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. 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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. 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[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. 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[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. 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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