; many short, non-coding RNAs-ie, microRNAs (miRNAs)-block gene expression and protein translation. These molecules are crucial to calcium cycling and ventricular hypertrophy. The actions of miRNAs can be blocked by a new class of drugs, antagomirs, some of which have been shown to improve cardiac function in animal models of heart failure; cell therapy, with autologous bone marrow derived mononuclear cells, or autogenous mesenchymal cells, which can be administered as cryopreserved off the shelf products, seem to be promising in both preclinical and early clinical heart failure trials; and long-term ventricular assistance devices are now used increasingly as a destination therapy in patients with advanced heart failure. In selected patients, left ventricular assistance can lead to myocardial recovery and explantation of the device. The approaches to the treatment of heart failure described, when used alone or in combination, could become important weapons in the war against heart failure.
C1 [Braunwald, Eugene] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA.
[Braunwald, Eugene] Harvard Univ, Sch Med, Dept Med, Boston, MA USA.
RP Braunwald, E (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
EM ebraunwald@partners.org
NR 162
TC 84
Z9 89
U1 24
U2 77
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 28
PY 2015
VL 385
IS 9970
BP 812
EP 824
DI 10.1016/S0140-6736(14)61889-4
PG 13
WC Medicine, General & Internal
SC General & Internal Medicine
GA CC0UD
UT WOS:000350051700036
PM 25467564
ER
PT J
AU del Re, EC
Spencer, KM
Oribe, N
Mesholam-Gately, RI
Goldstein, J
Shenton, ME
Petryshen, T
Seidman, LJ
McCarley, RW
Niznikiewicz, MA
AF del Re, Elisabetta C.
Spencer, Kevin M.
Oribe, Naoya
Mesholam-Gately, Raquelle I.
Goldstein, Jill
Shenton, Martha E.
Petryshen, Tracey
Seidman, Larry J.
McCarley, Robert W.
Niznikiewicz, Margaret A.
TI Clinical high risk and first episode schizophrenia: Auditory
event-related potentials
SO PSYCHIATRY RESEARCH-NEUROIMAGING
LA English
DT Article
DE N100; P200; P3a; P3b
ID TEMPORAL GYRUS VOLUME; ANTERIOR CINGULATE CORTEX; P300 AMPLITUDE;
1ST-EPISODE PSYCHOSIS; INITIAL PRODROME; FOLLOW-UP; INDIVIDUALS;
ABNORMALITIES; PREDICTION; RELIABILITY
AB The clinical high risk (CUR) period is a phase denoting a risk for overt psychosis during which subacute symptoms often appear, and cognitive functions may deteriorate. To compare biological indices during this phase with those during first episode schizophrenia, we cross-sectionally examined sex- and age-matched clinical high risk (CHR, n=21), first episode schizophrenia patients (FESZ, n=20) and matched healthy controls (HC, n=25) on oddball and novelty paradigms and assessed the N100, P200, P3a and P3b as indices of perceptual, attentional and working memory processes. To our knowledge, this is the only such comparison using all of these event-related potentials (ERPs) in two paradigms. We hypothesized that the ERPs would differentiate between the three groups and allow prediction of a diagnostic group. The majority of ERPs were significantly affected in CUR and FESZ compared with controls, with similar effect sizes. Nonetheless, in logistic regression, only the P3a and N100 distinguished CUR and FESZ from healthy controls, suggesting that ERPs not associated with an overt task might be more sensitive to prediction of group membership. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
C1 [del Re, Elisabetta C.; Spencer, Kevin M.; Oribe, Naoya; Shenton, Martha E.; McCarley, Robert W.; Niznikiewicz, Margaret A.] VA Boston Healthcare Syst, Brockton, MA 02130 USA.
[del Re, Elisabetta C.; Spencer, Kevin M.; Oribe, Naoya; Mesholam-Gately, Raquelle I.; Shenton, Martha E.; Petryshen, Tracey; McCarley, Robert W.; Niznikiewicz, Margaret A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA.
[Oribe, Naoya] Kyushu Univ, Grad Sch Med Sci, Dept Neuropsychiat, Fukuoka 812, Japan.
[Mesholam-Gately, Raquelle I.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Mental Hlth Ctr,Div Publ Psychiat,Dept Psychiat, Boston, MA 02215 USA.
[Goldstein, Jill; Seidman, Larry J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA.
[Goldstein, Jill] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA.
[Goldstein, Jill] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA.
[Goldstein, Jill] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
[del Re, Elisabetta C.; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat,Psychiat Neuroimaging Lab, Boston, MA 02115 USA.
[del Re, Elisabetta C.; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA.
[Petryshen, Tracey] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.
[Petryshen, Tracey] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Psychiat, Boston, MA 02114 USA.
RP del Re, EC (reprint author), VA Boston Healthcare Syst, Brockton, MA 02130 USA.
EM elisabetta_delre@hms.harvard.edu
FU Department of Veterans' Affairs Medical Research Awards (Schizophrenia
Center, Merit Awards); National Institute of Mental Health [K05MH070047,
R01MH50747, R01MH40799, R01MH052807, CIDAR P50MH080272]
FX Support was provided by Department of Veterans' Affairs Medical Research
Awards (Schizophrenia Center, Merit Awards to R.W.M. and M.ES.) and
National Institute of Mental Health (K05MH070047 and R01MH50747 to
M.E.S., R01MH40799 and R01MH052807 to R.W.M., CIDAR P50MH080272 to
R.W.M. and M.E.S.).
NR 90
TC 5
Z9 5
U1 3
U2 11
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
IRELAND
SN 0925-4927
EI 1872-7506
J9 PSYCHIAT RES-NEUROIM
JI Psychiatry Res. Neuroimaging
PD FEB 28
PY 2015
VL 231
IS 2
BP 126
EP 133
DI 10.1016/j.pscychresns.2014.11.012
PG 8
WC Clinical Neurology; Neuroimaging; Psychiatry
SC Neurosciences & Neurology; Psychiatry
GA CA3YN
UT WOS:000348841200005
PM 25557063
ER
PT J
AU Annamalai, B
Won, JS
Choi, S
Singh, I
Singh, AK
AF Annamalai, Balasubramaniam
Won, Je-Seong
Choi, Seungho
Singh, Inderjit
Singh, Avtar K.
TI Role of S-nitrosoglutathione mediated mechanisms in tau
hyper-phosphorylation
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Calpain; Cdk5; GSK-3 beta; p25; S-nitrosoglutathione; Tau
ID NITRIC-OXIDE SYNTHASE; BETA-AMYLOID PEPTIDE; ALZHEIMERS-DISEASE; RAT
MODEL; IN-VIVO; CDK5; NITROSYLATION; PEROXYNITRITE; CALPAIN; P25
AB Hyperphosphorylation and polymerization of microtubule-associated protein tau into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease (AD). Here we report that neuronal tau hyperphosphorylation under AD conditions is regulated by S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier molecule. In cultured rat cortical primary neurons, we observed that GSNO treatment decreased the beta-amyloid (A beta(25-35))-induced pathological tau hyperphosphorylation (Ser396, Ser404, and Ser202/Thr205). The decreased tau hyperphosphorylation correlated with decreased activity of calpain and decreased p35 proteolysis into p25 and Cdk5 activation. GSNO treatment also attenuated the Alias (-35)-induced activation of GSK-3 beta which is known to play critical role in tau hyperphosphorylation in addition to Cdk5. Consistent with above studies using cultured neurons, we also observed that systemic GSNO treatment of transgenic mouse model of AD (APP(Sw)/PS1(dE9)) attenuated calpain-mediated p35 proteolysis and Cdk5/GSK-3 beta activities as well as tau hyperphosphorylation. In addition, GSNO treatment provided neuro- and cognitive protection in APP(Sw)/PS1(dE9) mice. This study describing the GSNO-mediated regulation of tau hyperphosphorylation and cognitive function, for the first time, suggests for therapeutic potential of GSNO as neuro- and cognitive-protective agent for AD. Published by Elsevier Inc.
C1 [Annamalai, Balasubramaniam; Won, Je-Seong; Singh, Avtar K.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA.
[Choi, Seungho; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA.
[Singh, Avtar K.] Ralph H Johnson Vet Adm Med Ctr, Dept Pathol & Lab Med Serv, Charleston, SC USA.
RP Singh, AK (reprint author), Med Univ S Carolina, Charles P Darby Children Res Inst, 504D,173 Ashley Ave, Charleston, SC 29425 USA.
EM avtar.singh@va.gov
FU NIH; VA [NS072511, BX001062, NS037766, BX001072]
FX This work was supported in part by grants from NIH and VA (NS072511,
BX001062, NS037766 and BX001072).
NR 33
TC 8
Z9 8
U1 0
U2 6
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD FEB 27
PY 2015
VL 458
IS 1
BP 214
EP 219
DI 10.1016/j.bbrc.2015.01.093
PG 6
WC Biochemistry & Molecular Biology; Biophysics
SC Biochemistry & Molecular Biology; Biophysics
GA CD7DB
UT WOS:000351249900035
PM 25640839
ER
PT J
AU Yenikomshian, MA
Guignard, AP
Haguinet, F
LaCasce, AS
Skarin, AT
Trahey, A
Karner, P
Duh, MS
AF Yenikomshian, Mihran A.
Guignard, Adrienne P.
Haguinet, Francois
LaCasce, Ann S.
Skarin, Arthur T.
Trahey, Alex
Karner, Paul
Duh, Mei Sheng
TI The epidemiology of herpes zoster and its complications in Medicare
cancer patients
SO BMC INFECTIOUS DISEASES
LA English
DT Article
DE herpes zoster; Neoplasms; Incidence; Elderly; Risk factors; Neuralgia;
Postherpetic neuralgia
ID CLINICAL COMORBIDITY INDEX; ADMINISTRATIVE DATABASE; POSTHERPETIC
NEURALGIA; RATES
AB Background: Literature on the epidemiology of herpes zoster (HZ) in cancer patients is sparse and does not include the elderly. The objectives of this study were to determine the incidence of HZ and related complications in elderly cancer patients and assess risk factors associated with HZ.
Methods: Patients >= 65 years diagnosed with cancer in 1991-2007 were identified from the Surveillance, Epidemiology, and End Results (SEER) cancer registry-Medicare linked database in this retrospective, longitudinal, open cohort study. The observation period spanned from first cancer diagnosis until the end of data availability. A random group of non-cancer Medicare patients served as the comparison group. Cases of HZ and related complications were ascertained from medical claims. Incidence rates (IR) and adjusted IR ratios were reported.
Results: The study population consisted of 82,832 hematologic (HEM) and 944,777 solid cancer patients (SOLID). During follow-up, 9.2% of HEM and 6.3% of SOLID were diagnosed with HZ. The IR of HZ was significantly higher in HEM than SOLID (31.0 vs. 14.9 per 1,000 patient-years, p <0.01). The adjusted IR ratio vs. non-cancer elderly patients was 2.4 in HEM and 1.2 in SOLID. The proportion of patients with complications was higher in HEM than SOLID (17.8% vs. 15.8%, p <0.01). Age, gender, race, certain cancer therapies, and immunosuppression were HZ risk factors.
Conclusions: Elderly cancer patients run a 1.2-2.4 times higher risk of developing HZ than those without cancer. The rates of HZ and HZ-related complications are significantly higher for hematologic than solid cancer patients.
C1 [Yenikomshian, Mihran A.; Trahey, Alex; Karner, Paul; Duh, Mei Sheng] Anal Grp Inc, Boston, MA 02199 USA.
[Guignard, Adrienne P.; Haguinet, Francois] GlaxoSmithKline Vaccines, Wavre, Belgium.
[LaCasce, Ann S.; Skarin, Arthur T.] Dana Farber Canc Inst, Boston, MA 02115 USA.
RP Yenikomshian, MA (reprint author), Anal Grp Inc, 111 Huntington Ave,Tenth Floor, Boston, MA 02199 USA.
EM Mihran.Yenikomshian@analysisgroup.com
FU GlaxoSmithKline Biologicals SA, Belgium; GlaxoSmithKline Vaccines
FX Research support was provided to Analysis Group, Inc. by GlaxoSmithKline
Biologicals SA, Belgium. M. Yenikomshian, P. Karner, A. Trahey, and M.
Duh were employees of Analysis Group, Inc. at the time the study was
conducted A. Guignard and F. Haguinet are employees of the
GlaxoSmithKline group of companies, A. Guignard receives stock equity as
part of her compensation. A. Skarin and A. LaCasce are employees of the
Dana-Farber Cancer Institute and have received consultation fees from
GlaxoSmithKline Vaccines for this study.
NR 23
TC 0
Z9 1
U1 0
U2 1
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2334
J9 BMC INFECT DIS
JI BMC Infect. Dis.
PD FEB 27
PY 2015
VL 15
AR 106
DI 10.1186/s12879-015-0810-6
PG 10
WC Infectious Diseases
SC Infectious Diseases
GA CC5WH
UT WOS:000350435200001
PM 25888128
ER
PT J
AU Nahrendorf, M
Swirski, FK
AF Nahrendorf, Matthias
Swirski, Filip K.
TI Lifestyle Effects on Hematopoiesis and Atherosclerosis
SO CIRCULATION RESEARCH
LA English
DT Review
DE atherosclerosis; bone marrow; cell proliferation; diet; hematopoiesis;
macrophages; monocytes; psychosocial; stress; sleep; spleen
ID OBSTRUCTIVE SLEEP-APNEA; ACUTE MYOCARDIAL-INFARCTION; POSITIVE AIRWAY
PRESSURE; STEM-CELL PROLIFERATION; MACROPHAGE ACCUMULATION;
ADIPOSE-TISSUE; DIM LIGHT; CARDIOVASCULAR-DISEASE; LESION FORMATION;
RISK-FACTORS
AB Diet, exercise, stress, and sleep are receiving attention as environmental modifiers of chronic inflammatory diseases, including atherosclerosis, the culprit condition of myocardial infarction and stroke. Accumulating data indicate that psychosocial stress and a high-fat, high-cholesterol diet aggravate cardiovascular disease, whereas regular physical activity and healthy sleeping habits help prevent it. Here, we raise the possibility that inflammation-associated leukocyte production plays a causal role in lifestyle effects on atherosclerosis progression. Specifically, we explore whether and how potent real-life disease modifiers influence hematopoiesis' molecular and cellular machinery. Lifestyle, we hypothesize, may rearrange hematopoietic topography, diverting production from the bone marrow to the periphery, thus propagating a quantitative and qualitative drift of the macrophage supply chain. These changes may involve progenitor-extrinsic and intrinsic communication nodes that connect organ systems along neuroimmune and immunometabolic axes, ultimately leading to an altered number and phenotype of lesional macrophages. We propose that, in conjunction with improved public health policy, future therapeutics could aim to modulate the quantitative and qualitative output, as well as the location, of the hematopoietic tree to decrease the risk of atherosclerosis complications.
C1 [Nahrendorf, Matthias; Swirski, Filip K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
RP Nahrendorf, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
EM mnahrendorf@mgh.harvard.edu; fswirski@mgh.harvard.edu
FU MGH Research Scholar Award; Howard M. Goodman Fellowship;
[R01HL117829]; [R01NS084863]; [R01HL095612]; [R56AI104695]
FX This work was supported by grants R01HL117829, R01NS084863, MGH Research
Scholar Award (to M. Nahrendorf), and R01HL095612, R56AI104695, and
Howard M. Goodman Fellowship (to F.K. Swirski).
NR 127
TC 11
Z9 14
U1 1
U2 11
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD FEB 27
PY 2015
VL 116
IS 5
BP 884
EP 894
DI 10.1161/CIRCRESAHA.116.303550
PG 11
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
Disease
SC Cardiovascular System & Cardiology; Hematology
GA CC5JR
UT WOS:000350395400019
PM 25722442
ER
PT J
AU Pelle, KG
Oh, K
Buchholz, K
Narasimhan, V
Joice, R
Milner, DA
Brancucci, NMB
Ma, SY
Voss, TS
Ketman, K
Seydel, KB
Taylor, TE
Barteneva, NS
Huttenhower, C
Marti, M
AF Pelle, Karell G.
Oh, Keunyoung
Buchholz, Kathrin
Narasimhan, Vagheesh
Joice, Regina
Milner, Danny A.
Brancucci, Nicolas M. B.
Ma, Siyuan
Voss, Till S.
Ketman, Ken
Seydel, Karl B.
Taylor, Terrie E.
Barteneva, Natasha S.
Huttenhower, Curtis
Marti, Matthias
TI Transcriptional profiling defines dynamics of parasite tissue
sequestration during malaria infection
SO GENOME MEDICINE
LA English
DT Article
ID PLASMODIUM-FALCIPARUM GAMETOCYTES; PROTEIN-INTERACTION NETWORK;
RED-BLOOD-CELLS; PFMC-2TM SUPERFAMILIES; INHIBITORY ANTIBODIES;
TRANSMISSION STAGES; SEXUAL DEVELOPMENT; GENE; GENOME; IDENTIFICATION
AB Background: During intra-erythrocytic development, late asexually replicating Plasmodium falciparum parasites sequester from peripheral circulation. This facilitates chronic infection and is linked to severe disease and organ-specific pathology including cerebral and placental malaria. Immature gametocytes - sexual stage precursor cells -likewise disappear from circulation. Recent work has demonstrated that these sexual stage parasites are located in the hematopoietic system of the bone marrow before mature gametocytes are released into the bloodstream to facilitate mosquito transmission. However, as sequestration occurs only in vivo and not during in vitro culture, the mechanisms by which it is regulated and enacted (particularly by the gametocyte stage) remain poorly understood.
Results: We generated the most comprehensive P. falciparum functional gene network to date by integrating global transcriptional data from a large set of asexual and sexual in vitro samples, patient-derived in vivo samples, and a new set of in vitro samples profiling sexual commitment. We defined more than 250 functional modules (clusters) of genes that are co-expressed primarily during the intra-erythrocytic parasite cycle, including 35 during sexual commitment and gametocyte development. Comparing the in vivo and in vitro datasets allowed us, for the first time, to map the time point of asexual parasite sequestration in patients to 22 hours post-invasion, confirming previous in vitro observations on the dynamics of host cell modification and cytoadherence. Moreover, we were able to define the properties of gametocyte sequestration, demonstrating the presence of two circulating gametocyte populations: gametocyte rings between 0 and approximately 30 hours post-invasion and mature gametocytes after around 7 days post-invasion.
Conclusions: This study provides a bioinformatics resource for the functional elucidation of parasite life cycle dynamics and specifically demonstrates the presence of the gametocyte ring stages in circulation, adding significantly to our understanding of the dynamics of gametocyte sequestration in vivo.
C1 [Pelle, Karell G.; Buchholz, Kathrin; Joice, Regina; Milner, Danny A.; Brancucci, Nicolas M. B.; Marti, Matthias] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA.
[Oh, Keunyoung; Narasimhan, Vagheesh; Ma, Siyuan; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
[Milner, Danny A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
[Brancucci, Nicolas M. B.; Voss, Till S.] Swiss Trop & Publ Hlth Inst, CH-4051 Basel, Switzerland.
[Ketman, Ken; Barteneva, Natasha S.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.
[Seydel, Karl B.; Taylor, Terrie E.] Michigan State Univ, Coll Osteopath Med, E Lansing, MI 48825 USA.
[Seydel, Karl B.; Taylor, Terrie E.] Univ Malawi, Blantyre Malaria Project, Coll Med, Blantyre 3, Malawi.
[Barteneva, Natasha S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA.
[Huttenhower, Curtis] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
RP Huttenhower, C (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
EM chuttenh@hsph.harvard.edu; mmarti@hsph.harvard.edu
OI Narasimhan, Vagheesh/0000-0001-8651-8844
FU Milton Fund award; Harvard Incubator seed fund; NIH [R01AI07558]; NSF
[DBI-1053486]; New England Biolabs; postdoctoral Feodor Lynen fellowship
from the Alexander von Humboldt foundation; Swiss National Science
Foundation
FX We would like to thank the patients and their families in Malawi for
their participation in this project. We would like to thank the team of
clinicians in Malawi who admit and care for the patients, as well as the
lab technicians who collected blood samples and performed routine
microscopy. We also like to acknowledge Jimmy Vareta and Mavis Menyere
for excellent technical support on site. This work was funded by a
Milton Fund award, a Harvard Incubator seed fund and NIH R01AI07558
(MM), and NSF DBI-1053486 (CH). Dr Karell Pelle was supported by a
graduate fellowship from New England Biolabs. Dr. Kathrin Buchholz was
supported by a postdoctoral Feodor Lynen fellowship from the Alexander
von Humboldt foundation. Dr Nicolas Brancucci was supported through a
postdoctoral fellowship from the Swiss National Science Foundation.
NR 68
TC 13
Z9 13
U1 0
U2 3
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1756-994X
J9 GENOME MED
JI Genome Med.
PD FEB 27
PY 2015
VL 7
AR 19
DI 10.1186/s13073-015-0133-7
PG 20
WC Genetics & Heredity
SC Genetics & Heredity
GA CC5FP
UT WOS:000350384800001
PM 25722744
ER
PT J
AU Tokhtaeva, E
Capri, J
Marcus, EA
Whitelegge, JP
Khuzakhmetova, V
Bukharaeva, E
Deiss-Yehiely, N
Dada, LA
Sachs, G
Fernandez-Salas, E
Vagin, O
AF Tokhtaeva, Elmira
Capri, Joe
Marcus, Elizabeth A.
Whitelegge, Julian P.
Khuzakhmetova, Venera
Bukharaeva, Ellya
Deiss-Yehiely, Nimrod
Dada, Laura A.
Sachs, George
Fernandez-Salas, Ester
Vagin, Olga
TI Septin Dynamics Are Essential for Exocytosis
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID EVOKED QUANTAL RELEASE; NEUROTRANSMITTER RELEASE; MICROTUBULE
ORGANIZATION; SNARE-COMPLEX; NEUROMUSCULAR-JUNCTIONS;
ENDOPLASMIC-RETICULUM; SYNAPTIC VESICLE; BARRIER FUNCTION; SEC6/8
COMPLEX; ALPHA-SNAP
AB Septins are a family of 14 cytoskeletal proteins that dynamically form hetero-oligomers and organize membrane microdomains for protein complexes. The previously reported interactions with SNARE proteins suggested the involvement of septins in exocytosis. However, the contradictory results of up-or down-regulation of septin-5 in various cells and mouse models or septin-4 in mice suggested either an inhibitory or a stimulatory role for these septins in exocytosis. The involvement of the ubiquitously expressed septin-2 or general septin polymerization in exocytosis has not been explored to date. Here, by nano-LC with tandem MS and immunoblot analyses of the septin-2 interactome in mouse brain, we identified not only SNARE proteins but also Munc-18-1 (stabilizes assembled SNARE complexes), N-ethylmaleimide-sensitive factor (NSF) (disassembles SNARE complexes after each membrane fusion event), and the chaperones Hsc70 and synucleins (maintain functional conformation of SNARE proteins after complex disassembly). Importantly, alpha-soluble NSF attachment protein (SNAP), the adaptor protein that mediates NSF binding to the SNARE complex, did not interact with septin-2, indicating that septins undergo reorganization during each exocytosis cycle. Partial depletion of septin-2 by siRNA or impairment of septin dynamics by forchlorfenuron inhibited constitutive and stimulated exocytosis of secreted and transmembrane proteins in various cell types. Forchlorfenuron impaired the interaction between SNAP-25 and its chaperone Hsc70, decreasing SNAP-25 levels in cultured neuroendocrine cells, and inhibited both spontaneous and stimulated acetylcholine secretion in mouse motor neurons. The results demonstrate a stimulatory role of septin-2 and the dynamic reorganization of septin oligomers in exocytosis.
C1 [Sachs, George] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA.
[Marcus, Elizabeth A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA.
[Tokhtaeva, Elmira; Marcus, Elizabeth A.; Sachs, George; Vagin, Olga] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA.
[Capri, Joe; Whitelegge, Julian P.] Univ Calif Los Angeles, Pasarow Mass Spectrometry Lab, Semel Inst, Neuropsychiat Inst, Los Angeles, CA 90024 USA.
[Khuzakhmetova, Venera; Bukharaeva, Ellya] Russian Acad Sci, Kazan Sci Ctr, Kazan Inst Biochem & Biophys, Kazan 420111, Russia.
[Bukharaeva, Ellya] Kazan Fed Univ, Kazan 420008, Russia.
[Deiss-Yehiely, Nimrod; Dada, Laura A.] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60611 USA.
[Fernandez-Salas, Ester] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA.
RP Vagin, O (reprint author), Univ Calif Los Angeles, Dept Physiol & Med, VAGLAHS West LA, 11301 Wilshire Blvd,Bldg 113,Rm 324, Los Angeles, CA 90073 USA.
EM olgav@ucla.edu
FU National Institutes of Health from the NHLBI [R01HL113350]; National
Institutes of Health from the NIDDK [UL1TR000124, K08DK100661-01,
P30DK063491]; UCLA Children's Discovery and Innovation Institute;
Program of Competitive Growth of Kazan Federal University; Russian
Foundation for Basic Research [15-04-02983a]
FX This work was supported, in whole or in part, by National Institutes of
Health Grants R01HL113350 from the NHLBI (to L. A. D. and O. V.),
UL1TR000124 (to the UCLA Clinical and Translational Science Institute
and E. A. M.), and K08DK100661-01 (to E. A. M.) and P30DK063491 from the
NIDDK (to J. P. W) This work was also supported by the UCLA Children's
Discovery and Innovation Institute (to E. A. M.), the Program of
Competitive Growth of Kazan Federal University (to E. B. and V. K.), and
Russian Foundation for Basic Research Grant 15-04-02983a (to E. B. and
V. K.).
NR 69
TC 11
Z9 11
U1 3
U2 10
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 27
PY 2015
VL 290
IS 9
BP 5280
EP 5297
DI 10.1074/jbc.M114.616201
PG 18
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA CC0RS
UT WOS:000350044200005
PM 25575596
ER
PT J
AU Papapetropoulos, S
Mitsi, G
Espay, AJ
AF Papapetropoulos, Spyros
Mitsi, Georgia
Espay, Alberto J.
TI Digital health revolution: is it time for affordable remote monitoring
for Parkinson's disease?
SO FRONTIERS IN NEUROLOGY
LA English
DT Editorial Material
DE Parkinson's disease; health outcomes; digital health; disease
management; remote monitoring
ID MOTOR FLUCTUATIONS; TELEMEDICINE; TRIAL; CARE; LEVODOPA
C1 [Papapetropoulos, Spyros] Univ Miami, Miller Sch Med, Dept Neurol, Boston, MA USA.
[Papapetropoulos, Spyros] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Mitsi, Georgia] Apptomics LLC, Wellesley Hills, MA USA.
[Espay, Alberto J.] Univ Cincinnati, Inst Neurosci, James J & Joan A Gardner Ctr Parkinsons Dis & Mov, Cincinnati, OH USA.
RP Papapetropoulos, S (reprint author), Univ Miami, Miller Sch Med, Dept Neurol, Boston, MA USA.
EM spapapetropoulos@mgh.harvard.edu
NR 25
TC 4
Z9 4
U1 0
U2 1
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 1664-2295
J9 FRONT NEUROL
JI Front. Neurol.
PD FEB 26
PY 2015
VL 6
AR UNSP 34
DI 10.3389/fneur.2015.00034
PG 3
WC Clinical Neurology; Neurosciences
SC Neurosciences & Neurology
GA CU8BJ
UT WOS:000363765700001
PM 25767462
ER
PT J
AU Montero, J
Sarosiek, KA
DeAngelo, JD
Maertens, O
Ryan, J
Ercan, D
Piao, HY
Horowitz, NS
Berkowitz, RS
Matulonis, U
Janne, PA
Amrein, PC
Cichowski, K
Drapkin, R
Letai, A
AF Montero, Joan
Sarosiek, Kristopher A.
DeAngelo, Joseph D.
Maertens, Ophelia
Ryan, Jeremy
Ercan, Dalia
Piao, Huiying
Horowitz, Neil S.
Berkowitz, Ross S.
Matulonis, Ursula
Jaenne, Pasi A.
Amrein, Philip C.
Cichowski, Karen
Drapkin, Ronny
Letai, Anthony
TI Drug-Induced Death Signaling Strategy Rapidly Predicts Cancer Response
to Chemotherapy
SO CELL
LA English
DT Article
ID EGFR KINASE INHIBITORS; CAUSES RESISTANCE; APOPTOSIS; PATIENT; PI3K;
MITOCHONDRIA; SENSITIVITY; SURVIVAL; MODELS; T790M
AB There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early druginduced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chennotherapeutics in vivo.
C1 [Montero, Joan; Sarosiek, Kristopher A.; DeAngelo, Joseph D.; Ryan, Jeremy; Ercan, Dalia; Piao, Huiying; Horowitz, Neil S.; Berkowitz, Ross S.; Matulonis, Ursula; Jaenne, Pasi A.; Drapkin, Ronny; Letai, Anthony] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA.
[Amrein, Philip C.] Massachusetts Gen Hosp, Dept Med Hematol Oncol, Boston, MA 02114 USA.
[Maertens, Ophelia; Horowitz, Neil S.; Berkowitz, Ross S.; Jaenne, Pasi A.; Cichowski, Karen; Drapkin, Ronny] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02215 USA.
RP Letai, A (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA.
EM anthony_letai@dfci.harvard.edu
RI Drapkin, Ronny/E-9944-2016
OI Drapkin, Ronny/0000-0002-6912-6977
FU Beatriu de Pinos programme from la Generalitat de Catalunya in Spain;
NIH [RO1CA129974, R01CA135257, P01CA068484, P01CA139980, U01CA152990]
FX We gratefully acknowledge funding from the Beatriu de Pinos programme
from la Generalitat de Catalunya in Spain (J.M.), and NIH grants
RO1CA129974, R01CA135257, P01CA068484, and P01CA139980. A.L. is a
Leukemia and Lymphoma Society Scholar. R.D. would like to thank the Dr.
Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF) and NIH
grant U01CA152990. We thank the Pasquarello Tissue Bank and the DFCI
Flow Cytometry. We also thank Richard P. Oakley Jr. and
http://www.servier.com/Powerpoint-image-bank (licensed under Creative
Commons Attribution 3.0 Unported License) for allowing usto use some
images to elaborate Figure 1 and the Graphical Abstract.
NR 34
TC 46
Z9 48
U1 5
U2 32
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 26
PY 2015
VL 160
IS 5
BP 977
EP 989
DI 10.1016/j.cell.2015.01.042
PG 13
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA CD5GN
UT WOS:000351116100019
PM 25723171
ER
PT J
AU Lindsley, RC
Mar, BG
Mazzola, E
Grauman, PV
Shareef, S
Allen, SL
Pigneux, A
Wetzler, M
Stuart, RK
Erba, HP
Damon, LE
Powel, BL
Lindeman, N
Steensma, DP
Wadleigh, M
DeAngelo, DJ
Neuberg, D
Stone, RM
Ebert, BL
AF Lindsley, R. Coleman
Mar, Brenton G.
Mazzola, Emanuele
Grauman, Peter V.
Shareef, Sarah
Allen, Steven L.
Pigneux, Arnaud
Wetzler, Meir
Stuart, Robert K.
Erba, Harry P.
Damon, Lloyd E.
Powel, Bayard L.
Lindeman, Neal
Steensma, David P.
Wadleigh, Martha
DeAngelo, Daniel J.
Neuberg, Donna
Stone, Richard M.
Ebert, Benjamin L.
TI Acute myeloid leukemia ontogeny is defined by distinct somatic mutations
SO BLOOD
LA English
DT Article
ID THERAPY-RELATED MYELODYSPLASIA; ACUTE NONLYMPHOCYTIC LEUKEMIA; CLONAL
HEMATOPOIESIS; GENETIC PATHWAYS; OLDER PATIENTS; AGE; OUTCOMES;
CHEMOTHERAPY; ARCHITECTURE; NEOPLASMS
AB Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.
C1 [Lindsley, R. Coleman; Steensma, David P.; Wadleigh, Martha; DeAngelo, Daniel J.; Stone, Richard M.] Dana Farber Canc Inst, Div Hematol Malignancies, Dept Med Oncol, Boston, MA 02215 USA.
[Mar, Brenton G.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
[Mazzola, Emanuele; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.
[Grauman, Peter V.; Shareef, Sarah; Ebert, Benjamin L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Hematol, Boston, MA 02115 USA.
[Allen, Steven L.] Hofstra North Shore LIJ Sch Med, Hempstead, NY USA.
[Pigneux, Arnaud] Ctr Hosp Univ Bordeaux, Hop Haut Leveque, Pessac, France.
[Wetzler, Meir] Roswell Pk Canc Inst, Buffalo, NY 14263 USA.
[Stuart, Robert K.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA.
[Erba, Harry P.] Univ Alabama Birmingham, Div Hematol & Oncol, Birmingham, AL USA.
[Damon, Lloyd E.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA.
[Powel, Bayard L.] Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27109 USA.
[Lindeman, Neal] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA.
RP Stone, RM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.
EM richard_stone@dfci.harvard.edu; bebert@partners.org
OI Allen, Steven/0000-0002-3482-3182; Mar, Brenton/0000-0002-3857-9324
FU Friends of Dana-Farber Cancer Institute; Edward P. Evans Foundation;
Harvard Catalyst KL2/CMeRIT Award; Lady Tata Memorial Trust; National
Institutes of Health (National Cancer Institute) [T32CA00917237, P01
CA108631]; National Institutes of Health (National Institute of General
Medical Sciences) [T32GM007753]; National Institutes of Health (National
Heart, Lung, and Blood Insitute) [R01HL082945]; Gabrielle's Angel
Foundation; Leukemia and Lymphoma Society; Flames/Pan Mass Challenge;
Ted Rubin Foundation
FX This work was supported by the Friends of Dana-Farber Cancer Institute
(R.C.L.), the Edward P. Evans Foundation (R.C.L.), a Harvard Catalyst
KL2/CMeRIT Award (R.C.L.), the Lady Tata Memorial Trust (R.C.L.), the
National Institutes of Health (National Cancer Institute grants
T32CA00917237 and P01 CA108631, National Institute of General Medical
Sciences grant T32GM007753, and National Heart, Lung, and Blood Insitute
grant R01HL082945), the Gabrielle's Angel Foundation (B.L.E), Leukemia
and Lymphoma Society Scholar and SCOR Awards (B.L.E.), Flames/Pan Mass
Challenge (R.M.S.), and the Ted Rubin Foundation (R.M.S.).
NR 31
TC 79
Z9 82
U1 1
U2 12
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 26
PY 2015
VL 125
IS 9
BP 1367
EP 1376
DI 10.1182/blood-2014-11-610543
PG 10
WC Hematology
SC Hematology
GA CD1FT
UT WOS:000350820900007
PM 25550361
ER
PT J
AU Jacobsen, ED
Sharman, JP
Oki, Y
Advani, RH
Winter, JN
Bello, CM
Spitzer, G
Palanca-Wessels, MC
Kennedy, DA
Levine, P
Yang, J
Bartlett, NL
AF Jacobsen, Eric D.
Sharman, Jeff P.
Oki, Yasuhiro
Advani, Ranjana H.
Winter, Jane N.
Bello, Celeste M.
Spitzer, Gary
Palanca-Wessels, Maria Corinna
Kennedy, Dana A.
Levine, Pamela
Yang, Jing
Bartlett, Nancy L.
TI Brentuximab vedotin demonstrates objective responses in a phase 2 study
of relapsed/refractory DLBCL with variable CD30 expression
SO BLOOD
LA English
DT Article
ID B-CELL LYMPHOMA; SALVAGE CHEMOTHERAPY; HODGKINS LYMPHOMA; RITUXIMAB;
LENALIDOMIDE; THERAPY; TRANSPLANTATION; SIGNATURE; DEFINES
AB Several non-Hodgkinlymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), variably express CD30. This phase 2, open-label study evaluated the efficacy of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in relapsed/refractory CD30(+) NHL. This planned subset analysis of B-cell NHLs includes 49 patients with DLBCL and 19 with other B-cell NHLs. Objective response rate was 44% for DLBCL, including 8 (17%) complete remissions (CRs) with a median duration of 16.6 months thus far (range, 2.7 to 22.7+ months). There was no statistical correlation between response and level of CD30 expression; however, all responding patients had quantifiable CD30 by computer assisted assessment of immunohistochemistry. DLBCL patients were generally refractory to first-line (76%) and most recent therapies (82%), and 44% of these refractory patients responded (15% CRs). Patients with other B-cell lymphomas also responded: 1 CR, 2 partial responses (PRs) of 6 with gray zone, 1 CR of 6 with primary mediastinal B-cell, and 1 CR of 3 with posttransplant lymphoproliferative disorder. Adverse events were consistent with known toxicities. The combination of brentuximab vedotin with rituximab was generally well tolerated and had activity similar to brentuximab vedotin alone. Overall, significant activity with brentuximab vedotin was observed in relapsed/refractory DLBCL, and responses occurred across a range of CD30 expression. This study was registered at www.clinicaltrials.gov as #NCT01421667.
C1 [Jacobsen, Eric D.] Dana Farber Canc Inst, Boston, MA 02215 USA.
[Sharman, Jeff P.] US Oncol Res, Willamette Valley Canc Inst, Eugene, OR USA.
[Sharman, Jeff P.] US Oncol Res, Res Ctr, Eugene, OR USA.
[Oki, Yasuhiro] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
[Advani, Ranjana H.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA.
[Winter, Jane N.] Northwestern Univ, Chicago, IL 60611 USA.
[Bello, Celeste M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA.
[Spitzer, Gary] Upstate Oncol Associates, St Francis Hosp, Greenville, SC USA.
[Palanca-Wessels, Maria Corinna; Kennedy, Dana A.; Levine, Pamela; Yang, Jing] Seattle Genet Inc, Bothell, WA USA.
[Bartlett, Nancy L.] Washington Univ, Sch Med, St Louis, MO USA.
RP Jacobsen, ED (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Rm MA221, Boston, MA 02215 USA.
EM eric_jacobsen@dfci.harvard.edu
FU Seattle Genetics, Inc.
FX The study was supported by Seattle Genetics, Inc.
NR 32
TC 52
Z9 52
U1 3
U2 12
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 26
PY 2015
VL 125
IS 9
BP 1394
EP 1402
DI 10.1182/blood-2014-09-598763
PG 9
WC Hematology
SC Hematology
GA CD1FT
UT WOS:000350820900011
PM 25573987
ER
PT J
AU Jang, IH
Lu, YF
Zhao, L
Wenzel, PL
Kume, T
Datta, SM
Arora, N
Guiu, J
Lagha, M
Kim, PG
Do, EK
Kim, JH
Schlaeger, TM
Zon, LI
Bigas, A
Burns, CE
Daley, GQ
AF Jang, Il Ho
Lu, Yi-Fen
Zhao, Long
Wenzel, Pamela L.
Kume, Tsutomu
Datta, Sumon M.
Arora, Natasha
Guiu, Jordi
Lagha, Mounia
Kim, Peter G.
Do, Eun Kyoung
Kim, Jae Ho
Schlaeger, Thorsten M.
Zon, Leonard I.
Bigas, Anna
Burns, Caroline E.
Daley, George Q.
TI Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on
hemogenic endothelium
SO BLOOD
LA English
DT Article
ID EMBRYONIC STEM-CELLS; HAEMOGENIC ENDOTHELIUM; TRANSCRIPTION FACTORS;
RUNX1 EXPRESSION; MOUSE EMBRYO; IN-VIVO; PATHWAY; FATE; DIFFERENTIATION;
PROGENITORS
AB Hematopoietic and vascular development share many common features, including cell surface markers and sites of origin. Recent lineage-tracing studies have established that definitive hematopoietic stem and progenitor cells arise from vascular endothelial-cadherin(+) hemogenic endothelial cells of the aorta-gonad-mesonephros region, but the genetic programs underlying the specification of hemogenic endothelial cells remain poorly defined. Here, we discovered that Notch induction enhances hematopoietic potential and promotes the specification of hemogenic endothelium in differentiating cultures of mouse embryonic stem cells, and we identified Foxc2 as a highly upregulated transcript in the hemogenic endothelial population. Studies in zebrafish and mouse embryos revealed that Foxc2 and its orthologs are required for the proper development of definitive hematopoiesis and function downstream of Notch signaling in the hemogenic endothelium. These data establish a pathway linking Notch signaling to Foxc2 in hemogenic endothelial cells to promote definitive hematopoiesis.
C1 [Jang, Il Ho; Lu, Yi-Fen; Wenzel, Pamela L.; Datta, Sumon M.; Arora, Natasha; Kim, Peter G.; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Harvard Univ, Sch Med, Childrens Hosp Boston, Stem Cell Program, Boston, MA 02115 USA.
[Jang, Il Ho; Lu, Yi-Fen; Wenzel, Pamela L.; Datta, Sumon M.; Arora, Natasha; Kim, Peter G.; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA.
[Jang, Il Ho; Lu, Yi-Fen; Wenzel, Pamela L.; Datta, Sumon M.; Arora, Natasha; Kim, Peter G.; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA.
[Jang, Il Ho; Lu, Yi-Fen; Wenzel, Pamela L.; Arora, Natasha; Kim, Peter G.; Daley, George Q.] Childrens Hosp Boston, Manton Ctr Orphan Dis Res, Stem Cell Transplantat Program, Boston, MA USA.
[Jang, Il Ho; Lu, Yi-Fen; Wenzel, Pamela L.; Arora, Natasha; Kim, Peter G.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
[Jang, Il Ho; Lu, Yi-Fen; Wenzel, Pamela L.; Arora, Natasha; Kim, Peter G.; Schlaeger, Thorsten M.; Zon, Leonard I.; Burns, Caroline E.; Daley, George Q.] Harvard Stem Cell Inst, Boston, MA USA.
[Jang, Il Ho; Do, Eun Kyoung; Kim, Jae Ho] Pusan Natl Univ, Sch Med, Dept Physiol, Yangsan, South Korea.
[Zhao, Long; Burns, Caroline E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA.
[Kume, Tsutomu] Northwestern Univ, Chicago, IL 60611 USA.
[Guiu, Jordi; Bigas, Anna] Inst Hosp Mar Invest Med, Canc Res Program, Barcelona, Spain.
[Lagha, Mounia] Inst Pasteur, Dept Dev Biol, CNRS, Unite Rech Associee 2578, Paris, France.
RP Daley, GQ (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Stem Cell Program, Boston, MA 02115 USA.
EM cburns6@partners.org; george.daley@childrens.harvard.edu
RI Zhao, Long/A-6439-2014
FU Boston Children's Hospital [PLE1009-0111, SAF2010-15450]; National
Institutes of Health, National Heart, Lung, and Blood Institute
Progenitor Cell Biology Consortium [UO1-HL100001]; National Institutes
of Health, National Institute of Diabetes and Digestive and Kidney
Diseases [R24DK092760]; Doris Duke Medical Foundation
FX This work was supported by grants from the Boston Children's Hospital
(PLE1009-0111 and SAF2010-15450); the National Institutes of Health,
National Heart, Lung, and Blood Institute Progenitor Cell Biology
Consortium (grant UO1-HL100001); the National Institutes of Health,
National Institute of Diabetes and Digestive and Kidney Diseases (grant
R24DK092760); and the Doris Duke Medical Foundation. G.Q.D. is an
investigator of the Howard Hughes Medical Institute and the Manton
Center for Orphan Disease Research.
NR 56
TC 15
Z9 15
U1 1
U2 14
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 26
PY 2015
VL 125
IS 9
BP 1418
EP 1426
DI 10.1182/blood-2014-04-568170
PG 9
WC Hematology
SC Hematology
GA CD1FT
UT WOS:000350820900014
PM 25587036
ER
PT J
AU Tsai, TY
Dimitriou, D
Li, JS
Nam, KW
Li, GA
Kwon, YM
AF Tsai, Tsung-Yuan
Dimitriou, Dimitris
Li, Jing-Sheng
Nam, Kwang Woo
Li, Guoan
Kwon, Young-Mm
TI Asymmetric hip kinematics during gait in patients with unilateral total
hip arthroplasty: In vivo 3-dimensional motion analysis
SO JOURNAL OF BIOMECHANICS
LA English
DT Article
DE Hip; Total hip arthroplasty; Gait; Kinematics; Fluoroscope
ID REPLACEMENT PATIENTS; WALKING EFFICIENCY; SURGICAL APPROACH; RECOVERY;
JOINTS; WOMEN; VITRO; KNEE; THA
AB Asymmetric limb loading has been reported in unilateral total hip arthroplasty (THA) patients during gait. However, restoration of 3D motion symmetry of the hip following unilateral THA remains unclear. The purpose of this study was to investigate the in vivo 3D kinematics of the hip in unilateral THA patients during gait. Eight unilateral THA patients were evaluated for both hips during treadmill gait using a dual fluoroscopic imaging system. Reduced hip range of motion in sagittal plane, decreased peak hip extension and asymmetric pelvic rotation of the THA were observed. Furthermore, significant pelvic anterior/posterior tilt asymmetry, higher internal rotation (increased by 8.6 degrees +/- 4.6 degrees) during stance phase and higher adduction (increased by 4.5 degrees +/- 3.2 degrees) during swing phase of the THA were found in this cohort of patients. The results demonstrated that there was 3D motion asymmetry of the hip and pelvis in unilateral THA patients during gait. The data could provide insights into optimizing kinematics and to restoring normal hip function after THA. (C) 2015 Elsevier Ltd. All rights reserved.
C1 [Tsai, Tsung-Yuan; Dimitriou, Dimitris; Li, Jing-Sheng; Nam, Kwang Woo; Li, Guoan; Kwon, Young-Mm] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA.
RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA.
EM gli1@mgh.harvard.edu
OI Tsai, Tsung-Yuan/0000-0003-1522-2987; Dimitriou,
Dimitris/0000-0002-9558-7080
FU Department of Orthopaedic Surgery, Massachusetts General
Hospital/Harvard Medical School; MAKO Surgical Corp. (Stryker Medical)
FX financial support from Department of Orthopaedic Surgery, Massachusetts
General Hospital/Harvard Medical School, and MAKO Surgical Corp.
(Stryker Medical).
NR 26
TC 4
Z9 4
U1 1
U2 9
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0021-9290
EI 1873-2380
J9 J BIOMECH
JI J. Biomech.
PD FEB 26
PY 2015
VL 48
IS 4
BP 555
EP 559
DI 10.1016/j.jbiomech.2015.01.021
PG 5
WC Biophysics; Engineering, Biomedical
SC Biophysics; Engineering
GA CC7DD
UT WOS:000350527000001
PM 25655464
ER
PT J
AU Sacks, CA
AF Sacks, Chana A.
TI In Memory of Daniel - Reviving Research to Prevent Gun Violence
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Editorial Material
C1 Massachusetts Gen Hosp, Boston, MA 02114 USA.
RP Sacks, CA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.
NR 5
TC 6
Z9 6
U1 0
U2 3
PU MASSACHUSETTS MEDICAL SOC
PI WALTHAM
PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA
SN 0028-4793
EI 1533-4406
J9 NEW ENGL J MED
JI N. Engl. J. Med.
PD FEB 26
PY 2015
VL 372
IS 9
BP 800
EP 801
DI 10.1056/NEJMp1415128
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB8SQ
UT WOS:000349901700004
PM 25714158
ER
PT J
AU Unizony, SH
Kim, ND
Hoang, MP
AF Unizony, Sebastian H.
Kim, Nancy D.
Hoang, Mai P.
TI Case 7-2015: A 25-Year-Old Man with Oral Ulcers, Rash, and Odynophagia
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Article
ID DOUBLE-BLIND TRIAL; BEHCETS-DISEASE; LYMPHOGRANULOMA-VENEREUM;
PAPULOPUSTULAR LESIONS; GONOCOCCAL-INFECTION; ERYTHEMA MULTIFORME;
CLINICAL-FEATURES; CROHNS-DISEASE; DIAGNOSIS; MANAGEMENT
C1 [Unizony, Sebastian H.; Kim, Nancy D.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.
[Hoang, Mai P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
[Unizony, Sebastian H.; Kim, Nancy D.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA.
[Hoang, Mai P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA.
RP Unizony, SH (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.
NR 44
TC 2
Z9 2
U1 0
U2 6
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 26
PY 2015
VL 372
IS 9
BP 864
EP 872
DI 10.1056/NEJMcpc1413303
PG 9
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB8SQ
UT WOS:000349901700013
PM 25714165
ER
PT J
AU Walker, SR
Liu, S
Xiang, M
Nicolais, M
Hatzi, K
Giannopoulou, E
Elemento, O
Cerchietti, L
Melnick, A
Frank, DA
AF Walker, S. R.
Liu, S.
Xiang, M.
Nicolais, M.
Hatzi, K.
Giannopoulou, E.
Elemento, O.
Cerchietti, L.
Melnick, A.
Frank, D. A.
TI The transcriptional modulator BCL6 as a molecular target for breast
cancer therapy
SO ONCOGENE
LA English
DT Article
ID B-CELL LYMPHOMAS; HUMAN TUMORS; BTB DOMAIN; CHIP-SEQ; IN-VITRO;
EXPRESSION; STAT5; DIFFERENTIATION; IDENTIFICATION; COREPRESSOR
AB Inappropriate expression or activation of transcription factors can drive patterns of gene expression, leading to the malignant behavior of breast cancer cells. We have found that the transcriptional repressor BCL6 is highly expressed in breast cancer cell lines, and its locus is amplified in about half of primary breast cancers. To understand how BCL6 regulates gene expression in breast cancer cells, we used chromatin immunoprecipitation followed by deep sequencing to identify the BCL6 binding sites on a genomic scale. This revealed that BCL6 regulates a unique cohort of genes in breast cancer cell lines compared with B-cell lymphomas. Furthermore, BCL6 expression promotes the survival of breast cancer cells, and targeting BCL6 with a peptidomimetic inhibitor leads to apoptosis of these cells. Finally, combining a BCL6 inhibitor and a signal transducer and activator of transcription3 inhibitor provided enhanced cell killing in triple-negative breast cancer cell lines, suggesting that combination therapy may be particularly useful. Thus, targeting BCL6 alone or in conjunction with other signaling pathways may be a useful therapeutic strategy for treating breast cancer.
C1 [Walker, S. R.; Liu, S.; Xiang, M.; Nicolais, M.; Frank, D. A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
[Walker, S. R.; Liu, S.; Frank, D. A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.
[Walker, S. R.; Liu, S.; Frank, D. A.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Hatzi, K.; Cerchietti, L.; Melnick, A.] Weill Cornell Med Coll, Dept Med & Pharmacol, New York, NY USA.
[Giannopoulou, E.; Elemento, O.] Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsa, New York, NY USA.
[Giannopoulou, E.; Elemento, O.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA.
RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,M522B, Boston, MA 02215 USA.
EM david_frank@dfci.harvard.edu
OI Cerchietti, Leandro/0000-0003-0608-1350
FU BCRF-AACR grant for Translational Breast Cancer Research; National
Cancer Institute [R01-CA160979]; Susan G Komen for the Cure; Brent
Leahey Fund; Friends of the Dana-Farber Cancer Institute
FX This work was supported by a BCRF-AACR grant for Translational Breast
Cancer Research, and grants from the National Cancer Institute
(R01-CA160979), Susan G Komen for the Cure, the Brent Leahey Fund and
Friends of the Dana-Farber Cancer Institute.
NR 38
TC 10
Z9 11
U1 1
U2 7
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 26
PY 2015
VL 34
IS 9
BP 1073
EP 1082
DI 10.1038/onc.2014.61
PG 10
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
Heredity
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
Heredity
GA CC1RY
UT WOS:000350122100001
PM 24662818
ER
PT J
AU Chang, CC
Chow, CC
Tellier, LCAM
Vattikuti, S
Purcell, SM
Lee, JJ
AF Chang, Christopher C.
Chow, Carson C.
Tellier, Laurent C. A. M.
Vattikuti, Shashaank
Purcell, Shaun M.
Lee, James J.
TI Second-generation PLINK: rising to the challenge of larger and richer
datasets
SO GIGASCIENCE
LA English
DT Article
DE GWAS; Population genetics; Whole-genome sequencing; High-density SNP
genotyping; Computational statistics
ID HARDY-WEINBERG EQUILIBRIUM; GENOME-WIDE ASSOCIATION; FISHERS EXACT TEST;
LINKAGE DISEQUILIBRIUM; CONTINGENCY-TABLES; EXACT TESTS; ALGORITHM;
PERMUTATION; PERFORMANCE; IDENTITY
AB Background: PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for faster and scalable implementations of key functions, such as logistic regression, linkage disequilibrium estimation, and genomic distance evaluation. In addition, GWAS and population-genetic data now frequently contain genotype likelihoods, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format.
Findings: To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(root n)-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. We have also developed an extension to the data format which adds low-overhead support for genotype likelihoods, phase, multiallelic variants, and reference vs. alternate alleles, which is the basis of our planned second release ( PLINK 2.0).
Conclusions: The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.
C1 [Chang, Christopher C.] Complete Genom, Mountain View, CA 94043 USA.
[Chang, Christopher C.; Tellier, Laurent C. A. M.] BGI Cognit Genom Lab, Shenzhen 518083, Peoples R China.
[Chow, Carson C.; Vattikuti, Shashaank; Lee, James J.] NIDDK, Math Biol Sect, LBM, NIH, Bethesda, MD 20892 USA.
[Tellier, Laurent C. A. M.] Univ Copenhagen, Bioinformat Ctr, DK-2200 Copenhagen, Denmark.
[Purcell, Shaun M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.
[Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Dept Psychiat, New York, NY 10029 USA.
[Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA.
[Purcell, Shaun M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.
[Lee, James J.] Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN 55455 USA.
RP Chang, CC (reprint author), Complete Genom, 2071 Stierlin Court, Mountain View, CA 94043 USA.
EM chrchang@alumni.caltech.edu
FU BGI Hong Kong; Shenzhen Municipal Government of China
[CXB201108250094A]; Intramural Research Program of the NIH, NIDDK
FX Christopher Chang and Laurent Tellier were supported by BGI Hong Kong
and Shenzhen Municipal Government of China grant CXB201108250094A.
Carson Chow and Shashaank Vattikuti were supported by the Intramural
Research Program of the NIH, NIDDK.
NR 44
TC 184
Z9 184
U1 15
U2 30
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
EI 2047-217X
J9 GIGASCIENCE
JI GigaScience
PD FEB 25
PY 2015
VL 4
AR 7
DI 10.1186/s13742-015-0047-8
PG 16
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CX4IB
UT WOS:000365662000001
PM 25722852
ER
PT J
AU Kawabori, M
Kacimi, R
Kauppinen, T
Calosing, C
Kim, JY
Hsieh, CL
Nakamura, MC
Yenari, MA
AF Kawabori, Masahito
Kacimi, Rachid
Kauppinen, Tiina
Calosing, Cyrus
Kim, Jong Youl
Hsieh, Christine L.
Nakamura, Mary C.
Yenari, Midori A.
TI Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Deficiency
Attenuates Phagocytic Activities of Microglia and Exacerbates Ischemic
Damage in Experimental Stroke
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
DE ischemia; neuroprotection; permanent ischemia; phagocytosis; stroke;
triggering receptor expressed on myeloid cells-2
ID FOCAL CEREBRAL-ISCHEMIA; NASU-HAKOLA-DISEASE; SCLEROSING
LEUKOENCEPHALOPATHY; IN-VITRO; MACROPHAGES; MECHANISM; DEMENTIA;
NEURONS; SYSTEM; TRANSPLANTATION
AB Clearing cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified receptor expressed on microglia and is thought to phagocytose damaged brain cells. The precise role of TREM2 during ischemic stroke has not been fully understood. We explore TREM2 in both in vitro and in vivo stroke models and identify a potential endogenous TREM2 ligand. TREM2 knockdown in microglia reduced microglial activation to an amoeboid phenotype and decreased the phagocytosis of injured neurons. Phagocytosis and infarcted brain tissue resorption was reduced in TREM2 knock-out (KO) mice compared with wild-type (WT) mice. TREM2 KO mice also had worsened neurological recovery and decreased viable brain tissue in the ipsilateral hemisphere. The numbers of activated microglia and phagocytes in TREM2 KO mice were decreased compared with WT mice, and foamy macrophages were nearly absent in the TREM2 KO mice. Postischemia, TREM2 was highly expressed on microglia and TREM2-Fc fusion protein (used as a probe to identify potential TREM2 binding partners) bound to an unknown TREM2 ligand that colocalized to neurons. Oxygen glucose deprivation-exposed neuronal media, or cellular fractions containing nuclei or purified DNA, but not cytosolic fractions, stimulated signaling through TREM2. TREM2-Fc fusion protein pulled down nucleic acids from ischemic brain lysate. These findings establish the relevance of TREM2 in the phagocytosis of the infarcted brain and emphasize its role in influencing neurological outcomes following stroke. Further, nucleic acids may be one potential ligand of TREM2 in brain ischemia.
C1 [Kawabori, Masahito; Kacimi, Rachid; Calosing, Cyrus; Kim, Jong Youl; Hsieh, Christine L.; Nakamura, Mary C.; Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA.
[Kawabori, Masahito; Kacimi, Rachid; Calosing, Cyrus; Kim, Jong Youl; Hsieh, Christine L.; Nakamura, Mary C.; Yenari, Midori A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA.
[Kacimi, Rachid; Hsieh, Christine L.; Yenari, Midori A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA.
[Kauppinen, Tiina] Kleysen Inst Adv Med, Winnipeg, MB R3E 0Z3, Canada.
RP Yenari, MA (reprint author), Univ Calif San Francisco, Dept Neurol, 4150 Clement St,MS 127, San Francisco, CA 94121 USA.
EM yenari@alum.mit.edu
OI Kauppinen, Tiina/0000-0001-7219-9862
FU National Institutes of Health [NS40516, AR0038]; Veteran's Merit Awards;
Uehara Foundation Research Fellowship; Department of Veterans Affairs,
Veterans Health Administration, Office of Research and Development,
Biomedical Laboratory Research and Development Career Development
Award-2; American Heart Association [0835222N]; resources of the
Veterans Affairs Medical Center, San Francisco, California; Rosalind
Russell Arthritis Center
FX This work was supported by National Institutes of Health Grants NS40516
to M.A.Y. and AR0038 to M.C.N.; Veteran's Merit Awards to M.A.Y. and
M.C.N.; a Uehara Foundation Research Fellowship to M.K.; a Department of
Veterans Affairs, Veterans Health Administration, Office of Research and
Development, Biomedical Laboratory Research and Development Career
Development Award-2 to C.L.H.; and American Heart Association Grant
0835222N to T.K. Grants to M.A.Y., M.C.N., and T.K. were administered by
the Northern California Institute for Research and Education, and
supported by resources of the Veterans Affairs Medical Center, San
Francisco, California. M.C.N. also received support from the Rosalind
Russell Arthritis Center. The authors thank Dr. Nick Cairns for labeling
the TREM2 fusion protein.
NR 46
TC 29
Z9 29
U1 1
U2 10
PU SOC NEUROSCIENCE
PI WASHINGTON
PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA
SN 0270-6474
J9 J NEUROSCI
JI J. Neurosci.
PD FEB 25
PY 2015
VL 35
IS 8
BP 3384
EP 3396
DI 10.1523/JNEUROSCI.2620-14.2015
PG 13
WC Neurosciences
SC Neurosciences & Neurology
GA CD0CV
UT WOS:000350738800010
PM 25716838
ER
PT J
AU Dilekoz, E
Houben, T
Eikermann-Haerter, K
Balkaya, M
Lenselink, AM
Whalen, MJ
Spijker, S
Ferrari, MD
van den Maagdenberg, AMJM
Ayata, C
AF Dilekoz, Ergin
Houben, Thijs
Eikermann-Haerter, Katharina
Balkaya, Mustafa
Lenselink, A. Mariette
Whalen, Michael J.
Spijker, Sabine
Ferrari, Michel D.
van den Maagdenberg, Arn M. J. M.
Ayata, Cenk
TI Migraine Mutations Impair Hippocampal Learning Despite Enhanced
Long-Term Potentiation
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
DE hippocampus; learning; long-term depression; long-term potentiation;
memory; migraine
ID FAMILIAL HEMIPLEGIC MIGRAINE; CORTICAL SPREADING DEPRESSION; TRANSIENT
GLOBAL AMNESIA; QUALITY-OF-LIFE; SYNAPTIC PLASTICITY; COGNITIVE
FUNCTIONS; EMOTIONAL BEHAVIOR; CALCIUM-CHANNELS; CONTEXTUAL FEAR;
DENTATE GYRUS
AB To explain cognitive and memory difficulties observed in some familial hemiplegic migraine (FHM) patients, we examined hippocampal neurotransmission and plasticity in knock-in mice expressing theFHMtype 1 (FHM1) R192Q gain-of function mutation in the CACNA1A gene that encodes the alpha(1A) subunit of neuronal Ca(V)2.1 channels. We determined stimulus intensity-response curves for anterior commissure-evoked hippocampal CA1 field potentials in strata pyramidale and radiatum and assessed neuroplasticity by inducing long-term potentiation (LTP) and long-term depression (LTD) in anesthetized mice in vivo. We also studied learning and memory using contextual fear-conditioning, Morris water maze, and novel object recognition tests. Hippocampal field potentials were significantly enhanced in R192Q mice compared with wild-type controls. Stimulus intensity-response curves were shifted to the left and displayed larger maxima in the mutants. LTP was augmented by twofold in R192Q mice, whereas LTD was unchanged compared with wild-type mice. R192Q mice showed significant spatialmemorydeficits in contextual fear-conditioning and Morris water maze tests compared with wild-type controls. Novel object recognition was not impaired in R192Q mice; however, mice carrying the more severe S218L CACNA1A mutation showed marked deficits in this test, suggesting a genotype-phenotype relationship. Thus, whereas FHM1 gain-of-function mutations enhance hippocampal excitatory transmission and LTP, learning and memory are paradoxically impaired, providing a possible explanation for cognitive changes detected in FHM. Data suggest that abnormally enhanced plasticity can be as detrimental to efficient learning as reduced plasticity and highlight how genetically enhanced neuronal excitability may impact cognitive function.
C1 [Dilekoz, Ergin; Houben, Thijs; Eikermann-Haerter, Katharina; Balkaya, Mustafa; Ayata, Cenk] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Neurovasc Res Lab, Charlestown, MA USA.
[Houben, Thijs; Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.] Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RC Leiden, Netherlands.
[van den Maagdenberg, Arn M. J. M.] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands.
[Lenselink, A. Mariette; Spijker, Sabine] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, NL-1081 HV Amsterdam, Netherlands.
[Whalen, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat Crit Care Med, Boston, MA 02114 USA.
[Ayata, Cenk] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Stroke Serv, Boston, MA 02114 USA.
[Ayata, Cenk] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Neurosci Intens Care Unit, Boston, MA 02114 USA.
RP Ayata, C (reprint author), Massachusetts Gen Hosp, Neurovasc Res Lab, 149 13th St,Room 6408, Charlestown, MA 02129 USA.
EM cayata@partners.org
OI Spijker, Sabine/0000-0002-6814-2019
FU National Institutes of Health [NS061505]; Fondation Leducq; Andrew David
Heitman Foundation; Ellison Foundation; Netherlands Consortium for
Systems Biology/Center for Medical Systems Biology in the framework of
the Netherlands Genomics Initiative; European Union EUROHEADPAIN
[602633]; International Headache Society Fellowship Award
FX This work was supported by National Institutes of Health Grant NS061505,
Fondation Leducq, the Neuroendovascular Research Fund from the Andrew
David Heitman Foundation, the Ellison Foundation, the Netherlands
Consortium for Systems Biology/Center for Medical Systems Biology in the
framework of the Netherlands Genomics Initiative, the European Union nr
602633 EUROHEADPAIN, and the International Headache Society 2012
Fellowship Award.
NR 41
TC 5
Z9 5
U1 2
U2 11
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 25
PY 2015
VL 35
IS 8
BP 3397
EP 3402
DI 10.1523/JNEUROSCI.2630-14.2015
PG 6
WC Neurosciences
SC Neurosciences & Neurology
GA CD0CV
UT WOS:000350738800011
PM 25716839
ER
PT J
AU Premereur, E
Janssen, P
Vanduffel, W
AF Premereur, Elsie
Janssen, Peter
Vanduffel, Wim
TI Effector Specificity in Macaque Frontal and Parietal Cortex
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
DE fMRI; saccades
ID MEDIAL PARIETOOCCIPITAL CORTEX; LATERAL INTRAPARIETAL AREA; SACCADIC
EYE-MOVEMENTS; DORSAL PREMOTOR CORTEX; EVENT-RELATED FMRI; SUPERIOR
COLLICULUS; VISUAL-CORTEX; TOPOGRAPHIC ORGANIZATION; REACHING ACTIVITY;
BRAIN LOCATION
AB Single neurons in the frontal eye fields (FEFs) and lateral intraparietal area (LIP) of macaques are preferentially activated by saccadeversus reach-related processes. fMRI studies focusing on saccade-and reach-specific activity in human cortex, however, provided conflicting evidence for effector specificity. To gain further insights into effector preferences throughout monkey cortex using the same technique as in humans, we performed a mixed block/event-related fMRI experiment in macaques. Within single fMRI runs, monkeys alternated between a visually guided saccade task, a visually guided arm movement task, and a fixation-only task requiring no saccades or arm movements. The detection of a peripheral pop-out go cue initiating the required operant behavior and the identification of a target among distractors was identical in the arm and saccade tasks. We found saccade-related activity in parietal areas V6, V6A, LIP, and caudal intraparietal area and frontal areas FEF, 45a, 45b, and 46. Areas 45 and FEF even showed markedly decreased fMRI activity during arm movements relative to fixation only. Conversely, medial and anterior intraparietal areas (MIP and AIP), and parietal area PEip; somatosensory areas S1 and S2; and (pre) motor areas F1, F3, F5, and F6 showed increased arm movement-related activity. F1, F5, PEip, and somatosensory cortex also showed deactivations during saccades relative to fixation only. Control experiments showed that such deactivations in both operant-specific functional networks did not depend on training history or rapid task switching requiring active suppression of the unpreferred operant behavior. Therefore, although both tasks required divided attention to detect a pop-out go cue and target, two largely segregated and mainly effector-driven cortical networks were activated.
C1 [Premereur, Elsie; Janssen, Peter; Vanduffel, Wim] Katholieke Univ Leuven, Lab Neurophysiol & Psychophysiol, B-3000 Louvain, Belgium.
[Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.
[Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA.
RP Vanduffel, W (reprint author), Katholieke Univ Leuven, Lab Neuro & Psychofysiol, O&N 2 Herestr 49 Bus 1021, B-3000 Louvain, Belgium.
EM Wim.Vanduffel@med.kuleuven.be
FU Research Foundation Flanders (FWO) [G0A5613N, G062208.10, G083111.10,
G059309]; Geconcerteerde onderzoeksacties [GOA/10/19]; Inter university
attraction poles IUAP [VII/11]; Program Financing [PFV/10/008]; Odysseus
[G0007.12]; Hercules foundation
FX This work was supported by the Research Foundation Flanders (FWO grants
G0A5613N, G062208.10, G083111.10, G059309); Geconcerteerde
onderzoeksacties GOA/10/19; Inter university attraction poles IUAP
VII/11; Program Financing PFV/10/008; Odysseus G0007.12, and the
Hercules foundation. We thank Anne Coeman, Stijn Verstraeten, Piet
Kayenbergh, Gerrit Meulemans, Marc De Paep, and Inez Puttemans for
assistance and Steve Raiguel for comments on a previous version of this
manuscript.
NR 103
TC 5
Z9 5
U1 2
U2 5
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 25
PY 2015
VL 35
IS 8
BP 3446
EP 3459
DI 10.1523/JNEUROSCI.3710-14.2015
PG 14
WC Neurosciences
SC Neurosciences & Neurology
GA CD0CV
UT WOS:000350738800016
PM 25716844
ER
PT J
AU Ayton, S
Lei, P
Hare, DJ
Duce, JA
George, JL
Adlard, PA
McLean, C
Rogers, JT
Cherny, RA
Finkelstein, DI
Bush, AI
AF Ayton, Scott
Lei, Peng
Hare, Dominic J.
Duce, James A.
George, Jessica L.
Adlard, Paul A.
McLean, Catriona
Rogers, Jack T.
Cherny, Robert A.
Finkelstein, David I.
Bush, Ashley I.
TI Parkinson's Disease Iron Deposition Caused by Nitric Oxide-Induced Loss
of beta-Amyloid Precursor Protein
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
DE APP; iron; nitric oxide
ID ANIMAL-MODELS; NEURODEGENERATION; NEUROTOXICITY; CONTRIBUTES; NEURONS;
EXPORT; MICE
AB Elevation of both neuronal iron and nitric oxide (NO) in the substantia nigra are associated with Parkinson's disease (PD) pathogenesis. We reported previously that the Alzheimer-associated beta-amyloid precursor protein (APP) facilitates neuronal iron export. Here we report markedly decreased APP expression in dopaminergic neurons of human PD nigra and that APP(-/-) mice develop iron-dependent nigral cell loss. Conversely, APP-overexpressing mice are protected in the MPTP PD model. NO suppresses APP translation in mouse MPTP models, explaining how elevated NO causes iron-dependent neurodegeneration in PD.
C1 [Ayton, Scott; Lei, Peng; Hare, Dominic J.; Duce, James A.; George, Jessica L.; Adlard, Paul A.; McLean, Catriona; Cherny, Robert A.; Finkelstein, David I.; Bush, Ashley I.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3010, Australia.
[Duce, James A.] Univ Leeds, Fac Biol Sci, Sch Mol & Cellular Biol, Leeds LS2 9JT, N Yorkshire, England.
[McLean, Catriona] Alfred Hosp, Dept Anat Pathol, Prahran, Vic 3004, Australia.
[Rogers, Jack T.] Massachusetts Gen Hosp East, Dept Psychiat Neurosci, Neurochem Lab, Charlestown, MA 02129 USA.
[Hare, Dominic J.] Univ Technol Sydney, Elemental Bioimaging Facil, Broadway, NSW 2007, Australia.
[Hare, Dominic J.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA.
RP Bush, AI (reprint author), Florey Inst Neurosci & Mental Hlth, 30 Royal Parade, Parkville, Vic 3052, Australia.
EM ashley.bush@florey.edu.au
RI Bush, Ashley/A-1186-2007
OI Bush, Ashley/0000-0001-8259-9069
FU Australian Research Council; Australian National Health and Medical
Research Council; Bethlehem Griffiths Research Foundation; University of
Melbourne; Florey Institute of Neuroscience and Mental Health; Alfred
Hospital; Victorian Forensic Institute of Medicine
FX This work was supported by funds from the Australian Research Council,
the Australian National Health and Medical Research Council, the
Bethlehem Griffiths Research Foundation, and the Operational
Infrastructure Support from the Victorian State Government. The
Victorian Brain Bank Network is supported by the University of
Melbourne, the Florey Institute of Neuroscience and Mental Health, the
Alfred Hospital, and the Victorian Forensic Institute of Medicine.
NR 22
TC 22
Z9 22
U1 0
U2 9
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 25
PY 2015
VL 35
IS 8
BP 3591
EP 3597
DI 10.1523/JNEUROSCI.3439-14.2015
PG 7
WC Neurosciences
SC Neurosciences & Neurology
GA CD0CV
UT WOS:000350738800029
PM 25716857
ER
PT J
AU Gagnon, L
Sakadzic, S
Lesage, F
Musacchia, JJ
Lefebvre, J
Fang, QQ
Yucel, MA
Evans, KC
Mandeville, ET
Cohen-Adad, J
Polimeni, JR
Yaseen, MA
Lo, EH
Greve, DN
Buxton, RB
Dale, AM
Devor, A
Boas, DA
AF Gagnon, Louis
Sakadzic, Sava
Lesage, Frederic
Musacchia, Joseph J.
Lefebvre, Joel
Fang, Qianqian
Yuecel, Meryem A.
Evans, Karleyton C.
Mandeville, Emiri T.
Cohen-Adad, Juelien
Polimeni, Jonaethan R.
Yaseen, Mohammad A.
Lo, Eng H.
Greve, Douglas N.
Buxton, Richard B.
Dale, Anders M.
Devor, Anna
Boas, David A.
TI Quantifying the Microvascular Origin of BOLD-fMRI from First Principles
with Two-Photon Microscopy and an Oxygen-Sensitive Nanoprobe
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
DE BOLD-fMRI; modeling; Monte Carlo; two-photon microscopy
ID BRAIN BLOOD-FLOW; MAGNETIC-RESONANCE; NEURONAL-ACTIVITY; BASE-LINE;
VASCULAR NETWORK; PARTIAL-PRESSURE; FUNCTIONAL MRI; IN-VIVO; 7 T; SIGNAL
AB The blood oxygenation level-dependent (BOLD) contrast is widely used in functional magnetic resonance imaging (fMRI) studies aimed at investigating neuronal activity. However, the BOLD signal reflects changes in blood volume and oxygenation rather than neuronal activity per se. Therefore, understanding the transformation of microscopic vascular behavior into macroscopic BOLD signals is at the foundation of physiologically informed noninvasive neuroimaging. Here, we use oxygen-sensitive two-photon microscopy to measure the BOLD-relevant microvascular physiology occurring within a typical rodent fMRI voxel and predict the BOLD signal from first principles using those measurements. The predictive power of the approach is illustrated by quantifying variations in the BOLD signal induced by the morphological folding of the human cortex. This framework is then used to quantify the contribution of individual vascular compartments and other factors to the BOLD signal for different magnet strengths and pulse sequences.
C1 [Gagnon, Louis; Sakadzic, Sava; Musacchia, Joseph J.; Fang, Qianqian; Yuecel, Meryem A.; Evans, Karleyton C.; Mandeville, Emiri T.; Polimeni, Jonaethan R.; Yaseen, Mohammad A.; Lo, Eng H.; Greve, Douglas N.; Devor, Anna; Boas, David A.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA USA.
[Gagnon, Louis; Boas, David A.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA.
[Lesage, Frederic; Lefebvre, Joel; Cohen-Adad, Juelien] Ecole Polytech, Dept Elect Engn, Montreal, PQ H3C 3A7, Canada.
[Dale, Anders M.; Devor, Anna] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA.
[Buxton, Richard B.; Dale, Anders M.; Devor, Anna] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA.
RP Gagnon, L (reprint author), Massachusetts Gen Hosp, Charlestown, MA 02114 USA.
EM lgagnon@nmr.mgh.harvard.edu
RI Polimeni, Jonathan/P-1395-2014
OI Polimeni, Jonathan/0000-0002-1348-1179
FU NIH [P41RR14075, R01NS057476, R00NS067050, R01NS057198, R01EB000790];
American Heart Association [11SDG7600037]; Advanced Multimodal
NeuroImaging Training Program [R90DA023427]
FX This work was supported by NIH Grants P41RR14075, R01NS057476,
R00NS067050, R01NS057198, and R01EB000790, American Heart Association
Grant 11SDG7600037, and the Advanced Multimodal NeuroImaging Training
Program (R90DA023427 to L.G.). We thank Elfar Adalsteinsson, Jerrold
Boxerman, Jean Chen, Audrey Fan, Valerie Griffeth, Sune Jesperson, David
Kleinfeld, Joseph Mandeville, Leif Ostergaard, Axel Pries, Bruce Rosen,
Aaron Simon, Vivek Srinivasan, Bojana Stefanovic, and Larry Wald for
fruitful discussions.
NR 57
TC 21
Z9 22
U1 1
U2 20
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 25
PY 2015
VL 35
IS 8
BP 3663
EP 3675
DI 10.1523/JNEUROSCI.3555-14.2015
PG 13
WC Neurosciences
SC Neurosciences & Neurology
GA CD0CV
UT WOS:000350738800036
PM 25716864
ER
PT J
AU Ryu, SJ
Choi, HS
Yoon, KY
Lee, OH
Kim, KJ
Lee, BY
AF Ryu, Su-Jung
Choi, Hyeon-Son
Yoon, Kye-Yoon
Lee, Ok-Hwan
Kim, Kui-Jin
Lee, Boo-Yong
TI Oleuropein Suppresses LPS-Induced Inflammatory Responses in RAW 264.7
Cell and Zebrafish
SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
LA English
DT Article
DE oleuropein; anti-inflammation; RAW 264.7 cell; zebrafish; NF-kappa
B(p-65)
ID NF-KAPPA-B; NITRIC-OXIDE; STIMULATED MACROPHAGES; INNATE IMMUNITY;
ACTIVATION; CYTOKINES; KINASE
AB Oleuropein is one of the primary phenolic compounds present in olive leaf. In this study, the anti-inflammatory effect of oleuropein was investigated using lipopolysaccharide (LPS)-stimulated RAW 264.7 and a zebrafish model. The inhibitory effect of oleuropein on LPS-induced NO production in macrophages was supported by the suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, our enzyme immunoassay showed that oleuropein suppressed the release of pro-inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6). Oleuropein inhibited the translocation of p65 by suppressing phosphorylation of inhibitory kappa B-a (I kappa B-alpha). Oleuropein also decreased activation of ERK1/2 and JNK, which are associated with LPS-induced inflammation, and its downstream gene of AP-1. Furthermore, oleuropein inhibited LPS-stimulated NO generation in a zebrafish model. Taken together, our results demonstrated that oleuropein could reduce inflammatory responses by inhibiting TLR and MAPK signaling, and may be used as an anti-inflammatory agent.
C1 [Ryu, Su-Jung; Yoon, Kye-Yoon] CHA Univ, Dept Biomed Sci, Kyonggi Do 463836, South Korea.
[Choi, Hyeon-Son] Seoul Womens Univ, Dept Food Sci & Technol, Seoul 139774, South Korea.
[Lee, Ok-Hwan] Kangwon Natl Univ, Dept Food Sci & Biotechnol, Chunchenon 200701, South Korea.
[Kim, Kui-Jin] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Lab Lipid Med & Technol,Dept Med, Charlestown, MA 02129 USA.
[Lee, Boo-Yong] CHA Univ, Dept Food Sci & Biotechnol, Kyonggi Do 463836, South Korea.
RP Lee, BY (reprint author), CHA Univ, Dept Food Sci & Biotechnol, Kyonggi Do 463836, South Korea.
EM bylee@cha.ac.kr
OI Lee, Ok-Hwan/0000-0001-6855-3136
NR 39
TC 10
Z9 12
U1 1
U2 18
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 0021-8561
EI 1520-5118
J9 J AGR FOOD CHEM
JI J. Agric. Food Chem.
PD FEB 25
PY 2015
VL 63
IS 7
BP 2098
EP 2105
DI 10.1021/jf505894b
PG 8
WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science &
Technology
SC Agriculture; Chemistry; Food Science & Technology
GA CC2RX
UT WOS:000350193400024
PM 25613688
ER
PT J
AU Heuberger, BD
Pal, A
Del Frate, F
Topkar, VV
Szostak, JW
AF Heuberger, Benjamin D.
Pal, Ayan
Del Frate, Francesca
Topkar, Ved V.
Szostak, Jack W.
TI Replacing Uridine with 2-Thiouridine Enhances the Rate and Fidelity of
Nonenzymatic RNA Primer Extension
SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
LA English
DT Article
ID TEMPLATE-DIRECTED SYNTHESIS; REPLICATION; MODEL; OLIGOADENYLATES;
RIBONUCLEOTIDES; STABILITY; THYMIDINE; DUPLEXES; CODON
AB The nonenzymatic replication of RNA oligonucleotides is thought to have played a key role in the origin of life prior to the evolution of ribozyme-catalyzed RNA replication. Although the copying of oligo-C templates by 2-methylimidazole-activated G monomers can be quite efficient, the copying of mixed sequence templates, especially those containing A and U, is particularly slow and error-prone. The greater thermodynamic stability of the 2-thio-U(s(2)U):A base pair, relative to the canonical U:A base pair, suggests that replacing U with s(2)U might enhance the rate and fidelity of the nonenzymatic copying of RNA templates. Here we report that this single atom substitution in the activated monomer improves both the kinetics and the fidelity of nonenzymatic primer extension on mixed-sequence RNA templates. In addition, the mean lengths of primer extension products obtained with s(2)U is greater than those obtained with U, augmenting the potential for nonenzymatic replication of heritable function-rich sequences. We suggest that noncanonical nucleotides such as s(2)U may have played a role during the infancy of the RNA world by facilitating the nonenzymatic replication of genomic RNA oligonucleotides.
C1 [Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.
Massachusetts Gen Hosp, Dept Mol Biol, Simches Res Ctr, Boston, MA 02114 USA.
RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.
EM szostak@molbio.mgh.harvard.edu
FU National Science Foundation [CHE-0809413]; Simons Foundation [290363]
FX We thank A. Engelhart, T. Jia, A. Larsen, T. Olsen, T. Walton, A.
Fahrenbach, and A. Bjorkbom for helpful discussions and U. Kim for help
with next generation sequencing. This work was supported in part by
grant CHE-0809413 from the National Science Foundation and by grant
290363 from the Simons Foundation to J.W.S. who is an investigator from
the Howard Hughes Medical Institute.
NR 32
TC 11
Z9 12
U1 6
U2 23
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 0002-7863
J9 J AM CHEM SOC
JI J. Am. Chem. Soc.
PD FEB 25
PY 2015
VL 137
IS 7
BP 2769
EP 2775
DI 10.1021/jacs.5b00445
PG 7
WC Chemistry, Multidisciplinary
SC Chemistry
GA CC2RQ
UT WOS:000350192700050
PM 25654265
ER
PT J
AU Bucay, I
O'Brien, ET
Wulfe, SD
Superfine, R
Wolberg, AS
Falvo, MR
Hudson, NE
AF Bucay, Igal
O'Brien, E. Tim, III
Wulfe, Steven D.
Superfine, Richard
Wolberg, Alisa S.
Falvo, Michael R.
Hudson, Nathan E.
TI Physical Determinants of Fibrinolysis in Single Fibrin Fibers
SO PLOS ONE
LA English
DT Article
ID PLASMINOGEN-BINDING SITES; ALPHA-C-DOMAINS; ELECTRON-MICROSCOPY;
MODELING FIBRINOLYSIS; MOLECULAR-MECHANISMS; CLOT STRUCTURE;
TPA-BINDING; NETWORKS; EXTENSIBILITY; ELASTICITY
AB Fibrin fibers form the structural backbone of blood clots; fibrinolysis is the process in which plasmin digests fibrin fibers, effectively regulating the size and duration of a clot. To understand blood clot dissolution, the influence of clot structure and fiber properties must be separated from the effects of enzyme kinetics and perfusion rates into clots. Using an inverted optical microscope and fluorescently-labeled fibers suspended between micropatterned ridges, we have directly measured the lysis of individual fibrin fibers. We found that during lysis 64 +/- 6% of fibers were transected at one point, but 29 +/- 3% of fibers increase in length rather than dissolving or being transected. Thrombin and plasmin dose-response experiments showed that the elongation behavior was independent of plasmin concentration, but was instead dependent on the concentration of thrombin used during fiber polymerization, which correlated inversely with fiber diameter. Thinner fibers were more likely to lyse, while fibers greater than 200 +/- 30 nm in diameter were more likely to elongate. Because lysis rates were greatly reduced in elongated fibers, we hypothesize that plasmin activity depends on fiber strain. Using polymer physics-and continuum mechanics-based mathematical models, we show that fibers polymerize in a strained state and that thicker fibers lose their prestrain more rapidly than thinner fibers during lysis, which may explain why thick fibers elongate and thin fibers lyse. These results highlight how subtle differences in the diameter and prestrain of fibers could lead to dramatically different lytic susceptibilities.
C1 [Bucay, Igal; O'Brien, E. Tim, III; Wulfe, Steven D.; Superfine, Richard; Falvo, Michael R.] Univ N Carolina, Dept Phys & Astron, Chapel Hill, NC USA.
[Wolberg, Alisa S.] UNC Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA.
[Hudson, Nathan E.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA.
[Hudson, Nathan E.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
RP Hudson, NE (reprint author), Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA.
EM hudson@crystal.harvard.edu
OI Hudson, Nathan/0000-0003-0573-7661
FU National Institutes of Health [P41-EB002025]; National Science
Foundation grant [CMMI-1030640]
FX This work was supported by National Institutes of Health grant
P41-EB002025 http://www.nih.gov/; and by National Science Foundation
grant CMMI-1030640 http://www.nsf.gov/. The funders had no role in study
design, data collection and analysis, decision to publish, or
preparation of the manuscript.
NR 45
TC 9
Z9 9
U1 1
U2 21
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 25
PY 2015
VL 10
IS 2
AR e0116350
DI 10.1371/journal.pone.0116350
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC2IM
UT WOS:000350168700017
PM 25714359
ER
PT J
AU Varughese, RS
Ridgeon, E
Mathew, A
Sola-Del Valle, D
AF Varughese, Rachel S.
Ridgeon, Elliott
Mathew, Anna
Sola-Del Valle, David
TI A rapidly enlarging swelling of the left orbit
SO BMJ-BRITISH MEDICAL JOURNAL
LA English
DT Editorial Material
ID RHABDOMYOSARCOMA; CHILDHOOD; SURVIVAL; ONCOLOGY
C1 [Varughese, Rachel S.; Ridgeon, Elliott] Univ Oxford, Sch Med, Oxford OX1 2JD, England.
[Mathew, Anna] Worthing Dist Hosp, Dept Paediat, Worthing, W Sussex, England.
[Sola-Del Valle, David] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA.
RP Varughese, RS (reprint author), Univ Oxford, Sch Med, S Parks Rd, Oxford OX1 2JD, England.
EM rachel.varughese@btinternet.com
NR 16
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 25
PY 2015
VL 350
AR h799
DI 10.1136/bmj.h799
PG 4
WC Medicine, General & Internal
SC General & Internal Medicine
GA CC4AM
UT WOS:000350292900010
PM 25716818
ER
PT J
AU Dewhirst, FE
Klein, EA
Bennett, ML
Croft, JM
Harris, SJ
Marshall-Jones, ZV
AF Dewhirst, Floyd E.
Klein, Erin A.
Bennett, Marie-Louise
Croft, Julie M.
Harris, Stephen J.
Marshall-Jones, Zoe V.
TI The feline oral microbiome: A provisional 16S rRNA gene based taxonomy
with full-length reference sequences
SO VETERINARY MICROBIOLOGY
LA English
DT Article
DE Feline; Oral; Bacteria; Microbiome; 16S rRNA; Phylogeny
ID DATABASE
AB The human oral microbiome is known to play a significant role in human health and disease. While less well studied, the feline oral microbiome is thought to play a similarly important role. To determine roles oral bacteria play in health and disease, one first has to be able to accurately identify bacterial species present. 16S rRNA gene sequence information is widely used for molecular identification of bacteria and is also useful for establishing the taxonomy of novel species.
The objective of this research was to obtain full 16S rRNA gene reference sequences for feline oral bacteria, place the sequences in species-level phylotypes, and create a curated 16S rRNA based taxonomy for common feline oral bacteria.
Clone libraries were produced using "universal" and phylum-selective PCR primers and DNA from pooled subgingival plaque from healthy and periodontally diseased cats. Bacteria in subgingival samples were also cultivated to obtain isolates. Full-length 16S rDNA sequences were determined for clones and isolates that represent 171 feline oral taxa. A provisional curated taxonomy was developed based on the position of each taxon in 16S rRNA phylogenetic trees.
The feline oral microbiome curated taxonomy and 16S rRNA gene reference set will allow investigators to refer to precisely defined bacterial taxa. A provisional name such as "Propionibacterium sp. feline oral taxon FOT-327" is an anchor to which clone, strain or GenBank names or accession numbers can point. Future next-generation-sequencing studies of feline oral bacteria will be able to map reads to taxonomically curated full-length 16S rRNA gene sequences. (C) 2014 The Authors. Published by Elsevier B.V.
C1 [Dewhirst, Floyd E.; Klein, Erin A.] Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA.
[Dewhirst, Floyd E.] Harvard Univ, Dept Oral Med Infect & Immun, Sch Dent Med, Boston, MA 02115 USA.
[Bennett, Marie-Louise; Croft, Julie M.] Mars Care & Treats Europe, Birstall WF17 9LU, Batley, England.
[Harris, Stephen J.; Marshall-Jones, Zoe V.] Mars Petcare, WALTHAM Ctr Pet Nutr, Melton Mowbray LE14 4RT, Melton Mowbray, England.
RP Dewhirst, FE (reprint author), Forsyth Inst, Dept Microbiol, 245 First St, Cambridge, MA 02142 USA.
EM fdewhirst@forsyth.org
FU WALTHAM Centre for Pet Nutrition; National Institute of Dental and
Craniofacial Research of the National Institutes of Health [R37DE016937]
FX This work was supported by the WALTHAM Centre for Pet Nutrition.
Research reported in this publication was supported in part by The
National Institute of Dental and Craniofacial Research of the National
Institutes of Health under award number R37DE016937 (F.E. Dewhirst). The
content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institute of
Health. We thank Sara Barbuto for her assistance in DNA sequencing and
Lisa Milella for plaque sample collection.
NR 18
TC 6
Z9 8
U1 3
U2 18
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1135
EI 1873-2542
J9 VET MICROBIOL
JI Vet. Microbiol.
PD FEB 25
PY 2015
VL 175
IS 2-4
BP 294
EP 303
DI 10.1016/j.vetmic.2014.11.019
PG 10
WC Microbiology; Veterinary Sciences
SC Microbiology; Veterinary Sciences
GA CA5MI
UT WOS:000348952100015
PM 25523504
ER
PT J
AU Lin, MI
Price, EN
Boatman, S
Hagedorn, EJ
Trompouki, E
Satishchandran, S
Carspecken, CW
Uong, A
DiBiase, A
Yang, S
Canver, MC
Dahlberg, A
Lu, ZG
Zhang, CC
Orkin, SH
Bernstein, ID
Aster, JC
White, RM
Zon, LI
AF Lin, Michelle I.
Price, Emily N.
Boatman, Sonja
Hagedorn, Elliott J.
Trompouki, Eirini
Satishchandran, Sruthi
Carspecken, Charles W.
Uong, Audrey
DiBiase, Anthony
Yang, Song
Canver, Matthew C.
Dahlberg, Ann
Lu, Zhigang
Zhang, Cheng Cheng
Orkin, Stuart H.
Bernstein, Irwin D.
Aster, Jon C.
White, Richard M.
Zon, Leonard I.
TI Angiopoietin-like proteins stimulate HSPC development through
interaction with Notch receptor signaling
SO ELIFE
LA English
DT Article
ID HEMATOPOIETIC STEM-CELLS; EX-VIVO EXPANSION; C-MYC; VASCULAR
DEVELOPMENT; AORTIC ENDOTHELIUM; MOUSE EMBRYO; DEFINITIVE HEMATOPOIESIS;
LYMPHOBLASTIC-LEUKEMIA; ZEBRAFISH EMBRYOS; SELF-RENEWAL
AB Angiopoietin-like proteins (angptis) are capable of ex vivo expansion of mouse and human hematopoietic stem and progenitor cells (HSPCs). Despite this intriguing ability, their mechanism is unknown. Here, we show that angpti2 overexpression is sufficient to expand definitive HSPCs in zebrafish embryos. Angpti1/2 are required for definitive hematopoiesis and vascular specification of the hemogenic endothelium. The loss-of-function phenotype is reminiscent of the notch mutant mindbomb (mib) and a strong genetic interaction occurs between angptis and notch. Overexpressing angpti2 rescues mib while overexpressing notch rescues angpti1/2 morphants. Gene expression studies in AngptI2-stimulated CD34(+) cells showed a strong Myc activation signature and myc overexpression in angpti1/2 morphants or mib restored HSPCs formation. AngptI2 can increase Notch activation in cultured cells and Angptl receptor interacted with Notch to regulate Notch cleavage. Together our data provide insight to the angpti-mediated notch activation through receptor interaction and subsequent activation of myc targets.
C1 [Lin, Michelle I.; Price, Emily N.; Boatman, Sonja; Hagedorn, Elliott J.; Trompouki, Eirini; Satishchandran, Sruthi; Carspecken, Charles W.; Uong, Audrey; DiBiase, Anthony; Yang, Song; Canver, Matthew C.; Orkin, Stuart H.; Zon, Leonard I.] Harvard Univ, Sch Med, Bostons Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA.
[Lin, Michelle I.; Price, Emily N.; Boatman, Sonja; Hagedorn, Elliott J.; Trompouki, Eirini; Satishchandran, Sruthi; Carspecken, Charles W.; Uong, Audrey; DiBiase, Anthony; Yang, Song; Canver, Matthew C.; Orkin, Stuart H.; Zon, Leonard I.] Harvard Univ, Sch Med, Bostons Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA.
[Lin, Michelle I.; Price, Emily N.; Boatman, Sonja; Hagedorn, Elliott J.; Trompouki, Eirini; Satishchandran, Sruthi; Carspecken, Charles W.; Uong, Audrey; DiBiase, Anthony; Yang, Song; Canver, Matthew C.; Orkin, Stuart H.; Zon, Leonard I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Harvard Stem Cell Inst, Boston, MA 02115 USA.
[Dahlberg, Ann; Bernstein, Irwin D.] Fred Hutchinson Canc Res Ctr, Pediat Oncol Clin Div, Seattle, WA 98109 USA.
[Lu, Zhigang; Zhang, Cheng Cheng] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA.
[Dahlberg, Ann; Lu, Zhigang] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA.
[Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.
[Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
[White, Richard M.] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA.
[White, Richard M.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.
RP Zon, LI (reprint author), Harvard Univ, Sch Med, Bostons Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA.
EM zon@enders.tch.harvard.edu
OI Trompouki, Eirini/0000-0002-7242-8810
FU NIH [P50-N540828, P30-HD18655]
FX We would like to thank Y. Kubota, Y. Oike, T. Suda, S. Black low, H.
Wang, Y. L. Wong, K. Vasudevan J. Ganis, J. Lahvic, I. Shestopalov and
A. Gutierrez for providing reagents; C. Blobel, S. Black low and T. A.
Springer for helpful discussion and critical comments; Y. Zhou for
bioinformatics discussions; and N. Lawson for providing the
Tg(Tplbglob:eGFP)um14. The microarray expression experiments were
processed by the Microarray Core Facility of the Molecular Genetics Core
Facility at Children's Hospital Boston supported by NIH P50-N540828 and
NIH P30-HD18655. This work was supported by NIH 5R01HL048801-21, NIH
5P30DK49216-19, NIH R24DK092760-02, NIH 5U01HL10001-05, NIH
5P01HL32262-32, NIH 5R01DK53298 and HHMI (to LIZ.); Canadian Institutes
of Health Research Fellowship and the American Heart Association
Postdoctoral Fellowship, 11P05T4920031 (to M.I.L.); Hyundai Hope On
Wheels Grant (to A.D.); NIH 1U01HL100395-06 and Leukemia & Lymphoma
Society TRP 6407-13 (to I.D.B.); NIH K08AR055368, Melanoma Research
Alliance Young Investigator Award, and ASCO/AACR Young Investigator
Award (to R.M.W.), NIH 1R01CA172268 (to 32 C.C.Z.). L.I.Z. is a founder
and stockholder of Fate, Inc. and Scholar Rock, and a scientific advisor
for Stemgent.
NR 77
TC 6
Z9 6
U1 0
U2 1
PU ELIFE SCIENCES PUBLICATIONS LTD
PI CAMBRIDGE
PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND
SN 2050-084X
J9 ELIFE
JI eLife
PD FEB 25
PY 2015
VL 4
AR e05544
DI 10.7554/eLife.05544
PG 49
WC Biology
SC Life Sciences & Biomedicine - Other Topics
GA CC2ZE
UT WOS:000350212900004
ER
PT J
AU Kosmicki, JA
Sochat, V
Duda, M
Wall, DP
AF Kosmicki, J. A.
Sochat, V.
Duda, M.
Wall, D. P.
TI Searching for a minimal set of behaviors for autism detection through
feature selection-based machine learning
SO TRANSLATIONAL PSYCHIATRY
LA English
DT Article
ID DIAGNOSTIC OBSERVATION SCHEDULE; SPECTRUM DISORDER; IDENTIFICATION;
RESOURCE; RISK
AB Although the prevalence of autism spectrum disorder (ASD) has risen sharply in the last few years reaching 1 in 68, the average age of diagnosis in the United States remains close to 4-well past the developmental window when early intervention has the largest gains. This emphasizes the importance of developing accurate methods to detect risk faster than the current standards of care. In the present study, we used machine learning to evaluate one of the best and most widely used instruments for clinical assessment of ASD, the Autism Diagnostic Observation Schedule (ADOS) to test whether only a subset of behaviors can differentiate between children on and off the autism spectrum. ADOS relies on behavioral observation in a clinical setting and consists of four modules, with module 2 reserved for individuals with some vocabulary and module 3 for higher levels of cognitive functioning. We ran eight machine learning algorithms using stepwise backward feature selection on score sheets from modules 2 and 3 from 4540 individuals. We found that 9 of the 28 behaviors captured by items from module 2, and 12 of the 28 behaviors captured by module 3 are sufficient to detect ASD risk with 98.27% and 97.66% accuracy, respectively. A greater than 55% reduction in the number of behaviorals with negligible loss of accuracy across both modules suggests a role for computational and statistical methods to streamline ASD risk detection and screening. These results may help enable development of mobile and parent-directed methods for preliminary risk evaluation and/or clinical triage that reach a larger percentage of the population and help to lower the average age of detection and diagnosis.
C1 [Kosmicki, J. A.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
[Kosmicki, J. A.] Harvard Univ, Sch Med, Boston, MA USA.
[Kosmicki, J. A.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.
[Sochat, V.] Stanford Univ, Grad Program Biomed Informat, Stanford, CA 94305 USA.
[Duda, M.; Wall, D. P.] Stanford Univ, Div Syst Med, Dept Pediat & Psychiat, Stanford, CA 94305 USA.
RP Wall, DP (reprint author), Stanford Univ, Div Syst Med, Dept Pediat & Psychiat, Med Sch Off Bldg,1265 Welch Rd, Stanford, CA 94305 USA.
EM dpwall@stanford.edu
RI Sochat, Vanessa/C-6893-2015
OI Sochat, Vanessa/0000-0002-4387-3819
FU Simons Foundation; Nancy Lurie Marks Family Foundation; Harvard Catalyst
Program; National Institutes of Health [1R01MH090611-01A1]
FX We thank all the members of the Wall lab and the Analytical and
Translational Genetics Unit (ATGU) for critical input on study design
and results interpretation, especially Mark Daly, Elise Robinson, Todd
DeLuca and Elaine Lim for their time and assistance. Additionally, we
would like to thank the reviewers whose comments substantially improved
the quality of the manuscript. Finally, we thank all the families who
enrolled in the AC, AGRE, NDAR, SSC and SVIP projects. The work was
supported in part by funds to DPW from the Simons Foundation, Nancy
Lurie Marks Family Foundation, the Harvard Catalyst Program and grant
1R01MH090611-01A1 from the National Institutes of Health.
NR 28
TC 8
Z9 8
U1 1
U2 6
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 24
PY 2015
VL 5
AR e514
DI 10.1038/tp.2015.7
PG 7
WC Psychiatry
SC Psychiatry
GA DA2UM
UT WOS:000367652200002
PM 25710120
ER
PT J
AU Weissmiller, AM
Natera-Naranjo, O
Reyna, SM
Pearn, ML
Zhao, XB
Nguyen, P
Cheng, S
Goldstein, LSB
Tanzi, RE
Wagner, SL
Mobley, WC
Wu, CB
AF Weissmiller, April M.
Natera-Naranjo, Orlangie
Reyna, Sol M.
Pearn, Matthew L.
Zhao, Xiaobei
Phuong Nguyen
Cheng, Soan
Goldstein, Lawrence S. B.
Tanzi, Rudolph E.
Wagner, Steven L.
Mobley, William C.
Wu, Chengbiao
TI A gamma-Secretase Inhibitor, but Not a gamma-Secretase Modulator,
Induced Defects in BDNF Axonal Trafficking and Signaling: Evidence for a
Role for APP
SO PLOS ONE
LA English
DT Article
ID AMYLOID PRECURSOR PROTEIN; CARBOXYL-TERMINAL FRAGMENT;
ALZHEIMER-DISEASE; A-BETA; IN-VIVO; MOUSE MODEL; DOWN-SYNDROME;
SOLUBLE-DERIVATIVES; CORTICAL-NEURONS; TRANSGENIC MICE
AB Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that A beta peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of A beta peptides have been discovered such as.-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce A beta levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative.
C1 [Weissmiller, April M.; Natera-Naranjo, Orlangie; Zhao, Xiaobei; Phuong Nguyen; Cheng, Soan; Wagner, Steven L.; Mobley, William C.; Wu, Chengbiao] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA.
[Reyna, Sol M.; Goldstein, Lawrence S. B.] Univ Calif San Diego, Dept Cellular & Mol Med, San Diego, CA 92103 USA.
[Pearn, Matthew L.] Univ Calif San Diego, Dept Anesthesiol, San Diego, CA 92103 USA.
[Pearn, Matthew L.] VA San Diego Healthcare Syst, San Diego, CA USA.
[Tanzi, Rudolph E.] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA USA.
RP Mobley, WC (reprint author), Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA.
EM wmobley@ucsd.edu; chw049@ucsd.edu
FU NIH [PN2 EY016525]; Down Syndrome Research and Treatment Foundation;
Larry L. Hillblom Foundation; Thrasher Research Fund; Cure Alzheimer's
Fund; ADRC Pilot Grant; NIH Neuroplasticity of Aging Predoctoral
training grant; SfN Neuroscience Scholars Program; Genetics Training
grant; Cellular and Molecular Medicine Electron Microscopy Facility of
UCSD; UCSD Neuroscience Microscopy Shared Facility [P30 NS047101];
[NIH-AG032180]
FX This work was supported by NIH (PN2 EY016525) and the Down Syndrome
Research and Treatment Foundation (AMW, CW, WCM), the Larry L. Hillblom
Foundation (CW, WCM), the Thrasher Research Fund (WCM), the Cure
Alzheimer's Fund (SLW, WCM), the ADRC Pilot Grant (CW) and NIH-AG032180
grant to LSBG. The authors thank the NIH Neuroplasticity of Aging
Predoctoral training grant (AMW, ONN), SfN Neuroscience Scholars Program
(AMW), and Genetics Training grant (SMR). The authors thank Dr M.
Farquhar, Y. Jones and T. Meerloo and the Cellular and Molecular
Medicine Electron Microscopy Facility of UCSD for performing embedding
and sectioning of coverslips and the UCSD Neuroscience Microscopy Shared
Facility (Grant P30 NS047101). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the
manuscript.
NR 103
TC 11
Z9 13
U1 0
U2 2
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD FEB 24
PY 2015
VL 10
IS 2
AR UNSP e0118379
DI 10.1371/journal.pone.0118379
PG 24
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC9IY
UT WOS:000350683900054
PM 25710492
ER
PT J
AU Guidon, AC
AF Guidon, Amanda C.
TI Comment: A growing role for nerve ultrasound in diagnosis and management
of CIDP?
SO NEUROLOGY
LA English
DT Article
ID DISEASE
AB Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated polyneuropathy characterized by segmental demyelination, sometimes accompanied by axonal loss. Nerve size and architecture are altered. Despite composite criteria, diagnosis can be challenging. Furthermore, objective measurements to follow disease activity are limited. High-resolution nerve ultrasound could potentially aid in diagnosis and disease monitoring; it is inexpensive, widely available, noninvasive, and can rapidly image long segments of multiple nerves. However, few studies have examined the relationship between nerve morphology and function in CIDP using ultrasound.(1 3 cm, and older age; HRs for progression between 1.32 and 2.88, P <= .002; HRs for cancer-specific survival between 1.28 and 2.08, P <= .02).
Conclusion
In this large analysis of outcomes and prognostic factors in HGT1 bladder cancer, deep lamina propria invasion had the largest negative impact, and other previously proposed prognostic factors were also confirmed. These factors should be used for prognostication and patient stratification in future clinical trials, and depth of invasion should be considered for inclusion in TNM staging criteria. This meta-analysis can also help define selection criteria for early cystectomy in HGT1 bladder cancer, particularly for patients with deep lamina propria invasion combined with other risk factors.
C1 [Martin-Doyle, William] Univ Massachusetts, Sch Med, Worcester, MA USA.
[Leow, Jeffrey J.; Chang, Steven L.; Bellmunt, Joaquim] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Bladder Canc Ctr, Cambridge, MA 02138 USA.
[Leow, Jeffrey J.; Chang, Steven L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cambridge, MA 02138 USA.
[Orsola, Anna] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA.
[Bellmunt, Joaquim] Univ Hosp Mar Invest Med, IMIM, Barcelona, Spain.
RP Bellmunt, J (reprint author), Dana Farber Brigham & Womens Canc Ctr, Bladder Canc Ctr, 450 Brookline Ave, Boston, MA 02215 USA.
EM joaquim_bellmunt@dfci.harvard.edu
NR 60
TC 26
Z9 26
U1 0
U2 1
PU AMER SOC CLINICAL ONCOLOGY
PI ALEXANDRIA
PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA
SN 0732-183X
EI 1527-7755
J9 J CLIN ONCOL
JI J. Clin. Oncol.
PD FEB 20
PY 2015
VL 33
IS 6
BP 643
EP U165
DI 10.1200/JCO.2014.57.6967
PG 10
WC Oncology
SC Oncology
GA CF4MS
UT WOS:000352523800020
PM 25559810
ER
PT J
AU Dimopoulos, MA
Hillengass, J
Usmani, S
Zamagni, E
Lentzsch, S
Davies, FE
Raje, N
Sezer, O
Zweegman, S
Shah, J
Badros, A
Shimizu, K
Moreau, P
Chim, CS
Lahuerta, JJ
Hou, J
Jurczyszyn, A
Goldschmidt, H
Sonneveld, P
Palumbo, A
Ludwig, H
Cavo, M
Barlogie, B
Anderson, K
Roodman, GD
Rajkumar, SV
Durie, BGM
Terpos, E
AF Dimopoulos, Meletios A.
Hillengass, Jens
Usmani, Saad
Zamagni, Elena
Lentzsch, Suzanne
Davies, Faith E.
Raje, Noopur
Sezer, Orhan
Zweegman, Sonja
Shah, Jatin
Badros, Ashraf
Shimizu, Kazuyuki
Moreau, Philippe
Chim, Chor-Sang
Lahuerta, Juan Jose
Hou, Jian
Jurczyszyn, Artur
Goldschmidt, Hartmut
Sonneveld, Pieter
Palumbo, Antonio
Ludwig, Heinz
Cavo, Michele
Barlogie, Bart
Anderson, Kenneth
Roodman, G. David
Rajkumar, S. Vincent
Durie, Brian G. M.
Terpos, Evangelos
TI Role of Magnetic Resonance Imaging in the Management of Patients With
Multiple Myeloma: A Consensus Statement
SO JOURNAL OF CLINICAL ONCOLOGY
LA English
DT Article
ID WHOLE-BODY MRI; STEM-CELL TRANSPLANTATION; CONTRAST-ENHANCED MRI;
POSITRON-EMISSION-TOMOGRAPHY; BONE-MARROW INVOLVEMENT; MONOCLONAL
GAMMOPATHY; UNDETERMINED SIGNIFICANCE; PROGNOSTIC-SIGNIFICANCE;
DIAGNOSTIC PERFORMANCE; EXTRAMEDULLARY DISEASE
AB Purpose
The aim of International Myeloma Working Group was to develop practical recommendations for the use of magnetic resonance imaging (MRI) in multiple myeloma (MM).
Methods
An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations for the value of MRI based on data published through March 2014.
Recommendations
MRI has high sensitivity for the early detection of marrow infiltration by myeloma cells compared with other radiographic methods. Thus, MRI detects bone involvement in patients with myeloma much earlier than the myeloma-related bone destruction, with no radiation exposure. It is the gold standard for the imaging of axial skeleton, for the evaluation of painful lesions, and for distinguishing benign versus malignant osteoporotic vertebral fractures. MRI has the ability to detect spinal cord or nerve compression and presence of soft tissue masses, and it is recommended for the workup of solitary bone plasmacytoma. Regarding smoldering or asymptomatic myeloma, all patients should undergo whole-body MRI (WB-MRI; or spine and pelvic MRI if WB-MRI is not available), and if they have > one focal lesion of a diameter > 5 mm, they should be considered to have symptomatic disease that requires therapy. In cases of equivocal small lesions, a second MRI should be performed after 3 to 6 months, and if there is progression on MRI, the patient should be treated as having symptomatic myeloma. MRI at diagnosis of symptomatic patients and after treatment (mainly after autologous stem-cell transplantation) provides prognostic information; however, to date, this does not change treatment selection. (C) 2015 by American Society of Clinical Oncology
C1 [Dimopoulos, Meletios A.; Terpos, Evangelos] Univ Athens, Sch Med, Athens 11528, Greece.
[Hillengass, Jens; Goldschmidt, Hartmut] Univ Heidelberg Hosp, Heidelberg, Germany.
[Usmani, Saad] Carolinas Healthcare Syst, Charlotte, NC USA.
[Zamagni, Elena; Cavo, Michele] Univ Bologna, Sch Med, Bologna, Italy.
[Palumbo, Antonio] Univ Turin, S Giovanni Battista Hosp, Turin, Italy.
[Lentzsch, Suzanne] Columbia Univ, Coll Physicians & Surg, New York, NY USA.
[Davies, Faith E.] Inst Canc Res, Sutton, Surrey, England.
[Raje, Noopur] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA.
[Anderson, Kenneth] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA.
[Sezer, Orhan] Mem Sisli Hosp, Istanbul, Turkey.
[Zweegman, Sonja] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
[Sonneveld, Pieter] Erasmus Univ, Med Ctr, Rotterdam, Netherlands.
[Shah, Jatin] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA.
[Badros, Ashraf] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA.
[Shimizu, Kazuyuki] Tokai Cent Hosp, Kakamigahara, Japan.
[Moreau, Philippe] Univ Hosp Hotel Dieu, Nantes, France.
[Chim, Chor-Sang] Univ Hong Kong, Queen Mary Hosp, Hong Kong, Hong Kong, Peoples R China.
[Hou, Jian] Second Mil Med Univ, Changzheng Hosp, Shanghai, Peoples R China.
[Lahuerta, Juan Jose] Hosp Univ 12 Octubre, Madrid, Spain.
[Jurczyszyn, Artur] Univ Hosp, Krakow, Poland.
[Ludwig, Heinz] Wilhelminenspital Stadt Wien, Vienna, Austria.
[Barlogie, Bart] Univ Arkansas Med Sci, Little Rock, AR 72205 USA.
[Roodman, G. David] Indiana Univ, Sch Med, Indianapolis, IN USA.
[Rajkumar, S. Vincent] Mayo Clin, Rochester, MN USA.
[Durie, Brian G. M.] Samuel Oschin Comprehens Canc Inst, Los Angeles, CA USA.
RP Dimopoulos, MA (reprint author), Univ Athens, Sch Med, Alexandra Gen Hosp, Dept Clin Therapeut, 80 Vas Sofias Ave, Athens 11528, Greece.
EM mdimop@med.uoa.gr
RI richard, chrystelle/K-8595-2015;
OI CAVO, MICHELE/0000-0003-4514-3227
FU Celgene; Onyx Pharmaceuticals; Janssen-Cilag; Array BioPharma;
Pharmacyclics; Eli Lilly; Acetylon Pharmaceuticals; Celgene (Inst);
Janssen-Cilag (Inst); Millennium Pharmaceuticals (Inst); Novartis;
Janssen Pharmaceuticals (Inst); Novartis (Inst); Chugai Pharmaceutical
(Inst; Takeda Pharmaceuticals (Inst); Eli Lilly (Inst); Expenses:
Janssen-Cilag; Genesis
FX Celgene, Onyx Pharmaceuticals, Janssen-Cilag, Array BioPharma,
Pharmacyclics; Celgene; Eli Lilly, Acetylon Pharmaceuticals; Celgene
(Inst), Janssen-Cilag (Inst), Millennium Pharmaceuticals (Inst);
Celgene, Millennium Pharmaceuticals, Novartis, Onyx Pharmaceuticals,
Array BioPharma; Janssen Pharmaceuticals (Inst), Celgene (Inst),
Novartis (Inst), Chugai Pharmaceutical (Inst); Celgene (Inst), Onyx
Pharmaceuticals (Inst), Janssen-Cilag (Inst); Takeda Pharmaceuticals
(Inst); Celgene; Eli Lilly (Inst); Amgen (Inst), Janssen-Cilag (Inst)
NR 68
TC 45
Z9 46
U1 1
U2 9
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 20
PY 2015
VL 33
IS 6
BP 657
EP U186
DI 10.1200/JCO.2014.57.9961
PG 12
WC Oncology
SC Oncology
GA CF4MS
UT WOS:000352523800023
PM 25605835
ER
PT J
AU Luke, JJ
Lezcano, C
Hodi, FS
Murphy, GF
AF Luke, Jason J.
Lezcano, Cecilia
Hodi, F. Stephen
Murphy, George F.
TI Antitumor Granuloma Formation by CD4(+) T Cells in a Patient With
Rapidly Progressive Melanoma Experiencing Spiking Fevers, Neuropathy,
and Other Immune-Related Toxicity After Treatment With Ipilimumab
SO JOURNAL OF CLINICAL ONCOLOGY
LA English
DT Article
ID REGIONAL LYMPH-NODES; SARCOID REACTIONS; CANCER-IMMUNOTHERAPY; ADVERSE
EVENTS; CARCINOMA; ANTIBODY; BLOCKADE
C1 [Luke, Jason J.; Hodi, F. Stephen] Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02115 USA.
[Luke, Jason J.; Lezcano, Cecilia; Hodi, F. Stephen; Murphy, George F.] Brigham & Womens Hosp, Boston, MA 02115 USA.
[Luke, Jason J.; Lezcano, Cecilia; Hodi, F. Stephen; Murphy, George F.] Harvard Univ, Sch Med, Boston, MA USA.
RP Luke, JJ (reprint author), Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02115 USA.
FU NCI NIH HHS [R01 CA158467, R01 CA138231]
NR 25
TC 6
Z9 6
U1 0
U2 1
PU AMER SOC CLINICAL ONCOLOGY
PI ALEXANDRIA
PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA
SN 0732-183X
EI 1527-7755
J9 J CLIN ONCOL
JI J. Clin. Oncol.
PD FEB 20
PY 2015
VL 33
IS 6
BP E32
EP E35
DI 10.1200/JCO.2013.49.7735
PG 4
WC Oncology
SC Oncology
GA CF4MS
UT WOS:000352523800002
PM 24616309
ER
PT J
AU Snuderl, M
Triscott, J
Northcott, PA
Shih, HA
Kong, E
Robinson, H
Dunn, SE
Iafrate, AJ
Yip, S
AF Snuderl, Matija
Triscott, Joanna
Northcott, Paul A.
Shih, Helen A.
Kong, Esther
Robinson, Hayley
Dunn, Sandra E.
Iafrate, A. John
Yip, Stephen
TI Deep Sequencing Identifies IDH1 R132S Mutation in Adult Medulloblastoma
SO JOURNAL OF CLINICAL ONCOLOGY
LA English
DT Article
ID CRANIOSPINAL RADIATION-THERAPY; ADJUVANT CHEMOTHERAPY; CHILDREN;
GLIOBLASTOMA; DISTINCT
C1 [Snuderl, Matija] NYU, Langone Med Ctr, New York, NY 10012 USA.
[Snuderl, Matija] NYU, Sch Med, New York, NY USA.
[Triscott, Joanna; Kong, Esther; Dunn, Sandra E.; Yip, Stephen] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada.
[Northcott, Paul A.] German Canc Res Ctr, Heidelberg, Germany.
[Shih, Helen A.; Robinson, Hayley; Iafrate, A. John] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Shih, Helen A.; Robinson, Hayley; Iafrate, A. John] Harvard Univ, Sch Med, Boston, MA USA.
RP Snuderl, M (reprint author), NYU, Langone Med Ctr, New York, NY 10012 USA.
OI Snuderl, Matija/0000-0003-0752-0917
FU Paul Calabresi Career Development Award in Clinical Oncology at
Massachusetts General Hospital [2K12CA090354-11]; Brain Care BC;
Hannah's Heros Foundation; Mitacs; Michael Cuccione Foundation
FX M.S. is the recipient of a Paul Calabresi Career Development Award in
Clinical Oncology (2K12CA090354-11) at Massachusetts General Hospital.
This project was supported by Brain Care BC (S.Y.), Hannah's Heros
Foundation, Mitacs, and the Michael Cuccione Foundation (S.E.D.).
NR 24
TC 3
Z9 3
U1 0
U2 5
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 20
PY 2015
VL 33
IS 6
BP E27
EP E31
DI 10.1200/JCO.2013.49.4864
PG 5
WC Oncology
SC Oncology
GA CF4MS
UT WOS:000352523800001
PM 24616312
ER
PT J
AU Salmon, AB
AF Salmon, Adam B.
TI About-face on the metabolic side effects of rapamycin
SO ONCOTARGET
LA English
DT Editorial Material
ID LIFE-SPAN; MICE
C1 [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA.
[Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA.
[Salmon, Adam B.] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA.
RP Salmon, AB (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA.
EM salmona@uth-scsa.edu
OI Salmon, Adam/0000-0002-1475-7843
NR 8
TC 1
Z9 1
U1 0
U2 2
PU IMPACT JOURNALS LLC
PI ALBANY
PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA
SN 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD FEB 20
PY 2015
VL 6
IS 5
BP 2585
EP 2586
PG 2
WC Oncology; Cell Biology
SC Oncology; Cell Biology
GA CF6VK
UT WOS:000352694400002
PM 25691064
ER
PT J
AU Pride, H
Yu, Z
Sunchu, B
Mochnick, J
Coles, A
Zhang, YQ
Buffenstein, R
Hornsby, PJ
Austad, SN
Perez, VI
AF Pride, Harrison
Yu, Zhen
Sunchu, Bharath
Mochnick, Jillian
Coles, Alexander
Zhang, Yiqiang
Buffenstein, Rochelle
Hornsby, Peter J.
Austad, Steven N.
Perez, Viviana I.
TI Long-lived species have improved proteostasis compared to
phylogenetically-related shorter-lived species
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Protein homeostasis; Autophagy; Proteasome; Heat shock response;
Long-lived species
ID NAKED MOLE-RAT; PROTEIN HOMEOSTASIS; OXIDATIVE STRESS; LIVING RODENT;
LIFE-SPAN; AUTOPHAGY; RESISTANCE; LONGEVITY; FIBROBLASTS; ELEGANS
AB Our previous studies have shown that the liver from Naked Mole Rats (NMRs), a long-lived rodent, has increased proteasome activity and lower levels of protein ubiquitination compared to mice. This suggests that protein quality control might play a role in assuring species longevity. To determine whether enhanced proteostasis is a common mechanism in the evolution of other long-lived species, here we evaluated the major players in protein quality control including autophagy, proteasome activity, and heat shock proteins (HSPs), using skin fibroblasts from three phylogenetically-distinct pairs of short- and long-lived mammals: rodents, marsupials, and bats. Our results indicate that in all cases, macroautophagy was significantly enhanced in the longer-lived species, both at basal level and after induction by serum starvation. Similarly, basal levels of most HSPs were elevated in all the longer-lived species. Proteasome activity was found to be increased in the long-lived rodent and marsupial but not in bats. These observations suggest that long-lived species may have superior mechanisms to ensure protein quality, and support the idea that protein homeostasis might play an important role in promoting longevity. (C) 2015 Elsevier Inc. All rights reserved.
C1 [Pride, Harrison; Yu, Zhen; Sunchu, Bharath; Mochnick, Jillian; Perez, Viviana I.] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA.
[Coles, Alexander] Univ Michigan, Dept Chem & Biochem, Flint, MI 48502 USA.
[Zhang, Yiqiang; Buffenstein, Rochelle; Hornsby, Peter J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA.
[Zhang, Yiqiang; Buffenstein, Rochelle; Hornsby, Peter J.; Austad, Steven N.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA.
[Hornsby, Peter J.] South Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78249 USA.
[Austad, Steven N.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cell & Struct Biol, San Antonio, TX 78229 USA.
[Perez, Viviana I.] Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USA.
RP Perez, VI (reprint author), Oregon State Univ, Dept Biochem & Biophys, Linus Pauling Inst, 307 Linus Pauling Sci Ctr, Corvallis, OR 97331 USA.
EM viviana.perez@oregonstate.edu
FU Ellison Medical foundation; American Federation for Aging Research;
Comparative Biology of Aging Core in the San Antonio Nathan Shock
Center; Linus Pauling Institute; Biochemistry and Biophysics Dept.,
Oregon State University
FX Financial support was provided by Ellison Medical foundation (V.I.P),
American Federation for Aging Research (V.I.P), Comparative Biology of
Aging Core in the San Antonio Nathan Shock Center, and funds from The
Linus Pauling Institute, and Biochemistry and Biophysics Dept., Oregon
State University.
NR 24
TC 10
Z9 10
U1 2
U2 16
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD FEB 20
PY 2015
VL 457
IS 4
BP 669
EP 675
DI 10.1016/j.bbrc.2015.01.046
PG 7
WC Biochemistry & Molecular Biology; Biophysics
SC Biochemistry & Molecular Biology; Biophysics
GA CD1MK
UT WOS:000350838800030
PM 25615820
ER
PT J
AU Hanchate, AD
Kapoor, A
Katz, JN
McCormick, D
Lasser, KE
Feng, C
Manze, MG
Kressin, NR
AF Hanchate, Amresh D.
Kapoor, Alok
Katz, Jeffrey N.
McCormick, Danny
Lasser, Karen E.
Feng, Chen
Manze, Meredith G.
Kressin, Nancy R.
TI Massachusetts health reform and disparities in joint replacement use:
difference in differences study
SO BMJ-BRITISH MEDICAL JOURNAL
LA English
DT Article
ID STATES MEDICARE POPULATION; TOTAL KNEE ARTHROPLASTY; TOTAL
HIP-REPLACEMENT; UNITED-STATES; CARE REFORM; SOCIOECONOMIC-STATUS;
COST-EFFECTIVENESS; ACCESS; OUTCOMES; COVERAGE
AB Objective To estimate the impact of the insurance expansion in 2006 on use of knee and hip replacement procedures by race/ethnicity, area income, and the use of hospitals that predominantly serve poor people ("safety net hospitals").
Design Quasi-experimental difference in differences study examining change after reform in the share of procedures performed in safety net hospitals by race/ethnicity and area income, with adjustment for patients' residence, demographics, and comorbidity.
Setting State of Massachusetts, United States.
Participants Massachusetts residents aged 40-64 as the target beneficiaries of reform and similarly aged residents of New Jersey, New York, and Pennsylvania as the comparison (control) population.
Main outcomes measures Number of knee and hip replacement procedures per 10 000 population and use of safety net hospitals. Procedure counts from state discharge data for 2.5 years before and after reform, and multivariate difference in differences. Poisson regression was used to adjust for demographics, economic conditions, secular time, and geographic factors to estimate the change in procedure rate associated with health reform by race/ethnicity and area income.
Results Before reform, the number of procedures (/10 000) in Massachusetts was lower among Hispanic people (12.9, P<0.001) than black people (28.1) and white people (30.1). Overall, procedure use increased 22.4% during the 2.5 years after insurance expansion; reform in Massachusetts was associated with a 4.7% increase. The increase associated with reform was significantly higher among Hispanic people (37.9%, P<0.001) and black people (11.4%, P<0.05) than among white people (2.8%). Lower income was not associated with larger increases in procedure use. The share of knee and hip replacement procedures performed in safety net hospitals in Massachusetts decreased by 1.0% from a level of 12.7% before reform. The reduction was larger among Hispanic people (-6.4%, P<0.001) than white people (-1.0%), and among low income residents (-3.9%, p<0.001) than high income residents (0%).
Conclusions Insurance expansion can help reduce disparities by race/ethnicity but not by income in access to elective surgical care and could shift some elective surgical care away from safety net hospitals.
C1 [Hanchate, Amresh D.; Kressin, Nancy R.] VA Boston Healthcare Syst, Boston, MA USA.
[Hanchate, Amresh D.; Lasser, Karen E.; Kressin, Nancy R.] Boston Univ, Sch Med, Boston, MA 02118 USA.
[Kapoor, Alok] Univ Massachusetts, Sch Med, Worcester, MA USA.
[Katz, Jeffrey N.] Brigham & Womens Hosp, Boston, MA 02115 USA.
[Katz, Jeffrey N.] Harvard Univ, Sch Med, Boston, MA USA.
[McCormick, Danny] Cambridge Hlth Alliance, Cambridge, MA USA.
[McCormick, Danny] Harvard Univ, Sch Med, Cambridge, MA 02138 USA.
[Lasser, Karen E.; Feng, Chen] Boston Med Ctr, Boston, MA USA.
[Manze, Meredith G.] CUNY, Sch Publ Hlth, New York, NY 10021 USA.
RP Hanchate, AD (reprint author), Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA.
EM hanchate@bu.edu
FU US National Institutes of Health [1R21NS062677, 1U01HL105342-01]; Rx
foundation; Department of Veterans Affairs, Health Services Research and
Development Service [RCS 02-066-1]
FX This research was funded by US National Institutes of Health grants
(1R21NS062677, ADH, principal investigator, and 1U01HL105342-01, NRK,
principal investigator) and a grant from the Rx foundation. NRK is
supported in part by a senior research career scientist award from the
Department of Veterans Affairs, Health Services Research and Development
Service (RCS 02-066-1). The views expressed in this article are those of
the authors and do not necessarily represent the views of the National
Institutes of Health, the Rx foundation, Boston University, or the
Department of Veterans Affairs.
NR 61
TC 7
Z9 7
U1 1
U2 8
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 20
PY 2015
VL 350
AR h440
DI 10.1136/bmj.h440
PG 10
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB8WF
UT WOS:000349911800002
PM 25700849
ER
PT J
AU Menche, J
Sharma, A
Kitsak, M
Ghiassian, SD
Vidal, M
Loscalzo, J
Barabasi, AL
AF Menche, Joerg
Sharma, Amitabh
Kitsak, Maksim
Ghiassian, Susan Dina
Vidal, Marc
Loscalzo, Joseph
Barabasi, Albert-Laszlo
TI Uncovering disease-disease relationships through the incomplete
interactome
SO SCIENCE
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; PROTEIN-INTERACTION NETWORKS; INTERACTION
DATASETS; MOLECULAR NETWORKS; CANDIDATE GENES; CELIAC-DISEASE; GWAS
DATA; MEDICINE; BIOLOGY; DISORDERS
AB According to the diseasemodule hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, themap of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data have sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant coexpression patterns, symptom similarity, and comorbidity, whereas diseases residing in separated network neighborhoods are phenotypically distinct. These tools represent an interactome-based platform to predict molecular commonalities between phenotypically related diseases, even if they do not share primary disease genes.
C1 [Menche, Joerg; Sharma, Amitabh; Kitsak, Maksim; Ghiassian, Susan Dina; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Networks Res, Dana Res Ctr 111, Boston, MA 02115 USA.
[Menche, Joerg; Sharma, Amitabh; Kitsak, Maksim; Ghiassian, Susan Dina; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Dana Res Ctr 111, Boston, MA 02115 USA.
[Menche, Joerg; Sharma, Amitabh; Kitsak, Maksim; Ghiassian, Susan Dina; Vidal, Marc; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA.
[Menche, Joerg; Sharma, Amitabh; Kitsak, Maksim; Ghiassian, Susan Dina; Vidal, Marc; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.
[Menche, Joerg; Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary.
[Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
[Loscalzo, Joseph; Barabasi, Albert-Laszlo] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA.
RP Barabasi, AL (reprint author), Northeastern Univ, Ctr Complex Networks Res, Dana Res Ctr 111, 110 Forsyth St, Boston, MA 02115 USA.
EM alb@neu.edu
RI Menche, Jorg/G-3994-2015
OI Menche, Jorg/0000-0002-1583-6404
FU NIH from NHGRI [P50-HG004233, U01-HG001715, UO1-HG007690]; NIH from
NHLBI [PO1-HL083069, R37-HL061795, RC2-HL101543, U01-HL108630]
FX We thank A.-R. Carvunis, S. Pevzner, and T. Rolland for providing
invaluable insights into the y2h data set; J. Bagrow and F. Simini for
many discussions on the network methods; and G. Musella for figure
design. This work was supported by NIH grants P50-HG004233,
U01-HG001715, and UO1-HG007690 from NHGRI and PO1-HL083069,
R37-HL061795, RC2-HL101543, and U01-HL108630 from NHLBI.
NR 50
TC 105
Z9 108
U1 18
U2 75
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 20
PY 2015
VL 347
IS 6224
AR 1257601
DI 10.1126/science.1257601
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB6UB
UT WOS:000349761100035
PM 25700523
ER
PT J
AU Srinivasa, S
Fitch, KV
Lo, J
Kadar, H
Knight, R
Wong, K
Abbara, S
Gauguier, D
Capeau, J
Boccara, F
Grinspoon, SK
AF Srinivasa, Suman
Fitch, Kathleen V.
Lo, Janet
Kadar, Hanane
Knight, Rachel
Wong, Kimberly
Abbara, Suhny
Gauguier, Dominique
Capeau, Jacqueline
Boccara, Franck
Grinspoon, Steven K.
TI Plaque burden in HIV-infected patients is associated with serum
intestinal microbiota-generated trimethylamine
SO AIDS
LA English
DT Article
DE coronary plaque; gut microbiota; HIV; inflammation; trimethylamine;
trimethylamine-N-oxide
ID MYOCARDIAL-INFARCTION; COMPUTED-TOMOGRAPHY; CARDIOVASCULAR-DISEASE;
IMMUNE ACTIVATION; GUT MICROBIOTA; RISK-FACTORS; N-OXIDE;
ATHEROSCLEROSIS; METABOLISM; CHOLINE
AB Objective: Some intestinal microbiota-generated metabolites of phosphatidylcholine are recognized to be proatherogenic. As the HIV population is vulnerable to cardiovascular disease and can develop intestinal dysbiosis associated with systemic inflammation, we investigated the novel relationship between microbiota-derived metabolites of phosphatidylcholine and coronary atherosclerosis in HIV.
Design/ Methods: One hundred and fifty-five HIV-infected and 67 non-HIV-infected individuals without known history of cardiovascular disease were previously recruited to assess coronary plaque by computed tomography angiography. In the current study, we evaluate whether serum choline, trimethylamine (TMA), or trimethylamine-N-oxide (TMAO) levels are associated with plaque features.
Results: Young, asymptomatic HIV-infected patients (age 47 +/- 7 years) demonstrated significantly higher prevalence of plaque (53 vs. 35%, P = 0.01) and number of total plaque segments (1.8 +/- 2.5 vs. 1.2 +/- 2.2, P = 0.03) when compared with well matched noninfected individuals with similar comorbidities. TMA was significantly associated with calcium score (r = 0.22, P = 0.006), number of total (r = 0.20, P = 0.02) and calcified (r = 0.18, P = 0.03) plaque segments, and calcium plaque volume (r = 0.19, P = 0.02) and mass (r = 0.22, P = 0.009) in the HIV cohort only. In multivariate modeling among HIV-infected patients, TMA remained significantly associated with calcium score (P = 0.008), number of total (P = 0.005) and calcified (P = 0.02) plaque segments, and calcium plaque volume (P = 0.01) and mass (P = 0.007), independent of Framingham risk score. In contrast, there was no association of TMAO to coronary plaque features in either cohort.
Conclusion: A link between TMA and atherosclerosis has not previously been established. The current study suggests that TMA may be a nontraditional risk factor related to the number of plaque segments and severity of calcified plaque burden in HIV. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.
C1 [Srinivasa, Suman; Fitch, Kathleen V.; Lo, Janet; Wong, Kimberly; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA.
[Srinivasa, Suman; Fitch, Kathleen V.; Lo, Janet; Wong, Kimberly; Grinspoon, Steven K.] Harvard Univ, Sch Med, Boston, MA USA.
[Kadar, Hanane; Gauguier, Dominique] Cordeliers Res Ctr, INSERM, UMRS1138, Paris, France.
[Kadar, Hanane; Gauguier, Dominique; Capeau, Jacqueline] Univ Paris 06, Hosp Pitie Salpetriere, Inst Cardiometab & Nutr, Paris, France.
[Knight, Rachel] Univ Rochester, Sch Med, Rochester, NY USA.
[Abbara, Suhny] UTSW Med Ctr, Dept Radiol, Cardiothorac Imaging Div, Dallas, TX USA.
[Capeau, Jacqueline] Univ Paris 06, Hop Tenon, AP HP Paris, CDR St Antoine,Inserm,UMR S938,Inst Cardiometab &, Paris, France.
[Boccara, Franck] Univ Paris 06, St Antoine Hosp, Fac Med Pierre & Marie Curie, Dept Cardiol,Inserm,U938, Paris, France.
RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA.
EM sgrinspoon@mgh.harvard.edu
FU Bristol Myers Squibb, Inc; National Institutes of Health [K24 DK064545,
R01 HL095123-04, K23 HL092792, NS37654, M01 RR01066, 1 UL1 RR025758-01,
UL1 TR001102]; Harvard Clinical and Translational Science Center from
the National Center for Research Resources; Nutrition Obesity Research
Center at Harvard [P30 DK040561]; Institute of Cardiometabolism and
Nutrition (ICAN) [ANR-10-IAHU-05]; European Commission [METACARDIS
HEALTH-F4-2012-305312]; Ile de France Region [CORDDIM 120167]
FX Source of funding: This work was supported by Bristol Myers Squibb, Inc;
the National Institutes of Health K24 DK064545 and R01 HL095123-04 to
S.K.G., K23 HL092792 to J.L., NS37654, M01 RR01066, 1 UL1 RR025758-01
and UL1 TR001102, Harvard Clinical and Translational Science Center,
from the National Center for Research Resources, and P30 DK040561 from
the Nutrition Obesity Research Center at Harvard; the Institute of
Cardiometabolism and Nutrition (ICAN, ANR-10-IAHU-05) to D.G. and J.C.;
the European Commission (METACARDIS HEALTH-F4-2012-305312) to D.G.; and
an equipment grant from Ile de France Region (CORDDIM 120167) to D.G.
Funding sources had no role in the design of the study, data analysis or
the writing of the manuscript.
NR 32
TC 15
Z9 15
U1 5
U2 13
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 2015
VL 29
IS 4
BP 443
EP 452
DI 10.1097/QAD.0000000000000565
PG 10
WC Immunology; Infectious Diseases; Virology
SC Immunology; Infectious Diseases; Virology
GA CA6FG
UT WOS:000349004400006
PM 25565500
ER
PT J
AU Ziller, MJ
Edri, R
Yaffe, Y
Donaghey, J
Pop, R
Mallard, W
Issner, R
Gifford, CA
Goren, A
Xing, J
Gu, HC
Cacchiarelli, D
Tsankov, AM
Epstein, C
Rinn, JL
Mikkelsen, TS
Kohlbacher, O
Gnirke, A
Bernstein, BE
Elkabetz, Y
Meissner, A
AF Ziller, Michael J.
Edri, Reuven
Yaffe, Yakey
Donaghey, Julie
Pop, Ramona
Mallard, William
Issner, Robbyn
Gifford, Casey A.
Goren, Alon
Xing, Jeffrey
Gu, Hongcang
Cacchiarelli, Davide
Tsankov, Alexander M.
Epstein, Charles
Rinn, John L.
Mikkelsen, Tarjei S.
Kohlbacher, Oliver
Gnirke, Andreas
Bernstein, Bradley E.
Elkabetz, Yechiel
Meissner, Alexander
TI Dissecting neural differentiation regulatory networks through epigenetic
footprinting
SO NATURE
LA English
DT Article
ID PARTIAL LEAST-SQUARES; HUMAN GENOME; TRANSCRIPTION FACTORS; STEM-CELLS;
CHIP DATA; COUP-TFI; HUMAN ES; RNA-SEQ; DNA; EXPRESSION
AB Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system(1-3). Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFPreporter human embryonic stem cell line(4). Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.
C1 [Ziller, Michael J.; Donaghey, Julie; Pop, Ramona; Mallard, William; Issner, Robbyn; Gifford, Casey A.; Goren, Alon; Xing, Jeffrey; Gu, Hongcang; Cacchiarelli, Davide; Tsankov, Alexander M.; Epstein, Charles; Rinn, John L.; Mikkelsen, Tarjei S.; Gnirke, Andreas; Bernstein, Bradley E.; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
[Ziller, Michael J.; Donaghey, Julie; Pop, Ramona; Gifford, Casey A.; Tsankov, Alexander M.; Rinn, John L.; Meissner, Alexander] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
[Ziller, Michael J.; Donaghey, Julie; Pop, Ramona; Mallard, William; Gifford, Casey A.; Tsankov, Alexander M.; Rinn, John L.; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
[Edri, Reuven; Yaffe, Yakey; Elkabetz, Yechiel] Tel Aviv Univ, Dept Cell & Dev Biol, Sackler Sch Med, IL-6997801 Ramat Aviv, Israel.
[Goren, Alon; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
[Goren, Alon; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Goren, Alon; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
[Goren, Alon; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.
[Kohlbacher, Oliver] Univ Tubingen, Ctr Bioinformat, D-72076 Tubingen, Germany.
[Kohlbacher, Oliver] Univ Tubingen, Quantitat Biol Ctr, D-72076 Tubingen, Germany.
RP Elkabetz, Y (reprint author), Tel Aviv Univ, Dept Cell & Dev Biol, Sackler Sch Med, IL-6997801 Ramat Aviv, Israel.
EM elkabetz@tauex.tau.ac.il; alexander_meissner@harvard.edu
FU NIH [U01ES017155]; NHGRI [HG006911]; NIGMS [P01GM099117]; New York Stem
Cell Foundation; Israel Science Foundation (ISF) [1126/10, 1710/10];
Marie Curie International Reintegration Grant [IRG277151]; Charles H.
Hood Foundation
FX We would like to thank all members of the Meissner and Elkabetz
laboratories; we thank L. Studer (Sloan-Kettering Institute) for the
HES5::eGFP reporter line; we also thank F. Kelley and other members of
the Broad Sequencing Platform, J. Doench and members of the Genome
Perturbation Platform at the Broad Institute, D.-A. Landau for critical
reading of the manuscript, as well as to I. Shur and O. Sagi-Assif at
Tel Aviv University for their extensive FACS operation. We also thank L.
Gaffney for graphical support. This work was funded by the NIH Common
Fund (U01ES017155), NHGRI (HG006911), NIGMS (P01GM099117), the New York
Stem Cell Foundation, the Israel Science Foundation (ISF) (1126/10,
1710/10) and a Marie Curie International Reintegration Grant
(IRG277151). A.Go. is supported by the Charles H. Hood Foundation and
A.M. is a New York Stem Cell Foundation Robertson Investigator.
NR 63
TC 41
Z9 42
U1 11
U2 36
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 19
PY 2015
VL 518
IS 7539
BP 355
EP 359
DI 10.1038/nature13990
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400033
PM 25533951
ER
PT J
AU Farh, KKH
Marson, A
Zhu, J
Kleinewietfeld, M
Housley, WJ
Beik, S
Shoresh, N
Whitton, H
Ryan, RJH
Shishkin, AA
Hatan, M
Carrasco-Alfonso, MJ
Mayer, D
Luckey, CJ
Patsopoulos, NA
De Jager, PL
Kuchroo, VK
Epstein, CB
Daly, MJ
Hafler, DA
Bernstein, BE
AF Farh, Kyle Kai-How
Marson, Alexander
Zhu, Jiang
Kleinewietfeld, Markus
Housley, William J.
Beik, Samantha
Shoresh, Noam
Whitton, Holly
Ryan, Russell J. H.
Shishkin, Alexander A.
Hatan, Meital
Carrasco-Alfonso, Marlene J.
Mayer, Dita
Luckey, C. John
Patsopoulos, Nikolaos A.
De Jager, Philip L.
Kuchroo, Vijay K.
Epstein, Charles B.
Daly, Mark J.
Hafler, David A.
Bernstein, Bradley E.
TI Genetic and epigenetic fine mapping of causal autoimmune disease
variants
SO NATURE
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; REGULATORY T-CELLS; SUSCEPTIBILITY LOCI;
TRANSCRIPTION FACTORS; ENHANCER LANDSCAPE; FOXP3 OCCUPANCY; READ
ALIGNMENT; CROHNS-DISEASE; RISK VARIANTS; B-CELLS
AB Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that similar to 90% of causal variants are non-coding, with similar to 60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, mostnon-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.
C1 [Farh, Kyle Kai-How; Zhu, Jiang; Kleinewietfeld, Markus; Beik, Samantha; Shoresh, Noam; Whitton, Holly; Ryan, Russell J. H.; Shishkin, Alexander A.; Hatan, Meital; Patsopoulos, Nikolaos A.; De Jager, Philip L.; Epstein, Charles B.; Daly, Mark J.; Hafler, David A.; Bernstein, Bradley E.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
[Farh, Kyle Kai-How; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
[Marson, Alexander] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
[Marson, Alexander] Univ Calif San Francisco, Div Infect Dis, Dept Med, San Francisco, CA 94143 USA.
[Zhu, Jiang; Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
[Zhu, Jiang; Ryan, Russell J. H.; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
[Zhu, Jiang; Ryan, Russell J. H.; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Zhu, Jiang; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
[Zhu, Jiang; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.
[Kleinewietfeld, Markus; Housley, William J.; Hafler, David A.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06511 USA.
[Kleinewietfeld, Markus; Housley, William J.; Hafler, David A.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06511 USA.
[Shishkin, Alexander A.] CALTECH, Pasadena, CA 91125 USA.
[Carrasco-Alfonso, Marlene J.; Mayer, Dita; Luckey, C. John] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
[Carrasco-Alfonso, Marlene J.; Mayer, Dita; Luckey, C. John] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Patsopoulos, Nikolaos A.; De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Inst Neurosci, Dept Neurol, Boston, MA 02142 USA.
[Patsopoulos, Nikolaos A.; De Jager, Philip L.] Harvard Univ, Sch Med, Boston, MA 02142 USA.
[Patsopoulos, Nikolaos A.; De Jager, Philip L.] Harvard Univ, Div Genet, Dept Med, Brigham & Womens Hosp,Med Sch, Boston, MA 02142 USA.
[Kuchroo, Vijay K.] Harvard Univ, Ctr Neurol Dis, Brigham & Womens Hosp, Sch Med, Boston, MA 02142 USA.
RP Marson, A (reprint author), Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
EM alexander.marson@ucsf.edu
FU NIH Common Fund [ES017155]; National Human Genome Research Institute
[HG004570]; National Institute of Allergy and Infectious Disease
[AI045757, AI046130, AI070352, AI039671]; National Institute of
Neurological Disorders and Stroke [NS24247, NS067305]; National
Institute of General Medical Sciences [GM093080]; National Multiple
Sclerosis Society [CA1061-A-18]; UCSF Sandler Fellowship; Penates
Foundation; Nancy Taylor Foundation; Howard Hughes Medical Institute
FX We thank members of the NIH Epigenomics Consortium, M. Greenberg, H.
Chang and G. Haliburton for constructive comments. We also thank IIBDGC
and P. Sullivan for sharing data pre-publication, and G. Cvetanovich, S.
Bhela, C. Hartnick, F. Preffer, D. Dombkowski and the Brigham and
Women's Hospital PhenoGenetic Project for assistance with data
collection. This research was supported by the NIH Common Fund
(ES017155), the National Human Genome Research Institute (HG004570), the
National Institute of Allergy and Infectious Disease (AI045757,
AI046130, AI070352, AI039671), the National Institute of Neurological
Disorders and Stroke (NS24247, NS067305), the National Institute of
General Medical Sciences (GM093080), the National Multiple Sclerosis
Society (CA1061-A-18), the UCSF Sandler Fellowship, a gift from Jake
Aronov, the Penates Foundation, the Nancy Taylor Foundation, and the
Howard Hughes Medical Institute.
NR 67
TC 267
Z9 270
U1 19
U2 76
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 19
PY 2015
VL 518
IS 7539
BP 337
EP 343
DI 10.1038/nature13835
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400030
PM 25363779
ER
PT J
AU Ioannidis, A
Magana, M
Bologa, CG
Oprea, TI
Paulsen, IT
Tegos, GP
AF Ioannidis, Anastasios
Magana, Maria
Bologa, Cristian G.
Oprea, Tudor I.
Paulsen, Ian T.
Tegos, George P.
TI Defining the microbial effluxome in the content of the host-microbiome
interaction
SO FRONTIERS IN PHARMACOLOGY
LA English
DT Editorial Material
DE efflux transporters; multidrug resistance; microbiome; host-pathogen
interaction; effluxome
ID MULTIDRUG TRANSPORTER BMR; CAENORHABDITIS-ELEGANS; ESCHERICHIA-COLI;
ABC-TRANSPORTERS; ANTIMICROBIAL PEPTIDES; SUBSTRATE-SPECIFICITY; PLANT
ANTIMICROBIALS; DRUG-RESISTANCE; PUMP INHIBITORS; RND-TYPE
C1 [Ioannidis, Anastasios; Magana, Maria] Univ Peloponnese, Fac Human Movement & Qual Life Sci, Dept Nursing, Sparta, Greece.
[Magana, Maria] Aeginit Hosp, Athens Med Sch, Dept Clin Microbiol, Athens, Greece.
[Bologa, Cristian G.; Oprea, Tudor I.] Univ New Mexico, Hlth Sci Ctr, Dept Internal Med, Translat Informat Div, Albuquerque, NM 87131 USA.
[Oprea, Tudor I.] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark.
[Paulsen, Ian T.] Macquarie Univ, Dept Chem & Biomol Sci, N Ryde, NSW 2109, Australia.
[Tegos, George P.] Torrey Pines Inst Mol Studies, Port St Lucie, FL 34987 USA.
[Tegos, George P.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA.
[Tegos, George P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.
RP Tegos, GP (reprint author), Torrey Pines Inst Mol Studies, Port St Lucie, FL 34987 USA.
EM gtegos@tpims.org
RI Paulsen, Ian/K-3832-2012;
OI Paulsen, Ian/0000-0001-9015-9418; Bologa, Cristian/0000-0003-2232-4244;
Oprea, Tudor/0000-0002-6195-6976
NR 59
TC 0
Z9 0
U1 0
U2 10
PU FRONTIERS RESEARCH FOUNDATION
PI LAUSANNE
PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND
SN 1663-9812
J9 FRONT PHARMACOL
JI Front. Pharmacol.
PD FEB 19
PY 2015
VL 6
AR 31
DI 10.3389/fphar.2015.00031
PG 5
WC Pharmacology & Pharmacy
SC Pharmacology & Pharmacy
GA CF8TJ
UT WOS:000352834500001
PM 25745401
ER
PT J
AU Bancovik, J
Moreira, DF
Carrasco, D
Yao, J
Porter, D
Moura, R
Camargo, A
Fontes-Oliveira, CC
Malpartida, MG
Carambula, S
Vannier, E
Strauss, BE
Wakamatsu, A
Alves, VAF
Logullo, AF
Soares, FA
Polyak, K
Belizario, JE
AF Bancovik, Jasna
Moreira, Dayson F.
Carrasco, Daniel
Yao, Jun
Porter, Dale
Moura, Ricardo
Camargo, Anamaria
Fontes-Oliveira, Cibely C.
Malpartida, Miguel G.
Carambula, Silvia
Vannier, Edouard
Strauss, Bryan E.
Wakamatsu, Alda
Alves, Venancio A. F.
Logullo, Angela F.
Soares, Fernando A.
Polyak, Kornelia
Belizario, Jose E.
TI Dermcidin exerts its oncogenic effects in breast cancer via modulation
of ERBB signaling
SO BMC CANCER
LA English
DT Article
DE Breast cancer; Dermcidin; ERBB signaling; Oncogene; Apoptosis
ID PROTEOLYSIS-INDUCING FACTOR; GROWTH-FACTOR RECEPTOR; CELL-LINES;
MONOCLONAL-ANTIBODY; LACRIMAL GLAND; SWEAT GLANDS; IN-VIVO; EXPRESSION;
SURVIVAL; IDENTIFICATION
AB Background: We previously identified dermicidin (DCD), which encodes a growth and survival factor, as a gene amplified and overexpressed in a subset of breast tumors. Patients with DCD-positive breast cancer have worse prognostic features. We therefore searched for specific molecular signatures in DCD-positive breast carcinomas from patients and representative cell lines.
Methods: DCD expression was evaluated by qRT-PCR, immunohistochemical and immunoblot assays in normal and neoplastic tissues and cell lines. To investigate the role of DCD in breast tumorigenesis, we analyzed the consequences of its downregulation in human breast cancer cell lines using three specific shRNA lentiviral vectors. Genes up- and down-regulated by DCD were identified using Affymetrix microarray and analyzed by MetaCore Platform.
Results: We identified DCD splice variant (DCD-SV) that is co-expressed with DCD in primary invasive breast carcinomas and in other tissue types and cell lines. DCD expression in breast tumors from patients with clinical follow up data correlated with high histological grade, HER2 amplification and luminal subtype. We found that loss of DCD expression led to reduced cell proliferation, resistance to apoptosis, and suppressed tumorigenesis in immunodeficient mice. Network analysis of gene expression data revealed perturbed ERBB signaling following DCD shRNA expression including changes in the expression of ERBB receptors and their ligands.
Conclusions: These findings imply that DCD promotes breast tumorigenesis via modulation of ERBB signaling pathways. As ERBB signaling is also important for neural survival, HER2+ breast tumors may highjack DCD's neural survival-promoting functions to promote tumorigenesis.
C1 [Bancovik, Jasna; Moreira, Dayson F.; Fontes-Oliveira, Cibely C.; Malpartida, Miguel G.; Belizario, Jose E.] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo, SP, Brazil.
[Carrasco, Daniel] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Dis Ctr, Boston, MA 02215 USA.
[Yao, Jun] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Neurooncol Res, Houston, TX 77030 USA.
[Porter, Dale] Novartis Inst Biomed Res, Oncol Dis Area, Cambridge, MA 02139 USA.
[Porter, Dale] Novartis Inst Biomed Res, Dev & Mol Pathways Grp, Cambridge, MA 02139 USA.
[Moura, Ricardo; Camargo, Anamaria] Hosp Sirio Libanes, Ludwig Inst Canc Res, BR-01409000 Sao Paulo, SP, Brazil.
[Carambula, Silvia; Vannier, Edouard] Tufts Med Ctr, Div Geog Med & Infect Dis, Boston, MA 02111 USA.
[Strauss, Bryan E.] Canc Inst Sao Paulo, BR-01246000 Sao Paulo, SP, Brazil.
[Wakamatsu, Alda; Alves, Venancio A. F.] Univ Sao Paulo, Sch Med, Dept Pathol, BR-05403000 Sao Paulo, SP, Brazil.
[Logullo, Angela F.] Univ Fed Sao Paulo, Paulista Sch Med, Dept Pathol, BR-04021001 Sao Paulo, SP, Brazil.
[Soares, Fernando A.] AC Camargo Canc Ctr, Dept Pathol, BR-01509010 Sao Paulo, SP, Brazil.
[Polyak, Kornelia] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
RP Belizario, JE (reprint author), Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Av Lineu Prestes 1524, BR-05508900 Sao Paulo, SP, Brazil.
EM jebeliza@usp.br
RI Camargo, Anamaria/E-9388-2012; Strauss, Bryan/L-5070-2016;
OI Camargo, Anamaria/0000-0002-6076-9597; Strauss,
Bryan/0000-0002-4113-9450; Fontes-Oliveira, Cibely/0000-0003-1112-6015;
Soares, Fernando Augusto/0000-0003-1647-7842
FU FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)
[2001/01000-7, 2005/56909-0]; FAPESP fellowships; NIH; Novartis
FX We are indebted to Akihiko Kimura for providing the G-81 anti-DCD
antibody and Genentech Inc. for providing Herceptin antibody
(OR-208654). We thank Dr Maria M Brentani, University of Sao Paulo
School of Medicine, and Dr Victor Piana Andrade, AC Camargo Cancer
Center for their help in TMA experiments and Ricardo Garcia and Carla
Pietro for their help in SK-BR-3 cells experiments and fruitful
discussions. This work was funded by FAPESP (Fundacao de Amparo a
Pesquisa do Estado de Sao Paulo) grant 2001/01000-7 and 2005/56909-0
(JEB), FAPESP fellowships (MGM, COF, and DFM), NIH (DP), and by Novartis
(KP).
NR 40
TC 2
Z9 2
U1 2
U2 11
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 19
PY 2015
VL 15
AR 70
DI 10.1186/s12885-015-1022-6
PG 13
WC Oncology
SC Oncology
GA CC7ZJ
UT WOS:000350587200001
PM 25879571
ER
PT J
AU Hatchi, E
Skourti-Stathaki, K
Ventz, S
Pinello, L
Yen, A
Kamieniarz-Gdula, K
Dimitrov, S
Pathania, S
McKinney, KM
Eaton, ML
Kellis, M
Hill, SJ
Parmigiani, G
Proudfoot, NJ
Livingston, DM
AF Hatchi, Elodie
Skourti-Stathaki, Konstantina
Ventz, Steffen
Pinello, Luca
Yen, Angela
Kamieniarz-Gdula, Kinga
Dimitrov, Stoil
Pathania, Shailja
McKinney, Kristine M.
Eaton, Matthew L.
Kellis, Manolis
Hill, Sarah J.
Parmigiani, Giovanni
Proudfoot, Nicholas J.
Livingston, David M.
TI BRCA1 Recruitment to Transcriptional Pause Sites Is Required for
R-Loop-Driven DNA Damage Repair
SO MOLECULAR CELL
LA English
DT Article
ID RNA-POLYMERASE-II; GENOME INSTABILITY; MESSENGER-RNA; BREAST-CANCER;
MUTATIONAL PROCESSES; TUMOR SUPPRESSION; SEN1 HELICASE; COMPLEX; YEAST;
SENATAXIN
AB The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Although R-loops are normal transcriptional intermediates, they are also associated with genomic instability. Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcription termination regions. There it mediates the recruitment of a specific, physiological binding partner, senataxin (SETX). Disruption of this complex led to R-loop-driven DNA damage at those loci as reflected by adjacent gamma-H2AX accumulation and ssDNA breaks within the untranscribed strand of relevant R-loop structures. Genome-wide analysis revealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transcribed genes. Strikingly, within some of these genes in BRCA1 null breast tumors, there are specific insertion/deletion mutations located close to R-loop-mediated BRCA1 binding sites within TRs. Thus, BRCA1/SETX complexes support a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites.
C1 [Hatchi, Elodie; Dimitrov, Stoil; Pathania, Shailja; McKinney, Kristine M.; Hill, Sarah J.; Livingston, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA.
[Hatchi, Elodie; Dimitrov, Stoil; Pathania, Shailja; McKinney, Kristine M.; Hill, Sarah J.; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.
[Skourti-Stathaki, Konstantina; Kamieniarz-Gdula, Kinga; Proudfoot, Nicholas J.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England.
[Ventz, Steffen; Pinello, Luca; Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.
[Ventz, Steffen; Pinello, Luca; Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
[Yen, Angela; Eaton, Matthew L.; Kellis, Manolis] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
[Yen, Angela; Eaton, Matthew L.; Kellis, Manolis] MIT, CSAIL, Cambridge, MA 02139 USA.
RP Hatchi, E (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA.
EM elodiey_hatchi@dfci.harvard.edu; david_livingston@dfci.harvard.edu
OI Proudfoot, Nicholas/0000-0001-8646-3222
FU National Cancer Institute (NCI) - Mechanisms of Breast Development and
Carcinogenesis [2PO1CA80111-16]; BRCA1 Function in Post Damage Foci
[5R01CA136512-05]; Marie Curie IEF; Wellcome Trust; NCI [5P30
CA006516-46]
FX We thank all D.M.L. laboratory members for support, technical advice,
and helpful discussions. E.H. and other D.M.L. members were supported by
grants from the National Cancer Institute (NCI) - Mechanisms of Breast
Development and Carcinogenesis (2PO1CA80111-16) and BRCA1 Function in
Post Damage Foci (5R01CA136512-05). K.K.-G. was supported by Marie Curie
IEF. K.S.-S. and N.J.P. were supported by a Programme grant from the
Wellcome Trust and G.P. by NCI 5P30 CA006516-46.
NR 66
TC 33
Z9 33
U1 0
U2 15
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 19
PY 2015
VL 57
IS 4
BP 636
EP 647
DI 10.1016/j.molcel.2015.01.011
PG 12
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA CC0BR
UT WOS:000350000500008
PM 25699710
ER
PT J
AU Liu, PD
Gan, WJ
Guo, CG
Xie, AY
Gao, DM
Guo, JP
Zhang, JF
Willis, N
Su, A
Asara, JM
Scully, R
Wei, WY
AF Liu, Pengda
Gan, Wenjian
Guo, Chunguang
Xie, Anyong
Gao, Daming
Guo, Jianping
Zhang, Jinfang
Willis, Nicholas
Su, Arthur
Asara, John M.
Scully, Ralph
Wei, Wenyi
TI Akt-Mediated Phosphorylation of XLF Impairs Non-Homologous End-Joining
DNA Repair
SO MOLECULAR CELL
LA English
DT Article
ID STRAND BREAK REPAIR; F-BOX PROTEINS; CELL-CYCLE; HOMOLOGOUS
RECOMBINATION; TUMOR-SUPPRESSOR; DAMAGE RESPONSE; BETA-TRCP;
MAMMALIAN-CELLS; IV COMPLEX; CANCER
AB Deficiency in repair of damaged DNA leads to genomic instability and is closely associated with tumorigenesis. Most DNA double-strand-breaks (DSBs) are repaired by two major mechanisms, homologous-recombination (HR) and non-homologous-end-joining (NHEJ). Although Akt has been reported to suppress HR, its role in NHEJ remains elusive. Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3b leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF beta-TRCP in a CKI-dependent manner. Physiologically, upon DNA damage, XLF-T181E expressing cells display impaired NHEJ and elevated cell death. Whereas a cancer-patient-derived XLF-R178Q mutant, deficient in XLF-T181 phosphorylation, exhibits an elevated tolerance of DNA damage. Together, our results reveal a pivotal role for Akt in suppressing NHEJ and highlight the tight connection between aberrant Akt hyper-activation and deficiency in timely DSB repair, leading to genomic instability and tumorigenesis.
C1 [Liu, Pengda; Gan, Wenjian; Gao, Daming; Guo, Jianping; Zhang, Jinfang; Wei, Wenyi] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA.
[Guo, Chunguang; Su, Arthur] Childrens Hosp, Howeard Hughes Med Inst, Immune Dis Inst, Boston, MA 02115 USA.
[Guo, Chunguang; Su, Arthur] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Xie, Anyong; Willis, Nicholas; Asara, John M.; Scully, Ralph] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA.
[Xie, Anyong] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Hangzhou 310016, Zhejiang, Peoples R China.
[Xie, Anyong] Zhejiang Univ, Sch Med, Inst Translat Med, Hangzhou 310016, Zhejiang, Peoples R China.
RP Wei, WY (reprint author), Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA.
EM wwei2@bidmc.harvard.edu
RI Scully, Ralph/F-5008-2013
FU NIH [R01CA177910, R01GM094777, R01GM073894, R01CA095175];
[1K99CA181342]
FX We thank Brian North, Alan Lau, Hiroyuki Inuzuka and other members of
the Wei laboratory for critical reading of the manuscript, Catherin Yan
for providing valuable reagents, Min Yuan and Susanne Breitkopf for mass
spectrometry experiments and members of the Wei and Scully laboratories
for useful discussions. W.W. is an ACS scholar. P.L. is supported by
1K99CA181342. This work was supported in part by the NIH grants
(R01CA177910 and R01GM094777 to W.W.; R01GM073894 and R01CA095175 to
R.S.).
NR 61
TC 8
Z9 8
U1 1
U2 6
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 19
PY 2015
VL 57
IS 4
BP 648
EP 661
DI 10.1016/j.molcel.2015.01.005
PG 14
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA CC0BR
UT WOS:000350000500009
PM 25661488
ER
PT J
AU Amato, MBP
Meade, MO
Slutsky, AS
Brochard, L
Costa, ELV
Schoenfeld, DA
Stewart, TE
Briel, M
Talmor, D
Mercat, A
Richard, JCM
Carvalho, CRR
Brower, RG
AF Amato, Marcelo B. P.
Meade, Maureen O.
Slutsky, Arthur S.
Brochard, Laurent
Costa, Eduardo L. V.
Schoenfeld, David A.
Stewart, Thomas E.
Briel, Matthias
Talmor, Daniel
Mercat, Alain
Richard, Jean-Christophe M.
Carvalho, Carlos R. R.
Brower, Roy G.
TI Driving Pressure and Survival in the Acute Respiratory Distress Syndrome
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Article
ID END-EXPIRATORY PRESSURE; ACUTE LUNG INJURY; RANDOMIZED CONTROLLED-TRIAL;
TIDAL VOLUME VENTILATION; MECHANICAL VENTILATION; PULMONARY-EDEMA;
STRATEGY; HYPERINFLATION; RECRUITMENT; AMPLITUDE
AB BACKGROUND
Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (V-T), and higher positive end-expiratory pressures (PEEPs) can improve survival in patients with the acute respiratory distress syndrome (ARDS), but the relative importance of each of these components is uncertain. Because respiratory-system compliance (C-RS) is strongly related to the volume of aerated remaining functional lung during disease (termed functional lung size), we hypothesized that driving pressure (Delta P=V-T/C-RS), in which V-T is intrinsically normalized to functional lung size (instead of predicted lung size in healthy persons), would be an index more strongly associated with survival than V-T or PEEP in patients who are not actively breathing.
METHODS
Using a statistical tool known as multilevel mediation analysis to analyze individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, we examined Delta P as an independent variable associated with survival. In the mediation analysis, we estimated the isolated effects of changes in Delta P resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease.
RESULTS
Among ventilation variables, Delta P was most strongly associated with survival. A 1-SD increment in Delta P (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31 to 1.51; P<0.001), even in patients receiving "protective" plateau pressures and V-T (relative risk, 1.36; 95% CI, 1.17 to 1.58; P<0.001). Individual changes in V-T or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in Delta P (mediation effects of Delta P, P=0.004 and P=0.001, respectively).
CONCLUSIONS
We found that Delta P was the ventilation variable that best stratified risk. Decreases in Delta P owing to changes in ventilator settings were strongly associated with increased survival. (Funded by Fundacao de Amparo e Pesquisa do Estado de Sao Paulo and others.)
C1 [Amato, Marcelo B. P.; Costa, Eduardo L. V.; Carvalho, Carlos R. R.] Univ Sao Paulo, Heart Inst Incor, Div Pulm, Cardiopulm Dept, BR-01246903 Sao Paulo, Brazil.
[Costa, Eduardo L. V.] Hosp Sirio Libanes, Res & Educ Inst, Sao Paulo, Brazil.
[Meade, Maureen O.; Stewart, Thomas E.; Briel, Matthias] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada.
[Meade, Maureen O.; Stewart, Thomas E.; Briel, Matthias] McMaster Univ, Dept Med, Hamilton, ON, Canada.
[Slutsky, Arthur S.; Brochard, Laurent] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON M5B 1W8, Canada.
[Slutsky, Arthur S.; Brochard, Laurent] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada.
[Slutsky, Arthur S.; Brochard, Laurent] Univ Toronto, Dept Med, Toronto, ON, Canada.
[Schoenfeld, David A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Biostat Ctr, Boston, MA USA.
[Talmor, Daniel] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02215 USA.
[Talmor, Daniel] Harvard Univ, Sch Med, Boston, MA USA.
[Briel, Matthias] Univ Basel Hosp, Basel Inst Clin Epidemiol & Biostat, CH-4031 Basel, Switzerland.
[Mercat, Alain] Angers Univ Hosp, Dept Intens Care & Hyperbar Med, Angers, France.
[Richard, Jean-Christophe M.] Gen Hosp Annecy, Emergency Dept, Annecy, France.
[Richard, Jean-Christophe M.] Hop Henri Mondor, INSERM, UMR 955, F-94010 Creteil, France.
[Brower, Roy G.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD USA.
RP Amato, MBP (reprint author), Univ Sao Paulo, Fac Med, Av Dr Arnaldo 455,Sala 2144 2nd Fl, BR-01246903 Sao Paulo, Brazil.
EM amato.marcelo.bp@gmail.com
OI Briel, Matthias/0000-0002-2070-5230
FU Fundacao de Amparo e Pesquisa do Estado de Sao Paulo
FX Funded by Fundacao de Amparo e Pesquisa do Estado de Sao Paulo and
others.)
NR 34
TC 191
Z9 200
U1 6
U2 27
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 19
PY 2015
VL 372
IS 8
BP 747
EP 755
DI 10.1056/NEJMsa1410639
PG 9
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB7PB
UT WOS:000349818700008
PM 25693014
ER
PT J
AU Wessels, MR
Brigham, KS
DeMaria, A
AF Wessels, Michael R.
Brigham, Kathryn S.
DeMaria, Alfred, Jr.
TI Case 6-2015: A 16-Year-Old Boy with Coughing Spells
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Article
ID ACELLULAR PERTUSSIS-VACCINE; IMMUNIZATION PRACTICES ACIP;
BORDETELLA-PERTUSSIS; ADVISORY-COMMITTEE; PREVENTING TETANUS; ADULT
TETANUS; CHILDREN; DIPHTHERIA; RECOMMENDATIONS; INFECTION
C1 [Wessels, Michael R.] Boston Childrens Hosp, Dept Med, Boston, MA 02115 USA.
[Brigham, Kathryn S.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA.
[DeMaria, Alfred, Jr.] Massachusetts Dept Publ Hlth, William A Hinton State Lab Inst, Boston, MA USA.
[Wessels, Michael R.; Brigham, Kathryn S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA.
[DeMaria, Alfred, Jr.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA.
RP Wessels, MR (reprint author), Boston Childrens Hosp, Dept Med, Boston, MA 02115 USA.
NR 37
TC 1
Z9 1
U1 0
U2 8
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 19
PY 2015
VL 372
IS 8
BP 765
EP 773
DI 10.1056/NEJMcpc1411928
PG 9
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB7PB
UT WOS:000349818700013
PM 25693017
ER
PT J
AU Kundaje, A
Meuleman, W
Ernst, J
Bilenky, M
Yen, A
Heravi-Moussavi, A
Kheradpour, P
Zhang, Z
Wang, J
Ziller, MJ
Amin, V
Whitaker, JW
Schultz, MD
Ward, LD
Sarkar, A
Quon, G
Sandstrom, RS
Eaton, ML
Wu, YC
Pfenning, AR
Wang, X
Claussnitzer, M
Liu, Y
Coarfa, C
Harris, RA
Shoresh, N
Epstein, CB
Gjoneska, E
Leung, D
Xie, W
Hawkins, RD
Lister, R
Hong, C
Gascard, P
Mungall, AJ
Moore, R
Chuah, E
Tam, A
Canfield, TK
Hansen, RS
Kaul, R
Sabo, PJ
Bansal, MS
Carles, A
Dixon, JR
Farh, KH
Feizi, S
Karlic, R
Kim, AR
Kulkarni, A
Li, D
Lowdon, R
Elliott, G
Mercer, TR
Neph, SJ
Onuchic, V
Polak, P
Rajagopal, N
Ray, P
Sallari, RC
Siebenthall, KT
Sinnott-Armstrong, NA
Stevens, M
Thurman, RE
Wu, J
Zhang, B
Zhou, X
Beaudet, AE
Boyer, LA
De Jager, PL
Farnham, PJ
Fisher, SJ
Haussler, D
Jones, SJM
Li, W
Marra, MA
McManus, MT
Sunyaev, S
Thomson, JA
Tlsty, TD
Tsai, LH
Wang, W
Waterland, RA
Zhang, MQ
Chadwick, LH
Bernstein, BE
Costello, JF
Ecker, JR
Hirst, M
Meissner, A
Milosavljevic, A
Ren, B
Stamatoyannopoulos, JA
Wang, T
Kellis, M
AF Kundaje, Anshul
Meuleman, Wouter
Ernst, Jason
Bilenky, Misha
Yen, Angela
Heravi-Moussavi, Alireza
Kheradpour, Pouya
Zhang, Zhizhuo
Wang, Jianrong
Ziller, Michael J.
Amin, Viren
Whitaker, John W.
Schultz, Matthew D.
Ward, Lucas D.
Sarkar, Abhishek
Quon, Gerald
Sandstrom, Richard S.
Eaton, Matthew L.
Wu, Yi-Chieh
Pfenning, Andreas R.
Wang, Xinchen
Claussnitzer, Melina
Liu, Yaping
Coarfa, Cristian
Harris, R. Alan
Shoresh, Noam
Epstein, Charles B.
Gjoneska, Elizabeta
Leung, Danny
Xie, Wei
Hawkins, R. David
Lister, Ryan
Hong, Chibo
Gascard, Philippe
Mungall, Andrew J.
Moore, Richard
Chuah, Eric
Tam, Angela
Canfield, Theresa K.
Hansen, R. Scott
Kaul, Rajinder
Sabo, Peter J.
Bansal, Mukul S.
Carles, Annaick
Dixon, Jesse R.
Farh, Kai-How
Feizi, Soheil
Karlic, Rosa
Kim, Ah-Ram
Kulkarni, Ashwinikumar
Li, Daofeng
Lowdon, Rebecca
Elliott, GiNell
Mercer, Tim R.
Neph, Shane J.
Onuchic, Vitor
Polak, Paz
Rajagopal, Nisha
Ray, Pradipta
Sallari, Richard C.
Siebenthall, Kyle T.
Sinnott-Armstrong, Nicholas A.
Stevens, Michael
Thurman, Robert E.
Wu, Jie
Zhang, Bo
Zhou, Xin
Beaudet, Arthur E.
Boyer, Laurie A.
De Jager, Philip L.
Farnham, Peggy J.
Fisher, Susan J.
Haussler, David
Jones, Steven J. M.
Li, Wei
Marra, Marco A.
McManus, Michael T.
Sunyaev, Shamil
Thomson, James A.
Tlsty, Thea D.
Tsai, Li-Huei
Wang, Wei
Waterland, Robert A.
Zhang, Michael Q.
Chadwick, Lisa H.
Bernstein, Bradley E.
Costello, Joseph F.
Ecker, Joseph R.
Hirst, Martin
Meissner, Alexander
Milosavljevic, Aleksandar
Ren, Bing
Stamatoyannopoulos, John A.
Wang, Ting
Kellis, Manolis
CA Roadmap Epigenomics Consortium
TI Integrative analysis of 111 reference human epigenomes
SO NATURE
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; EMBRYONIC STEM-CELLS; DYNAMIC DNA METHYLATION;
CHROMATIN-STATE; HISTONE MODIFICATIONS; RISK LOCI; TRANSCRIPTION
FACTORS; ALZHEIMERS-DISEASE; REGULATORY REGIONS; MAMMALIAN GENOMES
AB The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
C1 [Kundaje, Anshul; Meuleman, Wouter; Ernst, Jason; Yen, Angela; Kheradpour, Pouya; Zhang, Zhizhuo; Wang, Jianrong; Ward, Lucas D.; Sarkar, Abhishek; Quon, Gerald; Eaton, Matthew L.; Wu, Yi-Chieh; Pfenning, Andreas R.; Wang, Xinchen; Claussnitzer, Melina; Liu, Yaping; Bansal, Mukul S.; Feizi, Soheil; Kim, Ah-Ram; Sallari, Richard C.; Sinnott-Armstrong, Nicholas A.; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.
[Kundaje, Anshul; Meuleman, Wouter; Ernst, Jason; Yen, Angela; Kheradpour, Pouya; Zhang, Zhizhuo; Wang, Jianrong; Ziller, Michael J.; Ward, Lucas D.; Sarkar, Abhishek; Quon, Gerald; Eaton, Matthew L.; Wu, Yi-Chieh; Pfenning, Andreas R.; Wang, Xinchen; Claussnitzer, Melina; Liu, Yaping; Shoresh, Noam; Epstein, Charles B.; Gjoneska, Elizabeta; Bansal, Mukul S.; Farh, Kai-How; Feizi, Soheil; Kim, Ah-Ram; Polak, Paz; Sallari, Richard C.; Sinnott-Armstrong, Nicholas A.; De Jager, Philip L.; Sunyaev, Shamil; Tsai, Li-Huei; Bernstein, Bradley E.; Meissner, Alexander; Kellis, Manolis] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.
[Kundaje, Anshul] Stanford Univ, Dept Genet, Dept Comp Sci, Stanford, CA 94305 USA.
[Ernst, Jason] Univ Calif Davis, Dept Biol Chem, Los Angeles, CA 90095 USA.
[Bilenky, Misha; Heravi-Moussavi, Alireza; Mungall, Andrew J.; Moore, Richard; Chuah, Eric; Tam, Angela; Jones, Steven J. M.; Marra, Marco A.; Hirst, Martin] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada.
[Ziller, Michael J.; Meissner, Alexander] Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
[Amin, Viren; Coarfa, Cristian; Harris, R. Alan; Onuchic, Vitor; Milosavljevic, Aleksandar] Baylor Coll Med, Epigenome Ctr, Houston, TX 77030 USA.
[Whitaker, John W.; Leung, Danny; Xie, Wei; Hawkins, R. David; Dixon, Jesse R.; Rajagopal, Nisha; Wang, Wei; Ren, Bing] Univ Calif San Diego, Inst Genom Med, Dept Cellular & Mol Med, Dept Chem & Biochem, La Jolla, CA 92093 USA.
[Schultz, Matthew D.; Lister, Ryan; Ecker, Joseph R.] Howard Hughes Med Inst, Genom Anal Lab, La Jolla, CA 92037 USA.
[Schultz, Matthew D.; Lister, Ryan; Ecker, Joseph R.] Salk Inst Biol Studies, La Jolla, CA 92037 USA.
[Sandstrom, Richard S.; Canfield, Theresa K.; Sabo, Peter J.; Neph, Shane J.; Siebenthall, Kyle T.; Thurman, Robert E.; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
[Wang, Xinchen; Boyer, Laurie A.] MIT, Dept Biol, Cambridge, MA 02142 USA.
[Gjoneska, Elizabeta; Tsai, Li-Huei] MIT, Picower Inst Learning & Memory, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA.
[Leung, Danny; Xie, Wei; Hawkins, R. David; Dixon, Jesse R.; Rajagopal, Nisha; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA.
[Hong, Chibo; Costello, Joseph F.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Neurosurg, San Francisco, CA 94158 USA.
[Gascard, Philippe; Tlsty, Thea D.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA.
[Hansen, R. Scott; Kaul, Rajinder] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98121 USA.
[Bansal, Mukul S.] Univ Connecticut, Dept Comp Sci & Engn, Storrs, CT 06269 USA.
[Carles, Annaick; Hirst, Martin] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada.
[Carles, Annaick; Hirst, Martin] Univ British Columbia, Ctr High Throughput Biol, Vancouver, BC V6T 1Z4, Canada.
[Karlic, Rosa] Univ Zagreb, Div Biol, Dept Mol Biol, Bioinformat Grp, Zagreb 10000, Croatia.
[Kulkarni, Ashwinikumar; Ray, Pradipta; Zhang, Michael Q.] Univ Texas Dallas, Dept Mol & Cell Biol, Ctr Syst Biol, NSERL, Dallas, TX 75080 USA.
[Li, Daofeng; Lowdon, Rebecca; Elliott, GiNell; Stevens, Michael; Zhang, Bo; Zhou, Xin; Wang, Ting] Washington Univ, Dept Genet, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA.
[Mercer, Tim R.] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia.
[Polak, Paz; De Jager, Philip L.; Sunyaev, Shamil] Brigham & Womens Hosp, Boston, MA 02115 USA.
[Wu, Jie] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA.
[Wu, Jie] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA.
[Beaudet, Arthur E.] Baylor Coll Med, Mol & Human Genet Dept, Houston, TX 77030 USA.
[De Jager, Philip L.; Sunyaev, Shamil] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Farnham, Peggy J.] Univ So Calif, Keck Sch Med, Dept Biochem, Los Angeles, CA 90089 USA.
[Fisher, Susan J.] Univ Calif San Francisco, San Francisco, CA 94143 USA.
[Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA.
[Jones, Steven J. M.] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada.
[Jones, Steven J. M.; Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z4, Canada.
[Li, Wei] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA.
[McManus, Michael T.] Univ Calif San Francisco, Ctr Diabet, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.
[Thomson, James A.] Univ Wisconsin, Madison, WI 53715 USA.
[Waterland, Robert A.] Baylor Coll Med, USDA ARS, Childrens Nutr Res Ctr, Houston, TX 77030 USA.
[Zhang, Michael Q.] Tsinghua Univ, Bioinformat Div, Ctr Synthet & Syst Biol, TNLIST, Beijing 100084, Peoples R China.
[Chadwick, Lisa H.] NIEHS, Res Triangle Pk, NC 27709 USA.
[Bernstein, Bradley E.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
[Thomson, James A.] Morgridge Inst Res, Madison, WI 53707 USA.
[Stevens, Michael] Washington Univ, Dept Comp Sci & Engn, St Louis, MO 63130 USA.
RP Kundaje, A (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, 32 Vassar St, Cambridge, MA 02139 USA.
EM manoli@mit.edu
RI Wang, Tao/E-5900-2015; Chen, Zhao/I-5625-2014; Lister, Ryan/B-5168-2012;
Li, Daofeng/E-5386-2011; Ecker, Joseph/B-9144-2008; Hariharan,
Manoj/N-2855-2015; Hirst, Martin/B-7684-2016; Marra, Marco/B-5987-2008;
Jones, Steven/C-3621-2009; Zhang, Bo/A-6874-2011;
OI Meuleman, Wouter/0000-0002-1196-5401; Pelizzola,
Mattia/0000-0001-6672-9636; Ward, Lucas/0000-0002-8017-809X; Tsai,
Linus/0000-0002-0134-6949; Mattick, John/0000-0002-7680-7527; Gu,
Junchen/0000-0002-0928-7453; /0000-0002-3447-9801; Wu,
Jie/0000-0002-0989-8115; Wang, Tao/0000-0002-1646-6863; Lister,
Ryan/0000-0001-6637-7239; Li, Daofeng/0000-0001-7492-3703; Ecker,
Joseph/0000-0001-5799-5895; Hariharan, Manoj/0000-0002-1006-5372; Zhang,
Bo/0000-0003-2962-5314; Farnham, Peggy/0000-0003-4469-7914; Robinson,
Joshua/0000-0002-2421-4535; Subramanian, Sai Lakshmi/0000-0003-1384-0722
FU NIH Common Fund as part of the NIH Roadmap Epigenomics Program
[U01ES017155, U01ES017154, U01ES017166, U01ES017156, U01DA025956]; NHGRI
[RC1HG005334, R01HG004037, R01HG004037-S1, RO1NS078839]; NIH [ES017166,
F32HL110473, K99HL119617]; NSFC [91019016]; NBRPC [2012CB316503]; NSF
CAREER [1254200]; [5R24HD000836]; [P30AG10161]; [R01AG15819];
[R01AG17917]; [U01AG46152]
FX This work was supported by the NIH Common Fund as part of the NIH
Roadmap Epigenomics Program through U01ES017155 (B.B. and A.M.),
U01ES017154 (J.C. and M.M.), U01ES017166 (B.R.), U01ES017156 (J.S.),
U01DA025956 (A.M. and A.B.), and by NHGRI through RC1HG005334,
R01HG004037 and R01HG004037-S1 (M.K.), RO1NS078839 (L.-H.T.), and by NIH
ES017166, NSFC 91019016 and NBRPC 2012CB316503 (M.Q.Z.). Sample
procurement was supported by grants 5R24HD000836 (I.A.G.) for staged
fetal tissues; P30AG10161, R01AG15819, R01AG17917 (D.A.B.) and
U01AG46152 (P.L.D. and D.A.B.) for adult brain samples. This work was
also supported by NIH fellowship grants F32HL110473 and K99HL119617
(S.L.), and NSF CAREER award 1254200 (J.E.). We acknowledge program
leadership by members of the NIH Epigenomics Workgroup, especially J.S.
Satterlee, F.L. Tyson, J. Rutter, K.A. McAllister, A. Haugen, C. Colvis
(NCATS), J. Battey (NIDCD), L. Birnbaum (NIEHS) and N. Volkow (NIDA). We
acknowledge feedback from our External Scientific Panel members M.
Bartolomei, S. Baylin, S. Beck, A. Chakravarti, L. Jackson-Grusby, J.
Lieb, S. Peckman, J. Quackenbush and S. Stice.
NR 112
TC 311
Z9 313
U1 21
U2 163
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 19
PY 2015
VL 518
IS 7539
BP 317
EP 330
DI 10.1038/nature14248
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3SA
UT WOS:000349547400028
ER
PT J
AU Walston, S
Hamstra, DA
Oh, K
Woods, G
Guiou, M
Olshefski, RS
Chakravarti, A
Williams, TM
AF Walston, Steve
Hamstra, Daniel A.
Oh, Kevin
Woods, Gary
Guiou, Michael
Olshefski, Randal S.
Chakravarti, Arnab
Williams, Terence M.
TI A multi-institutional experience in pediatric high-grade glioma
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE high-grade glioma; glioblastoma; pediatric cancer; chemotherapy;
radiation therapy
ID CHILDHOOD MALIGNANT GLIOMAS; GLIOBLASTOMA; TEMOZOLOMIDE; ASTROCYTOMA;
CHILDREN; TRIAL
AB Introduction: Pediatric high-grade gliomas are rare tumors with poor outcomes and incompletely defined management. We conducted a multi-institutional retrospective study to evaluate association of clinical, pathologic, and treatment characteristics with outcomes.
Materials and methods: Fifty-one patients treated from 1984 to 2008 at the Ohio State University or University of Michigan were included. Histologic subgroups were compared. Log-rank and stepwise Cox proportional hazard modeling were used to analyze progressionfree survival (PFS) and overall survival (OS) within the whole group, grade III subgroup, grade IV subgroup, and sub-total resection/biopsy subgroup.
Results: Median OS was 276 months. Grade III histology, complete tumor resection, and cerebral tumor location correlated with improved PFS and OS. Temozolomide use and chemotherapy after radiotherapy or chemoradiation (CRT) were associated with better PFS while seizure at presentation was associated with better OS. In multivariate analysis, complete resection and chemotherapy following radiotherapy or CRT were independent predictors for improved PFS and OS. For grade III and IV subgroups, complete resection was associated with improved OS (grade III) and seizure presentation was associated with improved OS (grade IV). In the incompletely resection subgroup, temozolomide use and concurrent CRT independently correlated with improved PFS, while higher radiation dose (>59.4 Gy) and adjuvant chemotherapy were independently associated with improved OS.
Discussion: Total resection and receiving chemotherapy adjuvant to radiation or CRT are most closely associated with improved PFS and OS. For higher risk incompletely resected patients, temozolomide use and treatment intensification with concurrent CRT, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes.
C1 [Walston, Steve; Guiou, Michael; Chakravarti, Arnab; Williams, Terence M.] Ohio State Univ, Wexner Med Ctr, Dept Radiat Oncol, Columbus, OH 43210 USA.
[Hamstra, Daniel A.] Univ Michigan Hlth Syst, Dept Radiat Oncol, Ann Arbor, MI USA.
[Oh, Kevin] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
[Woods, Gary; Olshefski, Randal S.] Nationwide Childrens Hosp, Dept Hematol Oncol, Columbus, OH USA.
RP Williams, TM (reprint author), Ohio State Univ, Ctr Comprehens Canc, Dept Radiat Oncol, James Canc Hosp,Solove Res Inst, 460 West 10th Ave,Room D252Q, Columbus, OH 43210 USA.
EM terence.williams@osumc.edu
NR 16
TC 1
Z9 1
U1 0
U2 0
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD FEB 18
PY 2015
VL 5
AR 28
DI 10.3389/fonc.2015.00028
PG 7
WC Oncology
SC Oncology
GA CO3RM
UT WOS:000359077000001
PM 25741472
ER
PT J
AU Xiong, XH
Du, ZW
Wang, Y
Feng, ZH
Fan, P
Yan, CH
Willers, HN
Zhang, JR
AF Xiong, Xiahui
Du, Zhanwen
Wang, Ying
Feng, Zhihui
Fan, Pan
Yan, Chunhong
Willers, Henning
Zhang, Junran
TI 53BP1 promotes microhomology-mediated end-joining in G1-phase cells
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID DOUBLE-STRAND BREAKS; CLASS SWITCH RECOMBINATION; DNA-LIGASE III;
HOMOLOGOUS RECOMBINATION; V(D)J RECOMBINATION; IONIZING-RADIATION;
MAMMALIAN-CELLS; REPLICATION ARREST; BRCA1 DEFICIENCY; DUAL ROLE
AB Alternative non-homologous end joining (alt-NHEJ) was originally identified as a backup repair mechanism in the absence of classical NHEJ (c-NHEJ) factors but recent studies have demonstrated that alt-NHEJ is active even when c-NHEJ as well as homologous recombination is available. The functions of 53BP1 in NHEJ processes are not well understood. Here, we report that 53BP1 promotes DNA double-strand break (DSB) repair and genomic stability not only in c-NHEJ-proficient but also -deficient human G1-phase cells. Using an array of repair substrates we show that these effects of 53BP1 are correlated with a promotion of microhomology-mediated end-joining (MMEJ), a subtype of alt-NHEJ, in G1-phase. Consistent with a specific role in MMEJ we confirm that 53BP1 status does not affect c-NHEJ. 53BP1 supports sequence deletion during MMEJ consistent with a putative role in facilitating end-resection. Interestingly, promotion of MMEJ by 53BP1 in G1-phase cells is only observed in the presence of functional BRCA1. Depletion of both 53BP1 and BRCA1 increases repair needing microhomology usage and augments loss of DNA sequence, suggesting that MMEJ is a highly regulated DSB repair process. Together, these findings significantly expand our understanding of the cell-cycle-dependent roles of 53BP1 in DSB repair.
C1 [Xiong, Xiahui; Du, Zhanwen; Wang, Ying; Feng, Zhihui; Zhang, Junran] Case Western Reserve Univ, Sch Med, Dept Radiat Oncol, Cleveland, OH 44106 USA.
[Fan, Pan] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21231 USA.
[Yan, Chunhong] Georgia Regents Univ, Dept Biochem & Mol Biol, Augusta, GA 30912 USA.
[Willers, Henning] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
RP Zhang, JR (reprint author), Case Western Reserve Univ, Sch Med, Dept Radiat Oncol, 10900 Euclid Ave,BRB 323, Cleveland, OH 44106 USA.
EM jxz321@case.edu
RI Du, Zhanwen/H-9903-2016
FU National Cancer Institute [R01CA154625]; American Cancer Society
[IRG-58-010-51]; Department of Radiation Oncology, Case Western Reserve
University School of Medicine; Case Comprehensive Cancer Center [P30
CA43703]
FX National Cancer Institute [R01CA154625]; American Cancer Society
[IRG-58-010-51]; Department of Radiation Oncology, Case Western Reserve
University School of Medicine [to J.Z.]. Genomics Core Facility,
Radiation Resources Core Facility and Cytometry & Imaging Microscopy
Core Facility of the Case Comprehensive Cancer Center [P30 CA43703].
Funding for open access charge: [R01CA154625]; [P30 CA43703].
NR 73
TC 9
Z9 10
U1 1
U2 8
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 18
PY 2015
VL 43
IS 3
BP 1659
EP 1670
DI 10.1093/nar/gku1406
PG 12
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA CE2HZ
UT WOS:000351638000034
PM 25586219
ER
PT J
AU Abo, RP
Ducar, M
Garcia, EP
Thorner, AR
Rojas-Rudilla, V
Lin, L
Sholl, LM
Hahn, WC
Meyerson, M
Lindeman, NI
Van Hummelen, P
MacConaill, LE
AF Abo, Ryan P.
Ducar, Matthew
Garcia, Elizabeth P.
Thorner, Aaron R.
Rojas-Rudilla, Vanesa
Lin, Ling
Sholl, Lynette M.
Hahn, William C.
Meyerson, Matthew
Lindeman, Neal I.
Van Hummelen, Paul
MacConaill, Laura E.
TI BreaKmer: detection of structural variation in targeted massively
parallel sequencing data using kmers
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID ACUTE MYELOID-LEUKEMIA; READ ALIGNMENT; CANCER GENOMES; TRANSLOCATIONS;
GENE; IDENTIFICATION; LANDSCAPES; RESOLUTION
AB Genomic structural variation (SV), a common hallmark of cancer, has important predictive and therapeutic implications. However, accurately detecting SV using high-throughput sequencing data remains challenging, especially for 'targeted' resequencing efforts. This is critically important in the clinical setting where targeted resequencing is frequently being applied to rapidly assess clinically actionable mutations in tumor biopsies in a cost-effective manner. We present BreaKmer, a novel approach that uses a 'kmer' strategy to assemble misaligned sequence reads for predicting insertions, deletions, inversions, tandem duplications and translocations at base-pair resolution in targeted resequencing data. Variants are predicted by realigning an assembled consensus sequence created from sequence reads that were abnormally aligned to the reference genome. Using targeted resequencing data from tumor specimens with orthogonally validated SV, non-tumor samples and whole-genome sequencing data, BreaKmer had a 97.4% overall sensitivity for known events and predicted 17 positively validated, novel variants. Relative to four publically available algorithms, BreaKmer detected SV with increased sensitivity and limited calls in non-tumor samples, key features for variant analysis of tumor specimens in both the clinical and research settings.
C1 [Abo, Ryan P.; Ducar, Matthew; Thorner, Aaron R.; Lin, Ling; Hahn, William C.; Meyerson, Matthew; Van Hummelen, Paul; MacConaill, Laura E.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA.
[Abo, Ryan P.; Ducar, Matthew; Thorner, Aaron R.; Lin, Ling; Hahn, William C.; Meyerson, Matthew; Van Hummelen, Paul; MacConaill, Laura E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
[Abo, Ryan P.; Ducar, Matthew; Thorner, Aaron R.; Lin, Ling; Hahn, William C.; Meyerson, Matthew; Van Hummelen, Paul; MacConaill, Laura E.] Harvard Univ, Sch Med, Boston, MA 02215 USA.
[Ducar, Matthew; Rojas-Rudilla, Vanesa; Sholl, Lynette M.; Meyerson, Matthew; Lindeman, Neal I.; MacConaill, Laura E.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA.
[Hahn, William C.; Meyerson, Matthew] Broad Inst Harvard, Cambridge, MA 02141 USA.
[Hahn, William C.; Meyerson, Matthew] MIT, Cambridge, MA 02141 USA.
RP MacConaill, LE (reprint author), Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA.
EM lauramacconaill@dfci.harvard.edu
FU Dana-Farber Cancer Institute; Brigham and Women's Hospital
FX Funding for open access charge: This work is supported by the
Dana-Farber Cancer Institute and Brigham and Women's Hospital.
NR 39
TC 13
Z9 13
U1 1
U2 3
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 18
PY 2015
VL 43
IS 3
AR e19
DI 10.1093/nar/gku1211
PG 13
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA CE2HZ
UT WOS:000351638000005
PM 25428359
ER
PT J
AU Jiang, FG
Yeh, CK
Wen, JC
Sun, YY
AF Jiang, Fuguang
Yeh, Chih-Ko
Wen, Jianchuan
Sun, Yuyu
TI N-trimethylchitosan/Alginate Layer-by-Layer Self Assembly Coatings Act
as "Fungal Repellents" to Prevent Biofilm Formation on Healthcare
Materials
SO ADVANCED HEALTHCARE MATERIALS
LA English
DT Article
ID CANDIDA-ALBICANS BIOFILMS; BIOMEDICAL APPLICATIONS; DRUG-DELIVERY;
POLYELECTROLYTE MULTILAYERS; QUATERNIZED CHITOSAN; ALGINATE HYDROGELS;
TRIMETHYL CHITOSAN; DENTURE MATERIALS; RESISTANCE; BIOMATERIALS
AB Fungal biofilm formation on healthcare materials is a significant clinical concern, often leading to medical-device-related infections, which are difficult to treat. A novel fungal repellent strategy is developed to control fungal biofilm formation. Methylacrylic acid (MAA) is grated onto poly methyl methacrylate (PMMA)-based biomaterials via plasma-initiated grafting polymerization. A cationic polymer, trimethylchitosan (TMC), is synthesized by reacting chitosan with methyl iodide. Sodium alginate (SA) is used as an anionic polymer. TMC/SA multilayers are coated onto the MAA-grafted PMMA via layer-by-layer self-assembly. The TMC/SA multilayer coatings significantly reduce fungal initial adhesion, and effectively prevent fungal biofilm formation. It is concluded that the anti-adhesive property of the surface is due to its hydrophilicity, and that the biofilm-inhibiting action is attributed to the antifungal activity of TMC as well as the chelating function of TMC and SA, which may have acted as fungal repellents. Phosphate buffered saline (PBS)-immersion tests show that the biofilm-modulating effect of the multilayer coatings is stable for more than 4 weeks. Furthermore, the presence of TMC/SA multilayer coatings improves the biocompatibility of the original PMMA, offering a simple, yet effective, strategy for controlling fungal biofilm formation.
C1 [Jiang, Fuguang; Wen, Jianchuan; Sun, Yuyu] Univ Massachusetts, Dept Chem, Lowell, MA 01854 USA.
[Yeh, Chih-Ko] Univ Texas Hlth Sci Ctr San Antonio, Dept Comprehens Dent, San Antonio, TX 78229 USA.
[Yeh, Chih-Ko] South Texas Vet Hlth Care Syst, Audie L Murphy Div, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA.
RP Sun, YY (reprint author), Univ Massachusetts, Dept Chem, Lowell, MA 01854 USA.
EM yuyu_sun@uml.edu
FU NIDCR; NIH [R01 DE021084]; VA Merit Review [1I01BX001103]
FX This study was supported by NIDCR, NIH (R01 DE021084), and VA Merit
Review (1I01BX001103). The authors thank Dr. David Dean (Professor,
Comprehensive Dentistry, UTHSCSA) for his careful review and editing of
this manuscript.
NR 35
TC 7
Z9 8
U1 11
U2 48
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 2192-2640
EI 2192-2659
J9 ADV HEALTHC MATER
JI Adv. Healthc. Mater.
PD FEB 18
PY 2015
VL 4
IS 3
DI 10.1002/adhm.201400428
PG 7
WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials
Science, Biomaterials
SC Engineering; Science & Technology - Other Topics; Materials Science
GA CB9OQ
UT WOS:000349961600015
PM 25295485
ER
PT J
AU Aspinall, SL
Good, CB
Zhao, XH
Cunningham, FE
Heron, BB
Geraci, M
Passero, V
Stone, RA
Smith, KJ
Rogers, R
Shields, J
Sartore, M
Boyle, DP
Giberti, S
Szymanski, J
Smith, D
Ha, A
Sessions, J
Depcinski, S
Fishco, S
Molina, I
Lepir, T
Jean, C
Cruz-Diaz, L
Motta, J
Calderon-Vargas, R
Maland, J
Keefe, S
Tague, M
Leone, A
Glovack, B
Kaplan, B
Cosgriff, S
Kaster, L
Tonnu-Mihara, I
Nguyen, K
Carmichael, J
Clifford, L
Lu, K
Chatta, G
AF Aspinall, Sherrie L.
Good, Chester B.
Zhao, Xinhua
Cunningham, Francesca E.
Heron, Bernadette B.
Geraci, Mark
Passero, Vida
Stone, Roslyn A.
Smith, Kenneth J.
Rogers, Renee
Shields, Jenna
Sartore, Megan
Boyle, D. Patrick
Giberti, Sherry
Szymanski, John
Smith, Doug
Ha, Allen
Sessions, Jolynn
Depcinski, Shawn
Fishco, Shane
Molina, Irvin
Lepir, Tanja
Jean, Carmela
Cruz-Diaz, Lymaris
Motta, Jessica
Calderon-Vargas, Rebeca
Maland, Janelle
Keefe, Sean
Tague, Marshall
Leone, Alice
Glovack, Brian
Kaplan, Blair
Cosgriff, Sean
Kaster, Lindsay
Tonnu-Mihara, Ivy
Nguyen, Kimmai
Carmichael, Jenna
Clifford, Linda
Lu, Kan
Chatta, Gurkamal
TI Adjuvant chemotherapy for stage III colon cancer: relative dose
intensity and survival among veterans
SO BMC CANCER
LA English
DT Article
DE Colon cancer; Chemotherapy; Relative dose intensity; Survival
ID INDIVIDUAL PATIENT DATA; 18 RANDOMIZED-TRIALS; COLORECTAL-CANCER;
COMORBIDITY; OXALIPLATIN; COHORT; AGE; FLUOROURACIL; BEVACIZUMAB;
LEUCOVORIN
AB Background: Given the paucity of information on dose intensity, the objective of this study is to describe the use of adjuvant chemotherapy for stage III colon cancer, focusing on relative dose intensity (RDI), overall survival (OS) and disease-free survival (DFS).
Methods: Retrospective cohort of 367 patients diagnosed with stage III colon cancer in 2003-2008 and treated at 19 VA medical centers. Kaplan-Meier curves summarize 5-year OS and 3-year DFS by chemotherapy regimen and RDI, and multivariable Cox proportional hazards regression was used to model these associations.
Results: 5-fluorouracil/leucovorin (FU/LV) was the most commonly initiated regimen in 2003 (94.4%) and 2004 (62.7%); in 2005-2008, a majority of patients (60%-74%) was started on an oxaliplatin-based regimen. Median RDI was 82.3%. Receipt of >70% RDI was associated with better 5-year OS (p < 0.001) and 3-year DFS (P = 0.009) than was receipt of <= 70% RDI, with 5-year OS rates of 66.3% and 50.5%, respectively and 3-year DFS rates of 66.1% and 52.7%, respectively. In the multivariable analysis of 5-year OS, oxaliplatin + 5-FU/LV (versus 5-FU/LV) (HR = 0.55; 95% CI = 0.34-0.91), >70% RDI at the first year (HR = 0.58; 95% CI = 0.37-0.89) and married status (HR = 0.66; 95% CI = 0.45-0.97) were associated with significantly decreased risk of death, while age >= 75 (versus 55-64) (HR = 2.06; 95% CI = 1.25-3.40), Charlson Comorbidity Index (HR = 1.17; 95% CI = 1.06-1.30), T4 tumor status (versus T1/T2) (HR = 5.88; 95% CI = 2.69-12.9), N2 node status (HR = 1.68; 95% CI = 1.12-2.50) and bowel obstruction (HR = 2.32, 95% CI = 1.36-3.95) were associated with significantly increased risk. Similar associations were observed for DFS.
Conclusion: Patients with stage III colon cancer who received >70% RDI had improved 5-year OS. The association between RDI and survival needs to be examined in studies of adjuvant chemotherapy for colon cancer outside of the VA.
C1 [Aspinall, Sherrie L.; Good, Chester B.; Cunningham, Francesca E.; Heron, Bernadette B.; Geraci, Mark] VA Pharm Benefits Management Serv, Hines, IL 60141 USA.
[Aspinall, Sherrie L.; Good, Chester B.; Zhao, Xinhua; Stone, Roslyn A.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA 15240 USA.
[Aspinall, Sherrie L.; Good, Chester B.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA.
[Good, Chester B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA.
[Passero, Vida; Rogers, Renee; Shields, Jenna; Sartore, Megan] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA.
[Stone, Roslyn A.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA.
[Smith, Kenneth J.] Univ Pittsburgh, Div Clin Modeling & Decis Sci, Pittsburgh, PA USA.
[Boyle, D. Patrick; Giberti, Sherry] VA Maine Hlth Care Syst, Augusta, ME USA.
[Szymanski, John] VA Connecticut Healthcare Syst, West Haven, CT USA.
[Smith, Doug] Martinsburg VA Med Ctr, Martinsburg, WV USA.
[Ha, Allen] Richmond VA Med Ctr, Richmond, VA USA.
[Sessions, Jolynn] Asheville VA Med Ctr, Asheville, NC USA.
[Depcinski, Shawn; Fishco, Shane] James Haley Vet Hosp, Tampa, FL USA.
[Molina, Irvin; Lepir, Tanja; Jean, Carmela] Miami VA Med Ctr, Miami, FL USA.
[Cruz-Diaz, Lymaris; Motta, Jessica; Calderon-Vargas, Rebeca] VA Caribbean Healthcare Syst, San Juan, PR USA.
[Maland, Janelle] Harry S Truman VA Hosp, Columbia, MO USA.
[Keefe, Sean] Kansas City VA Med Ctr, Kansas City, MO USA.
[Tague, Marshall] Iowa City VA Med Ctr, Iowa City, IA USA.
[Leone, Alice] Louis Stokes Cleveland VA Med Ctr, Cleveland, OH USA.
[Kaplan, Blair] Jesse Brown VA Med Ctr, Chicago, IL USA.
[Cosgriff, Sean] Portland VA Med Ctr, Portland, OR USA.
[Kaster, Lindsay] Boise VA Med Ctr, Boise, ID USA.
[Tonnu-Mihara, Ivy; Nguyen, Kimmai] Long Beach VA Med Ctr, Long Beach, CA USA.
[Carmichael, Jenna; Clifford, Linda] VA Sierra Nevada Hlth Care Syst, Reno, NV USA.
[Lu, Kan] Sacramento VA Med Ctr, Mather, CA USA.
[Chatta, Gurkamal] Virginia Mason Med Ctr, Seattle, WA 98101 USA.
RP Aspinall, SL (reprint author), VA Pharm Benefits Management Serv, Hines, IL 60141 USA.
EM sherrie.aspinall@va.gov
OI Jean, Carmela/0000-0003-0808-1047
FU VA Pharmacy Benefits Management Services, Hines, IL; VA Pittsburgh
Healthcare System, Pittsburgh, PA
FX There was no funding support for the work. These findings are the result
of work supported in kind by VA Pharmacy Benefits Management Services,
Hines, IL, VA Pittsburgh Healthcare System, Pittsburgh, PA, and the
other VA medical centers that participated in the study. None of the
authors has a relevant financial interest in this manuscript.
NR 28
TC 8
Z9 8
U1 0
U2 3
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 18
PY 2015
VL 15
AR 62
DI 10.1186/s12885-015-1038-y
PG 13
WC Oncology
SC Oncology
GA CC6QY
UT WOS:000350493200001
PM 25884851
ER
PT J
AU Weber, GF
AF Weber, Georg F.
TI Immune targeting of the pleural space by intercostal approach
SO BMC PULMONARY MEDICINE
LA English
DT Article
DE ICAPS; Pleural space; Immune cell trafficking; Airway inflammation
ID B-CELLS PROTECT; INFECTION; PNEUMONIA; INFLAMMATION; MACROPHAGES;
MANAGEMENT; DEATHS; CAVITY
AB Background: Infectious diseases of the airways are a major health care problem world wide. New treatment strategies focus on employing the body's immune system to enhance its protective capacities during airway disease. One source for immune-competent cells is the pleural space, however, its immune-physiological function remains poorly understood. The aim of this study was to develop an experimental technique in rodents that allows for an in vivo analysis of pleural space immune cells participating in the host defense during airway disease.
Methods: I developed an easy and reliable technique that I named the "InterCostal Approach of the Pleural Space" (ICAPS) model that allows for in vivo analysis of pleural space immune cells in rodents. By injection of immune cell altering fluids into or flushing of the pleural space the immune response to airway infections can be manipulated.
Results: The results reveal that (i) the pleural space cellular environment can be altered partially or completely as well as temporarily or permanently, (ii) depletion of pleural space cells leads to increased airway inflammation during pulmonary infection, (iii) the pleural space contributes immune competent B cells during airway inflammation and (iv) inhibition of B cell function results in reduced bacterial clearance during pneumonia.
Conclusion: As the importance for in-depth knowledge of participating immune cells during health and disease evolves, the presented technique opens new possibilities to experimentally elucidate immune cell function, trafficking and contribution of pleural space cells during airway diseases.
C1 [Weber, Georg F.] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Surg, D-01307 Dresden, Germany.
[Weber, Georg F.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
[Weber, Georg F.] Harvard Univ, Sch Med, Boston, MA USA.
RP Weber, GF (reprint author), Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Surg, Fetscherstr 74, D-01307 Dresden, Germany.
EM georg.weber@uniklinikum-dresden.de
FU German Research Foundation [WE 4892/1-2, 3-1]
FX This work was supported by the German Research Foundation WE 4892/1-2
and 3-1.
NR 27
TC 1
Z9 1
U1 1
U2 3
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2466
J9 BMC PULM MED
JI BMC Pulm. Med.
PD FEB 18
PY 2015
VL 15
AR 14
DI 10.1186/s12890-015-0010-6
PG 10
WC Respiratory System
SC Respiratory System
GA CC8AS
UT WOS:000350590800002
PM 25880308
ER
PT J
AU Lin, GN
Corominas, R
Lemmens, I
Yang, XP
Tavernier, J
Hill, DE
Vidal, M
Sebat, J
Iakoucheva, LM
AF Lin, Guan Ning
Corominas, Roser
Lemmens, Irma
Yang, Xinping
Tavernier, Jan
Hill, David E.
Vidal, Marc
Sebat, Jonathan
Iakoucheva, Lilia M.
TI Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late
Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric
Diseases
SO NEURON
LA English
DT Article
ID COPY-NUMBER VARIATION; DE-NOVO MUTATIONS; AUTISM SPECTRUM DISORDERS;
CELL NUCLEAR ANTIGEN; SACCHAROMYCES-CEREVISIAE; MOLECULAR PATHWAYS;
FUNCTIONAL IMPACT; GENE-EXPRESSION; SCHIZOPHRENIA; GENOME
AB The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. Here we investigate the dynamics of the 16p11.2 network by integrating physical interactions of 16p11.2 proteins with spatiotemporal gene expression from the developing human brain. We observe profound changes in protein interaction networks throughout different stages of brain development and/or in different brain regions. We identify the late mid-fetal period of cortical development as most critical for establishing the connectivity of 16p11.2 proteins with their co-expressed partners. Furthermore, our results suggest that the regulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate is crucial for controlling brain size and connectivity and that its dysregulation by de novo mutations may be a potential determinant of 16p11.2 CNV deletion and duplication phenotypes.
C1 [Lin, Guan Ning; Corominas, Roser; Sebat, Jonathan; Iakoucheva, Lilia M.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA.
[Lemmens, Irma; Tavernier, Jan] Univ Ghent VIB, Dept Med Prot Res, B-9000 Ghent, Belgium.
[Lemmens, Irma; Tavernier, Jan] Univ Ghent, Fac Med & Hlth Sci, Dept Biochem, B-9000 Ghent, Belgium.
[Yang, Xinping; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, CCSB, Boston, MA 02215 USA.
[Yang, Xinping; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02215 USA.
[Yang, Xinping; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA.
[Sebat, Jonathan] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, La Jolla, CA 92093 USA.
RP Iakoucheva, LM (reprint author), Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA.
EM lilyak@ucsd.edu
RI Corominas, Roser/H-4163-2016;
OI Corominas, Roser/0000-0001-8888-5402; Sebat,
Jonathan/0000-0002-9087-526X; Iakoucheva, Lilia/0000-0002-4542-5219
FU ERC [340941]; NIH [R01MH091350, R01HD065288, R21MH104766, R01MH105524]
FX We thank Katherine Tsimring and Keith Happawana for technical
assistance. We also thank Shuli Kang for help with protein interaction
dataset processing and Nidhi Sahni for advice during the experiments.
J.T. is the recipient of ERC Advanced Grant 340941. This work was
supported by NIH grants R01MH091350 (to L.M.I.), R01HD065288 (to L.M.I),
R21MH104766 (to L.M.I.), and R01MH105524 (to L.M.I.).
NR 64
TC 15
Z9 15
U1 5
U2 23
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 18
PY 2015
VL 85
IS 4
BP 742
EP 754
DI 10.1016/j.neuron.2015.01.010
PG 13
WC Neurosciences
SC Neurosciences & Neurology
GA CB9OA
UT WOS:000349959900012
PM 25695269
ER
PT J
AU Ly, DP
Seabury, SA
Jena, AB
AF Ly, Dan P.
Seabury, Seth A.
Jena, Anupam B.
TI Divorce among physicians and other healthcare professionals in the
United States: analysis of census survey data
SO BMJ-BRITISH MEDICAL JOURNAL
LA English
DT Article
ID INTERNAL-MEDICINE PHYSICIANS; OCCUPATIONAL GROUPS; AMERICAN SURGEONS;
BURNOUT; DOCTORS; SATISFACTION; MARRIAGE; CONFLICT; EARNINGS; GENDER
AB OBJECTIVES
To estimate the prevalence and incidence of divorce among US physicians compared with other healthcare professionals, lawyers, and non-healthcare professionals, and to analyze factors associated with divorce among physicians. DESIGN Retrospective analysis of nationally representative surveys conducted by the US census, 2008-13.
SETTING
United States.
PARTICIPANTS
48 881 physicians, 10 086 dentists, 13 883 pharmacists, 159 044 nurses, 18 920 healthcare executives, 59 284 lawyers, and 6 339 310 other non-healthcare professionals.
MAIN OUTCOME MEASURES
Logistic models of divorce adjusted for age, sex, race, annual income, weekly hours worked, number of years since marriage, calendar year, and state of residence. Divorce outcomes included whether an individual had ever been divorced (divorce prevalence) or became divorced in the past year (divorce incidence).
RESULTS
After adjustment for covariates, the probability of being ever divorced (or divorce prevalence) among physicians evaluated at the mean value of other covariates was 24.3% (95% confidence interval 23.8% to 24.8%); dentists, 25.2% (24.1% to 26.3%); pharmacists, 22.9% (22.0% to 23.8%); nurses, 33.0% (32.6% to 33.3%); healthcare executives, 30.9% (30.1% to 31.8%); lawyers, 26.9% (26.4% to 27.4%); and other non-healthcare professionals, 35.0% (34.9% to 35.1%). Similarly, physicians were less likely than those in most other occupations to divorce in the past year. In multivariable analysis among physicians, divorce prevalence was greater among women (odds ratio 1.51, 95% confidence interval 1.40 to 1.63). In analyses stratified by physician sex, greater weekly work hours were associated with increased divorce prevalence only for female physicians.
CONCLUSIONS
Divorce among physicians is less common than among non-healthcare workers and several health professions. Female physicians have a substantially higher prevalence of divorce than male physicians, which may be partly attributable to a differential effect of hours worked on divorce.
C1 [Ly, Dan P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.
[Seabury, Seth A.] Univ So Calif, Dept Emergency Med, Los Angeles, CA USA.
[Seabury, Seth A.] Univ So Calif, Leonard D Schaeffer Ctr Hlth Policy & Econ, Los Angeles, CA USA.
[Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA.
[Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Cambridge, MA USA.
[Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA.
RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA.
EM jena@hcp.med.harvard.edu
FU Office of the Director, National Institutes of Health
FX This study was supported by the Office of the Director, National
Institutes of Health.
NR 37
TC 7
Z9 7
U1 2
U2 7
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 18
PY 2015
VL 350
AR h706
DI 10.1136/bmj.h706
PG 8
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB8WC
UT WOS:000349911500006
PM 25694110
ER
PT J
AU Rodrigues, KD
Ben-Avi, E
Sliva, DD
Choe, MS
Drottar, M
Wang, RP
Fischl, B
Grant, PE
Zollei, L
AF Rodrigues, Katyucia de Macedo
Ben-Avi, Emma
Sliva, Danielle D.
Choe, Myong-sun
Drottar, Marie
Wang, Ruopeng
Fischl, Bruce
Grant, Patricia E.
Zoellei, Lilla
TI A FreeSurfer-compliant consistent manual segmentation of infant brains
spanning the 0-2 year age range
SO FRONTIERS IN HUMAN NEUROSCIENCE
LA English
DT Article
DE MRI imaging; pediatrics; neuroimaging; segmentation; atlas
ID SURFACE-BASED ANALYSIS; AUTOMATIC SEGMENTATION; NEONATAL BRAIN; NEWBORN
BRAIN; MR-IMAGES; MORPHOMETRY; ATLASES
AB We present a detailed description of a set of FreeSurfer compatible segmentation guidelines tailored to infant MRI scans, and a unique data set of manually segmented acquisitions, with subjects nearly evenly distributed between 0 and 2 years of age. We believe that these segmentation guidelines and this dataset will have a wide range of potential uses in medicine and neuroscience.
C1 [Rodrigues, Katyucia de Macedo; Sliva, Danielle D.; Choe, Myong-sun; Drottar, Marie; Grant, Patricia E.] Boston Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA USA.
[Ben-Avi, Emma; Wang, Ruopeng; Fischl, Bruce; Zoellei, Lilla] Massachusetts Gen Hosp, AA Martinos Ctr, Lab Computat Neuroimaging, Charlestown, MA 02129 USA.
[Sliva, Danielle D.] Boston Childrens Hosp, Dept Med, Div Dev Med, Labs Cognit Neurosci, Boston, MA USA.
[Fischl, Bruce] MIT, Dept Elect Engn & Comp Sci, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.
RP Zollei, L (reprint author), Massachusetts Gen Hosp, AA Martinos Ctr, 149 13th St,Rm 2301, Charlestown, MA 02129 USA.
EM lzollei@nmr.mgh.harvard.edu
FU NICHD [1K99HD061485-01A1, R00 HD061485-03]; Ralph Schlaeger Fellowship,
National Institutes of Health [1R01EB014947-01, K23 N542758-01];
National Center for Research Resources [P41-RR14075, U24 RR021382];
National Institute for Biomedical Imaging and Bioengineering
[R01EB006758]; National Institute on Aging [AG022381, 5R01AG008122-22];
National Center for Alternative Medicine [RC1 AT005728-01]; National
Institute for Neurological Disorders and Stroke [R01 NS052585-01,
1R21NS072652-01, 1R01N5070963]; Shared Instrumentation Grants
[1S10RR023401, 1S10RR019307, 1S10RR023043]; Autism & Dyslexia Project -
Ellison Medical Foundation; NIH Blueprint for Neuroscience Research,
multi-institutional Human Connectome Project [5U01-MH093765]
FX We acknowledge the meticulous and detail oriented work of several
students who also assisted us with the analysis of the above described
data set: Dan Turtel, Nicole Roy, Marisa Biondi, Ernie Fok, Klea
Kalionzes and Hannah Sigmon. Support for this research was provided in
part by NICHD grants 1K99HD061485-01A1 and R00 HD061485-03, the Ralph
Schlaeger Fellowship, National Institutes of Health (1R01EB014947-01,
K23 N542758-01), the National Center for Research Resources
(P41-RR14075, U24 RR021382), the National Institute for Biomedical
Imaging and Bioengineering (R01EB006758), the National Institute on
Aging (AG022381, 5R01AG008122-22), the National Center for Alternative
Medicine (RC1 AT005728-01), the National Institute for Neurological
Disorders and Stroke (R01 NS052585-01, 1R21NS072652-01, 1R01N5070963),
and was made possible by the resources provided by Shared
Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043.
Additional support was provided by The Autism & Dyslexia Project funded
by the Ellison Medical Foundation, and by the NIH Blueprint for
Neuroscience Research (5U01-MH093765), part of the multi-institutional
Human Connectome Project. In addition, BF has a financial interest in
CorticoMetrics, a company whose medical pursuits focus on brain imaging
and measurement technologies. BF's interests were reviewed and are
managed by Massachusetts General Hospital and Partners HealthCare in
accordance with their conflict of interest policies.
NR 26
TC 0
Z9 0
U1 3
U2 4
PU FRONTIERS RESEARCH FOUNDATION
PI LAUSANNE
PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND
SN 1662-5161
J9 FRONT HUM NEUROSCI
JI Front. Hum. Neurosci.
PD FEB 18
PY 2015
VL 9
AR 21
DI 10.3389/fnhum.2015.00021
PG 12
WC Neurosciences; Psychology
SC Neurosciences & Neurology; Psychology
GA CB3IO
UT WOS:000349521600001
ER
PT J
AU Fay, AP
Signoretti, S
Callea, M
Telo, GH
McKay, RR
Song, JX
Carvo, I
Lampron, ME
Kaymakcalan, MD
Poli-de-Figueiredo, CE
Bellmunt, J
Hodi, FS
Freeman, GJ
Elfiky, A
Choueiri, TK
AF Fay, Andre P.
Signoretti, Sabina
Callea, Marcella
Telo, Gabriela H.
McKay, Rana R.
Song, Jiaxi
Carvo, Ingrid
Lampron, Megan E.
Kaymakcalan, Marina D.
Poli-de-Figueiredo, Carlos E.
Bellmunt, Joaquim
Hodi, F. Stephen
Freeman, Gordon J.
Elfiky, Aymen
Choueiri, Toni K.
TI Programmed death ligand-1 expression in adrenocortical carcinoma: an
exploratory biomarker study
SO JOURNAL FOR IMMUNOTHERAPY OF CANCER
LA English
DT Article
DE Adrenocortical carcinoma; PD-L1; PD-1 inhibitors; Immunotherapy
ID GROWTH-FACTOR RECEPTOR; RENAL-CELL CARCINOMA; PROGNOSTIC-FACTORS;
ADVANCED MELANOMA; KIDNEY CANCER; PHASE-II; THERAPY; MITOTANE; B7-H1;
PD-1
AB Background: Adrenocortical carcinoma (ACC) is a rare tumor in which prognostic factors are still not well established. Programmed Death Ligand-1 (PD-L1) expression in ACC and its association with clinico-pathological features and survival outcomes are unknown.
Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 28 patients with ACC. PD-L1 expression was evaluated by immunohistochemistry (IHC) in both tumor cell membrane and tumor infiltrating mononuclear cells (TIMC). PD-L1 positivity on tumor cells was defined as >= 5% tumor cell membrane staining. TIMC were evaluated by IHC using a CD45 monoclonal antibody. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrates and percentage of positive cells was developed. Any score greater that zero was considered PD-L1 positive. Baseline clinico-pathological characteristics and follow up data were retrospectively collected. Comparisons between PD-L1 expression and clinico-pathological features were evaluated using unpaired t-test and Fisher's exact test. Kaplan-Meier method and log-rank test were used to assess association between PD-L1 expression and 5-year overall survival (OS).
Results: Among 28 patients with surgically treated ACC, 3 (10.7%) were considered PD-L1 positive on tumor cell membrane. On the other hand, PD-L1 expression in TIMC was performed in 27 specimens and PD-L1 positive staining was observed in 19 (70.4%) patients. PD-L1 positivity in either tumor cell membrane or TIMC was not significantly associated with higher stage at diagnosis, higher tumor grade, excessive hormone secretion, or OS.
Conclusions: PD-L1 expression can exist in ACC in both tumor cell membrane and TIMC with no relationship to clinico-pathologic parameters or survival.
C1 [Fay, Andre P.; McKay, Rana R.; Lampron, Megan E.; Kaymakcalan, Marina D.; Bellmunt, Joaquim; Hodi, F. Stephen; Freeman, Gordon J.; Elfiky, Aymen; Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02215 USA.
[Fay, Andre P.; Poli-de-Figueiredo, Carlos E.] Pontificia Univ Catolica Rio Grande do Sul, Fac Med, Programa Posgrad Med & Ciencias Saude, BR-90619900 Porto Alegre, RS, Brazil.
[Signoretti, Sabina; Callea, Marcella; McKay, Rana R.; Song, Jiaxi; Carvo, Ingrid; Bellmunt, Joaquim; Elfiky, Aymen; Choueiri, Toni K.] Brigham & Womens Hosp, Boston, MA 02215 USA.
[Signoretti, Sabina; McKay, Rana R.; Bellmunt, Joaquim; Hodi, F. Stephen; Freeman, Gordon J.; Elfiky, Aymen; Choueiri, Toni K.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Telo, Gabriela H.] Joslin Diabet Ctr, Boston, MA 02215 USA.
[Hodi, F. Stephen] Ctr Immuno Oncol, Boston, MA 02215 USA.
RP Choueiri, TK (reprint author), Dana Farber Canc Inst, 450 Brookline Ave DANA 1230, Boston, MA 02215 USA.
EM toni_choueiri@dfci.harvard.edu
RI Poli de Figueiredo, Carlos/A-2027-2013
OI Poli de Figueiredo, Carlos/0000-0002-7333-8884
FU NCI NIH HHS [T32 CA009172]
NR 45
TC 8
Z9 9
U1 1
U2 4
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 17
PY 2015
VL 3
AR 3
DI 10.1186/s40425-015-0047-3
PG 8
WC Oncology
SC Oncology
GA CU7RZ
UT WOS:000363740500001
PM 25767716
ER
PT J
AU Shenk, TE
Robinson, ME
Svaldi, DO
Abbas, K
Breedlove, KM
Leverenz, LJ
Nauman, EA
Talavage, TM
AF Shenk, Trey E.
Robinson, Meghan E.
Svaldi, Diana O.
Abbas, Kausar
Breedlove, Katherine M.
Leverenz, Larry J.
Nauman, Eric A.
Talavage, Thomas M.
TI fMRI of Visual Working Memory in High School Football Players
SO DEVELOPMENTAL NEUROPSYCHOLOGY
LA English
DT Article; Proceedings Paper
CT 2nd Annual Meeting of the CIC/Big Ten/Ivy League Traumatic Brain Injury
Summit
CY JUL 16-17, 2014
CL Philadelphia, PA
AB Visual working memory deficits have been observed in at-risk athletes. This study uses a visual N-back working memory functional magnetic resonance imaging task to longitudinally assess asymptomatic football athletes for abnormal activity. Athletes were increasingly "flagged" as the season progressed. Flagging may provide early detection of injury.
C1 [Shenk, Trey E.; Abbas, Kausar; Talavage, Thomas M.] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA.
[Robinson, Meghan E.; Svaldi, Diana O.; Nauman, Eric A.; Talavage, Thomas M.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA.
[Robinson, Meghan E.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders TRACTS, Neuroimaging Res Vet NeRVe Ctr, Boston, MA USA.
[Breedlove, Katherine M.; Leverenz, Larry J.] Purdue Univ, Dept Hlth & Kinesiol, W Lafayette, IN 47907 USA.
[Nauman, Eric A.] Purdue Univ, Sch Mech Engn, W Lafayette, IN 47907 USA.
[Nauman, Eric A.] Purdue Univ, Dept Basic Med Sci, W Lafayette, IN 47907 USA.
RP Shenk, TE (reprint author), Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA.
EM trey.shenk@gmail.com
FU Indiana Spinal Cord and Brain Injury Research Fund, a part of the
Indiana State Department of Health [SCBI 207-32, SCBI 207-5]
FX This work was supported by the Indiana Spinal Cord and Brain Injury
Research Fund, a part of the Indiana State Department of Health (SCBI
207-32, SCBI 207-5).
NR 10
TC 2
Z9 2
U1 2
U2 11
PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND
SN 8756-5641
EI 1532-6942
J9 DEV NEUROPSYCHOL
JI Dev. Neuropsychol.
PD FEB 17
PY 2015
VL 40
IS 2
SI SI
BP 63
EP 68
DI 10.1080/87565641.2015.1014088
PG 6
WC Psychology, Developmental; Psychology; Psychology, Experimental
SC Psychology
GA CH6UW
UT WOS:000354172800003
PM 25961587
ER
PT J
AU Robinson, ME
Shenk, TE
Breedlove, EL
Leverenz, LJ
Nauman, EA
Talavage, TM
AF Robinson, Meghan E.
Shenk, Trey E.
Breedlove, Evan L.
Leverenz, Larry J.
Nauman, Eric A.
Talavage, Thomas M.
TI The Role of Location of Subconcussive Head Impacts in fMRI Brain
Activation Change
SO DEVELOPMENTAL NEUROPSYCHOLOGY
LA English
DT Article; Proceedings Paper
CT 2nd Annual Meeting of the CIC/Big Ten/Ivy League Traumatic Brain Injury
Summit
CY JUL 16-17, 2014
CL Philadelphia, PA
ID HIGH-SCHOOL FOOTBALL; BIOMECHANICS; CONCUSSION
AB Monte-Carlo permutation analysis was used to identify sets of head impacts most predictive of functional magnetic resonance imaging (fMRI) changes in football players. The relative distribution of impact location was found to be more predictive of brain activation changes than the number of impacts, suggesting that fMRI changes are related to systematic playing style.
C1 [Robinson, Meghan E.; Shenk, Trey E.; Nauman, Eric A.; Talavage, Thomas M.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA.
[Robinson, Meghan E.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders TRACTS, Neuroimaging Res Vet NeRVe Ctr, Boston, MA 02132 USA.
[Shenk, Trey E.; Talavage, Thomas M.] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA.
[Breedlove, Evan L.; Nauman, Eric A.] Purdue Univ, Sch Mech Engn, W Lafayette, IN 47907 USA.
[Leverenz, Larry J.] Purdue Univ, Dept Hlth & Kinesiol, W Lafayette, IN 47907 USA.
[Nauman, Eric A.] Purdue Univ, Dept Basic Med Sci, W Lafayette, IN 47907 USA.
RP Robinson, ME (reprint author), VA Boston Healthcare Syst, TRACTS 182, 150 South Huntington Ave, Boston, MA 02132 USA.
EM meghan.robinson@va.gov
FU Indiana Spinal Cord and Brain Injury Research Fund, a part of the
Indiana State Department of Health; National Science Foundation; NDSEG
Graduate Research Fellowship Programs
FX This work was supported by the Indiana Spinal Cord and Brain Injury
Research Fund, a part of the Indiana State Department of Health. This
work was also partially supported through the National Science
Foundation and NDSEG Graduate Research Fellowship Programs.
NR 11
TC 4
Z9 4
U1 2
U2 8
PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND
SN 8756-5641
EI 1532-6942
J9 DEV NEUROPSYCHOL
JI Dev. Neuropsychol.
PD FEB 17
PY 2015
VL 40
IS 2
SI SI
BP 74
EP 79
DI 10.1080/87565641.2015.1012204
PG 6
WC Psychology, Developmental; Psychology; Psychology, Experimental
SC Psychology
GA CH6UW
UT WOS:000354172800005
PM 25961589
ER
PT J
AU Svaldi, DO
Joshi, C
Robinson, ME
Shenk, TE
Abbas, K
Nauman, EA
Leverenz, LJ
Talavage, TM
AF Svaldi, Diana O.
Joshi, Chetas
Robinson, Meghan E.
Shenk, Trey E.
Abbas, Kausar
Nauman, Eric A.
Leverenz, Larry J.
Talavage, Thomas M.
TI Cerebrovascular Reactivity Alterations in Asymptomatic High School
Football Players
SO DEVELOPMENTAL NEUROPSYCHOLOGY
LA English
DT Article; Proceedings Paper
CT 2nd Annual Meeting of the CIC/Big Ten/Ivy League Traumatic Brain Injury
Summit
CY JUL 16-17, 2014
CL Philadelphia, PA
ID CHRONIC TRAUMATIC ENCEPHALOPATHY; INJURY; CO2
AB Cerebrovascular reactivity (CVR) is impaired following brain injury, increasing susceptibility to subsequent injury. CVR was tracked in football and non-collision athletes throughout one season. CVR transiently decreased in football athletes during the first half of the season. Results indicate the brain adapts slowly to increases in loading, increasing risk for injury.
C1 [Svaldi, Diana O.; Robinson, Meghan E.; Nauman, Eric A.; Talavage, Thomas M.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA.
[Joshi, Chetas; Shenk, Trey E.; Abbas, Kausar; Talavage, Thomas M.] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA.
[Robinson, Meghan E.] VA Boston Hlth Care Syst, Translat Res Ctr TBI & Stress Disorders TRACTS, Neuroimaging Res Vet NeRVe Ctr, Boston, MA USA.
[Nauman, Eric A.] Purdue Univ, Sch Mech Engn, W Lafayette, IN 47907 USA.
[Nauman, Eric A.] Purdue Univ, Dept Basic Med Sci, W Lafayette, IN 47907 USA.
[Leverenz, Larry J.] Purdue Univ, Dept Hlth & Kinesiol, W Lafayette, IN 47907 USA.
RP Svaldi, DO (reprint author), Purdue Univ, Biomed Engn, 465 Northwestern Ave, W Lafayette, IN 47907 USA.
EM dianaotero7@gmail.com
NR 10
TC 3
Z9 3
U1 2
U2 3
PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND
SN 8756-5641
EI 1532-6942
J9 DEV NEUROPSYCHOL
JI Dev. Neuropsychol.
PD FEB 17
PY 2015
VL 40
IS 2
SI SI
BP 80
EP 84
DI 10.1080/87565641.2014.973959
PG 5
WC Psychology, Developmental; Psychology; Psychology, Experimental
SC Psychology
GA CH6UW
UT WOS:000354172800006
PM 25961590
ER
PT J
AU Irazoqui, JE
AF Irazoqui, Javier E.
TI Why Worms Watch Their Hemidesmosomes and Why You Should, Too
SO IMMUNITY
LA English
DT Editorial Material
ID TRANSLATIONAL INHIBITION; CAENORHABDITIS-ELEGANS; IMMUNITY; PATHWAY
AB Hemidesmosomes are cellular attachment structures of great importance to the epidermis. In this issue of Immunity, Zhang et al. (2015) have discovered that in addition to having structural functions, invertebrate and human hemidesmosomes are actively monitored by the cell as a novel mechanism for detecting pathogenic infection.
C1 [Irazoqui, Javier E.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Lab Comparat Immunol, Boston, MA 02114 USA.
[Irazoqui, Javier E.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
RP Irazoqui, JE (reprint author), Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Lab Comparat Immunol, Boston, MA 02114 USA.
EM jirazoqui@mgh.harvard.edu
OI Irazoqui, Javier/0000-0001-6553-1329
FU NIGMS NIH HHS [R01 GM101056]
NR 9
TC 0
Z9 0
U1 1
U2 3
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 17
PY 2015
VL 42
IS 2
BP 206
EP 208
DI 10.1016/j.immuni.2015.01.021
PG 3
WC Immunology
SC Immunology
GA CB8XT
UT WOS:000349916400003
PM 25692695
ER
PT J
AU DuPage, M
Chopra, G
Quiros, J
Rosenthal, WL
Morar, MM
Holohan, D
Zhang, R
Turka, L
Marson, A
Bluestone, JA
AF DuPage, Michel
Chopra, Gaurav
Quiros, Jason
Rosenthal, Wendy L.
Morar, Malika M.
Holohan, Dan
Zhang, Ruan
Turka, Laurence
Marson, Alexander
Bluestone, Jeffrey A.
TI The Chromatin-Modifying Enzyme Ezh2 Is Critical for the Maintenance of
Regulatory T Cell Identity after Activation
SO IMMUNITY
LA English
DT Article
ID TRANSCRIPTION FACTOR FOXP3; IN-VIVO; EPIGENETIC CHANGES; CYTOKINE GENES;
TYPE-2 CELLS; REG-CELLS; DIFFERENTIATION; EXPRESSION; SUBSETS;
HOMEOSTASIS
AB Regulatory T cells (Treg cells) are required for immune homeostasis. Chromatin remodeling is essential for establishing diverse cellular identities, but how the epigenetic program in Treg cells is maintained throughout the dynamic activation process remains unclear. Here we have shown that CD28 co-stimulation, an extracellular cue intrinsically required for Treg cell maintenance, induced the chromatin-modifying enzyme, Ezh2. Treg-specific ablation of Ezh2 resulted in spontaneous autoimmunity with reduced Foxp3(+) cells in non-lymphoid tissues and impaired resolution of experimental autoimmune encephalomyelitis. Utilizing a model designed to selectively deplete wild-type Treg cells in adult mice co-populated with Ezh2-deficient Treg cells, Ezh2-deficient cells were destabilized and failed to prevent autoimmunity. After activation, the transcriptome of Ezh2-deficient Treg cells was disrupted, with altered expression of Treg cell lineage genes in a pattern similar to Foxp3-deficient Treg cells. These studies reveal a critical role for Ezh2 in the maintenance of Treg cell identity during cellular activation.
C1 [DuPage, Michel; Chopra, Gaurav; Quiros, Jason; Rosenthal, Wendy L.; Morar, Malika M.; Holohan, Dan; Marson, Alexander; Bluestone, Jeffrey A.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
[DuPage, Michel; Chopra, Gaurav; Quiros, Jason; Rosenthal, Wendy L.; Morar, Malika M.; Holohan, Dan; Marson, Alexander; Bluestone, Jeffrey A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
[Marson, Alexander] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA.
[Marson, Alexander] Univ Calif Berkeley, IGI, Berkeley, CA 94720 USA.
[Zhang, Ruan; Turka, Laurence] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA.
RP Bluestone, JA (reprint author), Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
EM jeff.bluestone@ucsf.edu
FU NIH [R01 AI046643, UM1 AI-12-059, A1007334-23A1]; JDRF; Helen Hay
Whitney Foundation
FX We thank D. Erle, A. Barczak, R. Barbeau, and J. Pollack of the UCSF
Sandler Center Functional Genomics Core for assistance with RNAseq data;
M. Lee, V. Nguyen, N. Lescano, and J. Paw for assisting with flow
cytometry; K. Fasano for preparation of tissues for histological
analyses; N. Ali and M. Rosenblumfor assistance with harvesting cells
from mouse skin; and A. Abbas, M. S. Anderson, F. van Gool, S.A.
Villalta, and A.G. DuPage for critical reading of this manuscript. This
work was supported by NIH grants R01 AI046643 and UM1 AI-12-059. G.C.
was supported by a JDRF fellowship. M.D. was supported by the Helen Hay
Whitney Foundation and NIH T32 grant to UCSF (A1007334-23A1). J.A.B. is
the A.W. and Mary Margaret Clausen Distinguished Professor in Metabolism
and Endocrinology.
NR 47
TC 28
Z9 29
U1 0
U2 8
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 17
PY 2015
VL 42
IS 2
BP 227
EP 238
DI 10.1016/j.immuni.2015.01.007
PG 12
WC Immunology
SC Immunology
GA CB8XT
UT WOS:000349916400008
PM 25680271
ER
PT J
AU Martinez, GJ
Pereira, RM
Aijo, T
Kim, EY
Marangoni, F
Pipkin, ME
Togher, S
Heissmeyer, V
Zhang, YC
Crotty, S
Lamperti, ED
Ansel, KM
Mempel, TR
Lahdesmaki, H
Hogan, PG
Rao, A
AF Martinez, Gustavo J.
Pereira, Renata M.
Aijo, Tarmo
Kim, Edward Y.
Marangoni, Francesco
Pipkin, Matthew E.
Togher, Susan
Heissmeyer, Vigo
Zhang, Yi Chen
Crotty, Shane
Lamperti, Edward D.
Ansel, K. Mark
Mempel, Thorsten R.
Lahdesmaki, Harri
Hogan, Patrick G.
Rao, Anjana
TI The Transcription Factor NFAT Promotes Exhaustion of Activated CD8(+) T
Cells
SO IMMUNITY
LA English
DT Article
ID CHRONIC VIRAL-INFECTION; REGULATES PD-1 EXPRESSION;
MOLECULAR-MECHANISMS; TOLERANCE; TIM-3; DNA; CALCINEURIN; PROTEINS;
CALCIUM; MEMORY
AB During persistent antigen stimulation, CD8(+) T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) T cells to protect against Listeria infection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) T cells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.
C1 [Martinez, Gustavo J.; Pereira, Renata M.; Aijo, Tarmo; Pipkin, Matthew E.; Togher, Susan; Hogan, Patrick G.; Rao, Anjana] La Jolla Inst Allergy & Immunol, Dept Signaling & Gene Express, La Jolla, CA 92037 USA.
[Aijo, Tarmo; Lahdesmaki, Harri] Aalto Univ, Sch Sci, Dept Informat & Comp Sci, Aalto 00076, Finland.
[Kim, Edward Y.; Marangoni, Francesco; Mempel, Thorsten R.] Harvard Univ, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol,Med Sch, Boston, MA 02114 USA.
[Pipkin, Matthew E.] Scripps Res Inst, Dept Canc Biol, Jupiter, FL 33458 USA.
[Heissmeyer, Vigo] Helmholtz Zentrum Munchen, Inst Mol Immunol, D-81377 Munich, Germany.
[Heissmeyer, Vigo] Univ Munich, Inst Immunol, D-80336 Munich, Germany.
[Zhang, Yi Chen] Columbia Univ, St Lukes Roosevelt Hosp Ctr, Dept Radiol, New York, NY 10019 USA.
[Crotty, Shane] La Jolla Inst Allergy & Immunol, Dept Vaccine Discovery, La Jolla, CA 92037 USA.
[Lamperti, Edward D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA.
[Lamperti, Edward D.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA.
[Ansel, K. Mark] Univ Calif San Francisco, Dept Microbiol & Immunol, Sandler Asthma Basic Res Ctr, San Francisco, CA 94143 USA.
RP Lahdesmaki, H (reprint author), Aalto Univ, Sch Sci, Dept Informat & Comp Sci, Aalto 00076, Finland.
EM harri.lahdesmaki@aalto.fi; arao@liai.org
RI Marangoni, Francesco/I-9087-2012
OI Marangoni, Francesco/0000-0002-2490-849X
FU NIH [R01 CA42471, R01 AI40127, AI84167, R01 CA150975, U19 CA179563, R01
AI095634]; EU FP7 [EC-FP7-SYBILLA-201106]; Academy of Finland Centre of
Excellence in Molecular Systems Immunology and Physiology Research;
German Research foundation [SFB 1054 TP A03]; Leukemia & Lymphoma
Society; Jane Coffin Childs Memorial Fund; Pew Latin American Fellows
Program in the Biomedical Sciences; Finnish Doctoral Programme in
Computational Sciences FICS
FX We thank Drs. Stephan Feske and Ariel Quintana for help with calcium
influx experiments, Drs. Camille Fos and Sara Trifari for help with
signaling experiments, Ryan Hastie for help in maintaining the colony,
and Drs. Runqiang Chen and James Scott-Browne for providing retroviral
constructs containing shCD4 and shNFAT4. We thank C. Kim, K. Gunst, and
L. Nosworthy at the La Jolla Institute Flow Cytometry Facility for help
with cell sorting experiments and Dr. G. Seumois and J. Day of the La
Jolla Institute Sequencing facility, and the Genomics Core at The
Scripps Research Institute in Florida for help with next- generation
sequencing. This work was funded by NIH grants R01 CA42471 (to A.R.),
R01 AI40127 and AI84167 (to P.G.H. and A.R.), R01 CA150975 and U19
CA179563 ( to T.R.M), and R01 AI095634 ( to M.E.P.), by EU FP7 grant
EC-FP7-SYBILLA-201106 and the Academy of Finland Centre of Excellence in
Molecular Systems Immunology and Physiology Research (to T.A. and H.L.),
and by German Research foundation SFB 1054 TP A03 (to V.H.), and The
Leukemia & Lymphoma Society (to K.M.A.). G.J.M. was supported by a
postdoctoral fellowship from the Jane Coffin Childs Memorial Fund,
R.M.P. by a postdoctoral fellowship from the Pew Latin American Fellows
Program in the Biomedical Sciences, and T.A. by a graduate student
fellowship from by the Finnish Doctoral Programme in Computational
Sciences FICS.
NR 48
TC 43
Z9 44
U1 1
U2 13
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 17
PY 2015
VL 42
IS 2
BP 265
EP 278
DI 10.1016/j.immuni.2015.01.006
PG 14
WC Immunology
SC Immunology
GA CB8XT
UT WOS:000349916400011
PM 25680272
ER
PT J
AU Gur, C
Ibrahim, Y
Isaacson, B
Yamin, R
Abed, J
Gamliel, M
Enk, J
Bar-On, Y
Stanietsky-Kaynan, N
Coppenhagen-Glazer, S
Shussman, N
Almogy, G
Cuapio, A
Hofer, E
Mevorach, D
Tabib, A
Ortenberg, R
Markel, G
Miklic, K
Jonjic, S
Brennan, CA
Garrett, WS
Bachrach, G
Mandelboim, O
AF Gur, Chamutal
Ibrahim, Yara
Isaacson, Batya
Yamin, Rachel
Abed, Jawad
Gamliel, Moriya
Enk, Jonatan
Bar-On, Yotam
Stanietsky-Kaynan, Noah
Coppenhagen-Glazer, Shunit
Shussman, Noam
Almogy, Gideon
Cuapio, Angelica
Hofer, Erhard
Mevorach, Dror
Tabib, Adi
Ortenberg, Rona
Markel, Gal
Miklic, Karmela
Jonjic, Stipan
Brennan, Caitlin A.
Garrett, Wendy S.
Bachrach, Gilad
Mandelboim, Ofer
TI Binding of the Fap2 Protein of Fusobacterium nucleatum to Human
Inhibitory Receptor TIGIT Protects Tumors from Immune Cell Attack
SO IMMUNITY
LA English
DT Article
ID NATURAL-KILLER-CELLS; ORAL BACTERIA; NK CELLS; CYTOTOXICITY; CANCER;
RECOGNITION; MICROBIOTA; MICE; FADA; PVR
AB Bacteria, such as Fusobacterium nucleatum, are present in the tumor microenvironment. However, the immunological consequences of intra-tumoral bacteria remain unclear. Here, we have shown that natural killer (NK) cell killing of various tumors is inhibited in the presence of various F. nucleatum strains. Our data support that this F. nucleatum- mediated inhibition is mediated by human, but not by mouse TIGIT, an inhibitory receptor present on all human NK cells and on various T cells. Using a library of F. nucleatum mutants, we found that the Fap2 protein of F. nucleatum directly interacted with TIGIT, leading to the inhibition of NK cell cytotoxicity. We have further demonstrated that tumor- infiltrating lymphocytes expressed TIGIT and that T cell activities were also inhibited by F. nucleatum via Fap2. Our results identify a bacterium- dependent, tumorimmune evasion mechanism in which tumors exploit the Fap2 protein of F. nucleatum to inhibit immune cell activity via TIGIT.
C1 [Gur, Chamutal; Isaacson, Batya; Yamin, Rachel; Gamliel, Moriya; Enk, Jonatan; Bar-On, Yotam; Stanietsky-Kaynan, Noah; Mandelboim, Ofer] Hebrew Univ Hadassah Med Sch, IMRIC, Lautenberg Ctr Gen & Tumor Immunol, IL-91120 Jerusalem, Israel.
[Gur, Chamutal; Mevorach, Dror; Tabib, Adi] Hadassah Hebrew Univ, Rheumatol Res Ctr, IL-91120 Jerusalem, Israel.
[Ibrahim, Yara; Abed, Jawad; Coppenhagen-Glazer, Shunit; Bachrach, Gilad] Hebrew Univ Hadassah Sch Dent Med, Inst Dent Sci, IL-91120 Jerusalem, Israel.
[Shussman, Noam; Almogy, Gideon] Hadassah Hebrew Univ Med Ctr, Dept Gen Surg, IL-91120 Jerusalem, Israel.
[Cuapio, Angelica; Hofer, Erhard] Univ Vienna, Dept Vasc Biol & Thrombosis Res Med, A-1090 Vienna, Austria.
[Ortenberg, Rona; Markel, Gal] Sheba Med Ctr, Ella Inst Melanoma, IL-526260 Ramat Gan, Israel.
[Miklic, Karmela; Jonjic, Stipan] Univ Rijeka, Fac Med, Ctr Prote, Dept Histol & Embryol, Rijeka 51000, Croatia.
[Brennan, Caitlin A.; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA.
[Garrett, Wendy S.] Dana Farber Canc Inst, Boston, MA 02115 USA.
RP Bachrach, G (reprint author), Hebrew Univ Hadassah Sch Dent Med, Inst Dent Sci, IL-91120 Jerusalem, Israel.
EM giladba@ekmd.huji.ac.il; oferm@ekmd.huji.ac.il
RI Jonjic, Stipan/C-5657-2016
FU European Research Council under the European Union's Seventh Framework
Programme (FP) / ERC [320473-BacNK]; I-CORE Program of the Planning and
Budgeting Committee; Israel Science Foundation; I-Core on Chromatin and
RNA in Gene Regulation; GIF Foundation; Lewis family Foundation; ICRF
professorship grant; Israeli Science Foundation; Helmholtz Israel grant;
Rosetrees Trust; ICRF project grant; Israeli Science Foundation
(Morasha); Foulkes Foundation; Hoffman-LaRoche; Marie Curie European
Research Council program [FP7-MC-ITN-317013-NATURIMMUN]; ERC Advanced
Grant [322693]; [R01CA154426]
FX This study was supported by the European Research Council under the
European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant
Agreement number 320473-BacNK. Further support came from the I-CORE
Program of the Planning and Budgeting Committee and the Israel Science
Foundation and by the I-Core on Chromatin and RNA in Gene Regulation,
the GIF Foundation, the Lewis family Foundation, the ICRF professorship
grant, the Israeli Science Foundation, the Helmholtz Israel grant and
the Rosetrees Trust (all to O.M.). O.M. is a Crown Professor of
Molecular Immunology. This project was also supported by the Israeli
Science Foundation and the ICRF project grant to G. B. The work was also
supported by the Israeli Science Foundation (Morasha) and by the Foulkes
Foundation to C.G. This work was supported by R01CA154426 and a grant
from Hoffman-LaRoche to W.S.G., and A.C., E.H. and O.M are further
supported by the Marie Curie European Research Council program
(FP7-MC-ITN-317013-NATURIMMUN). S.J. is supported by the ERC Advanced
Grant (grant number 322693). We thank Dr. Stern-Ginossar for her help in
performing the pp65 proliferation assays.
NR 32
TC 52
Z9 53
U1 9
U2 29
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 17
PY 2015
VL 42
IS 2
BP 344
EP 355
DI 10.1016/j.immuni.2015.01.010
PG 12
WC Immunology
SC Immunology
GA CB8XT
UT WOS:000349916400017
PM 25680274
ER
PT J
AU Nettiksimmons, J
Ayonayon, H
Harris, T
Phillips, C
Rosano, C
Satterfield, S
Yaffe, K
AF Nettiksimmons, Jasmine
Ayonayon, Hilsa
Harris, Tamara
Phillips, Caroline
Rosano, Caterina
Satterfield, Suzanne
Yaffe, Kristine
CA Hlth ABC Study
TI Development and validation of risk index for cognitive decline using
blood-derived markers
SO NEUROLOGY
LA English
DT Article
ID CARDIOVASCULAR HEALTH COGNITION; C-REACTIVE PROTEIN; ALZHEIMERS-DISEASE;
SERUM-ALBUMIN; OLDER-ADULTS; TELOMERE LENGTH; CYSTATIN-C; A-BETA;
DEMENTIA; INTERLEUKIN-6
AB Objective:We sought to develop and validate a risk index for prospective cognitive decline in older adults based on blood-derived markers.Methods:The index was based on 8 markers that have been previously associated with cognitive aging: APOE genotype, plasma -amyloid 42/40 ratio, telomere length, cystatin C, glucose, C-reactive protein, interleukin-6, and albumin. The outcome was person-specific cognitive slopes (Modified Mini-Mental State Examination) from 11 years of follow-up. A total of 1,445 older adults comprised the development sample. An index based on dichotomized markers was divided into low-, medium-, and high-risk categories; the risk categories were validated with the remaining sample (n = 739) using linear regression. Amyloid was measured on a subsample (n = 865) and was included only in a secondary index.Results:The risk categories showed significant differences from each other and were predictive of prospective cognitive decline in the validation sample, even after adjustment for age and baseline cognitive score: the low-risk group (24.8%) declined 0.32 points/y (95% confidence interval [CI]: -0.46, -0.19), the medium-risk group (58.7%) declined 0.55 points/y (95% CI: -0.65, 0.45), and the high-risk group (16.6%) declined 0.69 points/y (95% CI: -0.85, -0.54). Using the secondary index, which included -amyloid 42/40 (validation n = 279), the low-risk group (26.9%) declined 0.20 points/y (95% CI: -0.42, 0.01), the medium-risk group (61.3%) declined 0.55 points/y (95% CI: -0.72, -0.38), and the high-risk group (11.8%) declined 0.83 points/y (95% CI: -1.14, -0.51).Conclusions:A risk index based on 8 blood-based markers was modestly able to predict cognitive decline over an 11-year follow-up. Further validation in other cohorts is necessary.
C1 [Nettiksimmons, Jasmine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA.
[Ayonayon, Hilsa] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.
[Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA.
[Phillips, Caroline] NIA, Neuroepidemiol Sect, Bethesda, MD 20892 USA.
[Rosano, Caterina] Univ Pittsburgh, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA.
[Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Knoxville, TN 37996 USA.
[Yaffe, Kristine] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Psychiat, San Francisco, CA 94143 USA.
[Yaffe, Kristine] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Neurol, San Francisco, CA 94143 USA.
[Yaffe, Kristine] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.
RP Nettiksimmons, J (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA.
EM jasmine.nettiksimmons@ucsf.edu
RI Newman, Anne/C-6408-2013;
OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506;
Rosano, Caterina/0000-0002-4271-6010
FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103,
N01-AG-6-2106]; NIA [R01-AG028050, K24AG031155]; National Institute of
Nursing Research [R01-NR012459]; NIH, NIA; American Health Assistance
Foundation [A201-0029]
FX National Institute on Aging (NIA) contracts N01-AG-6-2101,
N01-AG-6-2103, N01-AG-6-2106; NIA grant R01-AG028050; National Institute
of Nursing Research grant R01-NR012459. This research was supported in
part by the Intramural Research Program of the NIH, NIA, and by grant
A201-0029 from the American Health Assistance Foundation. Dr. Yaffe is
supported in part by a NIA grant (K24AG031155).
NR 36
TC 2
Z9 2
U1 0
U2 2
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 17
PY 2015
VL 84
IS 7
BP 696
EP 702
DI 10.1212/WNL.0000000000001263
PG 7
WC Clinical Neurology
SC Neurosciences & Neurology
GA CB7XV
UT WOS:000349843000014
PM 25609760
ER
PT J
AU Apostolova, LG
Hwang, KS
Avila, D
Elashoff, D
Kohannim, O
Teng, E
Sokolow, S
Jack, CR
Jagust, WJ
Shaw, L
Trojanowski, JQ
Weiner, MW
Thompson, PM
AF Apostolova, Liana G.
Hwang, Kristy S.
Avila, David
Elashoff, David
Kohannim, Omid
Teng, Edmond
Sokolow, Sophie
Jack, Clifford R.
Jagust, William J.
Shaw, Leslie
Trojanowski, John Q.
Weiner, Michael W.
Thompson, Paul M.
CA Alzheimer's Dis Neuroimaging
TI Brain amyloidosis ascertainment from cognitive, imaging, and peripheral
blood protein measures
SO NEUROLOGY
LA English
DT Article
ID ALZHEIMERS-DISEASE; HIPPOCAMPAL ATROPHY; NEUROTROPHIC FACTOR; PLASMA
CLUSTERIN; IMPAIRMENT; PROGRESSION; INFLAMMATION; BIOMARKERS; GENOTYPE;
RISK
AB Background:The goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.Methods:We developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF -amyloid 1-42 (A(42)) 192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio 1.5. We trained our classifier in the subcohort with CSF A(42) but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF A(42) data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.Results:The CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.Conclusions:Automated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.Classification of evidence:This study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).
C1 [Apostolova, Liana G.; Hwang, Kristy S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA.
[Elashoff, David] Univ Calif Los Angeles, David Geffen Sch Med, Med Stat Core, Los Angeles, CA 90095 USA.
[Sokolow, Sophie] Univ Calif Los Angeles, David Geffen Sch Med, Sch Nursing, Los Angeles, CA 90095 USA.
[Thompson, Paul M.] Univ So Calif, Keck Sch Med, Inst Neuroinformat, Los Angeles, CA 90033 USA.
[Teng, Edmond] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA.
[Jack, Clifford R.] Mayo Clin, Dept Diagnost Radiol, Rochester, MN USA.
[Jagust, William J.] Univ Calif Berkeley, Dept Publ Hlth & Neurosci, Berkeley, CA 94720 USA.
[Shaw, Leslie; Trojanowski, John Q.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA.
[Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA.
[Weiner, Michael W.] Dept Vet Affairs Med Ctr, San Francisco, CA USA.
RP Apostolova, LG (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA.
EM lapostolova@mednet.ucla.edu
RI Jack, Clifford/F-2508-2010;
OI Jack, Clifford/0000-0001-7916-622X; Preda, Adrian /0000-0003-3373-2438
FU Alzheimer's Disease Neuroimaging Initiative (ADNI) (NIH) [U01 AG024904];
DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute
on Aging, the National Institute of Biomedical Imaging and
Bioengineering; Canadian Institutes of Health Research; Easton
Consortium for Alzheimer's Drug Discovery and Biomarker Development, NIA
[R01 AG040770]; NIA [P50 AG16570, R01 AG040060]; NIMH [R01 MH097268];
UCLA Dissertation Year Fellowship; UCLA Medical Scientist Training
Program
FX Data collection and sharing for this project were funded by the
Alzheimer's Disease Neuroimaging Initiative (ADNI) (NIH grant U01
AG024904) and DOD ADNI (Department of Defense award number
W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging,
the National Institute of Biomedical Imaging and Bioengineering, and
through generous contributions from the following: Alzheimer's
Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.;
Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan
Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd.
and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics,
N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research &
Development, LLC.; Johnson & Johnson Pharmaceutical Research &
Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale
Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals
Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and
Takeda Pharmaceutical Company. The Canadian Institutes of Health
Research is providing funds to support ADNI clinical sites in Canada.
Private sector contributions are facilitated by the Foundation for the
National Institutes of Health (www.fnih.org). The grantee organization
is the Northern California Institute for Research and Education, and the
study is coordinated by the Alzheimer's Disease Cooperative Study at the
University of California, San Diego. ADNI data are disseminated by the
Laboratory for Neuro Imaging at the University of Southern California.
The analyses reported in this manuscript were funded by the Easton
Consortium for Alzheimer's Drug Discovery and Biomarker Development, NIA
R01 AG040770, NIA P50 AG16570. Algorithm development was also supported,
in part, by NIMH R01 MH097268 and NIA R01 AG040060 (to P.T.). O.K. was
supported, in part, by a UCLA Dissertation Year Fellowship, and by the
UCLA Medical Scientist Training Program.
NR 39
TC 10
Z9 10
U1 1
U2 11
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 17
PY 2015
VL 84
IS 7
BP 729
EP 737
DI 10.1212/WNL.0000000000001231
PG 9
WC Clinical Neurology
SC Neurosciences & Neurology
GA CB7XV
UT WOS:000349843000018
PM 25609767
ER
PT J
AU Coa, KI
Epstein, JB
Ettinger, D
Jatoi, A
McManus, K
Platek, ME
Price, W
Stewart, M
Teknos, TN
Moskowitz, B
AF Coa, Kisha I.
Epstein, Joel B.
Ettinger, David
Jatoi, Aminah
McManus, Kathy
Platek, Mary E.
Price, Wendy
Stewart, Meghan
Teknos, Theodoros N.
Moskowitz, Bruce
TI The Impact of Cancer Treatment on the Diets and Food Preferences of
Patients Receiving Outpatient Treatment
SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL
LA English
DT Article
ID QUALITY-OF-LIFE; BREAST-CANCER; WEIGHT-LOSS; CHEMOTHERAPY; TASTE;
PREVALENCE; PERCEPTION; NUTRITION; CACHEXIA; OUTCOMES
AB Patients undergoing cancer treatment experience a multitude of symptoms that can influence their ability to complete treatment as well as their quality of life during and after treatment. This cross-sectional study sought to describe the dietary changes experienced by cancer patients and to identify associations between these changes and common treatment symptoms. A convenience sample of 1199 cancer patients aged 18yr and older undergoing active treatment were recruited from 7 cancer centers to complete a self-administered paper-and-pencil survey. Descriptive analyses were conducted to estimate prevalence of dietary changes and chi-squared tests were used to examine associations between dietary changes and health outcomes. Approximately 40% of patients reported a decreased appetite since beginning treatment, and 67.2% of patients reported at least 1 chemosensory alteration. Increased taste sensitivities were more common than decreased taste sensitivities, with increased sensitivity to metallic being the most common taste sensitivity (18.6%). Patients also had increased sensitivities to certain smells including cleaning solutions (23.4%), perfume (22.4%), and food cooking (11.4%). Patients reported a wide range of food preferences and aversions. Patients who had less energy or lost weight since beginning treatment were more likely than others to report treatment-related dietary changes.
C1 [Coa, Kisha I.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA.
[Epstein, Joel B.; Stewart, Meghan] Cedars Sinai Samuel Oschin Comprehens Canc Inst, Los Angeles, CA USA.
[Epstein, Joel B.] City Hope Natl Med Ctr, Los Angeles, CA USA.
[Ettinger, David] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA.
[Jatoi, Aminah] Mayo Clin, Ctr Canc, Rochester, MN USA.
[McManus, Kathy] Dana Farber Canc Inst, Boston, MA 02115 USA.
[Platek, Mary E.] NYU, New York, NY USA.
[Price, Wendy] WHP Res Inc, Chevy Chase, MD USA.
[Teknos, Theodoros N.] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA.
[Moskowitz, Bruce] Bruce & Marsha Moskowitz Fdn, Palm Beach, FL USA.
RP Coa, KI (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, 624 N Broadway St, Baltimore, MD 21205 USA.
EM kcoa1@jhu.edu
FU Delaware North Companies; National Institutes of Health, National
Research Service Award [T32 CA009314]
FX This work was supported by Delaware North Companies. Kisha I. Coa was
supported by the National Institutes of Health, National Research
Service Award T32 CA009314.
NR 33
TC 4
Z9 4
U1 2
U2 4
PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND
SN 0163-5581
EI 1532-7914
J9 NUTR CANCER
JI Nutr. Cancer
PD FEB 17
PY 2015
VL 67
IS 2
BP 339
EP 353
DI 10.1080/01635581.2015.990577
PG 15
WC Oncology; Nutrition & Dietetics
SC Oncology; Nutrition & Dietetics
GA CC4QP
UT WOS:000350338300016
PM 25664980
ER
PT J
AU Zhao, QD
Viswanadhapalli, S
Williams, P
Shi, Q
Tan, CY
Yi, XL
Bhandari, B
Abboud, HE
AF Zhao, Qingwei David
Viswanadhapalli, Suryavathi
Williams, Paul
Shi, Qian
Tan, Chunyan
Yi, Xiaolan
Bhandari, Basant
Abboud, Hanna E.
TI NADPH Oxidase 4 Induces Cardiac Fibrosis and Hypertrophy Through
Activating Akt/mTOR and NF kappa B Signaling Pathways
SO CIRCULATION
LA English
DT Article
DE fibrosis; hypertrophy; mTORC1; NADPH oxidase; NF kappa B; reactive
oxygen species
ID ENDOTHELIAL GROWTH-FACTOR; TUBULAR EPITHELIAL-CELLS; ANGIOTENSIN-II;
OXIDATIVE STRESS; TRANSCRIPTION FACTORS; PROMOTES APOPTOSIS;
GENE-EXPRESSION; UP-REGULATION; RAT-HEART; IN-VIVO
AB Background-NADPH oxidase 4 (Nox4) has been implicated in cardiac remodeling, but its precise role in cardiac injury remains controversial. Furthermore, little is known about the downstream effector signaling pathways activated by Nox4-derived reactive oxygen species in the myocardium. We investigated the role of Nox4 and Nox4-associated signaling pathways in the development of cardiac remodeling.
Methods and Results-Cardiac-specific human Nox4 transgenic mice (c-hNox4Tg) were generated. Four groups of mice were studied: (1) control mice, littermates that are negative for hNox4 transgene but Cre positive; (2) c-hNox4 Tg mice; (3) angiotensin II (AngII)-infused control mice; and (4) c-hNox4Tg mice infused with AngII. The c-hNox4Tg mice exhibited an approximate to 10-fold increase in Nox4 protein expression and an 8-fold increase in the production of reactive oxygen species, and manifested cardiac interstitial fibrosis. AngII infusion to control mice increased cardiac Nox4 expression and induced fibrosis and hypertrophy. The Tg mice receiving AngII exhibited more advanced cardiac remodeling and robust elevation in Nox4 expression, indicating that AngII worsens cardiac injury, at least in part by enhancing Nox4 expression. Moreover, hNox4 transgene and AngII infusion induced the expression of cardiac fetal genes and activated the Akt-mTOR and NF kappa B signaling pathways. Treatment of AngII-infused c-hNox4Tg mice with GKT137831, a Nox4/Nox1 inhibitor, abolished the increase in oxidative stress, suppressed the Akt-mTOR and NF kappa B signaling pathways, and attenuated cardiac remodeling.
Conclusions-Upregulation of Nox4 in the myocardium causes cardiac remodeling through activating Akt-mTOR and NF kappa B signaling pathways. Inhibition of Nox4 has therapeutic potential to treat cardiac remodeling.
C1 Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.
South Texas Vet Hlth Care Syst, San Antonio, TX USA.
RP Zhao, QD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Dept Med, 7703 Floyd Curl Dr,MC 7882, San Antonio, TX 78229 USA.
EM zhaoq3@uthscsa.edu
FU JDRF [4-2010-511]; AHA [11SDG5380002]; [RO1DK033665]
FX This work was supported in part by grants from JDRF (Multi-Project grant
4-2010-511), AHA (11SDG5380002), and RO1DK033665.
NR 56
TC 26
Z9 27
U1 3
U2 14
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 17
PY 2015
VL 131
IS 7
BP 643
EP U152
DI 10.1161/CIRCULATIONAHA.114.011079
PG 38
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
SC Cardiovascular System & Cardiology
GA CB3OZ
UT WOS:000349539200012
PM 25589557
ER
PT J
AU Torres, A
Sibila, O
Ferrer, M
Polverino, E
Menendez, R
Mensa, J
Gabarrus, A
Sellares, J
Restrepo, MI
Anzueto, A
Niederman, MS
Agusti, C
AF Torres, Antoni
Sibila, Oriol
Ferrer, Miguel
Polverino, Eva
Menendez, Rosario
Mensa, Josep
Gabarrus, Albert
Sellares, Jacobo
Restrepo, Marcos I.
Anzueto, Antonio
Niederman, Michael S.
Agusti, Caries
TI Effect of Corticosteroids on Treatmmt Failure Among Hospitalized
Patients With Severe Community-Acquired Pneumonia and High Inflammatory
Response A Randomized Clinical Trial
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Article
ID HYDROCORTISONE THERAPY; RISK; PROGNOSIS; OUTCOMES; GLUCOCORTICOIDS;
DEXAMETHASONE; PREDICTION; GUIDELINES; MORTALITY; PATTERNS
AB IMPORTANCE In patients with severe community-acquired pneumonia, treatment failure is associated with excessive inflammatory response and worse outcomes. Corticosteroids may modulate cytokine release in these patients, but the benefit of this adjunctive therapy remains controversial.
OBJECTIVE To assess the effect of corticosteroids in patients with severe community-acquired pneumonia and high associated inflammatory response.
DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled trial conducted in 3 Spanish teaching hospitals involving patients with both severe community-acquired pneumonia and a high inflammatory response, which was defined as a level of C-reactive protein greater than 150 mg/L at admission. Patients were recruited and followed up from June 2004 through February 2012.
INTERVENTIONS Patients were randomized to receive either an intravenous bolus of 0.5 mg/kg per 12 hours of methylprednisolone (n = 61) or placebo (n = 59) for 5 days started within 36 hours of hospital admission.
MAIN OUTCOMES AND MEASURES The primary outcome was treatment failure (composite outcome of early treatment failure defined as [1] clinical deterioration indicated by development of shock, [2] need for invasive mechanical ventilation not present at baseline, or [3] death within 72 hours of treatment; or composite outcome of late treatment failure defined as [1] radiographic progression, [2] persistence of severe respiratory failure, [3] development of shock, [4] need for invasive mechanical ventilation not present at baseline, or [5] death between 72 hours and 120 hours after treatment initiation; or both early and late treatment failure). In-hospital mortality was a secondary outcome and adverse events were assessed.
RESULTS There was less treatment failure among patients from the methylprednisolone group (8 patients [13%]) compared with the placebo group (18 patients [31%]) (P = .02), with a difference between groups of 18% (95% CI, 3% to 32%). Corticosteroid treatment reduced the risk of treatment failure (odds ratio, 0.34 [95% CI, 0.14 to 0.87]; P = .02). In-hospital mortality did not differ between the 2 groups (6 patients [10%] in the methylprednisolone group vs 9 patients [15%] in the placebo group; P = .37); the difference between groups was 5% (95% CI, -6% to 17%). Hyperglycemia occurred in 11 patients (18%) in the methylprednisolone group and in 7 patients (12%) in the placebo group (P = .34).
CONCLUSIONS AND RELEVANCE Among patients with severe community-acquired pneumonia and high initial inflammatory response, the acute use of methylprednisolone compared with placebo decreased treatment failure. If replicated, these findings would support the use of corticosteroids as adjunctive treatment in this clinical population.
C1 [Torres, Antoni; Ferrer, Miguel; Polverino, Eva; Gabarrus, Albert; Sellares, Jacobo; Agusti, Caries] Hosp Clin Barcelona, Serv Pneumol, Inst Clin Torax, E-08036 Barcelona, Spain.
[Torres, Antoni; Ferrer, Miguel; Polverino, Eva; Mensa, Josep; Gabarrus, Albert; Sellares, Jacobo; Agusti, Caries] Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain.
[Torres, Antoni; Ferrer, Miguel; Polverino, Eva; Menendez, Rosario; Gabarrus, Albert; Sellares, Jacobo; Agusti, Caries] Ctr Invest Biomed Red Enfermedades Resp, Islas Baleares, Spain.
[Torres, Antoni] Univ Barcelona, Barcelona, Spain.
[Sibila, Oriol] Hosp Santa Creu & Sant Pau, Serv Pneumol, Barcelona, Spain.
[Sibila, Oriol] Inst Invest Biomed St Pau, Barcelona, Spain.
[Menendez, Rosario] Hosp Univ La Fe, Serv Neumol, Valencia, Spain.
[Mensa, Josep] Hosp Clin Barcelona, Serv Malalties Infeccioses, E-08036 Barcelona, Spain.
[Restrepo, Marcos I.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA.
[Restrepo, Marcos I.; Anzueto, Antonio] South Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA.
[Restrepo, Marcos I.] VERDICT, San Antonio, TX USA.
[Niederman, Michael S.] Winthrop Univ Hosp, Mineola, NY 11501 USA.
RP Torres, A (reprint author), Hosp Clin Barcelona, Serv Pneumol, C Villarroel 170, E-08036 Barcelona, Spain.
EM atorres@ub.edu
RI Menendez, Rosario/G-9723-2016
OI Menendez, Rosario/0000-0002-3592-3839
FU Sociedad Espanola de Neumologia; Societat Catalana de Pneumologia;
Fundacio Catalana de Pneumologia; Grup de Recerca de Qualitat de la
Generalitat de Catalunya [SGR-2011]; Fondo de Investigacion Sanitaria
[PI030113]; Institut dInvestigacions Biomediques August Pi i Sunyer;
Centro de Investigacion Biomedica En Red-Enfermedades Respiratorias
[CB06/06/0028]
FX This study was supported by the Sociedad Espanola de Neumologia, the
Societat Catalana de Pneumologia, the Fundacio Catalana de Pneumologia,
the Grup de Recerca de Qualitat de la Generalitat de Catalunya (grant
SGR-2011), the Fondo de Investigacion Sanitaria (grant PI030113), the
Institut dInvestigacions Biomediques August Pi i Sunyer, and the Centro
de Investigacion Biomedica En Red-Enfermedades Respiratorias (grant
CB06/06/0028).
NR 37
TC 85
Z9 96
U1 2
U2 26
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 17
PY 2015
VL 313
IS 7
BP 677
EP 686
DI 10.1001/jama.2015.88
PG 10
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB2RQ
UT WOS:000349476100013
PM 25688779
ER
PT J
AU Youngster, I
Hohmann, EL
AF Youngster, Ilan
Hohmann, Elizabeth L.
TI Fecal Microbiota Transplantation for Clostridium difficile Infection
Reply
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Letter
C1 [Youngster, Ilan] Boston Childrens Hosp, Div Infect Dis, Boston, MA 02445 USA.
[Hohmann, Elizabeth L.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.
RP Youngster, I (reprint author), Boston Childrens Hosp, Div Infect Dis, 300 Longwood Ave, Boston, MA 02445 USA.
EM ilan.youngster@childrens.harvard.edu
NR 4
TC 1
Z9 1
U1 0
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 17
PY 2015
VL 313
IS 7
BP 726
EP 726
PG 1
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB2RQ
UT WOS:000349476100022
PM 25688788
ER
PT J
AU Bartona, JP
Kardar, M
Chakraborty, AK
AF Bartona, John P.
Kardar, Mehran
Chakraborty, Arup K.
TI Scaling laws describe memories of host-pathogen riposte in the HIV
population
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE HIV; fitness landscape; neural networks; evolution; host-pathogen
interaction
ID T-CELL RESPONSES; VIRAL LOAD; SET-POINT; FITNESS; EVOLUTIONARY;
INFLUENZA; STATES
AB The enormous genetic diversity and mutability of HIV has prevented effective control of this virus by natural immune responses or vaccination. Evolution of the circulating HIV population has thus occurred in response to diverse, ultimately ineffective, immune selection pressures that randomly change from host to host. We show that the interplay between the diversity of human immune responses and the ways that HIV mutates to evade them results in distinct sets of sequences defined by similar collectively coupled mutations. Scaling laws that relate these sets of sequences resemble those observed in linguistics and other branches of inquiry, and dynamics reminiscent of neural networks are observed. Like neural networks that store memories of past stimulation, the circulating HIV population stores memories of host-pathogen combat won by the virus. We describe an exactly solvable model that captures the main qualitative features of the sets of sequences and a simple mechanistic model for the origin of the observed scaling laws. Our results define collective mutational pathways used by HIV to evade human immune responses, which could guide vaccine design.
C1 [Bartona, John P.; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA.
[Bartona, John P.; Kardar, Mehran; Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA.
[Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA.
[Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA.
[Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA.
[Chakraborty, Arup K.] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA.
RP Kardar, M (reprint author), MIT, Dept Phys, Cambridge, MA 02139 USA.
EM kardar@mit.edu; arupc@mit.edu
OI Barton, John/0000-0003-1467-421X
FU Ragon Institute of Massachusetts General Hospital; Massachusetts
Institute of Technology; Harvard
FX We thank Karthik Shekhar for analyzing haplotype data and pointing out
power law scaling of haplotype frequencies. This research was funded by
the Ragon Institute of Massachusetts General Hospital, Massachusetts
Institute of Technology, and Harvard.
NR 28
TC 5
Z9 5
U1 0
U2 7
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 17
PY 2015
VL 112
IS 7
BP 1965
EP 1970
DI 10.1073/pnas.1415386112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB2GV
UT WOS:000349446000044
PM 25646424
ER
PT J
AU Gaglia, JL
Harisinghani, M
Aganj, I
Wojtkiewicz, GR
Hedgire, S
Benoist, C
Mathis, D
Weissleder, R
AF Gaglia, Jason L.
Harisinghani, Mukesh
Aganj, Iman
Wojtkiewicz, Gregory R.
Hedgire, Sandeep
Benoist, Christophe
Mathis, Diane
Weissleder, Ralph
TI Noninvasive mapping of pancreatic inflammation in recent-onset type-1
diabetes patients
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE autoimmune diabetes; magnetic resonance imaging; nanoparticle;
insulitis; pancreas
ID CHRONIC KIDNEY-DISEASE; SURFACE-BASED ANALYSIS; NOD MICE; INSULITIS;
AUTOANTIBODIES; FERUMOXYTOL; PREDICTION; DESTRUCTION; MACROPHAGES;
RELATIVES
AB The inability to visualize the initiation and progression of type-1 diabetes (T1D) noninvasively in humans is a major research and clinical stumbling block. We describe an advanced, exportable method for imaging the pancreatic inflammation underlying T1D, based on MRI of the clinically approved magnetic nanoparticle (MNP) ferumoxytol. The MNP-MRI approach, which reflects nanoparticle uptake by macrophages in the inflamed pancreatic lesion, has been validated extensively in mouse models of T1D and in a pilot human study. The methodological advances reported here were enabled by extensive optimization of image acquisition at 3T, as well as by the development of improved MRI registration and visualization technologies. A proof-of-principle study on patients recently diagnosed with T1D versus healthy controls yielded two major findings: First, there was a clear difference in whole-pancreas nanoparticle accumulation in patients and controls; second, the patients with T1D exhibited pronounced inter-and intrapancreatic heterogeneity in signal intensity. The ability to generate noninvasive, 3D, high-resolution maps of pancreatic inflammation in autoimmune diabetes should prove invaluable in assessing disease initiation and progression and as an indicator of response to emerging therapies.
C1 [Gaglia, Jason L.] Joslin Diabet Ctr, Boston, MA 02215 USA.
[Harisinghani, Mukesh; Wojtkiewicz, Gregory R.; Hedgire, Sandeep; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
[Harisinghani, Mukesh; Aganj, Iman; Wojtkiewicz, Gregory R.; Hedgire, Sandeep; Weissleder, Ralph] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA.
[Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA.
[Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.
[Benoist, Christophe; Mathis, Diane] Brigham & Womens Hosp, Boston, MA 02115 USA.
RP Mathis, D (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA.
EM dm@hms.harvard.edu; rweissleder@mgh.harvard.edu
OI Gaglia, Jason/0000-0003-2904-312X; Aganj, Iman/0000-0002-4673-1293
FU NIH [P01-AI-054904, R01-NS083534, U01-HL080731, P50-CA86355,
U54-CA119349, U24-CA092782, P30-DK036836, KL2-TR001100]
FX This work was supported by NIH Grant P01-AI-054904; NIH Grant
R01-NS083534 (to Bruce Fischl); NIH Grants U01-HL080731, P50-CA86355,
U54-CA119349, and U24-CA092782 (for technology development); NIH Grant
P30-DK036836; NIH Grant KL2-TR001100; and philanthropic donors to the
Joslin Clinical Research Center.
NR 37
TC 24
Z9 26
U1 2
U2 9
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 17
PY 2015
VL 112
IS 7
BP 2139
EP 2144
DI 10.1073/pnas.1424993112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB2GV
UT WOS:000349446000074
PM 25650428
ER
PT J
AU Keskin, DB
Reinhold, BB
Zhang, GL
Ivanov, AR
Karger, BL
Reinherz, EL
AF Keskin, Derin B.
Reinhold, Bruce B.
Zhang, Guang Lan
Ivanov, Alexander R.
Karger, Barry L.
Reinherz, Ellis L.
TI Physical detection of influenza A epitopes identifies a stealth subset
on human lung epithelium evading natural CD8 immunity
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE mass spectrometry; T-cell epitopes; influenza A viruses; antigen
presentation; T-cell avidity
ID VIRUS-INFECTION; VACCINE DESIGN; T-CELLS; PROTECTION; PEPTIDES;
HEMAGGLUTININ; IMMUNOLOGY; PREDICTION; CHALLENGE; RESPONSES
AB Vaccines eliciting immunity against influenza A viruses (IAVs) are currently antibody-based with hemagglutinin-directed antibody titer the only universally accepted immune correlate of protection. To investigate the disconnection between observed CD8 T-cell responses and immunity to IAV, we used a Poisson liquid chromatography data-independent acquisition MS method to physically detect PR8/34 (H1N1), X31 (H3N2), and Victoria/75 (H3N2) epitopes bound to HLA-A*02:01 on human epithelial cells following in vitro infection. Among 32 PR8 peptides (8-10mers) with predicted IC50 < 60 nM, 9 were present, whereas 23 were absent. At 18 h postinfection, epitope copies per cell varied from a low of 0.5 for M1(3-11) to a high of >500 for M1(58-66) with PA, HA, PB1, PB2, and NA epitopes also detected. However, aside from M1(58-66), natural CD8 memory responses against conserved presented epitopes were either absent or only weakly observed by blood Elispot. Moreover, the functional avidities of the immunodominant M1(58-66)/HLA-A*02:01-specific T cells were so poor as to be unable to effectively recognize infected human epithelium. Analysis of T-cell responses to primary PR8 infection in HLA-A*02:01 transgenic B6 mice underscores the poor avidity of T cells recognizing M1(58-66). By maintaining high levels of surface expression of this epitope on epithelial and dendritic cells, the virus exploits the combination of immunodominance and functional inadequacy to evade HLA-A*02:01-restricted T-cell immunity. A rational approach to CD8 vaccines must characterize processing and presentation of pathogen-derived epitopes as well as resultant immune responses. Correspondingly, vaccines may be directed against "stealth" epitopes, overriding viral chicanery.
C1 [Keskin, Derin B.; Reinhold, Bruce B.; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA.
[Keskin, Derin B.; Reinhold, Bruce B.; Zhang, Guang Lan; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA.
[Keskin, Derin B.; Reinhold, Bruce B.; Zhang, Guang Lan; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
[Zhang, Guang Lan] Boston Univ, Metropolitan Coll, Dept Comp Sci, Boston, MA 02115 USA.
[Ivanov, Alexander R.; Karger, Barry L.] Northeastern Univ, Barnett Inst, Boston, MA 02115 USA.
RP Reinherz, EL (reprint author), Harvard Univ, Sch Med, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA.
EM ellis_reinherz@dfci.harvard.edu
FU National Institutes of Health [UO1 AI90043]; Dana-Farber Cancer
Institute institutional funds
FX This work was supported by National Institutes of Health Grant UO1
AI90043 as well as Dana-Farber Cancer Institute institutional funds
provided to the Cancer Vaccine Center.
NR 33
TC 13
Z9 13
U1 0
U2 9
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 17
PY 2015
VL 112
IS 7
BP 2151
EP 2156
DI 10.1073/pnas.1423482112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB2GV
UT WOS:000349446000076
PM 25646416
ER
PT J
AU Yang, XQ
Lyer, AK
Singh, A
Choy, E
Hornicek, FJ
Amiji, MM
Duan, ZF
AF Yang, Xiaoqian
Lyer, Arun K.
Singh, Amit
Choy, Edwin
Hornicek, Francis J.
Amiji, Mansoor M.
Duan, Zhenfeng
TI MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle
systems circumvent paclitaxel resistance in ovarian cancer
SO SCIENTIFIC REPORTS
LA English
DT Article
ID SMALL INTERFERING RNA; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE;
DRUG-RESISTANCE; MOLECULAR-MECHANISMS; GENE-EXPRESSION; CELL-LINES;
ABCB1 MDR1; TRANSPORTERS; PROGRESSION
AB Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer.
C1 [Yang, Xiaoqian; Choy, Edwin; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA.
[Yang, Xiaoqian; Choy, Edwin; Hornicek, Francis J.; Duan, Zhenfeng] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Yang, Xiaoqian] Zhengzhou Univ, Affiliated Hosp 3, Dept Gynecol & Obstet, Zhengzhou 450052, Henan Province, Peoples R China.
[Lyer, Arun K.; Singh, Amit; Amiji, Mansoor M.] Northeastern Univ, Sch Pharm, Dept Pharmaceut Sci, Boston, MA 02114 USA.
RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA.
EM zduan@mgh.harvard.edu
FU NIH/NCI, Cancer Nanotechnology Platform Partnership (CNPP) [U01-
CA151452]; Gattegno and Wechsler funds; Sarcoma Foundation of America
(SFA); Sarcoma SPORE (NCI); China Scholarship Council
FX This study is supported by the NIH/NCI, Cancer Nanotechnology Platform
Partnership (CNPP) grants U01- CA151452. Partial financial support was
also provided by grants from the Gattegno and Wechsler funds. Z.D. is
supported, in part, through a grant from Sarcoma Foundation of America
(SFA), a developmental research award from Sarcoma SPORE (NCI). X.Y. is
supported by a scholarship from China Scholarship Council.
NR 58
TC 22
Z9 23
U1 18
U2 75
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 2015
VL 5
AR 8509
DI 10.1038/srep08509
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB2KO
UT WOS:000349456300005
PM 25687880
ER
PT J
AU Groarke, JD
Tanguturi, VK
Hainer, J
Klein, J
Moslehi, JJ
Ng, A
Forman, DE
Di Carli, MF
Nohria, A
AF Groarke, John D.
Tanguturi, Varsha K.
Hainer, Jon
Klein, Josh
Moslehi, Javid J.
Ng, Andrea
Forman, Daniel E.
Di Carli, Marcelo F.
Nohria, Anju
TI Abnormal Exercise Response in Long-Term Survivors of Hodgkin Lymphoma
Treated With Thoracic Irradiation
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Article
DE abnormal heart rate recovery; cardiac autonomic dysfunction; elevated
resting heart rate; Hodgkin lymphoma; radiation therapy; prognosis
ID HEART-RATE RECOVERY; VENTRICULAR SYSTOLIC DYSFUNCTION;
CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; CHRONOTROPIC
INCOMPETENCE; BAROREFLEX SENSITIVITY; EUROPEAN-ASSOCIATION; SUBMAXIMAL
EXERCISE; TREADMILL EXERCISE; AMERICAN-SOCIETY
AB BACKGROUND Hodgkin lymphoma (HL) survivors treated with thoracic radiation therapy (RT) have impaired exercise tolerance and increased cardiovascular mortality.
OBJECTIVES The purpose of this study was to evaluate the prevalence of autonomic dysfunction and its implications on exercise capacity and mortality in long-term survivors of HL.
METHODS Exercise parameters in 263 HL survivors referred for exercise treadmill testing at a median interval of 19 years after RT were compared with 526 age-, sex-, and cardiovascular risk score-matched control subjects. Within the RT cohort, the presence of autonomic dysfunction, defined by an elevated resting heart rate (HR) (>= 80 beats/min) and abnormal heart rate recovery (HRR) at 1 min (<= 12 beats/min if active cool-down, or <= 18 beats/min if passive recovery), was correlated with exercise capacity and all-cause mortality over a median follow-up of 3 years.
RESULTS RT was associated with elevated resting HR and abnormal HRR after adjusting for age, sex, cardiovascular risk factors, medications, and indication for exercise treadmill testing: odds ratio: 3.96 (95% confidence interval [CI]: 2.52 to 6.23) and odds ratio: 5.32 (95% CI: 2.94 to 9.65), respectively. Prevalence of autonomic dysfunction increased with radiation dose and time from RT. Both elevated resting HR and abnormal HRR were associated with reduced exercise capacity in RT patients. Abnormal HRR was also associated with increased all-cause mortality (age-adjusted hazard ratio: 4.60 [95% CI: 1.62 to 13.02]).
CONCLUSIONS Thoracic RT is associated with autonomic dysfunction, as measured by elevated resting HR and abnormal HRR. These abnormalities are associated with impaired exercise tolerance, and abnormal HRR predicts increased all-cause mortality in RT patients. (C) 2015 by the American College of Cardiology Foundation.
C1 [Groarke, John D.; Tanguturi, Varsha K.; Moslehi, Javid J.; Forman, Daniel E.; Di Carli, Marcelo F.; Nohria, Anju] Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, Boston, MA 02115 USA.
[Groarke, John D.; Hainer, Jon; Klein, Josh; Forman, Daniel E.; Di Carli, Marcelo F.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Noninvas Cardiovasc Imaging Program, Boston, MA 02115 USA.
[Groarke, John D.; Hainer, Jon; Klein, Josh; Forman, Daniel E.; Di Carli, Marcelo F.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA.
[Moslehi, Javid J.; Nohria, Anju] Dana Farber Canc Inst, Cardiooncol Program, Boston, MA 02115 USA.
[Moslehi, Javid J.; Ng, Andrea; Nohria, Anju] Brigham & Womens Hosp, Boston, MA 02115 USA.
[Ng, Andrea] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA.
RP Nohria, A (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA.
EM anohria@partners.org
NR 39
TC 9
Z9 9
U1 0
U2 1
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 17
PY 2015
VL 65
IS 6
BP 573
EP 583
DI 10.1016/j.jacc.2014.11.035
PG 11
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA CB1BN
UT WOS:000349361600009
PM 25677317
ER
PT J
AU Kosslyn, SM
AF Kosslyn, Stephen M.
TI Stephen M. Kosslyn
SO CURRENT BIOLOGY
LA English
DT Editorial Material
C1 Keck Grad Inst, Minerva Sch, San Francisco, CA 94103 USA.
[Kosslyn, Stephen M.] Stanford Univ, Ctr Adv Study Behav Sci, Stanford, CA 94305 USA.
[Kosslyn, Stephen M.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA.
[Kosslyn, Stephen M.] Harvard Univ, Cambridge, MA 02138 USA.
[Kosslyn, Stephen M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.
[Kosslyn, Stephen M.] Harvard Univ, Sch Business, Mind Market Lab, Cambridge, MA 02138 USA.
RP Kosslyn, SM (reprint author), Keck Grad Inst, Minerva Sch, San Francisco, CA 94103 USA.
EM skosslyn@minerva.kgi.edu
NR 0
TC 0
Z9 0
U1 0
U2 3
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 16
PY 2015
VL 25
IS 4
BP R134
EP R136
PG 4
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA CB1GT
UT WOS:000349375900002
PM 25844422
ER
PT J
AU Rothenberg, SM
Concannon, K
Cullen, S
Boulay, G
Turke, AB
Faber, AC
Lockerman, EL
Rivera, MN
Engelman, JA
Maheswaran, S
Haber, DA
AF Rothenberg, S. Michael
Concannon, Kyle
Cullen, Sarah
Boulay, Gaylor
Turke, Alexa B.
Faber, Anthony C.
Lockerman, Elizabeth L.
Rivera, Miguel N.
Engelman, Jeffrey A.
Maheswaran, Shyamala
Haber, Daniel A.
TI Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6
dependent survival pathways
SO ELIFE
LA English
DT Article
ID INTEGRATIVE GENOMICS VIEWER; EMBRYONIC STEM-CELLS; TRANSCRIPTION
FACTORS; FEEDBACK INHIBITION; INDUCED APOPTOSIS; GENE-MUTATIONS;
RESISTANCE; GROWTH; SOX2; SENSITIVITY
AB Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, ultimately decreasing the emergence of acquired resistance, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOX06, leading to its induction of SOX2, which in turn represses the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death associated with the withdrawal of growth factor signaling and may therefore contribute to the development of resistance.
C1 [Rothenberg, S. Michael; Concannon, Kyle; Cullen, Sarah; Boulay, Gaylor; Turke, Alexa B.; Faber, Anthony C.; Lockerman, Elizabeth L.; Rivera, Miguel N.; Engelman, Jeffrey A.; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA.
[Rothenberg, S. Michael; Engelman, Jeffrey A.; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02129 USA.
[Boulay, Gaylor; Rivera, Miguel N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA.
[Maheswaran, Shyamala] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02129 USA.
[Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
RP Haber, DA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA.
EM haber@helix.mgh.harvard.edu
FU NIH [RO1 CA207186]; HHMI; National Institute of Health/National
Institute of Dental & Craniofacial Research [K08DE020139]; Burroughs
Wellcome Fund
FX The authors wish to thank Doug Robinson (JMP Life Sciences) for help
with array analysis, Charles Vanderburg (MGH Department of Neurology)
for technical help and Matthew J. Niederst for providing patient-derived
cell lines. This work was supported by NIH RO1 CA207186 (D.A.H.), HHMI
(D.A.H., M.N.R.), National Institute of Health/National Institute of
Dental & Craniofacial Research K08DE020139 (S.M.R.) and the Burroughs
Wellcome Fund (M.N.R).
NR 58
TC 1
Z9 2
U1 1
U2 7
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 16
PY 2015
VL 4
AR e06132
DI 10.7554/eLife.06132
PG 64
WC Biology
SC Life Sciences & Biomedicine - Other Topics
GA CB2MR
UT WOS:000349462300003
ER
PT J
AU Golberg, A
Bruinsma, BG
Uygun, BE
Yarmush, ML
AF Golberg, Alexander
Bruinsma, Bote G.
Uygun, Basak E.
Yarmush, Martin L.
TI Tissue heterogeneity in structure and conductivity contribute to cell
survival during irreversible electroporation ablation by "electric field
sinks''
SO SCIENTIFIC REPORTS
LA English
DT Article
ID HEPATOCELLULAR-CARCINOMA; SAFETY; BACTERIA; TUMORS
AB Irreversible electroporation (IRE) is an emerging, minimally invasive technique for solid tumors ablation, under clinical investigation for cancer therapy. IRE affects only the cell membrane, killing cells while preserving the extracellular matrix structure. Current reports indicate tumors recurrence rate after IRE averaging 31% of the cases, of which 10% are local recurrences. The mechanisms for these recurrences are not known and new explanations for incomplete cell death are needed. Using finite elements method for electric field distribution, we show that presence of vascular structures with blood leads to the redistribution of electric fields leading to the areas with more than 60% reduced electric field strength in proximity to large blood vessels and clustered vessel structures. In an in vivo rat model of liver IRE ablation, we show that cells located in the proximity of larger vessel structures and in proximity of clustered vessel structures appear less affected by IRE ablation than cells in the tissue parenchyma or in the proximity of small, more isolated vessels. These findings suggest a role for "electric field sinks'' in local tumors recurrences after IRE and emphasize the importance of the precise mapping of the targeted organ structure and conductivity for planning of electroporation procedures.
C1 [Golberg, Alexander; Bruinsma, Bote G.; Uygun, Basak E.; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Ctr Engn Med, Boston, MA 02114 USA.
[Golberg, Alexander; Bruinsma, Bote G.; Uygun, Basak E.; Yarmush, Martin L.] Shriners Burns Hosp, Boston, MA 02114 USA.
[Golberg, Alexander] Tel Aviv Univ, Porter Sch Environm Studies, IL-6997801 Tel Aviv, Israel.
[Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA.
RP Yarmush, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Ctr Engn Med, Boston, MA 02114 USA.
EM ireis@sbi.org
FU Shriners Grant [85120-BOS]; NCI Cancer Center [NIH 5 P30 CA06516]
FX We acknowledge Shriners Grant #85120-BOS for the support of this study.
We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of
the Rodent Histopathology Core, which provided histopathology service.
Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer
Center Support Grant # NIH 5 P30 CA06516.
NR 33
TC 18
Z9 19
U1 4
U2 13
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 16
PY 2015
VL 5
AR 8485
DI 10.1038/srep08485
PG 7
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB1AQ
UT WOS:000349359200001
PM 25684630
ER
PT J
AU Albacker, LA
Kohler, R
Weissleder, R
Sorger, PK
AF Albacker, Lee A.
Kohler, Rainer
Weissleder, Ralph
Sorger, Peter K.
TI The strength of drug selection determines the maximum fitness cost of
resistance mutations in culture and xenografts
SO CLINICAL CANCER RESEARCH
LA English
DT Meeting Abstract
CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance -
Improving Cancer Therapy
CY JUN 18-21, 2014
CL Orlando, FL
SP Amer Assoc Canc Res
C1 [Albacker, Lee A.; Sorger, Peter K.] Harvard Univ, Sch Med, Boston, MA USA.
[Kohler, Rainer; Weissleder, Ralph] Massachusetts Gen Hosp, Boston, MA 02114 USA.
NR 0
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 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
SU 4
MA PR07
DI 10.1158/1557-3265.PMS14-PR07
PG 2
WC Oncology
SC Oncology
GA CR5LZ
UT WOS:000361385600098
ER
PT J
AU Albacker, LA
Kohler, R
Weissleder, R
Sorger, PK
AF Albacker, Lee A.
Kohler, Rainer
Weissleder, Ralph
Sorger, Peter K.
TI The strength of drug selection determines the maximum fitness cost of
resistance mutations in culture and xenografts
SO CLINICAL CANCER RESEARCH
LA English
DT Meeting Abstract
CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance -
Improving Cancer Therapy
CY JUN 18-21, 2014
CL Orlando, FL
SP Amer Assoc Canc Res
C1 [Albacker, Lee A.; Sorger, Peter K.] Harvard Univ, Sch Med, Boston, MA USA.
[Kohler, Rainer; Weissleder, Ralph] Massachusetts Gen Hosp, Boston, MA 02114 USA.
NR 0
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 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
SU 4
MA B35
DI 10.1158/1557-3265.PMS14-B35
PG 1
WC Oncology
SC Oncology
GA CR5LZ
UT WOS:000361385600063
ER
PT J
AU Chen, L
Dastur, A
Yin, XQ
Benes, C
AF Chen, Li
Dastur, Anahita
Yin, Xunqin
Benes, Cyril
TI Transposon mutagenesis screen identifies genes conferring resistance to
BRAF inhibition in melanoma
SO CLINICAL CANCER RESEARCH
LA English
DT Meeting Abstract
CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance -
Improving Cancer Therapy
CY JUN 18-21, 2014
CL Orlando, FL
SP Amer Assoc Canc Res
C1 [Chen, Li; Dastur, Anahita; Yin, Xunqin; Benes, Cyril] Massachusetts Gen Hosp, Charlestown, MA USA.
NR 0
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 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
SU 4
MA A27
DI 10.1158/1557-3265.PMS14-A27
PG 1
WC Oncology
SC Oncology
GA CR5LZ
UT WOS:000361385600021
ER
PT J
AU Goetz, EM
Ghandi, M
Treacy, D
Wagle, N
Garraway, LA
AF Goetz, Eva M.
Ghandi, Mahmoud
Treacy, Daniel
Wagle, Nikhil
Garraway, Levi A.
TI Identification of ERK1/2 mutations that confer resistance to MAPK
pathway inhibitors
SO CLINICAL CANCER RESEARCH
LA English
DT Meeting Abstract
CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance -
Improving Cancer Therapy
CY JUN 18-21, 2014
CL Orlando, FL
SP Amer Assoc Canc Res
C1 [Goetz, Eva M.; Treacy, Daniel; Garraway, Levi A.] Dana Farber Canc Inst, Boston, MA 02115 USA.
[Ghandi, Mahmoud; Wagle, Nikhil] Broad Inst, Cambridge, MA USA.
NR 0
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 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
SU 4
MA PR02
DI 10.1158/1557-3265.PMS14-PR02
PG 1
WC Oncology
SC Oncology
GA CR5LZ
UT WOS:000361385600093
ER
PT J
AU Johannessen, C
Konieczkowski, D
Abudayyeh, O
Kim, JW
Cooper, Z
Piris, A
Frederick, D
Barzily-Rokni, M
Straussman, R
Haq, R
Fisher, D
Mesirov, J
Hahn, W
Flaherty, K
Wargo, J
Tamayo, P
Garraway, L
AF Johannessen, Cory
Konieczkowski, David
Abudayyeh, Omar
Kim, Jong Wook
Cooper, Zachary
Piris, Adriano
Frederick, Dennie
Barzily-Rokni, Michal
Straussman, Ravid
Haq, Rizwan
Fisher, David
Mesirov, Jill
Hahn, William
Flaherty, Keith
Wargo, Jennifer
Tamayo, Pablo
Garraway, Levi
TI A melanoma transcriptional state distinction influences sensitivity to
MAPK pathway inhibitors
SO CLINICAL CANCER RESEARCH
LA English
DT Meeting Abstract
CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance -
Improving Cancer Therapy
CY JUN 18-21, 2014
CL Orlando, FL
SP Amer Assoc Canc Res
C1 [Johannessen, Cory; Konieczkowski, David; Abudayyeh, Omar; Kim, Jong Wook; Barzily-Rokni, Michal; Mesirov, Jill; Hahn, William; Tamayo, Pablo; Garraway, Levi] Broad Inst Harvard & MIT, Cambridge, MA USA.
[Cooper, Zachary; Wargo, Jennifer] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
[Piris, Adriano; Frederick, Dennie; Haq, Rizwan; Fisher, David; Flaherty, Keith] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Straussman, Ravid] Weizmann Inst Sci, IL-76100 Rehovot, Israel.
NR 0
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 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
SU 4
MA PR04
DI 10.1158/1557-3265.PMS14-PR04
PG 1
WC Oncology
SC Oncology
GA CR5LZ
UT WOS:000361385600095
ER
PT J
AU Kwong, LN
Boland, G
Frederick, DT
Helms, T
Miller, JP
Jiang, S
Cooper, ZA
Protopopov, A
Mills, GB
Flaherty, K
Wargo, JA
Chin, L
AF Kwong, Lawrence N.
Boland, Genevieve
Frederick, Dennie T.
Helms, Timothy
Miller, John P.
Jiang, Shan
Cooper, Zachary A.
Protopopov, Alexei
Mills, Gordon B.
Flaherty, Keith
Wargo, Jennifer A.
Chin, Lynda
TI A co-clinical assessment of patterns of BRAF inhibitor resistance
SO CLINICAL CANCER RESEARCH
LA English
DT Meeting Abstract
CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance -
Improving Cancer Therapy
CY JUN 18-21, 2014
CL Orlando, FL
SP Amer Assoc Canc Res
C1 [Kwong, Lawrence N.; Boland, Genevieve; Helms, Timothy; Miller, John P.; Jiang, Shan; Cooper, Zachary A.; Protopopov, Alexei; Mills, Gordon B.; Wargo, Jennifer A.; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
[Frederick, Dennie T.; Flaherty, Keith] Massachusetts Gen Hosp, Boston, MA 02114 USA.
NR 0
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 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
SU 4
MA PR06
DI 10.1158/1557-3265.PMS14-PR06
PG 1
WC Oncology
SC Oncology
GA CR5LZ
UT WOS:000361385600097
ER
PT J
AU Stroebel, T
Madlener, S
Tuna, S
Vose, S
Morse, D
Tannous, BA
Lagerweij, T
Wurdinger, T
Marosi, C
Slavc, I
Vierlinger, K
Saydam, O
Price, BD
Demple, B
Saydam, N
AF Stroebel, Thomas
Madlener, Sibylle
Tuna, Serkan
Vose, Sarah
Morse, Daniella
Tannous, Bakhos A.
Lagerweij, Tonny
Wurdinger, Thomas
Marosi, Christine
Slavc, Irene
Vierlinger, Klemens
Saydam, Okay
Price, Brendan D.
Demple, Bruce
Saydam, Nurten
TI Ape1/Ref-1 directs DNA repair pathway choice, linked to Chk2 signaling,
critical for glioblastoma response to chemotherapy
SO CLINICAL CANCER RESEARCH
LA English
DT Meeting Abstract
CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance -
Improving Cancer Therapy
CY JUN 18-21, 2014
CL Orlando, FL
SP Amer Assoc Canc Res
C1 [Stroebel, Thomas; Madlener, Sibylle; Tuna, Serkan; Marosi, Christine; Slavc, Irene; Saydam, Okay; Saydam, Nurten] Med Univ Vienna, Vienna, Austria.
[Vose, Sarah] Vermont Dept Publ Hlth, Burlington, VT USA.
[Morse, Daniella; Tannous, Bakhos A.] Harvard Univ, Sch Med, Boston, MA USA.
[Lagerweij, Tonny; Wurdinger, Thomas] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
[Vierlinger, Klemens] Austrian Inst Technol, Vienna, Austria.
[Price, Brendan D.] Dana Farber Canc Inst, Boston, MA 02115 USA.
[Demple, Bruce] SUNY Stony Brook, Stony Brook, NY 11794 USA.
NR 0
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 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
SU 4
MA B26
DI 10.1158/1557-3265.PMS14-B26
PG 1
WC Oncology
SC Oncology
GA CR5LZ
UT WOS:000361385600059
ER
PT J
AU Wong, TC
Johannessen, CM
Garraway, LA
AF Wong, Terence C.
Johannessen, Cory M.
Garraway, Levi A.
TI Integration of genome-wide datasets identifies SOX10 as a
lineage-specific genetic dependency in melanoma
SO CLINICAL CANCER RESEARCH
LA English
DT Meeting Abstract
CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance -
Improving Cancer Therapy
CY JUN 18-21, 2014
CL Orlando, FL
SP Amer Assoc Canc Res
C1 [Wong, Terence C.; Johannessen, Cory M.] Broad Inst MIT & Harvard, Cambridge, MA USA.
[Garraway, Levi A.] Dana Farber Canc Inst, Boston, MA 02115 USA.
NR 0
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 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
SU 4
MA B33
DI 10.1158/1557-3265.PMS14-B33
PG 1
WC Oncology
SC Oncology
GA CR5LZ
UT WOS:000361385600062
ER
PT J
AU Wasfy, JH
Armstrong, K
Milford, CE
Sundt, TM
AF Wasfy, Jason H.
Armstrong, Katrina
Milford, Creagh E.
Sundt, Thoralf M.
TI Bicuspid aortic disease and decision making under uncertainty - The
limitations of clinical guidelines
SO INTERNATIONAL JOURNAL OF CARDIOLOGY
LA English
DT Editorial Material
DE Clinical decision making; Aortic aneurysm; Aortic valvular disease
ID DRUG-ELUTING STENTS; PERCUTANEOUS CORONARY INTERVENTION; ST-SEGMENT
ELEVATION; MANAGEMENT; SOCIETY; MODEL
C1 [Wasfy, Jason H.; Milford, Creagh E.] Harvard Univ, Sch Med, Massachusetts Gen Phys Org, Boston, MA USA.
[Wasfy, Jason H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA.
[Armstrong, Katrina; Milford, Creagh E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA.
[Sundt, Thoralf M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Surg Div,Dept Surg, Boston, MA USA.
RP Wasfy, JH (reprint author), Massachusetts Gen Hosp, Massachusetts Gen Phys Org, BUL 205,55 Fruit St, Boston, MA 02114 USA.
EM jwasfy@mgh.harvard.edu
NR 16
TC 2
Z9 2
U1 0
U2 0
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
IRELAND
SN 0167-5273
EI 1874-1754
J9 INT J CARDIOL
JI Int. J. Cardiol.
PD FEB 15
PY 2015
VL 181
BP 169
EP 171
DI 10.1016/j.ijcard.2014.12.020
PG 3
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA CE6DK
UT WOS:000351926500046
PM 25514508
ER
PT J
AU Cho, JL
Medoff, BD
AF Cho, Josalyn L.
Medoff, Benjamin D.
TI Lung T Cells in HIV Infection Driven to Exhaustion?
SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
LA English
DT Editorial Material
ID PATHOGENESIS; IMMUNOLOGY; ALVEOLITIS; DISEASE
C1 [Cho, Josalyn L.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA.
Harvard Univ, Sch Med, Boston, MA USA.
Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA.
RP Cho, JL (reprint author), Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA.
NR 16
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 FEB 15
PY 2015
VL 191
IS 4
BP 370
EP 371
PG 2
WC Critical Care Medicine; Respiratory System
SC General & Internal Medicine; Respiratory System
GA CC0GT
UT WOS:000350014500005
PM 25679103
ER
PT J
AU van der Valk, RJP
Kreiner-Moller, E
Kooijman, MN
Guxens, M
Stergiakouli, E
Saaf, A
Bradfield, JP
Geller, F
Hayes, MG
Cousminer, DL
Korner, A
Thiering, E
Curtin, JA
Myhre, R
Huikari, V
Joro, R
Kerkhof, M
Warrington, NM
Pitkanen, N
Ntalla, I
Horikoshi, M
Veijola, R
Freathy, RM
Teo, YY
Barton, SJ
Evans, DM
Kemp, JP
St Pourcain, B
Ring, SM
Smith, GD
Bergstrom, A
Kull, I
Hakonarson, H
Mentch, FD
Bisgaard, H
Chawes, B
Stokholm, J
Waage, J
Eriksen, P
Sevelsted, A
Melbye, M
van Duijn, CM
Medina-Gomez, C
Hofman, A
de Jongste, JC
Taal, HR
Uitterlinden, AG
Armstrong, LL
Eriksson, J
Palotie, A
Bustamante, M
Estivill, X
Gonzalez, JR
Llop, S
Kiess, W
Mahajan, A
Flexeder, C
Tiesler, CMT
Murray, CS
Simpson, A
Magnus, P
Sengpiel, V
Hartikainen, AL
Keinanen-Kiukaanniemi, S
Lewin, A
Alves, ADC
Blakemore, AI
Buxton, JL
Kaakinen, M
Rodriguez, A
Sebert, S
Vaarasmaki, M
Lakka, T
Lindi, V
Gehring, U
Postma, DS
Ang, W
Newnham, JP
Lyytikainen, LP
Pahkala, K
Raitakari, OT
Panoutsopoulou, K
Zeggini, E
Boomsma, DI
Groen-Blokhuis, M
Ilonen, J
Franke, L
Hirschhorn, JN
Pers, TH
Liang, L
Huang, J
Hocher, B
Knip, M
Saw, SM
Holloway, JW
Melen, E
Grant, SFA
Feenstra, B
Lowe, WL
Widen, E
Sergeyev, E
Grallert, H
Custovic, A
Jacobsson, B
Jarvelin, MR
Atalay, M
Koppelman, GH
Pennell, CE
Niinikoski, H
Dedoussis, GV
Mccarthy, MI
Frayling, TM
Sunyer, J
Timpson, NJ
Rivadeneira, F
Bonnelykke, K
Jaddoe, VWV
AF van der Valk, Ralf J. P.
Kreiner-Moller, Eskil
Kooijman, Marjolein N.
Guxens, Monica
Stergiakouli, Evangelia
Saaf, Annika
Bradfield, Jonathan P.
Geller, Frank
Hayes, M. Geoffrey
Cousminer, Diana L.
Koerner, Antje
Thiering, Elisabeth
Curtin, John A.
Myhre, Ronny
Huikari, Ville
Joro, Raimo
Kerkhof, Marjan
Warrington, Nicole M.
Pitkanen, Niina
Ntalla, Ioanna
Horikoshi, Momoko
Veijola, Riitta
Freathy, Rachel M.
Teo, Yik-Ying
Barton, Sheila J.
Evans, David M.
Kemp, John P.
St Pourcain, Beate
Ring, Susan M.
Smith, George Davey
Bergstrom, Anna
Kull, Inger
Hakonarson, Hakon
Mentch, Frank D.
Bisgaard, Hans
Chawes, Bo
Stokholm, Jakob
Waage, Johannes
Eriksen, Patrick
Sevelsted, Astrid
Melbye, Mads
van Duijn, Cornelia M.
Medina-Gomez, Carolina
Hofman, Albert
de Jongste, Johan C.
Taal, H. Rob
Uitterlinden, Andre G.
Armstrong, Loren L.
Eriksson, Johan
Palotie, Aarno
Bustamante, Mariona
Estivill, Xavier
Gonzalez, Juan R.
Llop, Sabrina
Kiess, Wieland
Mahajan, Anubha
Flexeder, Claudia
Tiesler, Carla M. T.
Murray, Clare S.
Simpson, Angela
Magnus, Per
Sengpiel, Verena
Hartikainen, Anna-Liisa
Keinanen-Kiukaanniemi, Sirkka
Lewin, Alexandra
Alves, Alexessander Da Silva Couto
Blakemore, Alexandra I.
Buxton, Jessica L.
Kaakinen, Marika
Rodriguez, Alina
Sebert, Sylvain
Vaarasmaki, Marja
Lakka, Timo
Lindi, Virpi
Gehring, Ulrike
Postma, Dirkje S.
Ang, Wei
Newnham, John P.
Lyytikainen, Leo-Pekka
Pahkala, Katja
Raitakari, Olli T.
Panoutsopoulou, Kalliope
Zeggini, Eleftheria
Boomsma, Dorret I.
Groen-Blokhuis, Maria
Ilonen, Jorma
Franke, Lude
Hirschhorn, Joel N.
Pers, Tune H.
Liang, Liming
Huang, Jinyan
Hocher, Berthold
Knip, Mikael
Saw, Seang-Mei
Holloway, John W.
Melen, Erik
Grant, Struan F. A.
Feenstra, Bjarke
Lowe, William L.
Widen, Elisabeth
Sergeyev, Elena
Grallert, Harald
Custovic, Adnan
Jacobsson, Bo
Jarvelin, Marjo-Riitta
Atalay, Mustafa
Koppelman, Gerard H.
Pennell, Craig E.
Niinikoski, Harri
Dedoussis, George V.
Mccarthy, Mark I.
Frayling, Timothy M.
Sunyer, Jordi
Timpson, Nicholas J.
Rivadeneira, Fernando
Bonnelykke, Klaus
Jaddoe, Vincent W. V.
CA Early Genetics Lifecourse
Genetic Invest ANthropometric
Early Growth Genetics EGG
TI A novel common variant in DCST2 is associated with length in early life
and height in adulthood
SO HUMAN MOLECULAR GENETICS
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; LOW-BIRTH-WEIGHT; DC-STAMP; GLUCOCEREBROSIDASE
MUTATIONS; GROWTH-RETARDATION; IMPUTED DATA; DISEASE; LOCI; GENE; TOOL
AB Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
C1 [van der Valk, Ralf J. P.; Kooijman, Marjolein N.; van Duijn, Cornelia M.; Medina-Gomez, Carolina; Hofman, Albert; Taal, H. Rob; Uitterlinden, Andre G.; Rivadeneira, Fernando; Jaddoe, Vincent W. V.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
[van der Valk, Ralf J. P.; Kooijman, Marjolein N.; de Jongste, Johan C.; Taal, H. Rob; Jaddoe, Vincent W. V.] Erasmus MC, Dept Paediat, Rotterdam, Netherlands.
[van der Valk, Ralf J. P.; Kooijman, Marjolein N.; Medina-Gomez, Carolina; Hofman, Albert; de Jongste, Johan C.; Uitterlinden, Andre G.; Rivadeneira, Fernando; Jaddoe, Vincent W. V.] Erasmus MC, Generat Study Grp R, Rotterdam, Netherlands.
[Medina-Gomez, Carolina; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
[Kreiner-Moller, Eskil; Bisgaard, Hans; Chawes, Bo; Stokholm, Jakob; Waage, Johannes; Eriksen, Patrick; Sevelsted, Astrid; Bonnelykke, Klaus] Univ Copenhagen, Copenhagen Prospect Studies Asthma Childhood, Fac Hlth Sci, Gentofte, Denmark.
[Kreiner-Moller, Eskil; Bisgaard, Hans; Chawes, Bo; Stokholm, Jakob; Waage, Johannes; Eriksen, Patrick; Sevelsted, Astrid; Bonnelykke, Klaus] Copenhagen Univ Hosp, Danish Pediat Asthma Ctr, Gentofte, Denmark.
[Guxens, Monica; Bustamante, Mariona; Gonzalez, Juan R.; Sunyer, Jordi] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain.
[Guxens, Monica; Bustamante, Mariona; Estivill, Xavier; Gonzalez, Juan R.; Llop, Sabrina; Sunyer, Jordi] CIBERESP, Madrid, Spain.
[Guxens, Monica; Bustamante, Mariona; Estivill, Xavier; Gonzalez, Juan R.; Sunyer, Jordi] UPF, Barcelona, Catalonia, Spain.
[Stergiakouli, Evangelia; Evans, David M.; Kemp, John P.; St Pourcain, Beate; Ring, Susan M.; Smith, George Davey; Timpson, Nicholas J.] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
[St Pourcain, Beate; Ring, Susan M.] Univ Bristol, ALSPAC, Sch Social & Community Med, Bristol, Avon, England.
[St Pourcain, Beate] Univ Bristol, Sch Oral & Dent Sci, Bristol, Avon, England.
[Saaf, Annika; Bergstrom, Anna; Melen, Erik] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden.
[Bradfield, Jonathan P.; Hakonarson, Hakon; Mentch, Frank D.; Grant, Struan F. A.] Childrens Hosp Philadelphia, Ctr Appl Genom, Abramson Res Ctr, Philadelphia, PA 19104 USA.
[Hakonarson, Hakon; Grant, Struan F. A.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA.
[Geller, Frank; Melbye, Mads; Feenstra, Bjarke] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark.
[Hayes, M. Geoffrey; Armstrong, Loren L.; Lowe, William L.] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA.
[Hayes, M. Geoffrey; Armstrong, Loren L.; Lowe, William L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA.
[Cousminer, Diana L.; Eriksson, Johan; Palotie, Aarno; Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.
[Knip, Mikael] Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland.
[Koerner, Antje; Kiess, Wieland; Sergeyev, Elena] Univ Leipzig, Univ Hosp Ctr Leipzig, Ctr Pediat Res, D-04109 Leipzig, Germany.
[Thiering, Elisabeth; Tiesler, Carla M. T.] Univ Munich, Div Metab & Nutr Med, Dr von Hauner Childrens Hosp, Med Ctr, Munich, Germany.
[Thiering, Elisabeth; Flexeder, Claudia; Tiesler, Carla M. T.] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany.
[Grallert, Harald] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.
[Grallert, Harald] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.
[Curtin, John A.; Murray, Clare S.; Simpson, Angela; Custovic, Adnan] Univ Manchester, Inst Inflammat & Repair, Ctr Resp Med & Allergy, Manchester, Lancs, England.
[Curtin, John A.; Murray, Clare S.; Simpson, Angela; Custovic, Adnan] Univ S Manchester Hosp, Manchester Acad Hlth Sci Ctr, Manchester M20 8LR, Lancs, England.
[Myhre, Ronny; Jacobsson, Bo] Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, Oslo, Norway.
[Magnus, Per] Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway.
[Huikari, Ville; Keinanen-Kiukaanniemi, Sirkka; Kaakinen, Marika; Sebert, Sylvain; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland.
[Hartikainen, Anna-Liisa] Univ Oulu, Inst Clin Med Obstet & Gynecol, Oulu, Finland.
[Kaakinen, Marika; Jarvelin, Marjo-Riitta] Univ Oulu, Biocenter Oulu, Oulu, Finland.
[Joro, Raimo; Lakka, Timo; Lindi, Virpi; Atalay, Mustafa] Univ Eastern Finland, Inst Biomed, Physiol, Kuopio, Finland.
[Ilonen, Jorma] Univ Eastern Finland, Dept Clin Microbiol, Kuopio, Finland.
[Kerkhof, Marjan] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.
[Kerkhof, Marjan; Postma, Dirkje S.; Koppelman, Gerard H.] Univ Groningen, Univ Med Ctr Groningen, Groningen Res Inst Asthma & COPD, Groningen, Netherlands.
[Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands.
[Koppelman, Gerard H.] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Pediat Pulmonol & Pediat Allergy, Groningen, Netherlands.
[Warrington, Nicole M.; Ang, Wei; Newnham, John P.; Pennell, Craig E.] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia.
[Warrington, Nicole M.; Evans, David M.; Kemp, John P.; Pahkala, Katja] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia.
[Pitkanen, Niina; Pahkala, Katja; Raitakari, Olli T.; Niinikoski, Harri] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
[Ilonen, Jorma] Univ Turku, Immunogenet Lab, Turku, Finland.
[Ntalla, Ioanna] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England.
[Ntalla, Ioanna; Dedoussis, George V.] Harokopio Univ Athens, Dept Nutr & Dietet, Athens 11527, Greece.
[Horikoshi, Momoko; Mahajan, Anubha; Mccarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
[Horikoshi, Momoko; Mccarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Oxford OX3 7LJ, England.
[Veijola, Riitta] Oulu Univ Hosp, Dept Pediat, Med Res Ctr, Oulu, Finland.
[Vaarasmaki, Marja] Oulu Univ Hosp, Dept Obstet & Gynecol, Oulu, Finland.
[Vaarasmaki, Marja] Oulu Univ Hosp, MRC Oulu, Oulu, Finland.
[Vaarasmaki, Marja] Univ Oulu, Oulu, Finland.
[Freathy, Rachel M.; Frayling, Timothy M.] Univ Exeter, Sch Med, Royal Devon & Exeter Hosp, Exeter EX2 5DW, Devon, England.
[Teo, Yik-Ying; Saw, Seang-Mei] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore.
[Teo, Yik-Ying] Natl Univ Singapore, Inst Life Sci, Singapore 117548, Singapore.
[Teo, Yik-Ying] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore.
[Barton, Sheila J.] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO9 5NH, Hants, England.
[Holloway, John W.] Univ Southampton, Human Genet & Genom Med, Human Dev & Hlth, Fac Med, Southampton SO9 5NH, Hants, England.
[Kull, Inger] Soder Sjukhuset, Dept Clin Sci & Educ, S-10064 Stockholm, Sweden.
[Kull, Inger; Melen, Erik] Karolinska Inst, Sachs Childrens Hosp, Stockholm, Sweden.
[Hakonarson, Hakon; Grant, Struan F. A.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA.
[Melbye, Mads] Stanford Sch Med, Dept Med, Stanford, CA USA.
[Palotie, Aarno] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
[Palotie, Aarno] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.
[Palotie, Aarno] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
[Hirschhorn, Joel N.; Pers, Tune H.] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA.
[Bustamante, Mariona; Estivill, Xavier] CRG, Barcelona, Spain.
[Estivill, Xavier; Sunyer, Jordi] IMIM Hosp del Mar Med Res Inst, Barcelona, Spain.
[Llop, Sabrina] FISABIO Publ Hlth, Fdn Promot Hlth & Biomed Res Valencian Reg, Valencia, Spain.
[Sengpiel, Verena; Jacobsson, Bo] Sahlgrens Univ Hosp, Sahlgrenska Acad, Dept Obstet & Gynecol, Gothenburg, Sweden.
[Lewin, Alexandra; Alves, Alexessander Da Silva Couto; Kaakinen, Marika; Rodriguez, Alina; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, MRC Hlth Protect Agcy HPE,Ctr Environm & Hlth, London W12 0NN, England.
[Blakemore, Alexandra I.; Buxton, Jessica L.] Univ London Imperial Coll Sci Technol & Med, Sect Investigat Med, Div Diabet Endocrinol & Metab, Fac Med, London W12 0NN, England.
[Rodriguez, Alina] Mid Sweden Univ, Dept Psychol, Ostersund, Sweden.
[Lakka, Timo] Kuopio Res Inst Exercise Med, Kuopio, Finland.
[Lakka, Timo] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland.
[Gehring, Ulrike] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands.
[Lyytikainen, Leo-Pekka] Fimlab Labs, Dept Clin Chem, Tampere, Finland.
[Lyytikainen, Leo-Pekka] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland.
Paavo Nurmi Ctr, Sports & Exercise Med Unit, Dept Phys Act & Hlth, Turku, Finland.
[Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland.
[Niinikoski, Harri] Turku Univ Hosp, Dept Pediat, FIN-20520 Turku, Finland.
[Panoutsopoulou, Kalliope; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Hinxton CB10 1HH, Cambs, England.
[Boomsma, Dorret I.; Groen-Blokhuis, Maria] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.
[Boomsma, Dorret I.; Groen-Blokhuis, Maria] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.
[Boomsma, Dorret I.; Groen-Blokhuis, Maria] Neurosci Campus Amsterdam, Amsterdam, Netherlands.
[Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
[Hirschhorn, Joel N.; Pers, Tune H.] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.
[Hirschhorn, Joel N.; Pers, Tune H.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.
[Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA.
[Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, Lyngby, Denmark.
Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02115 USA.
[Huang, Jinyan] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, Shanghai Inst Hematol, Shanghai 200030, Peoples R China.
[Hocher, Berthold] Univ Potsdam, Inst Nutr Sci, Potsdam, Germany.
[Hocher, Berthold] Jinan Univ, Affiliated Hosp 1, Guangzhou 510630, Guangdong, Peoples R China.
[Hocher, Berthold] Charite, Inst Pharmacol, Cardiovasc Res Ctr, Berlin, Germany.
[Liang, Liming; Huang, Jinyan; Knip, Mikael] Tampere Univ Hosp, Dept Pediat, Tampere, Finland.
[Knip, Mikael] Univ Helsinki, Childrens Hosp, Helsinki, Finland.
[Knip, Mikael] Univ Helsinki, Cent Hosp, Helsinki, Finland.
[Saw, Seang-Mei] Singapore Eye Res Inst, Singapore, Singapore.
[Saw, Seang-Mei] Duke NUS Grad Med Sch, Singapore, Singapore.
[Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, FI-90220 Oulu 90029, OYS, Finland.
[Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children & Young People & Families, FI-90101 Oulu, Finland.
[Mccarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England.
RP Jaddoe, VWV (reprint author), Sophias Childrens Hosp, Erasmus Med Ctr, Dept Epidemiol, Generat Study Grp R, Postbus 2060, NL-3000 CB Rotterdam, Netherlands.
EM v.jaddoe@erasmusmc.nl
RI Franke, Lude/P-7036-2016; Bisgaard, Hans/N-4761-2016; Davey Smith,
George/A-7407-2013; Sunyer, J/G-6909-2014; Rivadeneira,
Fernando/O-5385-2015; Lyytikainen, Leo-Pekka/C-8544-2016; Estivill,
Xavier/A-3125-2013; Custovic, Adnan/A-2435-2012; Korner,
Antje/B-3988-2015; Holloway, John/B-5424-2009; Warrington,
Nicole/P-4868-2014; Grallert, Harald/B-3424-2013; Pahkala,
Katja/D-7449-2013; Llop, Sabrina/L-2122-2015; Bustamante,
Mariona/M-7277-2015
OI Lakka, Timo/0000-0002-9199-2871; Zeggini,
Eleftheria/0000-0003-4238-659X; Kreiner, Eskil/0000-0003-1204-2438;
Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Medina-Gomez,
Carolina/0000-0001-7999-5538; Kull, Inger/0000-0001-6096-3771; Eriksson,
Johan/0000-0002-2516-2060; Kemp, John/0000-0002-9105-2249; Evans,
David/0000-0003-0663-4621; Stergiakouli, Evangelia/0000-0003-3586-0927;
Newnham, John/0000-0001-9983-7457; Franke, Lude/0000-0002-5159-8802;
Bisgaard, Hans/0000-0003-4131-7592; Davey Smith,
George/0000-0002-1407-8314; Sunyer, J/0000-0002-2602-4110; Curtin,
John/0000-0001-6299-9110; Thiering, Elisabeth/0000-0002-5429-9584; St
Pourcain, Beate/0000-0002-4680-3517; Barton, Sheila/0000-0003-4963-4242;
Kaakinen, Marika/0000-0002-9228-0462; Timpson,
Nicholas/0000-0002-7141-9189; Rivadeneira, Fernando/0000-0001-9435-9441;
Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Estivill,
Xavier/0000-0002-0723-2256; Custovic, Adnan/0000-0001-5218-7071; Korner,
Antje/0000-0001-6001-0356; Holloway, John/0000-0001-9998-0464;
Warrington, Nicole/0000-0003-4195-775X; Bustamante,
Mariona/0000-0003-0127-2860
FU Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust)
[085541/Z/08/Z]; Danish Council for Independent Research Medical
Sciences (FSS) The Alfred Benzon Foundation; Oak Foundation fellowship;
Wellcome Trust [090532]; European Research Council [SZ-245
50371-GLUCOSEGENES-FP7-IDEAS-ERC]; Netherlands Organization for Health
Research and Development [VIDI 016.136.367, VIDI 016.136.361]
FX R.M.F. is supported by a Sir Henry Wellcome Postdoctoral Fellowship
(Wellcome Trust grant 085541/Z/08/Z). T.H.P. is supported by The Danish
Council for Independent Research Medical Sciences (FSS) The Alfred
Benzon Foundation. B.F. is supported by an Oak Foundation fellowship.
M.M. is a Wellcome Trust Senior Investigator (Wellcome Trust grant
090532) and a NIHR Senior Investigator. T.M.F. is supported by the
European Research Council grant: SZ-245
50371-GLUCOSEGENES-FP7-IDEAS-ERC. F.R. (VIDI 016.136.367) and V.W.V.J.
(VIDI 016.136.361) received grants from the Netherlands Organization for
Health Research and Development. The other authors did not receive
funding for this manuscript.
NR 45
TC 11
Z9 11
U1 0
U2 11
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0964-6906
EI 1460-2083
J9 HUM MOL GENET
JI Hum. Mol. Genet.
PD FEB 15
PY 2015
VL 24
IS 4
BP 1155
EP 1168
DI 10.1093/hmg/ddu510
PG 14
WC Biochemistry & Molecular Biology; Genetics & Heredity
SC Biochemistry & Molecular Biology; Genetics & Heredity
GA CC1XI
UT WOS:000350138300021
PM 25281659
ER
PT J
AU Castaldi, PJ
Cho, MH
Zhou, XB
Qiu, WL
Mcgeachie, M
Celli, B
Bakke, P
Gulsvik, A
Lomas, DA
Crapo, JD
Beaty, TH
Rennard, S
Harshfield, B
Lange, C
Singh, D
Tal-Singer, R
Riley, JH
Quackenbush, J
Raby, BA
Carey, VJ
Silverman, EK
Hersh, CP
AF Castaldi, Peter J.
Cho, Michael H.
Zhou, Xiaobo
Qiu, Weiliang
Mcgeachie, Michael
Celli, Bartolome
Bakke, Per
Gulsvik, Amund
Lomas, David A.
Crapo, James D.
Beaty, Terri H.
Rennard, Stephen
Harshfield, Benjamin
Lange, Christoph
Singh, Dave
Tal-Singer, Ruth
Riley, John H.
Quackenbush, John
Raby, Benjamin A.
Carey, Vincent J.
Silverman, Edwin K.
Hersh, Craig P.
TI Genetic control of gene expression at novel and established chronic
obstructive pulmonary disease loci
SO HUMAN MOLECULAR GENETICS
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; SMOKING-BEHAVIOR; RISK; METAANALYSIS; VARIANTS;
GENOTYPE; IDENTIFICATION; DETERMINANT; DISCOVERY
AB Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPDeQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD41 T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.
C1 [Castaldi, Peter J.; Cho, Michael H.; Zhou, Xiaobo; Qiu, Weiliang; Mcgeachie, Michael; Harshfield, Benjamin; Raby, Benjamin A.; Carey, Vincent J.; Silverman, Edwin K.; Hersh, Craig P.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA.
[Castaldi, Peter J.; Celli, Bartolome] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, Boston, MA 02115 USA.
[Cho, Michael H.; Zhou, Xiaobo; Celli, Bartolome; Raby, Benjamin A.; Silverman, Edwin K.; Hersh, Craig P.] Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA.
Harvard Univ, Sch Med, Boston, MA USA.
[Bakke, Per; Gulsvik, Amund] Haukeland Hosp, N-5021 Bergen, Norway.
[Lomas, David A.] UCL, London, England.
[Crapo, James D.] Natl Jewish Hlth, Dept Med, Denver, CO USA.
[Beaty, Terri H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA.
[Rennard, Stephen] Univ Nebraska Med Ctr, Div Pulm & Crit Care Med, Omaha, NE USA.
[Lange, Christoph; Quackenbush, John] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA.
[Singh, Dave] Univ Manchester, Manchester, Lancs, England.
[Tal-Singer, Ruth] GlaxoSmithKline, King Of Prussia, PA USA.
[Riley, John H.] GlaxoSmithKline, Uxbridge, Middx, England.
[Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.
RP Castaldi, PJ (reprint author), Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA.
EM peter.castaldi@channing.harvard.edu
FU US National Institutes of Health (NIH) [K08HL102265, R01HL124233,
K08HL097029, R01HL094635, R01NR013377, R01 HL086601, P01HL105339,
R01HL111759, R01HL089897, R01HL089856]; Parker B Francis Foundation;
COPD Foundation; GlaxoSmithKline
FX This work was supported by US National Institutes of Health (NIH) grants
K08HL102265 and R01HL124233 (P.J.C.), K08HL097029 (M.H.C.), R01HL094635
(C.P.H.), R01NR013377 (C.P.H), R01 HL086601 (B.A.R.), P01HL105339
(E.K.S.), R01HL111759 (J.Q., E.K.S), R01HL089897 (J.D.C) and R01HL089856
(E.K.S). Additional support was provided by a grant from the Parker B
Francis Foundation (M.M.). The content is solely the responsibility of
the authors and does not necessarily represent the official views of the
National Institutes of Health. The COPDGene (R) project is also
supported by the COPD Foundation through contributions made to an
Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim,
Novartis, Pfizer, Siemens and Sunovion. The ECLIPSE study was supported
by GlaxoSmithKline.
NR 40
TC 13
Z9 14
U1 2
U2 5
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0964-6906
EI 1460-2083
J9 HUM MOL GENET
JI Hum. Mol. Genet.
PD FEB 15
PY 2015
VL 24
IS 4
BP 1200
EP 1210
DI 10.1093/hmg/ddu525
PG 11
WC Biochemistry & Molecular Biology; Genetics & Heredity
SC Biochemistry & Molecular Biology; Genetics & Heredity
GA CC1XI
UT WOS:000350138300025
PM 25315895
ER
PT J
AU Baden, LR
Liu, JY
Li, HL
Johnson, JA
Walsh, SR
Kleinjan, JA
Engelson, BA
Peter, L
Abbink, P
Milner, DA
Golden, KL
Viani, KL
Stachler, MD
Chen, BJ
Pau, MG
Weijtens, M
Carey, BR
Miller, CA
Swann, EM
Wolff, M
Loblein, H
Seaman, MS
Dolin, R
Barouch, DH
AF Baden, Lindsey R.
Liu, Jinyan
Li, Hualin
Johnson, Jennifer A.
Walsh, Stephen R.
Kleinjan, Jane A.
Engelson, Brian A.
Peter, Lauren
Abbink, Peter
Milner, Danny A., Jr.
Golden, Kevin L.
Viani, Kyle L.
Stachler, Matthew D.
Chen, Benjamin J.
Pau, Maria G.
Weijtens, Mo
Carey, Brittany R.
Miller, Caroline A.
Swann, Edith M.
Wolff, Mark
Loblein, Hayley
Seaman, Michael S.
Dolin, Raphael
Barouch, Dan H.
TI Induction of HIV-1-Specific Mucosal Immune Responses Following
Intramuscular Recombinant Adenovirus Serotype 26 HIV-1 Vaccination of
Humans
SO JOURNAL OF INFECTIOUS DISEASES
LA English
DT Article
DE HIV; vaccine; adenovirus; mucosal immunity
ID LYMPHOCYTES FOLLOWING VACCINATION; T-CELL RESPONSES; RHESUS-MONKEYS;
NEUTRALIZING ANTIBODIES; DOUBLE-BLIND; ENV VACCINE; IPCAVD 001; VECTORS;
TRIAL; EFFICACY
AB Background. Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans.
Methods. In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed.
Results. Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4(+) T lymphocytes following vaccination by either histopathology or flow cytometry.
Conclusions. These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation.
C1 [Baden, Lindsey R.; Johnson, Jennifer A.; Walsh, Stephen R.; Kleinjan, Jane A.; Engelson, Brian A.; Milner, Danny A., Jr.; Golden, Kevin L.; Viani, Kyle L.; Stachler, Matthew D.; Chen, Benjamin J.; Dolin, Raphael] Brigham & Womens Hosp, Boston, MA 02115 USA.
[Baden, Lindsey R.; Liu, Jinyan; Li, Hualin; Walsh, Stephen R.; Peter, Lauren; Abbink, Peter; Carey, Brittany R.; Miller, Caroline A.; Seaman, Michael S.; Dolin, Raphael; Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA.
[Baden, Lindsey R.; Liu, Jinyan; Li, Hualin; Johnson, Jennifer A.; Walsh, Stephen R.; Peter, Lauren; Abbink, Peter; Milner, Danny A., Jr.; Golden, Kevin L.; Viani, Kyle L.; Stachler, Matthew D.; Chen, Benjamin J.; Seaman, Michael S.; Dolin, Raphael; Barouch, Dan H.] Harvard Univ, Sch Med, Boston, MA USA.
[Baden, Lindsey R.; Seaman, Michael S.; Dolin, Raphael; Barouch, Dan H.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA.
[Pau, Maria G.; Weijtens, Mo] Crucell Holland BV, Leiden, Netherlands.
[Wolff, Mark; Loblein, Hayley] EMMES Corp, Rockville, MD USA.
[Swann, Edith M.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA.
RP Baden, LR (reprint author), Brigham & Womens Hosp, 15 Francis St, Boston, MA 02115 USA.
EM lbaden@partners.org
FU NIH [AI060354, AI066305, AI069412, AI078526, AI096040, RR025758]; Ragon
Institute of MGH, MIT, and Harvard
FX The project was supported in part by the NIH (grant numbers AI060354,
AI066305, AI069412, AI078526, AI096040, RR025758); and Ragon Institute
of MGH, MIT, and Harvard.
NR 29
TC 14
Z9 14
U1 1
U2 3
PU OXFORD UNIV PRESS INC
PI CARY
PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA
SN 0022-1899
EI 1537-6613
J9 J INFECT DIS
JI J. Infect. Dis.
PD FEB 15
PY 2015
VL 211
IS 4
BP 518
EP 528
DI 10.1093/infdis/jiu485
PG 11
WC Immunology; Infectious Diseases; Microbiology
SC Immunology; Infectious Diseases; Microbiology
GA CC3CJ
UT WOS:000350221800004
PM 25165165
ER
PT J
AU Berkowitz, AL
Raibagkar, P
Pritt, BS
Mateen, FJ
AF Berkowitz, Aaron L.
Raibagkar, Pooja
Pritt, Bobbi S.
Mateen, Farrah J.
TI Neurologic manifestations of the neglected tropical diseases
SO JOURNAL OF THE NEUROLOGICAL SCIENCES
LA English
DT Review
DE Central nervous system helminthiasis; Central nervous system parasitic
infections; Central nervous system protozoal infections; Neglected
diseases; Tropical medicine
ID HUMAN AFRICAN TRYPANOSOMIASIS; CENTRAL-NERVOUS-SYSTEM;
CHLAMYDIA-TRACHOMATIS INFECTION; UNIFORM MULTIDRUG THERAPY; VISCERAL
LARVA MIGRANS; DENGUE VIRUS-INFECTION; GUINEA-WORM ABSCESS; MR-IMAGING
FINDINGS; CHAGAS-DISEASE; HUMAN RABIES
AB Background: The World Health Organization has identified 17 neglected tropical diseases (NTDs) that disproportionately affect the world's poorest populations. The neurologic aspects of many of these NTDs have received relatively little attention.
Methods: A review was performed in PubMed (MedLine) for each NTD by disease name, name of its causative organism, and neurology, neurosurgery, neurologist, brain, spinal cord, peripheral nerve, muscle, nervous system, encephalitis, meningitis, encephalopathy, stroke, neuropathy, and myopathy (1968-Sept. 2013). The Oxford Center for Evidence-based Medicine guidelines were used to determine the level of evidence of neurological involvement and treatment based on the reports identified.
Results: Neurologic manifestations were reported for all NTDs except yaws. Neurologic involvement was described in systematic reviews for four NTDs (Chagas disease, echinococcosis, rabies, cysticercosis) (levels 2a-3a), retrospective cohort studies for six (dengue, human African hypanosoiniasis, leishmaniasis, leprosy, onchocerciasis, schistosomiasis) (levels 2b-3b), case series for one (foodbome trematodiasis) (level 4), and case reports for five (Buruli ulcer, dracunculiasis, filariasis, soil-transmitted helminthes, and trachoma). Level 1 evidence for treatment of neurologic manifestations of NTDs was found for human African trypanosomiasis, leprosy, and cysticercosis and level 2 evidence exists for treatment of neurologic involvement in Chagas disease. For the remaining NTDs, treatment of neurologic complications is described in case series and case reports only.
Conclusions: Neurologic manifestations of NTDs cause significant morbidity and mortality, although limited evidence exists on how best to treat these neurologic complications. Increased awareness of neurologic manifestations of the NTDs can increase their early identification and treatment, contributing to ongoing elimination and eradication campaigns. (C) 2015 Elsevier B.V. All rights reserved.
C1 [Berkowitz, Aaron L.; Raibagkar, Pooja] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA.
[Berkowitz, Aaron L.; Raibagkar, Pooja; Mateen, Farrah J.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Raibagkar, Pooja; Mateen, Farrah J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.
[Pritt, Bobbi S.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
RP Mateen, FJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, 165 Cambridge St,627, Boston, MA 02114 USA.
EM fmateen@partners.org
OI Pritt, Bobbi/0000-0003-0261-1326
NR 152
TC 7
Z9 7
U1 4
U2 22
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 2015
VL 349
IS 1-2
BP 20
EP 32
DI 10.1016/j.jns.2015.01.001
PG 13
WC Clinical Neurology; Neurosciences
SC Neurosciences & Neurology
GA CC6YZ
UT WOS:000350516200005
PM 25623803
ER
PT J
AU Min, L
Hodi, FS
Giobbie-Hurder, A
Ott, PA
Luke, JJ
Donahue, H
Davis, M
Carroll, RS
Kaiser, UB
AF Min, Le
Hodi, Frank Stephen
Giobbie-Hurder, Anita
Ott, Patrick A.
Luke, Jason J.
Donahue, Hilary
Davis, Meredith
Carroll, Rona S.
Kaiser, Ursula B.
TI Systemic High-Dose Corticosteroid Treatment Does Not Improve the Outcome
of Ipilimumab-Related Hypophysitis: A Retrospective Cohort Study
SO CLINICAL CANCER RESEARCH
LA English
DT Article
ID RADIATION-INDUCED HYPOPITUITARISM; LYMPHOCYTE-ASSOCIATED ANTIGEN-4;
METASTATIC MELANOMA; ADVERSE EVENTS; AUTOIMMUNE HYPOPHYSITIS; CANCER;
THERAPY; SAFETY; TRIAL; RESPONSES
AB Purpose: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS).
Experimental Design: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan-Meier.
Results: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms.
Conclusion: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given. (C) 2014 AACR.
C1 [Min, Le; Carroll, Rona S.; Kaiser, Ursula B.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA.
[Hodi, Frank Stephen; Giobbie-Hurder, Anita; Ott, Patrick A.; Luke, Jason J.; Donahue, Hilary; Davis, Meredith] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
[Luke, Jason J.] Univ Chicago, Melanoma & Dev Therapeut Clin, Chicago, IL 60637 USA.
RP Min, L (reprint author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 221 Longwood Ave, Boston, MA 02115 USA.
EM lmin1@partners.org
FU NICHD/NIH [K08 HD070957]
FX This work was supported by NICHD/NIH K08 HD070957 (to L. Min).
NR 27
TC 20
Z9 20
U1 0
U2 1
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
IS 4
BP 749
EP 755
DI 10.1158/1078-0432.CCR-14-2353
PG 7
WC Oncology
SC Oncology
GA CB8AT
UT WOS:000349851200013
PM 25538262
ER
PT J
AU Pham, E
Birrer, MJ
Eliasof, S
Garmey, EG
Lazarus, D
Lee, CR
Man, S
Matulonis, UA
Peters, CG
Xu, P
Krasner, C
Kerbel, RS
AF Pham, Elizabeth
Birrer, Michael J.
Eliasof, Scott
Garmey, Edward G.
Lazarus, Douglas
Lee, Christina R.
Man, Shan
Matulonis, Ursula A.
Peters, Christian G.
Xu, Ping
Krasner, Carolyn
Kerbel, Robert S.
TI Translational Impact of Nanoparticle-Drug Conjugate CRLX101 with or
without Bevacizumab in Advanced Ovarian Cancer
SO CLINICAL CANCER RESEARCH
LA English
DT Article
ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; ANTIANGIOGENIC THERAPY; ORAL
TOPOTECAN; CLINICAL DEVELOPMENT; ANTITUMOR-ACTIVITY; BLOOD-VESSELS;
SOLID TUMORS; ANGIOGENESIS; PHARMACOKINETICS; CHEMOTHERAPY
AB Purpose: Increased tumor hypoxia and hence elevated hypoxia-inducible factor-1 alpha (HIF1 alpha) is thought to limit the efficacy of vascular endothelial growth factor (VEGF) pathway-targeting drugs by upregulating adaptive resistance genes. One strategy to counteract this is to combine antiangiogenic drugs with agents able to suppress HIF1 alpha. One such possibility is the investigational drug CRLX101, a nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a known topoisomerase-I poison.
Experimental Design: CRLX101 was evaluated both as a monotherapy and combination with bevacizumab in a preclinical mouse model of advanced metastatic ovarian cancer. These preclinical studies contributed to the rationale for undertaking a phase II clinical study to evaluate CRLX101 monotherapy in patients with advanced platinum-resistant ovarian cancer.
Results: Preclinically, CRLX101 is highly efficacious as a monotherapy when administered at maximum-tolerated doses. Furthermore, chronic low-dose CRLX101 with bevacizumab reduced bevacizumab-induced HIF1 alpha upregulation and resulted in synergistic efficacy, with minimal toxicity in mice. In parallel, initial data reported here from an ongoing phase II clinical study of CRLX101 monotherapy shows measurable tumor reductions in 74% of patients and a 16% RECIST response rate to date.
Conclusions: Given these preclinical and initial clinical results, further clinical studies are currently evaluating CRLX101 in combination with bevacizumab in ovarian cancer and warrant the evaluation of this therapy combination in other cancer types where HIF1 alpha is implicated in pathogenesis, as it may potentially be able to improve the efficacy of antiangiogenic drugs. (C) 2014 AACR.
C1 [Pham, Elizabeth; Lee, Christina R.; Man, Shan; Xu, Ping; Kerbel, Robert S.] Sunnbrook Res Inst, Biol Sci Platform, Toronto, ON M4N 3M5, Canada.
[Birrer, Michael J.; Krasner, Carolyn] Massachusetts Gen Hosp, Gillette Ctr Gynecol Oncol, Boston, MA 02114 USA.
[Eliasof, Scott; Garmey, Edward G.; Lazarus, Douglas; Peters, Christian G.] Cerulean Pharma Inc, Cambridge, MA USA.
[Matulonis, Ursula A.] Dana Farber Canc Inst, Boston, MA 02115 USA.
[Kerbel, Robert S.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada.
RP Kerbel, RS (reprint author), Sunnbrook Res Inst, Biol Sci Platform, S217-2075 Bayview Ave, Toronto, ON M4N 3M5, Canada.
EM cndrasner@partners.org; robert.kerbel@sri.utoronto.ca
FU Canadian Institutes of Health (CIHR) [MOP-119499]; Canadian Breast
Cancer Foundation (CBCF); Israel Cancer Research Fund (ICRF); Cerulean
Pharma Inc.
FX This work was supported by grants to R.S. Kerbel from the Canadian
Institutes of Health (CIHR, grant number MOP-119499), the Canadian
Breast Cancer Foundation (CBCF, grant number not applicable), and a
donation from Dr. Rena Buckstein administered through the Israel Cancer
Research Fund (ICRF, grant number not applicable). Financial support was
also provided by Cerulean Pharma Inc.
NR 47
TC 19
Z9 19
U1 5
U2 13
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
IS 4
BP 808
EP 818
DI 10.1158/1078-0432.CCR-14-2810
PG 11
WC Oncology
SC Oncology
GA CB8AT
UT WOS:000349851200019
PM 25524310
ER
PT J
AU Cornell, L
Munck, JM
Alsinet, C
Villanueva, A
Ogle, L
Willoughby, CE
Televantou, D
Thomas, HD
Jackson, J
Burt, AD
Newell, D
Rose, J
Manas, DM
Shapiro, GI
Curtin, NJ
Reeves, HL
AF Cornell, Liam
Munck, Joanne M.
Alsinet, Clara
Villanueva, Augusto
Ogle, Laura
Willoughby, Catherine E.
Televantou, Despina
Thomas, Huw D.
Jackson, Jennifer
Burt, Alastair D.
Newell, David
Rose, John
Manas, Derek M.
Shapiro, Geoffrey I.
Curtin, Nicola J.
Reeves, Helen L.
TI DNA-PK-A Candidate Driver of Hepatocarcinogenesis and Tissue Biomarker
That Predicts Response to Treatment and Survival
SO CLINICAL CANCER RESEARCH
LA English
DT Article
ID STRAND BREAK REPAIR; HEPATOCELLULAR-CARCINOMA; CANCER; KINASE; CELLS;
MANAGEMENT; INHIBITOR; ATM
AB Purpose: Therapy resistance and associated liver disease make hepatocellular carcinomas (HCC) difficult to treat with traditional cytotoxic therapies, whereas newer targeted approaches offer only modest survival benefit. We focused on DNA-dependent protein kinase, DNA-PKcs, encoded by PRKDC and central to DNA damage repair by nonhomologous end joining. Our aim was to explore its roles in hepatocarcinogenesis and as a novel therapeutic candidate.
Experimental Design: PRKDC was characterized in liver tissues from of 132 patients [normal liver (n = 10), cirrhotic liver (n = 13), dysplastic nodules (n = 18), HCC (n = 91)] using Affymetrix U133 Plus 2.0 and 500 K Human Mapping SNP arrays (cohort 1). In addition, we studied a case series of 45 patients with HCC undergoing diagnostic biopsy (cohort 2). Histological grading, response to treatment, and survival were correlated with DNA-PKcs quantified immunohistochemically. Parallel in vitro studies determined the impact of DNA-PK on DNA repair and response to cytotoxic therapy.
Results: Increased PRKDC expression in HCC was associated with amplification of its genetic locus in cohort 1. In cohort 2, elevated DNA-PKcs identified patients with treatment-resistant HCC, progressing at a median of 4.5 months compared with 16.9 months, whereas elevation of activated pDNA-PK independently predicted poorer survival. DNA-PKcs was high in HCC cell lines, where its inhibition with NU7441 potentiated irradiation and doxorubicin-induced cytotoxicity, whereas the combination suppressed HCC growth in vitro and in vivo.
Conclusions: These data identify PRKDC/DNA-PKcs as a candidate driver of hepatocarcinogenesis, whose biopsy characterization at diagnosis may impact stratification of current therapies, and whose specific future targeting may overcome resistance. (C)2014 AACR.
C1 [Cornell, Liam; Munck, Joanne M.; Ogle, Laura; Willoughby, Catherine E.; Televantou, Despina; Thomas, Huw D.; Jackson, Jennifer; Newell, David; Curtin, Nicola J.; Reeves, Helen L.] Newcastle Univ, Sch Med, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.
[Cornell, Liam; Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA.
[Cornell, Liam; Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
[Alsinet, Clara; Villanueva, Augusto] Univ Barcelona, Ctr Invest Biomed Red Enfermedades Hepat & Digest, IDIBAPS, Hosp Clin,Barcelona Clin Liver Canc Grp BCLC Tran, Catalonia, Spain.
[Villanueva, Augusto] Kings Coll London, Div Transplantat & Mucosal Biol, Inst Liver Studies, London, England.
[Burt, Alastair D.] Newcastle Univ, Sch Med, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.
[Burt, Alastair D.] Univ Adelaide, Sch Med, Adelaide, SA, Australia.
[Rose, John] Freeman Rd Hosp, Dept Radiol, Newcastle Upon Tyne, Tyne & Wear, England.
[Manas, Derek M.; Reeves, Helen L.] Freeman Rd Hosp, Hepatopancreatobiliary Team, Newcastle Upon Tyne, Tyne & Wear, England.
RP Curtin, NJ (reprint author), Newcastle Univ, Northern Inst Canc Res, Paul OGormon Bldg, Newcastle Upon Tyne NE4 2HH, Tyne & Wear, England.
EM Nicola.curtin@ncl.ac.uk
RI Burt, Alastair/D-3634-2013;
OI Villanueva, Augusto/0000-0003-3585-3727; Burt,
Alastair/0000-0002-3011-7774; Willoughby, Catherine/0000-0002-0617-8833
FU patient support group, LIVErNORTH; European Community
[HEALTH-F2-2009-241762]; Cancer Research UK (CR UK); Newcastle
Experimental Cancer Medicine Center
FX L. Cornell was supported by the patient support group, LIVErNORTH. H. L.
Reeves and the creation of the Newcastle University Gastroenterology
Research Tissue Bank were supported by the European Community's Seventh
Framework Programme (FP7/2001-2013) under grant agreement
HEALTH-F2-2009-241762 for the project FLIP. J.M. Munck, D. Televantou,
H. D. Thomas, J. Jackson, and D. Newell were supported by programme
grants from Cancer Research UK (CR UK) and Newcastle Experimental Cancer
Medicine Center.
NR 30
TC 10
Z9 10
U1 0
U2 1
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD FEB 15
PY 2015
VL 21
IS 4
BP 925
EP 933
DI 10.1158/1078-0432.CCR-14-0842
PG 9
WC Oncology
SC Oncology
GA CB8AT
UT WOS:000349851200031
PM 25480831
ER
PT J
AU Althoff, KN
McGinnis, KA
Wyatt, CM
Freiberg, MS
Gilbert, C
Oursler, KK
Rimland, D
Rodriguez-Barradas, MC
Dubrow, R
Park, LS
Skanderson, M
Shiels, MS
Gange, SJ
Gebo, KA
Justice, AC
AF Althoff, Keri N.
McGinnis, Kathleen A.
Wyatt, Christina M.
Freiberg, Matthew S.
Gilbert, Cynthia
Oursler, Krisann K.
Rimland, David
Rodriguez-Barradas, Maria C.
Dubrow, Robert
Park, Lesley S.
Skanderson, Melissa
Shiels, Meredith S.
Gange, Stephen J.
Gebo, Kelly A.
Justice, Amy C.
CA VACS
TI Comparison of Risk and Age at Diagnosis of Myocardial Infarction,
End-Stage Renal Disease, and Non-AIDS-Defining Cancer in HIV-Infected
Versus Uninfected Adults
SO CLINICAL INFECTIOUS DISEASES
LA English
DT Article
DE HIV infection; aging; myocardial infarction; end-stage renal disease;
non-AIDS-defining cancers
ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIGH PREVALENCE; UNITED-STATES; VETERANS;
INDIVIDUALS; COINFECTION; POPULATION; COHORT; CARE; MEN
AB Background. Although it has been shown that human immunodeficiency virus (HIV)-infected adults are at greater risk for aging-associated events, it remains unclear as to whether these events happen at similar, or younger ages, in HIV-infected compared with uninfected adults. The objective of this study was to compare the median age at, and risk of, incident diagnosis of 3 age-associated diseases in HIV-infected and demographically similar uninfected adults.
Methods. The study was nested in the clinical prospective Veterans Aging Cohort Study of HIV-infected and demographically matched uninfected veterans, from 1 April 2003 to 31 December 2010. The outcomes were validated diagnoses of myocardial infarction (MI), end-stage renal disease (ESRD), and non-AIDS-defining cancer (NADC). Differences in mean age at, and risk of, diagnosis by HIV status were estimated using multivariate linear regression models and Cox proportional hazards models, respectively.
Results. A total of 98 687 (31% HIV-infected and 69% uninfected) adults contributed >450 000 person-years and 689 MI, 1135 ESRD, and 4179 NADC incident diagnoses. Mean age at MI (adjusted mean difference, -0.11; 95% confidence interval [CI], -.59 to .37 years) and NADC (adjusted mean difference, -0.10 [95% CI, -.30 to .10] years) did not differ by HIV status. HIV-infected adults were diagnosed with ESRD at an average age of 5.5 months younger than uninfected adults (adjusted mean difference, -0.46 [95% CI, -.86 to -.07] years). HIV-infected adults had a greater risk of all 3 outcomes compared with uninfected adults after accounting for important confounders.
Conclusions. HIV-infected adults had a higher risk of these age-associated events, but they occurred at similar ages than those without HIV.
C1 [Althoff, Keri N.; Gange, Stephen J.; Gebo, Kelly A.] Johns Hopkins Univ, Baltimore, MD USA.
[McGinnis, Kathleen A.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA.
[Wyatt, Christina M.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA.
[Freiberg, Matthew S.] Vanderbilt Univ Sch Med, Nashville, TN USA.
[Gilbert, Cynthia] Vet Affairs Med Ctr, Washington, DC 20422 USA.
[Gilbert, Cynthia] George Washington Univ, Med Ctr, Washington, DC 20037 USA.
[Oursler, Krisann K.] Salem Vet Affairs Med Ctr, Salem, VA USA.
[Oursler, Krisann K.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA.
[Rimland, David] Atlanta Vet Affairs Med Ctr, Atlanta, GA USA.
[Rimland, David] Emory Univ, Sch Med, Atlanta, GA 30322 USA.
[Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Houston, TX USA.
[Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA.
[Dubrow, Robert; Park, Lesley S.; Skanderson, Melissa; Justice, Amy C.] Vet Affairs Connecticut Healthcare Syst, New Haven, CT USA.
[Dubrow, Robert; Park, Lesley S.; Skanderson, Melissa; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA.
[Dubrow, Robert; Park, Lesley S.; Skanderson, Melissa; Justice, Amy C.] Yale Univ, Sch Publ Hlth, New Haven, CT USA.
[Shiels, Meredith S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA.
RP Althoff, KN (reprint author), Johns Hopkins Univ, 615 N Wolfe St,Rm E7142, Baltimore, MD 21231 USA.
EM kalthoff@jhu.edu
OI Justice, Amy/0000-0003-0139-5502
FU National Institutes of Health: National Institute on Alcohol Abuse and
Alcoholism [U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799,
U24-AA022001, U24 AA022007, U10 AA013566-]; National Heart, Lung, and
Blood Institute [R01-HL095136, R01-HL090342]; National Institute of
Allergy and Infectious Diseases (NIAID) [U01-A1069918]; National
Institute of Mental Health [P30-MH062294]; National Institute on Drug
Abuse [R01DA035616]; National Cancer Institute (NCI) [R01 CA173754];
Agency for Healthcare Research and Quality [R01-HS018372]; Veterans
Health Administration Office of Research and Development [VA REA
08-266]; Office of Academic Affiliations (Medical Informatics
Fellowship); NIAID [K01-AI093197]; NCI [F31-CA180775]; National
Institute of Diabetes and Digestive and Kidney Diseases [P01-DK056492];
Department of Veterans Affairs, Veterans Health Administration [VA I01
RX000667]; National Cancer Institute
FX The Veterans Aging Cohort Study is supported by the National Institutes
of Health: National Institute on Alcohol Abuse and Alcoholism (grant
numbers U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799,
U24-AA022001, U24 AA022007, U10 AA013566-completed); National Heart,
Lung, and Blood Institute (grant numbers R01-HL095136; R01-HL090342);
National Institute of Allergy and Infectious Diseases (NIAID) (grant
number U01-A1069918); National Institute of Mental Health (grant number
P30-MH062294); National Institute on Drug Abuse (grant number
R01DA035616); National Cancer Institute (NCI) (grant number R01
CA173754); Agency for Healthcare Research and Quality (grant number
R01-HS018372); and the Veterans Health Administration Office of Research
and Development (grant number VA REA 08-266, VA IRR Merit Award) and
Office of Academic Affiliations (Medical Informatics Fellowship).
Additional funding for this work includes K01-AI093197 funded by the
NIAID (to K. N. A.), F31-CA180775 funded by the NCI (to L. S. P.),
P01-DK056492 funded by the National Institute of Diabetes and Digestive
and Kidney Diseases (to C. M. W.), VA I01 RX000667 funded by the
Department of Veterans Affairs, Veterans Health Administration (to K. K.
O.), and the Intramural Research Program of the National Cancer
Institute (to M. S. S.).
NR 38
TC 40
Z9 42
U1 1
U2 8
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 2015
VL 60
IS 4
BP 627
EP 638
DI 10.1093/cid/ciu869
PG 12
WC Immunology; Infectious Diseases; Microbiology
SC Immunology; Infectious Diseases; Microbiology
GA CB6VI
UT WOS:000349764400020
PM 25362204
ER
PT J
AU Estrella, MM
Li, M
Tin, A
Abraham, AG
Shlipak, MG
Penugonda, S
Hussain, SK
Palella, FJ
Wolinsky, SM
Martinson, JJ
Parekh, RS
Kao, WHL
AF Estrella, Michelle M.
Li, Man
Tin, Adrienne
Abraham, Alison G.
Shlipak, Michael G.
Penugonda, Sudhir
Hussain, Shehnaz K.
Palella, Frank J., Jr.
Wolinsky, Steven M.
Martinson, Jeremy J.
Parekh, Rulan S.
Kao, W. H. Linda
TI The Association Between APOL1 Risk Alleles and Longitudinal Kidney
Function Differs by HIV Viral Suppression Status
SO CLINICAL INFECTIOUS DISEASES
LA English
DT Article
DE HIV; antiretroviral therapy; genetic; kidney disease
ID ACTIVE ANTIRETROVIRAL THERAPY; ALLOGRAFT SURVIVAL; AFRICAN-AMERICANS;
DISEASE; VARIANTS; NEPHROPATHY; PROGRESSION; GENOTYPE; COHORT; INFECTION
AB Background. Existing data suggest that human immunodeficiency virus (HIV)-infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study.
Methods. We genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects models were used to estimate the annual rate of estimated glomerular filtration rate (eGFR) decline, comparing men carrying 2 (high-risk) vs 0-1 risk allele (low-risk). Effect modification by HIV suppression status (defined as HIV type 1 RNA level <400 copies/mL for >90% of follow-up time) was evaluated using interaction terms and stratified analyses.
Results. Of the 333 African American men included in this study, 54 (16%) carried the APOL1 high-risk genotype. Among HIV-infected men with unsuppressed viral loads, those with the high-risk genotype had a 2.42 mL/minute/1.73 m(2) (95% confidence interval [CI], -3.52 to -1.32) faster annual eGFR decline than men with the low-risk genotype. This association was independent of age, comorbid conditions, baseline eGFR, ancestry, and HIV-related factors. In contrast, the rate of decline was similar by APOL1 genotype among men with sustained viral suppression (-0.16 mL/minute/1.73 m(2)/year; 95% CI, -.59 to .27; P for interaction <.001).
Conclusions. Unsuppressed HIV-infected African Americans with the APOL1 high-risk genotype experience an accelerated rate of kidney function decline; HIV suppression with antiretroviral therapy may reduce these deleterious renal effects.
C1 [Estrella, Michelle M.; Parekh, Rulan S.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21205 USA.
[Li, Man; Tin, Adrienne; Abraham, Alison G.; Parekh, Rulan S.; Kao, W. H. Linda] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA.
[Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Gen Internal Med, San Francisco, CA USA.
[Penugonda, Sudhir; Palella, Frank J., Jr.; Wolinsky, Steven M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA.
[Hussain, Shehnaz K.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA.
[Hussain, Shehnaz K.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA USA.
[Martinson, Jeremy J.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15260 USA.
[Parekh, Rulan S.] Hosp Sick Children, Univ Hlth Network, Toronto, ON M5G 1X8, Canada.
[Parekh, Rulan S.] Univ Toronto, Toronto, ON M5S 1A1, Canada.
RP Estrella, MM (reprint author), Johns Hopkins Univ, Dept Med, Sch Med, 1830 E Monument St,Ste 416, Baltimore, MD 21205 USA.
EM mestrel1@jhmi.edu
OI Martinson, Jeremy/0000-0003-4673-7238; Wolinsky,
Steven/0000-0002-9625-6697
FU National Institute of Diabetes and Digestive and Kidney Diseases
[K23DK081317]; National Kidney Foundation of Maryland; National Heart,
Lung, and Blood Institute (NHLBI) [T32HL007024]; Johns Hopkins
University Bloomberg School of Public Health [U01-AI35042]; Northwestern
University [U01-AI35039]; University of California, Los Angeles
[U01-AI35040]; University of Pittsburgh [U01-AI35041]; Center for
Analysis and Management of MACS, Johns Hopkins University Bloomberg
School of Public Health [UM1-AI35043]; National Institute of Allergy and
Infectious Diseases; National Cancer Institute; NHLBI; National
Institute on Deafness and Communication Disorders; Johns Hopkins
University Institute for Clinical and Translational Research
[UL1-TR000424]
FX M. M. E. received support for this work from the National Institute of
Diabetes and Digestive and Kidney Diseases (grant number K23DK081317)
and the National Kidney Foundation of Maryland. A. T. is supported by
the National Heart, Lung, and Blood Institute (NHLBI) (Cardiovascular
Epidemiology Training grant number T32HL007024). Data in this manuscript
were collected by the MACS with centers (principal investigators) at
Johns Hopkins University Bloomberg School of Public Health (Joseph
Margolick) (grant number U01-AI35042); Northwestern University (Steven
M. Wolinsky) (grant number U01-AI35039); University of California, Los
Angeles (Roger Detels) (grant number U01-AI35040); University of
Pittsburgh (Charles Rinaldo) (grant number U01-AI35041); the Center for
Analysis and Management of MACS, Johns Hopkins University Bloomberg
School of Public Health (Lisa Jacobson) (grant number UM1-AI35043). The
MACS is funded primarily by the National Institute of Allergy and
Infectious Diseases, with additional cofunding from the National Cancer
Institute. Targeted supplemental funding for specific projects was also
provided by the NHLBI and the National Institute on Deafness and
Communication Disorders. MACS data collection is also supported by the
Johns Hopkins University Institute for Clinical and Translational
Research (grant number UL1-TR000424; website located at
http://www.statepi.jhsph.edu/macs/macs.html).
NR 26
TC 7
Z9 7
U1 1
U2 3
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 2015
VL 60
IS 4
BP 646
EP 652
DI 10.1093/cid/ciu765
PG 7
WC Immunology; Infectious Diseases; Microbiology
SC Immunology; Infectious Diseases; Microbiology
GA CB6VI
UT WOS:000349764400022
PM 25281610
ER
PT J
AU O'Connell, G
Guo, G
Stricker, J
Quinn, LS
Ma, A
Pistilli, EE
AF O'Connell, Grant
Guo, Ge
Stricker, Janelle
Quinn, LeBris S.
Ma, Averil
Pistilli, Emidio E.
TI Muscle-specific deletion of exons 2 and 3 of the IL15RA gene in mice:
effects on contractile properties of fast and slow muscles
SO JOURNAL OF APPLIED PHYSIOLOGY
LA English
DT Article
DE myokine; fatigue; isometric contractile properties; interleukin
ID RECEPTOR-ALPHA-CHAIN; MEMORY T-CELLS; SKELETAL-MUSCLE; INTERLEUKIN-15
RECEPTOR; SOLUBLE IL-15R-ALPHA; IL-15 ACTIVITY; MESSENGER-RNA; MOTOR
UNITS; PPAR-DELTA; MDX MICE
AB Interleukin-15 (IL-15) is a putative myokine hypothesized to induce an oxidative skeletal muscle phenotype. The specific IL-15 receptor alpha subunit (IL-15R alpha) has also been implicated in specifying this contractile phenotype. The purposes of this study were to determine the muscle-specific effects of IL-15R alpha functional deficiency on skeletal muscle isometric contractile properties, fatigue characteristics, spontaneous cage activity, and circulating IL-15 levels in male and female mice. Muscle creatine kinase (MCK)-driven IL-15R alpha knockout mice (mIl15ra(fl/fl)/Cre(+)) were generated using the Cre-loxP system. We tested the hypothesis that IL-15R alpha functional deficiency in skeletal muscle would increase resistance to contraction-induced fatigue, cage activity, and circulating IL-15 levels. There was a significant effect of genotype on the fatigue curves obtained in extensor digitorum longus (EDL) muscles from female mIl15ra(fl/fl)/Cre(+) mice, such that force output was greater during the repeated contraction protocol compared with mIl15ra(fl/fl)/Cre(+) control mice. Muscles from female mIl15ra(fl/fl)/Cre(+) mice also had a twofold greater amount of the mitochondrial genome-specific COXII gene compared with muscles from mIl15ra(fl/fl)/Cre(+) control mice, indicating a greater mitochondrial density in these skeletal muscles. There was a significant effect of genotype on the twitch: tetanus ratio in EDL and soleus muscles from mIl15ra(fl/fl)/Cre(+) mice, such that the ratio was lower in these muscles compared with mIl15ra(fl/fl)/Cre(+) control mice, indicating a pro-oxidative shift in muscle phenotype. However, spontaneous cage activity was not different and IL-15 protein levels were lower in male and female mIl15ra(fl/fl)/Cre(+) mice compared with control. Collectively, these data support a direct effect of muscle IL-15R alpha deficiency in altering contractile properties and fatigue characteristics in skeletal muscles.
C1 [O'Connell, Grant; Guo, Ge; Stricker, Janelle; Pistilli, Emidio E.] W Virginia Univ, Div Exercise Physiol, Morgantown, WV 26506 USA.
[Pistilli, Emidio E.] W Virginia Univ, Ctr Cardiovasc & Resp Sci, Morgantown, WV 26506 USA.
[Pistilli, Emidio E.] W Virginia Univ, West Virginia Clin & Translat Sci Inst, Morgantown, WV 26506 USA.
[Stricker, Janelle] W Virginia Univ, Dept Physiol & Pharmacol, Morgantown, WV 26506 USA.
[Quinn, LeBris S.] Geriatr Res Educ & Clin Ctr, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA.
[Quinn, LeBris S.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA.
[Ma, Averil] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
RP Pistilli, EE (reprint author), W Virginia Univ, West Virginia Clin & Translat Sci Inst, Dept Human Performance & Appl Exercise Sci, Ctr Cardiovasc & Resp Sci,Div Exercise Physiol, Morgantown, WV 26506 USA.
EM epistilli2@hsc.wvu.edu
OI O'Connell, Grant/0000-0002-2642-6670
FU West Virginia University Research Funding Development Grant
FX This work was partially supported by the West Virginia University
Research Funding Development Grant (E. E. Pistilli).
NR 52
TC 2
Z9 2
U1 1
U2 5
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 8750-7587
EI 1522-1601
J9 J APPL PHYSIOL
JI J. Appl. Physiol.
PD FEB 15
PY 2015
VL 118
IS 4
BP 437
EP 448
DI 10.1152/japplphysiol.00704.2014
PG 12
WC Physiology; Sport Sciences
SC Physiology; Sport Sciences
GA CB6QR
UT WOS:000349752100006
PM 25505029
ER
PT J
AU Theoharides, TC
Athanassiou, M
Panagiotidou, S
Doyle, R
AF Theoharides, Theoharis C.
Athanassiou, Marianna
Panagiotidou, Smaro
Doyle, Robert
TI Dysregulated brain immunity and neurotrophin signaling in Rett syndrome
and autism spectrum disorders
SO JOURNAL OF NEUROIMMUNOLOGY
LA English
DT Review
DE Brain-derived neurotrophic factor; Inflammation; Mast cells; Microglia;
Mitochondria; Rett syndrome; Treatment
ID CORTICOTROPIN-RELEASING HORMONE; HUMAN MAST-CELLS;
CENTRAL-NERVOUS-SYSTEM; ENDOTHELIAL GROWTH-FACTOR; MOUSE MODEL; BDNF
LEVELS; T-CELLS; NEUROPSYCHIATRIC DISORDERS; MITOCHONDRIAL-DNA; MECP2
DEFICIENCY
AB Rett syndrome is a neurodevelopmental disorder, which occurs in about 1:15,000 females and presents with neurologic and communication defects. It is transmitted as an X-linked dominant linked to mutations of the methyl-CpG-binding protein (MeCP2), a gene transcription suppressor, but its definitive pathogenesis is unknown thus hindering development of effective treatments. Almost half of children with Rett syndrome also have behavioral symptoms consistent with those of autism spectrum disorders (ASDs). PubMed was searched (2005-2014) using the terms: allergy, atopy, brain, brain-derived neurotrophic factor (BDNF), corticotropin-releasing hormone (CRH), cytokines, gene mutations, inflammation, mast cells (MCs), microglia, mitochondria, neurotensin (NT), neurotrophins, seizures, stress, and treatment. There are a number of intriguing differences and similarities between Rett syndrome and ASDs. Rett syndrome occurs in females, while ASDs more often in males, and the former has neurologic disabilities unlike ASDs. There is evidence of dysregulated immune system early in life in both conditions. Lack of microglial phagocytosis and decreased levels of BDNF appear to distinguish Rett syndrome from ASDs, in which there is instead microglia activation and/or proliferation and possibly defective BDNF signaling. Moreover, brain mast cell (MC) activation and focal inflammation may be more prominent in ASDs than Rett syndrome. The flavonoid luteolin blocks microglia and MC activation, provides BDNF-like activity, reverses Rett phenotype in mouse models, and has a significant benefit in children with ASDs. Appropriate formulations of luteolin or other natural molecules may be useful in the treatment of Rett syndrome. (C) 2014 Elsevier B.V. All rights reserved.
C1 [Theoharides, Theoharis C.; Athanassiou, Marianna; Panagiotidou, Smaro] Tufts Univ, Sch Med, Dept Integrat Physiol & Pathobiol, Mol Immunopharmacol & Drug Discovery Lab, Boston, MA 02111 USA.
[Theoharides, Theoharis C.] Tufts Univ, Sch Med, Dept Internal Med, Boston, MA 02111 USA.
[Theoharides, Theoharis C.] Tufts Med Ctr, Boston, MA USA.
[Theoharides, Theoharis C.] Tufts Univ, Sch Med, Dept Psychiat, Boston, MA 02111 USA.
[Doyle, Robert] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA.
[Doyle, Robert] Harvard Univ, Sch Med, Boston, MA USA.
RP Theoharides, TC (reprint author), Tufts Univ, Sch Med, Dept Integrat Physiol & Pathobiol, Mol Immunopharmacol & Drug Discovery Lab, 136 Harrison Ave, Boston, MA 02111 USA.
EM theoharis.theoharides@tufts.edu
FU NIH [NS38326, AR47652]; Autism Collaborative; Autism Research Institute;
Johnson Botsford Johnson Fnd.; National Autism Association; Safe Minds
and Theta Biomedical Consulting and Development Co., Inc. (Brookline,
MA)
FX The aspects of our work described above were funded in part by NIH
grants NS38326 and AR47652, as well as the Autism Collaborative, the
Autism Research Institute, the Johnson Botsford Johnson Fnd., the
National Autism Association, Safe Minds and Theta Biomedical Consulting
and Development Co., Inc. (Brookline, MA) to TCT.
NR 142
TC 14
Z9 14
U1 6
U2 27
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0165-5728
EI 1872-8421
J9 J NEUROIMMUNOL
JI J. Neuroimmunol.
PD FEB 15
PY 2015
VL 279
BP 33
EP 38
DI 10.1016/j.jneuroim.2014.12.003
PG 6
WC Immunology; Neurosciences
SC Immunology; Neurosciences & Neurology
GA CC1GD
UT WOS:000350088300006
PM 25669997
ER
PT J
AU Mulliken, GH
Bichot, NP
Ghadooshahy, A
Sharma, J
Kornblith, S
Philcock, M
Desimone, R
AF Mulliken, Grant H.
Bichot, Narcisse P.
Ghadooshahy, Azriel
Sharma, Jitendra
Kornblith, Simon
Philcock, Michael
Desimone, Robert
TI Custom-fit radiolucent cranial implants for neurophysiological recording
and stimulation
SO JOURNAL OF NEUROSCIENCE METHODS
LA English
DT Article
DE Neurophysiology; Implant; Radiolucent; Macaque; Microdrive;
Brain-machine interface
ID BEHAVING MONKEYS; MOTORIZED MICRODRIVE; NONHUMAN-PRIMATES; SMALL
ANIMALS; CHAMBER; SYSTEM; CORTEX
AB Background: Recording and manipulating neural activity in awake behaving animal models requires long-term implantation of cranial implants that must address a variety of design considerations, which include preventing infection, minimizing tissue damage, mechanical strength of the implant, and MRI compatibility.
New method: Here we address these issues by designing legless, custom-fit cranial implants using structural MRI-based reconstruction of the skull and that are made from carbon-reinforced PEEK.
Results: We report several novel custom-fit radiolucent implant designs, which include a legless recording chamber, a legless stimulation chamber, a multi-channel microdrive and a head post. The fit to the skull was excellent in all cases, with no visible gaps between the base of the implants and the skull. The wound margin was minimal in size and showed no sign of infection or skin recession.
Comparison with existing methods: Cranial implants used for neurophysiological investigation in awake behaving animals often employ methyl methacrylate (MMA) to serve as a bonding agent to secure the implant to the skull. Other designs rely on radially extending legs to secure the implant. Both of these methods have significant drawbacks. MMA is toxic to bone and frequently leads to infection while radially extending legs cause the skin to recede away from the implant, ultimately exposing bone and proliferating granulation-tissue.
Conclusions: These radiolucent implants constitute a set of technologies suitable for reliable long-term recording, which minimize infection and tissue damage. (C) 2014 Elsevier B.V. All rights reserved.
C1 [Mulliken, Grant H.; Bichot, Narcisse P.; Ghadooshahy, Azriel; Desimone, Robert] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA.
[Sharma, Jitendra; Kornblith, Simon] MIT, Picower Ctr Learning & Memory, Cambridge, MA 02139 USA.
[Sharma, Jitendra] MIT, Picower Inst Learning & Memory, Boston, MA 02129 USA.
[Sharma, Jitendra] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA.
[Sharma, Jitendra] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02129 USA.
[Philcock, Michael] AnalyzeDirect Inc, Overland Pk, KS 66085 USA.
RP Mulliken, GH (reprint author), 77 Massachusetts Ave,46-6165, Cambridge, MA 02139 USA.
EM grantm@mit.edu
FU National Eye Institute [EY017291, EY017292]; NRSA Award [EY020692]
FX This work was supported by grants from the National Eye Institute
(EY017291, EY017292) and an NRSA Award to GHM (EY020692). We thank Brian
Rogers, Jose Estrada and Andrew Gallant for CAD design and CNC
expertise, Kostas Tomadakis and Andrew Ryan for machining expertise,
Mike Walsh for electronics design, and Drs. Atsushi Takahashi and Steven
Shannon for help with MR imaging. We thank Ellen Degennaro, Erica Pino,
Matthew Heard, Jonathan Winkle, and Grant Pielli for animal care and Dr.
Robert P. Marini for veterinary assistance.
NR 24
TC 1
Z9 1
U1 0
U2 8
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0165-0270
EI 1872-678X
J9 J NEUROSCI METH
JI J. Neurosci. Methods
PD FEB 15
PY 2015
VL 241
BP 146
EP 154
DI 10.1016/j.jneumeth.2014.12.011
PG 9
WC Biochemical Research Methods; Neurosciences
SC Biochemistry & Molecular Biology; Neurosciences & Neurology
GA CC2PW
UT WOS:000350188100017
PM 25542350
ER
PT J
AU Ceccaldi, R
O'Connor, KW
Mouw, KW
Li, AY
Matulonis, UA
D'Andrea, AD
Konstantinopoulos, PA
AF Ceccaldi, Raphael
O'Connor, Kevin W.
Mouw, Kent W.
Li, Adam Y.
Matulonis, Ursula A.
D'Andrea, Alan D.
Konstantinopoulos, Panagiotis A.
TI A Unique Subset of Epithelial Ovarian Cancers with Platinum Sensitivity
and PARP Inhibitor Resistance
SO CANCER RESEARCH
LA English
DT Article
ID CISPLATIN SENSITIVITY; BRCA2 MUTATIONS; EXCISION-REPAIR; CHEMOTHERAPY;
CARCINOMA; ASSOCIATION; GENOMICS; SURVIVAL; OLAPARIB; CELLS
AB Platinum and PARP inhibitor (PARPi) sensitivity commonly coexist in epithelial ovarian cancer (EOC) due to the high prevalence of alterations in the homologous recombination (HR) DNA repair pathway that confer sensitivity to both drugs. In this report, we describe a unique subset of EOC with alterations in another DNA repair pathway, the nucleotide excision repair (NER) pathway, which may exhibit a discordance in sensitivities to these drugs. Specifically, 8% of high-grade serous EOC from The Cancer Genome Atlas dataset exhibited NER alterations, including nonsynonymous or splice site mutations and homozygous deletions of NER genes. Tumors with NER alterations were associated with improved overall survival (OS) and progression-free survival (PFS), compared with patients without NER alterations or BRCA1/2 mutations. Furthermore, patients with tumors with NER alterations had similar OS and PFS as BRCA1/2-mutated patients, suggesting that NER pathway inactivation in EOC conferred enhanced platinum sensitivity, similar to BRCA1/2-mutated tumors. Moreover, two NER mutations (ERCC6-Q524* and ERCC4-A583T), identified in the two most platinum-sensitive tumors, were functionally associated with platinum sensitivity in vitro. Importantly, neither NER alteration affected HR or conferred sensitivity to PARPi or other double-strand break-inducing agents. Overall, our findings reveal a new mechanism of platinum sensitivity in EOC that, unlike defective HR, may lead to a discordance in sensitivity to platinum and PARPi, with potential implications for previously reported and ongoing PARPi trials in this disease. (C)2015 AACR.
C1 [Ceccaldi, Raphael; O'Connor, Kevin W.; Mouw, Kent W.; Li, Adam Y.; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA.
[Mouw, Kent W.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA 02115 USA.
[Matulonis, Ursula A.; Konstantinopoulos, Panagiotis A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Med Gynecol Oncol Program, Boston, MA 02115 USA.
RP Konstantinopoulos, PA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Med Gynecol Oncol Program, 44 Binney St, Boston, MA 02115 USA.
EM alan_dandrea@dfci.harvard.edu;
panagiotis_konstantinopoulos@dfci.harvard.edu
FU Ovarian Cancer Research Fellowship; DOD Ovarian Cancer Research Program
Ovarian Cancer Academy Award [W81XWH010-1-0585]
FX R. Ceccaldi is a recipient of the Ovarian Cancer Research Fellowship.
P.A. Konstantinopoulos is recipient of DOD Ovarian Cancer Research
Program Ovarian Cancer Academy Award W81XWH010-1-0585.
NR 24
TC 15
Z9 16
U1 1
U2 9
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD FEB 15
PY 2015
VL 75
IS 4
BP 628
EP 634
DI 10.1158/0008-5472.CAN-14-2593
PG 7
WC Oncology
SC Oncology
GA CB7XI
UT WOS:000349841600003
PM 25634215
ER
PT J
AU Uthamalingam, S
Kandala, J
Selyaraj, V
Martin, W
Daley, M
Patvardhan, E
Capodilupo, R
Moore, S
Januzzi, JL
AF Uthamalingam, Shanmugam
Kandala, Jagdesh
Selyaraj, Vijairam
Martin, William
Daley, Marlyn
Patvardhan, Eshan
Capodilupo, Robert
Moore, Stephanie
Januzzi, James L., Jr.
TI Outcomes of Patients With Acute Decompensated Heart Failure Managed by
Cardiologists Versus Noncardiologists
SO AMERICAN JOURNAL OF CARDIOLOGY
LA English
DT Article
ID HOSPITALIZED-PATIENTS; CLINICAL-OUTCOMES; PRACTICE PATTERNS; CORE
MEASURES; CARE; SPECIALTY; PERFORMANCE; READMISSION; PHYSICIANS;
SURVIVAL
AB Physician practice patterns in the management of hospitalized acute decompensated heart failure (ADHF) patients may vary by specialty; comparative practice patterns in ADHF management and clinical outcomes as a function of provider type have not been well reported. We studied a total of 496 patients discharged with the principal diagnosis of ADHF to analyze practice patterns among 3 provider types (cardiologists, hospitalists, and non-hospitalists). We examined outcomes of death and rehospitalization for HF and adherence to the Joint Cominission HF performance core measures. Cardiologists had the highest adherence in all 4 HF core measures compared with hospitalists and nonhospitalists. At 6 months, 6.0% of the patients cared by cardiologists died compared with 10.9% and 11.4% cared by hospitalist and nonhospitalists (p = 0.12). Patients cared for by cardiologists had a significantly lower 6-month ADHF readmission rate (16.2%) compared with hospitalists (40.1%) and nonhospitalists (34.9%, p <0.001). In multivariate analysis, both hospitalist and nonhospitalist provider types were an independent predictor for 6-month ADHF-related readmission (hospitalists vs cardiologists, hazard ratio(adjusted) 3.01; 95% confidence interval 1.84 to 4.89, p <0.001; and nonhospitalists vs cardiologists, hazard ratio(adjusted) 2.07; 95% confidence interval 1.24 to 3.46, p = 0.005). In conclusion, cardiologist-delivered ADHF care is associated with greater adherence to HF core measures and with significantly lower rates of adverse outcome compared with noncardiologists. (C) 2015 Elsevier Inc. All rights reserved.
C1 [Uthamalingam, Shanmugam] Baystate Med Ctr, Dept Cardiol, Springfield, MA USA.
[Selyaraj, Vijairam] Baystate Med Ctr, Dept Internal Med, Springfield, MA 01199 USA.
[Kandala, Jagdesh] Univ Arizona, Dept Cardiol, Sarver Heart Ctr, Tucson, AZ USA.
[Martin, William] Catholic Med Ctr, Dartmouth Hitchcock Clin, Hospitalist Div, Manchester, NH USA.
[Daley, Marlyn; Capodilupo, Robert] Catholic Med Ctr, Div Cardiol, New England Heart Inst, Manchester, NH USA.
[Patvardhan, Eshan] St Elizabeth Hosp, Div Cardiol, Boston, MA USA.
[Moore, Stephanie; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.
RP Selyaraj, V (reprint author), Baystate Med Ctr, Dept Internal Med, Springfield, MA 01199 USA.
EM vijairam.selvaraj@bhs.org
FU Roche Diagnostics; Siemens; Critical Diagnostics
FX Grant support: Dr. Januzzi reports receiving grant support from Roche
Diagnostics, Siemens, and Critical Diagnostics.
NR 16
TC 1
Z9 2
U1 1
U2 2
PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC
PI BRIDGEWATER
PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA
SN 0002-9149
EI 1879-1913
J9 AM J CARDIOL
JI Am. J. Cardiol.
PD FEB 15
PY 2015
VL 115
IS 4
BP 466
EP 471
DI 10.1016/j.amjcard.2014.11.034
PG 6
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA CB5FW
UT WOS:000349653900011
PM 25637324
ER
PT J
AU Brown, FD
Turley, SJ
AF Brown, Flavian D.
Turley, Shannon J.
TI Fibroblastic Reticular Cells: Organization and Regulation of the T
Lymphocyte Life Cycle
SO JOURNAL OF IMMUNOLOGY
LA English
DT Review
ID HIGH ENDOTHELIAL VENULES; NODE STROMAL CELLS; DENDRITIC CELLS; IN-VIVO;
NITRIC-OXIDE; CONDUIT SYSTEM; STEADY-STATE; ANTIGEN; TOLERANCE; NAIVE
AB The connective tissue of any organ in the body is generally referred to as stroma. This complex network is commonly composed of leukocytes, extracellular matrix components, mesenchymal cells, and a collection of nerves, blood, and lymphoid vessels. Once viewed primarily as a structural entity, stromal cells of mesenchymal origin are now being intensely examined for their ability to directly regulate various components of immune cell function. There is particular interest in the ability of stromal cells to influence the homeostasis, activation, and proliferation of T lymphocytes. One example of this regulation occurs in the lymph node, where fibroblastic reticular cells support the maintenance of naive T cells, induce Ag-specific tolerance, and restrict the expansion of newly activated T cells. In an effort to highlight the varied immunoregulatory properties of fibroblastic reticular cells, we reviewed the most recent advances in this field and provide some insights into potential future directions.
C1 [Brown, Flavian D.] Harvard Univ, Sch Med, Div Med Sci, Boston, MA 02115 USA.
[Brown, Flavian D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.
[Turley, Shannon J.] Genentech Inc, Dept Canc Immunol, San Francisco, CA 94080 USA.
RP Turley, SJ (reprint author), Genentech Inc, Dept Canc Immunol, One DNA Way, San Francisco, CA 94080 USA.
EM turley.shannon@gene.com
FU Howard Hughes Medical Institute Gilliam Fellowship for Advanced Study
FX This work was supported by a Howard Hughes Medical Institute Gilliam
Fellowship for Advanced Study (to F.D.B.).
NR 69
TC 12
Z9 12
U1 2
U2 12
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 2015
VL 194
IS 4
BP 1389
EP 1394
DI 10.4049/jimmunol.1402520
PG 6
WC Immunology
SC Immunology
GA CB2MP
UT WOS:000349462000001
PM 25663676
ER
PT J
AU Briercheck, EL
Trotta, R
Chen, L
Hartlage, AS
Cole, JP
Cole, TD
Mao, C
Banerjee, PP
Hsu, HT
Mace, EM
Ciarlariello, D
Mundy-Bosse, BL
Garcia-Cao, I
Scoville, SD
Yu, LB
Pilarski, R
Carson, WE
Leone, G
Pandolfi, PP
Yu, JH
Orange, JS
Caligiuri, MA
AF Briercheck, Edward L.
Trotta, Rossana
Chen, Li
Hartlage, Alex S.
Cole, Jordan P.
Cole, Tyler D.
Mao, Charlene
Banerjee, Pinaki P.
Hsu, Hsiang-Ting
Mace, Emily M.
Ciarlariello, David
Mundy-Bosse, Bethany L.
Garcia-Cao, Isabel
Scoville, Steven D.
Yu, Lianbo
Pilarski, Robert
Carson, William E., III
Leone, Gustavo
Pandolfi, Pier Paolo
Yu, Jianhua
Orange, Jordan S.
Caligiuri, Michael A.
TI PTEN Is a Negative Regulator of NK Cell Cytolytic Function
SO JOURNAL OF IMMUNOLOGY
LA English
DT Article
ID NATURAL-KILLER-CELLS; TUMOR-SUPPRESSOR PTEN; IMMUNOLOGICAL SYNAPSE;
GRANULE POLARIZATION; CYTOTOXIC ACTIVITY; IN-VIVO; EXPRESSION; CANCER;
GENE; DIFFERENTIATION
AB Human NK cells are characterized by their ability to initiate an immediate and direct cytolytic response to virally infected or malignantly transformed cells. Within human peripheral blood, the more mature CD56(dim) NK cell efficiently kills malignant targets at rest, whereas the less mature CD56(bright) NK cells cannot. In this study, we show that resting CD56(bright) NK cells express significantly more phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein when compared with CD56(dim) NK cells. Consistent with this, forced overexpression of PTEN in NK cells resulted in decreased cytolytic activity, and loss of PTEN in CD56(bright) NK cells resulted in elevated cytolytic activity. Comparable studies in mice showed PTEN overexpression did not alter NK cell development or NK cell-activating and inhibitory receptor expression yet, as in humans, did decrease expression of downstream NK activation targets MAPK and AKT during early cytolysis of tumor target cells. Confocal microscopy revealed that PTEN overexpression disrupts the NK cell's ability to organize immunological synapse components including decreases in actin accumulation, polarization of the microtubule organizing center, and the convergence of cytolytic granules. In summary, our data suggest that PTEN normally works to limit the NK cell's PI3K/AKT and MAPK pathway activation and the consequent mobilization of cytolytic mediators toward the target cell and suggest that PTEN is among the active regulatory components prior to human NK cells transitioning from the noncytolytic CD56(bright) NK cell to the cytolytic CD56(dim) NK cells.
C1 [Briercheck, Edward L.; Hartlage, Alex S.; Scoville, Steven D.; Carson, William E., III; Leone, Gustavo; Caligiuri, Michael A.] Ohio State Univ, Med Scientist Training Program, Columbus, OH 43210 USA.
[Briercheck, Edward L.; Hartlage, Alex S.; Scoville, Steven D.; Carson, William E., III; Leone, Gustavo; Caligiuri, Michael A.] Ohio State Univ, Biomed Sci Grad Program, Columbus, OH 43210 USA.
[Trotta, Rossana; Chen, Li; Cole, Jordan P.; Cole, Tyler D.; Mao, Charlene; Mundy-Bosse, Bethany L.; Carson, William E., III; Leone, Gustavo; Caligiuri, Michael A.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA.
[Trotta, Rossana; Chen, Li; Cole, Jordan P.; Cole, Tyler D.; Mao, Charlene; Mundy-Bosse, Bethany L.; Carson, William E., III; Leone, Gustavo; Caligiuri, Michael A.] Ohio State Univ, Arthur G James Canc Hosp, Columbus, OH 43210 USA.
[Trotta, Rossana; Chen, Li; Cole, Jordan P.; Cole, Tyler D.; Mao, Charlene; Mundy-Bosse, Bethany L.; Carson, William E., III; Leone, Gustavo; Caligiuri, Michael A.] Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43210 USA.
[Trotta, Rossana] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA.
[Trotta, Rossana] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA.
[Banerjee, Pinaki P.; Hsu, Hsiang-Ting; Mace, Emily M.; Orange, Jordan S.] Texas Childrens Hosp, Baylor Coll Med, Ctr Human Immunobiol, Houston, TX 77030 USA.
[Banerjee, Pinaki P.; Orange, Jordan S.] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA.
[Ciarlariello, David; Pandolfi, Pier Paolo] Ohio State Univ, Mol Cellular & Dev Biol Program, Columbus, OH 43210 USA.
[Garcia-Cao, Isabel; Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Genet Program,Dept Med & Pathol, Boston, MA 02215 USA.
[Yu, Lianbo] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA.
[Pilarski, Robert] Ohio State Univ, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA.
[Carson, William E., III] Ohio State Univ, Dept Surg, Columbus, OH 43210 USA.
[Leone, Gustavo] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA.
[Leone, Gustavo; Caligiuri, Michael A.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA.
[Yu, Jianhua; Caligiuri, Michael A.] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA.
RP Caligiuri, MA (reprint author), Ohio State Univ, Ctr Comprehens Canc, 460 West 12th Ave, Columbus, OH 43210 USA.
EM michael.caligiuri@osumc.edu
RI Carson, William/E-2846-2011; Pilarski, Robert/E-3871-2011;
OI orange, jordan/0000-0001-7117-7725
FU National Cancer Institute [CA16058, CA95426, CA68458]; Pelotonia
Fellowship Program (Columbus, OH); National Institutes of Health
Training Grant [T32-CA009338]
FX This work was supported by National Cancer Institute Grants CA16058 (to
M.A.C.), CA95426 (to M.A.C.), and CA68458 (to M.A.C.). E.L.B. is
supported by the Pelotonia Fellowship Program (Columbus, OH). B.L.M.-B.
is supported by National Institutes of Health Training Grant
T32-CA009338 (to M.A.C).
NR 56
TC 4
Z9 5
U1 1
U2 8
PU AMER ASSOC IMMUNOLOGISTS
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0022-1767
EI 1550-6606
J9 J IMMUNOL
JI J. Immunol.
PD FEB 15
PY 2015
VL 194
IS 4
BP 1832
EP 1840
DI 10.4049/jimmunol.1401224
PG 9
WC Immunology
SC Immunology
GA CB2MP
UT WOS:000349462000046
PM 25595786
ER
PT J
AU Ishikawa, K
Aguero, J
Tilemann, L
Ladage, D
Hammoudi, N
Kawase, Y
Santos-Gallego, CG
Fish, K
Levine, RA
Hajjar, RJ
AF Ishikawa, Kiyotake
Aguero, Jaume
Tilemann, Lisa
Ladage, Dennis
Hammoudi, Nadjib
Kawase, Yoshiaki
Santos-Gallego, Carlos G.
Fish, Kenneth
Levine, Robert A.
Hajjar, Roger J.
TI Reply to "Letter to the editor: Characterizing preclinical model of
ischemic heart failure: difference between LAD and LCx infarctions"
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Letter
ID MITRAL REGURGITATION; MYOCARDIAL-INFARCTION
C1 [Ishikawa, Kiyotake; Aguero, Jaume; Tilemann, Lisa; Ladage, Dennis; Hammoudi, Nadjib; Kawase, Yoshiaki; Santos-Gallego, Carlos G.; Fish, Kenneth; Hajjar, Roger J.] Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA.
[Levine, Robert A.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
RP Ishikawa, K (reprint author), Mt Sinai Sch Med, Cardiovasc Res Ctr, One Gustave L Levy Pl,Box 1030, New York, NY 10029 USA.
EM kiyotake.ishikawa@mssm.edu
RI ishikawa, kiyotake/I-6013-2015; Aguero, Jaume/I-8582-2016
OI Aguero, Jaume/0000-0001-7416-871X
NR 11
TC 0
Z9 0
U1 0
U2 2
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6135
EI 1522-1539
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD FEB 15
PY 2015
VL 308
IS 4
BP H365
EP H366
DI 10.1152/ajpheart.00855.2014
PG 2
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
Disease
SC Cardiovascular System & Cardiology; Physiology
GA CB0FD
UT WOS:000349300100012
PM 25684739
ER
PT J
AU Liu, F
Lagares, D
Choi, KM
Stopfer, L
Marinkovic, A
Vrbanac, V
Probst, CK
Hiemer, SE
Sisson, TH
Horowitz, JC
Rosas, IO
Fredenburgh, LE
Feghali-Bostwick, C
Varelas, X
Tager, AM
Tschumperlin, DJ
AF Liu, Fei
Lagares, David
Choi, Kyoung Moo
Stopfer, Lauren
Marinkovic, Aleksandar
Vrbanac, Vladimir
Probst, Clemens K.
Hiemer, Samantha E.
Sisson, Thomas H.
Horowitz, Jeffrey C.
Rosas, Ivan O.
Fredenburgh, Laura E.
Feghali-Bostwick, Carol
Varelas, Xaralabos
Tager, Andrew M.
Tschumperlin, Daniel J.
TI Mechanosignaling through YAP and TAZ drives fibroblast activation and
fibrosis
SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
LA English
DT Article
DE Hippo; idiopathic pulmonary fibrosis; mechanotransduction; plasminogen
activator inhibitor 1; extracellular matrix
ID IDIOPATHIC PULMONARY-FIBROSIS; GROWTH-FACTOR-BETA; EXTRACELLULAR-MATRIX;
HIPPO PATHWAY; TRANSCRIPTIONAL COACTIVATOR; LUNG FIBROSIS; MECHANICAL
MEMORY; STRESS FIBERS; SELF-RENEWAL; TGF-BETA
AB Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-beta signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.
C1 [Liu, Fei; Marinkovic, Aleksandar; Tschumperlin, Daniel J.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA.
[Lagares, David; Vrbanac, Vladimir; Probst, Clemens K.; Tager, Andrew M.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Charlestown, MA USA.
[Lagares, David; Vrbanac, Vladimir; Probst, Clemens K.; Tager, Andrew M.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA USA.
[Choi, Kyoung Moo; Stopfer, Lauren; Tschumperlin, Daniel J.] Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN USA.
[Hiemer, Samantha E.; Varelas, Xaralabos] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA.
[Sisson, Thomas H.; Horowitz, Jeffrey C.] Univ Michigan, Med Ctr, Dept Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA.
[Rosas, Ivan O.; Fredenburgh, Laura E.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA.
[Feghali-Bostwick, Carol] Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA.
RP Tschumperlin, DJ (reprint author), Mayo Clin, Coll Med, 200 1st St SW, Rochester, MN 55906 USA.
EM tschumperlin.daniel@mayo.edu
OI Varelas, Xaralabos/0000-0002-2882-4541; Horowitz,
Jeffrey/0000-0002-1505-2837
FU NIH [HL092961, HL113796, HL095732, HL108975, DK046200, HL105489,
HL078871, HL115106, HL114839]; Concern Cancer Foundation
FX This work was supported by NIH HL092961 and HL113796 (D. Tschumperlin),
NIH HL095732 and HL108975 (A. Tager), support from the Concern Cancer
Foundation and NIH DK046200 (X. Varelas), NIH HL105489 (J. Horowitz),
NIH HL078871 (T. Sisson), and NIH HL115106 and HL114839 (L.
Fredenburgh).
NR 63
TC 40
Z9 42
U1 4
U2 33
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 1040-0605
EI 1522-1504
J9 AM J PHYSIOL-LUNG C
JI Am. J. Physiol.-Lung Cell. Mol. Physiol.
PD FEB 15
PY 2015
VL 308
IS 4
BP L344
EP L357
DI 10.1152/ajplung.00300.2014
PG 14
WC Physiology; Respiratory System
SC Physiology; Respiratory System
GA CB0HB
UT WOS:000349305400004
PM 25502501
ER
PT J
AU Roy, A
Goodman, JH
Begum, G
Donnelly, BF
Pittman, G
Weinman, EJ
Sun, D
Subramanya, AR
AF Roy, Ankita
Goodman, Joshua H.
Begum, Gulnaz
Donnelly, Bridget F.
Pittman, Gabrielle
Weinman, Edward J.
Sun, Dandan
Subramanya, Arohan R.
TI Generation of WNK1 knockout cell lines by CRISPR/Cas-mediated genome
editing
SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
LA English
DT Article
DE WNK1; SLC12 cotransporters; genome editing; CRISPR/Cas system
ID K-CL COTRANSPORTER; KELCH-LIKE 3; RETICULUM-ASSOCIATED DEGRADATION;
CATION-CHLORIDE COTRANSPORTERS; SENSITIVE NACL COTRANSPORTER;
PROTEIN-KINASE; BLOOD-PRESSURE; ANGIOTENSIN-II; HYPERTENSION; MUTATIONS
AB Sodium-coupled SLC12 cation chloride cotransporters play important roles in cell volume and chloride homeostasis, epithelial fluid secretion, and renal tubular salt reabsorption. These cotransporters are phosphorylated and activated indirectly by With-No-Lysine (WNK) kinases through their downstream effector kinases, Ste20-and SPS1-related proline alanine-rich kinase (SPAK) and oxidative stress-responsive kinase 1 (OSR1). Multiple WNK kinases can coexist within a single cell type, although their relative contributions to SPAK/OSR1 activation and salt transport remain incompletely understood. Deletion of specific WNKs from cells that natively express a functional WNK-SPAK/OSR1 network will help resolve these knowledge gaps. Here, we outline a simple method to selectively knock out full-length WNK1 expression from mammalian cells using RNA-guided clustered regularly interspaced short palindromic repeats/Cas9 endonucleases. Two clonal cell lines were generated by using a single-guide RNA (sgRNA) targeting exon 1 of the WNK1 gene, which produced indels that abolished WNK1 protein expression. Both cell lines exhibited reduced endogenous WNK4 protein abundance, indicating that WNK1 is required for WNK4 stability. Consistent with an on-target effect, the reduced WNK4 abundance was associated with increased expression of the KLHL3/cullin-3 E3 ubiquitin ligase complex and was rescued by exogenous WNK1 overexpression. Although the morphology of the knockout cells was indistinguishable from control, they exhibited low baseline SPAK/OSR1 activity and failed to trigger regulatory volume increase after hypertonic stress, confirming an essential role for WNK1 in cell volume regulation. Collectively, our data show how this new, powerful, and accessible gene-editing technology can be used to dissect and analyze WNK signaling networks.
C1 [Roy, Ankita; Goodman, Joshua H.; Donnelly, Bridget F.; Pittman, Gabrielle; Subramanya, Arohan R.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA.
[Begum, Gulnaz; Sun, Dandan] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA.
[Subramanya, Arohan R.] Univ Pittsburgh, Sch Med, Dept Cell Biol, Pittsburgh, PA 15261 USA.
[Weinman, Edward J.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA.
[Sun, Dandan; Subramanya, Arohan R.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA.
RP Subramanya, AR (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Renal Electrolyte, S828A Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA.
EM ars129@pitt.edu
FU National Institute of Health [R01DK098145, P30DK79307, R01 NS038118,
NS075995, R01DK55881]; Mid-Level Career Development Award from the US
Department of Veterans Affairs; US Department of Veterans Affairs
Middleton Award
FX The study was supported by National Institute of Health Grants
R01DK098145 (to A. R. Subramanya), P30DK79307 (Pittsburgh Center for
Kidney Research), R01 NS038118, and NS075995 (to D. Sun), and R01DK55881
(to E.J. Weinman), a Mid-Level Career Development Award from the US
Department of Veterans Affairs (to A. R. Subramanya), and funds from a
US Department of Veterans Affairs Middleton Award (to E. J. Weinman).
NR 54
TC 10
Z9 10
U1 4
U2 24
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 1931-857X
EI 1522-1466
J9 AM J PHYSIOL-RENAL
JI Am. J. Physiol.-Renal Physiol.
PD FEB 15
PY 2015
VL 308
IS 4
BP F366
EP F376
DI 10.1152/ajprenal.00612.2014
PG 11
WC Physiology; Urology & Nephrology
SC Physiology; Urology & Nephrology
GA CB0CB
UT WOS:000349291200010
PM 25477473
ER
PT J
AU Su, Y
Blazey, TM
Snyder, AZ
Raichle, ME
Marcus, DS
Ances, BM
Bateman, RJ
Cairns, NJ
Aldea, P
Cash, L
Christensen, JJ
Friedrichsen, K
Hornbeck, RC
Farrar, AM
Owen, CJ
Mayeux, R
Brickman, AM
Klunk, W
Price, JC
Thompson, PM
Ghetti, B
Saykin, AJ
Sperling, RA
Johnson, KA
Schofield, PR
Buckles, V
Morris, JC
Benzinger, TLS
AF Su, Yi
Blazey, Tyler M.
Snyder, Abraham Z.
Raichle, Marcus E.
Marcus, Daniel S.
Ances, Beau M.
Bateman, Randall J.
Cairns, Nigel J.
Aldea, Patricia
Cash, Lisa
Christensen, Jon J.
Friedrichsen, Karl
Hornbeck, Russ C.
Farrar, Angela M.
Owen, Christopher J.
Mayeux, Richard
Brickman, Adam M.
Klunk, William
Price, Julie C.
Thompson, Paul M.
Ghetti, Bernadino
Saykin, Andrew J.
Sperling, Reisa A.
Johnson, Keith A.
Schofield, Peter R.
Buckles, Virginia
Morris, John C.
Benzinger, Tammie L. S.
CA Dominantly Inherited Alzheimer
TI Partial volume correction in quantitative amyloid imaging
SO NEUROIMAGE
LA English
DT Article
DE PET; Partial volume correction; PiB; Amyloid imaging
ID PITTSBURGH COMPOUND-B; POSITRON-EMISSION-TOMOGRAPHY; MILD COGNITIVE
IMPAIRMENT; ALZHEIMERS-DISEASE; GRAPHICAL ANALYSIS; PET; MRI;
DEPOSITION; BINDING; BETA
AB Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition. (C) 2014 Elsevier Inc. All rights reserved.
C1 [Su, Yi; Blazey, Tyler M.; Snyder, Abraham Z.; Raichle, Marcus E.; Marcus, Daniel S.; Ances, Beau M.; Aldea, Patricia; Cash, Lisa; Christensen, Jon J.; Friedrichsen, Karl; Hornbeck, Russ C.; Farrar, Angela M.; Owen, Christopher J.; Benzinger, Tammie L. S.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA.
[Snyder, Abraham Z.; Ances, Beau M.; Bateman, Randall J.; Buckles, Virginia; Morris, John C.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA.
[Cairns, Nigel J.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.
[Mayeux, Richard; Brickman, Adam M.] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA.
[Klunk, William] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA.
[Price, Julie C.] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA 15213 USA.
[Thompson, Paul M.] Univ So Calif, Imaging Genet Ctr, Inst Neuroimaging & Informat, Los Angeles, CA 90032 USA.
[Thompson, Paul M.] Univ So Calif, Dept Neurol, Los Angeles, CA 90032 USA.
[Thompson, Paul M.] Univ So Calif, Dept Psychiat, Los Angeles, CA 90032 USA.
[Thompson, Paul M.] Univ So Calif, Dept Engn, Los Angeles, CA 90032 USA.
[Thompson, Paul M.] Univ So Calif, Dept Radiol, Los Angeles, CA 90032 USA.
[Thompson, Paul M.] Univ So Calif, Dept Pediat, Los Angeles, CA 90032 USA.
[Thompson, Paul M.] Univ So Calif, Dept Ophthalmol, Los Angeles, CA 90032 USA.
[Ghetti, Bernadino] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA.
[Saykin, Andrew J.] Indiana Univ Sch Med, Ctr Neuroimaging, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA.
[Sperling, Reisa A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA.
[Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA.
[Schofield, Peter R.] Neurosci Res Australia, Sydney, NSW 2031, Australia.
[Schofield, Peter R.] Univ New S Wales, Sch Med Sci, Sydney, NSW 2052, Australia.
RP Su, Y (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Campus Box 8131,510 S Kingshighway Blvd, St Louis, MO 63110 USA.
EM suy@mir.wustl.edu
OI Ances, Beau/0000-0003-3862-7397
FU Knight Alzheimer's Disease Research Center grants [P50AG005681,
P01AG003991, P01AG026276, U19AG032438, P30NS048056]; Charles F. and
Joanne Knight Alzheimer's Initiative; David and Betty Farrell Medical
Research Fund
FX This research was supported by the Knight Alzheimer's Disease Research
Center grants (P50AG005681, P01AG003991, P01AG026276, U19AG032438, and
P30NS048056). Support was also provided by the Charles F. and Joanne
Knight Alzheimer's Initiative, the David and Betty Farrell Medical
Research Fund, and the generous support of F Simmons and O Mohan.
NR 46
TC 25
Z9 25
U1 3
U2 15
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 1053-8119
EI 1095-9572
J9 NEUROIMAGE
JI Neuroimage
PD FEB 15
PY 2015
VL 107
BP 55
EP 64
DI 10.1016/j.neuroimage.2014.11.058
PG 10
WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical
Imaging
SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging
GA AZ2CT
UT WOS:000348043100007
PM 25485714
ER
PT J
AU Reuter, M
Tisdall, MD
Qureshi, A
Buckner, RL
van der Kouwe, AJW
Fischl, B
AF Reuter, Martin
Tisdall, M. Dylan
Qureshi, Abid
Buckner, Randy L.
van der Kouwe, Andre J. W.
Fischl, Bruce
TI Head motion during MRI acquisition reduces gray matter volume and
thickness estimates
SO NEUROIMAGE
LA English
DT Article
DE Head motion; MRI; Cortical gray matter estimates; Spurious effect; Bias;
Volume; Thickness; Quality control
ID LONGITUDINAL NEUROIMAGE DATA; FUNCTIONAL CONNECTIVITY MRI; IMAGE-BASED
TRACKING; COORDINATE SYSTEM; CORTICAL SURFACE; BRAIN; DEHYDRATION;
DISEASE; ATROPHY
AB Imaging biomarkers derived from magnetic resonance imaging (MRI) data are used to quantify normal development, disease, and the effects of disease-modifying therapies. However, motion during image acquisition introduces image artifacts that, in turn, affect derived markers. A systematic effect can be problematic since factors of interest like age, disease, and treatment are often correlated with both a structural change and the amount of head motion in the scanner, confounding the ability to distinguish biology from artifact. Here we evaluate the effect of head motion during image acquisition on morphometric estimates of structures in the human brain using several popular image analysis software packages (FreeSurfer 5.3, VBM8 SPM, and FSL Siena 5.0.7). Within-session repeated T1-weighted MRIs were collected on 12 healthy volunteers while performing different motion tasks, including two still scans. We show that volume and thickness estimates of the cortical gray matter are biased by head motion with an average apparent volume loss of roughly 0.7%/mm/min of subject motion. Effects vary across regions and remain significant after excluding scans that fail a rigorous quality check. In view of these results, the interpretation of reported morphometric effects of movement disorders or other conditions with increased motion tendency may need to be revisited: effects may be overestimated when not controlling for head motion. Furthermore, drug studies with hypnotic, sedative, tranquilizing, or neuromuscular-blocking substances may contain spurious "effects" of reduced atrophy or brain growth simply because they affect motion distinct from true effects of the disease or therapeutic process. (C) 2014 Elsevier Inc. All rights reserved.
C1 [Reuter, Martin; Qureshi, Abid] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.
[Reuter, Martin; Tisdall, M. Dylan; Buckner, Randy L.; van der Kouwe, Andre J. W.; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.
[Reuter, Martin; Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.
[Reuter, Martin; Tisdall, M. Dylan; Qureshi, Abid; Buckner, Randy L.; van der Kouwe, Andre J. W.; Fischl, Bruce] Harvard Univ, Sch Med, Boston, MA 02115 USA.
RP Reuter, M (reprint author), AA Martinos Ctr Biomed Imaging, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA.
EM mreuter@nmr.mgh.harvard.edu
FU National Cancer Institute [1 K25-CA181632-01]; NIH Eunice Kennedy
Shriver National Institute of Child Health and Human Development
[R01-HD071664, K99-HD074649]; National Institute of Mental Health
[R21-MH096559]; National Center for Research Resources [P41-RR014075,
U24-RR021382, 1UL1-RR025758-01, 1S10-RR023401, 1S10-RR019307,
1S10-RR023043]; National Institute for Biomedical Imaging and
Bioengineering [8P41-EB015896-15]; National Institute on Aging
[5R01-AG008122-23, 2R01-AG016495, R21-AG046657]; National Institute for
Neurological Disorders and Stroke [5R21-NS072652-02, 5R01-NS070963-03,
1R01-NS083534]
FX Support for this research was provided in part by the National Cancer
Institute (1 K25-CA181632-01), the NIH Eunice Kennedy Shriver National
Institute of Child Health and Human Development (R01-HD071664,
K99-HD074649), the National Institute of Mental Health (R21-MH096559),
the National Center for Research Resources (P41-RR014075, U24-RR021382,
1UL1-RR025758-01, 1S10-RR023401, 1S10-RR019307, 1S10-RR023043), the
National Institute for Biomedical Imaging and Bioengineering
(8P41-EB015896-15), the National Institute on Aging (5R01-AG008122-23,
2R01-AG016495, R21-AG046657), and the National Institute for
Neurological Disorders and Stroke (5R21-NS072652-02, 5R01-NS070963-03,
1R01-NS083534). In addition, BF has a financial interest in
CorticoMetrics, a company whose medical pursuits focus on brain imaging
and measurement technologies. BF's interests were reviewed and are
managed by Massachusetts General Hospital and Partners HealthCare in
accordance with their conflict of interest policies. MR and MDT had full
access to all of the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
NR 33
TC 40
Z9 40
U1 1
U2 18
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 2015
VL 107
BP 107
EP 115
DI 10.1016/j.neuroimage.2014.12.006
PG 9
WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical
Imaging
SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging
GA AZ2CT
UT WOS:000348043100012
PM 25498430
ER
PT J
AU Yehuda, R
Flory, JD
Bierer, LM
Henn-Haase, C
Lehrner, A
Desarnaud, F
Makotkine, I
Daskalakis, NP
Marmar, CR
Meaney, MJ
AF Yehuda, Rachel
Flory, Janine D.
Bierer, Linda M.
Henn-Haase, Clare
Lehrner, Amy
Desarnaud, Frank
Makotkine, Iouri
Daskalakis, Nikolaos P.
Marmar, Charles R.
Meaney, Michael J.
TI Lower Methylation of Glucocorticoid Receptor Gene Promoter 1(F) in
Peripheral Blood of Veterans with Posttraumatic Stress Disorder
SO BIOLOGICAL PSYCHIATRY
LA English
DT Article
DE Biomarkers; Combat; Cortisol; Glucocorticoid receptor; HPA axis;
Methylation; NR3C1 gene; NR3C1-1(F) promoter; PTSD
ID DNA METHYLATION; MAJOR DEPRESSION; CHILDHOOD ABUSE; CORTISOL;
DEXAMETHASONE; TRAUMA; NR3C1; SENSITIVITY; SUPPRESSION; INSTRUMENT
AB BACKGROUND: Enhanced glucocorticoid receptor (GR) sensitivity is present in people with posttraumatic stress disorder (PTSD), but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptoms given that PTSD develops in only a subset of trauma survivors.
METHODS: Cytosine methylation of a relevant promoter of the GR gene (NR3C1-1(F) promoter) and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal axis function were examined in a sample of 122 combat veterans.
RESULTS: Lower NR3C1-1(F) promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared with combat-exposed veterans who did not develop PTSD. NR3C1-1(F) promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMCs' lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (.50 mg) dexamethasone suppression test, and 24-hour urinary cortisol excretion. Finally, NR3C1-1(F) promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD.
CONCLUSIONS: Alterations in NR3C1-1(F) promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. Because epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop PTSD.
C1 [Yehuda, Rachel; Flory, Janine D.; Bierer, Linda M.; Lehrner, Amy; Desarnaud, Frank; Makotkine, Iouri; Daskalakis, Nikolaos P.] James J Peters Vet Affairs Med Ctr, Mental Hlth Care Ctr, Bronx, NY USA.
[Yehuda, Rachel; Flory, Janine D.; Bierer, Linda M.; Lehrner, Amy; Desarnaud, Frank; Makotkine, Iouri; Daskalakis, Nikolaos P.] Icahn Sch Med Mt Sinai, Traumat Stress Studies Div, New York, NY 10029 USA.
[Yehuda, Rachel; Flory, Janine D.; Bierer, Linda M.; Lehrner, Amy; Desarnaud, Frank; Makotkine, Iouri; Daskalakis, Nikolaos P.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.
[Yehuda, Rachel] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA.
[Henn-Haase, Clare; Marmar, Charles R.] NYU, Sch Med, Steven & Alexandra Cohen Vet Ctr Study Posttrauma, New York, NY USA.
[Henn-Haase, Clare; Marmar, Charles R.] NYU, Sch Med, Dept Psychiat, New York, NY USA.
[Meaney, Michael J.] McGill Univ, Sackler Program Epigenet Psychobiol, Montreal, PQ, Canada.
[Meaney, Michael J.] McGill Univ, Dept Psychiat & Neurol, Montreal, PQ, Canada.
[Meaney, Michael J.] McGill Univ, Dept Neurosurg, Montreal, PQ H3A 2T5, Canada.
[Meaney, Michael J.] Singapore Inst Clin Sci, Singapore, Singapore.
RP Yehuda, R (reprint author), Icahn Sch Med Mt Sinai, James J Peters Vet Affairs Med Ctr, Traumat Stress Studies Div, Dept Psychiat, 526 OOMH PTSD 116-A,130 West Kingsbridge Rd, Bronx, NY 10468 USA.
EM rachel.yehuda@va.gov
RI Daskalakis, Nikolaos/B-7930-2014
OI Daskalakis, Nikolaos/0000-0003-1660-9112
FU Department of Defense [W911NF-09-1-0298, W81XWH-09-2-0044,
W81XWH-10-1-0021]
FX This work was supported by grant funding from the Department of Defense
(Grant No. W911NF-09-1-0298 to RY and Grant No. W81XWH-09-2-0044 to
CRM). We thank Dr. Owen Wolkowitz for scientific collaboration and for
funding that permitted additional recruitment (Department of Defense
Grant No. W81XWH-10-1-0021).
NR 44
TC 55
Z9 56
U1 4
U2 47
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 2015
VL 77
IS 4
BP 356
EP 364
DI 10.1016/j.biopsych.2014.02.006
PG 9
WC Neurosciences; Psychiatry
SC Neurosciences & Neurology; Psychiatry
GA AY9ZL
UT WOS:000347906200010
PM 24661442
ER
PT J
AU O'Donovan, A
Cohen, BE
Seal, KH
Bertenthal, D
Margaretten, M
Nishimi, K
Neylan, TC
AF O'Donovan, Aoife
Cohen, Beth E.
Seal, Karen H.
Bertenthal, Dan
Margaretten, Mary
Nishimi, Kristen
Neylan, Thomas C.
TI Elevated Risk for Autoimmune Disorders in Iraq and Afghanistan Veterans
with Posttraumatic Stress Disorder
SO BIOLOGICAL PSYCHIATRY
LA English
DT Article
DE Autoimmune disorders; Glucocorticoids; Immune system; Inflammation;
Military sexual trauma; Posttraumatic stress disorder; Traumatic stress;
Veterans
ID MENTAL-HEALTH DIAGNOSES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; QUALITY-OF-LIFE;
RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; SEX-DIFFERENCES;
HEART-DISEASE; GENDER-DIFFERENCES; IMMUNE FUNCTION; CORTISOL-LEVELS
AB BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with endocrine and immune abnormalities that could increase risk for autoimmune disorders. However, little is known about the risk for autoimmune disorders among individuals with PTSD.
METHODS: We conducted a retrospective cohort study of 666,269 Iraq and Afghanistan veterans under age 55 who were enrolled in the Department of Veterans Affairs health care system between October 7, 2001, and March 31, 2011. Generalized linear models were used to examine if PTSD, other psychiatric disorders, and military sexual trauma exposure increased risk for autoimmune disorders, including thyroiditis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and lupus erythematosus, adjusting for age, gender, race, and primary care visits.
RESULTS: PTSD was diagnosed in 203,766 veterans (30.6%), and psychiatric disorders other than PTSD were diagnosed in an additional 129,704 veterans (19.5%). Veterans diagnosed with PTSD had significantly higher adjusted relative risk (ARR) for diagnosis with any of the autoimmune disorders alone or in combination compared with veterans with no psychiatric diagnoses (ARR - 2.00; 95% confidence interval, 1.91-2.09) and compared with veterans diagnosed with psychiatric disorders other than PTSD (ARR = 1.51; 95% confidence interval, 1.43-1.59; p < .001). The magnitude of the PTSD-related increase in risk for autoimmune disorders was similar in women and men, and military sexual trauma exposure was independently associated with increased risk in both women and men.
CONCLUSIONS: Trauma exposure and PTSD may increase risk for autoimmune disorders. Altered immune function, lifestyle factors, or shared etiology may underlie this association.
C1 [O'Donovan, Aoife; Neylan, Thomas C.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA.
[Cohen, Beth E.; Seal, Karen H.; Margaretten, Mary] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA.
[O'Donovan, Aoife; Cohen, Beth E.; Seal, Karen H.; Bertenthal, Dan; Nishimi, Kristen; Neylan, Thomas C.] San Francisco VA Med Ctr, San Francisco, CA USA.
[O'Donovan, Aoife; Cohen, Beth E.; Seal, Karen H.; Bertenthal, Dan; Nishimi, Kristen; Neylan, Thomas C.] Northern Calif Inst Res & Educ, San Francisco, CA USA.
RP O'Donovan, A (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, 4150 Clement St 116H, San Francisco, CA 94121 USA.
EM aoife.odonovan@ucsf.edu
FU Society in Science-The Branco Weiss Fellowship; Mental Illness Research,
Education and Clinical Centers Program Director Dr. Thomas Neylan;
[NIH-K23 HL 094765-0]; [NIH-KL2TR000143]
FX We acknowledge support for the present manuscript from The Mental
Illness Research, Education and Clinical Centers; Society in Science-The
Branco Weiss Fellowship; and the National Institutes of Health, as well
as the Department of Veterans Affairs and the NCIRE-The Veterans Health
Research Institute. We also thank Ashkan Ahmadian for his excellent
assistance with this manuscript.; Dr. Aoife O'Donovan received salary
support from Society in Science-The Branco Weiss Fellowship. Dr. Beth
Cohen received salary support through NIH-K23 HL 094765-0. Mr. Dan
Bertenthal received grant salary support through grants to Dr. Karen
Seal and The Mental Illness Research, Education and Clinical Centers
Program Director Dr. Thomas Neylan. Dr. Mary Margaretten received grant
support through NIH-KL2TR000143. All other authors reported no
biomedical financial interests or potential conflicts of interest.
NR 65
TC 21
Z9 21
U1 0
U2 22
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 2015
VL 77
IS 4
BP 365
EP 374
DI 10.1016/j.biopsych.2014.06.015
PG 10
WC Neurosciences; Psychiatry
SC Neurosciences & Neurology; Psychiatry
GA AY9ZL
UT WOS:000347906200011
PM 25104173
ER
PT J
AU McLaughlin, KA
Koenen, KC
Friedman, MJ
Ruscio, AM
Karam, EG
Shahly, V
Stein, DJ
Hill, ED
Petukhova, M
Alonso, J
Andrade, LH
Angermeyer, MC
Borges, G
de Girolamo, G
de Graaf, R
Demyttenaere, K
Florescu, SE
Mladenova, M
Posada-Villa, J
Scott, KM
Takeshima, T
Kessler, RC
AF McLaughlin, Katie A.
Koenen, Karestan C.
Friedman, Matthew J.
Ruscio, Ayelet Meron
Karam, Elie G.
Shahly, Victoria
Stein, Dan J.
Hill, Eric D.
Petukhova, Maria
Alonso, Jordi
Andrade, Laura Helena
Angermeyer, Matthias C.
Borges, Guilherme
de Girolamo, Giovanni
de Graaf, Ron
Demyttenaere, Koen
Florescu, Silvia E.
Mladenova, Maya
Posada-Villa, Jose
Scott, Kate M.
Takeshima, Tadashi
Kessler, Ronald C.
TI Subthreshold Posttraumatic Stress Disorder in the World Health
Organization World Mental Health Surveys
SO BIOLOGICAL PSYCHIATRY
LA English
DT Article
DE Epidemiology; Nosology; Partial PTSD; Posttraumatic stress disorder;
PTSD; Subthreshold PTSD
ID PARTIAL PTSD; RISK-FACTORS; FULL PTSD; SYMPTOMS; VETERANS; PREVALENCE;
COMMUNITY; WAR; COMORBIDITY; PREDICTORS
AB BACKGROUND: Although only a few people exposed to a traumatic event (TE) develop posttraumatic stress disorder (PTSD), symptoms that do not meet full PTSD criteria are common and often clinically significant. Individuals with these symptoms sometimes have been characterized as having subthreshold PTSD, but no consensus exists on the optimal definition of this term. Data from a large cross-national epidemiologic survey are used in this study to provide a principled basis for such a definition.
METHODS: The World Health Organization World Mental Health Surveys administered fully structured psychiatric diagnostic interviews to community samples in 13 countries containing assessments of PTSD associated with randomly selected TEs. Focusing on the 23,936 respondents reporting lifetime TE exposure, associations of approximated DSM-5 PTSD symptom profiles with six outcomes (distress-impairment, suicidality, comorbid feardistress disorders, PTSD symptom duration) were examined to investigate implications of different subthreshold definitions.
RESULTS: Although consistently highest outcomes for distress-impairment, suicidality, comorbidity, and PTSD symptom duration were observed among the 3.0% of respondents with DSM-5 PTSD rather than other symptom profiles, the additional 3.6% of respondents meeting two or three of DSM-5 criteria B-E also had significantly elevated scores for most outcomes. The proportion of cases with threshold versus subthreshold PTSD varied depending on TE type, with threshold PTSD more common following interpersonal violence and subthreshold PTSD more common following events happening to loved ones.
CONCLUSIONS: Subthreshold DSM-5 PTSD is most usefully defined as meeting two or three of DSM-5 criteria B-E. Use of a consistent definition is critical to advance understanding of the prevalence, predictors, and clinical significance of subthreshold PTSD.
C1 [McLaughlin, Katie A.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA.
[Koenen, Karestan C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA.
[Friedman, Matthew J.] US Dept Vet Affairs, Natl Ctr PTSD, Hanover, NH USA.
[Friedman, Matthew J.] Geisel Sch Med Dartmouth, Hanover, NH USA.
[Ruscio, Ayelet Meron] Univ Penn, Dept Psychol, Philadelphia, PA 19104 USA.
[Karam, Elie G.] Balamand Univ, St George Hosp Univ Med Ctr, Inst Dev Res Advocacy & Appl Care, Med Inst Neuropsychol Disorders,Fac Med, Beirut, Lebanon.
[Shahly, Victoria; Hill, Eric D.; Petukhova, Maria; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA.
[Stein, Dan J.] Univ Cape Town, Dept Psychiat & Mental Hlth, ZA-7925 Cape Town, South Africa.
[Alonso, Jordi] Univ Pompeu Fabra, Hlth Serv Res Unit, Inst Hosp Mar Invest Med, Consorcio Invest Biomed Red Epidemiol & Salud Pub, Barcelona, Spain.
[Andrade, Laura Helena] Univ Sao Paulo, Sch Med, Sect Psychiat Epidemiology LIM 23, Dept Psychiat, Sao Paulo, Brazil.
[Andrade, Laura Helena] Univ Sao Paulo, Sch Med, Inst Psychiat, Sao Paulo, Brazil.
[Angermeyer, Matthias C.] Ctr Publ Mental Hlth, Gosing Am Wagram, Austria.
[Borges, Guilherme] Natl Inst Psychiat Mexico, Dept Epidemiol Res, Div Epidemiol & Psychosocial Res, Mexico City, DF, Mexico.
[Borges, Guilherme] Metropolitan Autonomous Univ, Mexico City, DF, Mexico.
[de Girolamo, Giovanni] Ctr S Giovanni di Dio Fatebenefratelli, Ist Ricovero & Cura Carattere Sci, Brescia, Italy.
[de Graaf, Ron] Netherlands Inst Mental Hlth & Addict, Utrecht, Netherlands.
[Demyttenaere, Koen] Univ Hosp Gasthuisberg, Dept Psychiat, Leuven, Belgium.
[Florescu, Silvia E.] Natl Sch Publ Hlth Management & Profess Dev, Hlth Serv Res & Evaluat Ctr, Bulgarian Ctr Human Relat, Bucharest, Romania.
[Mladenova, Maya] New Bulgarian Univ, Sofia, Bulgaria.
[Posada-Villa, Jose] Univ Colegio Mayor Cundinamarca, Dept Psychiat, Bogota, Colombia.
[Scott, Kate M.] Univ Otago, Dept Psychol Med, Dunedin, New Zealand.
[Takeshima, Tadashi] Natl Ctr Neurol & Psychiat, Natl Inst Mental Hlth, Kodaira, Tokyo, Japan.
RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA.
EM Kessler@hcp.med.harvard.edu
RI Alonso, Jordi/A-5514-2010; Koenen, Karestan/K-5402-2014; Andrade, Laura
Helena/F-3023-2010;
OI Alonso, Jordi/0000-0001-8627-9636; Koenen, Karestan/0000-0003-3293-4281;
Andrade, Laura Helena/0000-0002-2362-3521; Stein,
Dan/0000-0001-7218-7810; Borges, Guilherme/0000-0002-3269-0507;
McLaughlin, Katie/0000-0002-1362-2410
FU National Institute of Mental Health [R01 MH070884, R01 MH093612-01,
U01-MH60220]; John D. and Catherine T. MacArthur Foundation; Pfizer
Foundation; United States Public Health Service [R13-MH066849,
R01-MH069864, R01 DA016558]; Fogarty International Center [FIRCA
R03-TW006481]; Pan American Health Organization; Eli Lilly and Company;
Ortho-McNeil Pharmaceutical; GlaxoSmithKline; Bristol-Myers Squibb;
State of Sao Paulo Research Foundation Thematic Project [03/00204-3];
Ministry of Social Protection; Ministry of Health; National Center for
Public Health Protection; European Commission [QLG5-1999-01042, 2004123,
20081308]; Piedmont Region, Italy; Fondo de Investigacion Sanitaria;
Instituto de Salud Carlos III, Spain [00/0028]; Ministerio de Ciencia y
Tecnologia, Spain [SAF 2000-158-CE]; Departament de Salut, Generalitat
de Catalunya, Spain; Instituto de Salud Carlos III [CB06/02/0046,
RD06/0011 REM-TAP]; Grant for Research on Psychiatric and Neurological
Diseases and Mental Health [H13-SHOGAI-023, H14-TOKUBETSU-026,
H16-KOKORO-013]; Japan Ministry of Health, Labour and Welfare; National
Institute of Psychiatry Ramon de la Fuente [INPRFMDIES 4280]; National
Council on Science and Technology [CONACyT-G30544-H]; PanAmerican Health
Organization; New Zealand Ministry of Health, Alcohol Advisory Council;
Health Research Council; Ministry of Public Health (former Ministry of
Health); Substance Abuse and Mental Health Services Administration;
Robert Wood Johnson Foundation [044708]; John W. Alden Trust; Abbott
Laboratories; AstraZeneca; Jazz Pharmaceuticals; Johnson Johnson;
Lundbeck; Orion; Pfizer; Pharmacia; Roche; Servier; Solvay; Sumitomo;
Takeda; Tikvah; Wyeth; Analysis Group; EPIQ; Johnson & Johnson
Pharmaceuticals; Ortho-McNeil Janssen Scientific Affairs; Sanofi-Aventis
Groupe; Shire; Walgreens; DataStat, Inc
FX This work, carried out in conjunction with the World Health Organization
World Mental Health (WMH) Survey Initiative, was supported by the
National Institute of Mental Health (Grant Nos. R01 MH070884 and R01
MH093612-01), the John D. and Catherine T. MacArthur Foundation, the
Pfizer Foundation, the United States Public Health Service (Grant Nos.
R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty International
Center (Grant No. FIRCA R03-TW006481), the Pan American Health
Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical,
GlaxoSmithKline, and Bristol-Myers Squibb. We thank the staff of the WMH
Data Collection and Data Analysis Coordination Centres for assistance
with instrumentation, fieldwork, and consultation on data analysis. None
of the funders had any role in the design, analysis, interpretation of
results, or preparation of this article. A complete list of all
within-country and crossnational WMH publications can be found at
http://www.hcp.med.harvard.edu/wmh/.; The Sao Paulo Megacity Mental
Health Survey is supported by the State of Sao Paulo Research Foundation
Thematic Project Grant No. 03/00204-3. The Colombian National Study of
Mental Health is supported by the Ministry of Social Protection. The
Bulgarian Epidemiological Study of common mental disorders (EPIBUL) is
supported by the Ministry of Health and the National Center for Public
Health Protection. The European Study of the Epidemiology of Mental
Disorders (ESEMeD) project is funded by the European Commission
(Contracts QLG5-1999-01042, Health and Consumer Affairs (SANCO) 2004123,
and Executive Agency for Health and Consumers (EACH) 20081308); the
Piedmont Region, Italy; Fondo de Investigacion Sanitaria, Instituto de
Salud Carlos III, Spain (Grant No. Fund for Health of Spain (FIS)
00/0028); Ministerio de Ciencia y Tecnologia, Spain (Grant No. SAF
2000-158-CE); Departament de Salut, Generalitat de Catalunya, Spain;
Instituto de Salud Carlos III (Grant Nos. Networked Biomedical Research
Centres (CIBER) CB06/02/0046 and Cooperative Health Research Thematic
Networks (RETICS) RD06/0011 REM-TAP); and other local agencies and by an
unrestricted educational grant from GlaxoSmithKline. The World Mental
Health Japan Survey is supported by the Grant for Research on
Psychiatric and Neurological Diseases and Mental Health (Grant Nos.
H13-SHOGAI-023, H14-TOKUBETSU-026, and H16-KOKORO-013) from the Japan
Ministry of Health, Labour and Welfare. The Mexican National Comorbidity
Survey is supported by The National Institute of Psychiatry Ramon de la
Fuente (Grant No. INPRFMDIES 4280) and by the National Council on
Science and Technology (Grant No. CONACyT-G30544-H), with supplemental
support from the PanAmerican Health Organization. Te Rau Hinengaro: The
New Zealand Mental Health Survey is supported by the New Zealand
Ministry of Health, Alcohol Advisory Council, and Health Research
Council. The Romania WMH study projects "Policies in Mental Health Area"
and "National Study regarding Mental Health and Services Use" were
carried out by the National School of Public Health & Health Services
Management (former National Institute for Research & Development in
Health, present National School of Public Health Management &
Professional Development, Bucharest), with technical support of Metro
Media Transilvania, the National Institute of Statistics-National Centre
for Training in Statistics, SC, Cheyenne Services SRL, and Statistics
Netherlands, and were funded by the Ministry of Public Health (former
Ministry of Health) with supplemental support of Eli Lilly Romania SRL.
The U.S. National Comorbidity Survey Replication is supported by the
National Institute of Mental Health (Grant No. U01-MH60220) with
supplemental support from the National Institute of Drug Abuse, the
Substance Abuse and Mental Health Services Administration, the Robert
Wood Johnson Foundation (Grant No. 044708), and the John W. Alden
Trust.; DJS has received research grants or consultancy honoraria or
both from Abbott Laboratories, AstraZeneca, Eli Lilly and Company,
GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck,
Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda,
Tikvah, and Wyeth. KD has served on advisory boards and speaker bureaus
for and has research grants from AstraZeneca, Eli Lilly and Company,
GlaxoSmithKline, Lundbeck, Takeda, and Servier. RCK has been a
consultant for AstraZeneca, Analysis Group, Bristol-Myers Squibb, Cerner
Galt, Eli Lilly and Company, GlaxoSmithKline, HealthCore, Health Dialog,
Hoffmann-LaRoche, Integrated Benefits Institute, Wellness & Prevention,
Inc., John Snow, Inc., Kaiser Permanente, Lake Nona Institute, Matria
Healthcare, Mensante, Merck & Co, Ortho-McNeil Janssen Scientific
Affairs, Pfizer, Primary Care Network, Research Triangle Institute,
Sanofi-Aventis Groupe, Shire, SRA International, Inc., Takeda Global
Research & Development, Transcept Pharmaceuticals, and Wyeth-Ayerst; has
served on advisory boards for Appliance Computing Ii, Eli Lilly and
Company, Mindsite, Ortho-McNeil Janssen Scientific Affairs, Johnson &
Johnson, Plus One Health Management, and Wyeth-Ayerst; has had research
support for epidemiologic studies from Analysis Group, Bristol-Myers
Squibb, Eli Lilly and Company, EPIQ, GlaxoSmithKline, Johnson & Johnson
Pharmaceuticals, Ortho-McNeil Janssen Scientific Affairs, Pfizer,
Sanofi-Aventis Groupe, Shire, and Walgreens; and owns 25% share in
DataStat, Inc. All other authors report no biomedical financial
interests or potential conflicts of interest.
NR 42
TC 15
Z9 15
U1 3
U2 25
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 2015
VL 77
IS 4
BP 375
EP 384
DI 10.1016/j.biopsych.2014.03.028
PG 10
WC Neurosciences; Psychiatry
SC Neurosciences & Neurology; Psychiatry
GA AY9ZL
UT WOS:000347906200012
PM 24842116
ER
PT J
AU Lubitz, SA
Singh, JP
AF Lubitz, Steven A.
Singh, Jagmeet P.
TI Biventricular pacing: more is better!
SO EUROPEAN HEART JOURNAL
LA English
DT Editorial Material
ID CARDIAC-RESYNCHRONIZATION THERAPY; HEART-FAILURE; DEFIBRILLATOR
C1 [Singh, Jagmeet P.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
Harvard Univ, Sch Med, Boston, MA USA.
RP Singh, JP (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA.
EM jsingh@mgh.harvard.edu
NR 10
TC 2
Z9 2
U1 0
U2 1
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 14
PY 2015
VL 36
IS 7
BP 407
EP 409
DI 10.1093/eurheartj/ehu347
PG 3
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA CE1RG
UT WOS:000351589000008
PM 25298238
ER
PT J
AU McMurray, J
Packer, M
Desai, A
Gong, JJ
Greenlaw, N
Lefkowitz, M
Rizkala, A
Shi, V
Rouleau, J
Solomon, S
Swedberg, K
Zile, MR
Andersen, K
Arango, JL
Arnold, M
Belohlavek, J
Bohm, M
Boytsov, S
Burgess, L
Cabrera, W
Chen, CH
Erglis, A
Fu, M
Gomez, E
Gonzalez, A
Hagege, AA
Katova, T
Kiatchoosakun, S
Kim, KS
Bayram, E
Martinez, F
Merkely, B
Mendoza, I
Mosterd, A
Negrusz-Kawecka, M
Peuhkurinen, K
Ramires, F
Refsgaard, J
Senni, M
Sibulo, AS
Silva-Cardoso, J
Squire, I
Starling, RC
Vinereanu, D
Teerlink, JR
Wong, R
AF McMurray, John
Packer, Milton
Desai, Akshay
Gong, Jianjian
Greenlaw, Nicola
Lefkowitz, Martin
Rizkala, Adel
Shi, Victor
Rouleau, Jean
Solomon, Scott
Swedberg, Karl
Zile, Michael R.
Andersen, Karl
Arango, Juan Luis
Arnold, Malcolm
Belohlavek, Jan
Boehm, Michael
Boytsov, Sergey
Burgess, Lesley
Cabrera, Walter
Chen, Chen-Huan
Erglis, Andrejs
Fu, Michael
Gomez, Efrain
Gonzalez, Angel
Hagege, Albert-Alain
Katova, Tzvetana
Kiatchoosakun, Songsak
Kim, Kee-Sik
Bayram, Edmundo
Martinez, Felipe
Merkely, Bela
Mendoza, Ivan
Mosterd, Arend
Negrusz-Kawecka, Marta
Peuhkurinen, Keijo
Ramires, Felix
Refsgaard, Jens
Senni, Michele
Sibulo, Antonio S., Jr.
Silva-Cardoso, Jose
Squire, Iain
Starling, Randall C.
Vinereanu, Dragos
Teerlink, John R.
Wong, Raymond
CA PARADIGM-HF Comm Investigators
TI A putative placebo analysis of the effects of LCZ696 on clinical
outcomes in heart failure
SO EUROPEAN HEART JOURNAL
LA English
DT Article
DE Heart failure; Angiotensin II; Natriuretic peptides
ID ACTIVE-CONTROL TRIALS; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIAL;
NON-INFERIORITY; CAPTOPRIL; INHIBITION; ENALAPRIL; MORTALITY; SURVIVAL;
LOSARTAN
AB Aims Although active-controlled trials with reninangiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos.
Methods and results We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 3450%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 2144%; P < 0.0001) and heart failure hospitalization (49%, 3958%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 1539%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 2748%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 1645%; P < 0.0001) for cardiovascular death, 46% (3356%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 1139%; P < 0.0001) for all-cause mortality.
Conclusion These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.
C1 [McMurray, John] Univ Glasgow, British Heart Fdn Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland.
[Packer, Milton] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA.
[Desai, Akshay; Solomon, Scott] Brigham & Womens Hosp, Cardiovasc Med, Boston, MA 02115 USA.
[Gong, Jianjian; Lefkowitz, Martin; Rizkala, Adel; Shi, Victor] Novartis Pharmaceut, E Hanover, NJ USA.
[Greenlaw, Nicola] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
[Rouleau, Jean] Univ Montreal, Inst Cardiol, Montreal, PQ, Canada.
[Swedberg, Karl] Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden.
[Swedberg, Karl] Univ London Imperial Coll Sci Technol & Med, London, England.
[Zile, Michael R.] Med Univ S Carolina, Charles Ezra Daniel Prof Med, RHJ Dept VA Med Ctr, Charleston, SC 29425 USA.
[Andersen, Karl] Univ Iceland, Sch Hlth Sci, Cardiovasc Res Ctr, Reykjavik, Iceland.
[Arango, Juan Luis] Guatemalan Heart Inst, Guatemala City, Guatemala.
[Arnold, Malcolm] Western Univ, Schulich Sch Med & Dent, London Hlth Sci Ctr, Ottawa, ON, Canada.
[Belohlavek, Jan] Charles Univ Prague, Dept Med 2, Cardiovasc Med, Gen Teaching Hosp, Prague, Czech Republic.
[Belohlavek, Jan] Charles Univ Prague, Sch Med 1, Prague, Czech Republic.
[Boehm, Michael] Univ Saarland, Dept Cardiol, Homburg, Germany.
[Boytsov, Sergey] Natl Res Ctr Prevent Med, Moscow, Russia.
[Burgess, Lesley] Univ Stellenbosch, Cardiol Trial Unit, ZA-7600 Stellenbosch, South Africa.
[Cabrera, Walter] Clin Vesalio, Lima, Peru.
[Chen, Chen-Huan] Natl Yang Ming Univ, Fac Med, Taipei 112, Taiwan.
[Chen, Chen-Huan] Taipei Vet Gen Hosp, Dept Med Educ, Div Fac Dev, Taipei, Taiwan.
[Erglis, Andrejs] Univ Latvia, Fac Med, Riga, Latvia.
[Fu, Michael] Sahlgrens Univ Hosp, Dept Med, Ostra Hosp, Gothenburg, Sweden.
[Gomez, Efrain] Clin Shaio, Bogota, Colombia.
[Gonzalez, Angel] Inst Dominicano Cardiol, Santo Domingo, Dominican Rep.
[Hagege, Albert-Alain] Georges Pompidou European Hosp, Dept Cardiol, Paris, France.
[Katova, Tzvetana] Natl Cardiol Hosp, Dept Noninvas Cardiovasc Imaging & Funct Diagnost, Sofia, Bulgaria.
[Kiatchoosakun, Songsak] Khon Kaen Univ, Div Cardiol, Khon Kaen, Thailand.
[Kim, Kee-Sik] Daegu Catholic Univ, Med Ctr, Dept Cardiol, Daegu, South Korea.
[Bayram, Edmundo] Fdn Cardiovasc Aguascalientes, Ags, Mexico.
[Martinez, Felipe] Inst DAMIC Fdn Rusculleda, Cordoba, Argentina.
[Merkely, Bela] Semmelweis Univ, Heart & Vasc Ctr, H-1085 Budapest, Hungary.
[Mendoza, Ivan] Cent Univ Venezuela, Caracas, Venezuela.
[Mosterd, Arend] Meander Med Ctr, Dept Cardiol, Amsterdam, Netherlands.
[Negrusz-Kawecka, Marta] Wroclaw Med Univ, Dept & Clin Cardiol, Wroclaw, Poland.
[Peuhkurinen, Keijo] Univ Kuopio, Finnish Fdn Cardiovasc Res, FIN-70211 Kuopio, Finland.
[Ramires, Felix] Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo, SP, Brazil.
[Refsgaard, Jens] Viborg Hosp, Dept Cardiol, Viborg, Denmark.
[Senni, Michele] Osped Papa Giovanni XXIII, Cardiovasc Dept, Cardiol 1, Bergamo, Italy.
[Sibulo, Antonio S., Jr.] St Lukes Heart Inst, Manila, Philippines.
[Silva-Cardoso, Jose] Porto Med Sch, Oporto, Portugal.
[Squire, Iain] Univ Leicester, Leicester, Leics, England.
[Squire, Iain] NIHR Cardiovasc Res Unit, Leicester, Leics, England.
[Mendoza, Ivan; Starling, Randall C.] Cleveland Clin, Kaufman Ctr Heart Failure, Inst Heart & Vasc, Cleveland, OH 44106 USA.
[Vinereanu, Dragos] Univ Med & Pharm Carol Davila Emergency & Univ Ho, Bucharest, Romania.
[Teerlink, John R.] San Francisco VA Med Ctr, San Francisco, CA USA.
[Teerlink, John R.] Univ Calif San Francisco, San Francisco, CA 94143 USA.
[Belohlavek, Jan] Natl Univ Hearty Ctr, Dept Cardiol, Singapore, Singapore.
RP McMurray, J (reprint author), Univ Glasgow, British Heart Fdn Cardiovasc Res Ctr, 126 Univ Pl, Glasgow G12 8TA, Lanark, Scotland.
EM john.mcmurray@glasgow.ac.uk; milton.packer@utsouthwestern.edu
RI Ramires, Felix/D-5996-2012; Boytsov, Sergey/M-4486-2014; Drapkina,
Oxana/G-8443-2016;
OI Ramires, Felix/0000-0003-2437-2485; Boytsov, Sergey/0000-0001-6998-8406;
Drapkina, Oxana/0000-0002-4453-8430; mcmurray, john/0000-0002-6317-3975
FU Novartis; University of Glasgow
FX The PARADIGM-HF trial with LCZ696 (ClinicalTrials.gov number,
NCT01035255) was funded by Novartis. Funding to pay the Open Access
publication charges for this article was provided by University of
Glasgow.
NR 15
TC 25
Z9 27
U1 3
U2 23
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 14
PY 2015
VL 36
IS 7
BP 434
EP 439
DI 10.1093/eurheartj/ehu455
PG 6
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA CE1RG
UT WOS:000351589000015
PM 25416329
ER
PT J
AU McCullough, MB
Chou, AF
Solomon, JL
Petrakis, BA
Kim, B
Park, AM
Benedict, AJ
Hamilton, AB
Rose, AJ
AF McCullough, Megan B.
Chou, Ann F.
Solomon, Jeffrey L.
Petrakis, Beth Ann
Kim, Bo
Park, Angela M.
Benedict, Ashley J.
Hamilton, Alison B.
Rose, Adam J.
TI The interplay of contextual elements in implementation: an ethnographic
case study
SO BMC HEALTH SERVICES RESEARCH
LA English
DT Article
DE Organizational context; Contextual elements; Quality improvement;
Interplay; PARIHS; Implementation
ID PARIHS FRAMEWORK; HEALTH-CARE; ANTICOAGULATION CONTROL; QUALITY;
WARFARIN; SCIENCE; TRIAL
AB Background: Contextual elements have significant impact on uptake of health care innovations. While existing conceptual frameworks in implementation science suggest contextual elements interact with each other, little research has described how this might look in practice. To bridge this gap, this study identifies the interconnected patterns among contextual elements that influence uptake of an anticoagulation clinic improvement initiative.
Methods: We completed 51 semi-structured interviews and ethnographic observations across five case study sites involved in an evidence-based practice (EBP) quality improvement initiative. We analyzed data in NVivo 10 using an a priori approach based on the Promoting Action on Research Implementation in Health Services (PARIHS) model and an emergent thematic analysis.
Results: Key contextual elements, such as leadership, teamwork, and communication, interacted with each other in contributing to site-level uptake of the EBP, often yielding results that could not be predicted by looking at just one of these elements alone. Sites with context conducive to change in these areas predictably had high uptake, while sites with uniformly weak contextual elements had low uptake. Most sites presented a mixed picture, with contextual elements being strongly supportive of change in some areas and weak or moderate in others. In some cases, we found that sites with strong context in at least one area only needed to have adequate context in other areas to yield high uptake. At other sites, weak context in just one area had the potential to contribute to low uptake, despite countervailing strengths. Even a site with positive views of EBPs could not succeed when context was weak.
Conclusion: Interrelationships among different contextual elements can act as barriers to uptake at some sites and as facilitators at others. Accounting for interconnections among elements enables PARIHS to more fully describe the determinants of successful implementation as they operate in real-world settings.
C1 [McCullough, Megan B.; Solomon, Jeffrey L.; Petrakis, Beth Ann; Kim, Bo; Rose, Adam J.] ENRM Vet Hosp, VA HSR&D Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA.
[Chou, Ann F.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA.
[Park, Angela M.] VA New England Healthcare Syst, Bedford, MA USA.
[Benedict, Ashley J.] VA Sunshine Healthcare Network, St Petersburg, FL USA.
[Hamilton, Alison B.] VA Greater Los Angeles, VA HSR&D Ctr Study Healthcare Innovat Implementat, Los Angeles, CA USA.
[Hamilton, Alison B.] Univ Calif Los Angeles, Los Angeles, CA USA.
[Rose, Adam J.] Boston Univ, Sch Med, Boston, MA 02118 USA.
RP McCullough, MB (reprint author), ENRM Vet Hosp, VA HSR&D Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA.
EM Megan.Mccullough@va.gov
FU Department of Veterans Affairs, Veterans Health Administration, Office
of Research and Development, Health Services Research and Development
[SDP 12-249]
FX The views expressed in this article are those of the authors and do not
necessarily reflect the position or policy of the Department of Veterans
Affairs or the U.S. government. Funding is from Department of Veterans
Affairs, Veterans Health Administration, Office of Research and
Development, Health Services Research and Development SDP 12-249 (Rose,
PI). We would also like to acknowledge the assistance of CHOIR faculty,
especially Dr. Carol VanDeusen Lukas as well as Drs. Barbara Bokhour and
Rani Elwy.
NR 25
TC 2
Z9 2
U1 2
U2 7
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1472-6963
J9 BMC HEALTH SERV RES
JI BMC Health Serv. Res.
PD FEB 14
PY 2015
VL 15
DI 10.1186/s12913-015-0713-7
PG 12
WC Health Care Sciences & Services
SC Health Care Sciences & Services
GA CC5WR
UT WOS:000350436200001
PM 25890333
ER
PT J
AU Lao, TT
Glass, K
Qiu, WL
Polverino, F
Gupta, K
Morrow, J
Mancini, JD
Vuong, L
Perrella, MA
Hersh, CP
Owen, CA
Quackenbush, J
Yuan, GC
Silverman, EK
Zhou, XB
AF Lao, Taotao
Glass, Kimberly
Qiu, Weiliang
Polverino, Francesca
Gupta, Kushagra
Morrow, Jarrett
Mancini, John Dominic
Linh Vuong
Perrella, Mark A.
Hersh, Craig P.
Owen, Caroline A.
Quackenbush, John
Yuan, Guo-Cheng
Silverman, Edwin K.
Zhou, Xiaobo
TI Haploinsufficiency of Hedgehog interacting protein causes increased
emphysema induced by cigarette smoke through network rewiring
SO GENOME MEDICINE
LA English
DT Article
ID OBSTRUCTIVE PULMONARY-DISEASE; CD8(+) T-CELLS;
FUNCTIONAL-CHARACTERIZATION; BINDING PROTEIN; GENE-EXPRESSION; MICE;
LUNG; COPD; KLF4; RISK
AB Background: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis.
Methods: We exposed Hhip haploinsufficient mice (Hhip(+/-)) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis.
Results: We detected more severe airspace enlargement in Hhip(+/-) mice vs. wild-type littermates (Hhip(+/+)) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip(+/-) mice compared to Hhip(+/+) mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip(+/-) mice after CS exposure.
Conclusions: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state.
C1 [Lao, Taotao; Glass, Kimberly; Qiu, Weiliang; Morrow, Jarrett; Mancini, John Dominic; Linh Vuong; Hersh, Craig P.; Quackenbush, John; Silverman, Edwin K.; Zhou, Xiaobo] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.
[Lao, Taotao; Glass, Kimberly; Qiu, Weiliang; Polverino, Francesca; Gupta, Kushagra; Morrow, Jarrett; Mancini, John Dominic; Linh Vuong; Perrella, Mark A.; Hersh, Craig P.; Owen, Caroline A.; Quackenbush, John; Silverman, Edwin K.; Zhou, Xiaobo] Harvard Univ, Sch Med, Boston, MA USA.
[Glass, Kimberly; Quackenbush, John; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.
[Glass, Kimberly; Quackenbush, John; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
[Polverino, Francesca; Gupta, Kushagra; Perrella, Mark A.; Hersh, Craig P.; Owen, Caroline A.; Silverman, Edwin K.; Zhou, Xiaobo] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA.
[Polverino, Francesca; Owen, Caroline A.] Lovelace Resp Res Inst, Albuquerque, NM USA.
[Polverino, Francesca] Univ Parma, Dept Pulm, I-43100 Parma, Italy.
[Perrella, Mark A.] Brigham & Womens Hosp, Pediat Newborn Med, Boston, MA 02115 USA.
RP Silverman, EK (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
EM ed.silverman@channing.harvard.edu; xiaobo.zhou@channing.harvard.edu
RI Polverino, Francesca/F-3816-2017
OI Polverino, Francesca/0000-0001-9686-5698
FU U.S. National Institutes of Health (NIH) [R01 HL075478, P01 HL105339,
R01HL111759, R21HL120794, R01 AI111475-01, R21 HL111 835]; BWH-LRRI
Research Consortium; Flight Attendants Medical Research Institute
[CIA123046]
FX This work was supported by U.S. National Institutes of Health (NIH)
grants R01 HL075478 and P01 HL105339 (EKS), R01HL111759 (EKS, JQ, GCY),
R21HL120794 (EKS and XZ), R01 AI111475-01 and R21 HL111 835 (CO), the
BWH-LRRI Research Consortium ( CO), and the Flight Attendants Medical
Research Institute grant CIA123046 (CO).
NR 46
TC 9
Z9 10
U1 0
U2 6
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1756-994X
J9 GENOME MED
JI Genome Med.
PD FEB 14
PY 2015
VL 7
AR 12
DI 10.1186/s13073-015-0137-3
PG 13
WC Genetics & Heredity
SC Genetics & Heredity
GA CC8AP
UT WOS:000350590500001
PM 25763110
ER
PT J
AU Althabe, F
Belizan, JM
McClure, EM
Hemingway-Foday, J
Berrueta, M
Mazzoni, A
Ciganda, A
Goudar, SS
Kodkany, BS
Mahantshetti, NS
Dhaded, SM
Katageri, GM
Metgud, MC
Joshi, AM
Bellad, MB
Honnungar, NV
Derman, RJ
Saleem, S
Pasha, O
Ali, S
Hasnain, F
Goldenberg, RL
Esamai, F
Nyongesa, P
Ayunga, S
Liechty, EA
Garces, AL
Figueroa, L
Hambidge, KM
Krebs, NF
Patel, A
Bhandarkar, A
Waikar, M
Hibberd, PL
Chomba, E
Carlo, WA
Mwiche, A
Chiwila, M
Manasyan, A
Pineda, S
Meleth, S
Thorsten, V
Stolka, K
Wallace, DD
Koso-Thomas, M
Jobe, AH
Buekens, PM
AF Althabe, Fernando
Belizan, Jose M.
McClure, Elizabeth M.
Hemingway-Foday, Jennifer
Berrueta, Mabel
Mazzoni, Agustina
Ciganda, Alvaro
Goudar, Shivaprasad S.
Kodkany, Bhalachandra S.
Mahantshetti, Niranjana S.
Dhaded, Sangappa M.
Katageri, Geetanjali M.
Metgud, Mrityunjay C.
Joshi, Anjali M.
Bellad, Mrutyunjaya B.
Honnungar, Narayan V.
Derman, Richard J.
Saleem, Sarah
Pasha, Omrana
Ali, Sumera
Hasnain, Farid
Goldenberg, Robert L.
Esamai, Fabian
Nyongesa, Paul
Ayunga, Silas
Liechty, Edward A.
Garces, Ana L.
Figueroa, Lester
Hambidge, K. Michael
Krebs, Nancy F.
Patel, Archana
Bhandarkar, Anjali
Waikar, Manjushri
Hibberd, Patricia L.
Chomba, Elwyn
Carlo, Waldemar A.
Mwiche, Angel
Chiwila, Melody
Manasyan, Albert
Pineda, Sayury
Meleth, Sreelatha
Thorsten, Vanessa
Stolka, Kristen
Wallace, Dennis D.
Koso-Thomas, Marion
Jobe, Alan H.
Buekens, Pierre M.
TI A population-based, multifaceted strategy to implement antenatal
corticosteroid treatment versus standard care for the reduction of
neonatal mortality due to preterm birth in low-income and middle-income
countries: the ACT cluster-randomised trial
SO LANCET
LA English
DT Article
ID GESTATIONAL-AGE; GLOBAL-NETWORK; NEWBORN BABIES; SCALE-UP; DEATHS; RISK;
INTERVENTIONS; ATTENDANTS; STATEMENT; EXTENSION
AB Background Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries.
Methods In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096.
Findings The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47 394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50 743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0.0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0.96, 95% CI 0.87-1.06, p=0.65)and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1.67, 1.33-2.09, p<0.0001). Among the whole population, 28-day neonatal mortality was 27.4 per 1000 livebirths for the intervention group and 23.9 per 1000 livebirths for the control group (RR 1.12, 1.02-1.22, p=0.0127) and suspected maternal infection was reported in 1207 (3%) of 48 219 women in the intervention group and 867 (2%) of 51 523 in the control group (OR 1.45, 1.33-1.58, p<0.0001).
Interpretation Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3.5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased.
C1 [Althabe, Fernando; Belizan, Jose M.; Berrueta, Mabel; Mazzoni, Agustina; Ciganda, Alvaro] Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina.
[Ciganda, Alvaro] UNICEM, Montevideo, Uruguay.
[McClure, Elizabeth M.; Hemingway-Foday, Jennifer; Meleth, Sreelatha; Thorsten, Vanessa; Stolka, Kristen; Wallace, Dennis D.] RTI Int, Durham, NC USA.
[Goudar, Shivaprasad S.; Kodkany, Bhalachandra S.; Mahantshetti, Niranjana S.; Dhaded, Sangappa M.; Metgud, Mrityunjay C.; Joshi, Anjali M.; Bellad, Mrutyunjaya B.; Honnungar, Narayan V.] KLE Univ, Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, Karnataka, India.
[Katageri, Geetanjali M.] S Nijalingappa Med Coll, Bagalkot, Karnataka, India.
[Derman, Richard J.] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA.
[Saleem, Sarah; Hasnain, Farid] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan.
[Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA.
[Esamai, Fabian; Nyongesa, Paul; Ayunga, Silas] Moi Univ, Sch Med, Eldoret, Kenya.
[Liechty, Edward A.] Indiana Univ Sch Med, Indianapolis, IN USA.
[Garces, Ana L.; Figueroa, Lester; Pineda, Sayury] Fdn Alimentac Nutr, Ctr Amer & Panama, Guatemala City, Guatemala.
[Garces, Ana L.] Francisco Marroquin Univ, Guatemala City, Guatemala.
[Hambidge, K. Michael; Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA.
[Patel, Archana; Bhandarkar, Anjali; Waikar, Manjushri] Lata Med Res Fdn, Nagpur, Maharashtra, India.
[Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India.
[Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Chomba, Elwyn; Mwiche, Angel] Univ Teaching Hosp, Lusaka, Zambia.
[Carlo, Waldemar A.; Manasyan, Albert] Univ Alabama Birmingham, Birmingham, AL USA.
[Chiwila, Melody] Ctr Infect Dis Zambia, Lusaka, Zambia.
[Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA.
[Jobe, Alan H.] Cincinnati Childrens Hosp, Cincinnati, OH USA.
[Buekens, Pierre M.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA.
RP Althabe, F (reprint author), Inst Clin Effectiveness & Hlth Policy IECS, C1414CPV, Buenos Aires, DF, Argentina.
EM falthabe@iecs.org.ar
OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053; Belizan,
Jose/0000-0002-8412-3010
FU Eunice Kennedy Shriver National Institute of Child Health and Human
Development
FX Eunice Kennedy Shriver National Institute of Child Health and Human
Development.
NR 37
TC 40
Z9 42
U1 4
U2 16
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 14
PY 2015
VL 385
IS 9968
BP 629
EP 639
DI 10.1016/S0140-6736(14)61651-2
PG 11
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA9AZ
UT WOS:000349214000031
PM 25458726
ER
PT J
AU Kessinger, CW
Kim, JW
Henke, PK
Thompson, B
McCarthy, JR
Hara, T
Sillesen, M
Margey, RJP
Libby, P
Weissleder, R
Lin, CP
Jaffer, FA
AF Kessinger, Chase W.
Kim, Jin Won
Henke, Peter K.
Thompson, Brian
McCarthy, Jason R.
Hara, Tetsuya
Sillesen, Martin
Margey, Ronan J. P.
Libby, Peter
Weissleder, Ralph
Lin, Charles P.
Jaffer, Farouc A.
TI Statins Improve the Resolution of Established Murine Venous Thrombosis:
Reductions in Thrombus Burden and Vein Wall Scarring
SO PLOS ONE
LA English
DT Article
ID HUMAN ENDOTHELIAL-CELLS; INFERIOR VENA-CAVA; IN-VIVO; MOUSE MODEL;
POSTTHROMBOTIC SYNDROME; WHOLE-BLOOD; MICE; INHIBITION; EXPRESSION;
THROMBOEMBOLISM
AB Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins-lipid-lowering agents with anti-thrombotic and anti-inflammatory properties -in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy.
C1 [Kessinger, Chase W.; Kim, Jin Won; Hara, Tetsuya; Margey, Ronan J. P.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Cardiovasc Res Ctr, Boston, MA 02163 USA.
[Kim, Jin Won] Korea Univ, Guro Hosp, Multimodal Imaging & Theranost Lab, Ctr Cardiovasc, Seoul, South Korea.
[Henke, Peter K.] Univ Michigan, Dept Surg, Vasc Surg Sect, Ann Arbor, MI 48109 USA.
[Thompson, Brian; Lin, Charles P.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA.
[McCarthy, Jason R.; Weissleder, Ralph; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA USA.
[McCarthy, Jason R.; Weissleder, Ralph; Lin, Charles P.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
[Sillesen, Martin] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA USA.
[Libby, Peter] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA.
RP Jaffer, FA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Cardiovasc Res Ctr, Boston, MA 02163 USA.
EM fjaffer@mgh.harvard.edu
FU Merck, Ltd.; Kowa, Ltd.; U.S. National Institutes of Health (NIH) [R01
HL108229, T32 HL076136, UO1-HL080731]; American Heart Association
Scientist Development Grant [0830352N, 13GRNT17060040]; Howard Hughes
Medical Institute Early Career Award; Cardiovascular Research Foundation
FX F. Jaffer, Research Support, Merck and Kowa, Ltd. This research was
supported in part by grants from the U.S. National Institutes of Health
(NIH R01 HL108229, F.A.J.); T32 HL076136 (C.W.K).; and UO1-HL080731,
(R.W., J.R.M., and P.L.); by an American Heart Association Scientist
Development Grant (#0830352N, F.A.J.) and Grant-In-Aid (#13GRNT17060040,
F.A.J.), by a Howard Hughes Medical Institute Early Career Award
(F.A.J.), and by the Cardiovascular Research Foundation (J.W.K.). The
funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
NR 62
TC 9
Z9 9
U1 1
U2 9
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 13
PY 2015
VL 10
IS 2
AR UNSP e0116621
DI 10.1371/journal.pone.0116621
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC9IO
UT WOS:000350682600027
PM 25680183
ER
PT J
AU Waldo, SW
Brenner, DA
McCabe, JM
Dela Cruz, M
Long, B
Narla, VA
Park, J
Kulkarni, A
Sinclair, E
Chan, SY
Schick, SF
Malik, N
Ganz, P
Hsue, PY
AF Waldo, Stephen W.
Brenner, Daniel A.
McCabe, James M.
Dela Cruz, Mark
Long, Brian
Narla, Venkata A.
Park, Joseph
Kulkarni, Ameya
Sinclair, Elizabeth
Chan, Stephen Y.
Schick, Suzaynn F.
Malik, Namita
Ganz, Peter
Hsue, Priscilla Y.
TI A Novel Minimally-Invasive Method to Sample Human Endothelial Cells for
Molecular Profiling
SO PLOS ONE
LA English
DT Article
ID CORONARY-HEART-DISEASE; VASCULAR INFLAMMATION; PROGENITOR CELLS; RT-PCR;
BIOPSY; EXPRESSION
AB Objective
The endothelium is a key mediator of vascular homeostasis and cardiovascular health. Molecular research on the human endothelium may provide insight into the mechanisms underlying cardiovascular disease. Prior methodology used to isolate human endothelial cells has suffered from poor yields and contamination with other cell types. We thus sought to develop a minimally invasive technique to obtain endothelial cells derived from human subjects with higher yields and purity.
Methods
Nine healthy volunteers underwent endothelial cell harvesting from antecubital veins using guidewires. Fluorescence-activated cell sorting (FACS) was subsequently used to purify endothelial cells from contaminating cells using endothelial surface markers (CD34 / CD105 / CD146) with the concomitant absence of leukocyte and platelet specific markers (CD11b / CD45). Endothelial lineage in the purified cell population was confirmed by expression of endothelial specific genes and microRNA using quantitative polymerase chain reaction (PCR).
Results
A median of 4,212 (IQR: 2161 - 6583) endothelial cells were isolated from each subject. Quantitative PCR demonstrated higher expression of von Willebrand Factor (vWF, P<0.001), nitric oxide synthase 3 (NOS3, P<0.001) and vascular cell adhesion molecule 1 (VCAM-1, P<0.003) in the endothelial population compared to similarly isolated leukocytes. Similarly, the level of endothelial specific microRNA-126 was higher in the purified endothelial cells (P<0.001).
Conclusion
This state-of-the-art technique isolates human endothelial cells for molecular analysis in higher purity and greater numbers than previously possible. This approach will expedite research on the molecular mechanisms of human cardiovascular disease, elucidating its pathophysiology and potential therapeutic targets.
C1 [Waldo, Stephen W.; Brenner, Daniel A.; McCabe, James M.; Dela Cruz, Mark; Narla, Venkata A.; Park, Joseph; Kulkarni, Ameya; Chan, Stephen Y.; Ganz, Peter; Hsue, Priscilla Y.] Univ Calif San Francisco, San Francisco Gen Hosp, Div Cardiol, San Francisco, CA USA.
[Dela Cruz, Mark; Narla, Venkata A.; Ganz, Peter; Hsue, Priscilla Y.] Univ Calif San Francisco, San Francisco Gen Hosp, Ctr Excellence Vasc Res, San Francisco, CA USA.
[Long, Brian; Sinclair, Elizabeth] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA.
[Schick, Suzaynn F.; Malik, Namita] Univ Calif San Francisco, Div Occupat & Environm Med, San Francisco, CA 94143 USA.
RP Waldo, SW (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
EM swaldo@mgh.harvard.edu
FU Center for AIDS Research at the University of California, San Francisco;
NIH [R01HL095130, K24AI112393]
FX This work was supported by the Center for AIDS Research at the
University of California, San Francisco (DAB) and by the NIH
(R01HL095130, K24AI112393 both to PYH). The funders had no role in study
design, data collection and analysis, decision to publish or preparation
of the manuscript.
NR 23
TC 2
Z9 2
U1 2
U2 6
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 13
PY 2015
VL 10
IS 2
AR e0118081
DI 10.1371/journal.pone.0118081
PG 10
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CC9IO
UT WOS:000350682600107
PM 25679506
ER
PT J
AU Bokhour, BG
Saifu, H
Goetz, MB
Fix, GM
Burgess, J
Fletcher, MD
Knapp, H
Asch, SM
AF Bokhour, Barbara G.
Saifu, Hemen
Goetz, Matthew Bidwell
Fix, Gemmae M.
Burgess, Jane
Fletcher, Michael D.
Knapp, Herschel
Asch, Steven M.
TI The role of evidence and context for implementing a multimodal
intervention to increase HIV testing
SO IMPLEMENTATION SCIENCE
LA English
DT Article
DE HIV/AIDS; Health promotion/prevention; Qualitative research; Technology
adoption/diffusion; Primary care; Implementation
ID CLINICAL REMINDERS; BARRIERS
AB Background: Increasing the use of routine preventive care such as HIV testing is important, yet implementation of such evidence-based clinical care is complex. The Promoting Action on Research Implementation in Health Services (PARiHS) model for implementation posits that implementation will be most successful when the evidence, context, and facilitation strategies are strong for the clinical practice. We evaluated the relative importance of perceived evidence, context, and facilitation of HIV testing during the implementation of a multimodal intervention in US Department of Veterans Affairs primary care clinics.
Methods: A multimodal intervention including clinical reminders (CRs), academic detailing-providing education sessions for providers-and social marketing to improve HIV testing was implemented in 15 VA primary care clinics in three regions. We conducted qualitative formative and process evaluations using semi-structured interviews with HIV lead clinicians, primary care lead clinicians, nurse managers, and social workers. Interviews were analyzed thematically to identify barriers and facilitators to implementation of HIV testing and how these were addressed by the intervention. Sites were then rated high, medium, or low on the dimensions of perceived evidence and the context for testing. We then assessed the relationship of these ratings to improvements in HIV testing rates found in earlier quantitative analyses.
Results: Sites that showed greatest improvements in HIV testing rates also rated high on evidence and context. Conversely, sites that demonstrated the poorest improvements in testing rates rated low on both dimensions. Perceptions of evidence and several contextual aspects resulted in both barriers and facilitators to implementing testing. Evidence barriers included provider perceptions of evidence for routine testing as irrelevant to their population. Contextual barriers included clinical reminder overload, insufficient resources, onerous consent processes, stigma, provider discomfort, and concerns about linking individuals who test positive to HIV treatment. While most barriers were ameliorated by the intervention, HIV stigma in particular regions and concerns about linkage to care persisted.
Conclusions: Interventions to implement evidence-based practices such as HIV testing can be successful when utilizing proven quality improvement techniques. However, it is critical to address providers' perceptions of evidence and consider aspects of the local context in order to fully implement new routine clinical practices such as HIV testing.
C1 [Bokhour, Barbara G.; Saifu, Hemen; Goetz, Matthew Bidwell; Fix, Gemmae M.; Burgess, Jane; Fletcher, Michael D.; Asch, Steven M.] US Dept Vet Affairs, Qual Enhancement Res Initiat HIV & Hepatitis C, Bedford, MA 01730 USA.
[Bokhour, Barbara G.; Fix, Gemmae M.] Ctr Healthcare Org & Implementat Res, Concord, MA 01742 USA.
[Bokhour, Barbara G.; Fix, Gemmae M.; Fletcher, Michael D.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA.
[Saifu, Hemen; Goetz, Matthew Bidwell; Knapp, Herschel] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA.
[Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA.
[Burgess, Jane] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA.
[Asch, Steven M.] VA Palo Alto Hlth Care Syst, Menlo Pk, CA USA.
[Asch, Steven M.] Stanford Univ, Sch Med, Div Gen Med Disciplines, Palo Alto, CA 94304 USA.
RP Bokhour, BG (reprint author), US Dept Vet Affairs, Qual Enhancement Res Initiat HIV & Hepatitis C, Bedford, MA 01730 USA.
EM Barbara.Bokhour@va.gov
OI Fix, Gemmae/0000-0001-6055-4177
NR 22
TC 1
Z9 1
U1 1
U2 8
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1748-5908
J9 IMPLEMENT SCI
JI Implement. Sci.
PD FEB 13
PY 2015
VL 10
AR 22
DI 10.1186/s13012-015-0214-4
PG 12
WC Health Care Sciences & Services; Health Policy & Services
SC Health Care Sciences & Services
GA CC3OV
UT WOS:000350259700001
PM 25889388
ER
PT J
AU Nierhaus, T
Pach, D
Huang, WJ
Long, XY
Napadow, V
Roll, S
Liang, FR
Pleger, B
Villringer, A
Witt, CM
AF Nierhaus, Till
Pach, Daniel
Huang, Wenjing
Long, Xiangyu
Napadow, Vitaly
Roll, Stephanie
Liang, Fanrong
Pleger, Burkhard
Villringer, Arno
Witt, Claudia M.
TI Differential cerebral response to somatosensory stimulation of an
acupuncture point vs. two non-acupuncture points measured with EEG and
fMRI
SO FRONTIERS IN HUMAN NEUROSCIENCE
LA English
DT Article
DE somatosensory stimulation, functional magnetic resonance imaging (fMRI);
electroencephalography (EEG); acupuncture; background rhythm; functional
connectivity
ID RANDOMIZED CLINICAL-TRIAL; LOW-BACK-PAIN; HUMAN BRAIN; SENSORY
STIMULATION; CORTEX; CONNECTIVITY; ACTIVATION; NETWORKS; RHYTHMS; SYSTEM
AB Acupuncture can be regarded as a complex somatosensory stimulation. Here, we evaluate whether the point locations chosen for a somatosensory stimulation with acupuncture needles differently change the brain activity in healthy volunteers. We used EEG, event-related fMRI, and resting-state functional connectivity fMRI to assess neural responses to standardized needle stimulation of the acupuncture point ST36 (lower leg) and two control point locations (CP1 same dermatome, CP2 different dermatome). Cerebral responses were expected to differ for stimulation in two different dermatomes (CP2 different from ST36 and CP1), or stimulation at the acupuncture point vs. the control points. For EEG, mu rhythm power increased for ST36 compared to CP1 or CP2, but not when comparing the two control points. The fMRI analysis found more pronounced insula and S2 (secondary somatosensory cortex) activation, as well as precuneus deactivation during ST36 stimulation. The S2 seed-based functional connectivity analysis revealed increased connectivity to right precuneus for both comparisons, ST36 vs. CP1 and ST36 vs. CP2, however in different regions. Our results suggest that stimulation at acupuncture points may modulate somatosensory and saliency processing regions more readily than stimulation at non-acupuncture point locations. Also, our findings suggest potential modulation of pain perception due to acupuncture stimulation.
C1 [Nierhaus, Till; Villringer, Arno] Charite, Berlin Sch Mind & Brain, Mind Brain Inst, D-13353 Berlin, Germany.
[Nierhaus, Till; Villringer, Arno] Humboldt Univ, D-10117 Berlin, Germany.
[Nierhaus, Till; Long, Xiangyu; Pleger, Burkhard; Villringer, Arno] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany.
[Pach, Daniel; Huang, Wenjing; Roll, Stephanie; Witt, Claudia M.] Charite, Inst social Med Epidemiol & Hlth Econ, D-13353 Berlin, Germany.
[Huang, Wenjing; Liang, Fanrong] Chengdu Univ Tradit Chinese Med, Acupuncture & Tuina Sch, Chengdu, Peoples R China.
[Napadow, Vitaly] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA.
[Napadow, Vitaly] Logan Univ, Dept Radiol, Chesterfield, MO USA.
[Witt, Claudia M.] Univ Zurich Hosp, Inst Complementary & Integrat Med, CH-8091 Zurich, Switzerland.
RP Nierhaus, T (reprint author), Humboldt Univ, Mind Brain Inst, Luisenstr 56, D-10117 Berlin, Germany.
EM till.nierhaus@charite.de; daniel.pach@charite.de
FU Carstens Foundation; NCCAM; National Institutes of Health [R01-AT004714,
R01-AT005280, P01-AT006663, R21-DK097499, R01-AT007550]
FX This study had no additional funding. Wenjing Huang received a
scholarship from the Carstens Foundation. Vitaly Napadow was supported
by NCCAM, National Institutes of Health [R01-AT004714, R01-AT005280,
P01-AT006663, R21-DK097499, R01-AT007550].
NR 51
TC 5
Z9 6
U1 5
U2 29
PU FRONTIERS RESEARCH FOUNDATION
PI LAUSANNE
PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND
SN 1662-5161
J9 FRONT HUM NEUROSCI
JI Front. Hum. Neurosci.
PD FEB 13
PY 2015
VL 9
AR 74
DI 10.3389/fnhum.2015.00074
PG 17
WC Neurosciences; Psychology
SC Neurosciences & Neurology; Psychology
GA CA9ZN
UT WOS:000349284400002
PM 25741269
ER
PT J
AU Sunden, H
Holland, MC
Poutiainen, PK
Jaaskelainen, T
Pulkkinen, JT
Palvimo, JJ
Olsson, R
AF Sunden, Henrik
Holland, Mareike C.
Poutiainen, Pekka K.
Jaaskelainen, Tiina
Pulkkinen, Juha T.
Palvimo, Jorma J.
Olsson, Roger
TI Synthesis and Biological Evaluation of Second-Generation Tropanol-Based
Androgen Receptor Modulators
SO JOURNAL OF MEDICINAL CHEMISTRY
LA English
DT Article
ID RESISTANT PROSTATE-CANCER; ANTIANDROGEN RESISTANCE; ANTI-ANDROGENS;
BETA-AGONIST; DESIGN; ANTAGONISTS; POTENT; IDENTIFICATION; DISCOVERY;
SERIES
AB To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
C1 [Sunden, Henrik; Holland, Mareike C.; Olsson, Roger] Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden.
[Olsson, Roger] Lund Univ, Dept Expt Med Sci, S-22184 Lund, Sweden.
[Poutiainen, Pekka K.; Pulkkinen, Juha T.] Univ Eastern Finland, Sch Pharm, FI-70211 Kuopio, Finland.
[Poutiainen, Pekka K.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA 02129 USA.
[Jaaskelainen, Tiina] Univ Eastern Finland, Inst Dent, FI-70211 Kuopio, Finland.
[Jaaskelainen, Tiina; Palvimo, Jorma J.] Univ Eastern Finland, FI-70211 Kuopio, Finland.
[Palvimo, Jorma J.] Kuopio Univ Hosp, Dept Pathol, FI-70029 Kuopio, Finland.
RP Olsson, R (reprint author), Lund Univ, Dept Expt Med Sci, S-22184 Lund, Sweden.
EM roger.olsson@med.lu.se
RI Olsson, Roger/A-6112-2010; Sunden, Henrik/A-5477-2009
OI Olsson, Roger/0000-0002-7107-3472; Sunden, Henrik/0000-0001-6202-7557
FU Foundation for The North Savo Cancer Foundation; Alfred Kordelin
Foundation; Finnish Cultural Foundation (North Savo Regional Fund);
Finnish Cancer Organisations; University of Eastern Finland; Sigrid
Juselius Foundation
FX We thank Anja Probst-Larsen (University of Copenhagen) and Per-Ola
Norrby for fruitful discussions and computational technical support.
Financial support from The Foundation for The North Savo Cancer
Foundation (P.K.P.), The Alfred Kordelin Foundation (P.K.P.), The
Finnish Cultural Foundation (North Savo Regional Fund) (P.K.P), the
Finnish Cancer Organisations (J.J.P.), the strategic funding of the
University of Eastern Finland (J.J.P.), and the Sigrid Juselius
Foundation (J.J.P.) are gratefully acknowledged.
NR 39
TC 4
Z9 4
U1 2
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 12
PY 2015
VL 58
IS 3
BP 1569
EP 1574
DI 10.1021/jm501995n
PG 6
WC Chemistry, Medicinal
SC Pharmacology & Pharmacy
GA CB4BS
UT WOS:000349573800045
PM 25646649
ER
PT J
AU Shungin, D
Winkler, TW
Croteau-Chonka, DC
Ferreira, T
Lockes, AE
Magi, R
Strawbridge, RJ
Pers, TH
Fischer, K
Justice, AE
Workalemahu, T
Wu, JMW
Buchkovich, ML
Heard-Costa, NL
Roman, TS
Drong, AW
Song, C
Gustafsson, S
Day, FR
Esko, T
Fall, T
Kutalik, Z
Luan, JA
Randall, JC
Scherag, A
Vedantam, S
Wood, AR
Chen, J
Fehrmann, R
Karjalainen, J
Kahali, B
Liu, CT
Schmidt, EM
Absher, D
Amin, N
Anderson, D
Beekman, M
Bragg-Gresham, JL
Buyske, S
Demirkan, A
Ehret, GB
Feitosa, MF
Goel, A
Jackson, AU
Johnson, T
Kleber, ME
Kristiansson, K
Mangino, M
Leach, IM
Medina-Gomez, C
Palmer, CD
Pasko, D
Pechlivaniss, S
Peters, MJ
Prokopenko, I
Stancakova, A
Sung, YJ
Tanakam, T
Teumer, A
Van Vliet-Ostaptchouk, JV
Yengo, L
Zhang, WH
Albrecht, E
Arnlov, J
Arscott, GM
Bandinelli, S
Barrett, A
Bellis, C
Bennett, AJ
Berne, C
Bluher, M
Buhringer, S
Bonnet, F
Bottcher, Y
Bruinenberg, M
Carba, DB
Caspersen, IH
Clarke, R
Daw, EW
Deelen, J
Deelman, E
Delgado, G
Doney, ASF
Eklund, N
Erdos, MR
Estrada, K
Eury, E
Friedrichs, N
Garcia, ME
Giedraitis, V
Gigante, B
Go, AS
Golay, A
Grallert, H
Grammer, TB
Grassler, J
Grewal, J
Groves, CJ
Haller, T
Hallmans, G
Hartman, CA
Hassinen, M
Hayward, C
Heikkila, K
Herzig, KH
Helmer, Q
Hillege, HL
Holmen, O
Hunt, SC
Isaacs, A
Ittermann, T
James, AL
Johansson, I
Juliusdottir, T
Kalafati, IP
Kinnunen, L
Koenig, W
Kooner, IK
Kratzer, W
Lamina, C
Leander, K
Lee, NR
Lichtner, P
Lind, L
Lindstrom, J
Lobbens, S
Lorentzon, M
Mach, F
Magnusson, PKE
Mahajan, A
McArdle, WL
Menni, C
Merger, S
Mihailov, E
Milani, L
Mills, R
Moayyeri, A
Monda, KL
Mooijaart, SP
Muhleisen, TW
Mulas, A
Muller, G
Muller-Nurasyid, M
Nagaraja, R
Nalls, MA
Narisu, N
Glorioso, N
Nolte, IM
Olden, M
Rayner, NW
Renstrom, F
Ried, JS
Robertson, NR
Rose, LM
Sanna, S
Scharnagl, H
Scholtens, S
Sennblad, B
Seufferlein, T
Sitlani, CM
Smith, AV
Stirrups, K
Stringhams, HM
Sundstrom, J
Swertz, MA
Swift, AJ
Syvanen, AC
Tayo, BO
Thorand, B
Thorleifsson, G
Tomaschitz, A
Troffa, C
van Oort, FVA
Verweij, N
Vonk, JM
Waite, LL
Wennauer, R
Wilsgaard, T
Wojczynski, MK
Wong, A
Zhang, QY
Zhao, JH
Brennan, EP
Choi, M
Eriksson, P
Folkersen, L
Franco-Cereceda, A
Gharavi, AG
Hedman, AK
Hivert, MF
Huang, JY
Kanoni, S
Karpe, F
Keildson, S
Kiryluk, K
Liang, LM
Lifton, RP
Ma, BS
McKnight, AJ
McPherson, R
Metspalu, A
Min, JL
Moffatt, MF
Montgomery, GW
Murabito, JM
Nicholson, G
Nyholt, DR
Olsson, C
Perry, JRB
Reinmaa, E
Salem, RM
Sandholm, N
Schadt, EE
Scott, R
Stolk, L
Vallejo, EE
Westra, HJ
Zondervan, KT
Amouyel, P
Arveiler, D
Bakker, SJL
Beilby, J
Bergman, RN
Blangero, J
Brown, MJ
Burnier, M
Campbell, H
Chakravarti, A
Chiness, PS
Claudi-Boehmi, S
Collins, FS
Crawford, DC
Danesh, J
de Faire, U
de Geusl, EJC
Dorr, M
Erbel, R
Eriksson, JG
Farrall, M
Ferrannini, E
Ferrieres, J
Forouhi, NG
Forrester, T
Franco, OH
Gansevoort, RT
Gieger, C
Gudnason, V
Haiman, CA
Harris, TB
Hattersley, AT
Heliovaara, M
Hicks, AA
Hingorani, AD
Hoffmann, W
Hofman, A
Homuth, G
Humphries, SE
Hypponen, E
Illig, T
Jarvelin, MR
Johansen, B
Jousilahti, P
Jula, AM
Kaprio, J
Kee, F
Keinanen-Kiukaanniemi, SM
Kooner, JS
Kooperberg, C
Kovacs, P
Kraja, AT
Kumari, M
Kuulasmaa, K
Kuusisto, J
Lakka, TA
Langenberg, C
Le Marchand, L
Lehtimaki, T
Lyssenko, V
Mannisto, S
Marette, A
Matise, TC
McKenzie, CA
McKnight, B
Musk, AW
Mohlenkamp, S
Morris, AD
Nelis, M
Ohlsson, C
Oldehinkel, AJ
Ong, KK
Palmer, LJ
Penninx, BW
Peters, A
Pramstaller, PP
Raitakari, OT
Rankinen, T
Rao, DC
Rice, TK
Ridker, PM
Ritchie, MD
Rudan, I
Salomaa, V
Samani, NJ
Saramies, J
Sarzynski, MA
Schwarz, PEH
Shuldiner, AR
Staessen, JA
Steinthorsdottir, V
Stolk, RP
Strauch, K
Tonjes, A
Tremblay, A
Tremoli, E
Vohl, MC
Volker, U
Vollenweider, P
Wilson, JF
Witteman, JC
Adair, LS
Bochud, M
Boehm, BO
Bornstein, SR
Bouchard, C
Cauchi, S
Caulfield, MJ
Chambers, JC
Chasman, DI
Cooper, RS
Dedoussis, G
Ferrucci, L
Froguel, P
Grabe, HJ
Hamsten, A
Hui, JN
Hveem, K
Jockel, KH
Kivimaki, M
Kuh, D
Laakso, M
Liu, YM
Marz, W
Munroe, PB
Njolstad, I
Oostra, BA
Palmer, CNA
Pedersen, NL
Perola, M
Perusse, L
Peters, U
Power, C
Quertermous, T
Rauramaa, R
Rivadeneira, F
Saaristo, TE
Saleheen, D
Sinisalo, J
Slagboom, PE
Snieder, H
Spector, TD
Thorsteinsdottir, UR
Stumvoll, M
Tuomilehto, J
Uitterlinden, AG
Uusitupa, M
van der Harst, P
Veronesi, G
Walker, M
Wareham, NJ
Watkins, H
Wichmann, HE
Abecasis, GR
Assimes, TL
Berndt, SI
Boehnkes, M
Borecki, IB
Deloukas, P
Franke, L
Frayling, TM
Groop, LC
Hunter, DJ
Kaplan, RC
O'Connell, JR
Qi, L
Schlessinger, D
Strachan, DP
Stefansson, K
van Dujin, CM
Willer, CJ
Visscher, PM
Yang, J
Hirschhorn, JN
Zillikens, MC
McCarthy, MI
Speliotes, EK
North, KE
Fox, CS
Barroso, I
Franks, PW
Ingelsson, E
Heid, IM
Loos, RJF
Cupples, LA
Morris, AP
Lindgren, CM
Mohlke, KL
AF Shungin, Dmitry
Winkler, Thomas W.
Croteau-Chonka, Damien C.
Ferreira, Teresa
Lockes, Adam E.
Maegi, Reedik
Strawbridge, Rona J.
Pers, Tune H.
Fischer, Krista
Justice, Anne E.
Workalemahu, Tsegaselassie
Wu, Joseph M. W.
Buchkovich, Martin L.
Heard-Costa, Nancy L.
Roman, Tamara S.
Drong, Alexander W.
Song, Ci
Gustafsson, Stefan
Day, Felix R.
Esko, Tonu
Fall, Tove
Kutalik, Zoltan
Luan, Jian'an
Randall, Joshua C.
Scherag, Andre
Vedantam, Sailaja
Wood, Andrew R.
Chen, Jin
Fehrmann, Rudolf
Karjalainen, Juha
Kahali, Bratati
Liu, Ching-Ti
Schmidt, Ellen M.
Absher, Devin
Amin, Najaf
Anderson, Denise
Beekman, Marian
Bragg-Gresham, Jennifer L.
Buyske, Steven
Demirkan, Ayse
Ehret, Georg B.
Feitosa, Mary F.
Goel, Anuj
Jackson, Anne U.
Johnson, Toby
Kleber, Marcus E.
Kristiansson, Kati
Mangino, Massimo
Leach, Irene Mateo
Medina-Gomez, Carolina
Palmer, Cameron D.
Pasko, Dorota
Pechlivaniss, Sonali
Peters, Marjolein J.
Prokopenko, Inga
Stancakova, Alena
Sung, Yun Ju
Tanakam, Toshiko
Teumer, Alexander
Van Vliet-Ostaptchouk, Jana V.
Yengo, Loic
Zhang, Weihua
Albrecht, Eva
Arnlov, Johan
Arscott, Gillian M.
Bandinelli, Stefania
Barrett, Amy
Bellis, Claire
Bennett, Amanda J.
Berne, Christian
Blueher, Matthias
Buhringer, Stefan
Bonnet, Fabrice
Boettcher, Yvonne
Bruinenberg, Marcel
Carba, Delia B.
Caspersen, Ida H.
Clarke, Robert
Daw, E. Warwick
Deelen, Joris
Deelman, Ewa
Delgado, Graciela
Doney, Alex S. F.
Eklund, Niina
Erdos, Michael R.
Estrada, Karol
Eury, Elodie
Friedrichs, Nele
Garcia, Melissa E.
Giedraitis, Vilmantas
Gigante, Bruna
Go, Alan S.
Golay, Alain
Grallert, Harald
Grammer, Tanja B.
Graessler, Juergen
Grewal, Jagvir
Groves, Christopher J.
Haller, Toomas
Hallmans, Goran
Hartman, Catharina A.
Hassinen, Maija
Hayward, Caroline
Heikkila, Kauko
Herzig, Karl-Heinz
Helmer, Quinta
Hillege, Hans L.
Holmen, Oddgeir
Hunt, Steven C.
Isaacs, Aaron
Ittermann, Till
James, Alan L.
Johansson, Ingegerd
Juliusdottir, Thorhildur
Kalafati, Ioanna-Panagiota
Kinnunen, Leena
Koenig, Wolfgang
Kooner, Ishminder K.
Kratzer, Wolfgang
Lamina, Claudia
Leander, Karin
Lee, Nanette R.
Lichtner, Peter
Lind, Lars
Lindstrom, Jaana
Lobbens, Stephane
Lorentzon, Mattias
Mach, Francois
Magnusson, Patrik K. E.
Mahajan, Anubha
McArdle, Wendy L.
Menni, Cristina
Merger, Sigrun
Mihailov, Evelin
Milani, Lili
Mills, Rebecca
Moayyeri, Alireza
Monda, Ken L.
Mooijaart, Simon P.
Muehleisen, Thomas W.
Mulas, Antonella
Mueller, Gabriele
Mueller-Nurasyid, Martina
Nagaraja, Ramaiah
Nalls, Michael A.
Narisu, Narisu
Glorioso, Nicola
Nolte, Ilja M.
Olden, Matthias
Rayner, Nigel W.
Renstrom, Frida
Ried, Janina S.
Robertson, Neil R.
Rose, Lynda M.
Sanna, Serena
Scharnagl, Hubert
Scholtens, Salome
Sennblad, Bengt
Seufferlein, Thomas
Sitlani, Colleen M.
Smith, Albert Vernon
Stirrups, Kathleen
Stringham, Heather M.
Sundstrom, Johan
Swertz, Morris A.
Swift, Amy J.
Syvanen, Ann-Christine
Tayo, Bamidele O.
Thorand, Barbara
Thorleifsson, Gudmar
Tomaschitz, Andreas
Troffa, Chiara
van Oort, Floor V. A.
Verweij, Niek
Vonk, Judith M.
Waite, Lindsay L.
Wennauer, Roman
Wilsgaard, Tom
Wojczynski, Mary K.
Wong, Andrew
Zhang, Qunyuan
Zhao, Jing Hua
Brennan, Eoin P.
Choi, Murim
Eriksson, Per
Folkersen, Lasse
Franco-Cereceda, Anders
Gharavi, Ali G.
Hedman, Asa K.
Hivert, Marie-France
Huang, Jinyan
Kanoni, Stavroula
Karpe, Fredrik
Keildson, Sarah
Kiryluk, Krzysztof
Liang, Liming
Lifton, Richard P.
Ma, Baoshan
McKnight, Amy J.
McPherson, Ruth
Metspalu, Andres
Min, Josine L.
Moffatt, Miriam F.
Montgomery, Grant W.
Murabito, Joanne M.
Nicholson, George
Nyholt, Dale R.
Olsson, Christian
Perry, John R. B.
Reinmaa, Eva
Salem, Rany M.
Sandholm, Niina
Schadt, Eric E.
Scott, Robert A.
Stolk, Lisette
Vallejo, Edgar E.
Westra, Harm-Jan
Zondervan, Krina T.
Amouyel, Philippe
Arveiler, Dominique
Bakker, Stephan J. L.
Beilby, John
Bergman, Richard N.
Blangero, John
Brown, Morris J.
Burnier, Michel
Campbell, Harry
Chakravarti, Aravinda
Chiness, Peter S.
Claudi-Boehmi, Simone
Collins, Francis S.
Crawford, Dana C.
Danesh, John
de Faire, Ulf
de Geusl, Eco J. C.
Doerr, Marcus
Erbel, Raimund
Eriksson, Johan G.
Farrall, Martin
Ferrannini, Ele
Ferrieres, Jean
Forouhi, Nita G.
Forrester, Terrence
Franco, Oscar H.
Gansevoort, Ron T.
Gieger, Christian
Gudnason, Vilmundur
Haiman, Christopher A.
Harris, Tamara B.
Hattersley, Andrew T.
Heliovaara, Markku
Hicks, Andrew A.
Hingorani, Aroon D.
Hoffmann, Wolfgang
Hofman, Albert
Homuth, Georg
Humphries, Steve E.
Hyppoenen, Elina
Illig, Thomas
Jarvelin, Marjo-Riitta
Johansen, Berit
Jousilahti, Pekka
Jula, Antti M.
Kaprio, Jaakko
Kee, Frank
Keinanen-Kiukaanniemi, Sirkka M.
Kooner, Jaspal S.
Kooperberg, Charles
Kovacs, Peter
Kraja, Aldi T.
Kumari, Meena
Kuulasmaa, Kari
Kuusisto, Johanna
Lakka, Timo A.
Langenberg, Claudia
Le Marchand, Loic
Lehtimaki, Terho
Lyssenko, Valeriya
Mannisto, Satu
Marette, Andre
Matise, Tara C.
McKenzie, Colin A.
McKnight, Barbara
Musk, Arthur W.
Mohlenkamp, Stefan
Morris, Andrew D.
Nelis, Mari
Ohlsson, Claes
Oldehinkel, Albertine J.
Ong, Ken K.
Palmer, Lyle J.
Penninx, Brenda W.
Peters, Annette
Pramstaller, Peter P.
Raitakari, Olli T.
Rankinen, Tuomo
Rao, D. C.
Rice, Treva K.
Ridker, Paul M.
Ritchie, Marylyn D.
Rudan, Igor
Salomaa, Veikko
Samani, Nilesh J.
Saramies, Jouko
Sarzynski, Mark A.
Schwarz, Peter E. H.
Shuldiner, Alan R.
Staessen, Jan A.
Steinthorsdottir, Valgerdur
Stolk, Ronald P.
Strauch, Konstantin
Toenjes, Anke
Tremblay, Angelo
Tremoli, Elena
Vohl, Marie-Claude
Voelker, Uwe
Vollenweider, Peter
Wilson, James F.
Witteman, Jacqueline C.
Adair, Linda S.
Bochud, Murielle
Boehm, Bernhard O.
Bornstein, Stefan R.
Bouchard, Claude
Cauchi, Stephane
Caulfield, Mark J.
Chambers, John C.
Chasman, Daniel I.
Cooper, Richard S.
Dedoussis, George
Ferrucci, Luigi
Froguel, Philippe
Grabe, Hans-Joergen
Hamsten, Anders
Hui, Jennie
Hveem, Kristian
Joeckel, Karl-Heinz
Kivimaki, Mika
Kuh, Diana
Laakso, Markku
Liu, Yongmei
Maerz, Winfried
Munroe, Patricia B.
Njolstad, Inger
Oostra, Ben A.
Palmer, Colin N. A.
Pedersen, Nancy L.
Perola, Markus
Perusse, Louis
Peters, Ulrike
Power, Chris
Quertermous, Thomas
Rauramaa, Rainer
Rivadeneira, Fernando
Saaristo, Timo E.
Saleheen, Danish
Sinisalo, Juha
Slagboom, P. Eline
Snieder, Harold
Spector, Tim D.
Thorsteinsdottir, Unnur R.
Stumvoll, Michael
Tuomilehto, Jaakko
Uitterlinden, Andre G.
Uusitupa, Math
van der Harst, Pim
Veronesi, Giovanni
Walker, Mark
Wareham, Nicholas J.
Watkins, Hugh
Wichmann, H-Erich
Abecasis, Goncalo R.
Assimes, Themistocles L.
Berndt, Sonja I.
Boehnkes, Michael
Borecki, Ingrid B.
Deloukas, Panos
Franke, Lude
Frayling, Timothy M.
Groop, Leif C.
Hunter, David J.
Kaplan, Robert C.
O'Connell, Jeffrey R.
Qi, Lu
Schlessinger, David
Strachan, David P.
Stefansson, Kari
van Dujin, Cornelia M.
Willer, Cristen J.
Visscher, Peter M.
Yang, Jian
Hirschhorn, Joel N.
Zillikens, M. Carola
McCarthy, Mark I.
Speliotes, Elizabeth K.
North, Kari E.
Fox, Caroline S.
Barroso, Ines
Franks, Paul W.
Ingelsson, Erik
Heid, Iris M.
Loos, Ruth J. F.
Cupples, L. Adrienne
Morris, Andrew P.
Lindgren, Cecilia M.
Mohlke, Karen L.
CA ADIPOGEN Consortium
CARDIOGRAMplusC4D Consortium
CKDGen Consortium
GEFOS Consortium
GENIE Consortium
GLGC
ICBP
Int Endogene Consortium
LifeLines Cohort Study
MAGIC Investigators
MuTHER Consortium
PAGE Consortium
ReproGen Consortium
TI New genetic loci link adipose and insulin biology to body fat
distribution
SO NATURE
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; MESENCHYMAL STEM-CELLS; HUMAN HEIGHT;
ADIPOGENIC DIFFERENTIATION; ABDOMINAL ADIPOSITY; SUSCEPTIBILITY LOCI;
SEXUAL-DIMORPHISM; GLYCEMIC TRAITS; FALSE DISCOVERY; COMMON SNPS
AB Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
C1 [Shungin, Dmitry; Franks, Paul W.] Umea Univ, Med Unit, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden.
[Shungin, Dmitry; Renstrom, Frida; Franks, Paul W.] Lund Univ, Ctr Diabet, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, S-20502 Malmo, Sweden.
[Shungin, Dmitry; Johansson, Ingegerd] Umea Univ, Dept Oncol, S-90185 Umea, Sweden.
[Winkler, Thomas W.; Olden, Matthias; Heid, Iris M.] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.
[Croteau-Chonka, Damien C.; Buchkovich, Martin L.; Roman, Tamara S.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
[Croteau-Chonka, Damien C.; Hunter, David J.; Qi, Lu] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.
[Croteau-Chonka, Damien C.; Estrada, Karol; Ridker, Paul M.; Chasman, Daniel I.; Hunter, David J.; Qi, Lu] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Ferreira, Teresa; Maegi, Reedik; Drong, Alexander W.; Randall, Joshua C.; Goel, Anuj; Prokopenko, Inga; Juliusdottir, Thorhildur; Mahajan, Anubha; Rayner, Nigel W.; Robertson, Neil R.; Hedman, Asa K.; Keildson, Sarah; Perry, John R. B.; Zondervan, Krina T.; Farrall, Martin; Watkins, Hugh; McCarthy, Mark I.; Ingelsson, Erik; Morris, Andrew P.; Lindgren, Cecilia M.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
[Lockes, Adam E.; Bragg-Gresham, Jennifer L.; Jackson, Anne U.; Stringham, Heather M.; Abecasis, Goncalo R.; Boehnkes, Michael] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA.
[Maegi, Reedik; Fischer, Krista; Esko, Tonu; Haller, Toomas; Mihailov, Evelin; Milani, Lili; Metspalu, Andres; Reinmaa, Eva; Nelis, Mari; Perola, Markus; Morris, Andrew P.] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
[Strawbridge, Rona J.; Sennblad, Bengt; Eriksson, Per; Folkersen, Lasse; Hamsten, Anders] Karolinska Inst, Dept Med, Ctr Mol Med, Atherosclerosis Res Unit, S-17176 Stockholm, Sweden.
[Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.
[Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA.
[Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.
[Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Estrada, Karol; Salem, Rany M.; Hirschhorn, Joel N.; Lindgren, Cecilia M.] MIT, Broad Inst, Cambridge, MA 02142 USA.
[Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Estrada, Karol; Salem, Rany M.; Hirschhorn, Joel N.; Lindgren, Cecilia M.] Harvard Univ, Cambridge, MA 02142 USA.
[Pers, Tune H.; Esko, Tonu; Salem, Rany M.; Hirschhorn, Joel N.] Harvard Univ, Dept Genet, Boston, MA 02115 USA.
[Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark.
[Justice, Anne E.; Monda, Ken L.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA.
[Workalemahu, Tsegaselassie; Hunter, David J.; Qi, Lu; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
[Wu, Joseph M. W.; Liu, Ching-Ti; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.
[Heard-Costa, Nancy L.; Murabito, Joanne M.; Fox, Caroline S.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.
[Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.
[Song, Ci; Fall, Tove; Magnusson, Patrik K. E.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.
[Song, Ci; Gustafsson, Stefan; Fall, Tove; Arnlov, Johan; Syvanen, Ann-Christine; Hedman, Asa K.; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, S-75185 Uppsala, Sweden.
[Song, Ci; Gustafsson, Stefan; Fall, Tove; Arnlov, Johan; Hedman, Asa K.; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden.
[Day, Felix R.; Luan, Jian'an; Zhao, Jing Hua; Scott, Robert A.; Forouhi, Nita G.; Langenberg, Claudia; Ong, Ken K.; Wareham, Nicholas J.; Loos, Ruth J. F.] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England.
[Kutalik, Zoltan] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland.
[Kutalik, Zoltan; Johnson, Toby] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland.
[Kutalik, Zoltan; Johnson, Toby] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland.
[Randall, Joshua C.; Rayner, Nigel W.; Stirrups, Kathleen; Deloukas, Panos; Barroso, Ines] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
[Scherag, Andre; Pechlivaniss, Sonali; Joeckel, Karl-Heinz] Univ Hosp Essen, IMIBE, D-45147 Essen, Germany.
[Scherag, Andre] Jena Univ Hosp, CSCC, Clin Epidemiol Integrated Res & Treatment Ctr, D-07743 Jena, Germany.
[Wood, Andrew R.; Pasko, Dorota; Perry, John R. B.; Frayling, Timothy M.] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England.
[Chen, Jin; Willer, Cristen J.] Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.
[Fehrmann, Rudolf; Karjalainen, Juha; Swertz, Morris A.; Westra, Harm-Jan; van der Harst, Pim; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.
[Kahali, Bratati; Speliotes, Elizabeth K.] Univ Michigan, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48109 USA.
[Kahali, Bratati; Schmidt, Ellen M.; Willer, Cristen J.; Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
[Absher, Devin; Waite, Lindsay L.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA.
[Amin, Najaf; Demirkan, Ayse; Isaacs, Aaron; Oostra, Ben A.; van Dujin, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands.
[Anderson, Denise] Univ Western Australia, Telethon Inst Child Hlth Res, Ctr Child Hlth Res, Perth, WA 6008, Australia.
[Beekman, Marian; Buhringer, Stefan; Deelen, Joris; Helmer, Quinta; Mooijaart, Simon P.; Stolk, Lisette; Slagboom, P. Eline] Leiden Univ, Med Ctr, NCHA, NL-2300 RC Leiden, Netherlands.
[Beekman, Marian; Deelen, Joris; Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands.
[Bragg-Gresham, Jennifer L.] Univ Michigan, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA.
[Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ 08854 USA.
[Buyske, Steven; Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA.
[Demirkan, Ayse] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands.
[Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet c Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA.
[Ehret, Georg B.] Univ Hosp Geneva, Dept Specialties Internal Med, CH-1211 Geneva, Switzerland.
[Feitosa, Mary F.; Daw, E. Warwick; Zhang, Qunyuan; Kraja, Aldi T.; Rao, D. C.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA.
[Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England.
[Johnson, Toby] Univ Lausanne, CHUV, Univ Inst Social & Preventat Med, CH-1005 Lausanne, Switzerland.
[Kleber, Marcus E.; Delgado, Graciela; Grammer, Tanja B.; Smith, Albert Vernon; Maerz, Winfried] Heidelberg Univ, Dept Med Nephrol Hypertensiol Endocrinol Diabetol, Med Fac Mannheim, D-68187 Mannheim, Germany.
[Kleber, Marcus E.; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med 2, D-89081 Ulm, Germany.
[Kristiansson, Kati; Eklund, Niina; Kinnunen, Leena; Lindstrom, Jaana; Eriksson, Johan G.; Heliovaara, Markku; Jousilahti, Pekka; Jula, Antti M.; Kaprio, Jaakko; Kuulasmaa, Kari; Mannisto, Satu; Salomaa, Veikko; Perola, Markus; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland.
[Mangino, Massimo; Menni, Cristina; Moayyeri, Alireza; Perry, John R. B.; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.
[Leach, Irene Mateo; Hillege, Hans L.; Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands.
[Medina-Gomez, Carolina; Peters, Marjolein J.; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Dujin, Cornelia M.; Zillikens, M. Carola] NCHA, NL-3015 GE Rotterdam, Netherlands.
[Medina-Gomez, Carolina; Franco, Oscar H.; Hofman, Albert; Witteman, Jacqueline C.; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Dujin, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.
[Medina-Gomez, Carolina; Peters, Marjolein J.; Estrada, Karol; Stolk, Lisette; Rivadeneira, Fernando; Uitterlinden, Andre G.; Zillikens, M. Carola] Erasmus MC Univ Med Ctr, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.
[Prokopenko, Inga; Barrett, Amy; Bennett, Amanda J.; Groves, Christopher J.; Rayner, Nigel W.; Robertson, Neil R.; Karpe, Fredrik; McCarthy, Mark I.] Univ Oxford, Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England.
[Prokopenko, Inga; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, Hammersmith Hosp, London W12 0NN, England.
[Stancakova, Alena] Univ Eastern Finland, FI-70210 Kuopio, Finland.
[Sung, Yun Ju; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.
[Tanakam, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA.
[Teumer, Alexander; Homuth, Georg; Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany.
[Van Vliet-Ostaptchouk, Jana V.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands.
[Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] Inst Pasteur, Ctr Immunol & Biol Parasitaire, CNRS, UMR 8199, F-59019 Lille, France.
[Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] European Genom Inst Diabet, F-59000 Lille, France.
[Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] Univ Lille 2, F-59000 Lille, France.
[Zhang, Weihua; Grewal, Jagvir; Kooner, Ishminder K.; Mills, Rebecca; Kooner, Jaspal S.; Chambers, John C.] Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England.
[Zhang, Weihua; Grewal, Jagvir; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England.
[Albrecht, Eva; Grallert, Harald; Mueller-Nurasyid, Martina; Ried, Janina S.; Gieger, Christian; Strauch, Konstantin; Heid, Iris M.] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.
[Arnlov, Johan] Dalarna Univ, Sch Hlth & Social Studies, SE-79188 Falun, Sweden.
[Arscott, Gillian M.; Beilby, John; Hui, Jennie] PathWest Lab Med Western Australia, Nedlands, WA 6009, Australia.
[Bandinelli, Stefania] ASF, Geriatr Unit, I-50125 Florence, Italy.
[Bellis, Claire; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78227 USA.
[Bellis, Claire] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Genom Res Ctr, Brisbane, Qld 4001, Australia.
[Berne, Christian] Uppsala Univ, Dept Med Sci Endocrinol Diabet & Metab, S-75185 Uppsala, Sweden.
[Blueher, Matthias; Boettcher, Yvonne; Kovacs, Peter; Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Integrated Res & Treatment Ctr IFB Adipos Dis, D-04103 Leipzig, Germany.
[Blueher, Matthias; Kovacs, Peter; Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany.
[Buhringer, Stefan; Helmer, Quinta] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands.
[Bonnet, Fabrice] Univ Rennes, Dept Endocrinol, INSERM, UMR991, F-35000 Rennes, France.
[Bruinenberg, Marcel; Scholtens, Salome] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, NL-9700 RB Groningen, Netherlands.
[Carba, Delia B.; Lee, Nanette R.] Univ San Carlos, USC Off Populat Studies Fdn Inc, Cebu 6000, Philippines.
[Caspersen, Ida H.; Johansen, Berit] Norwegian Univ Sci & Technol, Dept Biol, N-7491 Trondheim, Norway.
[Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford OX3 7LF, England.
[Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford OX3 7LF, England.
[Deelman, Ewa] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA.
[Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland.
[Eklund, Niina; Kaprio, Jaakko; Perola, Markus; Groop, Leif C.] Univ Helsinki, Inst Mol Med, FI-00014 Helsinki, Finland.
[Erdos, Michael R.; Narisu, Narisu; Swift, Amy J.; Chiness, Peter S.; Collins, Francis S.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA.
[Estrada, Karol] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
[Friedrichs, Nele] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany.
[Garcia, Melissa E.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
[Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
[Gigante, Bruna; Leander, Karin; de Faire, Ulf] Karolinska Inst, Div Cardiovasc Epidemiol, Inst Environm Med, S-17177 Stockholm, Sweden.
[Go, Alan S.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA.
[Golay, Alain] Univ Hosp Geneva, Serv Therapeut Educ Diabet Obes & Chron Dis, CH-1211 Geneva, Switzerland.
[Grallert, Harald; Illig, Thomas; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.
[Grallert, Harald; Thorand, Barbara] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.
[Graessler, Juergen; Schwarz, Peter E. H.; Bornstein, Stefan R.] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Med 3, D-01307 Dresden, Germany.
[Hallmans, Goran] Umea Univ, Unit Nutr Res, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden.
[Hartman, Catharina A.; Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands.
[Hassinen, Maija; Lakka, Timo A.; Rauramaa, Rainer] Kuoplo Res Inst Exercise Med, FI-70100 Kuopio, Finland.
[Hayward, Caroline] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland.
[Heikkila, Kauko; Kaprio, Jaakko] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, FI-00014 Helsinki, Finland.
[Herzig, Karl-Heinz] Univ Oulu, Inst Biomed, FI-90014 Oulu, Finland.
[Herzig, Karl-Heinz] Med Res Ctr Oulu, FI-90014 Oulu, Finland.
[Herzig, Karl-Heinz] Oulu Univ Hosp, FI-90014 Oulu, Finland.
[Herzig, Karl-Heinz; Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, FI-90014 Oulu, Finland.
[Helmer, Quinta] Vrije Univ Amsterdam, Fac Psychol & Educ, NL-1081 BT Amsterdam, Netherlands.
[Hillege, Hans L.; Nolte, Ilja M.; Vonk, Judith M.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands.
[Holmen, Oddgeir; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7489 Trondheim, Norway.
[Hunt, Steven C.] Univ Utah, Cardiovasc Genet Div, Dept Internal Med, Salt Lake City, UT 84108 USA.
[Isaacs, Aaron; Oostra, Ben A.; van Dujin, Cornelia M.] Ctr Med Sytems Biol, NL-2300 RC Leiden, Netherlands.
[Ittermann, Till; Hoffmann, Wolfgang] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany.
[James, Alan L.] Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia.
[James, Alan L.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA 6009, Australia.
[Kalafati, Ioanna-Panagiota; Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens 17671, Greece.
[Kratzer, Wolfgang; Seufferlein, Thomas] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89081 Ulm, Germany.
[Lamina, Claudia] Med Univ Innsbruck, Div Genet Epidemiol, Dept Med Genet Mol & Clin Pharmacol, A-6020 Innsbruck, Austria.
[Lichtner, Peter] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, D-85764 Neuherberg, Germany.
[Lind, Lars; Sundstrom, Johan] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden.
[Lorentzon, Mattias; Ohlsson, Claes] Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden.
[McArdle, Wendy L.; Min, Josine L.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England.
[Merger, Sigrun; Claudi-Boehmi, Simone] Univ Ulm, Med Ctr, Div Endocrinol Diabet & Metab, D-89081 Ulm, Germany.
[Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia.
[Moayyeri, Alireza] UCL, Farr Inst Hlth Informat Res, London NW1 2DA, England.
[Monda, Ken L.] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA 91320 USA.
[Mooijaart, Simon P.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands.
[Muehleisen, Thomas W.] Univ Bonn, Life Brain Ctr, Dept Genom, D-53127 Bonn, Germany.
[Muehleisen, Thomas W.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany.
[Mulas, Antonella; Sanna, Serena] CNR, IRGB, I-09042 Cagliari, Sardinia, Italy.
[Mueller, Gabriele] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Ctr Evidence Based Healthcare, D-01307 Dresden, Germany.
[Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany.
[Mueller-Nurasyid, Martina; Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat, D-81377 Munich, Germany.
[Mueller-Nurasyid, Martina; Peters, Annette] Munich HeartAlliance, German Res Ctr Cardiovasc Res, Deutsch Forschungszentrum Herz Kreislauferkrankun, D-80636 Munich, Germany.
[Nagaraja, Ramaiah; Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA.
[Nalls, Michael A.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA.
[Glorioso, Nicola; Troffa, Chiara] Univ Sassari, Sch Med, Hypertens & Related Dis Ctr AOU, I-07100 Sassari, Italy.
[Rose, Lynda M.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA.
[Scharnagl, Hubert; Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria.
[Sennblad, Bengt] Karolinska Inst, Sci Life Lab, S-17165 Stockholm, Sweden.
[Sitlani, Colleen M.] Univ Washington, Dept Med, Seattle, WA 98101 USA.
[Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland.
[Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, IS-101 Reykjavik, Iceland.
[Stirrups, Kathleen; Kanoni, Stavroula; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England.
[Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, S-75144 Uppsala, Sweden.
[Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA.
[Thorand, Barbara; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm, Inst Epidemiol 2, D-85764 Neuherberg, Germany.
[Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Thorsteinsdottir, Unnur R.; Stefansson, Kari] Amgen Inc, deCODE Genet, IS-101 Reykjavik, Iceland.
[Tomaschitz, Andreas] Med Univ Graz, Dept Cardiol, A-8036 Graz, Austria.
[van Oort, Floor V. A.] Erasmus MC Univ Med Ctr, Dept Child & Adolescent Psychiat, NL-3000 CB Rotterdam, Netherlands.
[Wennauer, Roman] Univ Ulm, Med Ctr, Dept Clin Chem, D-89081 Ulm, Germany.
[Wilsgaard, Tom; Njolstad, Inger] UiT, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway.
[Wong, Andrew; Ong, Ken K.; Kuh, Diana] UCL, MRC Unit Lifelong Hlth & Ageing, London WC1B 5JU, England.
[Brennan, Eoin P.] Natl Univ Ireland Univ Coll Dublin, Diabet Complicat Res Ctr, Conway Inst, Sch Med & Med Sci, Dublin 4, Ireland.
[Choi, Murim] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul 110799, South Korea.
[Franco-Cereceda, Anders; Olsson, Christian] Karolinska Inst, Cardlothorac Surg Unit, Dept Mol Med & Surg, S-17176 Stockholm, Sweden.
[Gharavi, Ali G.; Kiryluk, Krzysztof] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA.
[Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA.
[Hivert, Marie-France] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Huang, Jinyan] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, State Key Lab Med Genom,Shanghai Inst Hematol, Shanghai 200025, Peoples R China.
[Huang, Jinyan; Liang, Liming; Ma, Baoshan; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
[Karpe, Fredrik] OUH Trust, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LE, England.
[Liang, Liming] Harvard Univ, Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
[Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, New Haven, CT 06520 USA.
[Ma, Baoshan] Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian 116026, Liaoning, Peoples R China.
[McKnight, Amy J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT9 7AB, Down, North Ireland.
[McPherson, Ruth] Univ Ottawa, Inst Heart, Ottawa, ON K1Y 4W7, Canada.
[Moffatt, Miriam F.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England.
[Montgomery, Grant W.; Nyholt, Dale R.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia.
[Murabito, Joanne M.] Boston Univ, Sch Med, Sect Gen Internal Med, Boston, MA 02118 USA.
[Nicholson, George] Univ Oxford, Dept Stat, Oxford OX1 3TG, England.
[Nicholson, George] MRC Harwell, Harwell OX11 0QG, Berks, England.
[Nyholt, Dale R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia.
[Sandholm, Niina] Aalto Univ, Sch Sci, Dept Biomed Engn & Computat Sci, FI-00076 Helsinki, Finland.
[Sandholm, Niina] Univ Helsinki, Cent Hosp, Div Nephrol, Dept Med, FI-00290 Helsinki, Finland.
[Sandholm, Niina] Folkhalsan Inst Genet, Folkhalsan Res Ctr, FI-00290 Helsinki, Finland.
[Schadt, Eric E.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10580 USA.
[Vallejo, Edgar E.] Tecnol Monterrey, Dept Comp Sci, Atizapan De Zaragoza 52926, Mexico.
[Zondervan, Krina T.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Oxford OX3 7BN, England.
[Amouyel, Philippe] Univ Lille 2, Inst Pasteur Lille, INSERM, U744, F-59000 Lille, France.
[Arveiler, Dominique] Univ Strasbourg, Fac Med, EA3430, Dept Epidemiol & Publ Hlth, Strasbourg, France.
[Bakker, Stephan J. L.; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 RB Groningen, Netherlands.
[Beilby, John; Hui, Jennie] Univ Western Australia, Perth, WA 6009, Australia.
[Bergman, Richard N.] Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA 90048 USA.
[Brown, Morris J.] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England.
[Burnier, Michel] Lausanne Univ Hosp CHUV, Dept Med, Serv Nephrol, CH-1005 Lausanne, Switzerland.
[Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland.
[Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37203 USA.
[Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.
[Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.
[de Geusl, Eco J. C.] Vrije Univ Amsterdam, NL-1081 BT Amsterdam, Netherlands.
[de Geusl, Eco J. C.; Penninx, Brenda W.] Vrije Univ Amsterdam, Inst Hlth & Care Res, Inst Res Extramural Med, NL-1081 BT Amsterdam, Netherlands.
[Doerr, Marcus] Univ Med Greifswald, Dept Internal Med B, D-17475 Greifswald, Germany.
[Doerr, Marcus; Hoffmann, Wolfgang; Voelker, Uwe] Partner Site Greifswald, DZHK, D-17475 Greifswald, Germany.
[Erbel, Raimund; Mohlenkamp, Stefan] Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, D-45122 Essen, Germany.
[Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth, FI-00290 Helsinki, Finland.
[Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, FI-00290 Helsinki, Finland.
[Ferrannini, Ele] Univ Pisa, Dept Internal Med, I-56100 Pisa, Italy.
[Ferrieres, Jean] Toulouse Univ, Sch Med, Rangueil Hosp, Dept Cardiol, F-31400 Toulouse, France.
[Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, UWI Solut Developing Countries, Kingston 7, Jamaica.
[Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA.
[Hattersley, Andrew T.] Univ Exeter, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England.
[Hicks, Andrew A.; Pramstaller, Peter P.] Bolzano EURAC, European Acad Bozen, Ctr Biomed, I-39100 Bolzano, Italy.
[Hicks, Andrew A.; Pramstaller, Peter P.] Inst Univ Lubeck, D-23562 Lubeck, Germany.
[Hingorani, Aroon D.] UCL, Inst Cardiovasc Sci, London WC1E 6BT, England.
[Humphries, Steve E.] UCL, Ctr Cardiovasc Genet, Inst Cardiovasc Sci, London WC1E 6JJ, England.
[Hyppoenen, Elina] Univ S Australia, Sansom Inst Hlth Res, Adelaide, SA 5000, Australia.
[Hyppoenen, Elina] Univ S Australia, Sch Populat Hlth, Adelaide, SA 5000, Australia.
[Hyppoenen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA 5000, Australia.
[Hyppoenen, Elina; Power, Chris] UCL, Inst Child Hlth, London WC1N 1EH, England.
[Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany.
[Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, FI-90101 Oulu, Finland.
[Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC Hlth Protect Agcy HPA Ctr Environ & Hlth, London W2 1PG, England.
[Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, FI-90014 Oulu, Finland.
[Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, FI-90014 Oulu, Finland.
[Kee, Frank] Queens Univ Belfast, UK Clin Res Collaborat Ctr Excellence Publ Hlth N, Belfast BT7 1NN, Antrim, North Ireland.
[Keinanen-Kiukaanniemi, Sirkka M.] Univ Oulu, Inst Hlth Sci, Fac Med, FI-90014 Oulu, Finland.
[Keinanen-Kiukaanniemi, Sirkka M.] Oulu Univ Hosp, Unit Primary Hlth Care Gen Practice, FI-90220 Oulu, Finland.
[Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England.
[Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.
[Kumari, Meena; Langenberg, Claudia; Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.
[Kumari, Meena] Univ Essex, Dept Biol & Social Epidemiol, Colchester CO4 3SQ, Essex, England.
[Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, Dept Med, FI-70210 Kuopio, Finland.
[Kuusisto, Johanna; Lakka, Timo A.; Laakso, Markku; Rauramaa, Rainer] Univ Eastern Finland, FI-70210 Kuopio, Finland.
[Lakka, Timo A.] Univ Eastern Finland, Inst Biomed, Dept Physiol, FI-70211 Kuopio, Finland.
[Lakka, Timo A.; Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, FI-70210 Kuopio, Finland.
[Le Marchand, Loic] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96813 USA.
[Lehtimaki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FI-33520 Tampere, Finland.
[Lehtimaki, Terho] Univ Tampere, Sch Med, FI-33520 Tampere, Finland.
[Lyssenko, Valeriya] Steno Diabet Ctr AS, DK-2820 Gentofte, Denmark.
[Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Lund Univ Diabet Ctr, S-22100 Malmo, Sweden.
[Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, S-22100 Malmo, Sweden.
[Marette, Andre] Univ Laval, Fac Med, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ G1V 0A6, Canada.
[Marette, Andre; Vohl, Marie-Claude; Perusse, Louis] Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ G1V 0A6, Canada.
[Musk, Arthur W.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
[Musk, Arthur W.] Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia.
[Palmer, Lyle J.] Univ Toronto, Toronto, ON M5G 1E2, Canada.
[Lakka, Timo A.; Rauramaa, Rainer] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada.
[Penninx, Brenda W.] Vrije Univ Amsterdam, Dept Psychiat, NL-1081 BT Amsterdam, Netherlands.
[Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, I-39100 Bolzano, Italy.
[Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FI-20521 Turku, Finland.
[Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FI-20521 Turku, Finland.
[Rankinen, Tuomo; Sarzynski, Mark A.; Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA.
[Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.
[Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA.
[Rudan, Igor] Univ Split, Croatian Ctr Global Hlth, Fac Med, Split 21000, Croatia.
[Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.
[Samani, Nilesh J.] Glenfield Gen Hosp, Natl Inst Hlth Res NIHR Leicester Cardiovasc Biom, Leicester LE3 9QP, Leics, England.
[Saramies, Jouko] South Carelia Cent Hosp, Lappeenranta 53130, Finland.
[Schwarz, Peter E. H.] Paul Langerhans Inst Dresden, German Ctr Diabet Res DZD, D-01307 Dresden, Germany.
[Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Divis Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA.
[Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Program Personalized & Genom Med, Sch Med, Baltimore, MD 21201 USA.
[Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA.
[Staessen, Jan A.] Maastricht Univ, Dept Epidemiol, NL-6229 HA Maastricht, Netherlands.
[Staessen, Jan A.] Univ Leuven, KU Leuven Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, B-3000 Louvain, Belgium.
[Tremblay, Angelo; Perusse, Louis] Univ Laval, Dept Kinesiol, Quebec City, PQ G1V 0A6, Canada.
[Tremoli, Elena] Univ Milan, Dipartimento Sci Farmacol & Biomol, I-20133 Milan, Italy.
[Tremoli, Elena] Inst Ricovero & Cura Carattere Sci, Ctr Cardiol Monzi, I-20133 Milan, Italy.
[Vohl, Marie-Claude] Univ Laval, Dept Food Sci & Nutr, Quebec City, PQ G1V 0A6, Canada.
[Vollenweider, Peter] Univ Hosp CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland.
[Vollenweider, Peter; Bochud, Murielle] Univ Lausanne, CH-1011 Lausanne, Switzerland.
[Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA.
[Bochud, Murielle] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland.
[Boehm, Bernhard O.] Imperial Coll London, Lee Kong Chian Sch Med, Singapore 637553, Singapore.
[Boehm, Bernhard O.] Nanyang Technol Univ, Singapore 637553, Singapore.
[Boehm, Bernhard O.] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89081 Ulm, Germany.
[Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Dept Clin Pharmacol, London EC1M 6BQ, England.
[Grabe, Hans-Joergen] HELIOS Hosp Stralsund, Univ Med Greifswald, Dept Psychiat & Psychotherapy, D-17475 Greifswald, Germany.
[Grabe, Hans-Joergen] German Ctr Neurodegenerat Dis DZNE, D-17475 Greifswald, Germany.
[Hui, Jennie] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia.
[Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA.
[Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, D-68163 Mannheim, Germany.
[Oostra, Ben A.] Erasmus MC Univ Med Ctr, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands.
[Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA.
[Saaristo, Timo E.] Finnish Diabet Assoc, FI-33680 Tampere, Finland.
[Saaristo, Timo E.] Pirkanmaa Hosp Dist, FI-33521 Tampere, Finland.
[Saleheen, Danish] Ctr Noncommunicable Dis, Karatchi, Pakistan.
[Saleheen, Danish] Univ Penn, Dept Med, Philadelphia, PA 19104 USA.
[Sinisalo, Juha] Univ Helsinki, Cent Hosp, Heart & Lung Ctr, Dept Med, FI-00290 Helsinki, Finland.
[Thorsteinsdottir, Unnur R.; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.
[Tuomilehto, Jaakko] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid 28046, Spain.
[Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia.
[Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria.
[Uusitupa, Math] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, FI-70211 Kuopio, Finland.
[van der Harst, Pim] Interuniv Cardiol Inst Netherlands, Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands.
[Veronesi, Giovanni] Univ Insubria, EPIMED Res Ctr, Dept Clin & Expt Med, I-21100 Varese, Italy.
[Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.
[Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, D-85764 Munich, Germany.
[Wichmann, H-Erich] Klinikum Grosshadern, D-81377 Munich, Germany.
[Wichmann, H-Erich] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, D-85764 Neuherberg, Germany.
[Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
[Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia.
[Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA.
[Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London SW17 0RE, England.
[Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.
[Visscher, Peter M.; Yang, Jian] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia.
[Visscher, Peter M.; Yang, Jian] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4012, Australia.
[McCarthy, Mark I.] Oxford Univ Hosp NHS Trust, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England.
[North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.
[Barroso, Ines] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge CB2 OQQ, England.
[Barroso, Ines] Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 OQQ, England.
[Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.
[Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.
[Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.
[Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England.
RP Mohlke, KL (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
EM celi@well.ox.ac.uk; mohlke@med.unc.edu
RI Veronesi, Giovanni/E-3859-2010; Onland-Moret, N. Charlotte/G-9185-2011;
Staessen, Jan/A-1065-2011; Gudnason, Vilmundur/K-6885-2015; Ripatti,
Samuli/H-9446-2014; Mattace- Raso, Francesco/L-2541-2015; Wilson, James
F/A-5704-2009; Polasek, Ozren/B-6002-2011; Montgomery,
Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Rivadeneira,
Fernando/O-5385-2015; Kessler, Thorsten/O-7426-2015; Prokopenko,
Inga/H-3241-2014; Grallert, Harald/B-3424-2013; Salumets,
Andres/J-2278-2015; Singleton, Andrew/C-3010-2009; Fall,
Tove/O-7226-2014; Meisinger, Christine/B-5358-2014; Visser, Jenny
/F-8156-2011; Moayyeri, Alireza/N-3332-2014; Bakker,
Stephan/J-4023-2015; Palmer, Colin/C-7053-2008; Boehm,
Bernhard/F-8750-2015; Fehrmann, Rudolf/E-2551-2011; Colaus,
PsyColaus/K-6607-2013; Kolcic, Ivana/E-2713-2017; Boban,
Mladen/E-2777-2017; Stathopoulou, Maria/H-7324-2016; Feitosa,
Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Ormel, Johan/C-6094-2013;
Karjalainen, Juha/P-8624-2016; Laan, Maris/A-4100-2011; Slagboom, P.
Eline/R-4790-2016; Verweij, Niek/A-4499-2017; Erdmann,
Jeanette/P-7513-2014; Franke, Andre/B-2151-2010; Magnusson,
Patrik/C-4458-2017; Balcells, Susana/C-5222-2017; Leander,
Karin/C-7261-2017; Yengo, Loic/D-2692-2017; Palmer, Lyle/K-3196-2014;
Nato, Alejandro/J-3880-2016; Yang, Jian/A-5852-2010; Khusnutdinova,
Elza/A-4810-2013; Matullo, Giuseppe/K-6383-2016; Deloukas,
Panos/B-2922-2013; kinnunen, leena/B-7059-2012; Study,
GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; mangino,
massimo/F-5134-2011; d'Adamo, Adamo Pio/G-4064-2011; Schwarz,
Peter/B-5127-2013; Johnson, Andrew/G-6520-2013; Franke,
Lude/P-7036-2016; Kronenberg, Florian/B-1736-2008; Sundstrom,
Johan/A-6286-2009; Sarzynski, Mark/A-9798-2014; Thorand,
Barbara/B-5349-2014; Peters, Annette/A-6117-2011; Lyytikainen,
Leo-Pekka/C-8544-2016; Tregouet, David-Alexandre/E-3961-2016; Urreizti,
Roser/M-6402-2014; Hypponen, Elina/B-2596-2014; Cauley,
Jane/N-4836-2015; Bovet, Pascal/F-4477-2011; Bouchard,
Claude/A-7637-2009; Smith, Albert/K-5150-2015;
OI Veronesi, Giovanni/0000-0002-4119-6615; Staessen,
Jan/0000-0002-3026-1637; Gudnason, Vilmundur/0000-0001-5696-0084;
Ripatti, Samuli/0000-0002-0504-1202; Wilson, James
F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Montgomery,
Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441;
Prokopenko, Inga/0000-0003-1624-7457; Salumets,
Andres/0000-0002-1251-8160; Moayyeri, Alireza/0000-0002-9143-2161;
Bakker, Stephan/0000-0003-3356-6791; Palmer, Colin/0000-0002-6415-6560;
Fehrmann, Rudolf/0000-0002-7516-315X; Mannisto,
Satu/0000-0002-8668-3046; Lakka, Timo/0000-0002-9199-2871; Mellstrom,
Dan/0000-0003-2761-3723; Gigante, Bruna/0000-0003-4508-7990; Luben,
Robert/0000-0002-5088-6343; Humphries, Stephen E/0000-0002-8221-6547;
Gieger, Christian/0000-0001-6986-9554; Mooijaart,
Simon/0000-0003-3106-3568; Adeyemo, Adebowale/0000-0002-3105-3231;
Semple, Robert/0000-0001-6539-3069; Kumari, Meena/0000-0001-9716-1035;
Arora, Pankaj/0000-0003-2420-3550; Peters,
Marjolein/0000-0003-3167-9063; Hosseini, Mohsen/0000-0003-3626-9928;
Zgaga, Lina/0000-0003-4089-9703; Sandholm, Niina/0000-0003-4322-6942;
Deelen, Joris/0000-0003-4483-3701; Kristiansson,
Kati/0000-0003-4688-107X; Tryggvadottir, Laufey/0000-0001-8067-9030;
Locke, Adam/0000-0001-6227-198X; Goessling, Wolfram/0000-0001-9972-1569;
Fuchsberger, Christian/0000-0002-5918-8947; Johnson,
Toby/0000-0002-5998-3270; Mulas, Antonella/0000-0002-6856-1483; van
Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Beekman,
Marian/0000-0003-0585-6206; Esko, Tonu/0000-0003-1982-6569; Scollen,
Serena/0000-0002-9311-1337; Org, Elin/0000-0003-1451-9375; Seshadri,
Sudha/0000-0001-6135-2622; Bush, William/0000-0002-9729-6519; Shungin,
Dmitry/0000-0001-7900-5856; Menni, Cristina/0000-0001-9790-0571; Franks,
Paul/0000-0002-0520-7604; TREMOLI, ELENA/0000-0002-0929-6106; Magi,
Reedik/0000-0002-2964-6011; Kolcic, Ivana/0000-0001-7918-6052;
Stathopoulou, Maria/0000-0003-4376-2083; Feitosa,
Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Kita,
Yoshikuni/0000-0002-2366-1106; Song, Ci/0000-0002-0947-9068; Day,
Felix/0000-0003-3789-7651; Strawbridge, Rona/0000-0001-8506-3585;
Melzer, David/0000-0002-0170-3838; Hocking, Lynne J/0000-0002-2414-2826;
Laan, Maris/0000-0002-8519-243X; Slagboom, P. Eline/0000-0002-2875-4723;
Erdmann, Jeanette/0000-0002-4486-6231; Franke,
Andre/0000-0003-1530-5811; Balcells, Susana/0000-0003-1211-1907;
Leander, Karin/0000-0002-1404-9222; Yengo, Loic/0000-0002-4272-9305;
Palmer, Lyle/0000-0002-1628-3055; Nato, Alejandro/0000-0002-8745-9046;
Yang, Jian/0000-0003-2001-2474; Deloukas, Panos/0000-0001-9251-070X;
kinnunen, leena/0000-0001-8739-4812; Bochud,
Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470;
d'Adamo, Adamo Pio/0000-0001-9367-4909; Schwarz,
Peter/0000-0001-6317-7880; Franke, Lude/0000-0002-5159-8802; Kronenberg,
Florian/0000-0003-2229-1120; Sundstrom, Johan/0000-0003-2247-8454;
Thorand, Barbara/0000-0002-8416-6440; Lyytikainen,
Leo-Pekka/0000-0002-7200-5455; Urreizti, Roser/0000-0003-3617-7134;
Hypponen, Elina/0000-0003-3670-9399; Cauley, Jane/0000-0003-0752-4408;
Bovet, Pascal/0000-0002-0242-4259; Smith, Albert/0000-0003-1942-5845;
Verweij, Niek/0000-0002-4303-7685; Kuulasmaa, Kari/0000-0003-2165-1411;
VALLEJO, EDGAR E./0000-0003-2805-7132; Karasik,
David/0000-0002-8826-0530; Hedman, Asa/0000-0001-5413-204X;
Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Forouhi,
Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630;
rossing, peter/0000-0002-1531-4294; ruggiero,
daniela/0000-0003-3898-7827; Nicholson, Geoffrey/0000-0002-0152-1153;
Buyske, Steven/0000-0001-8539-5416; Vandenput,
Liesbeth/0000-0002-1712-6131; Karpe, Fredrik/0000-0002-2751-1770;
Maxwell, Alexander P./0000-0002-6110-7253; Medina-Gomez,
Carolina/0000-0001-7999-5538; Visscher, Peter/0000-0002-2143-8760;
Marmot, Michael/0000-0002-2431-6419; Eriksson,
Johan/0000-0002-2516-2060; Prabhakaran, Dorairaj/0000-0002-3172-834X;
Falhammar, Henrik/0000-0002-5622-6987; Evans, David/0000-0003-0663-4621;
Assimes, Themistocles/0000-0003-2349-0009; Evangelou,
Evangelos/0000-0002-5488-2999; Ouwehand, Willem/0000-0002-7744-1790;
Folkersen, Lasse/0000-0003-0708-9530; Kaprio,
Jaakko/0000-0002-3716-2455; Lawlor, Debbie A/0000-0002-6793-2262;
Johansson, Asa/0000-0002-2915-4498; Pettersson Kymmer,
Ulrika/0000-0002-0557-9803; Hattersley, Andrew/0000-0001-5620-473X;
Sinisalo, Juha/0000-0002-0169-5137; Lahti, Jari/0000-0002-4310-5297; de
Geus, Eco/0000-0001-6022-2666; Kleber, Marcus/0000-0003-0663-7275;
Ganna, Andrea/0000-0002-8147-240X; Peters, Annette/0000-0001-6645-0985;
Wain, Louise/0000-0003-4951-1867
FU British Heart Foundation [FS/14/55/30806, RG/08/008/25291,
RG/08/014/24067, RG/10/12/28456, RG/13/2/30098]; Cancer Research UK
[14136]; Chief Scientist Office [CZB/4/710]; Diabetes UK [12/0004470];
Intramural NIH HHS [Z01 HG000024-14]; Medical Research Council
[MC_UU_12011/1, G0401527, G0601261, G0601463, G1000143, G1001799,
G9521010, MC_PC_U127561128, MC_U106179471, MC_U106179472,
MC_UP_A100_1003, MC_UP_A620_1014, MC_UU_12012/1, MC_UU_12013/1,
MC_UU_12015/1, MC_UU_12015/2, MC_UU_12015/5, MC_UU_12019/1,
MR/K006584/1, MR/K011480/1, MR/K013351/1, MR/L003120/1, MR/N01104X/1];
NCI NIH HHS [UM1 CA182910, UM1 CA182913]; NHGRI NIH HHS [U01 HG007376,
U01 HG007416, U01 HG007419]; NHLBI NIH HHS [K01 HL116770, R00 HL094535,
R01 HL109946, R01 HL117078, R01 HL117626, T32 HL007055, T32 HL069768];
NIA NIH HHS [R01 AG025941, R01 AG033193, R01 AG041517, U01 AG049505];
NIDA NIH HHS [R21 DA027040]; NIDDK NIH HHS [K23 DK080145, P30 DK020541,
P30 DK020572, P30 DK040561, P30 DK072488, P30 DK079637, P60 DK020541,
R01 DK062370, R01 DK072193, R01 DK075787, R01 DK078150, R01 DK089256,
R01 DK093757, R01 DK107437, U01 DK062370]; NIGMS NIH HHS [P30 GM103341,
T32 GM007092, T32 GM067553]; NIMHD NIH HHS [P20 MD006899]; Wellcome
Trust [084766, 085235, 097117, 098017, 098381, 098498, 100574]
NR 95
TC 165
Z9 166
U1 34
U2 213
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 12
PY 2015
VL 518
IS 7538
BP 187
EP U378
DI 10.1038/nature14132
PG 22
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300030
PM 25673412
ER
PT J
AU Locke, AE
Kahali, B
Berndt, SI
Justice, AE
Pers, TH
Felix, R
Powell, C
Vedantam, S
Buchkovich, ML
Yang, J
Croteau-Chonka, DC
Esko, T
Fall, T
Ferreira, T
Gustafsson, S
Kutalik, Z
Luan, JA
Magi, R
Randall, JC
Winkler, TW
Wood, AR
Workalemahu, T
Faul, JD
Smith, JA
Zhao, JH
Zhao, W
Chen, J
Fehrmann, R
Hedman, AK
Karjalainen, J
Schmidt, EM
Absher, D
Amin, N
Anderson, D
Beekman, M
Bolton, JL
Bragg-Gresham, L
Buyske, S
Demirkan, A
Deng, GH
Ehret, GB
Feenstra, B
Feitosa, MF
Fischer, K
Goel, A
Gong, J
Jackson, AU
Kanoni, S
Kleber, ME
Kristiansson, K
Lim, U
Lotay, V
Mangino, M
Leach, IM
Medina-Gomez, C
Medland, SE
Nalls, MA
Palmer, CD
Pasko, D
Pechlivanis, S
Peters, MJ
Prokopenko, I
Shungin, D
Stancakova, A
Strawbridge, RJ
Sung, YJ
Tanaka, T
Teumer, A
Trompet, S
van der Laan, SW
van Settee, J
Van Vliet-Ostaptchouk, JV
Wang, ZM
Yengo, L
Zhang, WH
Isaacs, A
Albrecht, E
Arnlov, J
Arscott, GM
Attwood, AP
Bandinelli, S
Barrett, A
Bas, IN
Bellis, C
Bennett, AJ
Berne, C
Blagieva, R
Bluher, M
Bohringer, S
Bonnycastle, LL
Bottcher, Y
Boyd, HA
Bruinenberg, M
Caspersen, IH
Chen, YD
Clarke, R
Daw, EW
de Craen, AJM
Delgado, G
Dimitriou, M
Doney, ASF
Eklund, N
Estrada, K
Eury, E
Folkersen, L
Fraser, RM
Garcia, ME
Geller, F
Giedraitis, V
Gigante, B
Go, AS
Golay, A
Goodall, AH
Gordon, SD
Gorski, M
Grabe, HJ
Grallert, H
Grammer, TB
Grassler, J
Gronberg, H
Groves, CJ
Gusto, G
Haessler, J
Hall, P
Haller, T
Hallmans, G
Hartman, CA
Hassinen, M
Hayward, C
Heard-Costa, NL
Helmer, Q
Hengstenberg, C
Holmen, O
Hottenga, JJ
James, AL
Jeff, JM
Johansson, A
Jolley, J
Juliusdottir, T
Kinnunen, L
Koenig, W
Koskenvuo, M
Kratzer, W
Laitinen, J
Lamina, C
Leander, K
Lee, NR
Lichtner, P
Lind, L
Lindstrom, J
Lo, KS
Lobbens, S
Lorbeer, R
Lu, YC
Mach, F
Magnusson, PKE
Mahajan, A
McArdle, WL
McLachlan, S
Menni, C
Merger, S
Mihailov, E
Milani, L
Moayyeri, A
Monda, KL
Morken, MA
Mulas, A
Muller, G
Muller-Nurasyid, M
Musk, AW
Nagaraja, R
Nothen, MM
Nolte, IM
Pilz, S
Rayner, NW
Renstrom, F
Rettig, R
Ried, JS
Ripke, S
Robertson, NR
Rose, LM
Sanna, S
Scharnagl, H
Scholtens, S
Schumacher, FR
Scott, WR
Seufferlein, T
Shi, JX
Smith, AV
Smolonska, J
Stanton, AV
Steinthorsdottir, V
Stirrups, K
Stringham, HM
Sundstrom, J
Swertz, MA
Swift, AJ
Syvanen, AC
Tan, ST
Tayo, BO
Thorand, B
Thorleifsson, G
Tyrer, JP
Uh, HW
Vandenput, L
Verhulst, FC
Vermeulen, SH
Verweij, N
Vonk, JM
Waite, LL
Warren, HR
Waterworth, D
Weedon, MN
Wilkens, LR
Willenborg, C
Wilsgaard, T
Wojczynski, MK
Wong, A
Wrightl, AF
Zhang, QY
Brennan, EP
Choi, M
Dastani, Z
Drong, AW
Eriksson, P
Franco-Cereceda, A
Gadin, JR
Gharavi, AG
Goddard, ME
Handsaker, RE
Huang, JY
Karpe, F
Kathiresan, S
Keildson, S
Kiryluk, K
Kubo, M
Lee, JY
Liang, L
Lifton, RP
Ma, BS
McCarroll, SA
McKnight, AJ
Min, JL
Moffatt, MF
Montgomery, GW
Murabito, JM
Nicholson, G
Nyholt, DR
Okada, Y
Perry, JRB
Dorajoo, R
Reinmaa, E
Salem, RM
Sandholm, N
Scott, RA
Stolk, L
Takahashi, A
Tanaka, T
van 't Hooft, FM
Vinkhuyzen, AAE
Westra, HJ
Zheng, W
Zondervan, KT
Heath, AC
Arveiler, D
Bakker, SJL
Beilby, J
Bergman, RN
Blangero, J
Bovet, P
Campbell, H
Caulfield, MJ
Cesana, G
Chakravarti, A
Chasman, DI
Chines, PS
Collins, FS
Crawford, DC
Cupples, LA
Cusi, D
Danesh, J
de Faire, U
den Ruijter, HM
Dominiczak, AF
Erbel, R
Erdmann, J
Eriksson, JG
Farrall, M
Felix, SB
Ferrannini, E
Ferrieres, J
Ford, I
Forouhi, NG
Forrester, T
Franco, OH
Gansevoort, RT
Gejman, PV
Gieger, C
Gottesman, O
Gudnason, V
Gyllensten, U
Hall, AS
Harris, TB
Hattersley, AT
Hicks, AA
Hindorff, LA
Hingorani, AD
Hofman, A
Homuth, G
Hovingh, GK
Humphries, SE
Hunt, SC
Hypponen, E
Illig, T
Jacobs, KB
Jarvelin, MR
Jockel, KH
Johansen, B
Jousilahti, P
Jukema, JW
Jula, AM
Kaprio, J
Kastelein, JJP
Keinanen-Kiukaanniemi, SM
Kiemeney, LA
Knekt, P
Kooner, JS
Kooperberg, C
Kovacs, P
Kraja, AT
Kumari, M
Kuusisto, J
Lakka, TA
Langenberg, C
Le Marchand, L
Lehtimaki, T
Lyssenko, V
Mannisto, S
Marette, A
Matise, TC
McKenzie, CA
McKnight, B
Moll, FL
Morris, AD
Morris, AP
Murray, JC
Nelis, M
Ohlsson, C
Oldehinkel, AJ
Ong, KK
Madden, PAF
Pasterkamp, G
Peden, JF
Peters, A
Postma, DS
Pramstaller, PP
Price, JF
Qi, L
Raitakari, OT
Rankinen, T
Rao, DC
Rice, TK
Ridker, PM
Rioux, JD
Ritchie, MD
Rudan, I
Salomaa, V
Samani, NJ
Saramines, J
Sarzynski, MA
Schunkert, H
Schwarz, PEH
Sever, P
Shuldiner, AR
Sinisalo, J
Stolk, RP
Strauch, K
Tonjes, A
Tregouet, DA
Tremblay, A
Tremoli, E
Virtamo, J
Vohl, MC
Volker, U
Waeber, G
Willemsen, G
Witteman, JC
Zillikens, MC
Adair, LS
Amouyel, P
Asselbergs, FW
Assimes, TL
Bochud, M
Boehm, BO
Boerwinkle, E
Bornstein, SR
Bottinger, EP
Bouchard, C
Cauchi, S
Chambers, JC
Chanock, SJ
Cooper, RS
de Bakker, PIW
Dedoussis, G
Ferrucci, L
Franks, PW
Froguel, P
Groop, LC
Haiman, CA
Hamsten, A
Hui, JN
Hunter, DJ
Hveem, K
Kaplan, RC
Kivimaki, M
Kuh, D
Laakso, M
Liu, YM
Martin, NG
Marz, W
Melbve, M
Metspalu, A
Moebus, S
Munroe, PB
Njolstad, I
Oostra, BA
Palmer, CNA
Pedersen, NL
Perola, M
Perusse, L
Peters, U
Power, C
Quertermous, T
Rauramaa, R
Rivadeneira, F
Saaristo, TE
Saleheen, D
Sattar, N
Schadt, EE
Schlessinger, D
Slagboom, PE
Snieder, H
Spector, TD
Thorsteinsdottir, UR
Stumvoll, M
Tuomilehto, J
Uitterlinden, AG
Uusitupa, M
van der Harst, P
Walker, M
Wallaschofski, H
Wareham, NJ
Watkins, H
Weir, DR
Wichmann, HE
Wilson, JF
Zanen, P
Borecki, IB
Deloukas, P
Fox, CS
Heid, IM
O'Connell, JR
Strachan, DP
Stefansson, K
van Duijri, CM
Abecasis, GR
Franke, L
Frayling, TM
McCarthy, MI
Visscher, PM
Scherag, A
Willer, CJ
Boehnke, M
Mohlke, KL
Lindgren, CM
Beckmann, JS
Barroso, I
North, KE
Ingelsson, E
Hirschhorn, JN
Loos, RJF
Speliotes, EK
AF Locke, Adam E.
Kahali, Bratati
Berndt, Sonja I.
Justice, Anne E.
Pers, Tune H.
Day, Felix R.
Powell, Corey
Vedantam, Sailaja
Buchkovich, Martin L.
Yang, Jian
Croteau-Chonka, Damien C.
Esko, Tonu
Fall, Tove
Ferreira, Teresa
Gustafsson, Stefan
Kutalik, Zoltan
Luan, Jian'an
Maegi, Reedik
Randall, Joshua C.
Winkler, Thomas W.
Wood, Andrew R.
Workalemahu, Tsegaselassie
Faul, Jessica D.
Smith, Jennifer A.
Zhao, Jing Hua
Zhao, Wei
Chen, Jin
Fehrmann, Rudolf
Hedman, Asa K.
Karjalainen, Juha
Schmidt, Ellen M.
Absher, Devin
Amin, Najaf
Anderson, Denise
Beekman, Marian
Bolton, Jennifer L.
Bragg-Gresham, L.
Buyske, Steven
Demirkan, Ayse
Deng, Guohong
Ehret, Georg B.
Feenstra, Bjarke
Feitosa, Mary F.
Fischer, Krista
Goel, Anuj
Gong, Jian
Jackson, Anne U.
Kanoni, Stavroula
Kleber, Marcus E.
Kristiansson, Kati
Lim, Unhee
Lotay, Vaneet
Mangino, Massimo
Leach, Irene Mateo
Medina-Gomez, Carolina
Medland, Sarah E.
Nalls, Michael A.
Palmer, Cameron D.
Pasko, Dorota
Pechlivanis, Sonali
Peters, Marjolein J.
Prokopenko, Inga
Shungin, Dmitry
Stancakova, Alena
Strawbridge, Rona J.
Sung, Yun Ju
Tanaka, Toshiko
Teumer, Alexander
Trompet, Stella
van der Laan, Sander W.
van Settee, Jessica
Van Vliet-Ostaptchouk, Jana V.
Wang, Zhaoming
Yengo, Loic
Zhang, Weihua
Isaacs, Aaron
Albrecht, Eva
Arnlov, Johan
Arscott, Gillian M.
Attwood, Antony P.
Bandinelli, Stefania
Barrett, Amy
Bas, Isabelita N.
Bellis, Claire
Bennett, Amanda J.
Berne, Christian
Blagieva, Roza
Blueher, Matthias
Bohringer, Stefan
Bonnycastle, Lori L.
Boettcher, Yvonne
Boyd, Heather A.
Bruinenberg, Marcel
Caspersen, Ida H.
Chen, Yii-Der Ida
Clarke, Robert
Daw, E. Warwick
de Craen, Anton J. M.
Delgado, Graciela
Dimitriou, Maria
Doney, Alex S. F.
Eklund, Niina
Estrada, Karol
Eury, Elodie
Folkersen, Lasse
Fraser, Ross M.
Garcia, Melissa E.
Geller, Frank
Giedraitis, Vilmantas
Gigante, Bruna
Go, Alan S.
Golay, Alain
Goodall, Alison H.
Gordon, Scott D.
Gorski, Mathias
Grabe, Hans-Joergen
Grallert, Harald
Grammer, Tanja B.
Graessler, Jurgen
Gronberg, Henrik
Groves, Christopher J.
Gusto, Gaeelle
Haessler, Jeffrey
Hall, Per
Haller, Toomas
Hallmans, Goran
Hartman, Catharina A.
Hassinen, Maija
Hayward, Caroline
Heard-Costa, Nancy L.
Helmer, Qinta
Hengstenberg, Christian
Holmen, Oddgeir
Hottenga, Jouke-Jan
James, Alan L.
Jeff, Janina M.
Johansson, Asa
Jolley, Jennifer
Juliusdottir, Thorhildur
Kinnunen, Leena
Koenig, Wolfgang
Koskenvuo, Markku
Kratzer, Wolfgang
Laitinen, Jaana
Lamina, Claudia
Leander, Karin
Lee, Nanette R.
Lichtner, Peter
Lind, Lars
Lindstrom, Jaana
Lo, Ken Sin
Lobbens, Stephane
Lorbeer, Roberto
Lu, Yingchang
Mach, Francois
Magnusson, Patrik K. E.
Mahajan, Anubha
McArdle, Wendy L.
McLachlan, Stela
Menni, Cristina
Merger, Sigrun
Mihailov, Evelin
Milani, Lili
Moayyeri, Alireza
Monda, Keri L.
Morken, Mario A.
Mulas, Antonella
Mueller, Gabriele
Mueller-Nurasyid, Martina
Musk, Arthur W.
Nagaraja, Ramaiah
Noethen, Markus M.
Nolte, Ilja M.
Pilz, Stefan
Rayner, Nigel W.
Renstrom, Frida
Rettig, Rainer
Ried, Janina S.
Ripke, Stephan
Robertson, Neil R.
Rose, Lynda M.
Sanna, Serena
Scharnagl, Hubert
Scholtens, Salome
Schumacher, Fredrick R.
Scott, William R.
Seufferlein, Thomas
Shi, Jianxin
Smith, Albert Vernon
Smolonska, Joanna
Stanton, Alice V.
Steinthorsdottir, Valgerdur
Stirrups, Kathleen
Stringham, Heather M.
Sundstrom, Johan
Swertz, Morris A.
Swift, Amy J.
Syvanen, Ann-Christine
Tan, Sian-Tsung
Tayo, Bamidele O.
Thorand, Barbara
Thorleifsson, Gudmar
Tyrer, Jonathan P.
Uh, Hae-Won
Vandenput, Liesbeth
Verhulst, Frank C.
Vermeulen, Sita H.
Verweij, Niek
Vonk, Judith M.
Waite, Lindsay L.
Warren, Helen R.
Waterworth, Dawn
Weedon, Michael N.
Wilkens, Lynne R.
Willenborg, Christina
Wilsgaard, Tom
Wojczynski, Mary K.
Wong, Andrew
Wrightl, Alan F.
Zhang, Qunyuan
Brennan, Eoin P.
Choi, Murim
Dastani, Zari
Drong, Alexander W.
Eriksson, Per
Franco-Cereceda, Anders
Gadin, Jesper R.
Gharavi, Ali G.
Goddard, Michael E.
Handsaker, Robert E.
Huang, Jinyan
Karpe, Fredrik
Kathiresan, Sekar
Keildson, Sarah
Kiryluk, Krzysztof
Kubo, Michiaki
Lee, Jong-Young
Liang, Liming
Lifton, Richard P.
Ma, Baoshan
McCarroll, Steven A.
McKnight, Amy J.
Min, Josine L.
Moffatt, Miriam F.
Montgomery, Grant W.
Murabito, Joanne M.
Nicholson, George
Nyholt, Dale R.
Okada, Yukinori
Perry, John R. B.
Dorajoo, Rajkumar
Reinmaa, Eva
Salem, Rany M.
Sandholm, Niina
Scott, Robert A.
Stolk, Lisette
Takahashi, Atsushi
Tanaka, Toshihiro
van 't Hooft, Ferdinand M.
Vinkhuyzen, Anna A. E.
Westra, Harm-Jan
Zheng, Wei
Zondervan, Krina T.
Heath, Andrew C.
Arveiler, Dominique
Bakker, Stephan J. L.
Beilby, John
Bergman, Richard N.
Blangero, John
Bovet, Pascal
Campbell, Harry
Caulfield, Mark J.
Cesana, Giancarlo
Chakravarti, Aravinda
Chasman, Daniel I.
Chines, Peter S.
Collins, Francis S.
Crawford, Dana C.
Cupples, L. Adrienne
Cusi, Daniele
Danesh, John
de Faire, Ulf
den Ruijter, Hester M.
Dominiczak, Anna F.
Erbel, Raimund
Erdmann, Jeanette
Eriksson, Johan G.
Farrall, Martin
Felix, Stephan B.
Ferrannini, Ele
Ferrieres, Jean
Ford, Ian
Forouhi, Nita G.
Forrester, Terrence
Franco, Oscar H.
Gansevoort, Ron T.
Gejman, Pablo V.
Gieger, Christian
Gottesman, Omri
Gudnason, Vilmundur
Gyllensten, Ulf
Hall, Alistair S.
Harris, Tamara B.
Hattersley, Andrew T.
Hicks, Andrew A.
Hindorff, Lucia A.
Hingorani, Aroon D.
Hofman, Albert
Homuth, Georg
Hovingh, G. Kees
Humphries, Steve E.
Hunt, Steven C.
Hypponen, Elina
Illig, Thomas
Jacobs, Kevin B.
Jarvelin, Marjo-Riitta
Joeckel, Karl-Heinz
Johansen, Berit
Jousilahti, Pekka
Jukema, J. Wouter
Jula, Antti M.
Kaprio, Jaakko
Kastelein, John J. P.
Keinanen-Kiukaanniemi, Sirkka M.
Kiemeney, Lambertus A.
Knekt, Paul
Kooner, Jaspal S.
Kooperberg, Charles
Kovacs, Peter
Kraja, Aldi T.
Kumari, Meena
Kuusisto, Johanna
Lakka, Timo A.
Langenberg, Claudia
Le Marchand, Laic
Lehtimaki, Terho
Lyssenko, Valeriya
Mannisto, Satu
Marette, Andre
Matise, Tara C.
McKenzie, Colin A.
McKnight, Barbara
Moll, Frans L.
Morris, Andrew D.
Morris, Andrew P.
Murray, Jeffrey C.
Nelis, Mari
Ohlsson, Claes
Oldehinkel, Albertine J.
Ong, Ken K.
Madden, Pamela A. F.
Pasterkamp, Gerard
Peden, John F.
Peters, Annette
Postma, Dirkje S.
Pramstaller, Peter P.
Price, Jackie F.
Qi, Lu
Raitakari, Olli T.
Rankinen, Tuomo
Rao, D. C.
Rice, Treva K.
Ridker, Paul M.
Rioux, John D.
Ritchie, Marylyn D.
Rudan, Igor
Salomaa, Veikko
Samani, Nilesh J.
Saramines, Jouko
Sarzynski, Mark A.
Schunkert, Heribert
Schwarz, Peter E. H.
Sever, Peter
Shuldiner, Alan R.
Sinisalo, Juha
Stolk, Ronald P.
Strauch, Konstantin
Toenjes, Anke
Tregouet, David-Alexandre
Tremblay, Angelo
Tremoli, Elena
Virtamo, Jarmo
Vohl, Marie-Claude
Voelker, Uwe
Waeber, Gerard
Willemsen, Gonneke
Witteman, Jacqueline C.
Zillikens, M. Carola
Adair, Linda S.
Amouyel, Philippe
Asselbergs, Folkert W.
Assimes, Themistocles L.
Bochud, Murielle
Boehm, Bernhard O.
Boerwinkle, Eric
Bornstein, Stefan R.
Bottinger, Erwin P.
Bouchard, Claude
Cauchi, Stephane
Chambers, John C.
Chanock, Stephen J.
Cooper, Richard S.
de Bakker, Paul I. W.
Dedoussis, George
Ferrucci, Luigi
Franks, Paul W.
Froguel, Philippe
Groop, Leif C.
Haiman, Christopher A.
Hamsten, Anders
Hui, Jennie
Hunter, David J.
Hveem, Kristian
Kaplan, Robert C.
Kivimaki, Mika
Kuh, Diana
Laakso, Markku
Liu, Yongmei
Martin, Nicholas G.
Maerz, Winfried
Melbve, Mads
Metspalu, Andres
Moebus, Susanne
Munroe, Patricia B.
Njolstad, Inger
Oostra, Ben A.
Palmer, Colin N. A.
Pedersen, Nancy L.
Perola, Markus
Perusse, Louis
Peters, Ulrike
Power, Chris
Quertermous, Thomas
Rauramaa, Rainer
Rivadeneira, Fernando
Saaristo, Timo E.
Saleheen, Danish
Sattar, Naveed
Schadt, Eric E.
Schlessinger, David
Slagboom, P. Eline
Snieder, Harold
Spector, Tim D.
Thorsteinsdottir, Unnu R.
Stumvoll, Michael
Tuomilehto, Jaakko
Uitterlinden, Andre G.
Uusitupa, Matti
van der Harst, Pim
Walker, Mark
Wallaschofski, Henri
Wareham, Nicholas J.
Watkins, Hugh
Weir, David R.
Wichmann, H-Erich
Wilson, James F.
Zanen, Pieter
Borecki, Ingrid B.
Deloukas, Panos
Fox, Caroline S.
Heid, Iris M.
O'Connell, Jeffrey R.
Strachan, David P.
Stefansson, Kari
van Duijri, Cornelia M.
Abecasis, Goncalo R.
Franke, Lude
Frayling, Timothy M.
McCarthy, Mark I.
Visscher, Peter M.
Scherag, Andre
Willer, Cristen J.
Boehnke, Michael
Mohlke, Karen L.
Lindgren, Cecilia M.
Beckmann, Jacques S.
Barroso, Ines
North, Kari E.
Ingelsson, Erik
Hirschhorn, Joel N.
Loos, Ruth J. F.
Speliotes, Elizabeth K.
CA LifeLines Cohort Study
ADIPOGen Consortium
AGEN-BMI Working Grp
CARDIOGRAMplusC4D Consortium
CKDGen Consortium
GLGC
ICBP
MAGIC Investigators
MuTHER Consortium
MIGen Consortium
PAGE Consortium
ReproGen Consortium
GENIE Consortium
Int Endogene Consortium
TI Genetic studies of body mass index yield new insights for obesity
biology
SO NATURE
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; PROVIDES INSIGHTS; GLYCEMIC TRAITS; HUMAN
HEIGHT; LOCI; METAANALYSIS; VARIANTS; EXPRESSION; PATHWAYS; ARCHITECTURE
AB Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for similar to 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous systemin obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
C1 [Locke, Adam E.; Bragg-Gresham, L.; Jackson, Anne U.; Stringham, Heather M.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
[Kahali, Bratati; Powell, Corey; Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA.
[Kahali, Bratati; Powell, Corey; Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
[Berndt, Sonja I.; Wang, Zhaoming; Jacobs, Kevin B.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
[Justice, Anne E.; Monda, Keri L.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA.
[Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.
[Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA.
[Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.
[Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Palmer, Cameron D.; Estrada, Karol; Handsaker, Robert E.; Kathiresan, Sekar; McCarroll, Steven A.; Salem, Rany M.; Lindgren, Cecilia M.; Hirschhorn, Joel N.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA.
[Pers, Tune H.; Esko, Tonu; Handsaker, Robert E.; McCarroll, Steven A.; Salem, Rany M.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
[Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark.
[Day, Felix R.; Luan, Jian'an; Zhao, Jing Hua; Scott, Robert A.; Forouhi, Nita G.; Langenberg, Claudia; Ong, Ken K.; Wareham, Nicholas J.; Loos, Ruth J. F.] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge CB2 0QQ, England.
[Buchkovich, Martin L.; Croteau-Chonka, Damien C.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
[Yang, Jian; Vinkhuyzen, Anna A. E.; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia.
[Yang, Jian; Visscher, Peter M.] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4012, Australia.
[Croteau-Chonka, Damien C.; Qi, Lu; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.
[Esko, Tonu; Maegi, Reedik; Fischer, Krista; Haller, Toomas; Mihailov, Evelin; Milani, Lili; Reinmaa, Eva; Morris, Andrew P.; Nelis, Mari; Metspalu, Andres; Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
[Fall, Tove; Gronberg, Henrik; Hall, Per; Magnusson, Patrik K. E.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.
[Fall, Tove; Gustafsson, Stefan; Hedman, Asa K.; Arnlov, Johan; Syvanen, Ann-Christine; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, S-75185 Uppsala, Sweden.
[Fall, Tove; Gustafsson, Stefan; Hedman, Asa K.; Arnlov, Johan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden.
[Ferreira, Teresa; Maegi, Reedik; Randall, Joshua C.; Hedman, Asa K.; Goel, Anuj; Prokopenko, Inga; Juliusdottir, Thorhildur; Mahajan, Anubha; Rayner, Nigel W.; Robertson, Neil R.; Drong, Alexander W.; Keildson, Sarah; Perry, John R. B.; Zondervan, Krina T.; Farrall, Martin; Morris, Andrew P.; Watkins, Hugh; McCarthy, Mark I.; Lindgren, Cecilia M.; Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
[Kutalik, Zoltan] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland.
[Kutalik, Zoltan; Beckmann, Jacques S.] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland.
[Kutalik, Zoltan; Beckmann, Jacques S.] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland.
[Randall, Joshua C.; Rayner, Nigel W.; Stirrups, Kathleen; Deloukas, Panos; Barroso, Ines] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.
[Winkler, Thomas W.; Gorski, Mathias; Heid, Iris M.] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.
[Wood, Andrew R.; Pasko, Dorota; Weedon, Michael N.; Perry, John R. B.; Frayling, Timothy M.] Univ Exeter, Univ Exeter Med Sch, Exeter EX1 2LU, Devon, England.
[Workalemahu, Tsegaselassie; Qi, Lu; Franks, Paul W.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
[Faul, Jessica D.; Weir, David R.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48104 USA.
[Smith, Jennifer A.; Zhao, Wei] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA.
[Chen, Jin; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA.
[Fehrmann, Rudolf; Karjalainen, Juha; Smolonska, Joanna; Swertz, Morris A.; Westra, Harm-Jan; van der Harst, Pim; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.
[Schmidt, Ellen M.; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
[Absher, Devin; Waite, Lindsay L.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA.
[Amin, Najaf; Demirkan, Ayse; Isaacs, Aaron; Oostra, Ben A.; van Duijri, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands.
[Anderson, Denise] Univ Western Australia, Ctr Child Hlth Res, Telethon Inst Child Hlth Res, Perth, WA 6008, Australia.
[Beekman, Marian; Bohringer, Stefan; Helmer, Qinta; Uh, Hae-Won; Stolk, Lisette; Slagboom, P. Eline] Leiden Univ, Med Ctr, NCHA, NL-2300 RC Leiden, Netherlands.
[Beekman, Marian; Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands.
[Bolton, Jennifer L.; Fraser, Ross M.; McLachlan, Stela; Campbell, Harry; Price, Jackie F.; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland.
[Bragg-Gresham, L.] Univ Michigan, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA.
[Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ 08854 USA.
[Buyske, Steven; Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA.
[Demirkan, Ayse] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands.
[Deng, Guohong; Zhang, Weihua; Scott, William R.; Tan, Sian-Tsung; Kooner, Jaspal S.; Chambers, John C.] Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England.
[Deng, Guohong] Univ London Imperial Coll Sci Technol & Med, Dept Gastroenterol & Hepatol, London W2 1PG, England.
[Deng, Guohong] Third Mil Med Univ, Southwest Hosp, Inst Infect Dis, Chongqing, Peoples R China.
[Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA.
[Ehret, Georg B.; Mach, Francois] Univ Hosp Geneva, Dept Specialties Internal Med, CH-1211 Geneva, Switzerland.
[Feenstra, Bjarke; Boyd, Heather A.; Geller, Frank] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark.
[Feitosa, Mary F.; Daw, E. Warwick; Wojczynski, Mary K.; Zhang, Qunyuan; Kraja, Aldi T.; Rao, D. C.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA.
[Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovacular Med, Oxford OX3 9DU, England.
[Gong, Jian; Haessler, Jeffrey; Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.
[Kanoni, Stavroula; Stirrups, Kathleen; Deloukas, Panos] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England.
[Kleber, Marcus E.; Delgado, Graciela; Grammer, Tanja B.; Maerz, Winfried] Heidelberg Univ, Dept Med Nephrol Hypertensiol Endocrinol Diabetol, Med Fac Mannheim, D-68187 Mannheim, Germany.
[Kleber, Marcus E.; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med 2, D-89081 Ulm, Germany.
[Kristiansson, Kati; Eklund, Niina; Kinnunen, Leena; Lindstrom, Jaana; Eriksson, Johan G.; Jousilahti, Pekka; Jula, Antti M.; Kaprio, Jaakko; Knekt, Paul; Mannisto, Satu; Salomaa, Veikko; Virtamo, Jarmo; Perola, Markus; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland.
[Lim, Unhee; Wilkens, Lynne R.; Le Marchand, Laic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96813 USA.
[Lotay, Vaneet; Jeff, Janina M.; Lu, Yingchang; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.
[Mangino, Massimo; Menni, Cristina; Moayyeri, Alireza; Perry, John R. B.; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.
[Leach, Irene Mateo; Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands.
[Medina-Gomez, Carolina; Peters, Marjolein J.; Franco, Oscar H.; Hofman, Albert; Zillikens, M. Carola; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijri, Cornelia M.] NCHA, NL-3015 GE Rotterdam, Netherlands.
[Medina-Gomez, Carolina; Franco, Oscar H.; Hofman, Albert; Witteman, Jacqueline C.; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijri, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.
[Medina-Gomez, Carolina; Peters, Marjolein J.; Estrada, Karol; Stolk, Lisette; Zillikens, M. Carola; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC Univ Med Ctr, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.
[Medland, Sarah E.; Gordon, Scott D.; Montgomery, Grant W.; Nyholt, Dale R.; Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia.
[Nalls, Michael A.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA.
[Pechlivanis, Sonali; Joeckel, Karl-Heinz; Moebus, Susanne; Scherag, Andre] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol IMIBE, D-45147 Essen, Germany.
[Prokopenko, Inga; Barrett, Amy; Bennett, Amanda J.; Groves, Christopher J.; Rayner, Nigel W.; Robertson, Neil R.; Karpe, Fredrik; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England.
[Prokopenko, Inga; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England.
[Shungin, Dmitry; Renstrom, Frida; Franks, Paul W.] Skane Univ Hosp, Dept Clin Sci, Genet & Mol Epidemiol Unit, S-20502 Malmo, Sweden.
[Shungin, Dmitry; Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden.
[Shungin, Dmitry] Umea Univ, Dept Odontol, S-90185 Umea, Sweden.
[Stancakova, Alena] Univ Eastern Finland, FI-70210 Kuopio, Finland.
[Strawbridge, Rona J.; Folkersen, Lasse; Eriksson, Per; Gadin, Jesper R.; van 't Hooft, Ferdinand M.; Hamsten, Anders] Karolinska Inst, Dept Med, Ctr Mol Med, Atherosclerosis Res Unit, S-17176 Stockholm, Sweden.
[Sung, Yun Ju; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.
[Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA.
[Teumer, Alexander; Homuth, Georg; Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany.
[Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands.
[Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands.
[van der Laan, Sander W.; den Ruijter, Hester M.; Pasterkamp, Gerard] Univ Med Ctr Utrecht, Div Heart & Lungs, Expt Cardiol Lab, NL-3584 CX Utrecht, Netherlands.
[van Settee, Jessica; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands.
[Van Vliet-Ostaptchouk, Jana V.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands.
[Wang, Zhaoming; Jacobs, Kevin B.] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21702 USA.
[Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Smith, Albert Vernon; Cauchi, Stephane; Froguel, Philippe] Inst Pasteur, Ctr Immunol & Biol Parasitaire, CNRS, UMR 8199, F-59019 Lille, France.
[Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Smith, Albert Vernon; Cauchi, Stephane; Froguel, Philippe] European Genom Inst Diabet, F-59000 Lille, France.
[Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] Univ Lille 2, F-59000 Lille, France.
[Zhang, Weihua; Scott, William R.; Jarvelin, Marjo-Riitta; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England.
[Isaacs, Aaron; Oostra, Ben A.; van Duijri, Cornelia M.] Ctr Med Sytems Biol, NL-2300 RC Leiden, Netherlands.
[Albrecht, Eva; Grallert, Harald; Mueller-Nurasyid, Martina; Ried, Janina S.; Gieger, Christian; Strauch, Konstantin; Heid, Iris M.] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.
[Arnlov, Johan] Dalarna Univ, Sch Hlth & Social Studies, SE-79188 Falun, Sweden.
[Arscott, Gillian M.; Beilby, John; Hui, Jennie] PathWest Lab Med Western Australia, Nedlands, WA 6009, Australia.
[Attwood, Antony P.; Jolley, Jennifer] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England.
[Attwood, Antony P.; Jolley, Jennifer] NHS Blood & Transplant, Cambridge CB2 0PT, England.
[Bandinelli, Stefania] ASF, Geriatr Unit, I-50125 Florence, Italy.
[Bas, Isabelita N.; Lee, Nanette R.] Univ San Carlos, USC Off Populat Studies Fdn Inc, Cebu 6000, Philippines.
[Bellis, Claire; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78227 USA.
[Bellis, Claire] Queensland Univ Technol, Genom Res Ctr, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia.
[Berne, Christian] Uppsala Univ, Dept Med Sci Endocrinol Diabet & Metab, S-75185 Uppsala, Sweden.
[Blagieva, Roza; Merger, Sigrun] Univ Ulm, Med Ctr, Div Endocrinol Diabet & Metab, D-89081 Ulm, Germany.
[Blueher, Matthias; Boettcher, Yvonne; Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, Integrated Res & Treatment Ctr IFB Adipos Dis, D-04103 Leipzig, Germany.
[Blueher, Matthias; Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany.
[Bohringer, Stefan; Helmer, Qinta; Uh, Hae-Won] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands.
[Bonnycastle, Lori L.; Morken, Mario A.; Swift, Amy J.; Chines, Peter S.; Collins, Francis S.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA.
[Bruinenberg, Marcel; Scholtens, Salome] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, NL-9700 RB Groningen, Netherlands.
[Caspersen, Ida H.; Johansen, Berit] Norwegian Univ Sci & Technol, Dept Biol, N-7491 Trondheim, Norway.
[Chen, Yii-Der Ida] Univ Calif Los Angeles, Dept Pediat, Torrance, CA 90502 USA.
[Chen, Yii-Der Ida] Los Angeles Biomed Res Inst, Transgen Inst, Torrance, CA 90502 USA.
[Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford OX3 7LF, England.
[Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford OX3 7LF, England.
[Dimitriou, Maria; Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens 17671, Greece.
[Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland.
[Eklund, Niina; Kaprio, Jaakko; Groop, Leif C.; Perola, Markus] Univ Helsinki, Inst Mol Med, FI-00014 Helsinki, Finland.
[Estrada, Karol; Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
[Estrada, Karol; Ripke, Stephan] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Garcia, Melissa E.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
[Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
[Gigante, Bruna; Leander, Karin; de Faire, Ulf] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-17177 Stockholm, Sweden.
[Go, Alan S.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA.
[Golay, Alain] Univ Hosp Geneva, Serv Therapeut Educ Diabet Obes & Chron Dis, CH-1211 Geneva, Switzerland.
[Goodall, Alison H.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.
[Goodall, Alison H.; Samani, Nilesh J.] Glenfield Gen Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England.
[Gorski, Mathias] Univ Hosp Regensburg, Dept Nephrol, D-93053 Regensburg, Germany.
[Grabe, Hans-Joergen] HELIOS Hosp Stralsund, Univ Med Greifswald, Dept Psychiat & Psychotherapy, D-17475 Greifswald, Germany.
[Grabe, Hans-Joergen] German Ctr Neurodegenerat Dis DZNE, D-17475 Greifswald, Germany.
[Grallert, Harald; Illig, Thomas; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.
[Grallert, Harald; Thorand, Barbara] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.
[Graessler, Jurgen; Schwarz, Peter E. H.; Bornstein, Stefan R.] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Med 3, D-01307 Dresden, Germany.
[Gusto, Gaeelle] Inst Inter Reg Sante, F-37520 La Riche, France.
[Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Unit Nutr Res, S-90187 Umea, Sweden.
[Hartman, Catharina A.; Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands.
[Hassinen, Maija; Lakka, Timo A.; Rauramaa, Rainer] Kuoplo Res Inst Exercise Med, Kuopio 70100, Finland.
[Hayward, Caroline; Wrightl, Alan F.] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland.
[Heard-Costa, Nancy L.; Murabito, Joanne M.; Cupples, L. Adrienne; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.
[Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.
[Helmer, Qinta] Vrije Univ Amsterdam, Fac Psychol & Educ, NL-1081 BT Amsterdam, Netherlands.
[Hengstenberg, Christian; Mueller-Nurasyid, Martina; Peters, Annette; Schunkert, Heribert] Munich Heart Alliance, German Res Ctr Cardiovasc Res, Deutsch Forschungszentrum Herz Kreislauferkrankun, D-80636 Munich, Germany.
[Hengstenberg, Christian; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80636 Munich, Germany.
[Holmen, Oddgeir; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7489 Trondheim, Norway.
[Hottenga, Jouke-Jan; Willemsen, Gonneke] Vrije Univ Amsterdam, NL-1081 BT Amsterdam, Netherlands.
[James, Alan L.] Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia.
[Johansson, Asa; Gyllensten, Ulf] Univ Western Australia, Sch Med & Pharmacol, Crawley 6009, Australia.
[Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Immunol, SciLifeLab, Rudbeck Lab, SE-75185 Uppsala, Sweden.
[Koskenvuo, Markku; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, FI-00014 Helsinki, Finland.
[Kratzer, Wolfgang; Seufferlein, Thomas] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89081 Ulm, Germany.
[Laitinen, Jaana] Finnish Inst Occupat Hlth, FI-90100 Oulu, Finland.
[Lamina, Claudia] Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, A-6020 Innsbruck, Austria.
[Lichtner, Peter] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, D-85764 Neuherberg, Germany.
[Lind, Lars; Sundstrom, Johan] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden.
[Lo, Ken Sin; Rioux, John D.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.
[Lorbeer, Roberto] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany.
[Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.
[McArdle, Wendy L.; Min, Josine L.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England.
[Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia.
[Moayyeri, Alireza] UCL, Farr Inst Hlth Informat Res, London NW1 2DA, England.
[Monda, Keri L.] Amgen Inc, Ctr Observat Res, Newbury Pk, CA 91320 USA.
[Mulas, Antonella; Sanna, Serena] CNR, IRGB, I-09042 Cagliari, Sardinia, Italy.
[Mueller, Gabriele] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Ctr Evidence Based Healthcare, D-01307 Dresden, Germany.
[Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany.
[Mueller-Nurasyid, Martina; Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany.
[Musk, Arthur W.] Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia.
[Nagaraja, Ramaiah; Schlessinger, David] NIA, Lab Genet, Baltimore, MD 21224 USA.
[Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany.
[Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany.
[Nolte, Ilja M.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands.
[Pilz, Stefan] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Inst Res Extramural Med, Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands.
[Pilz, Stefan] Med Univ Graz, Dept Internal Med, Div Endocrinol & Metab, A-8036 Graz, Austria.
[Rettig, Rainer] Univ Med Greifswald, Inst Physiol, D-17495 Karlsburg, Germany.
[Ripke, Stephan; McCarroll, Steven A.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.
[Rose, Lynda M.; Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA.
[Scharnagl, Hubert; Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria.
[Schumacher, Fredrick R.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA.
[Shi, Jianxin] NCI, Bethesda, MD 20892 USA.
[Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland.
[Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, IS-101 Reykjavik, Iceland.
[Smolonska, Joanna; Vonk, Judith M.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands.
[Stanton, Alice V.] Royal Coll Surgeons Ireland, Dublin 2, Ireland.
[Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Thorsteinsdottir, Unnu R.; Stefansson, Kari] Amgen Inc, deCODE Genet, IS-101 Reykjavik, Iceland.
[Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, S-75144 Uppsala, Sweden.
[Tan, Sian-Tsung; Moffatt, Miriam F.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England.
[Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA.
[Thorand, Barbara; Peters, Annette] Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.
[Tyrer, Jonathan P.] Univ Cambridge, Dept Oncol, Cambridge CB2 0QQ, England.
[Tyrer, Jonathan P.] Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden.
[Verhulst, Frank C.] Erasmus MC Univ Med Ctr, Dept Child & Adolescent Psychiat Psychol, NL-3000 CB Rotterdam, Netherlands.
[Vermeulen, Sita H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6500 HB Nijmegen, Netherlands.
[Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Dept Genet, NL-6500 HB Nijmegen, Netherlands.
[Warren, Helen R.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Dept Clin Pharmacol, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England.
[Waterworth, Dawn] GlaxoSmithKline, Genet, King Of Prussia, PA 19406 USA.
[Willenborg, Christina; Erdmann, Jeanette] Partner Site Hamburg Lubeck Kiel, German Ctr Cardiovasc Res, D-23562 Lubeck, Germany.
[Willenborg, Christina; Erdmann, Jeanette] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany.
[Wilsgaard, Tom; Njolstad, Inger] UiT, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway.
[Wong, Andrew; Ong, Ken K.; Kuh, Diana] UCL, MRC Unit Lifelong Hlth & Ageing, London WC1B 5JU, England.
[Brennan, Eoin P.] Natl Univ Ireland Univ Coll Dublin, Sch Med & Med Sci, Diabet Complicat Res Ctr, Conway Inst, Dublin 4, Ireland.
[Choi, Murim] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea.
[Dastani, Zari] McGill Univ, Lady Davis Inst, Dept Human Genet, Montreal, PQ H3T 1E2, Canada.
[Dastani, Zari] McGill Univ, Lady Davis Inst, Dept Epidemiol, Montreal, PQ H3T 1E2, Canada.
[Dastani, Zari] McGill Univ, Lady Davis Inst, Dept Biostat, Montreal, PQ H3T 1E2, Canada.
[Franco-Cereceda, Anders] Karolinska Inst, Cardiothoracic Surg Unit, Dept Mol Med & Surg, S-17176 Stockholm, Sweden.
[Gharavi, Ali G.; Kiryluk, Krzysztof] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA.
[Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Bundoora, Vic 3083, Australia.
[Goddard, Michael E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic 3010, Australia.
[Huang, Jinyan; Liang, Liming; Ma, Baoshan; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
[Huang, Jinyan] Shanghai Jiao Tong Univ, State Key Lab Med Genom, Shanghai Inst Hematol, Rui Jin Hosp,Sch Med, Shanghai 200030, Peoples R China.
[Karpe, Fredrik] OUH Trust, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LE, England.
[Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA.
[Kubo, Michiaki] RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa 2300045, Japan.
[Lee, Jong-Young] Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do 363951, Chungbuk, South Korea.
[Liang, Liming] Harvard Univ, Dept Biostat, Harvard Sch Publ Hlth, Boston, MA 02115 USA.
[Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, New Haven, CT 06520 USA.
[Ma, Baoshan] Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian 116026, Liaoning, Peoples R China.
[McKnight, Amy J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT9 7AB, Down, North Ireland.
[Murabito, Joanne M.] Boston Univ, Sch Med, Sect Gen Internal Med, Boston, MA 02118 USA.
[Nicholson, George] Univ Oxford, Dept Stat, Oxford OX1 3TG, England.
[Nicholson, George] MRC Harwell, Harwell OX11 0QG, Berks, England.
[Nyholt, Dale R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia.
[Okada, Yukinori; Takahashi, Atsushi] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa 2300045, Japan.
[Okada, Yukinori; Tanaka, Toshihiro] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Divers, Tokyo 1138510, Japan.
[Dorajoo, Rajkumar] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore.
[Sandholm, Niina] Aalto Univ, Dept Biomed Engn & Computat Sci, Sch Sci, FI-00076 Helsinki, Finland.
[Sandholm, Niina] Univ Helsinki, Cent Hosp, Dept Med, Div Nephrol, FI-00290 Helsinki, Finland.
[Sandholm, Niina] Folkhalsan Res Ctr, Folkhalsan Inst Genet, FI-00290 Helsinki, Finland.
[Tanaka, Toshihiro] RIKEN Ctr Integrat Med Sci, Lab Cardiovasc Dis, Yokohama, Kanagawa 2300045, Japan.
[Tanaka, Toshihiro] Tokyo Med & Dent Univ, Bioresource Res Ctr, Div Dis Divers, Tokyo 1138510, Japan.
[Zheng, Wei] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, Nashville, TN 37075 USA.
[Zheng, Wei] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Nashville, TN 37075 USA.
[Zheng, Wei] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN 37075 USA.
[Zondervan, Krina T.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Oxford OX3 7BN, England.
[Heath, Andrew C.; Madden, Pamela A. F.; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.
[Arveiler, Dominique] Univ Strasbourg, Fac Med, Dept Epidemiol & Publ Hlth, EA3430, Strasbourg, France.
[Bakker, Stephan J. L.; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 RB Groningen, Netherlands.
[Beilby, John; Hui, Jennie] Univ Western Australia, Nedlands, WA 6009, Australia.
[Bergman, Richard N.] Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA 90048 USA.
[Bovet, Pascal; Bochud, Murielle] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland.
[Bovet, Pascal; Bochud, Murielle] Univ Lausanne, CH-1010 Lausanne, Switzerland.
[Bovet, Pascal; Bochud, Murielle] Minist Hlth, Victoria, Seychelles.
[Cesana, Giancarlo] Univ Milan, I-20126 Bicocca, Italy.
[Chasman, Daniel I.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37203 USA.
[Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.
[Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.
[Cusi, Daniele] Univ Milan, Dept Hlth Sci, I-20142 Milan, Italy.
[Cusi, Daniele] Fdn Filarete, I-20139 Milan, Italy.
[Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.
[den Ruijter, Hester M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3584 CX Utrecht, Netherlands.
[Dominiczak, Anna F.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland.
[Erbel, Raimund] Univ Hosp Essen, Clin Cardiol, West German Heart Ctr, D-45147 Essen, Germany.
[Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FI-00290 Helsinki, Finland.
[Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, FIN-00290 Helsinki, Finland.
[Felix, Stephan B.] Univ Med Greifswald, Dept Internal Med B, D-17475 Greifswald, Germany.
[Felix, Stephan B.; Voelker, Uwe; Wallaschofski, Henri] Partner Site Greifswald, DZHK, D-17475 Greifswald, Germany.
[Ferrannini, Ele] Univ Pisa, Dept Internal Med, I-56100 Pisa, Italy.
[Ferrannini, Ele] Univ Pisa, Inst Clin Physiol, Natl Res Council, I-56124 Pisa, Italy.
[Ferrieres, Jean] Toulouse Univ, Sch Med, Ranguell Hosp, Dept Cardiol, F-31400 Toulouse, France.
[Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow G12 8QQ, Lanark, Scotland.
[Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, UWI Solut Developing Countries, Kingston 7, Jamaica.
[Gejman, Pablo V.] NorthShore Univ HealthSyst, Evanston, IL 60201 USA.
[Gejman, Pablo V.] Univ Chicago, Chicago, IL 60637 USA.
[Hall, Alistair S.] Univ Leeds, Leeds MRC Med Bioinformat Ctr, Leeds LS2 9LU, W Yorkshire, England.
[Hattersley, Andrew T.] Univ Exeter, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England.
[Hicks, Andrew A.; Pramstaller, Peter P.] Bolzano EURAC, European Acad Bozen, Ctr Biomed, I-39100 Bolzano, Italy.
[Hicks, Andrew A.; Pramstaller, Peter P.] Inst Univ Lubeck, D-23562 Lubeck, Germany.
[Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA.
[Hingorani, Aroon D.; Asselbergs, Folkert W.] UCL, Inst Cardiovasc Sci, London WC1E 6BT, England.
[Hovingh, G. Kees; Kastelein, John J. P.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands.
[Humphries, Steve E.] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London WC1E 6JJ, England.
[Hunt, Steven C.] Univ Utah, Dept Internal Med, Cardiovasc Genet Div, Salt Lake City, UT 84108 USA.
[Hypponen, Elina] Univ S Australia, Sansom Inst Hlth Res, Adelaide, SA 5000, Australia.
[Hypponen, Elina] Univ S Australia, Sch Populat Hlth, Adelaide, SA 5000, Australia.
[Hypponen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA 5000, Australia.
[Hypponen, Elina; Power, Chris] UCL, Inst Child Hlth, London WC1N 1EH, England.
[Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany.
[Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, FI-90101 Oulu, Finland.
[Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, MRC Hlth Protect Agcy HPA, Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England.
[Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, FI-90220 Oulu, Finland.
Univ Oulu, Bioctr Oulu, FI-90014 Oulu, Finland.
[Jarvelin, Marjo-Riitta; Keinanen-Kiukaanniemi, Sirkka M.] Univ Oulu, Inst Hlth Sci, FI-90014 Oulu, Finland.
[Jukema, J. Wouter; Asselbergs, Folkert W.; van der Harst, Pim] Interuniv Cardiol Inst Netherlands ICIN, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands.
[Jukema, J. Wouter; Asselbergs, Folkert W.; van der Harst, Pim] Interuniv Cardiol Inst Netherlands ICIN, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands.
[Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands ICIN, NL-3501 DG Utrecht, Netherlands.
[Keinanen-Kiukaanniemi, Sirkka M.] Oulu Univ Hosp, Unit Primary Hlth Care Gen Practice, FI-90220 Oulu, Finland.
[Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6500 HB Nijmegen, Netherlands.
[Kooner, Jaspal S.; Chambers, John C.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England.
[Kumari, Meena; Langenberg, Claudia; Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.
[Kumari, Meena] Univ Essex, Dept Biol & Social Epidemiol, Colchester CO4 3SQ, Essex, England.
[Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, Dept Med, FI-70210 Kuopio, Finland.
[Kuusisto, Johanna; Lakka, Timo A.; Laakso, Markku; Rauramaa, Rainer] Univ Eastern Finland, FI-70210 Kuopio, Finland.
[Lakka, Timo A.] Univ Eastern Finland, Inst Biomed, Dept Physiol, FI-70211 Kuopio, Finland.
[Lakka, Timo A.; Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, FI-70210 Kuopio, Finland.
[Lehtimaki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FI-33520 Tampere, Finland.
[Lehtimaki, Terho] Univ Tampere, Sch Med, FI-33520 Tampere, Finland.
[Lyssenko, Valeriya] Steno Diabet Ctr AS, DK-2820 Gentofte, Denmark.
[Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Lund Univ Diabet Ctr, S-22100 Malmo, Sweden.
[Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, S-22100 Malmo, Sweden.
[Marette, Andre] Univ Laval, Fac Med, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ G1V 0A6, Canada.
[McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
[Moll, Frans L.] Univ Med Ctr Utrecht, Dept Surg, NL-3584 CX Utrecht, Netherlands.
[Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England.
[Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA.
[Peden, John F.] Illumina Inc, Cambridge CB10 1XL, England.
[Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Med & TB, Groningen, Netherlands.
[Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy.
[Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FI-20521 Turku, Finland.
[Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FI-20521 Turku, Finland.
[Rankinen, Tuomo; Sarzynski, Mark A.; Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA.
[Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA.
[Rudan, Igor] Univ Split, Fac Med, Croatian Ctr Global Hlth, Split 21000, Croatia.
[Saramines, Jouko] South Carelia Cent Hosp, Lappeenranta 53130, Finland.
[Schwarz, Peter E. H.] German Ctr Diabet Res DZD, Paul Langerhans Inst Dresden, D-01307 Dresden, Germany.
[Sever, Peter] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, London W2 1PG, England.
[Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA.
[Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA.
[Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA.
[Sinisalo, Juha] Univ Helsinki, Cent Hosp, Heart & Lung Ctr, Dept Med, FI-00290 Helsinki, Finland.
[Tregouet, David-Alexandre] Univ Paris 06, Sorbonne Univ, UMR S 1166, F-75013 Paris, France.
[Tregouet, David-Alexandre] Univ Paris 06, INSERM, UMR S 1166, Team Genom & Physiopathol Cardiovasc Dis, F-75013 Paris, France.
[Tregouet, David-Alexandre] ICAN, F-75013 Paris, France.
[Tremblay, Angelo; Perusse, Louis] Univ Laval, Dept Kinesiol, Quebec City, PQ G1V 0A6, Canada.
[Tremoli, Elena] Univ Milan, Dipartimento Sci Farmacol & Biomol, I-20133 Milan, Italy.
[Tremoli, Elena] Inst Ricoveroe Cura & Carattere Sci, Ctr Cardiol Monzino, I-20133 Milan, Italy.
[Vohl, Marie-Claude] Univ Laval, Dept Food Sci & Nutr, Quebec City, PQ G1V 0A6, Canada.
[Waeber, Gerard] Univ Hosp CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland.
[Waeber, Gerard] Univ Lausanne, CH-1011 Lausanne, Switzerland.
[Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA.
[Amouyel, Philippe] Inst Pasteur, F-59000 Lille, France.
[Amouyel, Philippe] INSERM, U744, F-59000 Lille, France.
[Amouyel, Philippe] Univ Lille 2, F-59000 Lille, France.
[Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, NL-3584 CX Utrecht, Netherlands.
[Assimes, Themistocles L.; Melbve, Mads; Quertermous, Thomas] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA.
[Boehm, Bernhard O.] Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, Singapore 637553, Singapore.
[Boehm, Bernhard O.] Nanyang Technol Univ, Singapore 637553, Singapore.
[Boehm, Bernhard O.] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89081 Ulm, Germany.
[Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA.
[de Bakker, Paul I. W.] Harvard Univ, Dept Med, Div Genet, Brigham & Womens Hosp,Med Sch, Boston, MA 02115 USA.
[de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands.
[Hui, Jennie] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia.
[Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA.
[Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA.
[Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, D-68163 Mannheim, Germany.
[Melbve, Mads] Univ Copenhagen, Dept Clin Med, DK-2200 Copenhagen, Denmark.
[Oostra, Ben A.] Erasmus MC Univ Med Ctr, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands.
[Saaristo, Timo E.] Finnish Diabet Assoc, FI-33680 Tampere, Finland.
[Saaristo, Timo E.] Pirkanmaa Hosp Dist, FI-33521 Tampere, Finland.
[Saleheen, Danish] Ctr Noncommunicable Dis, Karatchi, Pakistan.
[Saleheen, Danish] Univ Penn, Dept Med, Philadelphia, PA 19104 USA.
[Sattar, Naveed] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Div Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland.
[Schadt, Eric E.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10580 USA.
[Thorsteinsdottir, Unnu R.; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.
[Tuomilehto, Jaakko] Univ Hosp La Paz IdiPaz, Inst Hlth Res, Madrid 28046, Spain.
[Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia.
[Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria.
[Uusitupa, Matti] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Kuopio, Finland.
[Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, FI-70210 Kuopio, Finland.
[Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.
[Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany.
[Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, D-85764 Munich, Germany.
[Wichmann, H-Erich] Klinikum Grosshadern, D-81377 Munich, Germany.
[Wichmann, H-Erich] Helmholtz Zentrum Munchen, Inst Epidemiol 1, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.
[Zanen, Pieter] Univ Med Ctr Utrecht, Dept Pulmonol, NL-3584 CX Utrecht, Netherlands.
[Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia.
[Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London SW17 0RE, England.
[McCarthy, Mark I.] Oxford Univ Hosp NHS Trust, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England.
[Scherag, Andre] Jena Univ Hosp, Clin Epidemiol Integrated Res & Treatment Ctr, CSCC, D-07743 Jena, Germany.
[Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.
[Beckmann, Jacques S.] CHUV Univ Hosp, Serv Med Genet, CH-1011 Lausanne, Switzerland.
[Barroso, Ines] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge CB2 0QQ, England.
[Barroso, Ines] Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England.
[North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.
[Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.
RP Speliotes, EK (reprint author), Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA.
EM joelh@broadinstitute.org; ruth.loos@mssm.edu; espeliot@med.umich.edu
RI Singleton, Andrew/C-3010-2009; Fehrmann, Rudolf/E-2551-2011; Colaus,
PsyColaus/K-6607-2013; Grallert, Harald/B-3424-2013; Fall,
Tove/O-7226-2014; Kiemeney, Lambertus/D-3357-2009; de Bakker,
Paul/B-8730-2009; Meisinger, Christine/B-5358-2014; Visser, Jenny
/F-8156-2011; Moayyeri, Alireza/N-3332-2014; Palmer, Colin/C-7053-2008;
Boehm, Bernhard/F-8750-2015; Schwarz, Peter/B-5127-2013; Ramos ,
Rafel/D-9627-2016; Johnson, Andrew/G-6520-2013; Franke,
Lude/P-7036-2016; Ormel, Johan/C-6094-2013; Karjalainen,
Juha/P-8624-2016; Laan, Maris/A-4100-2011; Slagboom, P.
Eline/R-4790-2016; Verweij, Niek/A-4499-2017; Erdmann,
Jeanette/P-7513-2014; Franke, Andre/B-2151-2010; Magnusson,
Patrik/C-4458-2017; Johansson, Asa/G-5270-2011; Bovet,
Pascal/F-4477-2011; Bouchard, Claude/A-7637-2009; Smith,
Albert/K-5150-2015; Kubo, Michiaki/N-7947-2015; Nato,
Alejandro/J-3880-2016; Yang, Jian/A-5852-2010; Matullo,
Giuseppe/K-6383-2016; Deloukas, Panos/B-2922-2013; kinnunen,
leena/B-7059-2012; Study, GoDARTS/K-9448-2016; Bochud,
Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Meitinger,
Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Kessler,
Thorsten/O-7426-2015; Prokopenko, Inga/H-3241-2014; Kronenberg,
Florian/B-1736-2008; Sundstrom, Johan/A-6286-2009; Tanaka,
Toshihiro/J-9310-2014; Sarzynski, Mark/A-9798-2014; Thorand,
Barbara/B-5349-2014; Peters, Annette/A-6117-2011; Lyytikainen,
Leo-Pekka/C-8544-2016; Tregouet, David-Alexandre/E-3961-2016; Vermeulen,
H.H.M./L-4716-2015; Hypponen, Elina/B-2596-2014; Salumets,
Andres/J-2278-2015; Bakker, Stephan/J-4023-2015; Rioux,
John/A-9599-2015; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason,
Vilmundur/K-6885-2015; Huang, Jiaxing/B-7521-2009; Ripatti,
Samuli/H-9446-2014; Mattace- Raso, Francesco/L-2541-2015; Wilson, James
F/A-5704-2009; Polasek, Ozren/B-6002-2011; Montgomery,
Grant/B-7148-2008; Beckmann, Jacques S /A-9772-2008; Leander,
Karin/C-7261-2017; Yengo, Loic/D-2692-2017; Palmer, Lyle/K-3196-2014;
Kolcic, Ivana/E-2713-2017; Boban, Mladen/E-2777-2017; Stathopoulou,
Maria/H-7324-2016; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017;
OI Fehrmann, Rudolf/0000-0002-7516-315X; Kiemeney,
Lambertus/0000-0002-2368-1326; de Bakker, Paul/0000-0001-7735-7858;
Moayyeri, Alireza/0000-0002-9143-2161; Palmer,
Colin/0000-0002-6415-6560; Schwarz, Peter/0000-0001-6317-7880; Ramos ,
Rafel/0000-0001-8146-5288; Franke, Lude/0000-0002-5159-8802; Laan,
Maris/0000-0002-8519-243X; Slagboom, P. Eline/0000-0002-2875-4723;
Erdmann, Jeanette/0000-0002-4486-6231; Franke,
Andre/0000-0003-1530-5811; Johansson, Asa/0000-0002-2915-4498; Bovet,
Pascal/0000-0002-0242-4259; Smith, Albert/0000-0003-1942-5845; Nato,
Alejandro/0000-0002-8745-9046; Yang, Jian/0000-0003-2001-2474; Deloukas,
Panos/0000-0001-9251-070X; kinnunen, leena/0000-0001-8739-4812; Bochud,
Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470;
Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko,
Inga/0000-0003-1624-7457; Kronenberg, Florian/0000-0003-2229-1120;
Sundstrom, Johan/0000-0003-2247-8454; Tanaka,
Toshihiro/0000-0001-6201-9784; Thorand, Barbara/0000-0002-8416-6440;
Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Hypponen,
Elina/0000-0003-3670-9399; Salumets, Andres/0000-0002-1251-8160; Bakker,
Stephan/0000-0003-3356-6791; Rioux, John/0000-0001-7560-8326; Gudnason,
Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202;
Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862;
Montgomery, Grant/0000-0002-4140-8139; Beckmann, Jacques S
/0000-0002-9741-1900; Leander, Karin/0000-0002-1404-9222; Yengo,
Loic/0000-0002-4272-9305; Palmer, Lyle/0000-0002-1628-3055; Kolcic,
Ivana/0000-0001-7918-6052; Stathopoulou, Maria/0000-0003-4376-2083;
Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411;
Franks, Paul/0000-0002-0520-7604; McCarroll, Steven/0000-0002-6954-8184;
Beekman, Marian/0000-0003-0585-6206; Stanton, Alice/0000-0002-4961-165X;
Day, Felix/0000-0003-3789-7651; Asselta, Rosanna/0000-0001-5351-0619;
Seshadri, Sudha/0000-0001-6135-2622; Bush, William/0000-0002-9729-6519;
Peters, Marjolein/0000-0003-3167-9063; Zgaga, Lina/0000-0003-4089-9703;
Shungin, Dmitry/0000-0001-7900-5856; Strawbridge,
Rona/0000-0001-8506-3585; Menni, Cristina/0000-0001-9790-0571; Goddard,
Michael/0000-0001-9917-7946; Melzer, David/0000-0002-0170-3838; TREMOLI,
ELENA/0000-0002-0929-6106; Magi, Reedik/0000-0002-2964-6011;
Fuchsberger, Christian/0000-0002-5918-8947; Mulas,
Antonella/0000-0002-6856-1483; van Vliet-Ostaptchouk,
Jana/0000-0002-7943-3153; Fraser, Ross/0000-0003-0488-2592; Org,
Elin/0000-0003-1451-9375; Esko, Tonu/0000-0003-1982-6569; Arora,
Pankaj/0000-0003-2420-3550; Hosseini, Mohsen/0000-0003-3626-9928;
Sandholm, Niina/0000-0003-4322-6942; Kristiansson,
Kati/0000-0003-4688-107X; Tryggvadottir, Laufey/0000-0001-8067-9030;
Locke, Adam/0000-0001-6227-198X; Gieger, Christian/0000-0001-6986-9554;
Goessling, Wolfram/0000-0001-9972-1569; Mannisto,
Satu/0000-0002-8668-3046; Lakka, Timo/0000-0002-9199-2871; Gigante,
Bruna/0000-0003-4508-7990; van der Laan, Sander W./0000-0001-6888-1404;
Humphries, Stephen E/0000-0002-8221-6547; Adeyemo,
Adebowale/0000-0002-3105-3231; Ramos , Rafel/0000-0001-7970-5537;
Kumari, Meena/0000-0001-9716-1035; Verweij, Niek/0000-0002-4303-7685;
Kuulasmaa, Kari/0000-0003-2165-1411; Karasik, David/0000-0002-8826-0530;
Hedman, Asa/0000-0001-5413-204X; Wolffenbuttel, Bruce
H.R./0000-0001-9262-6921; Forouhi, Nita/0000-0002-5041-248X; Jarvelin,
Marjo-Riitta/0000-0002-2149-0630; rossing, peter/0000-0002-1531-4294;
Nothen, Markus/0000-0002-8770-2464; ruggiero,
daniela/0000-0003-3898-7827; Buyske, Steven/0000-0001-8539-5416;
Vandenput, Liesbeth/0000-0002-1712-6131; Karpe,
Fredrik/0000-0002-2751-1770; Maxwell, Alexander P./0000-0002-6110-7253;
Vinkhuyzen, Anna/0000-0003-3352-0603; Medina-Gomez,
Carolina/0000-0001-7999-5538; Visscher, Peter/0000-0002-2143-8760;
Marmot, Michael/0000-0002-2431-6419; Eriksson,
Johan/0000-0002-2516-2060; Prabhakaran, Dorairaj/0000-0002-3172-834X;
Falhammar, Henrik/0000-0002-5622-6987; Evans, David/0000-0003-0663-4621;
Assimes, Themistocles/0000-0003-2349-0009; Ouwehand,
Willem/0000-0002-7744-1790; Folkersen, Lasse/0000-0003-0708-9530; Smith,
Jennifer/0000-0002-3575-5468; Medland, Sarah/0000-0003-1382-380X;
Kaprio, Jaakko/0000-0002-3716-2455; Lawlor, Debbie
A/0000-0002-6793-2262; Hattersley, Andrew/0000-0001-5620-473X; Sinisalo,
Juha/0000-0002-0169-5137; Lahti, Jari/0000-0002-4310-5297; Kleber,
Marcus/0000-0003-0663-7275; Ganna, Andrea/0000-0002-8147-240X; Peters,
Annette/0000-0001-6645-0985; Wain, Louise/0000-0003-4951-1867
FU British Heart Foundation [FS/14/55/30806, RG/08/008/25291,
RG/08/014/24067, RG/10/12/28456]; Cancer Research UK [14136]; Chief
Scientist Office [CZB/4/672, CZB/4/710]; Medical Research Council
[G0401527, G0601261, G1000143, G1001799, G9521010, MC_PC_U127561128,
MC_U106179471, MC_U106179472, MC_UP_A100_1003, MC_UU_12012/1,
MC_UU_12013/1, MC_UU_12015/1, MC_UU_12015/2, MC_UU_12015/5,
MC_UU_12019/1, MR/K006584/1, MR/K013351/1, MR/L003120/1, MR/N01104X/1];
NCATS NIH HHS [TL1 TR001066, UL1 TR000124, UL1 TR001067]; NCI NIH HHS
[UM1 CA182910, UM1 CA182913]; NHGRI NIH HHS [U01 HG007376, U01 HG007416,
U01 HG007419]; NHLBI NIH HHS [K01 HL116770, P30 HL107251, R01 HL109946,
R01 HL117078, R01 HL117626, T32 HL007055, T32 HL007824]; NIA NIH HHS
[R01 AG025941, R01 AG033193, R01 AG041517, U01 AG009740, U01 AG049505];
NIDA NIH HHS [R21 DA027040]; NIDDK NIH HHS [K23 DK080145, P30 DK020541,
P30 DK020572, P30 DK063491, P30 DK072488, P60 DK020541, R01 DK062370,
R01 DK072193, R01 DK075787, R01 DK078150, R01 DK089256, R01 DK093757,
U01 DK062370]; NIGMS NIH HHS [P30 GM103341, T32 GM080178]; NIMHD NIH HHS
[P20 MD006899]; NINDS NIH HHS [R01 NS017950]; Wellcome Trust [084766,
085235, 097117, 098017, 098381, 100574]
NR 73
TC 431
Z9 435
U1 63
U2 319
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 12
PY 2015
VL 518
IS 7538
BP 197
EP U401
DI 10.1038/nature14177
PG 23
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300031
PM 25673413
ER
PT J
AU Juric, D
Castel, P
Griffith, M
Griffith, OL
Won, HH
Ellis, H
Ebbesen, SH
Ainscough, BJ
Ramu, A
Iyer, G
Shah, RH
Huynh, T
Mino-Kenudson, M
Sgroi, D
Isakoff, S
Thabet, A
Elamine, L
Solit, DB
Lowe, S
Quadt, C
Peters, M
Derti, A
Schegel, R
Huang, A
Mardis, ER
Berger, MF
Baselga, J
Scaltriti, M
AF Juric, Dejan
Castel, Pau
Griffith, Malachi
Griffith, Obi L.
Won, Helen H.
Ellis, Haley
Ebbesen, Saya H.
Ainscough, Benjamin J.
Ramu, Avinash
Iyer, Gopa
Shah, Ronak H.
Huynh, Tiffany
Mino-Kenudson, Mari
Sgroi, Dennis
Isakoff, Steven
Thabet, Ashraf
Elamine, Leila
Solit, David B.
Lowe, ScottW.
Quadt, Cornelia
Peters, Malte
Derti, Adnan
Schegel, Robert
Huang, Alan
Mardis, Elaine R.
Berger, Michael F.
Baselga, Jose
Scaltriti, Maurizio
TI Convergent loss of PTEN leads to clinical resistance to a PI(3)K alpha
inhibitor
SO NATURE
LA English
DT Article
ID BREAST-CANCER; INTRATUMOR HETEROGENEITY; 3-KINASE PATHWAY; DOMAIN
MUTATIONS; SOLID TUMORS; EVOLUTION; METABOLISM; SAMPLES; GROWTH
AB Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones(1,2). There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)K alpha) mutation. The patient was treated with the PI(3)K alpha inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3) K p110 beta blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)K alpha inhibition.
C1 [Juric, Dejan; Huynh, Tiffany; Mino-Kenudson, Mari; Sgroi, Dennis; Isakoff, Steven; Thabet, Ashraf; Elamine, Leila] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.
[Castel, Pau; Won, Helen H.; Ellis, Haley; Iyer, Gopa; Shah, Ronak H.; Solit, David B.; Berger, Michael F.; Baselga, Jose; Scaltriti, Maurizio] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program HOPP, New York, NY 10065 USA.
[Griffith, Malachi; Mardis, Elaine R.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA.
[Griffith, Malachi; Griffith, Obi L.; Mardis, Elaine R.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO 63110 USA.
[Griffith, Malachi; Griffith, Obi L.; Ainscough, Benjamin J.; Ramu, Avinash; Mardis, Elaine R.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA.
[Griffith, Obi L.; Mardis, Elaine R.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.
[Won, Helen H.; Berger, Michael F.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA.
[Ebbesen, Saya H.; Lowe, ScottW.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.
[Iyer, Gopa; Solit, David B.] Mem Sloan Kettering Canc Ctr, Dept Med, Div Genitourinary Oncol, New York, NY 10065 USA.
[Lowe, ScottW.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Canc Biol & Genet Program, New York, NY 10065 USA.
[Quadt, Cornelia; Peters, Malte] Novartis Pharma AG, CH-4056 Basel, Switzerland.
[Derti, Adnan; Schegel, Robert; Huang, Alan] Novartis Inst BioMed Res, Cambridge, MA 02139 USA.
[Baselga, Jose] Mem Sloan Kettering Canc Ctr, Dept Med, Breast Med Serv, New York, NY 10065 USA.
RP Scaltriti, M (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program HOPP, 1275 York Ave,Box 20, New York, NY 10065 USA.
EM bergerm1@mskcc.org; baselgaj@mskcc.org; scaltrim@mskcc.org
FU "Stand Up to Cancer" Dream Team Translational Research Grant;
Entertainment Industry Foundation [SU2C-AACR-DT0209]; Breast Cancer
Research Foundation; Geoffrey Beene Cancer Research Center; Starr Cancer
Consortium; MMHCC [CA105388]; National Institutes of Health [T32
CA-71345-15]
FX We thank members of the MSKCC Diagnostic Molecular Pathology Laboratory
and the MSK Maria-Josee and Henry Kravis Center for Molecular Oncology
for assistance with sequencing. We thank M. Asher and U. Bhanot from the
MSKCC Pathology Core for assistance with tissue staining. This work was
funded by a "Stand Up to Cancer" Dream Team Translational Research
Grant, a Program of the Entertainment Industry Foundation
(SU2C-AACR-DT0209), the Breast Cancer Research Foundation, the Geoffrey
Beene Cancer Research Center, the Starr Cancer Consortium and an MMHCC
grant (CA105388). D.J. is also funded by a National Institutes of Health
Training Grant (T32 CA-71345-15) and by philanthropic support from
Stephen and Kathleen Chubb.
NR 27
TC 77
Z9 80
U1 2
U2 30
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 12
PY 2015
VL 518
IS 7538
BP 240
EP U230
DI 10.1038/nature13948
PG 15
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300040
PM 25409150
ER
PT J
AU Ceccaldi, R
Liu, JC
Amunugama, R
Hajdu, I
Primack, B
Petalcorin, MIR
O'Connor, KW
Konstantinopoulos, PA
Elledge, SJ
Boulton, SJ
Yusufzai, T
D'Andrea, AD
AF Ceccaldi, Raphael
Liu, Jessica C.
Amunugama, Ravindra
Hajdu, Ildiko
Primack, Benjamin
Petalcorin, Mark I. R.
O'Connor, Kevin W.
Konstantinopoulos, Panagiotis A.
Elledge, Stephen J.
Boulton, Simon J.
Yusufzai, Timur
D'Andrea, Alan D.
TI Homologous-recombination-deficient tumours are dependent on Pol
theta-mediated repair
SO NATURE
LA English
DT Article
ID STRAND BREAK REPAIR; DNA-DAMAGE; OVARIAN-CANCER; GENOMIC INSTABILITY;
HEMATOPOIETIC STEM; FANCONI-ANEMIA; HUMAN-CELLS; POLYMERASE; PATHWAY;
CHEMOTHERAPY
AB Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair(1). Loss of HR accounts for the genomic instability of EOCs and for their cellular hyper-dependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms(2-5). Previous studies have implicated the DNA polymerase theta (Pol theta also known as POLQ, encoded by POLQ) 6 in a pathway required for the repair of DNA double-strand breaks(7-9), referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway(10-13). Whether Pol theta interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Pol theta expression in EOCs. Knockdown of Pol theta in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Pol theta in HR-deficient EOCs enhances cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, Pol theta contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Pol theta-mediated repair in EOCs, and identify Pol theta as a novel druggable target for cancer therapy.
C1 [Ceccaldi, Raphael; Liu, Jessica C.; Primack, Benjamin; O'Connor, Kevin W.; Yusufzai, Timur; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA.
[Liu, Jessica C.; Yusufzai, Timur] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA.
[Liu, Jessica C.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA.
[Amunugama, Ravindra] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA.
[Hajdu, Ildiko; Elledge, Stephen J.] Brigham & Womens Hosp, Howard Hughes Med Inst, Div Genet, Boston, MA 02215 USA.
[Petalcorin, Mark I. R.; Boulton, Simon J.] London Res Inst, Canc Res UK, DNA Damage Response Lab, S Mimms EN6 3LD, Herts, England.
[Konstantinopoulos, Panagiotis A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Med Gynecol Oncol Program, Boston, MA 02215 USA.
RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA.
EM alan_dandrea@dfci.harvard.edu
OI Petalcorin, Mark/0000-0001-8211-9440
FU Philippe Foundation; Ovarian Cancer Research Fellowship (OCRF); NIH
[P50CA168504, R01HL52725]; OCRF; BCRF
FX We thank N. Shima, D. Chowdhury, G. Shapiro, J. Walter, D. Kozono, J.
Ablain, M. Delord, J.-B. Lazaro and members of the D'Andrea laboratory
for discussions. We also thank H. Kim for providing DNA constructs, L.
Moldovan for providing GST tagged RAD51, S. Johnson for providing MDA-MB
436 cells, A. Y. Li for technical assistance, L. Moreau for chromosomal
breakage analysis, and K. Mouw for critical reading of the manuscript.
We thank H. Zhang for providing access to shRNA screening data shown in
Extended Data Fig. 6i. We thank C. Cazaux and J.-S. Hoffmann for
providing pcDNA Flag-tagged Pol theta. R.C. received support from the
Philippe Foundation and is a recipient of the Ovarian Cancer Research
Fellowship (OCRF). This work was supported by NIH grants P50CA168504 and
R01HL52725 and by grants from OCRF and BCRF.
NR 39
TC 99
Z9 102
U1 8
U2 55
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 12
PY 2015
VL 518
IS 7538
BP 258
EP U306
DI 10.1038/nature14184
PG 21
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8SD
UT WOS:000349190300044
PM 25642963
ER
PT J
AU Slanetz, PJ
Freer, PE
Birdwell, RL
AF Slanetz, Priscilla J.
Freer, Phoebe E.
Birdwell, Robyn L.
TI Breast-Density Legislation - Practical Considerations
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Editorial Material
ID MAMMOGRAPHY; CANCER
C1 [Slanetz, Priscilla J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA.
[Slanetz, Priscilla J.; Freer, Phoebe E.; Birdwell, Robyn L.] Harvard Univ, Sch Med, Boston, MA USA.
[Freer, Phoebe E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA.
[Birdwell, Robyn L.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA.
RP Slanetz, PJ (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA.
OI Slanetz, Priscilla/0000-0003-1248-5116; Freer,
Phoebe/0000-0001-6886-7100
NR 5
TC 15
Z9 15
U1 0
U2 8
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 12
PY 2015
VL 372
IS 7
BP 593
EP 595
DI 10.1056/NEJMp1413728
PG 3
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA8CK
UT WOS:000349143900001
PM 25671249
ER
PT J
AU Sanders, J
AF Sanders, Justin
TI Finding the Right Words at the Right Time - High-Value Advance Care
Planning
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Editorial Material
ID INTERVENTIONS
C1 [Sanders, Justin] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA.
[Sanders, Justin] Ariadne Labs, Serious Illness Care Program, Boston, MA USA.
[Sanders, Justin] Harvard Univ, Sch Med, Boston, MA USA.
RP Sanders, J (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA.
NR 5
TC 3
Z9 3
U1 1
U2 5
PU MASSACHUSETTS MEDICAL SOC
PI WALTHAM
PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA
SN 0028-4793
EI 1533-4406
J9 NEW ENGL J MED
JI N. Engl. J. Med.
PD FEB 12
PY 2015
VL 372
IS 7
BP 598
EP 599
DI 10.1056/NEJMp1411717
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA8CK
UT WOS:000349143900003
PM 25671251
ER
PT J
AU Schlumberger, M
Tahara, M
Wirth, LJ
Robinson, B
Brose, MS
Elisei, R
Habra, MA
Newbold, K
Shah, MH
Hoff, AO
Gianoukakis, AG
Kiyota, N
Taylor, MH
Kim, SB
Krzyzanowska, MK
Dutcus, CE
de las Heras, B
Zhu, JM
Sherman, SI
AF Schlumberger, Martin
Tahara, Makoto
Wirth, Lori J.
Robinson, Bruce
Brose, Marcia S.
Elisei, Rossella
Habra, Mouhammed Amir
Newbold, Kate
Shah, Manisha H.
Hoff, Ana O.
Gianoukakis, Andrew G.
Kiyota, Naomi
Taylor, Matthew H.
Kim, Sung-Bae
Krzyzanowska, Monika K.
Dutcus, Corina E.
de las Heras, Begona
Zhu, Junming
Sherman, Steven I.
TI Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Article
ID TUMOR PROGRESSION; DOUBLE-BLIND; LYMPH-NODE; CARCINOMA; PAPILLARY;
ANGIOGENESIS; METASTASES; THERAPY; TARGETS; E7080
AB Background
Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor a, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).
Methods
In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety.
Results
The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.
Conclusions
Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.)
C1 [Schlumberger, Martin] Inst Gustave Roussy, Ctr Reference Tumeurs Refractaires Thyroide, Dept Nucl Med & Endocrine Oncol, Villejuif, France.
[Schlumberger, Martin] Univ Paris Sud, Villejuif, France.
[Tahara, Makoto] Natl Canc Ctr Hosp East, Dept Head & Neck Med Oncol, Kashiwa, Chiba, Japan.
[Kiyota, Naomi] Kobe Univ Hosp, Dept Med Oncol & Hematol, Kobe, Hyogo, Japan.
[Wirth, Lori J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.
[Robinson, Bruce] Univ Sydney, Kolling Inst Med Res, Sydney, NSW 2006, Australia.
[Brose, Marcia S.] Univ Penn, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA.
[Brose, Marcia S.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA.
[Elisei, Rossella] Univ Pisa, Dept Clin & Expt Med, Endocrine Unit, Pisa, Italy.
[Habra, Mouhammed Amir; Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Div Internal Med, Houston, TX 77030 USA.
[Newbold, Kate] Royal Marsden Hosp NHS Trust, London, England.
[de las Heras, Begona] Eisai, Hatfield, Herts, England.
[Shah, Manisha H.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Columbus, OH 43210 USA.
[Hoff, Ana O.] Univ Sao Paulo, Dept Endocrinol, Endocrine Oncol Unit, Inst Canc Estado Sao Paulo, Sao Paulo, Brazil.
[Gianoukakis, Andrew G.] Harbor Univ Calif Los Angeles Med Ctr, Div Endocrinol & Metab, Torrance, CA USA.
[Taylor, Matthew H.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA.
[Kim, Sung-Bae] Univ Ulsan, Coll Med, Dept Oncol, Asan Med Ctr, Seoul, South Korea.
[Krzyzanowska, Monika K.] Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada.
[Dutcus, Corina E.; Zhu, Junming] Eisai, Woodcliff Lake, NJ USA.
RP Schlumberger, M (reprint author), Inst Gustave Roussy, Ctr Reference Tumeurs Refractaires Thyroide, Dept Nucl Med & Endocrine Oncol, Villejuif, France.
EM martin.schlumberger@gustaveroussy.fr
RI Kiyota, Naomi/K-3226-2016;
OI Sherman, Steven/0000-0002-3079-5153
FU Eisai
FX Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.
NR 32
TC 149
Z9 158
U1 1
U2 52
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 12
PY 2015
VL 372
IS 7
BP 621
EP 630
DI 10.1056/NEJMoa1406470
PG 10
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA8CK
UT WOS:000349143900006
PM 25671254
ER
PT J
AU Shaw, AT
Solomon, BJ
AF Shaw, Alice T.
Solomon, Benjamin J.
TI Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer Reply
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Letter
C1 [Shaw, Alice T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.
[Solomon, Benjamin J.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia.
RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.
EM ashaw1@partners.org
NR 0
TC 21
Z9 23
U1 2
U2 5
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 12
PY 2015
VL 372
IS 7
BP 683
EP 684
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA8CK
UT WOS:000349143900019
PM 25671264
ER
PT J
AU LeBoeuf, NR
McDermott, S
Harris, NL
AF LeBoeuf, Nicole R.
McDermott, Shaunagh
Harris, Nancy L.
TI Case 5-2015: A 69-Year-Old Woman with Recurrent Skin Lesions after
Treatment for Lymphoma
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Article
ID LARGE-CELL LYMPHOMA; CD30(+) LYMPHOPROLIFERATIVE DISORDERS;
HODGKINS-DISEASE; PAPULOSIS; LEUKEMIA/LYMPHOMA; CLASSIFICATION;
INVOLVEMENT; EXPRESSION; DIAGNOSIS; EORTC
C1 [LeBoeuf, Nicole R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA.
[LeBoeuf, Nicole R.] Harvard Univ, Dana Farber Brigham & Womens Canc Ctr, Ctr Cutaneous Oncol, Sch Med, Boston, MA 02115 USA.
[McDermott, Shaunagh] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA.
[Harris, Nancy L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA.
[LeBoeuf, Nicole R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA.
[McDermott, Shaunagh] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA.
[Harris, Nancy L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA.
RP LeBoeuf, NR (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA.
FU Harvard Medical School Department of Continuing Education
FX This case was presented at the Harvard Medical School postgraduate
course "Dermatopathology Update," directed by Lyn M. Duncan, M.D., Mai
P. Hoang, M.D., Martin C. Mihm, Jr., M.D., George F. Murphy, M.D., and
Steven R. Tahan, M.D., and sponsored by the Harvard Medical School
Department of Continuing Education.
NR 29
TC 0
Z9 0
U1 1
U2 1
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 12
PY 2015
VL 372
IS 7
BP 650
EP 659
DI 10.1056/NEJMcpc1314241
PG 10
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA8CK
UT WOS:000349143900011
PM 25671258
ER
PT J
AU Kostic, AD
Gevers, D
Siljander, H
Vatanen, T
Hyotylainen, T
Hamalainen, AM
Peet, A
Tillmann, V
Poho, P
Mattila, I
Lahdesmaki, H
Franzosa, EA
Vaarala, O
de Goffau, M
Harmsen, H
Ilonen, J
Virtanen, SM
Clish, CB
Oresic, M
Huttenhower, C
Knip, M
Xavier, RJ
AF Kostic, Aleksandar D.
Gevers, Dirk
Siljander, Heli
Vatanen, Tommi
Hyotylainen, Tuulia
Hamalainen, Anu-Maaria
Peet, Aleksandr
Tillmann, Vallo
Poho, Paivi
Mattila, Ismo
Lahdesmaki, Harri
Franzosa, Eric A.
Vaarala, Outi
de Goffau, Marcus
Harmsen, Hermie
Ilonen, Jorma
Virtanen, Suvi M.
Clish, Clary B.
Oresic, Matej
Huttenhower, Curtis
Knip, Mikael
Xavier, Ramnik J.
CA DIABIMMUNE Study Grp
TI The Dynamics of the Human Infant Gut Microbiome in Development and in
Progression toward Type 1 Diabetes
SO CELL HOST & MICROBE
LA English
DT Article
ID NF-KAPPA-B; INTESTINAL MICROBIOTA; METABOLIC-CONTROL; EPITHELIAL-CELLS;
CROHNS-DISEASE; IGE LEVELS; DIVERSITY; CHILDREN; ACID; HOMEOSTASIS
AB Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from non-progressors.
C1 [Kostic, Aleksandar D.; Gevers, Dirk; Vatanen, Tommi; Clish, Clary B.; Huttenhower, Curtis; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
[Kostic, Aleksandar D.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.
[Kostic, Aleksandar D.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Kostic, Aleksandar D.; Franzosa, Eric A.; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
[Siljander, Heli; Knip, Mikael] Univ Helsinki, Childrens Hosp, FIN-00290 Helsinki, Finland.
[Siljander, Heli; Knip, Mikael] Helsinki Univ Hosp, Helsinki 00290, Finland.
[Siljander, Heli; Vaarala, Outi; Knip, Mikael] Univ Helsinki, Res Program Unit, FIN-00290 Helsinki, Finland.
[Vatanen, Tommi; Lahdesmaki, Harri] Aalto Univ, Sch Sci, Dept Informat & Comp Sci, Espoo 02150, Finland.
[Hyotylainen, Tuulia; Mattila, Ismo] Steno Diabet Ctr, DK-2820 Gentofte, Denmark.
[Poho, Paivi] Univ Helsinki, Fac Farm, FIN-00290 Helsinki, Finland.
[Hamalainen, Anu-Maaria] Jorvi Hosp, Dept Pediat, SF-02740 Espoo, Finland.
[Peet, Aleksandr; Tillmann, Vallo] Univ Tartu, Dept Pediat, Tartu, Estonia.
[Peet, Aleksandr; Tillmann, Vallo] Tartu Univ Hosp, EE-51014 Tartu, Estonia.
[Hyotylainen, Tuulia; Poho, Paivi; Mattila, Ismo; Oresic, Matej] VTT Tech Res Ctr Finland, Espoo 02044, Finland.
[de Goffau, Marcus; Harmsen, Hermie] Univ Groningen, Univ Med Ctr Groningen, Dept Med Microbiol, NL-9713 GZ Groningen, Netherlands.
[Ilonen, Jorma] Univ Turku, Immunogenet Lab, FIN-20520 Turku, Finland.
[Ilonen, Jorma] Univ Eastern Finland, Dept Clin Microbiol, Kuopio 70211, Finland.
[Virtanen, Suvi M.] Natl Inst Hlth & Welf, Dept Lifestyle & Participat, Helsinki 00271, Finland.
[Virtanen, Suvi M.] Univ Tampere, Sch Hlth Sci, Tampere 33014, Finland.
[Virtanen, Suvi M.] Pirkanmaa Hosp Dist, Ctr Sci, Tampere 33521, Finland.
[Knip, Mikael] Folkhalsan Res Ctr, Helsinki 00290, Finland.
[Knip, Mikael] Tampere Univ Hosp, Dept Pediat, Tampere 33521, Finland.
[Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA.
[Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA.
[Xavier, Ramnik J.] MIT, Ctr Microbiome Informat & Therapeut, Cambridge, MA 02139 USA.
RP Xavier, RJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
EM xavier@molbio.mgh.harvard.edu
RI Uibo, Raivo/G-8940-2015; Tillmann, Vallo/G-8118-2012;
OI Tillmann, Vallo/0000-0002-5279-4493; Karapetyan,
Tatyana/0000-0001-8129-8133; Dorshakova, Natalia/0000-0003-1072-9164;
Kostic, Aleksandar/0000-0002-0837-4360; Poho, Paivi/0000-0001-9963-4027;
von Mutius, Erika/0000-0002-8893-4515; Oresic, Matej/0000-0002-2856-9165
FU European Union [202063]; Juvenile Diabetes Research Foundation
[17-2011-529, 17-2014-305]; Academy of Finland Centre of Excellence in
Molecular Systems Immunology and Physiology Research [250114]; National
Institutes of Health [P30 DK043351, U54 DK102557]
FX We thank Tiffany Poon (Broad Institute) for sample, sequencing, and data
coordination; Timothy L. Tickle, Emma Schwager, and Xochitl C. Morgan
(Harvard School of Public Health) for assistance with statistical
analysis and helpful discussions; Natalia Nedelsky (MGH) for editorial
assistance; Niina Lietzen, Leena Ohrnberg, Anna-Liisa Ruskeepaa, and
Heli Nygren (VTT Technical Research Centre of Finland) for assistance in
metabolomics analysis; and Katriina Koski and Matti Koski (Institute of
Clinical Medicine, University of Helsinki) for the coordination and data
base work of the DIABIMMUNE Study. This work was supported by the
European Union Seventh Framework Programme FP7/2007-2013 under grant
agreement number 202063; Juvenile Diabetes Research Foundation grants
17-2011-529 and 17-2014-305; The Academy of Finland Centre of Excellence
in Molecular Systems Immunology and Physiology Research grant Decision
number 250114, 2012-2017; and National Institutes of Health P30 DK043351
and U54 DK102557. Outi Vaarala was an employee of AstraZeneca Research &
Development beginning August 1, 2014.
NR 51
TC 117
Z9 117
U1 24
U2 78
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 1931-3128
EI 1934-6069
J9 CELL HOST MICROBE
JI Cell Host Microbe
PD FEB 11
PY 2015
VL 17
IS 2
BP 260
EP 273
DI 10.1016/j.chom.2015.01.001
PG 14
WC Microbiology; Parasitology; Virology
SC Microbiology; Parasitology; Virology
GA CB6UH
UT WOS:000349761700015
PM 25662751
ER
PT J
AU Barnes, DE
Mehling, W
Wu, E
Beristianos, M
Yaffe, K
Skultety, K
Chesney, MA
AF Barnes, Deborah E.
Mehling, Wolf
Wu, Eveline
Beristianos, Matthew
Yaffe, Kristine
Skultety, Karyn
Chesney, Margaret A.
TI Preventing Loss of Independence through Exercise (PLIE): A Pilot
Clinical Trial in Older Adults with Dementia
SO PLOS ONE
LA English
DT Article
ID MINI-MENTAL-STATE; QUALITY-OF-LIFE; MODERATE ALZHEIMERS-DISEASE;
RANDOMIZED-CONTROLLED-TRIAL; TAI CHI; COGNITIVE IMPAIRMENT; OUTCOMES;
METAANALYSIS; PERFORMANCE; INVENTORY
AB Background
Current dementia medications have small effect sizes, many adverse effects and do not change the disease course. Therefore, it is critically important to study alternative treatment strategies. The goal of this study was to pilot-test a novel, integrative group exercise program for individuals with mild-to-moderate dementia called Preventing Loss of Independence through Exercise (PLIE), which focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection.
Methods
We performed a 36-week cross-over pilot clinical trial to compare PLIE with usual care (UC) at an adult day program for individuals with dementia in San Francisco, CA. Assessments of physical performance, cognitive function, physical function, dementia-related behaviors, quality of life and caregiver burden were performed by blinded assessors at baseline, 18 weeks (cross-over) and 36 weeks. Our primary outcomes were effect sizes based on between-group comparisons of change from baseline to 18 weeks; secondary outcomes were within-group comparisons of change before and after cross-over.
Results
Twelve individuals enrolled (7 PLIE, 5 UC) and 2 withdrew (1 PLIE, 18 weeks; 1 UC, 36 weeks). Participants were 82% women (mean age, 84 +/- 4 years); caregivers were 82% daughters (mean age, 56 +/- 13 years). Effect sizes were not statistically significant but suggested potentially clinically meaningful (>= 0.25 SDs) improvement with PLIE versus UC for physical performance (Cohen's D: 0.34 SDs), cognitive function (0.76 SDs) and quality of life (0.83 SDs) as well as for caregiver measures of participant's quality of life (0.33 SDs) and caregiver burden (0.49 SDs). Results were similar when within-group comparisons were made before and after cross-over.
Conclusions
PLIE is a novel, integrative exercise program that shows promise for improving physical function, cognitive function, quality of life and caregiver burden in individuals with mild-to-moderate dementia. Larger randomized, controlled trials are warranted.
C1 [Barnes, Deborah E.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA.
[Barnes, Deborah E.; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.
[Barnes, Deborah E.; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA.
[Mehling, Wolf] Univ Calif San Francisco, Dept Family & Community Med, San Francisco, CA 94143 USA.
[Mehling, Wolf; Wu, Eveline; Chesney, Margaret A.] Univ Calif San Francisco, Osher Ctr Integrat Med, San Francisco, CA 94143 USA.
[Wu, Eveline] Calif Inst Integral Studies, San Francisco, CA USA.
[Beristianos, Matthew] Northern Calif Inst Res & Educ, San Francisco, CA USA.
[Beristianos, Matthew] Calif Sch Profess Psychol, San Francisco, CA USA.
[Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA.
[Skultety, Karyn] Inst Aging, San Francisco, CA USA.
[Chesney, Margaret A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
RP Barnes, DE (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA.
EM Deborah.barnes@ucsf.edu
FU UCSF Osher Center for Integrative Medicine
FX We thank Drew and Ellen Bradley for their generous support of the UCSF
Osher Center for Integrative Medicine, which enabled the development and
pilot-testing of the Preventing Loss of Independence through Exercise
(PLIE) program.
NR 63
TC 4
Z9 4
U1 4
U2 27
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 11
PY 2015
VL 10
IS 2
AR UNSP e0113367
DI 10.1371/journal.pone.0113367
PG 19
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB3RF
UT WOS:000349545300002
PM 25671576
ER
PT J
AU Hanson, MC
Abraham, W
Crespo, MP
Chen, SH
Liu, HP
Szeto, GL
Kim, M
Reinherz, EL
Irvine, DJ
AF Hanson, Melissa C.
Abraham, Wuhbet
Crespo, Monica P.
Chen, Stephanie H.
Liu, Haipeng
Szeto, Greg Lee
Kim, Mikyung
Reinherz, Ellis L.
Irvine, Darrell J.
TI Liposomal vaccines incorporating molecular adjuvants and intrastructural
T-cell help promote the immunogenicity of HIV membrane-proximal external
region peptides
SO VACCINE
LA English
DT Article
DE Liposome; Adjuvant; HIV vaccine; Lipid membrane; MPER; Nanoparticle
ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES;
EPITOPE-SCAFFOLDS; IMMUNE-RESPONSES; GP41; DESIGN; PROTEIN; SIZE;
IMMUNODOMINANCE; IMMUNIZATION
AB An HIV vaccine capable of inducing high and durable levels of broadly neutralizing antibodies has thus far proven elusive. A promising antigen is the membrane-proximal external region (MPER) from gp41, a segment of the viral envelope recognized by a number of broadly neutralizing antibodies. Though an attractive vaccine target due to the linear nature of the epitope and its highly conserved sequence, MPER peptides are poorly immunogenic and may require display on membranes to achieve a physiological conformation matching the native virus. Here we systematically explored how the structure and composition of liposomes displaying MPER peptides impacts the strength and durability of humoral responses to this antigen as well as helper T-cell responses in mice. Administration of MPER peptides anchored to the surface of liposomes induced MPER-specific antibodies whereas MPER administered in oil-based emulsion adjuvants or alum did not, even when combined with Toll-like receptor agonists. High-titer IgG responses to liposomal MPER required the inclusion of molecular adjuvants such as monophosphoryl lipid A. Anti-MPER humoral responses were further enhanced by incorporating high-T-m lipids in the vesicle bilayer and optimizing the MPER density to a mean distance of similar to 10-15 nm between peptides on the liposomes' surfaces. Encapsulation of helper epitopes within the vesicles allowed efficient "intrastructural" T-cell help, which promoted IgG responses to MPER while minimizing competing B-cell responses against the helper sequence. These results define several key properties of liposome formulations that promote durable, high-titer antibody responses against MPER peptides, which will be a prerequisite for a successful MPER-targeting vaccine. (C) 2014 Elsevier Ltd. All rights reserved.
C1 [Hanson, Melissa C.; Szeto, Greg Lee; Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA.
[Hanson, Melissa C.; Abraham, Wuhbet; Crespo, Monica P.; Liu, Haipeng; Szeto, Greg Lee; Irvine, Darrell J.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA.
[Chen, Stephanie H.; Szeto, Greg Lee; Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA.
[Szeto, Greg Lee; Irvine, Darrell J.] MIT, Ragon Inst MGH, Cambridge, MA 02139 USA.
[Szeto, Greg Lee; Irvine, Darrell J.] Harvard, Cambridge, MA 02139 USA.
[Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.
[Kim, Mikyung; Reinherz, Ellis L.] Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA.
[Kim, Mikyung; Reinherz, Ellis L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
RP Irvine, DJ (reprint author), MIT, 500 Main St,76-261, Cambridge, MA 02139 USA.
EM djirvine@mit.edu
RI Crespo, Manuel/H-8868-2015;
OI Crespo, Manuel/0000-0001-9016-0515; Hanson, Melissa/0000-0003-3270-8460;
Szeto, Gregory/0000-0001-7604-1333
FU Bill & Melinda Gates Foundation; NIH [A1091 693]
FX We thank the Koch Institute Swanson Biotechnology Center for technical
support. This work was supported in part by the Bill & Melinda Gates
Foundation and the NIH (A1091 693). DJI is an investigator of the Howard
Hughes Medical Institute.
NR 50
TC 12
Z9 12
U1 2
U2 22
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0264-410X
EI 1873-2518
J9 VACCINE
JI Vaccine
PD FEB 11
PY 2015
VL 33
IS 7
BP 861
EP 868
DI 10.1016/j.vaccine.2014.12.045
PG 8
WC Immunology; Medicine, Research & Experimental
SC Immunology; Research & Experimental Medicine
GA CB3AU
UT WOS:000349500900005
PM 25559188
ER
PT J
AU Alyea, EP
AF Alyea, Edwin P.
TI Time to Reconsider the Role of Allogeneic Transplantation for Patients
With Acute Myeloid Leukemia and NPM1 Mutation?
SO JOURNAL OF CLINICAL ONCOLOGY
LA English
DT Editorial Material
ID STEM-CELL TRANSPLANTATION; EUROPEAN LEUKEMIANET; NORMAL KARYOTYPE;
CLINICAL-TRIALS; RECOMMENDATIONS; PROGNOSIS
C1 [Alyea, Edwin P.] Dana Farber Canc Inst, Boston, MA USA.
Dana Farber Canc Inst, Boston, MA 02115 USA.
RP Alyea, EP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.
NR 12
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 2015
VL 33
IS 5
BP 381
EP U11
DI 10.1200/JCO.2014.58.6818
PG 3
WC Oncology
SC Oncology
GA CF3OK
UT WOS:000352458200004
PM 25547505
ER
PT J
AU Yurgelun, MB
AF Yurgelun, Matthew B.
TI Next-Generation Strategies for Hereditary Colorectal Cancer Risk
Assessment
SO JOURNAL OF CLINICAL ONCOLOGY
LA English
DT Article
ID MISMATCH REPAIR DEFICIENCY; LYNCH-SYNDROME; GERMLINE MUTATIONS;
FAMILY-HISTORY; CLINICAL-CRITERIA; PREDICTIVE MODELS; IDENTIFICATION;
PREVALENCE; GUIDELINES; STATEMENT
AB An asymptomatic 36-year-old woman was recommended by her primary care physician to undergo her first-ever screening colonoscopy because of her family history (Fig 1). Her brother died of metastatic microsatellite stable rectal adenocarcinoma at age 45 years. Her 70-year-old father had a lifetime total of eight colorectal adenomas beginning at age 50 years. After a high-quality bowel preparation, colonoscopy successfully visualized the entire colon with intubation of the ileocecal valve; it revealed a 1-cm adenoma in the ascending colon, two 5-mm adenomas in the descending colon, a 4-mm rectal hyperplastic polyp, and a 4-cm ulcerated mass in the sigmoid colon. Biopsy of the mass showed low-grade invasive adenocarcinoma. Immunohistochemistry (IHC) of the adenocarcinoma revealed intact staining of the MLH1, MSH2, MSH6, and PMS2 proteins. Molecular testing identified a somatic KRAS G12C mutation and revealed stability at five of five mononucleotide microsatellite markers (BAT25, BAT26, NR21, NR24, and NR27) by polymerase chain reaction. Computed tomography showed no evidence of metastatic disease in the chest, abdomen, or pelvis. Laboratory testing demonstrated a carcinoembryonic antigen level of 4.3 ng/mL. Before undergoing surgical resection, she was referred for consideration of genetic testing to evaluate for an underlying hereditary cancer predisposition syndrome.
C1 Dana Farber Canc Inst, Boston, MA 02115 USA.
RP Yurgelun, MB (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.
FU Myriad Genetic Laboratories
FX Research Funding: Myriad Genetic Laboratories
NR 38
TC 6
Z9 6
U1 0
U2 2
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 2015
VL 33
IS 5
BP 388
EP U21
DI 10.1200/JCO.2014.58.9895
PG 8
WC Oncology
SC Oncology
GA CF3OK
UT WOS:000352458200007
PM 25559814
ER
PT J
AU Tamrat, R
Peralta, CA
Tajuddin, SM
Evans, MK
Zonderman, AB
Crews, DC
AF Tamrat, Ruth
Peralta, Carmen A.
Tajuddin, Salman M.
Evans, Michele K.
Zonderman, Alan B.
Crews, Deidra C.
TI Apolipoprotein L1, income and early kidney damage
SO BMC NEPHROLOGY
LA English
DT Article
DE APOL1; Chronic kidney disease; Socioeconomic status; African American;
Renal; Albuminuria
ID AFRICAN-AMERICANS; APOL1 VARIANTS; SOCIOECONOMIC-STATUS;
RACIAL-DIFFERENCES; FUNCTION DECLINE; RENAL-DISEASE; UNITED-STATES;
CYSTATIN C; RISK; ASSOCIATION
AB Background: The degree to which genetic or environmental factors are associated with early kidney damage among African Americans (AAs) is unknown.
Methods: Among 462 AAs in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, we examined the cross-sectional association between apolipoprotein L1 (APOL1) risk variants and income with: 1) mildly reduced eGFR (<75 mL/min/1.73 m(2), creatinine-cystatin C equation) and 2) elevated urine albumin-to-creatinine ratio (ACR) (>= 17 in men and >= 25 mg/g in women). High risk APOL1 status was defined by 2 copies of high-risk variants; low risk if 0 or 1 copy. Income groups were dichotomized as < $ 14,000/year (lowest income group) or >= $ 14,000/year. Logistic regression models were adjusted for age, sex, and % European ancestry.
Results: Overall, participants' mean age was 47 years and 16% (n = 73) had high risk APOL1 status. Mean eGFR was 99 mL/min/1.73 m(2). Mildly reduced eGFR was prevalent among 11% (n = 51). The lowest income group had higher adjusted odds (aOR) of mildly reduced eGFR than the higher income group (aOR 1.8, 95% CI 1.2-2.7). High-risk APOL1 was not significantly associated with reduced eGFR (aOR 1.5, 95% CI 0.9-2.5). Among 301 participants with ACR data, 7% (n = 21) had elevated ACR. Compared to low-risk, persons with high-risk APOL1 had higher odds of elevated ACR (aOR 3.8, 95% CI 2.0-7.3). Income was not significantly associated with elevated ACR (aOR 1.8, 95% CI 0.7-4.5). There were no significant interactions between APOL1 and income.
Conclusions: Both genetic and socioeconomic factors may be important determinants of early kidney damage among AAs.
C1 [Tamrat, Ruth; Crews, Deidra C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA.
[Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
[Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA.
[Tajuddin, Salman M.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA.
[Crews, Deidra C.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA.
[Crews, Deidra C.] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA.
[Crews, Deidra C.] Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, Div Nephrol, Baltimore, MD 21224 USA.
RP Crews, DC (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA.
EM dcrews1@jhmi.edu
OI Zonderman, Alan B/0000-0002-6523-4778; Tajuddin, Salman
M./0000-0002-7919-8528
FU Intramural Research Program of the National Institute on Aging, National
Institutes of Health (NIH); Robert Wood Johnson Foundation; National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
[K23DK097184]; Gilbert S. Omenn Anniversary Fellowship of the Institute
of Medicine
FX This work was supported by the Intramural Research Program of the
National Institute on Aging, National Institutes of Health (NIH). Dr.
Crews was supported by the Harold Amos Medical Faculty Development
Program of the Robert Wood Johnson Foundation, grant K23DK097184 from
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), NIH, and the Gilbert S. Omenn Anniversary Fellowship of the
Institute of Medicine.
NR 32
TC 2
Z9 2
U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2369
J9 BMC NEPHROL
JI BMC Nephrol.
PD FEB 10
PY 2015
VL 16
AR 14
DI 10.1186/s12882-015-0008-6
PG 8
WC Urology & Nephrology
SC Urology & Nephrology
GA CD3ET
UT WOS:000350961400001
PM 25884165
ER
PT J
AU Huh, SJ
Clement, K
Jee, D
Merlini, A
Choudhury, S
Maruyama, R
Yoo, R
Chytil, A
Boyle, P
Ran, FA
Moses, HL
Barcellos-Hoff, MH
Jackson-Grusby, L
Meissner, A
Polyak, K
AF Huh, Sung Jin
Clement, Kendell
Jee, David
Merlini, Alessandra
Choudhury, Sibgat
Maruyama, Reo
Yoo, Ronnie
Chytil, Anna
Boyle, Patrick
Ran, Fei Ann
Moses, Harold L.
Barcellos-Hoff, Mary Helen
Jackson-Grusby, Laurie
Meissner, Alexander
Polyak, Kornelia
TI Age- and Pregnancy-Associated DNA Methylation Changes in Mammary
Epithelial Cells
SO STEM CELL REPORTS
LA English
DT Article
ID STEM-CELL; BREAST-CANCER; GLAND MORPHOGENESIS; DIFFERENTIATION;
PROLIFERATION; ACTIVATION; MAINTENANCE; POPULATION; LANDSCAPE; EPIGENOME
AB Postnatal mammary gland development and differentiation occur during puberty and pregnancy. To explore the role of DNA methylation in these processes, we determined the genome-wide DNA methylation and gene expression profiles of CD24(+)CD61(+)CD29(hi), CD24(+)CD61(+)CD29(lo), and CD24(+)CD61(-)CD29(lo) cell populations that were previously associated with distinct biological properties at different ages and reproductive stages. We found that pregnancy had the most significant effects on CD24(+)CD61(+)CD29(hi) and CD24(+)CD61(+)CD29(lo) cells, inducing distinct epigenetic states that were maintained through life. Integrated analysis of gene expression, DNA methylation, and histone modification profiles revealed cell-type- and reproductive-stage-specific changes. We identified p27 and TGF beta signaling as key regulators of CD24(+)CD61(+)CD29(lo) cell proliferation, based on their expression patterns and results from mammary gland explant cultures. Our results suggest that relatively minor changes in DNA methylation occur during luminal differentiation compared with the effects of pregnancy on CD24(+)CD61(+)CD29(hi) and CD24(+)CD61(+)CD29(lo) cells.
C1 [Huh, Sung Jin; Jee, David; Merlini, Alessandra; Choudhury, Sibgat; Maruyama, Reo; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
[Huh, Sung Jin; Jee, David; Choudhury, Sibgat; Maruyama, Reo; Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.
[Huh, Sung Jin; Jee, David; Choudhury, Sibgat; Maruyama, Reo; Polyak, Kornelia] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA.
[Clement, Kendell; Boyle, Patrick; Meissner, Alexander; Polyak, Kornelia] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
[Clement, Kendell; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.
[Clement, Kendell; Jackson-Grusby, Laurie; Meissner, Alexander; Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
[Clement, Kendell] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA.
[Merlini, Alessandra] Univ Pavia, Dept Mol Med, Unit Immunol & Gen Pathol, I-27100 Pavia, Italy.
[Yoo, Ronnie; Ran, Fei Ann; Jackson-Grusby, Laurie; Polyak, Kornelia] Harvard Univ, Program Biol & Biomed Sci, Sch Med, Boston, MA 02115 USA.
[Yoo, Ronnie; Ran, Fei Ann; Jackson-Grusby, Laurie] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA.
[Chytil, Anna; Moses, Harold L.] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA.
[Chytil, Anna; Moses, Harold L.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA.
[Barcellos-Hoff, Mary Helen] NYU, Sch Med, Dept Radiat Oncol, New York, NY 10016 USA.
[Barcellos-Hoff, Mary Helen] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA.
RP Meissner, A (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
EM alexander_meissner@harvard.edu; kornelia_polyak@dfci.harvard.edu
OI Barcellos-Hoff, Mary Helen/0000-0002-5994-9558
FU National Cancer Institute [F32 CA156991, P01 CA080111]; Giovanni
Armenise-Harvard Foundation Summer Fellowship Program; Susan G. Komen
Foundation; Terri Brodeur Foundation; New York Stem Cell Foundation;
U.S. Army Congressionally Directed Research [W81XWH-07-1-0294]
FX We thank the staffs of the Dana-Farber Cancer Institute Flow Cytometry
Core Facilities, Molecular Biology Core Facilities, and Confocal and
Light Microscopy Core Facilities for their outstanding services and
technical support. This work was supported by the National Cancer
Institute (F32 CA156991 to S.J.H. and P01 CA080111 to K.P.), the
Giovanni Armenise-Harvard Foundation Summer Fellowship Program (A.
Merlini), the Susan G. Komen Foundation (R.M.), the Terri Brodeur
Foundation (S.C.), the New York Stem Cell Foundation (A. Meissner), and
U.S. Army Congressionally Directed Research (W81XWH-07-1-0294 to K.P.).
A. Meissner is a New York Stem Cell Foundation-Robertson Investigator.
This article is dedicated to the memory of Dr. Edward Fox.
NR 36
TC 6
Z9 6
U1 0
U2 4
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 10
PY 2015
VL 4
IS 2
BP 297
EP 311
DI 10.1016/j.stemcr.2014.12.009
PG 15
WC Cell & Tissue Engineering; Cell Biology
SC Cell Biology
GA CB4WM
UT WOS:000349629000011
PM 25619437
ER
PT J
AU Yao, C
Chen, BH
Joehanes, R
Otlu, B
Zhang, XL
Liu, CY
Huan, TX
Tastan, O
Cupples, LA
Meigs, JB
Fox, CS
Freedman, JE
Courchesne, P
O'Donnell, CJ
Munson, PJ
Keles, S
Levy, D
AF Yao, Chen
Chen, Brian H.
Joehanes, Roby
Otlu, Burcak
Zhang, Xiaoling
Liu, Chunyu
Huan, Tianxiao
Tastan, Oznur
Cupples, L. Adrienne
Meigs, James B.
Fox, Caroline S.
Freedman, Jane E.
Courchesne, Paul
O'Donnell, Christopher J.
Munson, Peter J.
Keles, Sunduz
Levy, Daniel
TI Integromic Analysis of Genetic Variation and Gene Expression Identifies
Networks for Cardiovascular Disease Phenotypes
SO CIRCULATION
LA English
DT Article
DE cardiovascular disease; gene expression/regulation network; genetic
variation
ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; SMOKING-BEHAVIOR; LOCI;
VARIANTS; RISK; CYTOSCAPE; DISCOVERY; TRAITS; MODELS
AB Background-Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown.
Methods and Results-We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P <= 5x10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes.
Conclusions-Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD.
C1 [Yao, Chen; Chen, Brian H.; Joehanes, Roby; Zhang, Xiaoling; Liu, Chunyu; Huan, Tianxiao; Cupples, L. Adrienne; Fox, Caroline S.; Courchesne, Paul; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Framingham Heart Study, NIH, Bethesda, MD 20892 USA.
[Yao, Chen; Chen, Brian H.; Joehanes, Roby; Zhang, Xiaoling; Liu, Chunyu; Huan, Tianxiao; Courchesne, Paul; Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.
[Joehanes, Roby; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA.
[Otlu, Burcak] Middle E Tech Univ, Dept Chem Engn, TR-06531 Ankara, Turkey.
[Tastan, Oznur] Bilkent Univ, Dept Comp Engn, Ankara, Turkey.
[Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA.
[Meigs, James B.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA.
[Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA.
[Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA.
[O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.
[Keles, Sunduz] Univ Wisconsin Madison, Dept Stat, Madison, WI USA.
[Keles, Sunduz] Univ Wisconsin Madison, Dept Biostat & Med Informat, Madison, WI USA.
RP Levy, D (reprint author), NHLBI, Framingham Heart Study, Populat Sci Branch, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA.
EM LevyD@nih.gov
FU National Institutes of Health [N01-HC-25195, U01 HG007019]; Division of
Intramural Research, National Heart, Lung, and Blood Institute, National
Institutes of Health; Division of Intramural Research, National Heart,
Lung, and Blood Institute; Center for Information Technology, National
Institutes of Health, Bethesda, MD; Bilim Akademisi, The Science
Academy, Turkey, under the BAGEP program; L'Oreal-UNESCO under the
UNESCO-L'Oreal National Fellowships Program for Young Women in Life
Sciences; Scientific and Technological Research Council of Turkey
(TUBITAK) [2211-C]; [K24 DK080140]
FX The FHS 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. 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, and a National
Institutes of Health grant (U01 HG007019). Dr Tastan acknowledges
support from Bilim Akademisi, The Science Academy, Turkey, under the
BAGEP program and support from L'Oreal-UNESCO under the UNESCO-L'Oreal
National Fellowships Program for Young Women in Life Sciences. B.O. is
supported by The Scientific and Technological Research Council of Turkey
(TUBITAK, 2211-C PhD Scholarship). J.B. Meigs is supported by K24
DK080140.
NR 50
TC 16
Z9 17
U1 3
U2 6
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 10
PY 2015
VL 131
IS 6
BP 536
EP U247
DI 10.1161/CIRCULATIONAHA.114.010696
PG 211
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
SC Cardiovascular System & Cardiology
GA CA9EM
UT WOS:000349223600010
PM 25533967
ER
PT J
AU Li, CW
Concepcion, E
Tomer, Y
AF Li, Cheuk Wun
Concepcion, Erlinda
Tomer, Yaron
TI Dissecting the role of the foxp3 gene in the joint genetic
susceptibility to autoimmune thyroiditis and diabetes: A genetic and
functional analysis
SO GENE
LA English
DT Article
DE Autoimmune thyroiditis; Type 1 diabetes; FOXP3; Gene splicing;
Transcription
ID REGULATORY T-CELLS; ORGAN-SPECIFIC AUTOANTIBODIES; LEUCINE-ZIPPER;
HASHIMOTOS-THYROIDITIS; 1ST-DEGREE RELATIVES; SPLICE VARIANTS;
GRAVES-DISEASE; TARGET GENES; FORK HEAD; TYPE-1
AB We have previously shown that a (TC)(n) microsatellite in intron 5 of the Forkhead Box Protein 3 (FOXP3) gene was associated with a variant of the autoimmune polyglandular syndrome type 3 (APS3v), that is defined as the co-occurrence of type 1 diabetes (T1D) and autoimmune thyroiditis (AITD). Allele 10, containing 25 repeats of the microsatellite (long repeats), is preferentially transmitted to offspring with APS3v, while allele 2, containing 14 repeats of the microsatellite (short repeats), is protective. We hypothesized that the long repeats of the intron 5 microsatellite decrease FOXP3 splicing and function, thereby reducing regulatory T cell activity and promoting the development of APS3v.
We cloned genomic DNA from two males hemizygous for the long and short repeats of the microsatellite on their X-chromosomes and transfected them into human embryonic kidney 293 (HEK 293) cells to perform direct splicing analysis.
We identified a novel splice variant of FOXP3 lacking exon 6, and showed that it is expressed in human thymus and lymph node. However, the length of the repeats in the microsatellite did not significantly influence the expression of this FOXP3 splice variant in vitro. Interestingly, this splice variant was expressed in human regulatory T cells, suggesting that it may play a role in their function.
In conclusion, we identified a novel splice variant FOXP3 Delta 6. The role of its expression in regulatory T cells in the development of autoimmunity remains to be determined. (C) 2014 Elsevier B.V. All rights reserved.
C1 [Li, Cheuk Wun; Concepcion, Erlinda; Tomer, Yaron] Icahn Sch Med Mt Sinai, Div Endocrinol, New York, NY 10029 USA.
[Tomer, Yaron] James J Peters VA Med Ctr, Bronx, NY USA.
RP Li, CW (reprint author), Icahn Sch Med Mt Sinai, Div Endocrinol, One Gustave L Levy Pl,Box 1055, New York, NY 10029 USA.
EM cheukwunli@mssm.edu
FU NIDDK [DK061659, DK067555, DK073681]; Department of Veterans Affairs
FX This work was supported in part by grants DK061659, DK067555 & DK073681
from NIDDK. In addition this material is based upon the work supported
in part by the Department of Veterans Affairs. We also thank Dr. Peter
Heeger's lab for their generous help on isolating regulatory T cells.
NR 78
TC 4
Z9 4
U1 0
U2 4
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD FEB 10
PY 2015
VL 556
IS 2
BP 142
EP 148
DI 10.1016/j.gene.2014.11.064
PG 7
WC Genetics & Heredity
SC Genetics & Heredity
GA CB4HW
UT WOS:000349589800009
PM 25481456
ER
PT J
AU Leshchiner, ES
Parkhitko, A
Bird, GH
Luccarelli, J
Bellairs, JA
Escudero, S
Opoku-Nsiah, K
Godes, M
Perrimon, N
Walensky, LD
AF Leshchiner, Elizaveta S.
Parkhitko, Andrey
Bird, Gregory H.
Luccarelli, James
Bellairs, Joseph A.
Escudero, Silvia
Opoku-Nsiah, Kwadwo
Godes, Marina
Perrimon, Norbert
Walensky, Loren D.
TI Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE RAS; inhibitor; SOS1; stapled peptide; cancer
ID MEDIATED NUCLEOTIDE EXCHANGE; K-RAS; EFFECTOR INTERACTIONS; SMALL
MOLECULES; ACTIVATION; PROTEIN; CANCER; EXPRESSION; DISCOVERY; BIND
AB Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of similar to 30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAHSOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. SAH-SOS1 peptides bound in a sequence- specific manner to KRAS and its mutants, and dose-responsively blocked nucleotide association. Importantly, this functional binding activity correlated with SAH-SOS1 cytotoxicity in cancer cells expressing wild-type or mutant forms of KRAS. The mechanism of action of SAH-SOS1 peptides was demonstrated by sequencespecific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophilamelanogaster model of Ras85DV12 activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer.
C1 [Leshchiner, Elizaveta S.; Bird, Gregory H.; Luccarelli, James; Bellairs, Joseph A.; Escudero, Silvia; Opoku-Nsiah, Kwadwo; Godes, Marina; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
[Leshchiner, Elizaveta S.; Bird, Gregory H.; Luccarelli, James; Bellairs, Joseph A.; Escudero, Silvia; Opoku-Nsiah, Kwadwo; Godes, Marina; Walensky, Loren D.] Dana Farber Canc Inst, Linde Program Canc Chem Biol, Boston, MA 02215 USA.
[Parkhitko, Andrey; Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
[Perrimon, Norbert] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA.
RP Walensky, LD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.
EM loren_walensky@dfci.harvard.edu
FU NIH [5R01GM090299, P01CA120964, T32GM007753]; Howard Hughes Medical
Institute; American Association of University Women International
Fellowship; Todd J. Schwartz Memorial Fund; Wolpoff Family Foundation
FX We thank Eric D. Smith for figure preparation and graphics assistance,
Marc Therrien for Ras1 antibodies, and John Tower for Actin-GS-Gal4
flies. This work was supported by NIH Grant 5R01GM090299 (to L.D.W.),
NIH Grant P01CA120964 and Howard Hughes Medical Institute (to N.P.), an
American Association of University Women International Fellowship (to
E.S.L.), NIH Grant T32GM007753 (to J.L.), the Todd J. Schwartz Memorial
Fund, and the Wolpoff Family Foundation.
NR 31
TC 29
Z9 29
U1 8
U2 38
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 10
PY 2015
VL 112
IS 6
BP 1761
EP 1766
DI 10.1073/pnas.1413185112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8XL
UT WOS:000349204200043
PM 25624485
ER
PT J
AU Giorgi, C
Bonora, M
Sorrentino, G
Missiroli, S
Poletti, F
Suski, JM
Ramirez, FG
Rizzuto, R
Di Virgilio, F
Zito, E
Pandolfi, PP
Wieckowski, MR
Mammano, F
Del Sal, G
Pinton, P
AF Giorgi, Carlotta
Bonora, Massimo
Sorrentino, Giovanni
Missiroli, Sonia
Poletti, Federica
Suski, Jan M.
Ramirez, Fabian Galindo
Rizzuto, Rosario
Di Virgilio, Francesco
Zito, Ester
Pandolfi, Pier Paolo
Wieckowski, Mariusz R.
Mammano, Fabio
Del Sal, Giannino
Pinton, Paolo
TI p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent
manner
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE p53; endoplasmic reticulum; mitochondria-associated membranes; calcium;
apoptosis
ID MITOCHONDRIA-ASSOCIATED MEMBRANES; ER STRESS; CALCIUM; CELLS; CA2+; PML;
LOCALIZATION; ACTIVATION; NETWORK; SITES
AB The tumor suppressor p53 is a key protein in preventing cell transformation and tumor progression. Activated by a variety of stimuli, p53 regulates cell-cycle arrest and apoptosis. Along with its well-documented transcriptional control over cell-death programs within the nucleus, p53 exerts crucial although still poorly understood functions in the cytoplasm, directly modulating the apoptotic response at the mitochondrial level. Calcium (Ca2+) transfer between the endoplasmic reticulum (ER) and mitochondria represents a critical signal in the induction of apoptosis. However, the mechanism controlling this flux in response to stress stimuli remains largely unknown. Here we show that, in the cytoplasm, WT p53 localizes at the ER and at specialized contact domains between the ER and mitochondria (mitochondria-associated membranes). We demonstrate that, upon stress stimuli, WT p53 accumulates at these sites and modulates Ca2+ homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca2+-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca2+ load, followed by an enhanced transfer to mitochondria. The consequent mitochondrial Ca2+ overload causes in turn alterations in the morphology of this organelle and induction of apoptosis. Pharmacological inactivation of WT p53 or naturally occurring p53 missense mutants inhibits SERCA pump activity at the ER, leading to a reduction of the Ca2+ signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca2+ signal-dependent apoptosis.
C1 [Giorgi, Carlotta; Bonora, Massimo; Missiroli, Sonia; Poletti, Federica; Di Virgilio, Francesco; Pinton, Paolo] Univ Ferrara, Sect Pathol Oncol & Expt Biol, Dept Morphol Surg & Expt Med, I-44121 Ferrara, Italy.
[Sorrentino, Giovanni; Del Sal, Giannino] Lab Nazl Consorzio Interuniv Biotecnol, I-34012 Trieste, Italy.
[Suski, Jan M.; Wieckowski, Mariusz R.] M Nencki Inst Expt Biol, Dept Biochem, PL-02093 Warsaw, Poland.
[Ramirez, Fabian Galindo; Mammano, Fabio] Univ Padua, Dept Phys & Astron, I-35129 Padua, Italy.
[Ramirez, Fabian Galindo; Mammano, Fabio] Venetian Inst Mol Med, I-35129 Padua, Italy.
[Rizzuto, Rosario] Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy.
[Zito, Ester] Ist Ric Farmacol Mario Negri, Dulbecco Telethon Inst, I-20156 Milan, Italy.
[Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Genet Program,Dept Med & Pathol, Boston, MA 02215 USA.
[Pandolfi, Pier Paolo; Del Sal, Giannino] Univ Trieste, Dipartimento Sci Vita, I-34128 Trieste, Italy.
RP Pinton, P (reprint author), Univ Ferrara, Sect Pathol Oncol & Expt Biol, Dept Morphol Surg & Expt Med, I-44121 Ferrara, Italy.
EM pnp@unife.it
RI Mammano, Fabio/I-5064-2012; Pinton, Paolo/J-8025-2012;
OI Mammano, Fabio/0000-0003-3751-1691; Pinton, Paolo/0000-0001-7108-6508;
Wieckowski, Mariusz/0000-0003-0789-4521; Giorgi,
Carlotta/0000-0002-2494-7405
FU Italian Association for Cancer Research; Italian Ministry of Education,
University and Research (COFIN, FIRB, and Futuro in Ricerca); NCI
grants; Polish National Science Centre [UMO-2011/01/M/NZ3/02128]; Polish
Ministry of Science and Higher Education [W100/HFSC/2011, HFSP
RGP0027/2011]; Telethon Career Award [TDEZ00112T]
FX This study was supported by the Italian Association for Cancer Research
(C.G., G.D.S., and P.P.); the Italian Ministry of Education, University
and Research (COFIN, FIRB, and Futuro in Ricerca; G.D.S. and P.P.); NCI
grants (to P.P.P.); Polish National Science Centre
(UMO-2011/01/M/NZ3/02128); Polish Ministry of Science and Higher
Education Grant W100/HFSC/2011 and Grant HFSP RGP0027/2011 (to M.R.W.);
and a Telethon Career Award (TDEZ00112T; to E.Z.).
NR 42
TC 39
Z9 41
U1 7
U2 27
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 10
PY 2015
VL 112
IS 6
BP 1779
EP 1784
DI 10.1073/pnas.1410723112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8XL
UT WOS:000349204200046
PM 25624484
ER
PT J
AU Lin, SG
Guo, CG
Su, A
Zhang, Y
Alt, FW
AF Lin, Sherry G.
Guo, Chunguang
Su, Arthur
Zhang, Yu
Alt, Frederick W.
TI CTCF-binding elements 1 and 2 in the Igh intergenic control region
cooperatively regulate V(D)J recombination
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE V(D)J recombination control; antibody repertoires; B-cell development
ID VH GENE SEGMENTS; HEAVY-CHAIN GENE; PRO-B CELLS; GENOMIC INTERACTIONS;
LOCUS; TRANSCRIPTION; REPERTOIRE; PAX5; REARRANGEMENTS; EXPRESSION
AB Ig heavy chain (IgH) variable region exons are assembled from V, D, and J gene segments during early B-lymphocyte differentiation. A several megabase region at the "distal" end of the mouse IgH locus (Igh) contains hundreds of V(H)s, separated by an intergenic region from Igh Ds, J(H)s, and constant region exons. Diverse primary Igh repertoires are generated by joining Vs, Ds, and Js in different combinations, with a given B cell productively assembling only one combination. The intergenic control region 1 (IGCR1) in the V-H-to-D intergenic region regulates Igh V(D) J recombination in the contexts of developmental order, lineage specificity, and feedback from productive rearrangements. IGCR1 also diversifies IgH repertoires by balancing proximal and distal V-H use. IGCR1 functions in all these regulatory contexts by suppressing predominant rearrangement of D-proximal VHs. Such IGCR1 functions were neutralized by simultaneous mutation of two CCCTC-binding factor (CTCF)-binding elements (CBE1 and CBE2) within it. However, it was unknown whether only one CBE mediates IGCR1 functions or whether both function in this context. To address these questions, we generated mice in which either IGCR1 CBE1 or CBE2 was replaced with scrambled sequences that do not bind CTCF. We found that inactivation of CBE1 or CBE2 individually led to only partial impairment of various IGCR1 functions relative to the far greater effects of inactivating both binding elements simultaneously, demonstrating that they function cooperatively to achieve full IGCR1 regulatory activity. Based on these and other findings, we propose an orientation-specific looping model for synergistic CBE1 and CBE2 functions.
C1 [Lin, Sherry G.; Guo, Chunguang; Su, Arthur; Zhang, Yu; Alt, Frederick W.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.
[Alt, Frederick W.] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA.
[Lin, Sherry G.; Zhang, Yu; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
RP Alt, FW (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.
EM alt@enders.tch.harvard.edu
FU National Institutes of Health [R01 AI020047]; Cancer Research Institute
of New York
FX We thank Hye Suk Yoon and Suvi Jain for helpful advice. This work was
supported by National Institutes of Health Grant R01 AI020047. F.W.A. is
an Investigator of the Howard Hughes Medical Institute. C.G. was
supported by a fellowship from the Cancer Research Institute of New
York.
NR 33
TC 20
Z9 20
U1 1
U2 5
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 10
PY 2015
VL 112
IS 6
BP 1815
EP 1820
DI 10.1073/pnas.1424936112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8XL
UT WOS:000349204200052
PM 25624508
ER
PT J
AU Kirienko, NV
Ausubel, FM
Ruvkun, G
AF Kirienko, Natalia V.
Ausubel, Frederick M.
Ruvkun, Gary
TI Mitophagy confers resistance to siderophore-mediated killing by
Pseudomonas aeruginosa
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE mitophagy; Pseudomonas; siderophore; innate immunity; C. elegans
ID NEMATODE CAENORHABDITIS-ELEGANS; TRANSLATIONAL INHIBITION; C. ELEGANS;
IRON; AUTOPHAGY; IMMUNITY; DAF-16; INFECTION; VIRULENCE; PATHWAY
AB In the arms race of bacterial pathogenesis, bacteria produce an array of toxins and virulence factors that disrupt core host processes. Hosts mitigate the ensuing damage by responding with immune countermeasures. The iron-binding siderophore pyoverdin is a key virulence mediator of the human pathogen Pseudomonas aeruginosa, but its pathogenic mechanism has not been established. Here we demonstrate that pyoverdin enters Caenorhabditis elegans and that it is sufficient to mediate host killing. Moreover, we show that iron chelation disrupts mitochondrial homeostasis and triggers mitophagy both in C. elegans and mammalian cells. Finally, we show that mitophagy provides protection both against the extracellular pathogen P. aeruginosa and to treatment with a xenobiotic chelator, phenanthroline, in C. elegans. Although autophagic machinery has been shown to target intracellular bacteria for degradation (a process known as xenophagy), our report establishes a role for authentic mitochondrial autophagy in the innate immune defense against P. aeruginosa.
C1 [Kirienko, Natalia V.; Ausubel, Frederick M.; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.
[Kirienko, Natalia V.; Ausubel, Frederick M.; Ruvkun, Gary] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
RP Ruvkun, G (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.
EM ruvkun@molbio.mgh.harvard.edu
FU Massachusetts Biomedical Research Corporation Tosteson Postdoctoral
Fellowship Award; Ruth L. Kirschstein National Research Service Award
[F32 AI-100501]; National Institutes of Health [R01 AI-085581, P30
DK040561, R01 AG16636]
FX The authors thank Dr. David Fay for providing the WY753 and W756
strains, Dr. Vamsi Mootha for providing the HEK293T cell line, and Dr.
Daniel Kirienko for technical assistance. This work was supported by a
Massachusetts Biomedical Research Corporation Tosteson Postdoctoral
Fellowship Award (to N.V.K.); Ruth L. Kirschstein National Research
Service Award F32 AI-100501 (to N.V.K.); and National Institutes of
Health Grants R01 AI-085581 and P30 DK040561 (to F.M.A.) and R01 AG16636
(to G.R.).
NR 36
TC 23
Z9 23
U1 8
U2 36
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 10
PY 2015
VL 112
IS 6
BP 1821
EP 1826
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8XL
UT WOS:000349204200053
PM 25624506
ER
PT J
AU Datta, M
Via, LE
Kamoun, WS
Liu, C
Chen, W
Seano, G
Weiner, DM
Schimel, D
England, K
Martin, JD
Gao, X
Xu, L
Barry, CE
Jain, RK
AF Datta, Meenal
Via, Laura E.
Kamoun, Walid S.
Liu, Chong
Chen, Wei
Seano, Giorgio
Weiner, Danielle M.
Schimel, Daniel
England, Kathleen
Martin, John D.
Gao, Xing
Xu, Lei
Barry, Clifton E., III
Jain, Rakesh K.
TI Anti-vascular endothelial growth factor treatment normalizes
tuberculosis granuloma vasculature and improves small molecule delivery
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE antiangiogenesis; hypoxia; host-directed therapy; Mycobacterium
tuberculosis; rabbit model
ID ANTITUBERCULOSIS DRUGS; TUMOR VASCULATURE; SOLID TUMORS; CANCER;
DISEASES; NANOMEDICINE; CHEMOTHERAPY; ANGIOGENESIS; STRATEGIES;
INFECTION
AB Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can "normalize" their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.
C1 [Datta, Meenal; Kamoun, Walid S.; Liu, Chong; Chen, Wei; Seano, Giorgio; Martin, John D.; Gao, Xing; Xu, Lei; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA.
[Datta, Meenal; Kamoun, Walid S.; Liu, Chong; Chen, Wei; Seano, Giorgio; Martin, John D.; Gao, Xing; Xu, Lei; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Datta, Meenal] Tufts Univ, Dept Chem & Biol Engn, Medford, MA 02155 USA.
[Via, Laura E.; Weiner, Danielle M.; Schimel, Daniel; England, Kathleen; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA.
[Martin, John D.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA.
[Barry, Clifton E., III] Univ Cape Town, Fac Hlth Sci, Dept Clin Lab Sci, ZA-7701 Rondebosch, South Africa.
RP Barry, CE (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
EM cbarry@mail.nih.gov; jain@steele.mgh.harvard.edu
RI Barry, III, Clifton/H-3839-2012; Martin, John/L-6892-2016; Seano,
Giorgio/R-6611-2016
OI Martin, John/0000-0002-9828-8203; Seano, Giorgio/0000-0002-7294-302X
FU Bill and Melinda Gates Foundation; American Cancer Society; Children's
Tumor Foundation; Susan G. Komen Foundation [PDF14301739]; Grand
Challenges in Global Health Program; Intramural Research Program of the
NIH/National Institute of Allergy and Infectious Diseases; Korean
Ministry of Health and Welfare; [P01CA080214]
FX We thank Carolyn Smith for outstanding technical support of the
immunohistochemistry studies, and Drs. Matija Snuderl and Rehka Samuel
for their scientific input. We thank all of the participants who
enrolled in the study, as well as the staff of the International
Tuberculosis Research Center, Asan Medical Center, Pusan National
University Hospital, and the National Medical Center for their
assistance with this work. We acknowledge Seokyong Eum for his service
as a pathologist for this study. This study was supported, in part, by
Grant P01CA080214 (to R.K.J.) and by grants from the Bill and Melinda
Gates Foundation (to R.K.J.), from the American Cancer Society (to
L.X.), from the Children's Tumor Foundation (to L.X.), and from the
Susan G. Komen Foundation [Grant PDF14301739 (to G.S.)]; through the
Grand Challenges in Global Health Program to Douglas Young, Imperial
College (to C.E.B.); by the Intramural Research Program of the
NIH/National Institute of Allergy and Infectious Diseases (C.E.B.); and
by the Korean Ministry of Health and Welfare.
NR 33
TC 33
Z9 33
U1 3
U2 26
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 10
PY 2015
VL 112
IS 6
BP 1827
EP 1832
DI 10.1073/pnas.1424563112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA8XL
UT WOS:000349204200054
PM 25624495
ER
PT J
AU Nath, AK
Ryu, JH
Jin, YN
Roberts, LD
Dejam, A
Gerszten, RE
Peterson, RT
AF Nath, Anjali K.
Ryu, Justine H.
Jin, Youngnam N.
Roberts, Lee D.
Dejam, Andre
Gerszten, Robert E.
Peterson, Randall T.
TI PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase
Phosphorylation
SO CELL REPORTS
LA English
DT Article
ID MITOCHONDRIAL PHOSPHATASE PTPMT1; CELLS; BIOSYNTHESIS; SECRETION; KINASE
AB Virtually all organisms seek to maximize fitness by matching fuel availability with energy expenditure. In vertebrates, glucose homeostasis is central to this process, with glucose levels finely tuned to match changing energy requirements. To discover new pathways regulating glucose levels in vivo, we performed a large-scale chemical screen in live zebrafish and identified the small molecule alexidine as a potent glucose-lowering agent. We found that alexidine inhibits the PTEN-like mitochondrial phosphatase PTPMT1 and that other pharmacological and genetic means of inactivating PTPMT1 also decrease glucose levels in zebrafish. Mutation of ptpmt1 eliminates the effect of alexidine, further confirming it as the glucose-lowering target of alexidine. We then identified succinate dehydrogenase (SDH) as a substrate of PTPMT1. Inactivation of PTPMT1 causes hyperphosphorylation and activation of SDH, providing a possible mechanism by which PTPMT1 coordinates glucose homeostasis. Therefore, PTPMT1 appears to be an important regulator of SDH phosphorylation status and glucose concentration.
C1 [Nath, Anjali K.; Ryu, Justine H.; Jin, Youngnam N.; Roberts, Lee D.; Dejam, Andre; Gerszten, Robert E.; Peterson, Randall T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Dept Med, Charlestown, MA 02129 USA.
[Nath, Anjali K.; Ryu, Justine H.; Jin, Youngnam N.; Roberts, Lee D.; Dejam, Andre; Gerszten, Robert E.; Peterson, Randall T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Charlestown, MA 02129 USA.
[Nath, Anjali K.; Ryu, Justine H.; Jin, Youngnam N.; Roberts, Lee D.; Dejam, Andre; Gerszten, Robert E.; Peterson, Randall T.] Broad Inst, Cambridge, MA 02142 USA.
RP Nath, AK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Dept Med, Charlestown, MA 02129 USA.
EM anjali.nath@aya.yale.edu; peterson@cvrc.mgh.harvard.edu
FU MGH ECOR Tosteson Award [2012A051526]; Charles and Ann Sanders MGH
Scholar Award; Inflammatory Bowel Disease [DK43351]; Boston Area
Diabetes and Endocrinology Research Center (BADERC) [DK57521];
Hoffmann-La Roche; Merck; [T32 HL007208]
FX Tg (ins:nfsB-mCherry) was a gift from Michael Parsons. Many thanks to
Quinn Peterson for thoughtful comments on the manuscript. This work was
supported by a T32 HL007208 and a MGH ECOR Tosteson Award (2012A051526)
(A.K.N.) and by a Charles and Ann Sanders MGH Scholar Award (R.T.P.).
Electron microscopy was performed in the Microscopy Core of the Center
for Systems Biology/Program in Membrane Biology, which is partially
supported by Inflammatory Bowel Disease grant DK43351 and Boston Area
Diabetes and Endocrinology Research Center (BADERC) award DK57521.
R.T.P. receives research funding from Hoffmann-La Roche and Merck.
NR 15
TC 7
Z9 7
U1 1
U2 5
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 10
PY 2015
VL 10
IS 5
BP 694
EP 701
DI 10.1016/j.celrep.2015.01.010
PG 8
WC Cell Biology
SC Cell Biology
GA CB1RA
UT WOS:000349404400006
ER
PT J
AU Chattopadhyay, S
Stewart, AL
Mukherjee, S
Huang, C
Hartwell, KA
Miller, PG
Subramanian, R
Carmody, LC
Yusuf, RZ
Sykes, DB
Paulk, J
Vetere, A
Vallet, S
Santo, L
Cirstea, DD
Hideshima, T
Dancik, V
Majireck, MM
Hussain, MM
Singh, S
Quiroz, R
Iaconelli, J
Karmacharya, R
Tolliday, NJ
Clemons, PA
Moore, MAS
Stern, AM
Shamji, AF
Ebert, BL
Golub, TR
Raje, NS
Scadden, DT
Schreiber, SL
AF Chattopadhyay, Shrikanta
Stewart, Alison L.
Mukherjee, Siddhartha
Huang, Cherrie
Hartwell, Kimberly A.
Miller, Peter G.
Subramanian, Radhika
Carmody, Leigh C.
Yusuf, Rushdia Z.
Sykes, David B.
Paulk, Joshiawa
Vetere, Amedeo
Vallet, Sonia
Santo, Loredana
Cirstea, Diana D.
Hideshima, Teru
Dancik, Vlado
Majireck, Max M.
Hussain, Mahmud M.
Singh, Shambhavi
Quiroz, Ryan
Iaconelli, Jonathan
Karmacharya, Rakesh
Tolliday, Nicola J.
Clemons, Paul A.
Moore, Malcolm A. S.
Stern, Andrew M.
Shamji, Alykhan F.
Ebert, Benjamin L.
Golub, Todd R.
Raje, Noopur S.
Scadden, David T.
Schreiber, Stuart L.
TI Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5
Inhibitor with Improved Selectivity over Hematopoietic Progenitors
SO CELL REPORTS
LA English
DT Article
ID SPINDLE PROTEIN INHIBITOR; TUMOR XENOGRAFT EFFICACY; SMALL-MOLECULE
INHIBITOR; MARROW CFU-GM; BONE-MARROW; IN-VITRO; DRUG-RESISTANCE; HUMAN
KSP; THERAPY; CELLS
AB Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin- 5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876' s mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets.
C1 [Chattopadhyay, Shrikanta; Stewart, Alison L.; Huang, Cherrie; Carmody, Leigh C.; Paulk, Joshiawa; Vetere, Amedeo; Dancik, Vlado; Majireck, Max M.; Hussain, Mahmud M.; Singh, Shambhavi; Quiroz, Ryan; Iaconelli, Jonathan; Karmacharya, Rakesh; Tolliday, Nicola J.; Clemons, Paul A.; Stern, Andrew M.; Shamji, Alykhan F.; Schreiber, Stuart L.] Broad Inst, Ctr Dev Therapeut, Ctr Sci Therapeut, Cambridge, MA 02142 USA.
[Chattopadhyay, Shrikanta; Huang, Cherrie; Yusuf, Rushdia Z.; Sykes, David B.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.
[Chattopadhyay, Shrikanta; Yusuf, Rushdia Z.; Sykes, David B.; Vallet, Sonia; Santo, Loredana; Raje, Noopur S.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.
[Mukherjee, Siddhartha] Columbia Univ, Sch Med, Dept Med, New York, NY 10032 USA.
[Mukherjee, Siddhartha] Columbia Univ, Sch Med, Irving Canc Res Ctr, New York, NY 10032 USA.
[Hartwell, Kimberly A.; Golub, Todd R.] Broad Inst, Canc Program, Cambridge, MA 02142 USA.
[Miller, Peter G.; Scadden, David T.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Subramanian, Radhika] Rockefeller Univ, New York, NY 10065 USA.
[Cirstea, Diana D.; Hideshima, Teru; Ebert, Benjamin L.; Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02115 USA.
[Paulk, Joshiawa; Majireck, Max M.; Hussain, Mahmud M.; Singh, Shambhavi; Scadden, David T.; Schreiber, Stuart L.] Harvard Univ, Cambridge, MA 02138 USA.
[Quiroz, Ryan] Univ Calif Los Angeles, Los Angeles, CA 90095 USA.
[Iaconelli, Jonathan; Karmacharya, Rakesh] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.
[Karmacharya, Rakesh] McLean Hosp, Schizophrenia & Bipolar Disorder Program, Belmont, MA 02478 USA.
[Moore, Malcolm A. S.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA.
[Stern, Andrew M.] Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15260 USA.
[Miller, Peter G.; Ebert, Benjamin L.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA.
[Hussain, Mahmud M.; Golub, Todd R.; Schreiber, Stuart L.] Broad Inst, Howard Hughes Med Inst, Cambridge, MA 02142 USA.
RP Chattopadhyay, S (reprint author), Broad Inst, Ctr Dev Therapeut, Ctr Sci Therapeut, Cambridge, MA 02142 USA.
EM schattopadhyay@partners.org; stuart_schreiber@harvard.edu
OI Vetere, Amedeo/0000-0001-5608-0773; Karmacharya,
Rakesh/0000-0002-0565-5482
FU Starr Cancer Consortium; NIH Dana-Farber/Harvard Cancer Center Multiple
Myeloma S.P.O.R.E [R01GM038627, RL1HG004671, R01DK050234, U54CA163191,
K08CA158149, P50CA100707]; Multiple Myeloma Research Foundation Research
Fellow Award
FX We wish to thank T. Hasaka, J. Bradner, T. Kapoor, L. VerPlank, M.
Bliss- Moreau, V. Raksakulthai, J. Negri, M. Palmer, J. Burbank, P.
Aspesi, Jr., D. Barker, K. Emmith, J. Bittker, B. Wagner, J. Perez, J.
Cheah, E. Price, S. Johnston, G. Walzer, Z. Boskovic, D. Walpita, A.
Bracha, C. Hon, J. McGrath, C. Hartland, J. Kotz, R. Bejar, I.
Pomerantseva, J. Vacanti, S. Pozzi, N. Vaghela, K. Patel, J.
Schoonmaker, K. Maxcy, Broad Compound Management, and the S.L.S.,
D.T.S., and N.S.R.laboratories for scientific discussions, technical
expertise, and/or reagents. This work was funded by grants from the
Starr Cancer Consortium, the NIH awards R01GM038627 (to S.L.S.),
RL1HG004671 (to S.L.S.), R01DK050234 (to D.T.S.), U54CA163191 (to
D.T.S.), K08CA158149 (to S.C.), P50CA100707 Dana-Farber/Harvard Cancer
Center Multiple Myeloma S.P.O.R.E. career development sub-award (to
S.C.), and the Multiple Myeloma Research Foundation Research Fellow
Award (to S.C.). The content of this publication is solely the
responsibility of the authors and 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. T.R.G. and S.L.S. are Investigators at
the Howard Hughes Medical Institute.
NR 49
TC 4
Z9 4
U1 3
U2 15
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 10
PY 2015
VL 10
IS 5
BP 755
EP 770
DI 10.1016/j.celrep.2015.01.017
PG 16
WC Cell Biology
SC Cell Biology
GA CB1RA
UT WOS:000349404400011
ER
PT J
AU Case, MA
Burwick, HA
Volpp, KG
Patel, MS
AF Case, Meredith A.
Burwick, Holland A.
Volpp, Kevin G.
Patel, Mitesh S.
TI Accuracy of Smartphone Applications and Wearable Devices for Tracking
Physical Activity Data
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Letter
C1 [Case, Meredith A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA.
[Burwick, Holland A.] Amherst Coll, Amherst, MA 01002 USA.
[Volpp, Kevin G.; Patel, Mitesh S.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA.
RP Patel, MS (reprint author), Univ Penn, 13th Floor Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA.
EM mpatel@upenn.edu
FU NIA NIH HHS [RC4 AG039114-01]
NR 5
TC 70
Z9 71
U1 15
U2 50
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 10
PY 2015
VL 313
IS 6
BP 625
EP 626
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA7AZ
UT WOS:000349070700024
PM 25668268
ER
PT J
AU Bertrand, PB
Verbrugge, FH
Verhaert, D
Smeets, CJP
Grieten, L
Mullens, W
Gutermann, H
Dion, RA
Levine, RA
Vandervoort, PM
AF Bertrand, Philippe B.
Verbrugge, Frederik H.
Verhaert, David
Smeets, Christophe J. P.
Grieten, Lars
Mullens, Wilfried
Gutermann, Herbert
Dion, Robert A.
Levine, Robert A.
Vandervoort, Pieter M.
TI Mitral Valve Area During Exercise After Restrictive Mitral Valve
Annuloplasty Importance of Diastolic Anterior Leaflet Tethering
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Article
DE exercise echocardiography; heart failure; mitral valve; valvuloplasty
ID PROSTHESIS-PATIENT MISMATCH; UNDERSIZED ANNULOPLASTY; TRANSMITRAL
GRADIENTS; REGURGITATION; STENOSIS; REPLACEMENT; IMPACT; PRESSURE;
REPAIR; GEOMETRY
AB BACKGROUND Restrictive mitral valve annuloplasty (RMA) for secondary mitral regurgitation might cause functional mitral stenosis, yet its clinical impact and underlying pathophysiological mechanisms remain debated.
OBJECTIVES The purpose of our study was to assess the hemodynamic and clinical impact of effective orifice area (EOA) after RMA and its relationship with diastolic anterior leaflet (AL) tethering at rest and during exercise.
METHODS Consecutive RMA patients (n = 39) underwent a symptom-limited supine bicycle exercise test with Doppler echocardiography and respiratory gas analysis. EOA, transmitral flow rate, mean transmitral gradient, and systolic pulmonary arterial pressure were assessed at different stages of exercise. AL opening angles were measured at rest and peak exercise. Mortality and heart failure readmission data were collected for at least 20 months after surgery.
RESULTS EOA and AL opening angle were 1.5 +/- 0.4 cm(2) and 68 +/- 10 degrees, respectively, at rest (r = 0.4; p = 0.014). EOA increased significantly to 2.0 +/- 0.5 cm(2) at peak exercise (p < 0.001), showing an improved correlation with AL opening angle (r = 0.6; p < 0.001). Indexed EOA (EOAi) at peak exercise was an independent predictor of exercise capacity (maximal oxygen uptake, p = 0.004) and was independently associated with freedom from all-cause mortality or hospital admission for heart failure (p = 0.034). Patients with exercise EOAi <0.9 cm(2)/m(2) (n = 14) compared with >= 0.9 cm(2)/m(2) (n = 25) had a significantly worse outcome (p = 0.048). In multivariate analysis, AL opening angle at peak exercise (p = 0.037) was the strongest predictor of exercise EOAi.
CONCLUSIONS In RMA patients, EOA increases during exercise despite fixed annular size. Diastolic AL tethering plays a key role in this dynamic process, with increasing AL opening during exercise being associated with higher exercise EOA. EOAi at peak exercise is a strong and independent predictor of exercise capacity and is associated with clinical outcome. Our findings stress the importance of maximizing AL opening by targeting the subvalvular apparatus in future repair algorithms for secondary mitral regurgitation. (C) 2015 by the American College of Cardiology Foundation.
C1 [Bertrand, Philippe B.; Verbrugge, Frederik H.; Verhaert, David; Grieten, Lars; Mullens, Wilfried; Vandervoort, Pieter M.] Ziekenhuis Oost Limburg, Dept Cardiol, B-3600 Genk, Belgium.
[Bertrand, Philippe B.; Verbrugge, Frederik H.; Smeets, Christophe J. P.; Grieten, Lars; Mullens, Wilfried; Vandervoort, Pieter M.] Hasselt Univ, Fac Med & Life Sci, Diepenbeek, Belgium.
[Gutermann, Herbert; Dion, Robert A.] Ziekenhuis Oost Limburg, Dept Cardiac Surg, B-3600 Genk, Belgium.
[Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA 02115 USA.
RP Vandervoort, PM (reprint author), Ziekenhuis Oost Limburg, Dept Cardiol, Schiepse Bos 6, B-3600 Genk, Belgium.
EM pieter.vandervoort@zol.be
OI Smeets, Christophe/0000-0002-1746-7585
FU Research Foundation-Flanders (FWO) [11N7214N]; foundation Limburg Sterk
Merk; Hasselt University; Ziekenhuis Oost-Limburg; Jessa Hospital;
Edwards Lifesciences; Johnson Johnson; Sorin Biomedica; Medtronic; St.
Jude Medical
FX Dr. Bertrand is supported by a grant of the Research Foundation-Flanders
(FWO, 11N7214N). Dr. Bertrand, Dr. Verbrugge, Mr. Smeets, Dr. Grieten,
Dr. Mullens, and Dr. Vandervoort are researchers for the Limburg
Clinical Research Program UHasselt-ZOL-Jessa, supported by the
foundation Limburg Sterk Merk, Hasselt University, Ziekenhuis
Oost-Limburg, and Jessa Hospital. Dr. Dion has received consulting fees
from Edwards Lifesciences, Johnson & Johnson, Sorin Biomedica,
Medtronic, and St. Jude Medical. All other authors have reported that
they have no relationships relevant to the contents of this paper to
disclose.
NR 35
TC 8
Z9 8
U1 0
U2 7
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0735-1097
EI 1558-3597
J9 J AM COLL CARDIOL
JI J. Am. Coll. Cardiol.
PD FEB 10
PY 2015
VL 65
IS 5
BP 452
EP 461
DI 10.1016/j.jacc.2014.11.037
PG 10
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA CA1IS
UT WOS:000348667000010
PM 25660923
ER
PT J
AU Mooster, JL
Le Bras, S
Massaad, MJ
Jabara, H
Yoon, J
Galand, C
Heesters, BA
Burton, OT
Mattoo, H
Manis, J
Geha, RS
AF Mooster, Jana L.
Le Bras, Severine
Massaad, Michel J.
Jabara, Haifa
Yoon, Juhan
Galand, Claire
Heesters, Balthasar A.
Burton, Oliver T.
Mattoo, Hamid
Manis, John
Geha, Raif S.
TI Defective lymphoid organogenesis underlies the immune deficiency caused
by a heterozygous S32I mutation in I kappa B alpha
SO JOURNAL OF EXPERIMENTAL MEDICINE
LA English
DT Article
ID TUMOR-NECROSIS-FACTOR; ANHIDROTIC ECTODERMAL DYSPLASIA;
LYMPHOTOXIN-BETA-RECEPTOR; ESSENTIAL MODULATOR MUTATION; FOLLICULAR
DENDRITIC CELLS; SPLENIC MARGINAL ZONE; DISTINCT ROLES; CONTACT
HYPERSENSITIVITY; ABNORMAL-DEVELOPMENT; ENDOTHELIAL-CELLS
AB Patients with ectodermal dysplasia with immunodeficiency (ED-ID) caused by mutations in the inhibitor of NF-kappa B alpha (I kappa B alpha) are susceptible to severe recurrent infections, despite normal T and B cell numbers and intact in vitro lymphocyte function. Moreover, the outcome of hematopoietic stem cell transplantation (HSCT) in these patients is poor despite good engraftment. Mice heterozygous for the I kappa B alpha S32I mutation found in patients exhibited typical features of ED-ID. Strikingly, the mice lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells and failed to develop contact hypersensitivity (CHS) or form germinal centers (GCs), all features not previously recognized in patients and typical of defective noncanonical NF-kappa B signaling. Lymphotoxin beta receptor (LT beta R)-driven induction of chemokines and adhesion molecules mediated by both canonical and noncanonical NF-kappa B pathways was impaired, and levels of p100 were markedly diminished in the mutant. I kappa B alpha mutant -> Rag2(-/-), but not WT -> I kappa B alpha mutant, bone marrow chimeras formed proper lymphoid organs and developed CHS and GCs. Defective architectural cell function explains the immunodeficiency and poor outcome of HSCT in patients with I kappa B alpha deficiency and suggests that correction of this niche is critical for reconstituting their immune function.
C1 [Mooster, Jana L.; Le Bras, Severine; Massaad, Michel J.; Jabara, Haifa; Yoon, Juhan; Galand, Claire; Burton, Oliver T.; Geha, Raif S.] Boston Childrens Hosp, Div Allergy & Immunol, Boston, MA 02115 USA.
[Heesters, Balthasar A.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.
[Mooster, Jana L.; Le Bras, Severine; Massaad, Michel J.; Jabara, Haifa; Yoon, Juhan; Galand, Claire; Burton, Oliver T.; Geha, Raif S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA.
[Manis, John] Harvard Univ, Sch Med, Div Transfus Med, Boston, MA 02115 USA.
[Manis, John] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA.
[Heesters, Balthasar A.] Univ Med Ctr Utrecht, Dept Med Microbiol, NL-3584 CX Utrecht, Netherlands.
[Mattoo, Hamid] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.
RP Geha, RS (reprint author), Boston Childrens Hosp, Div Allergy & Immunol, Boston, MA 02115 USA.
EM Raif.Geha@childrens.harvard.edu
FU National Institutes of Health (NIH) [5P01AI076210, 5T32-AI007512];
Talecris fellowship
FX This work was supported by National Institutes of Health (NIH) grants
5P01AI076210 and 5T32-AI007512 to R. S. Geha and by a Talecris
fellowship to J.L. Mooster.
NR 86
TC 4
Z9 5
U1 1
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 FEB 9
PY 2015
VL 212
IS 2
BP 185
EP 202
DI 10.1084/jem.20140979
PG 18
WC Immunology; Medicine, Research & Experimental
SC Immunology; Research & Experimental Medicine
GA CB3SO
UT WOS:000349549000007
PM 25601653
ER
PT J
AU Kodack, DP
Askoxylakis, V
Ferraro, GB
Fukumura, D
Jain, RK
AF Kodack, David P.
Askoxylakis, Vasileios
Ferraro, Gino B.
Fukumura, Dai
Jain, Rakesh K.
TI Emerging Strategies for Treating Brain Metastases from Breast Cancer
SO CANCER CELL
LA English
DT Article
ID CENTRAL-NERVOUS-SYSTEM; PROPHYLACTIC CRANIAL IRRADIATION; TUMOR-CELLS;
TRASTUZUMAB EMTANSINE; KINASE INHIBITOR; OPEN-LABEL; PHASE-II; GROWTH;
SURVIVAL; TRIAL
AB Brain metastasis is an end stage in breast cancer progression. Traditional treatment options have minimal efficacy, and overall survival is on the order of months. The incidence of brain metastatic disease is increasing with the improved management of systemic disease and prolongation of survival. Unfortunately, the targeted therapies that control systemic disease have diminished efficacy against brain lesions. There are reasons to be optimistic, however, as emerging therapies have shown promise in preclinical and early clinical settings. This review discusses recent advances in breast cancer brain metastasis therapy and potential approaches for successful treatment.
C1 [Kodack, David P.; Askoxylakis, Vasileios; Ferraro, Gino B.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Edwin L Steele Lab, Boston, MA 02114 USA.
[Kodack, David P.; Askoxylakis, Vasileios; Ferraro, Gino B.; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
RP Jain, RK (reprint author), Massachusetts Gen Hosp, Edwin L Steele Lab, Boston, MA 02114 USA.
EM jain@steele.mgh.harvard.edu
FU US Department of Defense Breast Cancer Research Innovator Award
[W81XWH-10-1-0016]; US National Cancer Institute [R01-CA126642,
P01-CA080124, R01-CA096915]; Federal Share Proton Beam Program Income;
German Research Foundation Grant (Deutsche Forschungsgemeinschaft, DFG)
[AS 422-2/1]; Enlight; Ophthotech; SynDevRx
FX We thank M. Badeaux, S. Goel, A. Batista, D. Duda, and A. Eichler for
their helpful suggestions and editing. This work was supported by US
Department of Defense Breast Cancer Research Innovator Award
W81XWH-10-1-0016 (to R.K.J.); US National Cancer Institute Grants
R01-CA126642 (to R.K.J.), P01-CA080124 (to R.K.J. and D.F.), and
R01-CA096915 (to D.F.); Federal Share Proton Beam Program Income (to
R.K.J.); and German Research Foundation Grant (Deutsche
Forschungsgemeinschaft, DFG) AS 422-2/1 (to V.A.). R.K.J. received
consultant fees from Enlight, Ophthotech, and SynDevRx. R.K.J. owns
equity in Enlight, Ophthotech, SynDevRx, and XTuit, and serves on the
Board of Directors of XTuit and the Boards of Trustees of Tekla
Healthcare Investors, Tekla Life Sciences Investors, and the Tekla
Healthcare Opportunities Fund.
NR 92
TC 23
Z9 24
U1 3
U2 28
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 9
PY 2015
VL 27
IS 2
BP 163
EP 175
DI 10.1016/j.ccell.2015.01.001
PG 13
WC Oncology; Cell Biology
SC Oncology; Cell Biology
GA CB3GC
UT WOS:000349515200006
PM 25670078
ER
PT J
AU Gandhi, PU
Januzzi, JL
AF Gandhi, Parul U.
Januzzi, James L., Jr.
TI Can copeptin emerge from the growing shadow of the troponins?
SO EUROPEAN HEART JOURNAL
LA English
DT Editorial Material
ID HIGH-SENSITIVITY TROPONIN; ACUTE MYOCARDIAL-INFARCTION; ACUTE CORONARY
SYNDROME; CHEST-PAIN; RAPID RULE; DIAGNOSIS; ASSAYS
C1 [Gandhi, Parul U.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA.
EM jjanuzzi@partners.org
NR 19
TC 4
Z9 4
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 7
PY 2015
VL 36
IS 6
BP 333
EP 336
DI 10.1093/eurheartj/ehu211
PG 4
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA CE1RD
UT WOS:000351588700006
PM 24847154
ER
PT J
AU Reid, ZZ
Regan, S
Kelley, JHK
Streck, JM
Ylioja, T
Tindle, HA
Chang, YC
Levy, DE
Park, ER
Singer, DE
Carpenter, KM
Reyen, M
Rigotti, NA
AF Reid, Zachary Z.
Regan, Susan
Kelley, Jennifer H. K.
Streck, Joanna M.
Ylioja, Thomas
Tindle, Hilary A.
Chang, Yuchiao
Levy, Douglas E.
Park, Elyse R.
Singer, Daniel E.
Carpenter, Kelly M.
Reyen, Michele
Rigotti, Nancy A.
TI Comparative effectiveness of post-discharge strategies for hospitalized
smokers: study protocol for the Helping HAND 2 randomized controlled
trial
SO BMC PUBLIC HEALTH
LA English
DT Article
DE Smoking cessation; Hospitalization; Pharmacotherapy; Counseling;
Interactive voice response; Randomized controlled trial
ID NICOTINE REPLACEMENT THERAPY; SMOKING-CESSATION; COST-EFFECTIVENESS;
TOBACCO QUITLINE; UNITED-STATES; PRIMARY-CARE; INTERVENTIONS; DRINKING;
EFFICACY; PROGRAM
AB Background: Smoking cessation interventions for hospitalized smokers are effective in promoting smoking cessation, but only if the tobacco dependence treatment continues after the patient leaves the hospital. Sustaining tobacco dependence treatment after hospital discharge is a challenge for health care systems. Our previous single-site randomized controlled trial demonstrated the effectiveness of an intervention that facilitated the delivery of comprehensive tobacco cessation treatment, including both medication and counseling, after hospital discharge. We subsequently streamlined the intervention model to increase its potential for dissemination. This new model is being tested in a larger multi-site trial with broader eligibility criteria in order to enroll a more representative sample of hospitalized smokers. This paper describes the trial design and contrasts it with the earlier study.
Methods/Design: A 2-arm, 3-site randomized controlled trial is testing the hypothesis that a multi-component Sustained Care intervention is more effective than Standard Care in helping hospitalized cigarette smokers stop smoking after hospital discharge. The trial enrolls adult daily cigarette smokers who are admitted to 1 of 3 participating hospitals in Massachusetts or Pennsylvania. Participants receive the same smoking cessation intervention in the hospital. They are randomly assigned to receive either Standard Care or Sustained Care after hospital discharge. Participants in the Sustained Care arm receive a free 3-month supply of FDA-approved smoking cessation medication and 5 interactive voice response calls that provide tailored motivational messages, medication refills, and access to a live tobacco treatment counselor. Participants in the Standard Care arm receive a smoking cessation medication recommendation and information about community resources. Outcomes are assessed at 1, 3, and 6 months after discharge. The primary outcome is biochemically-validated tobacco abstinence for the past 7 days at 6-month follow-up. Other outcome measures include self-reported tobacco abstinence measures, use of medication and counseling after discharge, hospital readmissions, and program cost-effectiveness.
Discussion: We adapted a proven intervention for hospitalized smokers to enhance its potential for dissemination and are testing it in a multi-site trial. Study enrollment data suggests that the trial achieved the goal of recruiting a broader sample of hospitalized smokers.
C1 [Reid, Zachary Z.; Regan, Susan; Kelley, Jennifer H. K.; Levy, Douglas E.; Park, Elyse R.; Reyen, Michele; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA.
[Reid, Zachary Z.; Kelley, Jennifer H. K.; Levy, Douglas E.; Park, Elyse R.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA.
[Reid, Zachary Z.; Kelley, Jennifer H. K.; Levy, Douglas E.; Park, Elyse R.; Rigotti, Nancy A.] Partners HealthCare, Boston, MA USA.
[Regan, Susan; Chang, Yuchiao; Singer, Daniel E.; Reyen, Michele; Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Internal Med Med Serv, Boston, MA 02114 USA.
[Regan, Susan; Chang, Yuchiao; Levy, Douglas E.; Singer, Daniel E.; Rigotti, Nancy A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA.
[Park, Elyse R.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA USA.
[Streck, Joanna M.] Univ Vermont, Dept Psychol, Burlington, VT USA.
[Ylioja, Thomas] Univ Pittsburgh, Sch Social Work, Pittsburgh, PA 15260 USA.
[Tindle, Hilary A.] Vanderbilt Univ, Med Ctr, Dept Med, VITAL Ctr, Nashville, TN USA.
[Carpenter, Kelly M.] Alere Wellbeing Inc, Res Ctr, Seattle, WA USA.
RP Reid, ZZ (reprint author), Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA.
EM zreid@partners.org
FU National Heart, Lung, and Blood Institute [1R01HL111821-01,
3R01HL111821-01S1]
FX This study is funded by grants #1R01HL111821-01 and #3R01HL111821-01S1
from the National Heart, Lung, and Blood Institute. The funding
organization had no role in the design and conduct of the study;
collection, management, analysis, and interpretation of the data;
preparation, review, or approval of the manuscript; or decision to
submit the manuscript for publication.
NR 35
TC 3
Z9 3
U1 3
U2 7
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2458
J9 BMC PUBLIC HEALTH
JI BMC Public Health
PD FEB 7
PY 2015
VL 15
AR 109
DI 10.1186/s12889-015-1484-0
PG 12
WC Public, Environmental & Occupational Health
SC Public, Environmental & Occupational Health
GA CB6ON
UT WOS:000349746500001
PM 25879193
ER
PT J
AU Yang, W
Yan, K
Wu, GX
Wu, W
Fu, Y
Lee, JC
Zhang, ZY
Wang, S
Chen, MH
AF Yang, Wei
Yan, Kun
Wu, Gong-Xiong
Wu, Wei
Fu, Ying
Lee, Jung-Chieh
Zhang, Zhong-Yi
Wang, Song
Chen, Min-Hua
TI Radiofrequency ablation of hepatocellular carcinoma in difficult
locations: Strategies and long-term outcomes
SO WORLD JOURNAL OF GASTROENTEROLOGY
LA English
DT Article
DE Radiofrequency ablation; Ultrasound guidance; Hepatocellular carcinoma;
Difficult location; Long-term outcome
ID PERCUTANEOUS ETHANOL INJECTION; PROGNOSTIC-FACTORS; LIVER-TUMORS;
THERMAL ABLATION; HEPATIC-TUMORS; COMPLICATIONS; RESECTION; EFFICACY;
SAFETY; METAANALYSIS
AB AIM: To investigate the treatment strategies and long-term outcomes of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) in difficult locations and to compare the results with non-difficult HCC.
METHODS: From 2004 to 2012, a total of 470 HCC patients underwent ultrasound-guided percutaneous RFA. Among these HCC patients, 382 with tumors located <= 5 mm from a major vessel/bile duct (n = 87), from peripheral important structures (n = 232) or from the liver capsule (n = 63) were regarded as difficult cases. There were 331 male patients and 51 female patients, with an average age of 55.3 +/- 10.1 years old. A total of 235 and 147 patients had Child-Pugh class A and class B liver function, respectively. The average tumor size was 3.4 +/- 1.2 cm. Individual treatment strategies were developed to treat these difficult cases. During the same period, 88 HCC patients with tumors that were not in difficult locations served as the control group. In the control group, 74 patients were male, and 14 patients were female, with an average age of 57.4 +/- 11.8 years old. Of these, 62 patients and 26 patients had Child-Pugh class A and class B liver function, respectively. Regular follow-up after RFA was performed to assess treatment efficacy. Survival results were generated from Kaplan-Meier estimates, and multivariate analysis was performed using the Cox regression model.
RESULTS: Early tumor necrosis rate in the difficult group was similar to that in the control group (97.6% vs 94.3%, P = 0.080). The complication rate in the difficult group was significantly higher than that in the control group (4.9% vs 0.8%, P = 0.041). The follow-up period ranged from 6 to 116 mo, with an average of 28 +/- 22.4 mo. Local progression rate in the difficult group was significantly higher than that in the control group (12.7% vs 7.1%, P = 0.046). However, the 1-, 3-, 5-, and 7- year overall survival rates in the difficult group were not significantly different from those in the control group (84.3%, 54.4%, 41.2%, and 29.9% vs 92.5%, 60.3%, 43.2%, and 32.8%, respectively, P = 0.371). Additionally, a multivariate analysis revealed that tumor location was not a significant risk factor for survival.
CONCLUSION: There was no significant difference in long-term overall survival between the two groups even though the local progression rate was higher in the difficult group.
C1 [Yang, Wei; Yan, Kun; Wu, Wei; Fu, Ying; Lee, Jung-Chieh; Zhang, Zhong-Yi; Wang, Song; Chen, Min-Hua] Peking Univ Canc Hosp & Inst, Minist Educ, Dept Ultrasound, Key Lab Carcinogenesis & Translat Res, Beijing 100142, Peoples R China.
[Wu, Gong-Xiong] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA.
[Wu, Gong-Xiong] Guangzhou Med Univ, Guangzhou Inst Cardiovasc Dis, Hosp Affiliated 2, Dept Cardiovasc, Guangzhou 510182, Guangdong, Peoples R China.
RP Chen, MH (reprint author), Peking Univ Canc Hosp & Inst, Minist Educ, Dept Ultrasound, Key Lab Carcinogenesis & Translat Res, 52 Fucheng Rd, Beijing 100142, Peoples R China.
EM minhuachen@vip.sina.com
OI Lee, Jung-chieh/0000-0003-0487-6897
FU National Natural Science Foundation of China [81101745]; Beijing
Municipal Health System Special Funds of High-Level Medical Personnel
Construction, [2013-3-086]; Training Program of the Health Research Plan
of the Capital Citizens [Z111107067311026]
FX Supported by National Natural Science Foundation of China, No. 81101745;
Grants from Beijing Municipal Health System Special Funds of High-Level
Medical Personnel Construction, No. 2013-3-086; and the Training Program
of the Health Research Plan of the Capital Citizens, No.
Z111107067311026.
NR 40
TC 8
Z9 8
U1 1
U2 4
PU BAISHIDENG PUBLISHING GROUP INC
PI PLEASANTON
PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA
SN 1007-9327
EI 2219-2840
J9 WORLD J GASTROENTERO
JI World J. Gastroenterol.
PD FEB 7
PY 2015
VL 21
IS 5
BP 1554
EP 1566
DI 10.3748/wjg.v21.i5.1554
PG 13
WC Gastroenterology & Hepatology
SC Gastroenterology & Hepatology
GA CB5KK
UT WOS:000349665700019
PM 25663774
ER
PT J
AU Verburg, JM
Testa, M
Seco, J
AF Verburg, Joost M.
Testa, Mauro
Seco, Joao
TI Range verification of passively scattered proton beams using prompt
gamma-ray detection
SO PHYSICS IN MEDICINE AND BIOLOGY
LA English
DT Article
DE proton therapy; passively scattered beam; range verification; prompt
gamma-ray detection
ID COMPTON CAMERA; THERAPY; SIMULATION; RADIOTHERAPY; EMISSION
AB We performed an experimental study to verify the range of passively scattered proton beams by detecting prompt gamma-rays emitted from proton-nuclear interactions. A method is proposed using a single scintillation detector positioned near the distal end of the irradiated target. Lead shielding was used to attenuate gamma-rays emitted along most of the entrance path of the beam. By synchronizing the prompt gamma-ray detector to the rotation of the range modulation wheel, the relation between the gamma emission from the distal part of the target and the range of the incident proton beam was determined. In experiments with a water phantom and an anthropomorphic head phantom, this relation was found to be sensitive to range shifts that were introduced. The wide opening angle of the detector enabled a sufficient signal-to-background ratio to be achieved in the presence of neutron-induced background from the scattering and collimating devices. Uniform range shifts were detected with a standard deviation of 0.1 mm to 0.2 mm at a dose level of 30 cGy to 50 cGy (RBE). The detectable magnitude of a range shift limited to a part of the treatment field area was approximately proportional to the ratio between the field area and the area affected by the range shift. We conclude that it is feasible to detect changes in the range of passively scattered proton beams using a relatively simple prompt gamma-ray detection system. The method can be employed for in vivo verification of the consistency of the delivered range in fractionated treatments.
C1 [Verburg, Joost M.; Testa, Mauro; Seco, Joao] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Verburg, Joost M.; Testa, Mauro; Seco, Joao] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
[Verburg, Joost M.] Eindhoven Univ Technol, Sch Med Phys & Engn, NL-5600 MB Eindhoven, Netherlands.
RP Verburg, JM (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA.
EM jverburg@fas.harvard.edu
FU Federal Share of program income earned by Massachusetts General Hospital
[C06-CA059267]; Proton Therapy Research and Treatment Center
FX The authors would like to thank E Cascio for developing the electronic
circuit to synchronize the data acquisition system with the range
modulation wheel. This work was supported by the Federal Share of
program income earned by Massachusetts General Hospital on C06-CA059267,
Proton Therapy Research and Treatment Center.
NR 18
TC 10
Z9 10
U1 1
U2 6
PU IOP PUBLISHING LTD
PI BRISTOL
PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND
SN 0031-9155
EI 1361-6560
J9 PHYS MED BIOL
JI Phys. Med. Biol.
PD FEB 7
PY 2015
VL 60
IS 3
BP 1019
EP 1029
DI 10.1088/0031-9155/60/3/1019
PG 11
WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging
SC Engineering; Radiology, Nuclear Medicine & Medical Imaging
GA CB2EB
UT WOS:000349438400012
PM 25585521
ER
PT J
AU Schwartz, SD
Regillo, CD
Lam, BL
Eliott, D
Rosenfeld, PJ
Gregori, NZ
Hubschman, JP
Davis, JL
Heilwell, G
Spirn, M
Maguire, J
Gay, R
Bateman, J
Ostrick, RM
Morris, D
Vincent, M
Anglade, E
Del Priore, LV
Lanza, R
AF Schwartz, Steven D.
Regillo, Carl D.
Lam, Byron L.
Eliott, Dean
Rosenfeld, Philip J.
Gregori, Ninel Z.
Hubschman, Jean-Pierre
Davis, Janet L.
Heilwell, Gad
Spirn, Marc
Maguire, Joseph
Gay, Roger
Bateman, Jane
Ostrick, Rosaleen M.
Morris, Debra
Vincent, Matthew
Anglade, Eddy
Del Priore, Lucian V.
Lanza, Robert
TI Human embryonic stem cell-derived retinal pigment epithelium in patients
with age-related macular degeneration and Stargardt's macular dystrophy:
follow-up of two open-label phase 1/2 studies
SO LANCET
LA English
DT Article
ID VISUAL FUNCTION QUESTIONNAIRE; RCS RATS; TRANSPLANTATION; TRANSLOCATION;
VITRECTOMY; SURGERY; NEOVASCULARIZATION; RESCUE; SAFETY
AB Background Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients.
Methods In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age > 18 years) and nine with atrophic age-related macular degeneration (age > 55 years). Three dose cohorts (50 000, 100 000, and 150 000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration).
Findings There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardt's macular dystrophy.
Interpretation The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.
C1 [Schwartz, Steven D.; Hubschman, Jean-Pierre; Heilwell, Gad; Ostrick, Rosaleen M.] Univ Calif Los Angeles, Jules Stein Eye Inst, Retina Div, Los Angeles, CA 90024 USA.
[Schwartz, Steven D.; Hubschman, Jean-Pierre; Heilwell, Gad; Ostrick, Rosaleen M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA.
[Regillo, Carl D.; Spirn, Marc; Maguire, Joseph] Thomas Jefferson Univ, Wills Eye Hosp, Philadelphia, PA 19107 USA.
[Lam, Byron L.; Gregori, Ninel Z.; Davis, Janet L.] Univ Miami, Bascom Palmer Eye Inst, Miami, FL USA.
[Eliott, Dean] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA.
[Eliott, Dean] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Gay, Roger; Bateman, Jane; Morris, Debra; Vincent, Matthew; Anglade, Eddy; Lanza, Robert] Adv Cell Technol, Marlborough, MA 01752 USA.
[Del Priore, Lucian V.] Med Univ S Carolina, Storm Eye Inst, Charleston, SC 29425 USA.
RP Lanza, R (reprint author), Adv Cell Technol, Marlborough, MA 01752 USA.
EM schwartz@jsei.ucla.edu; rlanza@advancedcell.com
FU Advanced Cell Technology
FX Advanced Cell Technology funded the study. We thank Maureen McMahon and
Jennifer Grossman for patient evaluation and follow-up; Donald Kohn,
Aisha Khan, Omaima Hanif, and Darlene Miller for good manufacturing
practice therapeutic material preparation; Tong Li, Deborah Peak, and
Judson Ratliff for their help in preparation and technical transfer of
the retinal pigment epithelium cells; and Robert Almanzor, Jennifer
Verriotto, Cristy Lage-Rodriguez, Nina Zelcer, and Logan Hitchcock for
clinical coordination and data monitoring.
NR 34
TC 183
Z9 202
U1 16
U2 90
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 7
PY 2015
VL 385
IS 9967
BP 509
EP 516
DI 10.1016/S0140-6736(14)61376-3
PG 8
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA9AV
UT WOS:000349213600029
PM 25458728
ER
PT J
AU Chrystal, JG
Glover, DL
Young, AS
Whelan, F
Austin, EL
Johnson, NK
Pollio, DE
Holt, CL
Stringfellow, E
Gordon, AJ
Kim, TA
Daigle, SG
Steward, JL
Kertesz, SG
AF Chrystal, Joya G.
Glover, Dawn L.
Young, Alexander S.
Whelan, Fiona
Austin, Erika L.
Johnson, Nancy K.
Pollio, David E.
Holt, Cheryl L.
Stringfellow, Erin
Gordon, Adam J.
Kim, Theresa A.
Daigle, Shanette G.
Steward, Jocelyn L.
Kertesz, Stefan G.
TI Experience of Primary Care among Homeless Individuals with Mental Health
Conditions
SO PLOS ONE
LA English
DT Article
ID MEDICAL-CARE; PROSPECTIVE COHORT; LOS-ANGELES; ADULTS; QUALITY; ILLNESS;
VETERANS; SERVICES; ACCESS; DETOXIFICATION
AB The delivery of primary care to homeless individuals with mental health conditions presents unique challenges. To inform healthcare improvement, we studied predictors of favorable primary care experience among homeless persons with mental health conditions treated at sites that varied in degree of homeless-specific service tailoring. This was a multi-site, survey-based comparison of primary care experiences at three mainstream primary care clinics of the Veterans Administration (VA), one homeless-tailored VA clinic, and one tailored non-VA healthcare program. Persons who accessed primary care service two or more times from July 2008 through June 2010 (N = 366) were randomly sampled. Predictor variables included patient and organization characteristics suggested by the patient perception model developed by Sofaer and Firminger (2005), with an emphasis on mental health. The primary care experience was assessed with the Primary Care Quality-Homeless (PCQ-H) questionnaire, a validated survey instrument. Multiple regression identified predictors of positive experiences (i.e. higher PCQ-H total score). Significant predictors of a positive experience included a site offering tailored service design, perceived choice among providers, and currently domiciled status. There was an interaction effect between site and severe psychiatric symptoms. For persons with severe psychiatric symptoms, a homeless-tailored service design was significantly associated with a more favorable primary care experience. For persons without severe psychiatric symptoms, this difference was not significant. This study supports the importance of tailored healthcare delivery designed for homeless persons' needs, with such services potentially holding special relevance for persons with mental health conditions. To improve patient experience among the homeless, organizations may want to deliver services that are tailored to homelessness and offer a choice of providers.
C1 [Chrystal, Joya G.; Glover, Dawn L.; Young, Alexander S.] Vet Affairs Greater Los Angeles Healthcare Syst, MIRECC, Los Angeles, CA 90073 USA.
[Young, Alexander S.; Whelan, Fiona] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA.
[Austin, Erika L.; Johnson, Nancy K.; Daigle, Shanette G.; Steward, Jocelyn L.; Kertesz, Stefan G.] Birmingham Vet Affairs Med Ctr, Ctr Surg Med Acute Care Res & Transit C SMART, Birmingham, AL USA.
[Pollio, David E.] Univ Alabama, Sch Social Work, Tuscaloosa, AL USA.
[Holt, Cheryl L.] Univ Maryland, Dept Behav & Community Hlth, College Pk, MD 20742 USA.
[Stringfellow, Erin] Boston Hlth Care Homeless Program, Boston, MA USA.
[Gordon, Adam J.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA.
[Gordon, Adam J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA.
[Kim, Theresa A.] Boston Med Ctr, Boston, MA USA.
[Kim, Theresa A.] Boston Univ, Sch Med, Boston, MA 02118 USA.
[Kertesz, Stefan G.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA.
RP Chrystal, JG (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, MIRECC, Los Angeles, CA 90073 USA.
EM Joya.Chrystal@va.gov
OI Kim, Theresa/0000-0001-6043-0721; Kertesz, Stefan/0000-0001-6101-8421
FU Department of Veterans Affairs, Health Services Research Development
[SDR-11-233, IAA-07-06902]; Desert Pacific Mental Illness Research,
Education and Clinical Center (MIRECC); United States Department of
Veterans Affairs Research and Development (RD) branch
FX Support was provided by the Department of Veterans Affairs, Health
Services Research & Development Grants SDR-11-233 and IAA-07-06902, and
the Desert Pacific Mental Illness Research, Education and Clinical
Center (MIRECC). The United States Department of Veterans Affairs
Research and Development (R&D) branch funded this project as part of its
competitive merit review program. The Department''s R&D branch functions
in a manner similar to the National Institutes of Health (USA),
assembling peer review and acting as "funder" and it has no role in
design, data collection, analysis or preparation of manuscripts. By
regulation the principal investigator must be an employee of the United
States Department of Veterans Affairs (typically within a VA Medical
Center). Applicable US federal regulations require a formal disclaimer
by the author of any VAfunded research, that underscores the separation
of the researcher from VA official views: "The views expressed in this
article are those of the authors and do not necessarily reflect the
position or policy of the Department of Veterans Affairs or the United
States government." Applicants for R&D funds include VA employees (noted
with asterisks below) who are eligible to serve as investigator.
However, the funder is VA Research and Development. J.G. Chrystal*
conceptualized this study, collected data, analyzed and interpreted
results, wrote the primary draft of results, and wrote revisions of the
article. D.L. Glover* analyzed and interpreted results, and contributed
to revisions of the article. A.S. Young* analyzed and interpreted
results, and contributed to revisions of the article. F. Whelan*
analyzed and interpreted results, and contributed to the primary draft
of the article. E.L. Austin* and N.K. Johnson* designed data collection
procedures, collected data, analyzed and interpreted results, and
contributed to the primary draft of the article. D.E. Pollio designed
data collection procedures, analyzed and interpreted results, and
contributed to the primary draft of the article. C.L. Holt
conceptualized and designed data collection procedures, analyzed and
interpreted results, and contributed to the primary draft of the
article. E. Stringfellow designed data collection procedures, collected
data, analyzed and interpreted results, and contributed to the primary
draft of the article. A. J. Gordon* and T.A. Kim conceptualized and
designed the primary study, analyzed and interpreted results, and
contributed to the primary draft of the article. S.G. Daigle* designed
data collection procedures, collected data, analyzed and interpreted
results, and contributed to the primary draft of the article. J.L.
Steward designed data collection procedures, collected data, and
analyzed and interpreted results. S.G. Kertesz* conceptualized and
designed the primary study where, designed the data collection
procedures, analyzed and interpreted results, and wrote revisions of the
article. All authors gave final approval of the article.
NR 51
TC 0
Z9 0
U1 2
U2 20
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 2015
VL 10
IS 2
AR e0117395
DI 10.1371/journal.pone.0117395
PG 14
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB2GK
UT WOS:000349444900141
PM 25659142
ER
PT J
AU Mehta, S
Williamson, CM
Ball, S
Tibbit, C
Beechey, C
Fray, M
Peters, J
AF Mehta, Stuti
Williamson, Christine M.
Ball, Simon
Tibbit, Charlotte
Beechey, Colin
Fray, Martin
Peters, Jo
TI Transcription Driven Somatic DNA Methylation within the Imprinted Gnas
Cluster
SO PLOS ONE
LA English
DT Article
ID PROTEIN ALPHA-SUBUNIT; GERM-CELL DEVELOPMENT; DE-NOVO METHYLATION;
CONTROL REGION; CHROMOSOME 2; GS-ALPHA; MOUSE; GENE; LOCUS;
IDENTIFICATION
AB Differential marking of genes in female and male gametes by DNA methylation is essential to genomic imprinting. In female gametes transcription traversing differentially methylated regions (DMRs) is a common requirement for de novo methylation at DMRs. At the imprinted Gnas cluster oocyte specific transcription of a protein-coding transcript, Nesp, is needed for methylation of two DMRs intragenic to Nesp, namely the Nespas-Gnasxl DMR and the Exon1A DMR, thereby enabling expression of the Gnas transcript and repression of the Gnasxl transcript. On the paternal allele, Nesp is repressed, the germline DMRs are unmethylated, Gnas is repressed and Gnasxl is expressed. Using mutant mouse models, we show that on the paternal allele, ectopic transcription of Nesp traversing the intragenic Exon1A DMR (which regulates Gnas expression) results in de novo methylation of the Exon1A DMR and de-repression of Gnas just as on the maternal allele. However, unlike the maternal allele, methylation on the mutant paternal allele occurs post-fertilisation, i.e. in somatic cells. This, to our knowledge is the first example of transcript/transcription driven DNA methylation of an intragenic CpG island, in somatic tissues, suggesting that transcription driven de novo methylation is not restricted to the germline in the mouse. Additionally, Gnasxl is repressed on a paternal chromosome on which Nesp is ectopically expressed. Thus, a paternally inherited Gnas cluster showing ectopic expression of Nesp is "maternalised" in terms of Gnasxl and Gnas expression. We show that these mice have a phenotype similar to mutants with two expressed doses of Gnas and none of Gnasxl.
C1 [Mehta, Stuti; Williamson, Christine M.; Ball, Simon; Tibbit, Charlotte; Beechey, Colin; Peters, Jo] MRC Harwell, Mammalian Genet Unit, Didcot OX11 0RD, Oxon, England.
[Fray, Martin] MRC Harwell, Mary Lyon Ctr, Didcot OX11 0RD, Oxon, England.
RP Mehta, S (reprint author), Massachusetts Gen Hosp, Thier 340,60 Blossom St, Boston, MA 02114 USA.
EM smehta6@mgh.harvard.edu
RI Mehta, Stuti/E-9477-2017
OI Mehta, Stuti/0000-0002-6810-6771
FU UK Medical Research Council; UK India Education and Research Initiative
FX This work was supported by the UK Medical Research Council. SM's
doctoral studies were supported by the UK India Education and Research
Initiative. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
NR 50
TC 0
Z9 1
U1 0
U2 3
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD FEB 6
PY 2015
VL 10
IS 2
AR e0117378
DI 10.1371/journal.pone.0117378
PG 20
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB2GK
UT WOS:000349444900140
PM 25659103
ER
PT J
AU Orikiriza, P
Tibenderana, B
Siedner, MJ
Mueller, Y
Byarugaba, F
Moore, CC
Evans, EE
Bonnet, M
Page, AL
Bazira, J
Boum, Y
AF Orikiriza, Patrick
Tibenderana, Becky
Siedner, Mark J.
Mueller, Yolanda
Byarugaba, Frederick
Moore, Christopher C.
Evans, Emily E.
Bonnet, Maryline
Page, Anne-Laure
Bazira, Joel
Boum, Yap, II
TI Low Resistance to First and Second Line Anti-Tuberculosis Drugs among
Treatment Naive Pulmonary Tuberculosis Patients in Southwestern Uganda
SO PLOS ONE
LA English
DT Article
ID MYCOBACTERIUM-TUBERCULOSIS
AB Background
There are limited data on region-specific drug susceptibility of tuberculosis (TB) in Uganda. We performed resistance testing on specimens collected from treatment-naive patients with pulmonary TB in Southwestern Uganda for first and second line anti-TB drugs. We sought to provide data to guide regional recommendations for empiric TB therapy.
Methods
Archived isolates, obtained from patients at Mbarara Regional Referral Hospital from February 2009 to February 2013, were tested for resistance to isoniazid and rifampicin using the MTBDRplus and Xpert MTB/RIF assays. A subset of randomly selected isolates was tested for second line agents, including fluoroquinolones (FQs), aminoglycosides, cyclic peptides, and ethambutol using the MTBDRs/assay. We performed confirmatory testing for FQ resistance using repeated MTBDRs/, the Mycobacteria growth indicator tube (MGIT) assay, and sequencing of the gyrA and gyrB genes.
Results
We tested isolates from 190 patients. The cohort had a median age of 33 years (IQR 2643), 69% (131/190) were male, and the HIV prevalence was 42% (80/190). No isolates (0/190) were rifampicin-resistant and only 1/190 (0.5%) was isoniazid-resistant. Among 92 isolates tested for second-line drug resistance, 71 (77%) had interpretable results, of which none were resistant to aminoglycosides, cyclic peptides or ethambutol. Although 7 (10%) initially tested as resistant to FQs by the MTBDRs/assay, they were confirmed as susceptible by repeat MTBDRs/testing as well as by MGIT and gyrase gene sequencing.
Conclusion
We found no MDR-TB and no resistance to ethambutol, FQs, or injectable anti-TB drugs in treatment naive patients with pulmonary TB in Southwestern Uganda. Standard treatment guidelines for susceptible TB should be adequate for most patients with TB in this population. Where possible, molecular susceptibility testing methods should be routinely validated by culture methods.
C1 [Orikiriza, Patrick; Mueller, Yolanda; Boum, Yap, II] Epictr Mbarara Res Ctr, Mbarara, Uganda.
[Orikiriza, Patrick; Byarugaba, Frederick; Bazira, Joel; Boum, Yap, II] Mbarara Univ Sci & Technol, Dept Microbiol, Mbarara, Uganda.
[Tibenderana, Becky; Moore, Christopher C.] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda.
[Siedner, Mark J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.
[Siedner, Mark J.] Harvard Univ, Sch Med, Boston, MA USA.
[Moore, Christopher C.; Evans, Emily E.] Univ Virginia, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA USA.
[Bonnet, Maryline; Page, Anne-Laure] Epictr Paris, Paris, France.
RP Boum, Y (reprint author), Epictr Mbarara Res Ctr, Mbarara, Uganda.
EM yap.boum@epicentre.msf.org
FU Office of Global AIDS Coordinator [5R24TW008886]; U.S. Department of
Health and Human Services; Health Resources and Services Administration;
National Institutes of Health; Pfizer Initiative in International
Health; Center for Global Health at the University of Virginia; Pfizer,
Inc.; National Institutes of Health [K23 MH099916]; MSF
FX This work was made possible by Medical Education for Equitable Services
to All Ugandans a Medical Education Partnership Initiative grant number
5R24TW008886 from the Office of Global AIDS Coordinator and the U.S.
Department of Health and Human Services, Health Resources and Services
Administration and National Institutes of Health. Funding for the study
was also provided in part by the Pfizer Initiative in International
Health and the Center for Global Health at the University of Virginia.
This initiative was conceived to fund global infectious disease research
and exchange programs between post-doctoral fellows and students from
the University of Virginia and several international partners to conduct
research on global health issues. The major purpose of this program is
to foster and enhance bidirectional research training. An independent
board at the University of Virginia determines which research proposals
are funded. Pfizer, Inc. provided funds to promote the Initiative but
has no role in the planning or execution of research protocols,
including the study described in the article. The funders had no role in
study design, data collection and analysis, decision to publish, or
preparation of the manuscript. MJS receives support from National
Institutes of Health K23 MH099916. Its contents are solely the
responsibility of the authors and do not necessarily represent the
official views of the government. The authors appreciate MSF for funding
the studies from which isolates were collected for this sub-study and
Uganda Research Student Support Fund (URSSF) for linking the study team.
NR 12
TC 4
Z9 4
U1 0
U2 3
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD FEB 6
PY 2015
VL 10
IS 2
AR e0118191
DI 10.1371/journal.pone.0118191
PG 5
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB2GK
UT WOS:000349444900274
PM 25658921
ER
PT J
AU Wheeler, SE
Egloff, AM
Wang, L
James, CD
Hammerman, PS
Grandis, JR
AF Wheeler, Sarah E.
Egloff, Ann Marie
Wang, Lin
James, C. David
Hammerman, Peter S.
Grandis, Jennifer R.
TI Challenges in EGFRvIII Detection in Head and Neck Squamous Cell
Carcinoma
SO PLOS ONE
LA English
DT Article
ID GROWTH-FACTOR RECEPTOR; CONFERS ENHANCED TUMORIGENICITY; FACTOR-ALPHA;
GENE-TRANSCRIPTION; KINASE INHIBITORS; BREAST-CANCER; PHASE-II;
EXPRESSION; GLIOBLASTOMA; THERAPY
AB Objective
Head and neck squamous cell carcinoma (HNSCC) accounts for more than 5% of all cancers worldwide. The mortality rate of HNSCC has remained unchanged (approximately 50%) over the last few decades. Ubiquitous overexpression of wild type EGFR in many solid tumors has led to the development of EGFR targeted therapies. EGFR can be constitutively activated via several mechanisms including the truncated, EGFR variant III isoform (EGFRvIII). EGFRvIII lacks exons 2-7 and has been reported to be present in up to 20-40% of HNSCC. EGFRvIII has been shown to contribute to cetuximab resistance. The mechanisms leading to EGFRvIII expression in HNSCC are unknown. The present investigation was undertaken to determine the etiology of EGFRvIII in HNSCC.
Materials and Methods
Fixed HNSCC and glioma tissues were analyzed by fluorescence in situ hybridization for EGFR amplification. DNA and RNA from fresh frozen specimens were used to determine the presence of EGFRvIII transcripts and the mechanisms of expression via PCR, RT-PCR and RNA sequencing.
Results
Unlike glioma, EGFRvIII expression in HNSCC did not correlate with EGFR amplification. We found evidence of genomic deletion of the exon 2-7 in 6 of 7 HNSCC cases examined, however, the presence of genomic deletion did not always result in mRNA expression of EGFRvIII. RNA sequencing with automated alignment did not identify EGFRvIII due to microhomology between intron 1 and exon 8. RNA sequencing analyzed by manual alignment methods did not correlate well with RT-PCR and PCR findings.
Conclusion
These findings suggest that genomic deletion as well as additional regulatory mechanisms may contribute to EGFRvIII expression in HNSCC. Further, large scale automated alignment of sequencing are unlikely to identify EGFRvIII and an assay specifically designed to detect EGFRvIII may be necessary to detect this altered form of EGFR in HNSCC tumors.
C1 [Wheeler, Sarah E.; Wang, Lin; Grandis, Jennifer R.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA.
[Egloff, Ann Marie; Grandis, Jennifer R.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA USA.
[Egloff, Ann Marie; Grandis, Jennifer R.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA.
[James, C. David] Northwestern Univ, Dept Neurol Surg, Chicago, IL 60611 USA.
[Hammerman, Peter S.; Grandis, Jennifer R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA USA.
[Grandis, Jennifer R.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA.
RP Grandis, JR (reprint author), Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA.
EM grandisjr@upmc.edu
FU National Institutes of Health [P50CA097190, R01CA77308]; American Cancer
Society [1F31DE020223]
FX Funding for this study was provided by the following: Grant Support:
(http://www.nih.gov/), National Institutes of Health: P50CA097190,
R01CA77308, the American Cancer Society (JRG), 1F31DE020223 (SW). The
funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
NR 41
TC 5
Z9 5
U1 1
U2 5
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD FEB 6
PY 2015
VL 10
IS 2
AR e0117781
DI 10.1371/journal.pone.0117781
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CB2GK
UT WOS:000349444900220
PM 25658924
ER
PT J
AU Elze, T
Pasquale, LR
Shen, LQ
Chen, TC
Wiggs, JL
Bex, PJ
AF Elze, Tobias
Pasquale, Louis R.
Shen, Lucy Q.
Chen, Teresa C.
Wiggs, Janey L.
Bex, Peter J.
TI Patterns of functional vision loss in glaucoma determined with
archetypal analysis
SO JOURNAL OF THE ROYAL SOCIETY INTERFACE
LA English
DT Article
DE vision loss; glaucoma; retinal nerve fibre layer
ID VISUAL-FIELD LOSS; FIBER BUNDLE TRAJECTORIES; OPEN-ANGLE GLAUCOMA;
IDENTIFY PATTERNS; CLASSIFICATION; VARIABILITY; THRESHOLD; DAMAGE;
ALGORITHMS; DEFECTS
AB Glaucoma is an optic neuropathy accompanied by vision loss which can be mapped by visual field (VF) testing revealing characteristic patterns related to the retinal nerve fibre layer anatomy. While detailed knowledge about these patterns is important to understand the anatomic and genetic aspects of glaucoma, current classification schemes are typically predominantly derived qualitatively. Here, we classify glaucomatous vision loss quantitatively by statistically learning prototypical patterns on the convex hull of the data space. In contrast to component-based approaches, this method emphasizes distinct aspects of the data and provides patterns that are easier to interpret for clinicians. Based on 13 231 reliable Humphrey VFs from a large clinical glaucoma practice, we identify an optimal solution with 17 glaucomatous vision loss prototypes which fit well with previously described qualitative patterns from a large clinical study. We illustrate relations of our patterns to retinal structure by a previously developed mathematical model. In contrast to the qualitative clinical approaches, our results can serve as a framework to quantify the various subtypes of glaucomatous visual field loss.
C1 [Elze, Tobias; Bex, Peter J.] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA.
[Elze, Tobias] Max Planck Inst Math Sci, Leipzig, Germany.
[Pasquale, Louis R.; Shen, Lucy Q.; Chen, Teresa C.; Wiggs, Janey L.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA.
[Pasquale, Louis R.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA.
RP Elze, T (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA.
EM tobias_elze@meei.harvard.edu
FU National Institutes of Health [R01 EY018664]; Harvard Glaucoma Center of
Excellence; Harvard Medical School Scholar award; Research to Prevent
Blindness Foundation in New York; American Glaucoma Society Young
Clinician Scientist Award
FX T.E. and P.B. were supported by National Institutes of Health Grant No.
R01 EY018664. L.R.P. was supported by the Harvard Glaucoma Center of
Excellence, a Harvard Medical School Scholar award and the Research to
Prevent Blindness Foundation in New York. L.Q.S. was supported by the
American Glaucoma Society Young Clinician Scientist Award, 2012. The
funders had no role in study design, data collection and analysis,
decision to publish or preparation of the manuscript.
NR 35
TC 0
Z9 0
U1 14
U2 43
PU ROYAL SOC
PI LONDON
PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND
SN 1742-5689
EI 1742-5662
J9 J R SOC INTERFACE
JI J. R. Soc. Interface
PD FEB 6
PY 2015
VL 12
IS 103
AR UNSP 20141118
DI 10.1098/rsif.2014.1118
PG 13
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA AW3BE
UT WOS:000346159500004
ER
PT J
AU Park, KK
Hosseini, A
Tsai, TY
Kwon, YM
Li, G
AF Park, Kwan Kyu
Hosseini, Ali
Tsai, Tsung-Yuan
Kwon, Young-Min
Li, Guoan
TI Elongation of the collateral ligaments after cruciate retaining total
knee arthroplasty and the maximum flexion of the knee
SO JOURNAL OF BIOMECHANICS
LA English
DT Article
DE Total knee arthroplasty; Collateral ligament; In vivo Biomechanics
ID LENGTH-CHANGE PATTERNS; FLUOROSCOPIC ANALYSIS; FEMORAL ROLLBACK;
WEIGHT-BEARING; KINEMATICS; REPLACEMENTS; EXTENSION; STRAIN; FORCES;
MOTION
AB The mechanisms that affect knee flexion after total knee arthroplasty (TKA) are still debatable. This study investigated the elongation of the superficial medial (sMCL) and lateral collateral ligaments (LCL) before and after a posterior cruciate retaining (CR) TKA. We hypothesized that overstretching of the collateral ligaments in high flexion after TKA could reduce maximal flexion of the knee. Three-dimensional models of 11 osteoarthritic knees of 11 patients including the insertions of the collateral ligaments were created using MR images. Each ligament was divided into three equal portions: anterior, middle and posterior portions. The shortest 3D wrapping length of each ligament portion was determined before and after the TKA surgery along a weight-bearing, single leg flexion path. The relationship between the changes of ligament elongation and the changes of the maximal knee flexion after TKAs was quantitatively analyzed. The sMCL showed significant increases in length only at low flexion after TKA; the LCL showed decreases in length at full extension, but increases with further flexion after TKA. The amount of increases of the maximum flexion angle after TKA was negatively correlated with the increases of the elongations of the anterior portion (p=0.010, r=0.733) and middle portion (p=0.049, r=0.604) of the sMCL as well as the anterior portion (p=0.010, r=0.733) of the LCL at maximal flexion of the knee. The results indicated that the increases of the length of the collateral ligaments at maximal flexion after TKA were associated with the decreases of the maximal flexion of the knee. Our data suggest that collateral ligament management should also be evaluated at higher knee flexion angles in order to optimize maximal flexion of the knee after TKAs. (C) 2014 Elsevier Ltd. All rights reserved.
C1 [Park, Kwan Kyu; Hosseini, Ali; Tsai, Tsung-Yuan; Kwon, Young-Min; Li, Guoan] Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA.
[Park, Kwan Kyu; Hosseini, Ali; Tsai, Tsung-Yuan; Kwon, Young-Min; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Park, Kwan Kyu] Yonsei Univ, Coll Med, Dept Orthoped Surg, Seoul 120749, South Korea.
RP Li, G (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA.
EM kkpark@yuhs.ac; ahosseini@partners.org; ttsai1@partners.org;
ymkwon@partners.org; gli1@partners.org
OI Tsai, Tsung-Yuan/0000-0003-1522-2987
NR 49
TC 1
Z9 1
U1 1
U2 1
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0021-9290
EI 1873-2380
J9 J BIOMECH
JI J. Biomech.
PD FEB 5
PY 2015
VL 48
IS 3
BP 418
EP 424
DI 10.1016/j.jbiomech.2014.12.036
PG 7
WC Biophysics; Engineering, Biomedical
SC Biophysics; Engineering
GA CB4GP
UT WOS:000349586500003
PM 25555307
ER
PT J
AU Maier, R
Moser, G
Chen, GB
Ripke, S
Coryell, W
Potash, JB
Scheftner, WA
Shi, JX
Weissman, MM
Hultman, CM
Landen, M
Levinson, DF
Kendler, KS
Smoller, JW
Wray, NR
Lee, SH
AF Maier, Robert
Moser, Gerhard
Chen, Guo-Bo
Ripke, Stephan
Coryell, William
Potash, James B.
Scheftner, William A.
Shi, Jianxin
Weissman, Myrna M.
Hultman, Christina M.
Landen, Mikael
Levinson, Douglas F.
Kendler, Kenneth S.
Smoller, Jordan W.
Wray, Naomi R.
Lee, S. Hong
CA Psychiat Genomics Consortium
TI Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk
Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive
Disorder
SO AMERICAN JOURNAL OF HUMAN GENETICS
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; RESTRICTED MAXIMUM-LIKELIHOOD; AVERAGE
INFORMATION; GENETIC RISK; LOCI; SELECTION; TRAITS; MODELS;
IDENTIFICATION; POPULATION
AB Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk.
C1 [Maier, Robert; Moser, Gerhard; Chen, Guo-Bo; Wray, Naomi R.; Lee, S. Hong] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia.
[Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
[Coryell, William; Potash, James B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA.
[Scheftner, William A.] Rush Univ, Dept Psychiat, Med Ctr, Chicago, IL 60612 USA.
[Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
[Weissman, Myrna M.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA.
[Weissman, Myrna M.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA.
[Hultman, Christina M.; Landen, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.
[Landen, Mikael] Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, S-41345 Gothenburg, Sweden.
[Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA.
[Kendler, Kenneth S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA.
[Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA.
RP Lee, SH (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia.
EM hong.lee@uq.edu.au
RI Collier, David/D-1649-2011; Zhang, Peng/N-2920-2014; Mattheisen,
Manuel/B-4949-2012; Breen, Gerome/A-5540-2010; Wray, Naomi/C-8639-2015;
Scherer, Stephen /B-3785-2013; Lee, Sang Hong/A-2569-2011; Kuntsi,
Jonna/G-9750-2011; Franke, Barbara/D-4836-2009; Moser,
Gerhard/H-7054-2012; Melle, Ingrid /B-4858-2011; Schumacher,
Johannes/F-4970-2015; Ruderfer, Douglas/M-5795-2016; Hansen, Thomas
Folkmann/O-5965-2014; Lohoff, Falk/M-7951-2016; BELLIVIER,
FRANK/H-5197-2012; McQuillin, Andrew/C-1623-2008; Lesch,
Klaus-Peter/J-4906-2013;
OI Collier, David/0000-0003-4087-1559; Zhang, Peng/0000-0003-1182-1392;
Mattheisen, Manuel/0000-0002-8442-493X; Breen,
Gerome/0000-0003-2053-1792; Wray, Naomi/0000-0001-7421-3357; Scherer,
Stephen /0000-0002-8326-1999; Lee, Sang Hong/0000-0001-9701-2718;
Franke, Barbara/0000-0003-4375-6572; Moser, Gerhard/0000-0003-3104-5730;
Melle, Ingrid /0000-0002-9783-548X; Schumacher,
Johannes/0000-0001-9217-6457; Ruderfer, Douglas/0000-0002-2365-386X;
Jamain, Stephane/0000-0002-4321-4100; Weissman,
Myrna/0000-0003-3490-3075; Hansen, Thomas Folkmann/0000-0001-6703-7762;
Kent, Lindsey/0000-0002-5315-3399; Anney, Richard/0000-0002-6083-407X;
Bruggeman, Richard/0000-0002-3238-8471; Nothen,
Markus/0000-0002-8770-2464; Donohoe, Gary/0000-0003-3037-7426; Oliveira,
Guiomar/0000-0002-7049-1277; Yu, Timothy/0000-0003-2988-7701; Thapar,
Anita/0000-0002-3689-737X; Etain, Bruno/0000-0002-5377-1488; de Geus,
Eco/0000-0001-6022-2666; Chen, Guo-Bo/0000-0001-5475-8237; Cormand,
Bru/0000-0001-5318-4382; Betancur, Catalina/0000-0002-3327-4804;
McQuillin, Andrew/0000-0003-1567-2240; Lesch,
Klaus-Peter/0000-0001-8348-153X; Bergen, Sarah/0000-0002-5888-0034;
Backlund, Lena/0000-0001-9399-5024; Zammit, Stanley/0000-0002-2647-9211;
McMahon, Francis/0000-0002-9469-305X; Hamilton,
Steven/0000-0001-8106-6260; Gallagher, Louise/0000-0001-9462-2836;
Tozzi, Federica/0000-0002-3536-2920; Myin-Germeys,
Inez/0000-0002-3731-4930
FU Australian Research Council [FT0991360, DE130100614]; National Health
and Medical Research Council [613608, 1011506, 1047956, 1080157];
National Institute of Mental Health (NIMH) [U01 MH085520]; Stanley
Center for Psychiatric Research; Sylvan Herman Foundation; Karolinska
Institutet, Karolinska University Hospital; Swedish Research Council;
Stockholm County Council; Soderstrom Konigska Foundation; Netherlands
Scientific Organization [NWO 645-000-003]; Netherlands Scientific
Organization (NOW) [480-05-003]; NIMH R01 [MH061686, MH059542, MH075131,
MH059552, MH059541, MH060912]; [NIMH R01 MH077139]
FX This study was supported by the Australian Research Council (FT0991360
and DE130100614) and the National Health and Medical Research Council
(613608, 1011506, 1047956, and 1080157). The Psychiatric Genomics
Consortium is supported by National Institute of Mental Health (NIMH)
grant U01 MH085520. We acknowledge the funding that supported the
Swedish schizophrenia study (NIMH R01 MH077139), the Stanley Center for
Psychiatric Research, the Sylvan Herman Foundation, the Karolinska
Institutet, Karolinska University Hospital, the Swedish Research
Council, the Stockholm County Council, the Soderstrom Konigska
Foundation, and the Netherlands Scientific Organization (NWO
645-000-003). Statistical analyses were carried out on the Genetic
Cluster Computer, which is financially supported by the Netherlands
Scientific Organization (NOW; 480-05-003). The GenRED GWAS project was
supported by NIMH R01 grants MH061686 (D.F.L.), MH059542 (W.C.),
MH075131 (W.B. Lawson), MH059552 (J.B.P.), MH059541 (W.A.S.), and
MH060912 (M.M.W.).
NR 45
TC 38
Z9 38
U1 6
U2 43
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 0002-9297
EI 1537-6605
J9 AM J HUM GENET
JI Am. J. Hum. Genet.
PD FEB 5
PY 2015
VL 96
IS 2
BP 283
EP 294
DI 10.1016/j.ajhg.2014.12.006
PG 12
WC Genetics & Heredity
SC Genetics & Heredity
GA CA9WY
UT WOS:000349276700010
PM 25640677
ER
PT J
AU Pardo-Saganta, A
Law, BM
Tata, PR
Villoria, J
Saez, B
Mou, HM
Zhao, R
Rajagopal, J
AF Pardo-Saganta, Ana
Law, Brandon M.
Tata, Purushothama Rao
Villoria, Jorge
Saez, Borja
Mou, Hongmei
Zhao, Rui
Rajagopal, Jayaraj
TI Injury Induces Direct Lineage Segregation of Functionally Distinct
Airway Basal Stem/Progenitor Cell Subpopulations
SO CELL STEM CELL
LA English
DT Article
ID STEM-CELLS; IN-VIVO; CILIATED CELLS; EPITHELIAL-CELLS; LUNG DEVELOPMENT;
MIND BOMB-1; NOTCH; REPAIR; DIFFERENTIATION; REGENERATION
AB Following injury, stem cells restore normal tissue architecture by producing the proper number and proportions of differentiated cells. Current models of airway epithelial regeneration propose that distinct cytokeratin 8-expressing progenitor cells, arising from p63(+) basal stem cells, subsequently differentiate into secretory and ciliated cell lineages. We now show that immediately following injury, discrete subpopulations of p63(+) airway basal stem/progenitor cells themselves express Notch pathway components associated with either secretory or ciliated cell fate commitment. One basal cell population displays intracellular Notch2 activation and directly generates secretory cells; the other expresses c-myb and directly yields ciliated cells. Furthermore, disrupting Notch ligand activity within the basal cell population at large disrupts the normal pattern of lineage segregation. These non-cell-autonomous effects demonstrate that effective airway epithelial regeneration requires intercellular communication within the broader basal stem/progenitor cell population. These findings have broad implications for understanding epithelial regeneration and stem cell heterogeneity.
C1 [Pardo-Saganta, Ana; Law, Brandon M.; Tata, Purushothama Rao; Villoria, Jorge; Saez, Borja; Mou, Hongmei; Zhao, Rui; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.
[Pardo-Saganta, Ana; Law, Brandon M.; Tata, Purushothama Rao; Villoria, Jorge; Mou, Hongmei; Zhao, Rui; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Dept Internal Med, Pulm & Crit Care Unit, Boston, MA 02114 USA.
[Pardo-Saganta, Ana; Law, Brandon M.; Tata, Purushothama Rao; Villoria, Jorge; Mou, Hongmei; Zhao, Rui; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Dept Pediat, Pulm & Crit Care Unit, Boston, MA 02114 USA.
[Pardo-Saganta, Ana; Law, Brandon M.; Tata, Purushothama Rao; Villoria, Jorge; Saez, Borja; Mou, Hongmei; Zhao, Rui; Rajagopal, Jayaraj] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
RP Rajagopal, J (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.
EM jrajagopal@mgh.harvard.edu
FU New York Stem Cell Foundation; NIH-NHLBI Early Career Research New
Faculty (P30) award [5P30HL101287-02]; NIH/NHLBI [R01HL118185]; Harvard
Stem Cell Institute Junior Investigator Grant
FX We thank Adam Glick for providing the CK5rtTA mice, Brigid Hogan for
providing Mib1 floxed mice (originally from Young-Yun Kong who kindly
offered to share the mice), and Ben Z. Stanger for providing the RBPJk
floxed mice. We also thank Barry Stripp for providing the goat
anti-SCGB1A1 antibody and Joseph Pearlberg for providing the lentiviral
donor vectors. We wish to extend our thanks to all of the members of the
Rajagopal Laboratory for their constructive criticisms and comments and
for valuable discussion and support. This research was supported by the
New York Stem Cell Foundation (J.R. is a New York Stem Cell
Foundation-Robertson Investigator), by an NIH-NHLBI Early Career
Research New Faculty (P30) award (5P30HL101287-02), an R01 (R01HL118185)
from NIH/NHLBI (to J.R.), and a Harvard Stem Cell Institute Junior
Investigator Grant (to J.R.).
NR 33
TC 23
Z9 23
U1 0
U2 11
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 1934-5909
EI 1875-9777
J9 CELL STEM CELL
JI Cell Stem Cell
PD FEB 5
PY 2015
VL 16
IS 2
BP 184
EP 197
DI 10.1016/j.stem.2015.01.002
PG 14
WC Cell & Tissue Engineering; Cell Biology
SC Cell Biology
GA CB2KC
UT WOS:000349455000014
PM 25658372
ER
PT J
AU Davidovich, C
Wang, XY
Cifuentes-Rojas, C
Goodrich, KJ
Gooding, AR
Lee, JT
Cech, TR
AF Davidovich, Chen
Wang, Xueyin
Cifuentes-Rojas, Catherine
Goodrich, Karen J.
Gooding, Anne R.
Lee, Jeannie T.
Cech, Thomas R.
TI Toward a Consensus on the Binding Specificity and Promiscuity of PRC2
for RNA
SO MOLECULAR CELL
LA English
DT Article
ID MOBILITY-SHIFT ASSAY; REPRESSIVE COMPLEX 2; XIST RNA; RESPONSE ELEMENT;
X-CHROMOSOME; COAT PROTEIN; POLYCOMB; RECOGNITION; SITE
AB Polycomb repressive complex-2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer. Early works suggested binding specificity of PRC2 to certain long non-coding RNAs for recruitment to chromatin. More recent studies provided evidence both in favor and against this idea. Here, we bridge the two existing models of PRC2-RNA interaction. RepA RNA is a good binding partner for PRC2, while multiple non-relevant RNAs, including bacterial mRNAs, also bind PRC2; K(d)s depend to some extent on the experimental conditions. Human and mouse PRC2 have broadly similar RNA-binding properties in vitro. Examination of evidence supporting an existing model for site-specific recruitment of PRC2 by a well-defined RNA motif in cells reveals that results are PRC2 independent. We conclude that promiscuous and specific RNA-binding activities of PRC2 in vitro are not mutually exclusive, and that binding specificity in vivo remains to be demonstrated.
C1 [Davidovich, Chen; Wang, Xueyin; Goodrich, Karen J.; Gooding, Anne R.; Cech, Thomas R.] Univ Colorado, BioFrontiers Inst, Dept Chem & Biochem, Howard Hughes Med Inst, Boulder, CO 80309 USA.
[Cifuentes-Rojas, Catherine; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA.
[Cifuentes-Rojas, Catherine; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
RP Lee, JT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA.
EM lee@molbio.mgh.harvard.edu; thomas.cech@colorado.edu
FU [NIH-F32-GM101828]; [NIH-R01-GM090278]
FX We thank Dr. Richard Jenner for providing luciferase reporter plasmids
and for open discussions to resolve the differences in our results.
C.C.-R. is supported by NIH-F32-GM101828 and J.T.L. by NIH-R01-GM090278.
T.R.C. and J.T.L. are investigators of the Howard Hughes Medical
Institute.
NR 32
TC 49
Z9 49
U1 1
U2 15
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 5
PY 2015
VL 57
IS 3
BP 552
EP 558
DI 10.1016/j.molcel.2014.12.017
PG 7
WC Biochemistry & Molecular Biology; Cell Biology
SC Biochemistry & Molecular Biology; Cell Biology
GA CB3TD
UT WOS:000349550700016
PM 25601759
ER
PT J
AU Xu, WX
Goldberg, SI
Shubina, M
Turchin, A
AF Xu, Wenxin
Goldberg, Saveli I.
Shubina, Maria
Turchin, Alexander
TI Optimal systolic blood pressure target, time to intensification, and
time to follow-up in treatment of hypertension: population based
retrospective cohort study
SO BMJ-BRITISH MEDICAL JOURNAL
LA English
DT Article
ID DIABETES-MELLITUS; BONFERRONI PROCEDURE; ENCOUNTER FREQUENCY; MULTIPLE
TESTS; RISK-FACTORS; VALIDATION; TRIAL; DATABASE; METAANALYSIS;
PREDICTORS
AB OBJECTIVES
To investigate the optimal systolic blood pressure goal above which new antihypertensive medications should be added or doses of existing medications increased ("systolic intensification threshold") and to determine the relation between delays in medication intensification and follow-up and the risk of cardiovascular events or death.
DESIGN
Retrospective cohort study.
SETTING
Primary care practices in the United Kingdom, 1986-2010.
PARTICIPANTS
88 756 adults with hypertension from The Health Improvement Network nationwide primary care research database.
MAIN OUTCOME MEASURES
Rates of acute cardiovascular events or death from any cause for patients with different hypertension treatment strategies (defined by systolic intensification threshold, time to intensification, and time to follow-up over the course of a 10 year treatment strategy assessment period) after adjustment for age, sex, smoking status, socioeconomic deprivation, history of diabetes, cardiovascular disease or chronic kidney disease, Charlson comorbidity index, body mass index, medication possession ratio, and baseline blood pressure.
RESULTS
During a median follow-up of 37.4 months after the treatment strategy assessment period, 9985 (11.3%) participants had an acute cardiovascular event or died. No difference in risk of the outcome was seen between systolic intensification thresholds of 130-150 mm Hg, whereas systolic intensification thresholds greater than 150 mm Hg were associated with progressively greater risk (hazard ratio 1.21, 95% confidence interval 1.13 to 1.30; P < 0.001 for intensification threshold of 160 mm Hg). Outcome risk increased progressively from the lowest (0-1.4 months) to the highest fifth of time to medication intensification (hazard ratio 1.12, 1.05 to 1.20; P = 0.009 for intensification between 1.4 and 4.7 months after detection of elevated blood pressure). The highest fifth of time to follow-up (> 2.7 months) was also associated with increased outcome risk (hazard ratio 1.18, 1.11 to 1.25; P < 0.001).
CONCLUSIONS
Systolic intensification thresholds higher than 150 mm Hg, delays of greater than 1.4 months before medication intensification after systolic blood pressure elevation, and delays of greater than 2.7 months before blood pressure follow-up after antihypertensive medication intensification were associated with increased risk of an acute cardiovascular event or death. These findings support the importance of timely medical management and follow-up in the treatment of patients with hypertension.
C1 [Xu, Wenxin] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA.
[Goldberg, Saveli I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
[Shubina, Maria; Turchin, Alexander] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA.
RP Turchin, A (reprint author), Brigham & Womens Hosp, Div Endocrinol, 221 Longwood Ave, Boston, MA 02115 USA.
EM aturchin@partners.org
RI Paul, Sanjoy/F-8199-2010
OI Paul, Sanjoy/0000-0003-0848-7194
FU Harvard Medical School Center for Primary Care
FX This study was funded by the Harvard Medical School Center for Primary
Care. This organization had no role in the study design; in the
collection, analysis, and interpretation of data; in the writing of the
report; or in the decision to submit the article for publication. All
researchers acted independently of funders.
NR 48
TC 23
Z9 23
U1 2
U2 9
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 5
PY 2015
VL 350
AR h158
DI 10.1136/bmj.h158
PG 9
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB0JX
UT WOS:000349313100001
PM 25655523
ER
PT J
AU Morinelli, TA
Walker, LP
Velez, JCQ
Ullian, ME
AF Morinelli, Thomas A.
Walker, Linda P.
Velez, Juan Carlos Q.
Ullian, Michael E.
TI Clathrin-dependent internalization of the angiotensin II AT(1A) receptor
links receptor internalization to COX-2 protein expression in rat aortic
vascular smooth muscle cells
SO EUROPEAN JOURNAL OF PHARMACOLOGY
LA English
DT Article
DE Angiotensin II; AT(1A) receptor; NF-kappa B; Cyclooxygenase 2;
Clathrin-mediated endocytosis; Vascular smooth muscle cells
ID ARRESTIN-BIASED LIGAND; BETA-ARRESTIN; NUCLEAR ACCUMULATION;
SIGNAL-TRANSDUCTION; COUPLED RECEPTORS; HEART-FAILURE; ACTIVATION;
ENDOCYTOSIS; TRV120027
AB The major effects of Angiutensin II (AngII) in vascular tissue are mediated by AngII AT(1A) receptor activation. Certain effects initiated by AT(1A) receptor activation require receptor internalization. In rat aortic vascular smooth muscle cells (RASMC). AngII stimulates cyclooxygenase 2 protein expression. We have previously shown this is mediated by beta-arrestin-dependent receptor internalization and NF-kappa B activation. In this study, a specific inhibitor of clathrin-mediated endocytosis (CME), pitstop-2, was used to test the hypothesis that clathrin-dependent internalization or activated AT(1A) receptor mediates NF-kappa B activation and subsequent cyclooxygenase 2 expression. Radioligand binding assays, real time qt-PCR and immunoblotting were used to document the effects of pitstop-2 on AngII binding and signaling in RASMC. Laser scanning confocal microscopy (LSCM) was used to image pitstop-2's effects on AT(1) receptor/GFP internalization in HEK-293 cells and p65 NF-kappa B nuclear localization in RASMC.
Pitstop-2 significantly inhibited internalization of AT(1A) receptor (44.7% +/- 3.1% Control vs. 13.2% perpendicular to 8.3% Pitstop-2; n=3) as determined by radioligand binding studies in RASMC. Studies utilizing AT(1A) receptor/GFP expressed in HEK 293 cells and LSCM confirmed these findings. Pitstop-2 significantly inhibited AngII-induced p65 NE-kappa B phosphorylation and nuclear localization, COX-2 message and protein expression in RASMC without altering activation of p42/44 ERK or TNF alpha signaling.
Pitstop-2, a specific inhibitor of clathrin-mediated endocytosis, confirms that internalization of activated AT(1A) receptor mediates AngII activation of cyclooxygenase 2 expression in RASMC. These data provide support for additional intracellular signaling pathways activated through beta-arrestin mediated internalization of G protein-coupled receptors, such as AT(1A) receptors. (C) 2014 Elsevier By. All rights reserved,
C1 [Morinelli, Thomas A.; Walker, Linda P.; Velez, Juan Carlos Q.; Ullian, Michael E.] Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA.
[Velez, Juan Carlos Q.; Ullian, Michael E.] Ralph H Johnson VA Med Ctr, Charleston, SC USA.
RP Morinelli, TA (reprint author), Med Univ S Carolina, Dept Med, Div Nephrol, 96 Jonathan Lucas St,MSC 629, Charleston, SC 29425 USA.
EM morinelt@musc.edu
RI Velez, Juan Carlos/N-3782-2016
FU Dialysis Clinic, Incorporated [C-3175]
FX This project was supported by funds provided by Dialysis Clinic,
Incorporated (#C-3175). The technical assistance of Jessalyn L. Rodgers
is gratefully acknowledged.
NR 26
TC 1
Z9 1
U1 0
U2 9
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0014-2999
EI 1879-0712
J9 EUR J PHARMACOL
JI Eur. J. Pharmacol.
PD FEB 5
PY 2015
VL 748
BP 143
EP 148
DI 10.1016/j.ejphar.2014.12.018
PG 6
WC Pharmacology & Pharmacy
SC Pharmacology & Pharmacy
GA CA3YH
UT WOS:000348840500018
PM 25542758
ER
PT J
AU Do, R
Stitziel, NO
Won, HH
Jorgensen, AB
Duga, S
Merlini, PA
Kiezun, A
Farrall, M
Goel, A
Zuk, O
Guella, I
Asselta, R
Lange, LA
Peloso, GM
Auer, PL
Girelli, D
Martinelli, N
Farlow, DN
DePristo, MA
Roberts, R
Stewart, AFR
Saleheen, D
Danesh, J
Epstein, SE
Sivapalaratnam, S
Hovingh, GK
Kastelein, JJ
Samani, NJ
Schunkert, H
Erdmann, J
Shah, SH
Kraus, WE
Davies, R
Nikpay, M
Johansen, CT
Wang, J
Hegele, RA
Hechter, E
Marz, W
Kleber, ME
Huang, J
Johnson, AD
Li, MY
Burke, GL
Gross, M
Liu, YM
Assimes, TL
Heiss, G
Lange, EM
Folsom, AR
Taylor, HA
Olivieri, O
Hamsten, A
Clarke, R
Reilly, DF
Yin, W
Rivas, MA
Donnelly, P
Rossouw, JE
Psaty, BM
Herrington, DM
Wilson, JG
Rich, SS
Bamshad, MJ
Tracy, RP
Cupples, LA
Rader, DJ
Reilly, MP
Spertus, JA
Cresci, S
Hartiala, J
Tang, WHW
Hazen, SL
Allayee, H
Reiner, AP
Carlson, CS
Kooperberg, C
Jackson, RD
Boerwinkle, E
Lander, ES
Schwartz, SM
Siscovick, DS
McPherson, R
Tybjaerg-Hansen, A
Abecasis, GR
Watkins, H
Nickerson, DA
Ardissino, D
Sunyaev, SR
O'Donnell, CJ
Altshuler, D
Gabriel, S
Kathiresan, S
AF Do, Ron
Stitziel, Nathan O.
Won, Hong-Hee
Jorgensen, Anders Berg
Duga, Stefano
Merlini, Pier Angelica
Kiezun, Adam
Farrall, Martin
Goel, Anuj
Zuk, Or
Guella, Illaria
Asselta, Rosanna
Lange, Leslie A.
Peloso, Gina M.
Auer, Paul L.
Girelli, Domenico
Martinelli, Nicola
Farlow, Deborah N.
DePristo, Mark A.
Roberts, Robert
Stewart, Alexander F. R.
Saleheen, Danish
Danesh, John
Epstein, Stephen E.
Sivapalaratnam, Suthesh
Hovingh, G. Kees
Kastelein, John J.
Samani, Nilesh J.
Schunkert, Heribert
Erdmann, Jeanette
Shah, Svati H.
Kraus, William E.
Davies, Robert
Nikpay, Majid
Johansen, Christopher T.
Wang, Jian
Hegele, Robert A.
Hechter, Eliana
Marz, Winfried
Kleber, Marcus E.
Huang, Jie
Johnson, Andrew D.
Li, Mingyao
Burke, Greg L.
Gross, Myron
Liu, Yongmei
Assimes, Themistocles L.
Heiss, Gerardo
Lange, Ethan M.
Folsom, Aaron R.
Taylor, Herman A.
Olivieri, Oliviero
Hamsten, Anders
Clarke, Robert
Reilly, Dermot F.
Yin, Wu
Rivas, Manuel A.
Donnelly, Peter
Rossouw, Jacques E.
Psaty, Bruce M.
Herrington, David M.
Wilson, James G.
Rich, Stephen S.
Bamshad, Michael J.
Tracy, Russell P.
Cupples, L. Adrienne
Rader, Daniel J.
Reilly, Muredach P.
Spertus, John A.
Cresci, Sharon
Hartiala, Jaana
Tang, W. H. Wilson
Hazen, Stanley L.
Allayee, Hooman
Reiner, Alex P.
Carlson, Christopher S.
Kooperberg, Charles
Jackson, Rebecca D.
Boerwinkle, Eric
Lander, Eric S.
Schwartz, Stephen M.
Siscovick, David S.
McPherson, Ruth
Tybjaerg-Hansen, Anne
Abecasis, Goncalo R.
Watkins, Hugh
Nickerson, Deborah A.
Ardissino, Diego
Sunyaev, Shamil R.
O'Donnell, Christopher J.
Altshuler, David
Gabriel, Stacey
Kathiresan, Sekar
CA NHLBI Exome Sequencing Project
TI Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk
for myocardial infarction
SO NATURE
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; SINGLE NUCLEOTIDE
POLYMORPHISMS; OF-FUNCTION MUTATIONS; HEART-DISEASE; RECEPTOR; VARIANTS;
HYPERCHOLESTEROLEMIA; TRIGLYCERIDES; CHOLESTEROL
AB Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance(1,2). When MI occurs early in life, genetic inheritance is a major component to risk(1). Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk inindividual families(3-8), whereas common variants at more than 45 loci have been associated with MI risk in the population(9-15). Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (<= 50 years inmales and <= 60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol(16). Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase(15,17) and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
C1 [Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.
[Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
[Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA.
[Do, Ron; Won, Hong-Hee; Kiezun, Adam; Zuk, Or; Peloso, Gina M.; Farlow, Deborah N.; DePristo, Mark A.; Hechter, Eliana; Folsom, Aaron R.; Lander, Eric S.; Sunyaev, Shamil R.; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Cambridge Ctr 7, Program Med & Populat Genet, Cambridge, MA 02142 USA.
[Stitziel, Nathan O.; Cresci, Sharon] Washington Univ, Div Cardiovasc, Dept Med, Sch Med, St Louis, MO 63110 USA.
[Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63110 USA.
[Jorgensen, Anders Berg; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Mol Genet Sect, Dept Clin Biochem KB3011, DK-1165 Copenhagen, Denmark.
[Jorgensen, Anders Berg; Tybjaerg-Hansen, Anne] Univ Copenhagen, Fac Hlth Sci, DK-1165 Copenhagen, Denmark.
[Duga, Stefano; Guella, Illaria; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, I-20122 Milan, Italy.
[Merlini, Pier Angelica] Osped Niguarda Ca Granda, Div Cardiol, I-20162 Milan, Italy.
[Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford OX1 2J, England.
[Lange, Leslie A.; Lange, Ethan M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
[Auer, Paul L.; Folsom, Aaron R.; Reiner, Alex P.; Carlson, Christopher S.; Kooperberg, Charles; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.
[Girelli, Domenico; Martinelli, Nicola; Olivieri, Oliviero] Univ Verona, Dept Med, Sch Med, I-37129 Verona, Italy.
[Roberts, Robert; Stewart, Alexander F. R.] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON K1Y 4W7, Canada.
[Saleheen, Danish; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England.
[Epstein, Stephen E.] MedStar Hlth Res Inst, Cardiovasc Res Inst, Hyattsville, MD 20782 USA.
[Sivapalaratnam, Suthesh; Hovingh, G. Kees; Kastelein, John J.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands.
[Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.
[Samani, Nilesh J.] Glenfield Gen Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England.
[Schunkert, Heribert] Tech Univ Munich, DZHK German Res Ctr Cardiovasc Res, Munich Heart Alliance, Deutsch Herzzentrum Munchen, D-13347 Berlin, Germany.
[Erdmann, Jeanette] Med Univ Lubeck, Med Klin 2, D-23562 Lubeck, Germany.
[Shah, Svati H.] Duke Univ, Ctr Human Genet, Durham, NC 27708 USA.
[Shah, Svati H.; Kraus, William E.] Duke Univ, Sch Med, Dept Cardiol, Durham, NC 27708 USA.
[Shah, Svati H.; Kraus, William E.] Duke Univ, Sch Med, Ctr Genom Med, Durham, NC 27708 USA.
[Davies, Robert; Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON K1Y 4W7, Canada.
[Johansen, Christopher T.; Wang, Jian; Hegele, Robert A.] Univ Western Ontario, Dept Biochem, Schulich Sch Med & Dent, Robarts Res Inst, London, ON N6A 3K7, Canada.
[Hegele, Robert A.] Univ Western Ontario, Dept Med, Schulich Sch Med & Dent, Robarts Res Inst, London, ON N6A 3K7, Canada.
[Marz, Winfried; Kleber, Marcus E.] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, D-68167 Mannheim, Germany.
[Marz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria.
[Marz, Winfried] Synlab Acad, D-68259 Mannheim, Germany.
[Huang, Jie; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.
[Johnson, Andrew D.] NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA 01702 USA.
[Li, Mingyao] Univ Penn, Dept Biostat & Epidemiol, Sch Med, Philadelphia, PA 19104 USA.
[Burke, Greg L.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35233 USA.
[Gross, Myron] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA.
[Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27106 USA.
[Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
[Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA.
[Lange, Ethan M.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA.
[Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA.
[Taylor, Herman A.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA.
[Hamsten, Anders] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, S-17177 Stockholm, Sweden.
[Hamsten, Anders] Karolinska Inst, Ctr Mol Med, S-17177 Stockholm, Sweden.
[Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford OX1 2JD, England.
[Clarke, Robert] Univ Oxford, Epidemiol Studies Unit, Oxford OX1 2JD, England.
[Reilly, Dermot F.; Yin, Wu] Merck Sharp & Dohme Corp, Rahway, NJ 08889 USA.
[Rivas, Manuel A.; Donnelly, Peter; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England.
[Donnelly, Peter] Univ Oxford, Dept Stat, Oxford OX1 2JD, England.
[Rossouw, Jacques E.] NHLBI, Bethesda, MD 20824 USA.
[Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA.
[Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA.
[Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA.
[Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA.
[Herrington, David M.] Wake Forest Sch Med, Sect Cardiol & Publ Hlth Sci, Winston Salem, NC 27106 USA.
[Wilson, James G.] Jackson State Univ, Med Ctr, Univ Mississippi, Jackson Heart Study, Jackson, MS 39217 USA.
[Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22904 USA.
[Bamshad, Michael J.] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA 98195 USA.
[Bamshad, Michael J.] Seattle Childrens Hosp, Seattle, WA 98105 USA.
[Bamshad, Michael J.; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
[Tracy, Russell P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA.
[Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.
[Rader, Daniel J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA.
[Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA.
[Spertus, John A.] Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA.
[Cresci, Sharon] Washington Univ, Dept Genet, St Louis, MO 63130 USA.
[Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA.
[Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA.
[Tang, W. H. Wilson; Hazen, Stanley L.] Cleveland Clin, Cleveland, OH 44195 USA.
[Reiner, Alex P.; Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.
[Jackson, Rebecca D.] Ohio State Univ, Columbus, OH 43210 USA.
[Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA.
[Siscovick, David S.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA.
[Tybjaerg-Hansen, Anne] Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen N, Denmark.
[Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MO 48109 USA.
[Ardissino, Diego] Parma Hosp, Dept Cardiol, I-43100 Parma, Italy.
[Sunyaev, Shamil R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA.
RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.
EM skathiresan@partners.org
RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; de Bakker,
Paul/B-8730-2009; Hegele, Robert/G-3301-2011; Martinelli,
Nicola/J-5622-2016; Johnson, Andrew/G-6520-2013; Erdmann,
Jeanette/P-7513-2014;
OI Turner, Emily/0000-0001-9040-9229; de Bakker, Paul/0000-0001-7735-7858;
Martinelli, Nicola/0000-0001-6465-5119; Erdmann,
Jeanette/0000-0002-4486-6231; Stewart, Alexandre/0000-0003-2673-9164;
Asselta, Rosanna/0000-0001-5351-0619; Seshadri,
Sudha/0000-0001-6135-2622; Stitziel, Nathan/0000-0002-4963-8211; Duga,
Stefano/0000-0003-3457-1410; Watkins, Hugh/0000-0002-5287-9016; Assimes,
Themistocles/0000-0003-2349-0009; Kleber, Marcus/0000-0003-0663-7275
FU National Heart, Lung, and Blood Institute (NHLBI); National Human Genome
Research Institute (NHGRI) of the US National Institutes of Health
(NIH); NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2
HL-102925, RC2 HL-102926, T32HL007604, T32HL007208]; NHGRI
[5U54HG003067-11]; NIH [P01 HL076491, P01 HL098055]; Massachusetts
General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan
Family Foundation [R01HL107816]; Fondation Leducq; Canadian Institutes
of Health Research; NIH/NHLBI [K08HL114642]; Foundation for
Barnes-Jewish Hospital; [RFPS-2007-3-644382]
FX The authors wish to acknowledge the support of the National Heart, Lung,
and Blood Institute (NHLBI) and the National Human Genome Research
Institute (NHGRI) of the US National Institutes of Health (NIH) and the
contributions of the research institutions, study investigators, field
staff and study participants in creating this resource for biomedical
research. Funding for the exome sequencing project (ESP) was provided by
NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2
HL-102924 (WHISP). Exome sequencing was performed through NHLBI grants
RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Exome sequencing
in the ATVB, PROCARDIS, and Ottawa studies was supported by NHGRI
5U54HG003067-11 to E.S.L. and S.G. Cleveland Clinic GeneBank was
supported by NIH grants P01 HL076491 and P01 HL098055. S.K. is supported
by a Research Scholar award from the Massachusetts General Hospital
(MGH), the Howard Goodman Fellowship from MGH, the Donovan Family
Foundation, R01HL107816, and a grant from Fondation Leducq. R.D. is
supported by a Banting Fellowship from the Canadian Institutes of Health
Research. N.O.S. is supported, in part, by a career development award
from the NIH/NHLBI K08HL114642 and by The Foundation for Barnes-Jewish
Hospital. N.O.S. was supported by award number T32HL007604 from the
NHLBI. G.M.P was supported by award number T32HL007208 from the NHLBI.
The content is solely the responsibility of the authors and does not
necessarily represent the official views of the NHLBI, NHGRI, or NIH.
The Italian ATVB Study was supported by a grant from RFPS-2007-3-644382.
A full listing of acknowledgements is provided in the Supplementary
Information.
NR 48
TC 90
Z9 91
U1 6
U2 42
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 5
PY 2015
VL 518
IS 7537
BP 102
EP +
DI 10.1038/nature13917
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7LE
UT WOS:000349098000040
PM 25487149
ER
PT J
AU Olson, KR
AF Olson, Kristian R.
TI Case 36-2014: A Woman with Fever, Pharyngitis, and Double Vision Reply
SO NEW ENGLAND JOURNAL OF MEDICINE
LA English
DT Letter
C1 Massachusetts Gen Hosp, Boston, MA 02114 USA.
RP Olson, KR (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.
EM krolson@partners.org
NR 3
TC 1
Z9 1
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 5
PY 2015
VL 372
IS 6
BP 581
EP 582
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA8CH
UT WOS:000349143600030
PM 25651266
ER
PT J
AU Valdez, IA
Teo, AKK
Kulkarni, RN
AF Valdez, Ivan A.
Teo, Adrian K. K.
Kulkarni, Rohit N.
TI Cellular stress drives pancreatic plasticity
SO SCIENCE TRANSLATIONAL MEDICINE
LA English
DT Article
ID INSULIN-SECRETING CELLS; ADULT-MOUSE PANCREAS; BETA-CELLS; DUCT
LIGATION; GROWTH-FACTOR; ACINAR-CELLS; RAT PANCREAS; ALPHA-CELLS;
IN-VITRO; DIFFERENTIATION
AB Controversy has long surrounded research on pancreatic beta cell regeneration. Some groups have used nonphysiological experimental methodologies to build support for the existence of pancreatic progenitor cells within the adult pancreas that constantly replenish the beta cell pool; others argue strongly against this mode of regeneration. Recent research has reinvigorated enthusiasm for the harnessing of pancreatic plasticity for therapeutic application-for example, the transdifferentiation of human pancreatic exocrine cells into insulin-secreting beta-like cells in vitro; the conversion of mouse pancreatic acinar cells to beta-like cells in vivo via cytokine treatment; and the potential redifferentiation of dedifferentiated mouse beta cells in vivo. Here, we highlight key findings in this provocative field and provide a perspective on possible exploitation of human pancreatic plasticity for therapeutic beta cell regeneration.
C1 [Valdez, Ivan A.; Teo, Adrian K. K.; Kulkarni, Rohit N.] Brigham & Womens Hosp, Dept Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA.
[Valdez, Ivan A.; Teo, Adrian K. K.; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Boston, MA 02215 USA.
[Valdez, Ivan A.] Harvard Univ, Grad Sch Arts & Sci, Program Biol & Biomed Sci, Dept Cell Biol, Cambridge, MA 02138 USA.
RP Teo, AKK (reprint author), Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore.
EM ateo@imcb.a-star.edu.sg; rohit.kulkarni@joslin.harvard.edu
RI Teo, Adrian/A-4009-2013
OI Teo, Adrian/0000-0001-5901-7075
FU U.S. National Institutes of Health (NIH) [F31DK098931]; Juvenile
Diabetes Research Foundation [3-2013-236]; HSCI [SG-0078-12-00]; NIH
[RO1 DK 67536, RO1 DK 103215, RO1 DK 055523]; AstraZeneca
FX A.V. is supported by a U.S. National Institutes of Health (NIH)
F31DK098931 award. A.K.K.T. is supported by Juvenile Diabetes Research
Foundation postdoctoral fellowship 3-2013-236 and currently by the
Institute of Molecular and Cell Biology (IMCB), A*STAR. R.N.K. is
supported by HSCI award SG-0078-12-00; NIH grants RO1 DK 67536, RO1 DK
103215, and RO1 DK 055523; and a grant from AstraZeneca.
NR 56
TC 4
Z9 4
U1 0
U2 4
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 4
PY 2015
VL 7
IS 273
AR 273ps2
DI 10.1126/scitranslmed.3010577
PG 5
WC Cell Biology; Medicine, Research & Experimental
SC Cell Biology; Research & Experimental Medicine
GA CB5XI
UT WOS:000349700900005
PM 25653218
ER
PT J
AU Sacchet, MD
LaPlante, RA
Wan, Q
Pritchett, DL
Lee, AKC
Hamalainen, M
Moore, CI
Kerr, CE
Jones, SR
AF Sacchet, Matthew D.
LaPlante, Roan A.
Wan, Qian
Pritchett, Dominique L.
Lee, Adrian K. C.
Haemaelaeinen, Matti
Moore, Christopher I.
Kerr, Catherine E.
Jones, Stephanie R.
TI Attention Drives Synchronization of Alpha and Beta Rhythms between Right
Inferior Frontal and Primary Sensory Neocortex
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
DE attention; inferior frontal cortex; magnetoencephalography; primary
somatosensory cortex; somatosensation; synchrony
ID PRIMARY SOMATOSENSORY CORTEX; VENTROLATERAL PREFRONTAL CORTEX;
VISUAL-SPATIAL ATTENTION; HUMAN CEREBRAL-CORTEX; COGNITIVE CONTROL; MU
RHYTHM; SURFACE RECONSTRUCTION; RESPONSE-INHIBITION; BAND OSCILLATIONS;
EVOKED-RESPONSES
AB The right inferior frontal cortex (rIFC) is specifically associated with attentional control via the inhibition of behaviorally irrelevant stimuli and motor responses. Similarly, recent evidence has shown that alpha (7-14 Hz) and beta (15-29 Hz) oscillations in primary sensory neocortical areas are enhanced in the representation of non-attended stimuli, leading to the hypothesis that allocation of these rhythms plays an active role in optimal inattention. Here, we tested the hypothesis that selective synchronization between rIFC and primary sensory neocortex occurs in these frequency bands during inattention. We used magnetoencephalography to investigate phase synchrony between primary somatosensory (SI) and rIFC regions during a cued-attention tactile detection task that required suppression of response to uncertain distractor stimuli. Attentional modulation of synchrony between SI and rIFC was found in both the alpha and beta frequency bands. This synchrony manifested as an increase in the alpha-band early after cue between non-attended SI representations and rIFC, and as a subsequent increase in beta-band synchrony closer to stimulus processing. Differences in phase synchrony were not found in several proximal control regions. These results are the first to reveal distinct interactions between primary sensory cortex and rIFC in humans and suggest that synchrony between rIFC and primary sensory representations plays a role in the inhibition of irrelevant sensory stimuli and motor responses.
C1 [Sacchet, Matthew D.] Stanford Univ, Sch Med, Neurosci Program, Stanford, CA USA.
[Sacchet, Matthew D.] Stanford Univ, Dept Psychol, Stanford, CA USA.
[LaPlante, Roan A.; Haemaelaeinen, Matti; Jones, Stephanie R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA.
[Wan, Qian] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA.
[Pritchett, Dominique L.] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA.
[Lee, Adrian K. C.] Univ Washington, Inst Learning & Brain Sci, Seattle, WA 98195 USA.
[Lee, Adrian K. C.] Univ Washington, Dept Speech & Hearing Sci, Seattle, WA 98195 USA.
[Moore, Christopher I.; Jones, Stephanie R.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA.
[Moore, Christopher I.; Jones, Stephanie R.] Brown Univ, Brown Inst Brain Sci, Providence, RI 02912 USA.
[Kerr, Catherine E.] Brown Alpert Med Sch, Dept Family Med, Providence, RI 02912 USA.
RP Jones, SR (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA.
EM Stephanie_Jones@brown.edu
OI Pritchett, Dominique/0000-0003-1187-1162
FU National Institutes of Health [P41RR14075, K25MH072941, K01AT003459,
K24AT004095, RO1-NS045130-01, T32GM007484]; National Science Foundation
[0316933, GRFP DGE-1147470]
FX This work was supported by National Institutes of Health Grants
P41RR14075, K25MH072941, K01AT003459, K24AT004095, RO1-NS045130-01, and
T32GM007484, and National Science Foundation Grants 0316933 and GRFP
DGE-1147470. We thank David Badre and Michael Frank for help in shaping
the scientific direction of the work; Tim Buschman for insight with
regard to phase analyses; and Daniel Wakeman for contributions to
inverse methods.
NR 81
TC 11
Z9 11
U1 0
U2 10
PU SOC NEUROSCIENCE
PI WASHINGTON
PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA
SN 0270-6474
J9 J NEUROSCI
JI J. Neurosci.
PD FEB 4
PY 2015
VL 35
IS 5
BP 2074
EP 2082
DI 10.1523/JNEUROSCI.1292-14.2015
PG 9
WC Neurosciences
SC Neurosciences & Neurology
GA CB5MI
UT WOS:000349671100022
PM 25653364
ER
PT J
AU Rao, VR
Lim, LE
Fong, D
Garga, NI
Parko, KL
AF Rao, Vikram R.
Lim, Leland E.
Fong, Dean
Garga, Nina I.
Parko, Karen L.
TI Multicentric Castleman's disease with voltage-gated potassium channel
antibody-positive limbic encephalitis: a case report
SO BMC NEUROLOGY
LA English
DT Article
DE Castleman's disease; Lymphoproliferative; Limbic encephalitis;
Voltage-gated potassium channel; VGKC; Paraneoplastic; Seizure
AB Background: Castleman's disease is a rare lymphoproliferative disorder which occurs in localized and multicentric forms and can mimic lymphoma. Despite its well-known association with certain autoimmune diseases, including paraneoplastic pemphigus and myasthenia gravis, Castleman's disease has not previously been associated with limbic encephalitis.
Case presentation: We report the case of a 47-year old Caucasian man who presented with subacute onset of constitutional symptoms, diffuse lymphadenopathy, and stereotyped spells involving olfactory aura, nausea, disorientation, and unresponsiveness. He was found to have focal dyscognitive seizures of temporal lobe origin, cerebrospinal fluid with lymphocytic pleocytosis, hyponatremia, and serum positive for voltage-gated potassium channel antibodies, consistent with limbic encephalitis. An extensive infectious workup was unrevealing, but lymph node biopsy revealed multicentric Castleman's disease. His symptoms improved with antiepileptic drugs and immunotherapy.
Conclusion: This case highlights the clinical diversity of voltage-gated potassium channel autoimmunity and expands the association of Castleman's disease and autoimmune syndromes to include limbic encephalitis. Clinicians should be aware that paraneoplastic disorders of the central nervous system can be related to underlying hematologic disorders such as Castleman's disease.
C1 [Rao, Vikram R.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA.
[Lim, Leland E.] Palo Alto Hlth Care Syst, Dept Vet Affairs, Neurol Serv, Palo Alto, CA 94304 USA.
[Lim, Leland E.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.
[Fong, Dean] Palo Alto Hlth Care Syst 113, Dept Vet Affairs, Pathol & Lab Med Serv, Palo Alto, CA 94304 USA.
[Garga, Nina I.; Parko, Karen L.] San Francisco VA Med Ctr, Epilepsy Ctr Excellence, San Francisco, CA 94121 USA.
RP Rao, VR (reprint author), Univ Calif San Francisco, Dept Neurol, 400 Parnassus Ave,8th Floor, San Francisco, CA 94143 USA.
EM vikram.rao@ucsf.edu
NR 17
TC 0
Z9 0
U1 0
U2 3
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2377
J9 BMC NEUROL
JI BMC Neurol.
PD FEB 4
PY 2015
VL 15
AR 4
DI 10.1186/s12883-015-0266-8
PG 5
WC Clinical Neurology
SC Neurosciences & Neurology
GA CB0YA
UT WOS:000349352400001
PM 25648431
ER
PT J
AU Orsola, A
Werner, L
de Torres, I
Martin-Doyle, W
Raventos, CX
Lozano, F
Mullane, SA
Leow, JJ
Barletta, JA
Bellmunt, J
Morote, J
AF Orsola, A.
Werner, L.
de Torres, I.
Martin-Doyle, W.
Raventos, C. X.
Lozano, F.
Mullane, S. A.
Leow, J. J.
Barletta, J. A.
Bellmunt, J.
Morote, J.
TI Reexamining treatment of high-grade T1 bladder cancer according to depth
of lamina propria invasion: a prospective trial of 200 patients
SO BRITISH JOURNAL OF CANCER
LA English
DT Article
DE high risk bladder cancer; HGT1; substaging; reTUR; prognosis
ID TRANSITIONAL-CELL CARCINOMA; RESTAGING TRANSURETHRAL RESECTION;
BACILLUS-CALMETTE-GUERIN; EORTC RISK TABLES; UROTHELIAL CARCINOMA;
PROGNOSTIC-SIGNIFICANCE; IN-SITU; PROGRESSION; TUMOR; RECURRENCE
AB Background: Management of high-grade T1 (HGT1) bladder cancer represents a major challenge. We studied a treatment strategy according to substaging by depth of lamina propria invasion.
Methods: In this prospective observational cohort study, patients received initial transurethral resection (TUR), mitomycin-C, and BCG. Subjects with shallower lamina propria invasion (HGT1a) were followed without further surgery, whereas subjects with HGT1b received a second TUR. Association of clinical and histological features with outcomes (primary: progression; secondary: recurrence and cancer-specific survival) was assessed using Cox regression.
Results: Median age was 71 years; 89.5% were males, with 89 (44.5%) cases T1a and 111 (55.5%) T1b. At median follow-up of 71 months, disease progression was observed in 31 (15.5%) and in univariate analysis, substaging, carcinoma in situ, tumour size, and tumour pattern predicted progression. On multivariate analysis only substaging, associated carcinoma in situ, and tumour size remained significant for progression.
Conclusions: In HGT1 bladder cancer, the strategy of performing a second TUR only in T1b cases results in a global low progression rate of 15.5%. Tumours deeply invading the lamina propria (HGT1b) showed a three-fold increase in risk of progression. Substaging should be routinely evaluated, with HGT1b cases being thoroughly evaluated for cystectomy. Inclusion in the TNM system should also be carefully considered.
C1 [Orsola, A.; Mullane, S. A.; Bellmunt, J.; Morote, J.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Hosp, Dept Oncol,Canc Ctr, Boston, MA 02215 USA.
[Werner, L.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Hosp, Dept Oncol,Canc Ctr, Boston, MA 02215 USA.
[de Torres, I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02215 USA.
[Werner, L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02215 USA.
[de Torres, I.] Vall Hebron Hosp, Dept Pathol, Barcelona 08035, Spain.
[Martin-Doyle, W.] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA.
[Raventos, C. X.; Lozano, F.] Vall Hebron Hosp, Dept Urol, Barcelona 08035, Spain.
[Leow, J. J.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02215 USA.
[Leow, J. J.] Brigham & Womens Hosp, Div Urol, Boston, MA 02215 USA.
[Barletta, J. A.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Hosp Canc Ctr, Dept Pathol, Boston, MA 02215 USA.
RP Orsola, A (reprint author), Harvard Univ, Sch Med, Dana Farber Brigham & Womens Hosp, Dept Oncol,Canc Ctr, Boston, MA 02215 USA.
EM annaorsola@gmail.com
NR 34
TC 7
Z9 7
U1 0
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 3
PY 2015
VL 112
IS 3
BP 468
EP 474
DI 10.1038/bjc.2014.633
PG 7
WC Oncology
SC Oncology
GA CB1QP
UT WOS:000349403200009
PM 25535728
ER
PT J
AU Cheng, VWT
Piragasam, RS
Rothery, RA
Maklashina, E
Cecchini, G
Weiner, JH
AF Cheng, Victor W. T.
Piragasam, Ramanaguru Siva
Rothery, Richard A.
Maklashina, Elena
Cecchini, Gary
Weiner, Joel H.
TI Redox State of Flavin Adenine Dinucleotide Drives Substrate Binding and
Product Release in Escherichia coli Succinate Dehydrogenase
SO BIOCHEMISTRY
LA English
DT Article
ID COVALENTLY BOUND FLAVIN; QUINOL-FUMARATE REDUCTASE;
SHEWANELLA-FRIGIDIMARINA NCIMB400; WOLINELLA-SUCCINOGENES QUINOL;
VANILLYL-ALCOHOL OXIDASE; IRON-SULFUR CLUSTERS; COMPLEX-II; RESPIRATORY
COMPLEX; ELECTRON-TRANSFER; ACTIVE-SITE
AB The Complex II family of enzymes, comprising respiratory succinate dehydrogenases and fumarate reductases, catalyzes reversible interconversion of succinate and fumarate. In contrast to the covalent flavin adenine dinucleotide (FAD) cofactor assembled in these enzymes, soluble fumarate reductases (e.g., those from Shewanella frigidimarina) that assemble a noncovalent FAD cannot catalyze succinate oxidation but retain the ability to reduce fumarate. In this study, an SdhA-H45A variant that eliminates the site of the 8 alpha-N3-histidyl covalent linkage between the protein and FAD was examined. Variants SdhA-R286A/K/Y and -H242A/Y that target residues thought to be important for substrate binding and catalysis were also studied. The variants SdhA-H45A and -R286A/K/Y resulted in the assembly of a noncovalent FAD cofactor, which led to a significant decrease (-87 mV or more) in its reduction potential. The variant enzymes were studied by electron paramagnetic resonance spectroscopy following stand-alone reduction and potentiometric titrations. The free and occupied states of the active site were linked to the reduced and oxidized states of FAD, respectively. Our data allow for a proposed model of succinate oxidation that is consistent with tunnel diode effects observed in the succinate dehydrogenase enzyme and a preference for fumarate reduction catalysis in fumarate reductase homologues that assemble a noncovalent FAD.
C1 [Cheng, Victor W. T.; Piragasam, Ramanaguru Siva; Rothery, Richard A.; Weiner, Joel H.] Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada.
[Maklashina, Elena; Cecchini, Gary] San Francisco VA Med Ctr, Div Mol Biol, San Francisco, CA 94121 USA.
[Maklashina, Elena; Cecchini, Gary] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
RP Weiner, JH (reprint author), Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada.
EM joel.weiner@UAlberta.ca
FU Canadian Institutes of Health Research [MDP98735]; Department of
Veterans Affairs [BX001077]; National Institutes of Health [GM61606]
FX This work was supported by the Canadian Institutes of Health Research
(Grant MDP98735 to J.H.W.), the Department of Veterans Affairs (Merit
Grant BX001077 to G.C.), and the National Institutes of Health (Grant
GM61606 to G.C.).
NR 68
TC 4
Z9 4
U1 1
U2 28
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 3
PY 2015
VL 54
IS 4
BP 1043
EP 1052
DI 10.1021/bi501350j
PG 10
WC Biochemistry & Molecular Biology
SC Biochemistry & Molecular Biology
GA CA6WZ
UT WOS:000349059400009
PM 25569225
ER
PT J
AU Varraso, R
Chiuve, SE
Fung, TT
Barr, RG
Hu, FB
Willett, WC
Camargo, CA
AF Varraso, Raphaelle
Chiuve, Stephanie E.
Fung, Teresa T.
Barr, R. Graham
Hu, Frank B.
Willett, Walter C.
Camargo, Carlos A.
TI Alternate Healthy Eating Index 2010 and risk of chronic obstructive
pulmonary disease among US women and men: prospective study
SO BMJ-BRITISH MEDICAL JOURNAL
LA English
DT Article
ID CURED MEAT CONSUMPTION; DIETARY PATTERNS; LUNG-FUNCTION; COPD;
MORTALITY; QUALITY; VALIDATION; OUTCOMES; CHINESE; CANCER
AB OBJECTIVE
To investigate the association between the Alternate Healthy Eating Index 2010 (AHEI-2010)-a measure of diet quality-and the risk of chronic obstructive pulmonary disease (COPD).
DESIGN
Prospective cohort study.
SETTING
Participants in the Nurses' Health Study and the Health Professionals Follow-up Study, United States.
PARTICIPANTS
73 228 female nurses from 1984 to 2000 and 47 026 men from 1986 to 1998, who completed biennial questionnaires.
MAIN OUTCOME MEASURES
The primary outcome was the self report of newly diagnosed COPD. Multivariable Cox proportional hazards models were adjusted for age, physical activity, body mass index, total energy intake, smoking, second hand tobacco exposure (only in the Nurses' Health Study), race/ethnicity, physician visits, US region, spouse's highest educational attainment (only in the Nurses' Health Study), and menopausal status (only in the Nurses' Health Study).
RESULTS
Over the study period, 723 cases of newly diagnosed COPD occurred in women and 167 in men. In the pooled analysis, a significant negative association was seen between the risk of newly diagnosed COPD and fifths of the AHEI-2010: hazard ratios were 0.81 (95% confidence interval 0.51 to 1.29) for the second fifth, 0.98 (0.80 to 1.18) for the third fifth, 0.74 (0.59 to 0.92) for the fourth fifth, and 0.67 (0.53 to 0.85) for participants who ate the healthiest diet according to the AHEI-2010 (that is, were in the highest fifth), compared with those who ate the less healthy diet (participants in the lowest fifth). Similar findings were observed among ex-smokers and current smokers.
CONCLUSIONS
A higher AHEI-2010 diet score (reflecting high intakes of whole grains, polyunsaturated fatty acids, nuts, and long chain omega-3 fats and low intakes of red/processed meats, refined grains, and sugar sweetened drinks) was associated with a lower risk of COPD in both women and men. These findings support the importance of a healthy diet in multi-interventional programs to prevent COPD.
C1 [Varraso, Raphaelle] INSERM, U1168, VIMA Aging & Chron Dis Epidemiol & Publ Hlth Appr, F-94807 Villejuif, France.
[Varraso, Raphaelle] Univ Versailles St Quentin En Yvelines, UMR S 1168, UVSQ, Versailles, France.
[Chiuve, Stephanie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02215 USA.
[Chiuve, Stephanie E.] Harvard Univ, Sch Med, Boston, MA 02215 USA.
[Chiuve, Stephanie E.; Fung, Teresa T.; Hu, Frank B.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
[Fung, Teresa T.] Simmons Coll, Dept Nutr, Boston, MA 02115 USA.
[Barr, R. Graham] Columbia Univ, Div Gen Med, Dept Med, Med Ctr, New York, NY 10032 USA.
[Barr, R. Graham] Columbia Univ, Dept Epidemiol, Med Ctr, New York, NY 10032 USA.
[Hu, Frank B.; Willett, Walter C.; Camargo, Carlos A.] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA.
[Hu, Frank B.; Willett, Walter C.; Camargo, Carlos A.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
[Hu, Frank B.; Willett, Walter C.; Camargo, Carlos A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
[Camargo, Carlos A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA.
RP Varraso, R (reprint author), INSERM, U1168, VIMA Aging & Chron Dis Epidemiol & Publ Hlth Appr, 16 Ave Paul Vaillant Couturier, F-94807 Villejuif, France.
EM raphaelle.varraso@inserm.fr
RI Varraso, Raphaelle/R-8740-2016
OI Varraso, Raphaelle/0000-0002-3338-7825
FU National Institutes of Health (Bethesda, MD, USA) [CA-87969, CA-167552,
HL-63841, AI-52338]
FX This study was supported by grants CA-87969, CA-167552, HL-63841, and
AI-52338 from the National Institutes of Health (Bethesda, MD, USA). The
design, conduct, and reporting were entirely the responsibility of the
authors, independent from funders.
NR 34
TC 9
Z9 9
U1 3
U2 6
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 3
PY 2015
VL 350
AR h286
DI 10.1136/bmj.h286
PG 11
WC Medicine, General & Internal
SC General & Internal Medicine
GA CB0IL
UT WOS:000349309100003
PM 25649042
ER
PT J
AU Platt, C
Houstis, N
Rosenzweig, A
AF Platt, Colin
Houstis, Nicholas
Rosenzweig, Anthony
TI Using Exercise to Measure and Modify Cardiac Function
SO CELL METABOLISM
LA English
DT Review
ID GROWTH-FACTOR-I; CHRONIC HEART-FAILURE; RANDOMIZED CONTROLLED-TRIALS;
PROLONGED AEROBIC EXERCISE; CRITICAL POWER; MYOCARDIAL-INFARCTION;
ENDURANCE EXERCISE; BLOOD-FLOW; RAT-HEART; MICE
AB Exercise is the archetype of physiologic demands placed on the cardiovascular system. Acute responses provide an informative assessment of cardiovascular function and fitness, while repeated exercise promotes cardiovascular health and evokes important molecular, structural, and functional changes contributing to its effects in primary and secondary prevention. Here we examine the use of exercise in murine models, both as a phenotypic assay and as a provocative intervention. We first review the advantages and limitations of exercise testing for assessing cardiac function, then highlight the cardiac structural and cellular changes elicited by chronic exercise and key molecular pathways that mediate these effects.
C1 [Platt, Colin; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA.
[Platt, Colin; Rosenzweig, Anthony] Harvard Univ, Sch Med, Boston, MA 02215 USA.
[Houstis, Nicholas; Rosenzweig, Anthony] Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02115 USA.
[Houstis, Nicholas; Rosenzweig, Anthony] Harvard Univ, Sch Med, Boston, MA 02115 USA.
RP Rosenzweig, A (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave, Boston, MA 02215 USA.
EM arosenzweig@partners.org
FU NIH [R01HL110733, R01HL122987, T32HL073734, T32GM007226]; LaDue
Fellowship Award from Harvard Medical School
FX This work was supported by grants from the NIH (AR[R01HL110733,
R01HL122987], XL[T32HL073734], and CP[T32GM007226]). N.H. was supported
by a LaDue Fellowship Award from Harvard Medical School. A.R. is a
principal faculty member of the Harvard Stem Cell Institute.
NR 100
TC 6
Z9 6
U1 0
U2 11
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 3
PY 2015
VL 21
IS 2
BP 227
EP 236
DI 10.1016/j.cmet.2015.01.014
PG 10
WC Cell Biology; Endocrinology & Metabolism
SC Cell Biology; Endocrinology & Metabolism
GA CB1IT
UT WOS:000349381400012
PM 25651177
ER
PT J
AU Parks, BW
Sallam, T
Mehrabian, M
Psychogios, N
Hui, ST
Norheim, F
Castellani, LW
Rau, CD
Pan, C
Phun, J
Zhou, ZQ
Yang, WP
Neuhaus, I
Gargalovic, PS
Kirchgessner, TG
Graham, M
Lee, R
Tontonoz, P
Gerszten, RE
Hevener, AL
Lusis, AJ
AF Parks, Brian W.
Sallam, Tamer
Mehrabian, Margarete
Psychogios, Nikolas
Hui, Simon T.
Norheim, Frode
Castellani, Lawrence W.
Rau, Christoph D.
Pan, Calvin
Phun, Jennifer
Zhou, Zhenqi
Yang, Wen-Pin
Neuhaus, Isaac
Gargalovic, Peter S.
Kirchgessner, Todd G.
Graham, Mark
Lee, Richard
Tontonoz, Peter
Gerszten, Robert E.
Hevener, Andrea L.
Lusis, Aldons J.
TI Genetic Architecture of Insulin Resistance in the Mouse
SO CELL METABOLISM
LA English
DT Article
ID GENOME-WIDE ASSOCIATION; GLUCOSE-HOMEOSTASIS; CARDIOVASCULAR-DISEASE;
METABOLIC SYNDROME; SKELETAL-MUSCLE; SENSITIVITY; MICE; RISK; LOCI;
OBESITY
AB Insulin resistance (IR) is a complex trait with multiple genetic and environmental components. Confounded by large differences between the sexes, environment, and disease pathology, the genetic basis of IR has been difficult to dissect. Here we examine IR and related traits in a diverse population of more than 100 unique male and female inbred mouse strains after feeding a diet rich in fat and refined carbohydrates. Our results show dramatic variation in IR among strains of mice and widespread differences between sexes that are dependent on genotype. We uncover more than 15 genome-wide significant loci and validate a gene, Agpat5, associated with IR. We also integrate plasma metabolite levels and global gene expression from liver and adipose tissue to identify metabolite quantitative trait loci (mQTL) and expression QTL (eQTL), respectively. Our results provide a resource for analysis of interactions between diet, sex, and genetic background in IR.
C1 [Parks, Brian W.; Sallam, Tamer; Mehrabian, Margarete; Hui, Simon T.; Castellani, Lawrence W.; Rau, Christoph D.; Lusis, Aldons J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA.
[Parks, Brian W.; Rau, Christoph D.; Pan, Calvin; Lusis, Aldons J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA.
[Parks, Brian W.; Lusis, Aldons J.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA.
[Sallam, Tamer; Tontonoz, Peter] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA.
[Psychogios, Nikolas; Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA.
[Psychogios, Nikolas; Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA.
[Norheim, Frode] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Fac Med, N-0317 Oslo, Norway.
[Phun, Jennifer; Zhou, Zhenqi; Hevener, Andrea L.] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA.
[Yang, Wen-Pin; Neuhaus, Isaac] Bristol Myers Squibb Co, Dept Appl Genom, Princeton, NJ 08543 USA.
[Gargalovic, Peter S.; Kirchgessner, Todd G.] Bristol Myers Squibb Co, Dept Cardiovasc Drug Discovery, Princeton, NJ 08543 USA.
[Graham, Mark; Lee, Richard] ISIS Pharmaceut, Carlsbad, CA 92008 USA.
[Tontonoz, Peter] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA.
RP Parks, BW (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA.
EM bparks@mednet.ucla.edu; jlusis@mednet.ucla.edu
OI Psychogios, Nikolaos/0000-0002-2747-6012; Sallam,
Tamer/0000-0001-7144-7393
FU NIH [HL28481, HD07228, HL123021, HL69766, DK063491, DK-HL081572,
DK06349, DK089109]; American Heart Association Fellowship
[13POST17080115]; Howard Hughes Medical Institute; Established
Investigator Award from the American Heart Association; UCLA Iris Cantor
Women's Health Foundation
FX This work was supported by an NIH grant to A.J.L. (HL28481). B.W.P. was
supported in part by an NIH training grant (HD07228) and an NIH Pathway
to Independence Award (HL123021). T.S. was supported by an American
Heart Association Fellowship (13POST17080115). C.D.R. was supported by
an NIH training grant (HL69766). P.T. is supported by the Howard Hughes
Medical Institute and NIH (DK063491). R.E.G. is supported by NIH
(DK-HL081572) and an Established Investigator Award from the American
Heart Association. A.L.H. is supported by the NIH (DK06349 and DK089109)
and the UCLA Iris Cantor Women's Health Foundation. Z.Z., W.-P.Y., I.N.,
P.S.G., and T.G.K. are employees and shareholders of Bristol-Myers
Squibb. M.G. and R.L. are employees and shareholders of Isis
Pharmaceuticals.
NR 50
TC 15
Z9 15
U1 1
U2 15
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 3
PY 2015
VL 21
IS 2
BP 334
EP 346
DI 10.1016/j.cmet.2015.01.002
PG 13
WC Cell Biology; Endocrinology & Metabolism
SC Cell Biology; Endocrinology & Metabolism
GA CB1IT
UT WOS:000349381400021
PM 25651185
ER
PT J
AU Shireman, PK
Rasmussen, TE
Jaramillo, CA
Pugh, MJ
AF Shireman, Paula K.
Rasmussen, Todd E.
Jaramillo, Carlos A.
Pugh, Mary Jo
TI VA Vascular Injury Study (VAVIS): VA-DoD extremity injury outcomes
collaboration
SO BMC SURGERY
LA English
DT Article
DE Extremity vascular injury; Limb salvage; Outcomes; Transitions of care;
Service members; Veterans; Iraq; Afghanistan
ID POPLITEAL ARTERY TRAUMA; ASSESSMENT PROJECT LEAP; DEPRESSIVE SYMPTOMS;
CHALLENGING INJURY; BYPASS-SURGERY; MEDICAL-CARE; GLOBAL WAR;
AMPUTATION; VETERANS; STATINS
AB Background: Limb injuries comprise 50-60% of U.S. Service member's casualties of wars in Afghanistan and Iraq. Combat-related vascular injuries are present in 12% of this cohort, a rate 5 times higher than in prior wars. Improvements in medical and surgical trauma care, including initial in-theatre limb salvage approaches (IILS) have resulted in improved survival and fewer amputations, however, the long-term outcomes such as morbidity, functional decline, and risk for late amputation of salvaged limbs using current process of care have not been studied. The long-term care of these injured warfighters poses a significant challenge to the Department of Defense (DoD) and Department of Veterans Affairs (VA).
Methods/Design: The VA Vascular Injury Study (VAVIS): VA-DoD Extremity Injury Outcomes Collaborative, funded by the VA, Health Services Research and Development Service, is a longitudinal cohort study of Veterans with vascular extremity injuries. Enrollment will begin April, 2015 and continue for 3 years. Individuals with a validated extremity vascular injury in the Department of Defense Trauma Registry will be contacted and will complete a set of validated demographic, social, behavioral, and functional status measures during interview and online/mailed survey. Primary outcome measures will: 1) Compare injury, demographic and geospatial characteristics of patients with IILS and identify late vascular surgery related limb complications and health care utilization in Veterans receiving VA vs. non-VA care, 2) Characterize the preventive services received by individuals with vascular repair and related outcomes, and 3) Describe patient-reported functional outcomes in Veterans with traumatic vascular limb injuries.
Discussion: This study will provide key information about the current process of care for Active Duty Service members and Veterans with polytrauma/vascular injuries at risk for persistent morbidity and late amputation. The results of this study will be the first step for clinicians in VA and military settings to generate evidence-based treatment and care approaches to these injuries. It will identify areas where rehabilitation medicine and vascular specialty care or telehealth options are needed to allow for better planning, resource utilization, and improved DoD-to-VA care transitions.
C1 [Shireman, Paula K.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, Sam & Ann Barshop Inst Longev & Aging Studies, Dept Surg, San Antonio, TX 78229 USA.
[Rasmussen, Todd E.] US Combat Casualty Care Res Program, Frederick, MD 20814 USA.
[Rasmussen, Todd E.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA.
[Jaramillo, Carlos A.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Healthcare Syst, Dept Rehabil Med, Merton Minter BLVD 7400,Polytrauma Rehabil Ctr, San Antonio, TX 78229 USA.
[Pugh, Mary Jo] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Healthcare Syst, Dept Epidemiol & Biostat, 7400 Merton Minter BLVD,Polytrauma Rehabil Ctr, San Antonio, TX 78229 USA.
RP Shireman, PK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, Sam & Ann Barshop Inst Longev & Aging Studies, Dept Surg, San Antonio, TX 78229 USA.
EM Shireman@uthscsa.edu; maryjo.pugh2@va.gov
FU Veterans Administration [IO1 HX001304]; Department of Defense
FX This study is funded by the Veterans Administration IO1 HX001304 and the
Department of Defense. In addition to the authors on this manuscript,
the VAVIS Collaborators include:; The University of Texas Health Science
Center and the South Texas Veterans Health Care System: Mary Bolinger,
PhD, Jacqueline A Pugh, MD, Judith Gail Walden, MPH, Polly H Noel, PhD,
Blessen Eapen, MD, Lori Pounds, MD, Animesh Agarwal, MD, Chen-Pin Wang,
PhD; Central Texas Veterans Health Care System: Laurel Copeland, PhD
Veterans Administration Puget Sound: Gayle Reiber, PhD Department of
Defense: Jessica Cross Rivera, MD, Diane Miller, BSN, Jean Orman, ScD.
NR 57
TC 0
Z9 0
U1 1
U2 4
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2482
J9 BMC SURG
JI BMC Surg.
PD FEB 3
PY 2015
VL 15
AR 13
DI 10.1186/1471-2482-15-13
PG 12
WC Surgery
SC Surgery
GA CA9QW
UT WOS:000349260900001
PM 25644593
ER
PT J
AU Inoue, A
Shen, L
Matoba, S
Zhang, Y
AF Inoue, Azusa
Shen, Li
Matoba, Shogo
Zhang, Yi
TI Haploinsufficiency, but Not Defective Paternal 5mC Oxidation, Accounts
for the Developmental Defects of Maternal Tet3 Knockouts
SO CELL REPORTS
LA English
DT Article
ID MOUSE PREIMPLANTATION DEVELOPMENT; DNA METHYLATION DYNAMICS; PRIMORDIAL
GERM-CELLS; MAMMALIAN ZYGOTE; DEMETHYLATION; GENOME; EMBRYOS;
GENERATION; ROLES; MICE
AB Paternal DNA demethylation in mammalian zygotes is achieved through Tet3-mediated iterative oxidation of 5-methylcytosine (5mC) coupled with replication-dependent dilution. Tet3-mediated paternal DNA demethylation is believed to play important roles in mouse development given that Tet3 heterozygous embryos derived from Tet3-deficient oocytes exhibit embryonic sublethality. Here, we demonstrate that the sublethality phenotype of the Tet3 maternal knockout mice is caused by haploinsufficiency but not defective paternal 5mC oxidation. We found that Tet3 heterozygous progenies derived from heterozygous father or mother also exhibit sublethality. Importantly, wild-type embryos reconstituted with paternal pronuclei that bypassed 5mC oxidation develop and grow to adulthood normally. Genome-scale DNA methylation analysis demonstrated that hypermethylation in maternal Tet3 knockout embryos is largely diminished by the blastocyst stage. Our study thus reveals that Tet3-mediated paternal 5mC oxidation is dispensable for mouse development and suggests the existence of a compensatory mechanism for defective 5mC oxidation in preimplantation embryos.
C1 [Inoue, Azusa; Shen, Li; Matoba, Shogo; Zhang, Yi] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA.
[Inoue, Azusa; Shen, Li; Matoba, Shogo; Zhang, Yi] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.
[Inoue, Azusa; Shen, Li; Matoba, Shogo; Zhang, Yi] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.
[Zhang, Yi] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA.
RP Zhang, Y (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, WAB 149G,200 Longwood Ave, Boston, MA 02115 USA.
EM yzhang@genetics.med.harvard.edu
FU NIH [U01-DK089565]
FX We thank L.M. Tuesta and S. Yamaguchi for critical readings of the
manuscript and G.L. Xu for the Tet3 antibody. The work was partly
supported by NIH grant U01-DK089565. S.M. is a research fellow for
Research Abroad of the Japan Society for the Promotion of Science. Y.Z.
is an investigator of the Howard Hughes Medical Institute.
NR 36
TC 10
Z9 11
U1 0
U2 6
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 3
PY 2015
VL 10
IS 4
BP 463
EP 470
DI 10.1016/j.celrep.2014.12.049
PG 8
WC Cell Biology
SC Cell Biology
GA CB1QX
UT WOS:000349404100002
PM 25640176
ER
PT J
AU Ljubicic, S
Polak, K
Fu, A
Wiwczar, J
Szlyk, B
Chang, YG
Alvarez-Perez, JC
Bird, GH
Walensky, LD
Garcia-Ocana, A
Danial, NN
AF Ljubicic, Sanda
Polak, Klaudia
Fu, Accalia
Wiwczar, Jessica
Szlyk, Benjamin
Chang, Yigang
Alvarez-Perez, Juan C.
Bird, Gregory H.
Walensky, Loren D.
Garcia-Ocana, Adolfo
Danial, Nika N.
TI Phospho-BAD BH3 Mimicry Protects beta Cells and Restores Functional beta
Cell Mass in Diabetes
SO CELL REPORTS
LA English
DT Article
ID INSULIN-SECRETION; GLUCOKINASE; PROTEINS; SURVIVAL; THERAPY; ISLETS;
MICE; REGENERATION; MECHANISMS; ACTIVATORS
AB Strategies that simultaneously enhance the survival and glucose responsiveness of insulin-producing beta cells will greatly augment beta cell replacement therapies in type 1 diabetes (T1D). We show that genetic and pharmacologic mimetics of the phosphorylated BCL-2 homology 3 (BH3) domain of BAD impart beta-cell-autonomous protective effects in the face of stress stimuli relevant to beta cell demise in T1D. Importantly, these benefits translate into improved engraftment of donor islets in transplanted diabetic mice, increased beta cell viability in islet grafts, restoration of insulin release, and diabetes reversal. Survival of beta cells in this setting is not merely due to the inability of phospho-BAD to suppress prosurvival BCL-2 proteins but requires its activation of the glucose-metabolizing enzyme glucokinase. Thus, BAD phospho-BH3 mimetics may prove useful in the restoration of functional beta cell mass in diabetes.
C1 [Ljubicic, Sanda; Polak, Klaudia; Fu, Accalia; Wiwczar, Jessica; Szlyk, Benjamin; Danial, Nika N.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.
[Ljubicic, Sanda; Fu, Accalia; Danial, Nika N.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA.
[Chang, Yigang] Univ Pittsburgh, Div Endocrinol, Pittsburgh, PA 15260 USA.
[Alvarez-Perez, Juan C.; Garcia-Ocana, Adolfo] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Diabet Obes & Metab Inst, New York, NY 10029 USA.
[Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.
[Bird, Gregory H.; Walensky, Loren D.] Boston Childrens Hosp, Boston, MA 02115 USA.
RP Danial, NN (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.
EM nika_danial@dfci.harvard.edu
RI Alvarez Perez, Juan/J-8294-2016
OI Alvarez Perez, Juan/0000-0001-6396-311X
FU U.S. NIH [R01DK078081, R01 DK067351, R01 DK077096, R01GM090299];
Burroughs Wellcome Fund Career Award in Biomedical Sciences; Juvenile
Diabetes Research Foundation [17-2011-595]; Barry and Mimi Sternlicht
Type 1 Diabetes Research Fund; Claudia Adams Barr Award in Innovative
Basic Cancer Research; Swiss National Science Foundation
FX We thank Elaura Patton and Gabriella Casinelli for technical support and
Jill Fisher for help with islet transplantation surgeries. This work was
supported by the U.S. NIH grants R01DK078081 (N.N.D.), R01 DK067351 and
R01 DK077096 (A.G.-O.), R01GM090299 (L.D.W.), Burroughs Wellcome Fund
Career Award in Biomedical Sciences (N.N.D.), Juvenile Diabetes Research
Foundation Grant 17-2011-595 (N.N.D.), Barry and Mimi Sternlicht Type 1
Diabetes Research Fund (N.N.D.), Claudia Adams Barr Award in Innovative
Basic Cancer Research (N.N.D.), and a Swiss National Science Foundation
postdoctoral fellowship (S.L.). The authors also acknowledge generous
support from John H. Lippincott. L.D.W. is a consultant and scientific
advisory board member for Aileron Therapeutics.
NR 29
TC 3
Z9 3
U1 0
U2 6
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 3
PY 2015
VL 10
IS 4
BP 497
EP 504
DI 10.1016/j.celrep.2014.12.056
PG 8
WC Cell Biology
SC Cell Biology
GA CB1QX
UT WOS:000349404100005
PM 25640178
ER
PT J
AU Tepe, G
Laird, J
Schneider, P
Brodmann, M
Krishnan, P
Micari, A
Metzger, C
Scheinert, D
Zeller, T
Cohen, DJ
Snead, DB
Alexander, B
Landini, M
Jaff, MR
AF Tepe, Gunnar
Laird, John
Schneider, Peter
Brodmann, Marianne
Krishnan, Prakash
Micari, Antonio
Metzger, Christopher
Scheinert, Dierk
Zeller, Thomas
Cohen, David J.
Snead, David B.
Alexander, Beaux
Landini, Mario
Jaff, Michael R.
CA IN PACT SFA Trial Investigators
TI Drug-Coated Balloon Versus Standard Percutaneous Transluminal
Angioplasty for the Treatment of Superficial Femoral and Popliteal
Peripheral Artery Disease 12-Month Results From the IN. PACT SFA
Randomized Trial
SO CIRCULATION
LA English
DT Article
DE drug-eluting balloons; peripheral arterial disease; peripheral vascular
diseases
ID PACLITAXEL-ELUTING STENTS; BARE-METAL STENTS; FEMOROPOPLITEAL ARTERY;
NITINOL STENTS; CLINICAL IMPACT; LOWER-EXTREMITY; TASK-FORCE;
RESTENOSIS; LESIONS; MANAGEMENT
AB Background-Drug-coated balloons (DCBs) have shown promise in improving the outcomes for patients with peripheral artery disease. We compared a paclitaxel-coated balloon with percutaneous transluminal angioplasty (PTA) for the treatment of symptomatic superficial femoral and popliteal artery disease.
Methods and Results-The IN.PACT SFA Trial is a prospective, multicenter, single-blinded, randomized trial in which 331 patients with intermittent claudication or ischemic rest pain attributable to superficial femoral and popliteal peripheral artery disease were randomly assigned in a 2:1 ratio to treatment with DCB or PTA. The primary efficacy end point was primary patency, defined as freedom from restenosis or clinically driven target lesion revascularization at 12 months. Baseline characteristics were similar between the 2 groups. Mean lesion length and the percentage of total occlusions for the DCB and PTA arms were 8.94 +/- 4.89 and 8.81 +/- 5.12 cm (P=0.82) and 25.8% and 19.5% (P=0.22), respectively. DCB resulted in higher primary patency versus PTA (82.2% versus 52.4%; P<0.001). The rate of clinically driven target lesion revascularization was 2.4% in the DCB arm in comparison with 20.6% in the PTA arm (P<0.001). There was a low rate of vessel thrombosis in both arms (1.4% after DCB and 3.7% after PTA [P=0.10]). There were no device-or procedure-related deaths and no major amputations.
Conclusions-In this prospective, multicenter, randomized trial, DCB was superior to PTA and had a favorable safety profile for the treatment of patients with symptomatic femoropopliteal peripheral artery disease.
C1 [Tepe, Gunnar] RodMed Klinikum, Rosenheim, Germany.
[Laird, John] Univ Calif Davis, Sacramento, CA USA.
[Schneider, Peter] Kaiser Permanente, Moanalua Med Ctr & Clin, Honolulu, HI USA.
[Brodmann, Marianne] Univ Klinikum, Landeskrankenhaus, Graz, Austria.
[Krishnan, Prakash] Mt Sinai Med Ctr, New York, NY 10029 USA.
[Micari, Antonio] GVM Care & Res, Lugo, Italy.
[Micari, Antonio] Maria Eleonora Hosp, Palermo, Italy.
[Metzger, Christopher] Wellmont Holston Valley Med Ctr, Kingsport, TN USA.
[Scheinert, Dierk] Pk Krankenhaus Leipzig, Leipzig, Germany.
[Zeller, Thomas] Univ Herzzentrum Freiburg, Bad Krozingen, Germany.
[Cohen, David J.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA.
[Cohen, David J.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA.
[Snead, David B.; Alexander, Beaux; Landini, Mario] Medtronic Inc, Santa Rosa, CA USA.
[Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
RP Laird, J (reprint author), UC Davis Vasc Ctr, Lawrence J Ellison Ambulatory Care Ctr, 4860 Y St,Suite 3400, Sacramento, CA 95817 USA.
EM john.laird@ucdmc.ucdavis.edu
FU Medtronic, Inc.
FX The study was funded by Medtronic, Inc.
NR 30
TC 99
Z9 106
U1 0
U2 10
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 3
PY 2015
VL 131
IS 5
BP 495
EP +
DI 10.1161/CIRCULATIONAHA.114.011004
PG 14
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
SC Cardiovascular System & Cardiology
GA CA9EK
UT WOS:000349223300013
PM 25472980
ER
PT J
AU Ogbechie, OA
Morley, KW
Sugai, D
Nambudiri, VE
Senna, MM
Hoang, MP
Saavedra, AP
AF Ogbechie, Oluwatobi A.
Morley, Keith W.
Sugai, Daniel
Nambudiri, Vinod E.
Senna, Maryanne M.
Hoang, Mai P.
Saavedra, Arturo P.
TI Limited Cutaneous Pseudovasculitis A Mild Variant of Cholesterol Emboli
Syndrome
SO CIRCULATION
LA English
DT Editorial Material
C1 [Ogbechie, Oluwatobi A.] Harvard Univ, Sch Med, Boston, MA USA.
[Morley, Keith W.; Sugai, Daniel; Nambudiri, Vinod E.] Harvard Combined Dermatol Residency Program, Boston, MA USA.
[Nambudiri, Vinod E.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA.
[Senna, Maryanne M.; Saavedra, Arturo P.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA.
[Hoang, Mai P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
RP Saavedra, AP (reprint author), Dermatol Associates, Med Dermatol, 50 Staniford St,2nd Floor, Boston, MA 02114 USA.
EM asoavedra@partners.org
NR 4
TC 1
Z9 1
U1 1
U2 1
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 3
PY 2015
VL 131
IS 5
BP 514
EP 515
DI 10.1161/CIRCULATIONAHA.114.013086
PG 2
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
SC Cardiovascular System & Cardiology
GA CA9EK
UT WOS:000349223300016
PM 25645613
ER
PT J
AU Zlatar, ZZ
McGregor, KM
Towler, S
Nocera, JR
Dzierzewski, JM
Crosson, B
AF Zlatar, Zvinka Z.
McGregor, Keith M.
Towler, Stephen
Nocera, Joer R.
Dzierzewski, Joseph M.
Crosson, Bruce
TI Self-reported physical activity and objective aerobic fitness:
differential associations with gray matter density in healthy aging
SO FRONTIERS IN AGING NEUROSCIENCE
LA English
DT Article
DE physical activity; aerobic fitness; voxel based morphometry; healthy
aging; MRI; gray matter density
ID OLDER-ADULTS; ALZHEIMERS-DISEASE; MR-IMAGES; EXERCISE; BRAIN; VOLUME;
SEDENTARY; RISK; EDUCATION; BEHAVIOR
AB Aerobic fitness (AF) and self-reported physical activity (srPA) do not represent the same construct. However, many exercise and brain aging studies interchangeably use AF and srPA measures, which may be problematic with regards to how these metrics are associated with brain outcomes, such as morphology. If AF and PA measures captured the same phenomena, regional brain volumes associated with these measures should directly overlap. This study employed the general linear model to examine the differential association between objectively-measured AF (treadmill assessment) and srPA (questionnaire) with gray matter density (GMd) in 29 cognitively unimpaired community-dwelling older adults using voxel based morphometry. The results show significant regional variance in terms of GMd when comparing AF and srPA as predictors. Higher AF was associated with greater GMd in the cerebellum only, while srPA displayed positive associations with GMd in occipito-temporal, left perisylvian, and frontal regions after correcting for age. Importantly, only AF level, and not srPA, modified the relationship between age and GMd, such that higher levels of AF were associated with increased GMd in older age, while decreased GMd was seen in those with lower AF as a function of age. These results support existing literature suggesting that both AF and PA exert beneficial effects on GMd, but only AF served as a buffer against age-related GMd loss. Furthermore, these results highlight the need for use of objective PA measurement and comparability of tools across studies, since results vary dependent upon the measures used and whether these are objective or subjective in nature.
C1 [Zlatar, Zvinka Z.] Univ Calif San Diego, Dept Psychiat, Stein Inst Res Aging, La Jolla, CA 92093 USA.
[McGregor, Keith M.; Towler, Stephen; Nocera, Joer R.; Crosson, Bruce] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA.
[McGregor, Keith M.; Towler, Stephen; Nocera, Joer R.; Crosson, Bruce] Atlanta VA Med Ctr, Ctr Visual & Neurocognit Rehabil, Decatur, GA USA.
[Dzierzewski, Joseph M.] Ctr Geriatr Res Educ & Clin Ctr, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA.
[Dzierzewski, Joseph M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA.
[Crosson, Bruce] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA.
RP Zlatar, ZZ (reprint author), Univ Calif San Diego, Dept Psychiat, Stein Inst Res Aging, La Jolla, CA 92093 USA.
EM zzlatar@ucsd.edu
OI McGregor, Keith/0000-0003-3654-351X
FU National Institutes of Health [T32 MH019934-21, T32 AG020499-08, P30
AG028740-03]; Department of Veteran Affairs (VA) Rehabilitation R&D
Center of Excellence [F2182C]; Senior Research Career Scientist [B6364L]
FX This work was supported by the National Institutes of Health grants T32
MH019934-21; T32 AG020499-08, and P30 AG028740-03 to Zvinka Z. Zlatar.
This work was also supported by a Department of Veteran Affairs (VA)
Rehabilitation R&D Center of Excellence #F2182C and Senior Research
Career Scientist (Bruce Crosson: #B6364L) award. We thank Michael
Marsiske, Ph.D. and Todd M. Manini, Ph.D. for their help with this
project and all the individuals who participated in this study.
NR 50
TC 0
Z9 0
U1 1
U2 17
PU FRONTIERS RESEARCH FOUNDATION
PI LAUSANNE
PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND
SN 1663-4365
J9 FRONT AGING NEUROSCI
JI Front. Aging Neurosci.
PD FEB 3
PY 2015
VL 7
AR 5
DI 10.3389/fnagi.2015.00005
PG 8
WC Geriatrics & Gerontology; Neurosciences
SC Geriatrics & Gerontology; Neurosciences & Neurology
GA CA5XF
UT WOS:000348981000001
PM 25691866
ER
PT J
AU Patel, MS
Asch, DA
Volpp, KG
AF Patel, Mitesh S.
Asch, David A.
Volpp, Kevin G.
TI Wearable Devices as Facilitators, Not Drivers, of Health Behavior Change
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Editorial Material
ID APPS
C1 [Patel, Mitesh S.; Asch, David A.; Volpp, Kevin G.] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA.
RP Patel, MS (reprint author), 423 Guardian Dr,Blockley Hall,12th Floor, Philadelphia, PA 19104 USA.
EM mpatel@upenn.edu
NR 6
TC 80
Z9 80
U1 9
U2 40
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 3
PY 2015
VL 313
IS 5
BP 459
EP 460
DI 10.1001/jama.2014.14781
PG 2
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA7AV
UT WOS:000349070300005
PM 25569175
ER
PT J
AU Merkow, RP
Ju, MH
Chung, JW
Hall, BL
Cohen, ME
Williams, MV
Tsai, TC
Ko, CY
Bilimoria, KY
AF Merkow, Ryan P.
Ju, Mila H.
Chung, Jeanette W.
Hall, Bruce L.
Cohen, Mark E.
Williams, Mark V.
Tsai, Thomas C.
Ko, Clifford Y.
Bilimoria, Karl Y.
TI Underlying Reasons Associated With Hospital Readmission Following
Surgery in the United States
SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
LA English
DT Article
ID QUALITY IMPROVEMENT PROGRAM; SURGICAL-CARE; MEDICARE BENEFICIARIES;
30-DAY READMISSION; AMERICAN-COLLEGE; PATIENT EXPERIENCE; HEART-FAILURE;
RISK-FACTORS; RATES; SITE
AB IMPORTANCE Financial penalties for readmission have been expanded beyond medical conditions to include surgical procedures. Hospitals are working to reduce readmissions; however, little is known about the reasons for surgical readmission.
OBJECTIVE To characterize the reasons, timing, and factors associated with unplanned postoperative readmissions.
DESIGN, SETTING, AND PARTICIPANTS Patients undergoing surgery at one of 346 continuously enrolled US hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) between January 1, 2012, and December 31, 2012, had clinically abstracted information examined. Readmission rates and reasons (ascertained by clinical data abstractors at each hospital) were assessed for all surgical procedures and for 6 representative operations: bariatric procedures, colectomy or proctectomy, hysterectomy, total hip or knee arthroplasty, ventral hernia repair, and lower extremity vascular bypass.
MAIN OUTCOMES AND MEASURES Unplanned 30day readmission and reason for readmission.
RESULTS The unplanned readmission rate for the 498 875 operations was 5.7%. For the individual procedures, the readmission rate ranged from 3.8% for hysterectomy to 14.9% for lower extremity vascular bypass. The most common reason for unplanned readmission was surgical site infection (SSI) overall (19.5%) and also after colectomy or proctectomy (25.8%), ventral hernia repair (26.5%), hysterectomy (28.8%), arthroplasty (18.8%), and lower extremity vascular bypass (36.4%). Obstruction or ileus was the most common reason for readmission after bariatric surgery (24.5%) and the second most common reason overall (10.3%), after colectomy or proctectomy (18.1%), ventral hernia repair (16.7%), and hysterectomy (13.4%). Only 2.3% of patients were readmitted for the same complication they had experienced during their index hospitalization. Only 3.3% of patients readmitted for SSIs had experienced an SSI during their index hospitalization. There was no time pattern for readmission, and early (<= 7 days postdischarge) and late (> 7 days postdischarge) readmissions were associated with the same 3 most common reasons: SSI, ileus or obstruction, and bleeding. Patient comorbidities, index surgical admission complications, nonhome discharge (hazard ratio [HR], 1.40 [95% CI, 1.351.46]), teaching hospital status (HR, 1.14 [95% CI 1.071.21]), and higher surgical volume (HR, 1.15 [95% CI, 1.071.25]) were associated with a higher risk of hospital readmission.
CONCLUSIONS AND RELEVANCE Readmissions after surgery were associated with new postdischarge complications related to the procedure and not exacerbation of prior index hospitalization complications, suggesting that readmissions after surgery are a measure of postdischarge complications. These data should be considered when developing quality indicators and any policies penalizing hospitals for surgical readmission.
C1 [Merkow, Ryan P.; Ju, Mila H.; Hall, Bruce L.; Cohen, Mark E.; Ko, Clifford Y.; Bilimoria, Karl Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA.
[Merkow, Ryan P.; Ju, Mila H.; Chung, Jeanette W.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Dept Surg, SOQIC, Chicago, IL 60611 USA.
[Merkow, Ryan P.; Ju, Mila H.; Chung, Jeanette W.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Ctr Healthcare Studies, Chicago, IL 60611 USA.
[Merkow, Ryan P.; Ju, Mila H.; Chung, Jeanette W.; Bilimoria, Karl Y.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Northwestern Inst Comparat Effectiveness Res Onco, SOQIC, Chicago, IL 60611 USA.
[Merkow, Ryan P.] Univ Chicago, Dept Surg, Div Biol Sci, Chicago, IL 60637 USA.
[Hall, Bruce L.] Washington Univ, Sch Med, Dept Surg, Barnes Jewish Hosp, St Louis, MO 63110 USA.
[Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, Olin Business Sch, St Louis, MO USA.
[Hall, Bruce L.] John Cochran Vet Affairs Med Ctr, Dept Surg, St Louis, MO USA.
[Hall, Bruce L.] BJC Healthcare, St Louis, MO USA.
[Williams, Mark V.] Univ Kentucky, Dept Internal Med, Ctr Hlth Serv Res, Lexington, KY 40506 USA.
[Tsai, Thomas C.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA.
[Tsai, Thomas C.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA.
[Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA.
[Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA.
RP Bilimoria, KY (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Surg, SOQIC, 633 N St Clair St,20th Floor, Chicago, IL 60611 USA.
EM k-bilimoria@northwestern.edu
FU American College of Surgeons Clinical Scholars in Residence Program;
Northwestern Institute for Comparative Effectiveness Research in
Oncology (NICER-Onc); National Institutes of Health (NIH)
[5T32HL094293]; NIH; Agency for Healthcare Research and Quality;
American Cancer Society; National Comprehensive Cancer Network; American
College of Surgeons; American Board of Surgery; Accreditation Council
for Graduate Medical Education; Health Care Services Corporation; Robert
H. Lurie Cancer Center of Northwestern University
FX Dr Merkow is supported by the American College of Surgeons Clinical
Scholars in Residence Program and the Northwestern Institute for
Comparative Effectiveness Research in Oncology (NICER-Onc). Dr Ju is
supported by the American College of Surgeons Clinical Scholars in
Residence Program and National Institutes of Health (NIH) grant
5T32HL094293. Dr Hall is a consultant to the American College of
Surgeons. Dr Bilimoria reported support from the NIH, Agency for
Healthcare Research and Quality, American Cancer Society, National
Comprehensive Cancer Network, American College of Surgeons, American
Board of Surgery, Accreditation Council for Graduate Medical Education,
Health Care Services Corporation, and the Robert H. Lurie Cancer Center
of Northwestern University.
NR 48
TC 110
Z9 110
U1 4
U2 23
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 3
PY 2015
VL 313
IS 5
BP 483
EP 495
DI 10.1001/jama.2014.18614
PG 13
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA7AV
UT WOS:000349070300012
PM 25647204
ER
PT J
AU Han, HS
Niemeyer, E
Huang, YH
Kamoun, WS
Martin, JD
Bhaumik, J
Chen, YC
Roberge, S
Cui, J
Martin, MR
Fukumura, D
Jain, RK
Bawendi, MG
Duda, DG
AF Han, Hee-Sun
Niemeyer, Elisabeth
Huang, Yuhui
Kamoun, Walid S.
Martin, John D.
Bhaumik, Jayeeta
Chen, Yunching
Roberge, Sylvie
Cui, Jian
Martin, Margaret R.
Fukumura, Dai
Jain, Rakesh K.
Bawendi, Moungi G.
Duda, Dan G.
TI Quantum dot/antibody conjugates for in vivo cytometric imaging in mice
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE quantum dots; in vivo imaging; single cell imaging; in vivo cytometry;
multiphoton microscopy
ID HEMATOPOIETIC STEM-CELLS; SIZE SERIES; DOTS; NANOCRYSTALS;
IDENTIFICATION; EXPRESSION; RECEPTORS; SYSTEM; NICHES; LABELS
AB Multiplexed, phenotypic, intravital cytometric imaging requires novel fluorophore conjugates that have an appropriate size for long circulation and diffusion and show virtually no nonspecific binding to cells/serum while binding to cells of interest with high specificity. In addition, these conjugates must be stable and maintain a high quantum yield in the in vivo environments. Here, we show that this can be achieved using compact (similar to 15 nm in hydrodynamic diameter) and biocompatible quantum dot (QD) -Ab conjugates. We developed these conjugates by coupling whole mAbs to QDs coated with norbornene-displaying polyimidazole ligands using tetrazine-norbornene cycloaddition. Our QD immunoconstructs were used for in vivo single-cell labeling in bone marrow. The intravital imaging studies using a chronic calvarial bone window showed that our QD-Ab conjugates diffuse into the entire bone marrow and efficiently label single cells belonging to rare populations of hematopoietic stem and progenitor cells (Sca(1+) c-Kit(+) cells). This in vivo cytometric technique may be useful in a wide range of structural and functional imaging to study the interactions between cells and between a cell and its environment in intact and diseased tissues.
C1 [Han, Hee-Sun; Cui, Jian] MIT, Dept Chem, Cambridge, MA 02139 USA.
[Martin, John D.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA.
[Niemeyer, Elisabeth; Huang, Yuhui; Kamoun, Walid S.; Martin, John D.; Bhaumik, Jayeeta; Chen, Yunching; Roberge, Sylvie; Martin, Margaret R.; Fukumura, Dai; Jain, Rakesh K.; Bawendi, Moungi G.; Duda, Dan G.] Massachusetts Gen Hosp, Edwin L Steele Lab, Boston, MA 02114 USA.
[Niemeyer, Elisabeth; Huang, Yuhui; Kamoun, Walid S.; Martin, John D.; Bhaumik, Jayeeta; Chen, Yunching; Roberge, Sylvie; Martin, Margaret R.; Fukumura, Dai; Jain, Rakesh K.; Bawendi, Moungi G.; Duda, Dan G.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
RP Jain, RK (reprint author), Massachusetts Gen Hosp, Edwin L Steele Lab, Boston, MA 02114 USA.
EM jain@steele.mgh.harvard.edu; mgb@mit.edu
RI Martin, John/L-6892-2016;
OI Martin, John/0000-0002-9828-8203; Huang, Yuhui/0000-0003-1985-3575
FU National Institute of Health [R01-CA126642, R01-CA115767, P01-CA080124,
R01-CA096915, U54-CA151884, P41-EB015871-26A1, R21-CA139168,
R01-CA159258]; Department of Defense Breast Cancer Research Innovator
Award [W81XWH-10-1-0016]; American Cancer Society
[RSG-11-073-01-346TBG]; Susan G.Komen Foundation; Samsung Scholarship;
Massachusetts Institutes of Technology Department of Chemistry
Instrumentation Facility [CHE-980806, DBI-9729592]; Institute for
Soldier Nanotechnology [W911NF-07-D-0004]; National Science
Foundation-Materials Research Science and Engineering Centers Program
[DMR-0117795]
FX This research is supported by National Institute of Health Grants
R01-CA126642, R01-CA115767, and P01-CA080124 (to R.K.J.), R01-CA096915
(to D.F.), U54-CA151884 and P41-EB015871-26A1 (to M.G.B.), R21-CA139168
(to D.G.D.), and R01-CA159258 (to D.G.D.); Department of Defense Breast
Cancer Research Innovator Award W81XWH-10-1-0016 (to R.K.J.); American
Cancer Society Grant RSG-11-073-01-346TBG (to D.G.D.); a postdoctoral
fellowship from the Susan G.Komen Foundation (to W.S.K.); a graduate
student fellowship from the Samsung Scholarship (to H.-S.H.);
Massachusetts Institutes of Technology Department of Chemistry
Instrumentation Facility Grants CHE-980806 and DBI-9729592; Institute
for Soldier Nanotechnology Grant W911NF-07-D-0004 (to M.G.B.); and
National Science Foundation-Materials Research Science and Engineering
Centers Program DMR-0117795 through the use of its shared user
facilities.
NR 27
TC 30
Z9 30
U1 6
U2 48
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 3
PY 2015
VL 112
IS 5
BP 1350
EP 1355
DI 10.1073/pnas.1421632111
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7HF
UT WOS:000349087700042
PM 25605916
ER
PT J
AU Magnuson, AM
Thurber, GM
Kohler, RH
Weissleder, R
Mathis, D
Benoist, C
AF Magnuson, Angela M.
Thurber, Greg M.
Kohler, Rainer H.
Weissleder, Ralph
Mathis, Diane
Benoist, Christophe
TI Population dynamics of islet-infiltrating cells in autoimmune diabetes
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE Treg; cell tracer; reporter
ID REGULATORY T-CELLS; ANTI-CD3 MONOCLONAL-ANTIBODY; PANCREATIC
LYMPH-NODES; MOUSE MODEL; IN-VIVO; MICE; INSULITIS; ONSET; EFFECTOR;
PHOTOCONVERSION
AB Type-1 diabetes in the nonobese diabetic (NOD) mouse starts with an insulitis stage, wherein a mixed population of leukocytes invades the pancreas, followed by overt diabetes once enough insulin-producing beta-cells are destroyed by invading immunocytes. Little is known of the dynamics of lymphocyte movement into the pancreas during disease progression. We used the Kaede transgenic mouse, whose photoconvertible fluorescent reporter permits noninvasive labeling and subsequent tracking of immunocytes, to investigate pancreatic infiltrate dynamics and the requirement for antigen specificity during progression of autoimmune diabetes in the unmanipulated NOD mouse. Our results indicate that the insulitic lesion is very open with constant cell influx and active turnover, predominantly of B and T lymphocytes, but also CD11b(+) c(+) myeloid cells. Both naive-and memory-phenotype lymphocytes trafficked to the insulitis, but Foxp3(+) regulatory T cells circulated less than their conventional CD4(+) counterparts. Receptor specificity for pancreatic antigens seemed irrelevant for this homing, because similar kinetics were observed in polyclonal and antigen-specific transgenic contexts. This "open" configuration was also observed after reversal of overt diabetes by anti-CD3 treatment. These results portray insulitis as a dynamic lesion at all stages of disease, continuously fed by a mixed influx of immunocytes, and thus susceptible to evolve over time in response to immunologic or environmental influences.
C1 [Magnuson, Angela M.; Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA.
[Thurber, Greg M.; Kohler, Rainer H.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.
[Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.
[Mathis, Diane; Benoist, Christophe] Brigham & Womens Hosp, Boston, MA 02115 USA.
RP Benoist, C (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA.
EM cbdm@hms.harvard.edu
OI Thurber, Greg/0000-0001-7570-2080
FU National Institutes of Health [P01 AI054904, AI051530, K01DK093766];
Juvenile Diabetes Research Foundation [3-2011-413]
FX We thank Drs. O. Kanagawa and M. Tomura for providing the Kaede/NOD
line, and Dr. J. Mohan for discussion. This work was supported National
Institutes of Health Grants P01 AI054904 (to D.M., C.B., and R.W.), and
AI051530 (to D.M. and C.B.), K Award K01DK093766 (to G.M.T.), and
Juvenile Diabetes Research Foundation Fellowship 3-2011-413 (to A.M.M.).
NR 49
TC 15
Z9 15
U1 0
U2 12
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 3
PY 2015
VL 112
IS 5
BP 1511
EP 1516
DI 10.1073/pnas.1423769112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7HF
UT WOS:000349087700069
PM 25605891
ER
PT J
AU Das, DK
Feng, YN
Mallis, RJ
Li, XL
Keskin, DB
Hussey, RE
Brady, SK
Wang, JH
Wagner, G
Reinherz, EL
Lang, MJ
AF Das, Dibyendu Kumar
Feng, Yinnian
Mallis, Robert J.
Li, Xiaolong
Keskin, Derin B.
Hussey, Rebecca E.
Brady, Sonia K.
Wang, Jia-Huai
Wagner, Gerhard
Reinherz, Ellis L.
Lang, Matthew J.
TI Force-dependent transition in the T-cell receptor beta-subunit
allosterically regulates peptide discrimination and pMHC bond lifetime
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE mechanosensor; T-cell receptor; peptide discrimination; optical
tweezers; catch bond
ID TCR FAB FRAGMENT; THYMIC SELECTION; ECTODOMAIN FRAGMENT; CORECEPTOR
FUNCTION; STRUCTURAL BASIS; SINGLE-MOLECULE; CATCH BONDS; FG LOOP; MHC;
COMPLEX
AB The alpha beta T-cell receptor (TCR) on each T lymphocyte mediates exquisite specificity for a particular foreign peptide bound to a major histocompatibility complex molecule (pMHC) displayed on the surface of altered cells. This recognition stimulates protection in the mammalian host against intracellular pathogens, including viruses, and involves piconewton forces that accompany pMHC ligation. Physical forces are generated by T-lymphocyte movement during immune surveillance as well as by cytoskeletal rearrangements at the immunological synapse following cessation of cell migration. The mechanistic explanation for how TCRs distinguish between foreign and self-peptides bound to a given MHC molecule is unclear: peptide residues themselves comprise few of the TCR contacts on the pMHC, and pathogen-derived peptides are scant among myriad self-peptides bound to the same MHC class arrayed on infected cells. Using optical tweezers and DNA tether spacer technology that permit piconewton force application and nanometer scale precision, we have determined how bioforces relate to self versus nonself discrimination. Single-molecule analyses involving isolated alpha beta-heterodimers as well as complete TCR complexes on T lymphocytes reveal that the FG loop in the beta-subunit constant domain allosterically controls both the variable domain module's catch bond lifetime and peptide discrimination via force-driven conformational transition. In contrast to integrins, the TCR interrogates its ligand via a strong force-loaded state with release through a weakened, extended state. Our work defines a key element of TCR mechanotransduction, explaining why the FG loop structure evolved for adaptive immunity in alpha beta but not gamma delta TCRs or immunoglobulins.
C1 [Das, Dibyendu Kumar; Feng, Yinnian; Brady, Sonia K.; Lang, Matthew J.] Vanderbilt Univ, Dept Chem & Biomol Engn, Nashville, TN 37235 USA.
[Mallis, Robert J.; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.
[Li, Xiaolong; Wang, Jia-Huai] Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Peoples R China.
[Keskin, Derin B.; Hussey, Rebecca E.; Wang, Jia-Huai; Reinherz, Ellis L.] Dana Farber Canc Inst, Immunobiol Lab, Dept Med Oncol, Boston, MA 02115 USA.
[Keskin, Derin B.; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
[Lang, Matthew J.] Vanderbilt Univ, Sch Med, Det Mol Physiol & Biophys, Nashville, TN 37235 USA.
RP Lang, MJ (reprint author), Vanderbilt Univ, Dept Chem & Biomol Engn, 221 Kirkland Hall, Nashville, TN 37235 USA.
EM gerhard_wagner@hms.harvard.edu; ellis_reinherz@dfci.harvard.edu;
matt.lang@vanderbilt.edu
FU NIH [VSV8/H2-Kb-alpha2A2, R01AI100643, R01AI37581,
P01GM047467]; Vanderbilt-Ingram Cancer Center (NIH) [CA68485];
Vanderbilt Digestive Disease Research Center (NIH) [DK058404]
FX We thank the NIH Tetramer Core Facility at Emory University and Cheng
Zhu for providing the VSV8/H2-Kb-alpha 2A2 tetramer. This
work is supported by NIH Grants R01AI100643, R01AI37581, and
P01GM047467. D.K.D. is a George Russell Chambers postdoctoral fellow.
Flow cytometry experiments were performed in the Vanderbilt University
Medical Center Flow Cytometry Shared Resource supported by The
Vanderbilt-Ingram Cancer Center (NIH Grant CA68485) and the Vanderbilt
Digestive Disease Research Center (NIH Grant DK058404).
NR 40
TC 21
Z9 21
U1 5
U2 24
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 3
PY 2015
VL 112
IS 5
BP 1517
EP 1522
DI 10.1073/pnas.1424829112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7HF
UT WOS:000349087700070
PM 25605925
ER
PT J
AU Heist, RS
Duda, DG
Sahani, DV
Ancukiewicz, M
Fidias, P
Sequist, LV
Temel, JS
Shaw, AT
Pennell, NA
Neal, JW
Gandhi, L
Lynch, TJ
Engelman, JA
Jain, RK
AF Heist, Rebecca S.
Duda, Dan G.
Sahani, Dushyant V.
Ancukiewicz, Marek
Fidias, Panos
Sequist, Lecia V.
Temel, Jennifer S.
Shaw, Alice T.
Pennell, Nathan A.
Neal, Joel W.
Gandhi, Leena
Lynch, Thomas J.
Engelman, Jeffrey A.
Jain, Rakesh K.
TI Improved tumor vascularization after anti-VEGF therapy with carboplatin
and nab-paclitaxel associates with survival in lung cancer
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE lung cancer; antiangiogenesis; bioimaging
ID RANDOMIZED PHASE-III; SOLID TUMORS; ANTIANGIOGENIC THERAPY; PLUS
CARBOPLATIN; 1ST-LINE THERAPY; BREAST-CANCER; BEVACIZUMAB; TRIAL;
NORMALIZATION; HYPERTENSION
AB Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non-small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment-while reducing blood flow, volume, and permeability in the overall population-may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.
C1 [Heist, Rebecca S.; Sequist, Lecia V.; Temel, Jennifer S.; Shaw, Alice T.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.
[Duda, Dan G.; Ancukiewicz, Marek; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
[Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA.
[Sahani, Dushyant V.] Harvard Univ, Sch Med, Boston, MA 02114 USA.
[Fidias, Panos] Univ Arizona, Canc Ctr Dign, Dept Med Oncol, Phoenix, AZ 85013 USA.
[Pennell, Nathan A.] Cleveland Clin, Dept Hematol & Med Oncol, Cleveland, OH 44195 USA.
[Neal, Joel W.] Stanford Univ, Dept Med, Div Oncol, Stanford Canc Inst, Palo Alto, CA 94305 USA.
[Gandhi, Leena] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA.
[Lynch, Thomas J.] Yale Canc Ctr, Dept Med Oncol, New Haven, CT 06520 USA.
RP Heist, RS (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.
EM rheist@partners.org; jain@steele.mgh.harvard.edu
OI Gandhi, Leena/0000-0002-2398-9179
FU National Institutes of Health [P01CA080124, R01CA159258]; Proton
Beam/Federal Share Program; Department of Defense Breast Cancer Research
Innovator Award [W81XWH10-1-0016]
FX We thank A. Khachatryan, C. Koppel, and O. Pulluqi for outstanding
technical support for biomarker studies. All data collection and
analysis were performed independently by the investigators of this
investigator-initiated clinical trial. This work was supported in part
by National Institutes of Health Grants P01CA080124 (to R.K.J.) and
R01CA159258 (to D.G.D.); the Proton Beam/Federal Share Program (R.K.J.
and D.G.D.); and Department of Defense Breast Cancer Research Innovator
Award W81XWH-10-1-0016 (to R.K.J.).
NR 34
TC 29
Z9 30
U1 4
U2 22
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 3
PY 2015
VL 112
IS 5
BP 1547
EP 1552
DI 10.1073/pnas.1424024112
PG 6
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7HF
UT WOS:000349087700075
PM 25605928
ER
PT J
AU Sun, A
Novobrantseva, TI
Coffre, M
Hewitt, SL
Jensen, K
Skok, JA
Rajewsky, K
Koralov, SB
AF Sun, Amy
Novobrantseva, Tatiana I.
Coffre, Maryaline
Hewitt, Susannah L.
Jensen, Kari
Skok, Jane A.
Rajewsky, Klaus
Koralov, Sergei B.
TI V-H replacement in primary immunoglobulin repertoire diversification
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
LA English
DT Article
DE VH replacement; receptor editing; lymphocyte development; secondary
rearrangement; V(D)J
ID HEAVY-CHAIN GENE; PRE-B-CELLS; V(D)J RECOMBINATION; TRANSGENIC MICE;
MECHANISM; SEGMENTS; REARRANGEMENT; LYMPHOCYTES; DIFFERENTIATION;
EXPRESSION
AB The genes encoding the variable (V) region of the B-cell antigen receptor (BCR) are assembled from V, D (diversity), and J (joining) elements through a RAG-mediated recombination process that relies on the recognition of recombination signal sequences (RSSs) flanking the individual elements. Secondary V(D) J rearrangement modifies the original Ig rearrangement if a nonproductive original joint is formed, as a response to inappropriate signaling from a self-reactive BCR, or as part of a stochastic mechanism to further diversify the Ig repertoire. V-H replacement represents a RAG-mediated secondary rearrangement in which an upstream V-H element recombines with a rearranged V(H)D(H)J(H) joint to generate a new BCR specificity. The rearrangement occurs between the cryptic RSS of the original V-H element and the conventional RSS of the invading V-H gene, leaving behind a footprint of up to five base pairs (bps) of the original V-H gene that is often further obscured by exonuclease activity and N-nucleotide addition. We have previously demonstrated that V-H replacement can efficiently rescue the development of B cells that have acquired two nonproductive heavy chain (IgH) rearrangements. Here we describe a novel knock-in mouse model in which the prerearranged IgH locus resembles an endogenously rearranged productive V(H)D(H)J(H) allele. Using this mouse model, we characterized the role of VH replacement in the diversification of the primary Ig repertoire through the modification of productive V(H)D(H)J(H) rearrangements. Our results indicate that V-H replacement occurs before Ig light chain rearrangement and thus is not involved in the editing of self-reactive antibodies.
C1 [Sun, Amy; Coffre, Maryaline; Hewitt, Susannah L.; Skok, Jane A.; Koralov, Sergei B.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA.
[Novobrantseva, Tatiana I.; Jensen, Kari; Rajewsky, Klaus] Immune Dis Inst, Boston, MA 02115 USA.
RP Koralov, SB (reprint author), NYU, Sch Med, Dept Pathol, New York, NY 10016 USA.
EM sergei.koralov@nyumc.org
OI Skok, Jane/0000-0002-4145-1516
FU Arnold and Mabel Beckman Foundation; Ralph S. French Charitable
Foundation; National Institutes of Health [R21AI110830,
5T32GM007308-36]; National Cancer Institute [5T32CA009161-39]
FX We thank Stefano Casola for the open and enjoyable discussions on the
complementary projects. This work was supported by the Arnold and Mabel
Beckman Foundation, the Ralph S. French Charitable Foundation, and the
National Institutes of Health [Grant R21AI110830 (to S.B.K.)]. A.S. was
supported by National Institutes of Health Grant 5T32GM007308-36 and
National Cancer Institute Grant 5T32CA009161-39.
NR 40
TC 5
Z9 5
U1 1
U2 12
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD FEB 3
PY 2015
VL 112
IS 5
BP E458
EP E466
DI 10.1073/pnas.1418001112
PG 9
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA7HF
UT WOS:000349087700012
PM 25609670
ER
PT J
AU Cummings, MT
Joh, RI
Motamedi, M
AF Cummings, Michael T.
Joh, Richard I.
Motamedi, Mo
TI PRIMED: PRIMEr Database for Deleting and Tagging All Fission and Budding
Yeast Genes Developed Using the Open-Source Genome Retrieval Script
(GRS)
SO PLOS ONE
LA English
DT Article
ID SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; VERSATILE;
RESOURCE; SEQUENCE; MODULES
AB The fission (Schizosaccharomyces pombe) and budding (Saccharomyces cerevisiae) yeasts have served as excellent models for many seminal discoveries in eukaryotic biology. In these organisms, genes are deleted or tagged easily by transforming cells with PCR-generated DNA inserts, flanked by short (50-100bp) regions of gene homology. These PCR reactions use especially designed long primers, which, in addition to the priming sites, carry homology for gene targeting. Primer design follows a fixed method but is tedious and time-consuming especially when done for a large number of genes. To automate this process, we developed the Python-based Genome Retrieval Script (GRS), an easily customizable open-source script for genome analysis. Using GRS, we created PRIMED, the complete PRIMEr D atabase for deleting and C-terminal tagging genes in the main S. pombe and five of the most commonly used S. cerevisiae strains. Because of the importance of noncoding RNAs (ncRNAs) in many biological processes, we also included the deletion primer set for these features in each genome. PRIMED are accurate and comprehensive and are provided as downloadable Excel files, removing the need for future primer design, especially for large-scale functional analyses. Furthermore, the open-source GRS can be used broadly to retrieve genome information from custom or other annotated genomes, thus providing a suitable platform for building other genomic tools by the yeast or other research communities.
C1 [Motamedi, Mo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA.
Harvard Univ, Sch Med, Dept Med, Charlestown, MA USA.
RP Motamedi, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA.
EM mmotamedi@hms.harvard.edu
OI Joh, Richard/0000-0003-0583-8032
FU NCI Proton Beam [C06 CA059267]; V Scholar Award
FX MTC is the 2014 Alvan T. and Viola D. Fuller American Cancer Society
Junior Research Fellow. This work was supported by an NCI Proton Beam
Grant (C06 CA059267) and a V Scholar Award (http://www.jimmyv.org/) to
MM. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
NR 13
TC 0
Z9 0
U1 0
U2 1
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD FEB 2
PY 2015
VL 10
IS 2
AR e0116657
DI 10.1371/journal.pone.0116657
PG 8
WC Multidisciplinary Sciences
SC Science & Technology - Other Topics
GA CA3QK
UT WOS:000348821200022
PM 25643023
ER
PT J
AU Dzik, WH
AF Dzik, Walter H.
TI Innocent lives lost and saved: the importance of blood transfusion for
children in sub-Saharan Africa
SO BMC Medicine
LA English
DT Editorial Material
DE Transfusion; sub-Saharan Africa; Severe anemia
AB Severe anemia in children is a leading indication for blood transfusion worldwide. Severe anemia, defined by the World Health Organization as a hemoglobin level <5 g/dL, is particularly common throughout sub-Saharan Africa. Analysis of data from the Fluid Expansion as Supportive Therapy (FEAST) trial offers new insights into the importance of blood transfusion for children with severe anemia. The principal findings of this analysis include the observations that life-threatening anemia in children is a frequent presenting condition in East Africa; that delays in transfusion therapy are lethal; and that inadequate transfusion is probably more common than currently recognized. The findings of this new study highlight the need for changes in blood inventory management in sub-Saharan hospitals and the need for more research on transfusion therapy for children in peril.
C1 Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA.
RP Dzik, WH (reprint author), Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA.
EM sdzik@partners.org
NR 8
TC 1
Z9 1
U1 0
U2 903
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 2
PY 2015
VL 13
AR 22
DI 10.1186/s12916-014-0248-5
PG 3
WC Medicine, General & Internal
SC General & Internal Medicine
GA CA5JH
UT WOS:000348944200002
PM 25640864
ER
PT J
AU Liu, MH
Christodoulou, A
de Souza, T
Christie, A
Weinstock, DM
AF Liu, M. H.
Christodoulou, A.
de Souza, T.
Christie, A.
Weinstock, D. M.
TI Targeting Eradication of BCR-ABL-Rearranged Acute Lymphoblastic Leukemia
SO ANNALS OF HEMATOLOGY
LA English
DT Meeting Abstract
C1 [Liu, M. H.; Christodoulou, A.; de Souza, T.; Christie, A.; Weinstock, D. M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
[Liu, M. H.; Christodoulou, A.; de Souza, T.; Christie, A.; Weinstock, D. M.] Harvard Univ, Sch Med, Boston, MA USA.
NR 6
TC 0
Z9 0
U1 0
U2 0
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 0939-5555
EI 1432-0584
J9 ANN HEMATOL
JI Ann. Hematol.
PD FEB
PY 2015
VL 94
SU 1
BP S60
EP S60
PG 1
WC Hematology
SC Hematology
GA DA0HS
UT WOS:000367478800037
ER
PT J
AU Stone, RM
AF Stone, R. M.
TI FLT3 Inhibitors in AML
SO ANNALS OF HEMATOLOGY
LA English
DT Meeting Abstract
ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; RISK
MYELODYSPLASTIC SYNDROME; ACUTE MYELOGENOUS LEUKEMIA; KINASE INHIBITOR;
MUTANT FLT3; SORAFENIB; CHEMOTHERAPY; MIDOSTAURIN; PKC412
C1 [Stone, R. M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Adult Leukemia Program, Boston, MA 02115 USA.
NR 20
TC 0
Z9 0
U1 1
U2 1
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 0939-5555
EI 1432-0584
J9 ANN HEMATOL
JI Ann. Hematol.
PD FEB
PY 2015
VL 94
SU 1
BP S101
EP S102
PG 2
WC Hematology
SC Hematology
GA DA0HS
UT WOS:000367478800126
ER
PT J
AU Vienberg, SG
Kleinridders, A
Suzuki, R
Kahn, CR
AF Vienberg, Sara Gry
Kleinridders, Andre
Suzuki, Ryo
Kahn, C. Ronald
TI Differential effects of angiopoietin-like 4 in brain and muscle on
regulation of lipoprotein lipase activity
SO MOLECULAR METABOLISM
LA English
DT Article
DE Angptl4; Lipid metabolism; Lipoprotein lipase
ID ALZHEIMERS-DISEASE; INSULIN-RESISTANCE; SKELETAL-MUSCLE; TRIGLYCERIDE
LEVELS; NERVOUS-SYSTEM; DIABETIC MICE; OBESITY; METABOLISM; PROTEIN-4;
ANGPTL4
AB Objective: Lipoprotein lipase (LPL) is a key regulator of circulating triglyceride rich lipoprotein hydrolysis. In brain LPL regulates appetite and energy expenditure. Angiopoietin-like 4 (Angptl4) is a secreted protein that inhibits LPL activity and, thereby, triglyceride metabolism, but the impact of Angptl4 on central lipid metabolism is unknown.
Methods: We induced type 1 diabetes by streptozotocin (STZ) in whole-body Angptl4 knockout mice (Angptl4(-/-)) and their wildtype littermates to study the role of Angptl4 in central lipid metabolism.
Results: In type 1 (streptozotocin, STZ) and type 2 (ob/ob) diabetic mice, there is a similar to 2-fold increase of Angptl4 in the hypothalamus and skeletal muscle. Intracerebroventricular insulin injection into STZ mice at levels which have no effect on plasma glucose restores Angptl4 expression in hypothalamus. Isolation of cells from the brain reveals that Angptl4 is produced in glia, whereas LPL is present in both glia and neurons. Consistent with the in vivo experiment, in vitro insulin treatment of glial cells causes a 50% reduction of Angptl4 and significantly increases LPL activity with no change in LPL expression. In Angptl4(-/-) mice, LPL activity in skeletal muscle is increased 3-fold, and this is further increased by STZ-induced diabetes. By contrast, Angptl4(-/-) mice show no significant difference in LPL activity in hypothalamus or brain independent of diabetic and nutritional status.
Conclusion: Thus, Angptl4 in brain is produced in glia and regulated by insulin. However, in contrast to the periphery, central Angptl4 does not regulate LPL activity, but appears to participate in the metabolic crosstalk between glia and neurons. (C) 2014 The Authors. Published by Elsevier GmbH.
C1 [Kahn, C. Ronald] Joslin Diabet Ctr, Boston, MA 02215 USA.
Harvard Univ, Sch Med, Boston, MA USA.
RP Kahn, CR (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA.
EM c.ronald.kahn@joslin.harvard.edu
FU NIDDK NIH HHS [P30 DK036836, R37 DK031036, R01 DK033201, R01 DK060837]
NR 46
TC 1
Z9 1
U1 0
U2 2
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 2212-8778
J9 MOL METAB
JI Mol. Metab.
PD FEB
PY 2015
VL 4
IS 2
BP 144
EP 150
DI 10.1016/j.molmet.2014.11.003
PG 7
WC Endocrinology & Metabolism
SC Endocrinology & Metabolism
GA CZ9QT
UT WOS:000367432800009
PM 25685701
ER
PT J
AU Yonekawa, Y
Miller, JW
Kim, IK
AF Yonekawa, Yoshihiro
Miller, Joan W.
Kim, Ivana K.
TI Age-Related Macular Degeneration: Advances in Management and Diagnosis
SO JOURNAL OF CLINICAL MEDICINE
LA English
DT Review
DE age-related macular degeneration; choroidal neovascularization; fundus
autofluorescence; fluorescein angiography; optical coherence tomography;
retina; vascular endothelial growth factor; visual impairment
ID BEAVER DAM EYE; SUBFOVEAL CHOROIDAL NEOVASCULARIZATION; NUTRITION
EXAMINATION SURVEY; RANDOMIZED CLINICAL-TRIALS; BLUE MOUNTAINS EYE;
VERTEPORFIN PLUS RANIBIZUMAB; ENDOTHELIAL GROWTH-FACTOR; 3RD
NATIONAL-HEALTH; GEOGRAPHIC ATROPHY; RISK-FACTORS
AB Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in older populations in industrialized nations. AMD is a late-onset deterioration of photoreceptors and retinal pigment epithelium in the central retina caused by various environmental and genetic factors. Great strides in our understanding of AMD pathogenesis have been made in the past several decades, which have translated into revolutionary therapeutic agents in recent years. In this review, we describe the clinical and pathologic features of AMD and present an overview of current diagnosis and treatment strategies.
C1 [Yonekawa, Yoshihiro; Miller, Joan W.; Kim, Ivana K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, Boston, MA 02114 USA.
RP Kim, IK (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, Boston, MA 02114 USA.
EM Yoshihiro_Yonekawa@meei.harvard.edu; joan_miller@meei.harvard.edu;
Ivana_Kim@meei.harvard.edu
NR 96
TC 11
Z9 12
U1 2
U2 6
PU MDPI AG
PI BASEL
PA POSTFACH, CH-4005 BASEL, SWITZERLAND
SN 2077-0383
J9 J CLIN MED
JI J. Clin. Med.
PD FEB
PY 2015
VL 4
IS 2
BP 343
EP 359
DI 10.3390/jcm4020343
PG 17
WC Medicine, General & Internal
SC General & Internal Medicine
GA CT9IY
UT WOS:000363131700008
PM 26239130
ER
PT J
AU Ebrahimzadeh, MH
Birjandinejad, A
Moradi, A
Choghadeh, MF
Rezazadeh, J
Omidi-Kashani, F
AF Ebrahimzadeh, Mohammad Hosein
Birjandinejad, Ali
Moradi, Ali
Choghadeh, Maysam Fathi
Rezazadeh, Jafar
Omidi-Kashani, Farzad
TI Clinical Instability of the Knee and Functional Differences Following
Tibial Plateau Fractures Versus Distal Femoral Fractures
SO TRAUMA MONTHLY
LA English
DT Article
DE Knee; Knee Instability; ACL; PCL; Quality of Life
ID SOFT-TISSUE INJURIES; LIGAMENT INJURIES; ARTHROSCOPIC EVALUATION;
COLLATERAL LIGAMENT; FEMUR FRACTURES; SHAFT FRACTURES; CLASSIFICATION;
SCHATZKER; OUTCOMES; SF-36
AB Background: Fractures of the knee account for about 6% of all trauma admissions. While its management is mostly focused on fracture treatment, it is not the only factor that defines the final outcome. Objectives: This study aimed to study objective and subjective outcomes after proximal tibial versus distal femoral fractures in terms of knee instability and health-related quality of life.
Patients and Methods: This retrospective, cross-sectional, cohort study was carried out on 80 patients with either isolated proximal tibial (n = 42) or distal femoral (n = 38) fractures, who underwent open reduction and internal fixation. All the fractures were classified based on the Schatzker and AO classification for tibial plateau and distal femoral fractures, respectively. The patients were followed and examined by an orthopedic knee surgeon for clinical assessment of knee instability. In their last follow-up visit, these patients completed a Lysholm knee score and the short-form (SF) 36 health survey.
Results: Among the 42 tibial plateau fractures, 25% were classified as Schatzker type 2. Of the 38 distal femoral fractures, we did not find any type BL or B3 fractures. The overall prevalence of anterior and posterior instability was 42% and zo%, respectively Medial Collateral Ligament (MCL) and Lateral Collateral Ligament (LCL) injuries were detected clinically in 50% and 28%, respectively. The incidence rates of ligament injuries in tibial plateau fractures were as follows: Anterior Collateral Ligament (ACL) 26%, Posterior Collateral Ligament (PCL) 7%, MCL 24%, and LCL14%. Medial collateral ligament injury was the most common in the Schatzker type 2(50% of the injuries). Distal femoral fractures were associated with ACL injury in 16%, PCL in 13%, MCL in 26% and LCL in 14%. However, final knee range of motion (ROM) and function (Lysholm score) were not associated with fracture location. No statistically significant difference was observed between the two groups, except for the valgus stress test at 30 Imee flexion, which was more positive in tibial fractures. All eight domains of SF-36 score in the distal femoral and proximal tibial fractures were significantly different from the normal values; however, there were no statistically significant differences between femoral and tibial fracture scores.
Conclusions: Although ROM is acceptable in knee joint fractures, instability is common. However, it seems that knee function and quality of life are not associated with the location of the fracture.
C1 [Ebrahimzadeh, Mohammad Hosein; Birjandinejad, Ali; Choghadeh, Maysam Fathi; Rezazadeh, Jafar; Omidi-Kashani, Farzad] Mashhad Univ Med Sci, Orthopaed Res Ctr, Ghaem Hosp, Mashhad, Iran.
[Moradi, Ali] Harvard Univ, Sch Med, Mass Gen Hosp, Boston, MA USA.
RP Birjandinejad, A (reprint author), Mashhad Univ Med Sci, Orthopaed Res Ctr, Mashhad, Iran.
EM Birjandinejada@mums.ac.ir
FU Mashhad University of Medical Sciences
FX Authors have received the research grant from Mashhad University of
Medical Sciences.
NR 26
TC 0
Z9 0
U1 1
U2 3
PU BAQIYATALLAH UNIV MEDICAL SCIENCES
PI TEHRAN
PA PUBL OFF, THIRD FL BAQIYATALLAH CENTRAL BLDG, MOLLASADRA AVE, VANAK SQ,
PO BOX 19395-5487, TEHRAN, 19395-5487, IRAN
SN 2251-7464
EI 2251-7472
J9 TRAUMA MON
JI Trauma Mon.
PD FEB
PY 2015
VL 20
IS 1
DI 10.5812/traumamon.21635
PG 6
WC Emergency Medicine
SC Emergency Medicine
GA CU0SV
UT WOS:000363229900004
ER
PT J
AU Homma, S
Beermann, ML
Boyce, FM
Miller, JB
AF Homma, Sachiko
Beermann, Mary Lou
Boyce, Frederick M.
Miller, Jeffrey Boone
TI Expression of FSHD-related DUX4-FL alters proteostasis and induces
TDP-43 aggregation
SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
LA English
DT Article
ID FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY; INCLUSION-BODY MYOSITIS;
AMYOTROPHIC-LATERAL-SCLEROSIS; UBIQUITIN-PROTEASOME SYSTEM;
SKELETAL-MUSCLE; GENE-EXPRESSION; CANDIDATE GENE; HEAT-SHOCK; PROTEIN;
DISEASE
AB Objective: Pathogenesis in facioscapulohumeral muscular dystrophy (FSHD) appears to be due to aberrant expression, particularly in skeletal muscle nuclei, of the full-length isoform of DUX4 (DUX4-FL). Expression of DUX4-FL is known to alter gene expression and to be cytotoxic, but cell responses to DUX4-FL are not fully understood. Our study was designed to identify cellular mechanisms of pathogenesis caused by DUX4-FL expression. Methods: We used human myogenic cell cultures to analyze the effects of DUX4-FL when it was expressed either from its endogenous promoter in FSHD cells or by exogenous expression using BacMam vectors. We focused on determining the effects of DUX4-FL on protein ubiquitination and turnover and on aggregation of TDP-43. Results: Human FSHD myotubes with endogenous DUX4-FL expression showed both altered nuclear and cytoplasmic distributions of ubiquitinated proteins and aggregation of TDP-43 in DUX4-FL-expressing nuclei. Similar changes were found upon exogenous expression of DUX4-FL, but were not seen upon expression of the non-toxic short isoform DUX4-S. DUX4-FL expression also inhibited protein turnover in a model system and increased the amounts of insoluble ubiquitinated proteins and insoluble TDP-43. Finally, inhibition of the ubiquitin-proteasome system with MG132 produced TDP-43 aggregation similar to DUX4-FL expression. Interpretations: Our results identify DUX4-FL-induced inhibition of protein turnover and aggregation of TDP-43, which are pathological changes also found in diseases such as amyotrophic lateral sclerosis and inclusion body myopathy, as potential pathological mechanisms in FSHD.
C1 [Homma, Sachiko; Beermann, Mary Lou; Miller, Jeffrey Boone] Boston Univ, Sch Med, Neuromuscular Biol & Dis Grp, Dept Neurol, Boston, MA 02118 USA.
[Homma, Sachiko; Beermann, Mary Lou; Miller, Jeffrey Boone] Boston Univ, Sch Med, Neuromuscular Biol & Dis Grp, Dept Physiol & Biophys, Boston, MA 02118 USA.
[Boyce, Frederick M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.
RP Miller, JB (reprint author), Boston Univ, Sch Med, Neuromuscular Biol & Dis Grp, 715 Albany St,W408G, Boston, MA 02118 USA.
EM millerjb@bu.edu
FU NCATS NIH HHS [UL1 TR000157]; NIAMS NIH HHS [R01 AR060328, R01 AR062578,
R01 AR062587]; NICHD NIH HHS [U54 HD060848]
NR 68
TC 6
Z9 6
U1 0
U2 0
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 2328-9503
J9 ANN CLIN TRANSL NEUR
JI Ann. Clin. Transl. Neurol.
PD FEB
PY 2015
VL 2
IS 2
BP 151
EP 166
DI 10.1002/acn3.158
PG 16
WC Clinical Neurology; Neurosciences
SC Neurosciences & Neurology
GA CZ3BS
UT WOS:000366979700005
PM 25750920
ER
PT J
AU Chen, ZH
Chen, JT
Johnson, M
Gossman, ZC
Hendrickson, M
Sakaie, K
Martinez-Rubio, C
Gale, JT
Trapp, BD
AF Chen, Zhihong
Chen, Jacqueline T.
Johnson, Matthew
Gossman, Zachary C.
Hendrickson, Megan
Sakaie, Ken
Martinez-Rubio, Clarissa
Gale, John T.
Trapp, Bruce D.
TI Cuprizone does not induce CNS demyelination in nonhuman primates
SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
LA English
DT Article
ID REMITTING MULTIPLE-SCLEROSIS; COGNITIVE IMPAIRMENT; CORTICAL-LESIONS;
MRI; SPACE
AB Cognitive decline is a common symptom in multiple sclerosis patients, with profound effects on the quality of life. A nonhuman primate model of multiple sclerosis would be best suited to test the effects of demyelination on complex cognitive functions such as learning and reasoning. Cuprizone has been shown to reliably induce brain demyelination in mice. To establish a nonhuman primate model of multiple sclerosis, young adult cynomolgus monkeys were administered cuprizone per os as a dietary supplement. The subjects received increasing cuprizone doses (0.3-3% of diet) for up to 18 weeks. Magnetic resonance imaging and immunohistological analyses did not reveal demyelination in these monkeys.
C1 [Chen, Zhihong; Chen, Jacqueline T.; Johnson, Matthew; Gossman, Zachary C.; Hendrickson, Megan; Gale, John T.; Trapp, Bruce D.] Cleveland Clin, Dept Neurosci, Cleveland, OH 44195 USA.
[Sakaie, Ken] Cleveland Clin, Neurol Inst, Cleveland, OH 44195 USA.
[Martinez-Rubio, Clarissa] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA.
[Gale, John T.] Cleveland Clin, Neurol Inst, Ctr Neurol Restorat, Cleveland, OH 44195 USA.
RP Trapp, BD (reprint author), Cleveland Clin, Lerner Res Inst, Dept Neurosci, Euclid Ave,NC30, Cleveland, OH 44195 USA.
EM trappb@ccf.org
OI Johnson, Matthew/0000-0002-0264-8498
NR 19
TC 0
Z9 0
U1 0
U2 2
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 2328-9503
J9 ANN CLIN TRANSL NEUR
JI Ann. Clin. Transl. Neurol.
PD FEB
PY 2015
VL 2
IS 2
BP 208
EP 213
DI 10.1002/acn3.159
PG 6
WC Clinical Neurology; Neurosciences
SC Neurosciences & Neurology
GA CZ3BS
UT WOS:000366979700010
PM 25750925
ER
PT J
AU Arias, JJ
Pham-Kanter, G
Campbell, EG
AF Arias, Jalayne J.
Pham-Kanter, Genevieve
Campbell, Eric G.
TI The growth and gaps of genetic data sharing policies in the United
States
SO JOURNAL OF LAW AND THE BIOSCIENCES
LA English
DT Article
DE data sharing; genetic; genomic; research; policy; scientific norms
ID GENOMIC RESEARCH; PARTICIPANTS
AB The 1996 Bermuda Principles launched a new era in data sharing, reflecting a growing belief that the rapid public dissemination of research data was crucial to scientific progress in genetics. A historical review of data sharing policies in the field of genetics and genomics reflects changing scientific norms and evolving views of genomic data, particularly related to human subjects' protections and privacy concerns. The 2013 NIH Draft Genomic Data Sharing (GDS) Policy incorporates the most significant protections and guidelines to date. The GDS Policy, however, will face difficult challenges ahead as geneticists seek to balance the very real concerns of research participants and the scientific norms that propel research forward. This article provides a novel evaluation of genetic and GDS policies' treatment of human subjects' protections. The article examines not only the policies, but also some of the most pertinent scientific, legal, and regulatory developments that occurred alongside data sharing policies. This historical perspective highlights the challenges that future data sharing policies, including the recently disseminated NIH GDS Draft Policy, will encounter.
C1 [Arias, Jalayne J.] Cleveland Clin, Cleveland, OH 44195 USA.
[Pham-Kanter, Genevieve] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA.
[Pham-Kanter, Genevieve] Harvard Univ, Cambridge, MA 02138 USA.
[Campbell, Eric G.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
[Campbell, Eric G.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
RP Arias, JJ (reprint author), Cleveland Clin, Cleveland, OH 44195 USA.
EM ariasj@ccf.org
OI Pham-Kanter, Genevieve/0000-0002-3044-7829
FU NHGRI NIH HHS [R01 HG006281]
NR 31
TC 3
Z9 3
U1 0
U2 2
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 2053-9711
J9 J LAW BIOSCI
JI J. Law Biosci.
PD FEB
PY 2015
VL 2
IS 1
BP 56
EP 68
DI 10.1093/jlb/lsu032
PG 13
WC Law
SC Government & Law
GA CY6HW
UT WOS:000366510800004
PM 27774180
ER
PT J
AU Lopez, DAE
Orta, DS
Quezada, LM
Garduno, AO
Vanegas, MAA
Fernandez, M
Gregorio, RV
Anschel, D
Fregni, F
AF Espinoza Lopez, D. A.
San Juan Orta, D.
Morales Quezada, L.
Orozco Garduno, A.
Alonso Vanegas, M. A.
Fernandez, M.
Vazquez Gregorio, R.
Anschel, D.
Fregni, F.
TI A RANDOMIZED CONTROLLED CLINICAL TRIAL OF CATHODAL TRANSCRANEAL DIRECT
CURRENT STIMULATION IN PATIENTS WITH TEMPORAL LOBE EPILEPSY WITH
HIPPOCAMPAL SCLEROSIS REFRACTORY TO PHARMACOLOGICAL TREATMENT
SO EPILEPSIA
LA English
DT Meeting Abstract
CT 31st International Epilepsy Congress
CY SEP 05-09, 2015
CL Istanbul, TURKEY
C1 [Espinoza Lopez, D. A.; San Juan Orta, D.; Fernandez, M.] Natl Inst Neurol & Neurosurg Manuel Velasco Suare, Neurophysiol, Mexico City, DF, Mexico.
[Morales Quezada, L.] Spaulding Rehabil Hosp, Lab Neuromodulat, Massachusets, MA USA.
[Morales Quezada, L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Lab Neuromodulat,Dept Phys Med & Rehabil,Spauldin, Massachusets, MA USA.
[Morales Quezada, L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Massachusets, MA USA.
[Alonso Vanegas, M. A.] Natl Inst Neurol & Neurosurg Manuel Velasco Suare, Neurosurg, Mexico City, DF, Mexico.
[Anschel, D.] Comprehens Epilepsy Ctr Long Isl, Neurophysiol, Long Isl City, NY USA.
[Fregni, F.] Hosp Massachusets, Massachusets, MA USA.
[Fregni, F.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Phys Med & Rehabil, Massachusets, MA USA.
NR 0
TC 0
Z9 0
U1 0
U2 0
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0013-9580
EI 1528-1167
J9 EPILEPSIA
JI Epilepsia
PD FEB
PY 2015
VL 56
SU 1
SI SI
MA 0069
BP 24
EP 25
PG 2
WC Clinical Neurology
SC Neurosciences & Neurology
GA CX5QG
UT WOS:000365756500064
ER
PT J
AU Yao, X
Tang, W
Mao, W
Liu, X
Li, Z
Zhang, N
Yang, Y
Wang, Y
Sun, W
AF Yao, X.
Tang, W.
Mao, W.
Liu, X.
Li, Z.
Zhang, N.
Yang, Y.
Wang, Y.
Sun, W.
TI FUNCTIONAL CONNECTIVITY IN JUVENILE MYOCLONIC EPILEPSY: MEG-BASED
NETWORK AND ANALYSIS
SO EPILEPSIA
LA English
DT Meeting Abstract
CT 31st International Epilepsy Congress
CY SEP 05-09, 2015
CL Istanbul, TURKEY
C1 [Yao, X.; Mao, W.; Liu, X.; Li, Z.; Zhang, N.; Yang, Y.; Wang, Y.; Sun, W.] Capital Med Univ, Dept Neurol, Xuan Wu Hosp, Beijing, Peoples R China.
[Tang, W.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA.
[Tang, W.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA.
NR 0
TC 0
Z9 0
U1 0
U2 0
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0013-9580
EI 1528-1167
J9 EPILEPSIA
JI Epilepsia
PD FEB
PY 2015
VL 56
SU 1
SI SI
MA p0830
BP 202
EP 202
PG 1
WC Clinical Neurology
SC Neurosciences & Neurology
GA CX5QG
UT WOS:000365756500615
ER
PT J
AU Djemie, T
Dejanovic, B
Suls, A
Grunewald, N
Craiu, D
Zemel, M
Gormley, P
Lal, D
Myers, CT
Mefford, H
Palotie, A
Helbig, I
De Jonghe, P
Schwarz, G
Weckhuysen, S
AF Djemie, T.
Dejanovic, B.
Suls, A.
Gruenewald, N.
Craiu, D.
Zemel, M.
Gormley, P.
Lal, D.
Myers, C. T.
Mefford, H.
Palotie, A.
Helbig, I.
De Jonghe, P.
Schwarz, G.
Weckhuysen, S.
CA EuroEPINOMICS Dravet Working Grp
TI SIMULTANEOUS IMPAIRMENT OF NEURONAL AND METABOLIC FUNCTION OF GEPHYRIN
IN A PATIENT WITH EPILEPTIC ENCEPHALOPATHY
SO EPILEPSIA
LA English
DT Meeting Abstract
CT 31st International Epilepsy Congress
CY SEP 05-09, 2015
CL Istanbul, TURKEY
C1 [Djemie, T.; Suls, A.; De Jonghe, P.; Weckhuysen, S.] VIB Dept Mol Genet, Neurogenet Grp, B-2020 Antwerp, Belgium.
[Djemie, T.; Suls, A.; De Jonghe, P.; Weckhuysen, S.] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, D-50931 Antwerp, Belgium.
[Dejanovic, B.; Schwarz, G.] Univ Cologne, Dept Chem, Inst Biochem, Cologne, Germany.
[Craiu, D.] Al Obregia Hosp, Pediat Neurol Clin, Bucharest, Romania.
[Craiu, D.] Carol Davila Univ Med & Pharm, Dept Neurol Pediat Neurol Psychiat Child & Adoles, Bucharest, 98195, Romania.
[Zemel, M.; Myers, C. T.; Mefford, H.] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA USA.
[Gormley, P.; Palotie, A.] Wellcome Trust Sanger Inst, Hinxton, 02114, England.
[Gormley, P.; Palotie, A.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA USA.
[Gormley, P.; Palotie, A.] Harvard Univ, Sch Med, Boston, MA USA.
[Gormley, P.; Palotie, A.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
[Gormley, P.; Palotie, A.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, D-50931 Cambridge, MA USA.
[Lal, D.] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne Ctr Genom, Cologne, Germany.
[Lal, D.] Univ Med Fac Giessen & Marburg, Dept Neuropediat, Giessen, Germany.
[Palotie, A.] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, 02114, Finland.
[Palotie, A.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
[Palotie, A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA.
[Helbig, I.] Univ Kiel, Univ Med Ctr Schleswig Holstein, Dept Neuropediat, Kiel, 19104, Germany.
[Helbig, I.] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA USA.
[De Jonghe, P.] Univ Antwerp Hosp, Div Neurol, D-50931 Antwerp, Belgium.
[Schwarz, G.] Univ Cologne, CMMC, D-50931 Cologne, Germany.
[Schwarz, G.] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany.
[Weckhuysen, S.] Univ Paris 06, Sorbonne Univ,Serv Neurol, Inst Cerveau & Moelle Epiniere,Inserm,U1127,UMR S, Hop La Pitie Salpetriere,AP HP,ICM,CNRS,UMR 7225, Paris, France.
NR 0
TC 0
Z9 0
U1 0
U2 0
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0013-9580
EI 1528-1167
J9 EPILEPSIA
JI Epilepsia
PD FEB
PY 2015
VL 56
SU 1
SI SI
MA p0909
BP 223
EP 224
PG 2
WC Clinical Neurology
SC Neurosciences & Neurology
GA CX5QG
UT WOS:000365756500676
ER
PT J
AU Nguyen, VH
Roger, BA
Dergalust, S
Wasterlain, CG
AF Nguyen, V. -H.
Roger, B. A.
Dergalust, S.
Wasterlain, C. G.
TI TIME-DEPENDENT EFFECTS OF LACOSAMIDE, KETAMINE AND COMBINATION KETAMINE
AND DIAZEPAM TREATMENT IN A RAT LITHIUM-PILOCARPINE MODEL OF STATUS
EPILEPTICUS
SO EPILEPSIA
LA English
DT Meeting Abstract
CT 31st International Epilepsy Congress
CY SEP 05-09, 2015
CL Istanbul, TURKEY
C1 [Nguyen, V. -H.; Dergalust, S.] VA Greater Los Angeles Healthcare Syst, Neurol & Pharm, Los Angeles, CA USA.
[Roger, B. A.; Wasterlain, C. G.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA.
[Wasterlain, C. G.] Univ Calif Los Angeles, Neurol, Los Angeles, CA USA.
NR 0
TC 0
Z9 0
U1 1
U2 2
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0013-9580
EI 1528-1167
J9 EPILEPSIA
JI Epilepsia
PD FEB
PY 2015
VL 56
SU 1
SI SI
MA p1054
BP 258
EP 258
PG 1
WC Clinical Neurology
SC Neurosciences & Neurology
GA CX5QG
UT WOS:000365756500783
ER
PT J
AU Bettger, JP
McCoy, L
Smith, EE
Fonarow, GC
Schwamm, LH
Peterson, ED
AF Bettger, Janet Prvu
McCoy, Lisa
Smith, Eric E.
Fonarow, Gregg C.
Schwamm, Lee H.
Peterson, Eric D.
TI Contemporary Trends and Predictors of Postacute Service Use and Routine
Discharge Home After Stroke
SO JOURNAL OF THE AMERICAN HEART ASSOCIATION
LA English
DT Article
DE rehabilitation; stroke; trends
ID POST-ACUTE CARE; PERFORMANCE-MEASURES; GUIDELINES-STROKE;
ISCHEMIC-STROKE; OUTCOMES
AB Background-Returning home after the hospital is a primary aim for healthcare; however, additional postacute care (PAC) services are sometimes necessary for returning stroke patients to their pre-event status. Recent trends in hospital discharge disposition specifying PAC use have not been examined across age groups or health insurance types.
Methods and Results-We examined trends in discharge to inpatient rehabilitation facilities (IRFs), skilled nursing facilities (SNFs), home with home health (HH), and home without services for 849 780 patients >= 18 years of age with ischemic or hemorrhagic stroke at 1687 hospitals participating in Get With The Guidelines-Stroke. Multivariable analysis was used to identify factors associated with discharge to any PAC (IRF, SNF, or HH) versus discharge home without services. From 2003 to 2011, there was a 2.1% increase (unadjusted P=0.001) in PAC use after a stroke hospitalization. Change was greatest in SNF use, an 8.3% decrease over the period. IRF and HH increased 6.9% and 3.6%, respectively. The 2 strongest clinical predictors of PAC use after acute care were patients not ambulating on the second day of their hospital stay (ambulation odds ratio [OR], 3.03; 95% confidence interval [CI], 2.86 to 3.23) and those who failed a dysphagia screen or had an order restricting oral intake (OR, 2.48; 95% CI, 2.37 to 2.59).
Conclusions-Four in 10 stroke patients are discharged home without services. Although little has changed overall in PAC use since 2003, further research is needed to explain the shift in service use by type and its effect on outcomes.
C1 [Bettger, Janet Prvu] Duke Univ, Sch Nursing, Durham, NC 27710 USA.
[Bettger, Janet Prvu; McCoy, Lisa; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA.
[Smith, Eric E.] Univ Calgary, Calgary, AB, Canada.
[Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA.
[Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
RP Bettger, JP (reprint author), Duke Univ, Sch Nursing, DUMC 3322,307 Trent Dr, Durham, NC 27710 USA.
EM janet.bettger@duke.edu
RI Smith, Eric/C-5443-2012
OI Smith, Eric/0000-0003-3956-1668
FU AHRQ K12 training grant [K12HS019479]; American Heart Association;
Pfizer Inc (New York, NY); Merck-Schering Plough Partnership (North
Wales, PA)
FX Dr Prvu Bettger was a Mentored Scholar in Comparative Effectiveness
Research (75% effort) supported by an AHRQ K12 training grant awarded to
Duke University (K12HS019479; PI: Oddone). Get With The
Guidelines-Stroke is funded by the American Heart Association. The Get
With The Guidelines program is also supported, in part, by unrestricted
educational grants from Pfizer Inc (New York, NY) and the Merck-Schering
Plough Partnership (North Wales, PA), which did not participate in the
design, analysis, manuscript preparation, or approval. The contents of
this article are solely the responsibility of the authors and do not
necessarily represent the official views of the funding agencies.
NR 17
TC 4
Z9 4
U1 1
U2 2
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 2047-9980
J9 J AM HEART ASSOC
JI J. Am. Heart Assoc.
PD FEB
PY 2015
VL 4
IS 2
AR e001038
DI 10.1161/JAHA.114.001038
PG 11
WC Cardiac & Cardiovascular Systems
SC Cardiovascular System & Cardiology
GA CX4NQ
UT WOS:000365678000001
ER
PT J
AU Hwang, JK
Alt, FW
Yeap, LS
AF Hwang, Joyce K.
Alt, Frederick W.
Yeap, Leng-Siew
TI Related Mechanisms of Antibody Somatic Hypermutation and Class Switch
Recombination
SO MICROBIOLOGY SPECTRUM
LA English
DT Article
ID CYTIDINE DEAMINASE AID; RNA-POLYMERASE-II; ACTIVATION-INDUCED DEAMINASE;
3' REGULATORY REGION; HEAVY-CHAIN LOCUS; DOUBLE-STRAND BREAKS; CENTER
B-CELLS; IMMUNOGLOBULIN GENE HYPERMUTATION; DEPENDENT PROTEIN-KINASE;
TARGETED DNA DEAMINATION
AB The primary antibody repertoire is generated by mechanisms involving the assembly of the exons that encode the antigen-binding variable regions of immunoglobulin heavy (IgH) and light (IgL) chains during the early development of B lymphocytes. After antigen-dependent activation, mature B lymphocytes can further alter their IgH and IgL variable region exons by the process of somatic hypermutation (SHM), which allows the selection of B cells in which SHMs resulted in the production of antibodies with increased antigen affinity. In addition, during antigen-dependent activation, B cells can also change the constant region of their IgH chain through a DNA double-strand-break (DSB) dependent process referred to as IgH class switch recombination (CSR), which generates B cell progeny that produce antibodies with different IgH constant region effector functions that are best suited for a elimination of a particular pathogen or in a particular setting. Both the mutations that underlie SHM and the DSBs that underlie CSR are initiated in target genes by activation-induced cytidine deaminase (AID). This review describes in depth the processes of SHM and CSR with a focus on mechanisms that direct AID cytidine deamination in activated B cells and mechanisms that promote the differential outcomes of such cytidine deamination.
C1 [Alt, Frederick W.] Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA.
Harvard Univ, Dept Genet, Sch Med, Boston, MA 02115 USA.
RP Alt, FW (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA.
EM alt@enders.tch.harvard.edu
FU Howard Hughes Medical Institute; NIAID NIH HHS [R01 AI077595]
NR 208
TC 10
Z9 10
U1 2
U2 7
PU AMER SOC MICROBIOLOGY
PI WASHINGTON
PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA
EI 2165-0497
J9 MICROBIOL SPECTR
JI Microbiol. Spectr.
PD FEB
PY 2015
VL 3
IS 1
AR MDNA3-0037-2014
DI 10.1128/microbiolspec.MDNA3-0037-2014
PG 22
WC Microbiology
SC Microbiology
GA CU2DI
UT WOS:000363332500008
PM 26104555
ER
PT J
AU Sheehan, J
Marasco, WA
AF Sheehan, Jared
Marasco, Wayne A.
TI Phage and Yeast Display
SO MICROBIOLOGY SPECTRUM
LA English
DT Article
ID HUMAN MONOCLONAL-ANTIBODIES; RESPIRATORY SYNDROME CORONAVIRUS;
HUMAN-IMMUNODEFICIENCY-VIRUS; WEST-NILE-VIRUS; BROADLY NEUTRALIZING
ANTIBODIES; BY-PASSING IMMUNIZATION; INFLUENZA-A VIRUSES; FILAMENTOUS
PHAGE; BOTULINUM NEUROTOXIN; HIGH-AFFINITY
AB Despite the availability of antimicrobial drugs, the continued development of microbial resistance-established through escape mutations and the emergence of resistant strains-limits their clinical utility. The discovery of novel, therapeutic, monoclonal antibodies (mAbs) offers viable clinical alternatives in the treatment and prophylaxis of infectious diseases. Human mAb-based therapies are typically nontoxic in patients and demonstrate high specificity for the intended microbial target. This specificity prevents negative impacts on the patient microbiome and avoids driving the resistance of nontarget species. The in vitro selection of human antibody fragment libraries displayed on phage or yeast surfaces represents a group of well-established technologies capable of generating human mAbs. The advantage of these forms of microbial display is the large repertoire of human antibody fragments present during a single selection campaign. Furthermore, the in vitro selection environments of microbial surface display allow for the rapid isolation of antibodies-and their encoding genes-against infectious pathogens and their toxins that are impractical within in vivo systems, such as murine hybridomas. This article focuses on the technologies of phage display and yeast display, as these strategies relate to the discovery of human mAbs for the treatment and vaccine development of infectious diseases.
C1 [Sheehan, Jared; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA.
RP Marasco, WA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA.
EM Wayne_Marasco@DFCI.Harvard.edu
NR 118
TC 0
Z9 0
U1 4
U2 11
PU AMER SOC MICROBIOLOGY
PI WASHINGTON
PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA
EI 2165-0497
J9 MICROBIOL SPECTR
JI Microbiol. Spectr.
PD FEB
PY 2015
VL 3
IS 1
AR AID-0028-2014
DI 10.1128/microbiolspec.AID-0028-2014
PG 17
WC Microbiology
SC Microbiology
GA CU2DI
UT WOS:000363332500003
PM 26104550
ER
PT J
AU Lo, J
Lu, MT
Ihenachor, EJ
Wei, J
Looby, SE
Fitch, KV
Oh, J
Zimmerman, CO
Hwang, J
Abbara, S
Plutzky, J
Robbins, G
Tawakol, A
Man