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 Mann, UH Grinspoon, SK AF Lo, Janet Lu, Michael T. Ihenachor, Ezinne J. Wei, Jeffrey Looby, Sara E. Fitch, Kathleen V. Oh, Jinhee Zimmerman, Chloe O. Hwang, Janice Abbara, Suhny Plutzky, Jorge Robbins, Gregory Tawakol, Ahmed Mann, Udo Hoff Grinspoon, Steven K. TI Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial SO LANCET HIV LA English DT Article ID MULTIDETECTOR COMPUTED-TOMOGRAPHY; ACUTE MYOCARDIAL-INFARCTION; ANTIRETROVIRAL THERAPY; CT ANGIOGRAPHY; PHOSPHOLIPASE A(2); INTRAVASCULAR ULTRASOUND; IMMUNE ACTIVATION; HEART-DISEASE; QUANTIFICATION; LESIONS AB Background HIV-infected patients have a high risk of myocardial infarction. We aimed to assess the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in this population. Methods In a randomised, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose (FDG)-PET, and LDL-cholesterol concentration of less than 3.37 mmol/L (130 mg/dL) were randomly assigned (1: 1) to 1 year of treatment with atorvastatin or placebo. Randomisation was by the Massachusetts General Hospital (MGH) Clinical Research Pharmacy with a permuted-block algorithm, stratified by sex with a fixed block size of four. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation as assessed by FDG-PET of the aorta. Additional prespecified endpoints were non-calcified and calcified plaque measures and high risk plaque features assessed with coronary CT angiography and biochemical measures. Analysis was done by intention to treat with all available data and without imputation for missing data. The trial is registered with ClinicalTrials.gov, number NCT00965185. Findings The study was done from Nov 13, 2009, to Jan 13, 2014. 19 patients were assigned to atorvastatin and 21 to placebo. 37 (93%) of 40 participants completed the study, with equivalent discontinuation rates in both groups. Baseline characteristics were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could be assessed in only 21 patients (atorvastatin. -0.03, 95% CI -0.17 to 0.12, vs placebo. -0.06, -0.25 to 0.13; p=0.77). Change in plaque could be assessed in all 37 people completing the study. Atorvastatin reduced non-calcified coronary plaque volume relative to placebo: median change -19.4% (IQR -39.2 to 9.3) versus 20.4% (-7.1 to 94.4; p=0.009, n=37). The number of high-risk plaques was significantly reduced in the atorvastatin group compared with the placebo group: change in number of low attenuation plaques -0.2 (95% CI -0.6 to 0.2) versus 0.4 (0.0, 0.7; p=0.03; n=37); and change in number of positively remodelled plaques -0.2 (-0.4 to 0.1) versus 0.4 (-0.1 to 0.8; p=0.04; n=37). Direct LDL-cholesterol (-1.00 mmol/L, 95% CI -1.38 to 0.61 vs 0.30 mmol/L, 0.04 to 0.55, p<0.0001) and lipoprotein-associated phospholipase A 2 (-52.2 ng/mL, 95% CI -70.4 to -34.0, vs -13.3 ng/mL, -32.8 to 6.2; p=0.005; n=37) decreased significantly with atorvastatin relative to placebo. Statin therapy was well tolerated, with a low incidence of clinical adverse events. Interpretation No significant effects of statin therapy on arterial inflammation of the aorta were seen as measured by FDG-PET. However, statin therapy reduced non-calcified plaque volume and high-risk coronary plaque features in HIV-infected patients. Further studies should assess whether reduction in high-risk coronary artery disease translates into effective prevention of cardiovascular events in this at-risk population. C1 [Lo, Janet; Ihenachor, Ezinne J.; Wei, Jeffrey; Looby, Sara E.; Fitch, Kathleen V.; Oh, Jinhee; Zimmerman, Chloe O.; Hwang, Janice; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Lu, Michael T.; Abbara, Suhny; Mann, Udo Hoff] Massachusetts Gen Hosp, Cardiovasc Imaging Sect, Dept Radiol, Boston, MA 02114 USA. [Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Robbins, Gregory] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Plutzky, Jorge] Harvard Univ, Sch Med, Boston, MA USA. [Plutzky, Jorge] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, LON-207,55 Fruit St, Boston, MA 02114 USA. EM sgrinspoon@mgh.harvard.edu FU NIH [K23HL092792, 5T32HL076136, 5K24HL113128, R01HL095123, P30 DK040561]; Harvard Clinical and Translational Science Center [1 UL1 RR025758-04]; National Center for Research Resources FX We thank the patients who generously donated their time to participate in this study and the nurses and bionutritionists at the MGH Clinical Research Center of the Harvard Clinical and Translational Science Center. This work was supported by NIH K23HL092792 (JL), NIH 5T32HL076136 (MTL), NIH 5K24HL113128 (UH), NIH R01HL095123 (SKG), NIH P30 DK040561 (SKG). The project described was also supported by Grant Number 1 UL1 RR025758-04, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. NR 51 TC 36 Z9 37 U1 0 U2 5 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD FEB PY 2015 VL 2 IS 2 BP E52 EP E63 DI 10.1016/S2352-3018(14)00032-0 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CU8KR UT WOS:000363791800007 PM 26424461 ER PT J AU Underhill, ML Chicko, L Berry, DL AF Underhill, Meghan L. Chicko, Lisa Berry, Donna L. TI A Nurse-Led Evidence-Based Practice Project to Monitor and Improve the Management of Chemotherapy-Induced Nausea and Vomiting SO CLINICAL JOURNAL OF ONCOLOGY NURSING LA English DT Article DE chemotherapy-induced nausea and vomiting; evidence-based practice; intervention ID COLORECTAL-CANCER; INTERVENTION; MASCC; RISK AB Chemotherapy-induced nausea and vomiting (CINV) is a common and severe symptom experienced by patients undergoing cancer treatment during the acute or delayed period. Individual characteristics can compound risk for CINV. Identification of risk factors for CINV and structured, nurse-led telephone follow-up are effective, evidence-based methods to support patients undergoing cancer treatment. The authors successfully implemented a structured, nurse-led CINV intervention to improve assessment, follow-up, and support for 30 patients undergoing chemotherapy within an adult ambulatory oncology clinic. At a Glance CINV is a common and severe symptom for patients undergoing chemotherapy. A nurse-led assessment and telephone follow-up intervention was able to successfully monitor patient-reported CINV during the acute and delayed periods. A structured, nurse-led telephone intervention is a feasible way to allow patients to report symptoms outside of a clinical visit. C1 [Underhill, Meghan L.; Berry, Donna L.] Dana Farber Canc Inst, Phyllis F Cantor Ctr Res Nursing & Patient Care S, Boston, MA 02115 USA. [Chicko, Lisa] Dana Farber New Hampshire Oncol Hematol, Londonderry, NH USA. RP Underhill, ML (reprint author), Dana Farber Canc Inst, Phyllis F Cantor Ctr Res Nursing & Patient Care S, Boston, MA 02115 USA. EM meghanl_underhill@dfci.harvard.edu OI Underhill, Meghan/0000-0002-1433-5915 FU Phyllis F. Cantor Center FX Funding for the work completed by M. Underhill was provided through the Phyllis F. Cantor Center. No financial relationships relevant to the content of this article have been disclosed by the editorial staff. Underhill can be reached at meghanl_underhill@dfci.harvard.edu, with copy to editor at CJONEditor@ons.org. NR 12 TC 0 Z9 0 U1 0 U2 10 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 EI 1538-067X J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD FEB PY 2015 VL 19 IS 1 BP 38 EP 40 DI 10.1188/15.CJON.38-40 PG 3 WC Oncology; Nursing SC Oncology; Nursing GA CF3KV UT WOS:000352448300010 PM 25689647 ER PT J AU Naholi, RM Nosek, CL Somayaji, D AF Naholi, Rowida Mohammed Nosek, Cheryl L. Somayaji, Darryl TI Stress Among New Oncology Nurses SO CLINICAL JOURNAL OF ONCOLOGY NURSING LA English DT Article DE stress; coping; coping strategies AB New oncology nurses face multiple stressors related to the predicted nursing shortage, demanding work responsibilities, and growing complexity of cancer care. The confluence of these stressors often causes new nurses to leave their profession. The loss of new nurses leads to staffing, economic, and safety concerns, which have a significant impact on the quality of oncology nursing care. At a Glance Oncology nurses are valuable resources in the healthcare system. A promising source of support identified by new oncology nurses is the use of a nurse educator coach to guide them on how to integrate self-care strategies into daily practice. The findings from the current study can be used to develop innovative interventions to achieve optimal job satisfaction, retention rates, and professional experience for new oncology nurses. C1 [Naholi, Rowida Mohammed] King Fahed Specialist Hosp, Dammam, Saudi Arabia. [Nosek, Cheryl L.] Daemen Coll, Div Hlth & Human Serv, Amherst, NY USA. [Somayaji, Darryl] Dana Farber Harvard Canc Ctr, Canc & Hlth dispar, Boston, MA USA. RP Naholi, RM (reprint author), King Fahed Specialist Hosp, Dammam, Saudi Arabia. EM rowida.naholi@daemen.edu NR 12 TC 2 Z9 2 U1 4 U2 6 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 EI 1538-067X J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD FEB PY 2015 VL 19 IS 1 BP 115 EP 117 DI 10.1188/15.CJON.115-117 PG 3 WC Oncology; Nursing SC Oncology; Nursing GA CF3KV UT WOS:000352448300022 ER PT J AU Blumenthal, KG Shenoy, ES Varughese, C Hurwitz, S Hooper, D Banerji, A AF Blumenthal, Kimberly G. Shenoy, Erica S. Varughese, Christy Hurwitz, Shelley Hooper, David Banerji, Aleena TI Impact of a Clinical Guideline for Prescribing Antibiotics to Inpatients with Reported Penicillin or Cephalosporin Allergies SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Blumenthal, Kimberly G.; Banerji, Aleena] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Rheumatol Allergy & Immunol, Boston, MA USA. [Blumenthal, Kimberly G.; Shenoy, Erica S.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Shenoy, Erica S.; Varughese, Christy; Hooper, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis,Infect Control Unit,Dept Med, Boston, MA USA. [Varughese, Christy] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Hurwitz, Shelley] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 752 BP AB232 EP AB232 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600751 ER PT J AU Kuhlen, JL Long, A Camargo, C Banerji, A AF Kuhlen, James L. Long, Aidan Camargo, Carlos, Jr. Banerji, Aleena TI Cefazolin Is a Common Cause of Perioperative Hypersensitivity Reactions SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Kuhlen, James L.; Long, Aidan; Camargo, Carlos, Jr.; Banerji, Aleena] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA USA. [Camargo, Carlos, Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 388 BP AB120 EP AB120 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600388 ER PT J AU Lax, TP Long, AD Wong, JT Wilson, MT Banerji, A AF Lax, Timothy P. Long, Aidan Wong, Johnson T. Wilson, Michael T. Banerji, Aleena TI Clinical Utility of Skin Testing Six Weeks after a Carboplatin Induced Hypersensitivity Reaction SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Lax, Timothy P.; Long, Aidan; Wong, Johnson T.; Wilson, Michael T.; Banerji, Aleena] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 754 BP AB233 EP AB233 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600753 ER PT J AU Lee, JXW Patel, AM Pham, AQ Lee, ST Flores, JB Yusin, JS AF Lee, Joyce X. W. Patel, Anil M. Pham, Andrew Q. Lee, Sabrina T. Flores, Jeffrey B. Yusin, Joseph S. TI Long-Term Adherence to Self-Injectable Epinephrine Prescription SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Lee, Joyce X. W.; Patel, Anil M.; Pham, Andrew Q.; Lee, Sabrina T.; Flores, Jeffrey B.; Yusin, Joseph S.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 762 BP AB236 EP AB236 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600761 ER PT J AU Lumry, WR Li, HH Magerl, M Maurer, M Bernstein, JA Riedl, MA Bas, M Banerji, A Rockich, K Schranz, J AF Lumry, William R. Li, H. Henry Magerl, Markus Maurer, Marcus Bernstein, Jonathan A. Riedl, Marc A. Bas, Murat Banerji, Aleena Rockich, Kevin Schranz, Jennifer TI Pharmacokinetics of Subcutaneous C1 Esterase Inhibitor (human) with Recombinant Human Hyaluronidase for the Prevention of Angioedema Attacks in Patients with Hereditary Angioedema SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Lumry, William R.] AARA Res Ctr, Dallas, TX USA. [Li, H. Henry] Inst Asthma & Allergy, Chevy Chase, MD USA. [Magerl, Markus] Charite, Dept Dermatol & Allergy, D-13353 Berlin, Germany. [Maurer, Marcus] Charite, D-13353 Berlin, Germany. [Bernstein, Jonathan A.] Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. [Riedl, Marc A.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Bas, Murat] Tech Univ Munich, Klinikum Rechts Isar, HNO Klin, D-80290 Munich, Germany. [Banerji, Aleena] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rockich, Kevin; Schranz, Jennifer] Shire, Wayne, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 622 BP AB192 EP AB192 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600621 ER PT J AU Olson, AA Manthei, DM Kim, C Mathur, SK AF Olson, Ashleigh A. Manthei, David M. Kim, Chloe Mathur, Sameer K. TI Significance of Food Skin Prick Testing in Adult Eosinophilic Esophagitis Patients SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Olson, Ashleigh A.; Manthei, David M.; Kim, Chloe; Mathur, Sameer K.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Mathur, Sameer K.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 131 BP AB42 EP AB42 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600132 ER PT J AU Patel, AM Yusin, JS AF Patel, Anil M. Yusin, Joseph S. TI Role of Patient Education in the Management and Control of Asthma in the Adult Population SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Patel, Anil M.; Yusin, Joseph S.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 220 BP AB68 EP AB68 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600221 ER PT J AU Riedl, MA Lumry, WR Li, HH Banerji, A Bernstein, JA Bas, M Magerl, M Maurer, M Chen, H Schranz, J AF Riedl, Marc A. Lumry, William R. Li, H. Henry Banerji, Aleena Bernstein, Jonathan A. Bas, Murat Magerl, Markus Maurer, Marcus Chen, Hongzi Schranz, Jennifer TI Subcutaneous Human C1-Inhibitor with Recombinant Human Hyaluronidase for the Prevention of Angioedema Attacks in Patients with Hereditary Angioedema: Results of a Randomized, Double-Blind, Dose-Ranging, Crossover Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Riedl, Marc A.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lumry, William R.] AARA Res Ctr, Dallas, TX USA. [Li, H. Henry] Inst Asthma & Allergy, Chevy Chase, MD USA. [Banerji, Aleena] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bernstein, Jonathan A.] Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. [Bas, Murat] Tech Univ Munich, Klinikum Rechts Isar, HNO Klin, D-80290 Munich, Germany. [Magerl, Markus] Charite, Dept Dermatol & Allergy, D-13353 Berlin, Germany. [Maurer, Marcus] Charite, D-13353 Berlin, Germany. [Chen, Hongzi; Schranz, Jennifer] Shire, Wayne, PA USA. NR 0 TC 3 Z9 3 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 904 BP AB278 EP AB278 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600903 ER PT J AU Sampson, HA Agbotounou, W Thebault, C Charles, R Martin, L Yang, WH Sussman, GL Brown-Whitehorn, TF Nadeau, KC Cheema, AS Leonard, SA Pongracic, JA Sauvage, C Assa'ad, AH de Blay, F Bird, JA Tilles, SA Boralevi, F Bourrier, T Shreffler, WG Hebert, J Green, TD van Wijk, RG Knulst, AC Kanny, G Kowalski, ML Schneider, LC Benhamou, PH Dupont, C AF Sampson, Hugh A. Agbotounou, Wence Thebault, Claude Charles, Ruban Martin, Laurent Yang, William H. Sussman, Gordon L. Brown-Whitehorn, Terri F. Nadeau, Kari C. Cheema, Amarjit Singh Leonard, Stephanie A. Pongracic, Jacqueline A. Sauvage, Christine Assa'ad, Amal H. de Blay, Frederic Bird, J. Andrew Tilles, Stephen A. Boralevi, Franck Bourrier, Thierry Shreffler, Wayne G. Hebert, Jacques Green, Todd David van Wijk, Roy Gerth Knulst, Andre C. Kanny, Gisele Kowalski, Marek L. Schneider, Lynda C. Benhamou, Pierre Henri Dupont, Christophe TI Epicutaneous Immunotherapy (EPIT) Is Effective and Safe to Treat Peanut Allergy: A Multi-National Double-Blind PlaceboControlled Randomized Phase IIb Trial SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Sampson, Hugh A.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Agbotounou, Wence; Thebault, Claude; Charles, Ruban; Martin, Laurent; Benhamou, Pierre Henri] DBV Technol, Bagneux, France. [Yang, William H.] Univ Ottawa, Sch Med, Ottawa, ON K1N 6N5, Canada. [Sussman, Gordon L.] Univ Toronto, Fac Med, Toronto, ON, Canada. [Brown-Whitehorn, Terri F.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Nadeau, Kari C.] Stanford Univ, Pediat Allergy Immunol, Stanford, CA 94305 USA. [Cheema, Amarjit Singh] Alpha Med Res, Mississauga, ON, Canada. [Leonard, Stephanie A.] Univ Calif San Diego, Rady Childrens Hosp, San Diego, CA USA. [Pongracic, Jacqueline A.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Sauvage, Christine] St Vincent de Paul Hosp, Lille, France. [Assa'ad, Amal H.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [de Blay, Frederic] CHRU Strasbourg, Strasbourg, France. [Bird, J. Andrew] UT Southwestern Med Ctr, Dallas, TX USA. [Tilles, Stephen A.] Northwest Asthma & Allergy Ctr, Seattle, WA USA. [Boralevi, Franck] Hop Pellegrin Enfants, Bordeaux, France. [Bourrier, Thierry] Lenval Hosp, Nice, France. [Shreffler, Wayne G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hebert, Jacques] Ctr Rech Appl Allergie Quebec, Quebec City, PQ, Canada. [Green, Todd David] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [van Wijk, Roy Gerth] Erasmus MC, Rotterdam, Netherlands. [Knulst, Andre C.] Univ Med Ctr, Utrecht, Netherlands. [Kanny, Gisele] CHU Nancy Hop Cent, Nancy, France. [Kowalski, Marek L.] Med Univ Lodz, Lodz, Poland. [Schneider, Lynda C.] Boston Childrens Hosp, Boston, MA USA. [Dupont, Christophe] Hop Necker Enfants Malad, Paris, France. NR 0 TC 6 Z9 6 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA L28 BP AB390 EP AB390 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600947 ER PT J AU Sedaghat, AR Matsui, EC Perzanowski, MS Bollinger, ME Miller, R Phipatanakul, W AF Sedaghat, Ahmad R. Matsui, Elizabeth C. Perzanowski, Matthew S. Bollinger, Mary E. Miller, Rachel Phipatanakul, Wanda TI Mouse Sensitivity Is an Independent Risk Factor for Rhinitis in Children with Asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Sedaghat, Ahmad R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Matsui, Elizabeth C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Perzanowski, Matthew S.] Columbia Univ, Dept Environm Hlth Sci, New York, NY USA. [Bollinger, Mary E.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Miller, Rachel] Columbia Univ, Div Pulm Allergy & Crit Care Med, New York, NY USA. [Phipatanakul, Wanda] Boston Childrens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 67 BP AB21 EP AB21 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600068 ER PT J AU Vickery, BP Beavers, A Berglund, J French, JP Hamilton, DK Herlihy, L Kim, EH Kulis, MD Szczepanski, N Steele, PH Virkud, Y Wright, BL Burks, AW AF Vickery, Brian P. Beavers, Ayeshia Berglund, Jelena French, Jill P. Hamilton, Deanna K. Herlihy, Lauren Kim, Edwin H. Kulis, Michael D., Jr. Szczepanski, Nicole Steele, Pamela H. Virkud, Yamini Wright, Benjamin L. Burks, A. Wesley TI High Rate of Sustained Unresponsiveness with Early-Intervention Peanut Oral Immunotherapy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Vickery, Brian P.; Beavers, Ayeshia; French, Jill P.; Hamilton, Deanna K.; Herlihy, Lauren; Kim, Edwin H.; Kulis, Michael D., Jr.; Szczepanski, Nicole; Steele, Pamela H.; Wright, Benjamin L.; Burks, A. Wesley] Univ N Carolina, Chapel Hill, NC USA. [Berglund, Jelena] Duke Univ, Durham, NC USA. [Virkud, Yamini] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 506 BP AB155 EP AB155 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600505 ER PT J AU Virkud, Y Vickery, BP Steele, PH Kulis, MD Burks, AW AF Virkud, Yamini Vickery, Brian P. Steele, Pamela H. Kulis, Michael D., Jr. Burks, A. Wesley TI Predictors of Elevated Rates of Adverse Events While on Peanut Oral Immunotherapy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Virkud, Yamini] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vickery, Brian P.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Steele, Pamela H.; Kulis, Michael D., Jr.; Burks, A. Wesley] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 510 BP AB156 EP AB156 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600509 ER PT J AU Wong, JT Banerji, A Lax, TP Long, AD AF Wong, Johnson T. Banerji, Aleena Lax, Timothy P. Long, Aidan TI Rituximab Hypersensitivity: Evaluation, Implications of Skin Testing, Potential Mechanisms, and Desensitization SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Wong, Johnson T.; Banerji, Aleena; Lax, Timothy P.; Long, Aidan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 755 BP AB233 EP AB233 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600754 ER PT J AU Heisler, JM Morales, J Donegan, JJ Jett, JD Redus, L O'Connor, JC AF Heisler, Jillian M. Morales, Juan Donegan, Jennifer J. Jett, Julianne D. Redus, Laney O'Connor, Jason C. TI The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Behavior; Issue 96; cognitive flexibility; prefrontal cortex; behavior; attention; mouse; neuropsychiatric symptom; cognitive dysfunction ID PREFRONTAL CORTEX; LESIONS; RAT AB Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity. C1 [Heisler, Jillian M.; Morales, Juan; Donegan, Jennifer J.; Jett, Julianne D.; Redus, Laney; O'Connor, Jason C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [O'Connor, Jason C.] South Texas Vet Hlth Care Syst, Audie L Murphy VA Hosp, San Antonio, TX USA. RP O'Connor, JC (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. EM oconnorj@uthscsa.edu FU National Institute of Mental Health [R01-MH090127, P30-MH089868]; National Center for Advancing Translational Sciences [UL1TR001120] FX This research was supported by grants R01-MH090127, P30-MH089868 from the National Institute of Mental Health and award number UL1TR001120 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH or NCATS. Additionally, we would like to gratefully acknowledge Dr. David Morilak for his valuable expertise in guiding the early method development. NR 15 TC 0 Z9 0 U1 4 U2 7 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD FEB PY 2015 IS 96 AR e51944 DI 10.3791/51944 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MH UT WOS:000361533700006 ER PT J AU Maeng, LY Cover, KK Landau, AJ Milad, MR Lebron-Milad, K AF Maeng, Lisa Y. Cover, Kara K. Landau, Aaron J. Milad, Mohammed R. Lebron-Milad, Kelimer TI Protocol for Studying Extinction of Conditioned Fear in Naturally Cycling Female Rats SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Behavior; Issue 96; estrogen; fear extinction; sex differences; estradiol; proestrus; metestrus; female; PTSD; anxiety ID POSTTRAUMATIC-STRESS-DISORDER; SEX-DIFFERENCES; GENDER-DIFFERENCES; ESTROGEN; TRAUMA; BRAIN; WOMEN; REPLACEMENT; ABILITIES; EXPOSURE AB Extinction of conditioned fear has been extensively studied in male rodents. Recently, there have been an increasing number of studies indicating that neural mechanisms for certain behavioral tasks and response behaviors are different in females and males. Using females in research studies can represent a challenge because of the variation of gonadal hormones during their estrous cycle. This protocol describes well-established procedures that are useful in investigating the role of estrogen in fear extinction memory consolidation in female rats. Phase of the estrous cycle and exogenous estrogen administration prior to extinction training can influence extinction recall 24 hr later. The vaginal swabbing technique for estrous phase identification described here aids the examination and manipulation of naturally cycling gonadal hormones. The use of this basic rodent model may further delineate the mechanisms by which estrogen can modulate fear extinction memory in females. C1 [Maeng, Lisa Y.; Cover, Kara K.; Landau, Aaron J.; Milad, Mohammed R.; Lebron-Milad, Kelimer] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Maeng, Lisa Y.; Milad, Mohammed R.; Lebron-Milad, Kelimer] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Lebron-Milad, K (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM kmilad@nmr.mgh.harvard.edu FU NIMH [R01 MH097880]; Department of Psychiatry at MGH FX Mohammed R. Milad is supported by NIMH grant R01 MH097880 and institutional funds from the Department of Psychiatry at MGH. NR 31 TC 0 Z9 0 U1 2 U2 2 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD FEB PY 2015 IS 96 AR e52202 DI 10.3791/52202 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MH UT WOS:000361533700012 ER PT J AU Padera, TP AF Padera, Timothy P. TI Blood-Brain Barrier in Health and Disease & Lymphatic vessels in health and disease SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Editorial Material ID VEGF-C; VASCULATURE; ENDOTHELIUM; METASTASIS; RECEPTOR; SYSTEM; CANCER; LYMPHANGIOGENESIS; EXPRESSION; REJECTION C1 [Padera, Timothy P.] Massachusetts Gen Hosp, Ctr Canc, Dept Radiat Oncol, EL Steele Labs, Boston, MA 02114 USA. [Padera, Timothy P.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Padera, TP (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Radiat Oncol, EL Steele Labs, Boston, MA 02114 USA. FU NIH HHS [DP2 OD008780] NR 34 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD FEB PY 2015 VL 38 DI 10.1016/j.semcdb.2015.03.007 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CF4ER UT WOS:000352502000002 PM 25868083 ER PT J AU Berbiglia, LB Shaik, M Gernand, J Saha, SK Surapaneni, A Wiese, D Arora, M Singh, T Saha, S AF Berbiglia, L. B. Shaik, M. Gernand, J. Saha, S. K. Surapaneni, A. Wiese, D. Arora, M. Singh, T. Saha, S. TI The Impact of Nodal Metastasis on Survival in Stage IV Colon Cancer: Analysis of National Cancer Data Base versus Surveillance, Epidemiology and End Results SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Berbiglia, L. B.; Shaik, M.; Gernand, J.; Surapaneni, A.; Wiese, D.; Arora, M.; Singh, T.; Saha, S.] McLaren Reg Med Ctr, Flint, MI USA. [Saha, S. K.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P138 BP S87 EP S87 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500238 ER PT J AU Chan, CH Williams, RT Dias-Santagata, D Iafrate, A Murphy, JE Ryan, DP Cusack, JC AF Chan, C. H. Williams, R. T. Dias-Santagata, D. Iafrate, A. Murphy, J. E. Ryan, D. P. Cusack, J. C. TI IDH1 Mutation in Small Bowel Adenocarcinoma SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Chan, C. H.; Williams, R. T.; Dias-Santagata, D.; Iafrate, A.; Murphy, J. E.; Ryan, D. P.; Cusack, J. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P347 BP S157 EP S157 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500440 ER PT J AU Fuentes, E Ahmad, R Hong, TS Kwak, EL Clark, JW Rattner, DW Mullen, JT AF Fuentes, E. Ahmad, R. Hong, T. S. Kwak, E. L. Clark, J. W. Rattner, D. W. Mullen, J. T. TI The Impact of Neoadjuvant Therapy for Gastroesophageal Adenocarcinoma on postoperative Morbidity and Mortality SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Fuentes, E.; Ahmad, R.; Hong, T. S.; Kwak, E. L.; Clark, J. W.; Rattner, D. W.; Mullen, J. T.] Massachusetts Gen Hosp, Surg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P367 BP S165 EP S165 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500460 ER PT J AU Harnsberger, CR Fuchs, HF Broderick, RC Jacobsen, GR Sandler, BJ Chang, DC Kelly, K Horgan, S AF Harnsberger, C. R. Fuchs, H. F. Broderick, R. C. Jacobsen, G. R. Sandler, B. J. Chang, D. C. Kelly, K. Horgan, S. TI A Simple preoperative Risk Scale Accurately Predicts perioperative Mortality following Gastric Resection for Malignancy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Harnsberger, C. R.; Fuchs, H. F.; Broderick, R. C.; Jacobsen, G. R.; Sandler, B. J.; Kelly, K.; Horgan, S.] Univ Calif San Diego, Dept Surg, Ctr Future Surg, San Diego, CA 92103 USA. [Chang, D. C.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA 77 BP S32 EP S32 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500077 ER PT J AU McEvoy, M Fiedler, AG Merrill, AL Coopey, SB Specht, MC Hughes, KS Gadd, MA Golshan, M Smith, BL AF McEvoy, M. Fiedler, A. G. Merrill, A. L. Coopey, S. B. Specht, M. C. Hughes, K. S. Gadd, M. A. Golshan, M. Smith, B. L. TI Risk of Axillary Recurrence in Breast Cancer Patients with a Negative Sentinel Node Biopsy (SNB) who do not Receive Radiation: Implications for Partial Breast Irradiation (PBI) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [McEvoy, M.; Fiedler, A. G.; Merrill, A. L.; Coopey, S. B.; Specht, M. C.; Hughes, K. S.; Gadd, M. A.; Smith, B. L.] Massachusetts Gen Hosp, Breast Surg Oncol, Boston, MA 02114 USA. [Golshan, M.] Brigham & Womens, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P81 BP S70 EP S70 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500183 ER PT J AU McEvoy, M Merrill, AL Coopey, SB Specht, MC Gadd, MA Hughes, KS Smith, BL AF McEvoy, M. Merrill, A. L. Coopey, S. B. Specht, M. C. Gadd, M. A. Hughes, K. S. Smith, B. L. TI Long-term Outcomes of Multiple Wire Localization for Breast Cancer: Multiple Wires do not Increase Recurrence, Unplanned Imaging or Biopsies SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [McEvoy, M.; Merrill, A. L.; Coopey, S. B.; Specht, M. C.; Gadd, M. A.; Hughes, K. S.; Smith, B. L.] Massachusetts Gen Hosp, Breast Surg Oncol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P61 BP S64 EP S64 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500163 ER PT J AU Merrill, AL Coopey, SB Tang, R Maureen, MP Specht, MC Hughes, KS Gadd, MA Smith, BL AF Merrill, A. L. Coopey, S. B. Tang, R. Maureen, M. P. Specht, M. C. Hughes, K. S. Gadd, M. A. Smith, B. L. TI Implications of New Lumpectomy Margin Guidelines for Breast-conserving Surgery: Changes in Re-excision Rates and Predicted Rates of Residual Tumor SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Merrill, A. L.; Coopey, S. B.; Tang, R.; Maureen, M. P.; Specht, M. C.; Hughes, K. S.; Gadd, M. A.; Smith, B. L.] Massachusetts Gen Hosp, Gen Surg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P44 BP S58 EP S58 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500147 ER PT J AU Miller, CL Coopey, SB Rafferty, EA Gadd, MA Smith, BL Specht, MC AF Miller, C. L. Coopey, S. B. Rafferty, E. A. Gadd, M. A. Smith, B. L. Specht, M. C. TI Comparison of Intraoperative Specimen Mammography to Standard Specimen Mammography: A Randomized Trial SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Miller, C. L.; Coopey, S. B.; Rafferty, E. A.; Gadd, M. A.; Smith, B. L.; Specht, M. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P86 BP S71 EP S72 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500188 ER PT J AU Nakhlis, F Gilmore, L Gelman, R King, TA Bedrosian, I Ludwig, K Hwang, E Wiley, S Hudis, C Iglehart, J Lawler, E Ryabin, N Golshan, M Schnitt, S AF Nakhlis, F. Gilmore, L. Gelman, R. King, T. A. Bedrosian, I. Ludwig, K. Hwang, E. Wiley, S. Hudis, C. Iglehart, J. Lawler, E. Ryabin, N. Golshan, M. Schnitt, S. TI The Incidence of Adjacent Synchronous Invasive Carcinoma and/or DCIS in Patients with Lobular Neoplasia on Core Biopsy: Results from a Prospective Multi-institutional Registry (TBCRC 020) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Nakhlis, F.; Golshan, M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gilmore, L.] Mt Auburn Hosp, Cambridge, MA USA. [Gelman, R.; Iglehart, J.; Lawler, E.; Ryabin, N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [King, T. A.; Hudis, C.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Bedrosian, I.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ludwig, K.] Indiana Univ Purdue Univ, Indianapolis, IN 46202 USA. [Wiley, S.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Hwang, E.] Duke Univ, Med Ctr, Durham, NC USA. [Schnitt, S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA 34 BP S17 EP S17 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500035 ER PT J AU Qu, M Lubitz, C Bergeron, S Rickard, J Wasif, N AF Qu, M. Lubitz, C. Bergeron, S. Rickard, J. Wasif, N. TI A Meta-analysis of the Association between Radiation Therapy and Survival for Surgically Resected Extremity and Trunk Soft Tissue Sarcoma SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Wasif, N.] Mayo Clin Arizona, Surg, Phoenix, AZ USA. [Qu, M.] Queens Univ, Kingston, ON, Canada. [Lubitz, C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bergeron, S.] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. [Rickard, J.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA 22 BP S13 EP S13 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500023 ER PT J AU Saha, S Shaik, M Berbiglia, LB Surapaneni, A Gernand, J Hicks, M Saha, SK Paez, G Grewal, S Arora, M AF Saha, S. Shaik, M. Berbiglia, L. B. Surapaneni, A. Gernand, J. Hicks, M. Saha, S. K. Paez, G. Grewal, S. Arora, M. TI Tumor Size as a Prognostic Factor in Colon Cancer: A Comparison of National Cancer Data Base versus Surveillance, Epidemiology and End-results Analysis SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Saha, S.; Shaik, M.; Berbiglia, L. B.; Surapaneni, A.; Gernand, J.; Hicks, M.; Paez, G.; Grewal, S.; Arora, M.] McLaren Reg Med Ctr, Flint, MI USA. [Saha, S. K.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P127 BP S84 EP S84 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500227 ER PT J AU Yao, K Rosenberg, S Belkora, J Sisco, M Novotny, P Liederbach, E Sepucha, K Tilburt, J Rabbitt, S Bedrosian, I AF Yao, K. Rosenberg, S. Belkora, J. Sisco, M. Novotny, P. Liederbach, E. Sepucha, K. Tilburt, J. Rabbitt, S. Bedrosian, I. TI Knowledge Deficits and Concern about Contralateral Breast Cancer Risk: A Prospective Study SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Sisco, M.; Liederbach, E.; Rabbitt, S.] NorthShore Univ HealthSyst, Surg, Evanston, IL USA. [Yao, K.] NorthShore Univ HealthSyst, Evanston, IL USA. [Rosenberg, S.; Sepucha, K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Belkora, J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Novotny, P.; Tilburt, J.] Mayo Clin, Rochester, MN USA. [Bedrosian, I.] MD Anderson, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P57 BP S62 EP S63 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500159 ER PT J AU Giedt, RJ Weissleder, R AF Giedt, R. J. Weissleder, R. TI Automated analysis of drug distribution in intravital imaging SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT AACR/SNMMI Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy CY FEB 11-14, 2015 CL San Diego, CA SP Amer Assoc Canc Res, Soc Nucl Med & Mol Imaging C1 [Giedt, R. J.; Weissleder, R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD FEB 1 PY 2015 VL 56 IS 2 SU 1 MA 22 BP 8 EP 8 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CP5PH UT WOS:000359935300023 ER PT J AU Breakefield, XO van der Vos, KE Abels, ER Edward, KY Carrizosa, E Tannous, BA Mempel, TR Lai, CP AF Breakefield, X. O. van der Vos, K. E. Abels, E. R. Edward, K. Y. Carrizosa, E. Tannous, B. A. Mempel, T. R. Lai, C. P. TI Extracellular vesicles/RNA as tactics in glioblastoma progression. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT AACR/SNMMI Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy CY FEB 11-14, 2015 CL San Diego, CA SP Amer Assoc Canc Res, Soc Nucl Med & Mol Imaging C1 [Breakefield, X. O.; van der Vos, K. E.; Abels, E. R.; Edward, K. Y.; Carrizosa, E.; Tannous, B. A.; Mempel, T. R.; Lai, C. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD FEB 1 PY 2015 VL 56 IS 2 SU 1 MA 3 BP 23 EP 23 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CP5PH UT WOS:000359935300072 ER PT J AU Hasan, T AF Hasan, T. TI New frontiers: combining molecular imaging and nanomedicine to light up and selectively destroy cancer. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT AACR/SNMMI Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy CY FEB 11-14, 2015 CL San Diego, CA SP Amer Assoc Canc Res, Soc Nucl Med & Mol Imaging C1 [Hasan, T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD FEB 1 PY 2015 VL 56 IS 2 SU 1 MA 11 BP 24 EP 24 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CP5PH UT WOS:000359935300080 ER PT J AU Yachimski, P Hur, C AF Yachimski, Patrick Hur, Chin TI Evidence-based endoscopic management of Barrett's esophagus SO GASTROENTEROLOGY REPORT LA English DT Review DE Barrett's esophagus; esophageal adenocarcinoma; endoscopic surveillance; endoscopic eradication therapy ID HIGH-GRADE DYSPLASIA; GASTROESOPHAGEAL-REFLUX DISEASE; RADIOFREQUENCY ABLATION; MUCOSAL RESECTION; INTRAMUCOSAL CARCINOMA; INTESTINAL METAPLASIA; COMMUNITY PRACTICE; EARLY NEOPLASIA; CANCER-RISK; ADENOCARCINOMA AB Barrett's esophagus (BE) develops as a consequence of chronic esophageal acid exposure, and is the major risk factor for esophageal adenocarcinoma (EAC). The practices of endoscopic screening for-and surveillance of-BE, while widespread, have failed to reduce the incidence of EAC. The majority of EACs are diagnosed in patients without a known history of BE, and current diagnostic tools are lacking in their ability to stratify patients with BE into those at low risk and those at high risk for progression to malignancy. Nonetheless, advances in endoscopic imaging and mucosal therapeutics have provided unprecedented opportunities for intervention for BE, and have vastly altered the approach to management of BE-associated mucosal neoplasia. C1 [Yachimski, Patrick] Vanderbilt Univ, Med Ctr, Div Gastroenterol Hepatol & Nutr, Nashville, TN 37232 USA. [Hur, Chin] Harvard Univ, Sch Med, Div Gastroenterol, Boston, MA USA. [Hur, Chin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. RP Yachimski, P (reprint author), Vanderbilt Univ, Med Ctr, Div Gastroenterol Hepatol & Nutr, Vanderbilt Clin 1660, Nashville, TN 37232 USA. EM patrick.yachimski@vanderbilt.edu OI Hur, Chin/0000-0002-2819-7576 NR 60 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND EI 2052-0034 J9 GASTROENTEROL REP PD FEB PY 2015 VL 3 IS 1 BP 54 EP 62 DI 10.1093/gastro/gou059 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CP5CQ UT WOS:000359899300007 PM 25237038 ER PT J AU Tang, MH Pinsky, EG AF Tang, Michael H. Pinsky, Elizabeth G. TI Mood and Affect Disorders SO PEDIATRICS IN REVIEW LA English DT Editorial Material AB Depressive disorders are common in children and adolescents, with estimates for depressive episodes as high as 18.2% for girls and 7.7% for boys by age 17 years, and are a major cause of morbidity and even mortality. The primary care pediatrician should be able to (1) diagnose depressive disorders and use standardized instruments; (2) ask about suicide, self-harm, homicide, substance use, mania, and psychosis; (3) triage the severity of illness; (4) be aware of the differential diagnosis, including normal development, other depressive disorders, bipolar disorders, and comorbid disorders, such as anxiety and substance use; (5) refer to evidenced-based psychotherapies; (6) prescribe first-line medications; and (7) provide ongoing coordination in a medical home. Pediatric bipolar disorders and the new disruptive mood dysregulation disorder (DMDD) diagnoses are controversial but not uncommon, with prevalence estimates ranging from 0.8% to 4.3% in children at various ages. Although the pediatrician is not likely to be prescribing medications for children with bipolar disorder and DMDD diagnoses, all clinicians should be familiar with common neuroleptics and other mood stabilizers, including important potential adverse effects. Basic management of depressive and bipolar disorders is an important skill for primary care pediatricians. C1 [Tang, Michael H.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Tang, Michael H.] McLean Hosp, Boston, MA USA. [Pinsky, Elizabeth G.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Pinsky, Elizabeth G.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Pinsky, Elizabeth G.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP Tang, MH (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 2 Z9 2 U1 1 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0191-9601 EI 1526-3347 J9 PEDIATR REV JI Pediatr. Rev. PD FEB PY 2015 VL 36 IS 2 BP 52 EP 61 PG 10 WC Pediatrics SC Pediatrics GA CP5LB UT WOS:000359922300003 PM 25646309 ER PT J AU Bhise, V Singh, H AF Bhise, Viraj Singh, Hardeep TI Measuring diagnostic safety of inpatients: time to set sail in uncharted waters SO DIAGNOSIS LA English DT Editorial Material C1 [Singh, Hardeep] VA Med Ctr 152, Houston, TX 77030 USA. [Bhise, Viraj; Singh, Hardeep] Michael E DeBakey VA Med Ctr, Houston Vet Affairs Ctr Innovat Qual Effectivenes, Houston, TX USA. [Bhise, Viraj; Singh, Hardeep] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Bhise, Viraj] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Management Policy & Community Hlth, Houston, TX 77030 USA. RP Singh, H (reprint author), VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.edu FU AHRQ HHS [R01 HS022087]; NCI NIH HHS [K23 CA125585] NR 10 TC 0 Z9 0 U1 0 U2 0 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 2194-8011 EI 2194-802X J9 DIAGNOSIS JI Diagnosis PD FEB PY 2015 VL 2 IS 1 BP 1 EP 2 DI 10.1515/dx-2015-0003 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CL9FA UT WOS:000357280000002 PM 26955511 ER PT J AU Szalat, R Munshi, NC AF Szalat, Raphael Munshi, Nikhil C. TI Genomic heterogeneity in multiple myeloma SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID INHERITED GENETIC SUSCEPTIBILITY; SINGLE-AGENT BORTEZOMIB; WORKING GROUP IMWG; HIGH-DOSE THERAPY; MOLECULAR CLASSIFICATION; MONOCLONAL GAMMOPATHY; EXPRESSION SIGNATURE; INTRACLONAL HETEROGENEITY; HISTONE METHYLTRANSFERASE; RISK-STRATIFICATION AB Multiple myeloma (MM) is an incurable malignancy in majority of patients characterized by clonal proliferation of plasma cells. To date, treatment is established based on general conditions and age of patients. However, MM is a heterogeneous disease, featured by various subtypes and different outcomes. Thus, the understanding of MM biology is currently a major challenge to eventually cure the disease. During the last decade, karyotype studies and gene expression profiling have identified robust prognostic markers as well as a widespread genomic landscape. More recently, studies of epigenetic, transcriptional modifications and next generation sequencing have allowed characterization of critical genes and pathways, clonal heterogeneity and mutational profiles involved in myelomagenesis. Altogether, these findings constitute important tools to develop new targeted and personalized therapies in MM. C1 [Szalat, Raphael; Munshi, Nikhil C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA USA. RP Munshi, NC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM nikhil_munshi@dfci.harvard.edu NR 77 TC 10 Z9 10 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X EI 1879-0380 J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD FEB PY 2015 VL 30 BP 56 EP 65 DI 10.1016/j.gde.2015.03.008 PG 10 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA CM1KL UT WOS:000357439700008 PM 25982873 ER PT J AU Dodson, MV Allen, RE Du, M Bergen, WG Velleman, SG Poulos, SP Fernyhough-Culver, M Wheeler, MB Duckett, SK Young, MRI Voy, BH Jiang, Z Hausman, GJ AF Dodson, M. V. Allen, R. E. Du, M. Bergen, W. G. Velleman, S. G. Poulos, S. P. Fernyhough-Culver, M. Wheeler, M. B. Duckett, S. K. Young, M. R. I. Voy, B. H. Jiang, Z. Hausman, G. J. TI INVITED REVIEW: Evolution of meat animal growth research during the past 50 years: Adipose and muscle stem cells SO JOURNAL OF ANIMAL SCIENCE LA English DT Review DE adipocytes; adipose tissue; animal growth; satellite cells; skeletal muscle tissue; stem cells ID SYNDECAN-4 CYTOPLASMIC DOMAIN; COMBINED TRENBOLONE ACETATE; BOVINE ADIPOCYTE CULTURES; BETA-ADRENERGIC AGONISTS; ADULT SKELETAL-MUSCLE; SATELLITE CELLS; FIBROBLAST-GROWTH; IN-VITRO; REGENERATIVE MEDICINE; ADIPONECTIN RECEPTORS AB If one were to compare today's animal growth research to research from a mere 50 yr ago, one would see programs with few similarities. The evolution of this research from whole-animal through cell-based and finally molecular and genomic studies has been enhanced by the identification, isolation, and in vitro evaluation of adipose- and muscle-derived stem cells. This paper will highlight the struggles and the milestones that make this evolving area of research what it is today. The contribution of adipose and muscle stem cell research to development and growth, tissue regeneration, and final carcass composition are reviewed. C1 [Dodson, M. V.; Du, M.; Jiang, Z.] Washington State Univ, Dept Anim Sci, Pullman, WA 99164 USA. [Allen, R. E.] Univ Arizona, Dept Anim Sci, Tucson, AZ 85721 USA. [Bergen, W. G.] Auburn Univ, Dept Anim Sci, Program Cell & Mol Biosci, Auburn, AL 36849 USA. [Velleman, S. G.] Ohio State Univ, OARDC, Wooster, OH 44691 USA. [Poulos, S. P.] Akeso Hlth LLC, Decatur, GA 30033 USA. [Fernyhough-Culver, M.] Abitec Corp, Columbus, OH 43215 USA. [Wheeler, M. B.] Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA. [Duckett, S. K.] Clemson Univ, Anim & Vet Sci, Clemson, SC 29634 USA. [Young, M. R. I.] Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC 29401 USA. [Young, M. R. I.] Med Univ S Carolina, Dept Otolaryngol, Charleston, SC 29401 USA. [Voy, B. H.] Univ Tennessee, Dept Anim Sci, Knoxville, TN 37996 USA. [Hausman, G. J.] Univ Georgia, Dept Anim & Dairy Sci, Athens, GA 30602 USA. RP Dodson, MV (reprint author), Washington State Univ, Dept Anim Sci, Pullman, WA 99164 USA. EM dodson@wsu.edu RI Du, Min/H-4311-2011; Jiang, Zhihua/A-3378-2008 OI Du, Min/0000-0002-7232-072X; Jiang, Zhihua/0000-0003-1986-088X NR 263 TC 2 Z9 2 U1 3 U2 20 PU AMER SOC ANIMAL SCIENCE PI CHAMPAIGN PA PO BOX 7410, CHAMPAIGN, IL 61826-7410 USA SN 0021-8812 EI 1525-3163 J9 J ANIM SCI JI J. Anim. Sci. PD FEB PY 2015 VL 93 IS 2 BP 457 EP 481 DI 10.2527/jas2014-8221 PG 25 WC Agriculture, Dairy & Animal Science SC Agriculture GA CL6OO UT WOS:000357086600001 PM 26020737 ER PT J AU Ebrahimzadeh, MH Moradi, A Vahedi, E Kachooei, AR AF Ebrahimzadeh, Mohammad H. Moradi, Ali Vahedi, Ehsan Kachooei, Amir Reza TI Mid-term clinical outcome of radial shortening for kienbock disease SO JOURNAL OF RESEARCH IN MEDICAL SCIENCES LA English DT Article DE Kienbock's disease; mid-term; radial shortening ID PROXIMAL ROW CARPECTOMY; FOLLOW-UP; BONE-GRAFT; OSTEOTOMY; FRACTURES; WRIST AB Background: To evaluate the intermediate-term outcomes of radius shortening as a treatment for Kienbock's disease. Materials and Methods: In a historical cohort, 16 skeletally mature patients (9 men and 7 women) with Kienbock disease, who were treated with radial shortening osteotomy between 2002 and 2012, were reviewed in our study. The mean age of our patients was 30 (range 18-43) years old. According to Litchman staging, there were 7 wrists at stage II and 9 wrists at stage III (6 at stage IIIA and 3 at stage IIIB). The data of grip strength, pain (visual analog scale (VAS) score), wrist range of motion (ROM), ulnar variance (according to Palmer method), and the Lichtman stage were gathered before and after surgery. We evaluated overall wrist function using the Mayo Wrist score and disabilities of the arm shoulder and hand (DASH) score before surgery and at the last follow-up. Results: The average of follow-up was 7 years (range from 5 to 9 years). Preoperative ulnar variance was -1.3 mm (range from 2.5 to 1) preoperatively. The mean postoperative ulnar variance was 1 mm positive (range from 0.5 to 1.5). The VAS pain score, the mean arc of wrist flexion and extension, and grip strength improved significantly preoperatively compared to after recovery from surgery. The Lichtman stage was unchanged in nine patients, one grade worse in six patients, and one grade better in one patient. The mean DASH and Mayo scores improved significantly postoperatively compare with preoperation. Comparing preoperative positive, neuter, and negative ulnar variance, there was no significant difference in terms of VAS, DASH, and Mayo scores as well as ROM and grip strength. Conclusion: Our study shows that radius shortening surgery improves pain and disability regardless of ulnar variance. C1 [Ebrahimzadeh, Mohammad H.; Moradi, Ali] Mashhad Univ Med Sci, Ghaem Hosp, Orthopaed Res Ctr, Mashhad 9176699199, Iran. [Moradi, Ali; Vahedi, Ehsan; Kachooei, Amir Reza] Mashhad Univ Med Sci, Mashhad 9176699199, Iran. [Moradi, Ali; Kachooei, Amir Reza] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Moradi, A (reprint author), Mashhad Univ Med Sci, Ghaem Hosp, Orthopaed Res Ctr, Mashhad 9176699199, Iran. EM Moradial@mums.ac.ir FU Mashhad University of Medical Sciences [87711] FX We would like to appreciate Dr. David Ring for his kind collaboration in scientific and English editing of the article. Also we should thank Mashhad University of Medical Sciences for approving and granting this project (Project number: 87711). NR 31 TC 0 Z9 0 U1 0 U2 1 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 1735-1995 EI 1735-7136 J9 J RES MED SCI JI J. Res. Med. Sci. PD FEB PY 2015 VL 20 IS 2 BP 146 EP 149 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CL9AC UT WOS:000357265300007 PM 25983766 ER PT J AU De Jager, PL Hacohen, N Mathis, D Regev, A Stranger, BE Benoist, C AF De Jager, Philip L. Hacohen, Nir Mathis, Diane Regev, Aviv Stranger, Barbara E. Benoist, Christophe TI ImmVar project: Insights and design considerations for future studies of "healthy" immune variation SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Genetic variation; eQTL; Healty immune variation; Genetic architecture ID GENE-EXPRESSION; INFECTION; SYSTEMS AB The Immune Variation (ImmVar) project is one of a series of recent efforts to map the extent of variation in immune function in healthy human subjects. The focus of our initial studies involved a careful mapping of the genetic architecture of the adaptive and innate immunologic transcriptomes. Our studies highlight the shared nature of this immunogenetic architecture across human populations, the important role of context in uncovering effects of genetic variation, and the fact that, over all tested genes, common genetic variation account for a minority of the variance in the immune transcriptome in healthy subjects. Yet, it is an element of the variance that can be measured very precisely and will play an important role in the design of future studies. We therefore discuss how insights from ImmVar and similar studies inform experimental strategies and frame the design of future studies of immune function in health and disease. (C) 2015 Elsevier Ltd. All rights reserved. C1 [De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Inst Neurosci, Dept Neurol, Boston, MA 02115 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Inst Neurosci, Dept Psychiat, Boston, MA 02115 USA. [De Jager, Philip L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [De Jager, Philip L.; Hacohen, Nir; Regev, Aviv] Broad Inst, Cambridge, MA 02142 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Regev, Aviv] Howard Hughes Med Inst, Chevy Chase, MD USA. [Regev, Aviv] MIT, Dept Biol, Cambridge, MA 02139 USA. [Stranger, Barbara E.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Stranger, Barbara E.] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. RP De Jager, PL (reprint author), 77 Ave Louis Pasteur,NRB168, Boston, MA 02115 USA. EM pdejager@partners.org OI Stranger, Barbara/0000-0001-9021-7331 NR 18 TC 10 Z9 11 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD FEB PY 2015 VL 27 IS 1 BP 51 EP 57 DI 10.1016/j.smim.2015.03.003 PG 7 WC Immunology SC Immunology GA CH6JI UT WOS:000354142500008 PM 25819567 ER PT J AU Dimitriadis, I Batsis, M Murtadi, G Wright, D Souter, I AF Dimitriadis, I. Batsis, M. Murtadi, G. Wright, D. Souter, I. TI Can Age and AMH Predict What We Will See in the Time-Lapse Incubator? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 63rd Annual Meeting of the Pacific-Coast-Reproductive-Society (PCRS) on Building Connections, Achieving Excellence CY MAR 11-15, 2015 CL Rancho Mirage, CA SP Pacific Coast Reprod Soc C1 [Dimitriadis, I.; Batsis, M.; Murtadi, G.; Wright, D.; Souter, I.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Obstet & Gynecol,Div Reprod Endocrinol & Inf, Boston, MA 02114 USA. [Dimitriadis, I.] Tufts Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2015 VL 103 IS 2 SU S MA P-59 BP E35 EP E35 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CH2GJ UT WOS:000353843400068 ER PT J AU Dimitriadis, I Murtadi, G Souter, I Petrozza, J AF Dimitriadis, I. Murtadi, G. Souter, I. Petrozza, J. TI Does a Prolonged Follicular Phase Affect Outcomes in PCOS/Anovulatory Patients Undergoing Ovulation Induction/Intrauterine Insemination (OI/IUI) Treatments? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 63rd Annual Meeting of the Pacific-Coast-Reproductive-Society (PCRS) on Building Connections, Achieving Excellence CY MAR 11-15, 2015 CL Rancho Mirage, CA SP Pacific Coast Reprod Soc C1 [Dimitriadis, I.; Murtadi, G.; Souter, I.; Petrozza, J.] Harvard Univ, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil,Sch Med, Boston, MA 02114 USA. [Dimitriadis, I.] Tufts Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2015 VL 103 IS 2 SU S MA P-21 BP E18 EP E18 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CH2GJ UT WOS:000353843400030 ER PT J AU Axelrad, J Bernheim, O Colombel, JF Malerba, S Ananthakrishnan, A Yajnik, V Hoffman, G Agrawal, M Lukin, D Desai, A Mceachern, E Bosworth, B Scherl, E Reyes, A Zaidi, H Mudireddy, P DiCaprio, D Sultan, K Korelitz, B Wang, E Williams, R Chen, L Katz, S Itzkowitz, S AF Axelrad, J. Bernheim, O. Colombel, J. -F. Malerba, S. Ananthakrishnan, A. Yajnik, V. Hoffman, G. Agrawal, M. Lukin, D. Desai, A. Mceachern, E. Bosworth, B. Scherl, E. Reyes, A. Zaidi, H. Mudireddy, P. DiCaprio, D. Sultan, K. Korelitz, B. Wang, E. Williams, R. Chen, L. Katz, S. Itzkowitz, S. TI Patients with Inflammatory Bowel Disease and a history of cancer: The risk of cancer following exposure to immunosuppression SO JOURNAL OF CROHNS & COLITIS LA English DT Meeting Abstract C1 [Axelrad, J.] Icahn Sch Med Mt Sinai, Med, New York, NY USA. [Bernheim, O.; Colombel, J. -F.; Itzkowitz, S.] Icahn Sch Med Mt Sinai, Div Gastroenterol, New York, NY USA. [Malerba, S.] Icahn Sch Med Mt Sinai, Dept Hlth Evidence & Policy, New York, NY USA. [Ananthakrishnan, A.; Yajnik, V.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Hoffman, G.] Albert Einstein Coll Med, Med, New York, NY USA. [Agrawal, M.] Montefiore Med Ctr, Med, New York, NY USA. [Lukin, D.] Montefiore Med Ctr, Div Gastroenterol & Liver Dis, New York, NY USA. [Desai, A.; Bosworth, B.; Scherl, E.] New York Presbyterian Weill Cornell Med Ctr, Div Gastroenterol, New York, NY USA. [Mceachern, E.] Weill Cornell Med Coll, Med, New York, NY USA. [Reyes, A.] North Shore Long Isl Jewish Univ Hosp, Med, Manhasset, NY USA. [Zaidi, H.; Sultan, K.] North Shore Long Isl Jewish Univ Hosp, Div Gastroenterol, Manhasset, NY USA. [Mudireddy, P.; Korelitz, B.] North Shore Long Isl Jewish Lenox Hill Hosp, Div Gastroenterol, New York, NY USA. [DiCaprio, D.] North Shore Long Isl Jewish Lenox Hill Hosp, Med, New York, NY USA. [Wang, E.; Williams, R.] NYU Langone Med Ctr, Med, New York, NY USA. [Chen, L.; Katz, S.] NYU Langone Med Ctr, Div Gastroenterol, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1873-9946 EI 1876-4479 J9 J CROHNS COLITIS JI J. Crohns Colitis PD FEB PY 2015 VL 9 SU 1 MA OP020 BP S12 EP S13 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CH1VW UT WOS:000353811200021 ER PT J AU Yajnik, V Khan, N Dubinsky, M Axler, J Green, A Abhyankar, B Lasch, K AF Yajnik, V. Khan, N. Dubinsky, M. Axler, J. Green, A. Abhyankar, B. Lasch, K. TI Efficacy and safety of vedolizumab with advancing age in patients with ulcerative colitis: Results from the GEMINI 1 study SO JOURNAL OF CROHNS & COLITIS LA English DT Meeting Abstract C1 [Yajnik, V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastroenterol, Boston, MA USA. [Khan, N.] Univ Penn, Perelman Sch Med, Med, Philadelphia, PA 19104 USA. [Dubinsky, M.] Mt Sinai Hosp, Pediat Gastroenterol, New York, NY 10029 USA. [Axler, J.] Univ Toronto, Toronto Digest Dis Associates, Gastroenterol, Toronto, ON, Canada. [Green, A.] Takeda Global Res & Dev Ctr Europe Ltd, Stat, London, England. [Abhyankar, B.] Takeda Global Res & Dev Ctr Europe Ltd, Clin Sci, London, England. [Lasch, K.] Takeda Pharmaceut Int Inc, Med Affairs, Deerfield, IL USA. NR 1 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1873-9946 EI 1876-4479 J9 J CROHNS COLITIS JI J. Crohns Colitis PD FEB PY 2015 VL 9 SU 1 MA P566 BP S363 EP S364 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CH1VW UT WOS:000353811200681 ER PT J AU Yajnik, V Khan, N Dubinsky, M Axler, J Green, A Abhyankar, B Lasch, K AF Yajnik, V. Khan, N. Dubinsky, M. Axler, J. Green, A. Abhyankar, B. Lasch, K. TI Efficacy and safety of vedolizumab with advancing age in patients with Crohn's disease: Results from the GEMINI 2 study SO JOURNAL OF CROHNS & COLITIS LA English DT Meeting Abstract C1 [Yajnik, V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastroenterol, Boston, MA USA. [Khan, N.] Univ Penn, Perelman Sch Med, Med, Philadelphia, PA 19104 USA. [Dubinsky, M.] Mt Sinai Hosp, Pediat Gastroenterol, New York, NY 10029 USA. [Axler, J.] Univ Toronto, Toronto Digest Dis Associates, Gastroenterol, Toronto, ON, Canada. [Green, A.] Takeda Global Res & Dev Ctr Europe Ltd, Stat, London, England. [Abhyankar, B.] Takeda Global Res & Dev Ctr Europe Ltd, Clin Sci, London, England. [Lasch, K.] Takeda Pharmaceut Int Inc, Med Affairs, Deerfield, IL USA. NR 1 TC 0 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1873-9946 EI 1876-4479 J9 J CROHNS COLITIS JI J. Crohns Colitis PD FEB PY 2015 VL 9 SU 1 MA P330 BP S244 EP S245 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CH1VW UT WOS:000353811200446 ER PT J AU Miao, HH Zhen, Y Ding, GN Hong, FX Xie, ZC Tian, M AF Miao Hui Hui Zhen Yu Ding Guan Nan Hong Fang Xiao Xie Zhong Cong Tian Ming TI Ginsenoside Rg1 Attenuates Isoflurane-induced Caspase-3 Activation via Inhibiting Mitochondrial Dysfunction SO BIOMEDICAL AND ENVIRONMENTAL SCIENCES LA English DT Article DE Ginsenoside Rg1; Isoflurane; Neurotoxicity; Mitochondrial dysfunction ID BETA-AMYLOID PROTEIN; CELL-DEATH; PERMEABILITY TRANSITION; PC12 CELLS; APOPTOSIS; MICE; ACCUMULATION; PERFORMANCE; ANESTHETICS; DESFLURANE AB Objective The inhalation anesthetic isoflurane has been shown to induce mitochondrial dysfunction and caspase activation, which may lead to learning and memory impairment. Ginsenoside Rg1 is reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rg1 can attenuate isoflurane-induced caspase activation via inhibiting mitochondrial dysfunction. Methods We investigated the effects of ginsenoside Rg1 at concentrations of 12.5, 25, and 50 mu mol/L and pretreatment times of 12 h and 24 h on isoflurane-induced caspase-3 activation in H4 naive and stably transfected H4 human neuroglioma cells that express full-length human amyloid precursor protein (APP) (H4-APP cells). For mitochondrial dysfunction, we assessed mitochondrial permeability transition pore (mPTP) and adenosine-5'-triphosphate (ATP) levels. We employed Western blot analysis, chemiluminescence, and flowcytometry. Results Here we show that pretreatment with 50 mu mol/L ginsenoside Rg1 for 12 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in H4-APP cells, while pretreatment with 25 and 50 mu mol/L ginsenoside Rg1 for 24 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in both H4 naive and H4-APP cells. Conclusion These data suggest that ginsenoside Rg1 may ameliorate isoflurane-induced caspase-3 activation by inhibiting mitochondrial dysfunction. Pending further studies, these findings might recommend the use of ginsenoside Rg1 in preventing and treating isoflurane-induced neurotoxicity. C1 [Miao Hui Hui; Zhen Yu; Ding Guan Nan; Hong Fang Xiao; Tian Ming] Capital Med Univ, Beijing Friendship Hosp, Beijing 100050, Peoples R China. [Xie Zhong Cong] Massachusetts Gen Hosp, Crit Care & Pain Med, Dept Anesthesia, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA. [Xie Zhong Cong] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Tian, M (reprint author), Capital Med Univ, Beijing Friendship Hosp, Beijing 100050, Peoples R China. EM tian_mz@139.com FU Beijing NOVA Program [Z131107000413044] FX This work was supported by 2013 Beijing NOVA Program (Z131107000413044). NR 34 TC 3 Z9 3 U1 1 U2 6 PU CHINESE CENTER DISEASE CONTROL & PREVENTION PI BEIJING PA 155 CHANGBAI RD, CHANGPING DISTRICT, BEIJING, 102206, PEOPLES R CHINA SN 0895-3988 J9 BIOMED ENVIRON SCI JI Biomed. Environ. Sci. PD FEB PY 2015 VL 28 IS 2 BP 116 EP 126 DI 10.3967/bes2015.014 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CG4YX UT WOS:000353296600004 PM 25716562 ER PT J AU Navarro, VM Bosch, MA Leon, S Simavli, S True, C Pinilla, L Carroll, RS Seminara, SB Tena-Sempere, M Ronnekleiv, OK Kaiser, UB AF Navarro, Vctor M. Bosch, Martha A. Leon, Silvia Simavli, Serap True, Cadence Pinilla, Leonor Carroll, Rona S. Seminara, Stephanie B. Tena-Sempere, Manuel Ronnekleiv, Oline K. Kaiser, Ursula B. TI The Integrated Hypothalamic Tachykinin-Kisspeptin System as a Central Coordinator for Reproduction SO ENDOCRINOLOGY LA English DT Article ID LUTEINIZING-HORMONE RELEASE; P-CONTAINING NEURONS; SUBSTANCE-P; NEUROKININ-B; ARCUATE NUCLEUS; FEMALE RAT; GENE-EXPRESSION; MESSENGER-RNA; GONADOTROPIN-SECRETION; OVARIECTOMIZED RATS AB Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r(-/-) mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons. C1 [Navarro, Vctor M.; Simavli, Serap; Carroll, Rona S.; Kaiser, Ursula B.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Navarro, Vctor M.; Simavli, Serap; Carroll, Rona S.; Kaiser, Ursula B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bosch, Martha A.; Ronnekleiv, Oline K.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97239 USA. [Leon, Silvia; Pinilla, Leonor; Tena-Sempere, Manuel] Univ Cordoba, Dept Cell Biol Physiol & Immunol, E-14004 Cordoba, Spain. [Leon, Silvia; Pinilla, Leonor; Tena-Sempere, Manuel] Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Cordoba 14004, Spain. [Leon, Silvia; Pinilla, Leonor; Tena-Sempere, Manuel] Inst Maimonides Invest Biomed, Cordoba 14004, Spain. [Leon, Silvia; Pinilla, Leonor; Tena-Sempere, Manuel] Hosp Univ Reina Sofia, Cordoba 14004, Spain. [Simavli, Serap] Pamukkale Univ, Sch Med, Dept Obstet & Gynecol, TR-20020 Denizli, Turkey. [True, Cadence; Seminara, Stephanie B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [True, Cadence; Seminara, Stephanie B.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Navarro, VM (reprint author), Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. EM vnavarro@partners.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, Specialized Cooperative Centers Program in Reproduction and Infertility Research grants from the National Institute of Health [U54 HD028138]; National Institutes of Health (NIH) [R01 HD019938]; Charles H. Hood Foundation for Child Health Research Program; Microgrant Program from The Biomedical Research Institute; Center for Faculty Development and Diversity's Office for Research Careers at the Brigham and Women's Hospital; Scientific and Technological Research Council of Turkey [2219]; NIH [K99 HD071970, R01 NS043330, R01 DK068098] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through cooperative agreement U54 HD028138 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research grants from the National Institute of Health and by National Institutes of Health (NIH) Grant R01 HD019938 (to U.B.K.); NIH Grant K99 HD071970, Charles H. Hood Foundation for Child Health Research Program and the Microgrant Program from The Biomedical Research Institute and the Center for Faculty Development and Diversity's Office for Research Careers at the Brigham and Women's Hospital (V.M.N.); by The Scientific and Technological Research Council of Turkey Grant 2219 (to S.S.); and by NIH Grants R01 NS043330 and R01 DK068098 (to O.K.R.). NR 53 TC 17 Z9 17 U1 1 U2 7 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2015 VL 156 IS 2 BP 627 EP 637 DI 10.1210/en.2014-1651 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG2UV UT WOS:000353131800022 PM 25422875 ER PT J AU Calligaris, D Feldman, DR Norton, I Brastianos, PK Dunn, IF Santagata, S Agar, NYR AF Calligaris, David Feldman, Daniel R. Norton, Isaiah Brastianos, Priscilla K. Dunn, Ian F. Santagata, Sandro Agar, Nathalie Y. R. TI Molecular typing of meningiomas by desorption electrospray ionization mass spectrometry imaging for surgical decision-making SO INTERNATIONAL JOURNAL OF MASS SPECTROMETRY LA English DT Article DE DESI-MSI; Meningioma; Subtyping; Real-time diagnosis; Surgery ID HUMAN BRAIN-TUMORS; ATMOSPHERIC-PRESSURE; AMBIENT CONDITIONS; PSAMMOMA BODIES; RAPID ANALYSIS; IN-VIVO; TISSUE; SAMPLES; MUTATIONS; RESECTION AB Meningiomas are the most frequent intracranial tumors. The majority are benign slow-growing tumors, but they can be difficult to treat depending on their location and size. While meningiomas are well delineated on magnetic resonance imaging by their uptake of contrast, surgical limitations still present themselves from not knowing the extent of invasion of the dura matter by meningioma cells. The development of tools to characterize tumor tissue in real or near real time could prevent recurrence after tumor resection by allowing for more precise surgery, i.e., removal of tumor with preservation of healthy tissue. The development of ambient ionization mass spectrometry for molecular characterization of tissue and its implementation in the surgical decision-making workflow carry the potential to fulfill this need. Here, we present the characterization of meningioma and dura mater by desorption electrospray ionization mass spectrometry to validate the technique for the molecular assessment of surgical margins and diagnosis of meningioma from surgical tissue in real-time. Nine stereotactically resected surgical samples and three autopsy samples were analyzed by standard histopathology and mass spectrometry imaging. All samples indicated a strong correlation between results from both techniques. We then highlight the value of desorption electrospray ionization mass spectrometry for the molecular subtyping/subgrouping of meningiomas from a series of forty genetically characterized specimens. The minimal sample preparation required for desorption electrospray ionization mass spectrometry offers a distinct advantage for applications relying on real-time information such as surgical decision-making. The technology here was tested to distinguish meningioma from dura mater as an approach to precisely define surgical margins. In addition, we classify meningiomas into fibroblastic and meningothelial subtypes and more notably recognize meningiomas with NF2 genetic aberrations. (C) 2014 Elsevier B.V. All rights reserved. C1 [Calligaris, David; Norton, Isaiah; Dunn, Ian F.; Agar, Nathalie Y. R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. [Feldman, Daniel R.; Santagata, Sandro] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Brastianos, Priscilla K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Agar, Nathalie Y. R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Agar, Nathalie Y. R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Agar, NYR (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. EM Nathalie_Agar@dfci.harvard.edu OI Brastianos, Priscilla/0000-0003-4470-8425 FU Daniel E. Ponton fund for the Neurosciences; DFCI Pediatric Low-Grade Astrocytoma program; NIH Director's New Innovator Award [1DP2OD007383-01]; NIH [K08NS064168]; National Center for Research Resources; National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health [P41EB015898, P41RR019703] FX The authors are grateful to the patient and their families who consented to participate in this research. This work received support from Daniel E. Ponton fund for the Neurosciences, the DFCI Pediatric Low-Grade Astrocytoma program, and the NIH Director's New Innovator Award (grant 1DP2OD007383-01 to N.Y.R. Agar). S.S. is supported by NIH grant K08NS064168. The authors would also like to acknowledge support from the Advanced Multimodality Image Guided Operating (AMIGO) suite team and facility, supported by the National Center for Research Resources and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health through grant numbers P41EB015898 and P41RR019703. NR 61 TC 8 Z9 9 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1387-3806 EI 1873-2798 J9 INT J MASS SPECTROM JI Int. J. Mass Spectrom. PD FEB 1 PY 2015 VL 377 SI SI BP 690 EP 698 DI 10.1016/j.ijms.2014.06.024 PG 9 WC Physics, Atomic, Molecular & Chemical; Spectroscopy SC Physics; Spectroscopy GA CG1BD UT WOS:000353007100072 PM 25844057 ER PT J AU Hamarneh, SR Murphy, CA Shih, CW Frontera, W Torriani, M Irazoqui, JE Makimura, H AF Hamarneh, Sulaiman R. Murphy, Caitlin A. Shih, Cynthia W. Frontera, Walter Torriani, Martin Irazoqui, Javier E. Makimura, Hideo TI Relationship Between Serum IGF-1 and Skeletal Muscle IGF-1 mRNA Expression to Phosphocreatine Recovery After Exercise in Obese Men With Reduced GH SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-HORMONE TREATMENT; MAGNETIC-RESONANCE-SPECTROSCOPY; PLACEBO-CONTROLLED TRIAL; IN-VITRO MEASUREMENTS; ABDOMINAL OBESITY; PHYSICAL-ACTIVITY; MITOCHONDRIAL-FUNCTION; OXIDATIVE-METABOLISM; POSTMENOPAUSAL WOMEN; ENERGY-EXPENDITURE AB Context: GHand IGF-1 are believed to be physiological regulators of skeletal muscle mitochondria. Objective: The Objective: of this study was to examine the relationship between GH/IGF-1 and skeletal muscle mitochondria in obese subjects with reduced GH secretion in more detail. Design: Fifteen abdominally obese men with reduced GH secretion were treated for 12 weeks with recombinant human GH. Subjects underwent P-31-magnetic resonance spectroscopy to assess phosphocreatine (PCr) recovery as an in vivo measure of skeletal muscle mitochondrial function and percutaneous muscle biopsies to assess mRNA expression of IGF-1 and mitochondrial-related genes at baseline and 12 weeks. Results: At baseline, skeletal muscle IGF-1 mRNA expression was significantly associated with PCr recovery (r = 0.79; P = .01) and nuclear respiratory factor-1 (r = 0.87; P = .001), mitochondrial transcription factor A (r = 0.86; P = .001), peroxisome proliferator-activated receptor (PPAR)gamma (r = 0.72; P = .02), and PPAR alpha (r = 0.75; P = .01) mRNA expression, and trended to an association with PPAR gamma coactivator 1-alpha (r = 0.59; P = .07) mRNA expression. However, serum IGF-1 concentration was not associated with PCr recovery or any mitochondrial gene expression (all P = > .10). Administration of recombinant human GH increased both serumIGF-1 (change, 218 +/- 29 mu g/L; P < .0001) and IGF-1 mRNA in muscle(fold change, 2.1 +/- 0.3; P = .002). Increases inserum IGF-1 were associated with improvements in total body fat (r = -0.53; P = .04), trunk fat (r = - 0.55; P = .03), and lean mass (r = 0.58; P = .02), but not with PCr recovery (P > .10). Conversely, increase in muscle IGF-1 mRNA was associated with improvements in PCr recovery (r = 0.74; P = .02), but not with body composition parameters (P > .10). Conclusion: These data demonstrate a novel association of skeletal muscle mitochondria with muscle IGF-1 mRNA expression, but independent of serum IGF-1 concentrations. C1 [Hamarneh, Sulaiman R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Hamarneh, Sulaiman R.; Makimura, Hideo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Murphy, Caitlin A.; Shih, Cynthia W.; Makimura, Hideo] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Shih, Cynthia W.] Harvard Univ, Boston, MA 02138 USA. [Frontera, Walter] Vanderbilt Univ, Med Ctr, Dept Phys Med & Rehabil, Nashville, TN 37212 USA. [Frontera, Walter] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA 02114 USA. [Frontera, Walter] Univ Puerto Rico, Sch Med, Dept Physiol, San Juan, PR 00936 USA. [Torriani, Martin] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Irazoqui, Javier E.] Massachusetts Gen Hosp, Study Inflammatory Bowel Dis, Lab Comparat Immunol, Boston, MA 02114 USA. RP Makimura, H (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON 207, Boston, MA 02114 USA. EM hmakimura@partners.org OI Irazoqui, Javier/0000-0001-6553-1329 FU Pfizer, Inc; National Institutes of Health Grant [K23DK087857, 1UL1RR025758-04, 8UL1TR000170-05]; Harvard Clinical and Translational Science Center, from National Center for Research Resources FX This study, including the provision of the study drug, was supported by an investigator-initiated research grant from Pfizer, Inc (to H.M.). H.M. also receives support from National Institutes of Health Grant K23DK087857. The project was supported by the National Institutes of Health Grants 1UL1RR025758-04 and 8UL1TR000170-05, the Harvard Clinical and Translational Science Center, from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 45 TC 2 Z9 2 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2015 VL 100 IS 2 BP 617 EP 625 DI 10.1210/jc.2014-2711 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5RF UT WOS:000353350900067 PM 25375982 ER PT J AU Leder, BZ O'Dea, LS Zanchetta, JR Kumar, P Banks, K Mckay, K Lyttle, CR Hattersley, G AF Leder, Benjamin Z. O'Dea, Louis St. L. Zanchetta, Jose R. Kumar, Prasana Banks, Kathleen Mckay, Kathleen Lyttle, C. Richard Hattersley, Gary TI Effects of Abaloparatide, a Human Parathyroid Hormone-Related Peptide Analog, on Bone Mineral Density in Postmenopausal Women with Osteoporosis SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ZOLEDRONIC ACID; HR-PQCT; TERIPARATIDE; ALENDRONATE; THERAPY; FRACTURES; STRENGTH; PROTEIN; RISEDRONATE AB Context: Abaloparatide is a novel synthetic peptide analog of parathyroid hormone-related protein (PTHrP) that is currently being developed as a potential anabolic agent in the treatment of postmenopausal osteoporosis. Objective: This study sought to assess the effects of abaloparatide on bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck in postmenopausal women with osteoporosis. Design: Multi-center, multi-national, double-blind placebo controlled trial in which postmenopausal women were randomly assigned to receive 24 weeks of treatment with daily sc injections of placebo, abaloparatide, 20, 40, or 80 mu g, or teriparatide, 20 mu g. A 24-week extension was also performed in a subset of subjects. Participants: Postmenopausal women with osteoporosis (n = 222). Main Outcome Measures: BMD by dual-x-ray absorptiometry and biochemical markers of bone turnover. Results: At 24 weeks, lumbar spine BMD increased by 2.9, 5.2, and 6.7% in the abaloparatide, 20-, 40-, and 80-mu g groups, respectively, and 5.5% in the teriparatide group. The increases in the 40and 80-mu g abaloparatide groups and the teriparatide group were significantly greater than placebo (1.6%). Femoral neck BMD increased by 2.7, 2.2, and 3.1% in abaloparatide, 20-, 40-, and 80-mu g groups, respectively, and 1.1% in the teriparatide group. The increase in femoral neck BMD with abaloparatide, 80 mu g was significantly greater than placebo (0.8%). Total hip BMD increased by 1.4, 2.0, and 2.6% in the abaloparatide, 20-, 40-, and 80-mu g groups, respectively. The total hip increases in the 40- and 80-mu g abaloparatide groups were greater than both placebo (0.4%) and teriparatide (0.5%). Conclusions: Compared with placebo, 24 weeks of daily sc abaloparatide increases BMD of the lumbar spine, femoral neck, and total hip in a dose-dependent fashion. Moreover, the abaloparatide-induced BMD increases at the total hip are greater than with the marketed dose of teriparatide. These results support the further investigation of abaloparatide as an anabolic therapy in postmenopausal osteoporosis. C1 [Leder, Benjamin Z.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit,Dept Med, Boston, MA 02114 USA. [O'Dea, Louis St. L.; Banks, Kathleen; Mckay, Kathleen; Lyttle, C. Richard; Hattersley, Gary] Radius Hlth Inc, Waltham, MA 02451 USA. [Zanchetta, Jose R.] Inst Diagnost & Invest Metabol, Buenos Aires, DF, Argentina. RP Leder, BZ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Bulfinch 327,Fruit St, Boston, MA 02114 USA. EM bzleder@partners.org FU Radius Health Inc. FX This work was supported by Radius Health Inc. NR 31 TC 39 Z9 40 U1 2 U2 9 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2015 VL 100 IS 2 BP 697 EP 706 DI 10.1210/jc.2014-3718 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5RF UT WOS:000353350900077 PM 25393645 ER PT J AU Carter, PH Dean, T Bhayana, B Khatri, A Rajur, R Gardella, TJ AF Carter, Percy H. Dean, Thomas Bhayana, Brijesh Khatri, Ashok Rajur, Raj Gardella, Thomas J. TI Actions of the Small Molecule Ligands SW106 and AH-3960 on the Type-1 Parathyroid Hormone Receptor SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-COUPLED-RECEPTOR; NONPEPTIDE ANTAGONISTS; I RECEPTOR; AGONIST; PEPTIDE; BINDING; ANALOGS; CONFORMATIONS; DISCOVERY; REGION AB The parathyroid hormone receptor-1 (PTHR1) plays critical roles in regulating blood calcium levels and bone metabolism and is thus of interest for small-molecule ligand development. Of the few small-molecule ligands reported for the PTHR1, most are of low affinity, and none has a well-defined mechanism of action. Here, we show that SW106 and AH-3960, compounds previously identified to act as an antagonist and agonist, respectively, on the PTHR1, each bind to PTHR1-delNT, a PTHR1 construct that lacks the large amino-terminal extracellular domain used for binding endogenous PTH peptide ligands, with the same micromolar affinity with which it binds to the intact PTHR1. SW106 antagonized PTHR1-mediated cAMP signaling induced by the peptide analog, M-PTH(1-11), as well as by the native PTH(1-9) sequence, as tethered to the extracellular end of transmembrane domain (TMD) helix-1 of the receptor. SW106, however, did not function as an inverse agonist on either PTHR1-H223R or PTHR1-T410P, which have activating mutations at the cytoplasmic ends of TMD helices 2 and 6, respectively. The overall data indicate that SW106 and AH-3960 each bind to the PTHR1 TMD region and likely to within an extracellularly exposed area that is occupied by the N-terminal residues of PTH peptides. Additionally, they suggest that the inhibitory effects of SW106 are limited to the extracellular portions of the TMD region that mediate interactions with agonist ligands but do not extend to receptor-activation determinants situated more deeply in the helical bundle. The study helps to elucidate potential mechanisms of small-molecule binding at the PTHR1. C1 [Dean, Thomas; Khatri, Ashok; Gardella, Thomas J.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02492 USA. [Dean, Thomas; Bhayana, Brijesh; Khatri, Ashok; Gardella, Thomas J.] Harvard Univ, Sch Med, Boston, MA 02492 USA. [Bhayana, Brijesh] Massachusetts Gen Hosp, Dept Photomed, Boston, MA 02492 USA. [Rajur, Raj] CreaGen Biosci Inc, Woburn, MA 01801 USA. [Carter, Percy H.] Bristol Myers Squibb Co, Princeton, NJ 08543 USA. RP Gardella, TJ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Thier 10,50 Blossom St, Boston, MA 02114 USA. EM gardella@helix.mgh.harvard.edu FU National Institutes of Health [DK-11794] FX This work was supported by the National Institutes of Health Grant DK-11794. NR 38 TC 4 Z9 4 U1 2 U2 5 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD FEB PY 2015 VL 29 IS 2 BP 307 EP 321 DI 10.1210/me.2014-1129 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG4XD UT WOS:000353291200013 PM 25584411 ER PT J AU Cahana-Amitay, D Spiro, A Cohen, JA Oveis, AC Ojo, EA Sayers, JT Obler, LK Albert, ML AF Cahana-Amitay, Dalia Spiro, Avron, III Cohen, Jason A. Oveis, Abigail C. Ojo, Emmanuel A. Sayers, Jesse T. Obler, Loraine K. Albert, Martin L. TI Effects of Metabolic Syndrome on Language Functions in Aging SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Health; Risk factors; Lexical retrieval; Sentence processing; Cerebrovascular; Accuracy; Reaction time ID IMPAIRED GLUCOSE-TOLERANCE; ISCHEMIC BRAIN-LESIONS; CARDIOVASCULAR-DISEASE; OLDER-ADULTS; COGNITION; RISK; HEALTH; COMPREHENSION; HYPERTENSION; OBESITY AB This study explored effects of the metabolic syndrome (MetS) on language in aging. MetS is a constellation of five vascular and metabolic risk factors associated with the development of chronic diseases and increased risk of mortality, as well as brain and cognitive impairments. We tested 281 English-speaking older adults aged 55-84, free of stroke and dementia. Presence of MetS was based on the harmonized criteria (Alberti et al., 2009). Language performance was assessed by measures of accuracy and reaction time on two tasks of lexical retrieval and two tasks of sentence processing. Regression analyses, adjusted for age, education, gender, diabetes, hypertension, and heart disease, demonstrated that participants with MetS had significantly lower accuracy on measures of lexical retrieval (action naming) and sentence processing (embedded sentences, both subject and object relative clauses). Reaction time was slightly faster on the test of embedded sentences among those with MetS. MetS adversely affects the language performance of older adults, impairing accuracy of both lexical retrieval and sentence processing. This finding reinforces and extends results of earlier research documenting the negative influence of potentially treatable medical conditions (diabetes, hypertension) on language performance in aging. The unanticipated finding that persons with MetS were faster in processing embedded sentences may represent an impairment of timing functions among older individuals with MetS. C1 [Cahana-Amitay, Dalia; Spiro, Avron, III; Oveis, Abigail C.; Ojo, Emmanuel A.; Sayers, Jesse T.; Obler, Loraine K.; Albert, Martin L.] VA Boston Healthcare Syst, Boston, MA USA. [Cahana-Amitay, Dalia; Oveis, Abigail C.; Ojo, Emmanuel A.; Sayers, Jesse T.; Obler, Loraine K.; Albert, Martin L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Spiro, Avron, III] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Cohen, Jason A.] Albert Einstein Coll Med, Dept Neurol, New York, NY USA. [Obler, Loraine K.] CUNY, Grad Ctr, New York, NY USA. RP Cahana-Amitay, D (reprint author), Vet Affairs Boston Healthcare Syst, Harold Goodglass Aphasia Res Ctr, 150 South Huntington Ave 12A, Boston, MA 02130 USA. EM dcamitay@bu.edu FU NIA Grant [R01-AG014345]; VA Clinical Science RD Service FX We thank Rebecca Williams, Mira Goral, Christopher Brady, Rossie Clark-Cotton, Rebecca Brown, Shelley Amberg, Keely Sayers, Josh Berger, and Elaine Dibbs for their help with conducting the Language in the Aging Brain project, and are grateful to our participants for their time and efforts. This study was supported by NIA Grant R01-AG014345 (Martin Albert & Loraine Obler, Co-PIs). Avron Spiro was also supported by a Senior Research Career Scientist award from the VA Clinical Science R&D Service. NR 51 TC 1 Z9 1 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 EI 1469-7661 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD FEB PY 2015 VL 21 IS 2 BP 116 EP 125 DI 10.1017/S1355617715000028 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA CF8HA UT WOS:000352795600003 PM 25854271 ER PT J AU Bettcher, BM Yaffe, K Boudreau, RM Neuhaus, J Aizenstein, H Ding, J Kritchevsky, SB Launer, LJ Liu, Y Satterfield, S Rosano, C AF Bettcher, Brianne Magouirk Yaffe, Kristine Boudreau, Robert M. Neuhaus, John Aizenstein, Howard Ding, Jingzhong Kritchevsky, Stephen B. Launer, Lenore J. Liu, Yongmei Satterfield, Suzanne Rosano, Caterina CA Health ABC Study TI Declines in inflammation predict greater white matter microstructure in older adults SO NEUROBIOLOGY OF AGING LA English DT Article DE CRP; Pro-inflammatory; Diffusion tensor imaging; Longitudinal ID C-REACTIVE PROTEIN; MILD COGNITIVE IMPAIRMENT; NECROSIS-FACTOR-ALPHA; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASE; CARDIOVASCULAR-DISEASE; VASCULAR DYSFUNCTION; DIFFUSION TENSOR; HEALTH ABC; TNF-ALPHA AB Protracted systemic inflammation has been associated with adverse effects on cognition and brain structure and may accelerate neurodegenerative disease processes; however, it is less clear whether changes in inflammation are associated with brain structure. We studied 276 black and white older adults (mean age = 83 years at time of imaging) enrolled in a prospective study of aging. Inflammation (measured with c-reactive protein, CRP) was assessed repeatedly over 6 years (i.e., year 2, 4, 6, and 8). Brain magnetic resonance imaging (MRIs) were obtained at years 10-11 with diffusion tensor imaging; regions of interest included late-myelinating areas vulnerable to aging, including frontal-parietal (superior longitudinal fasciculus [SLF]-dorsal) and temporal (SLF-temporal; uncinate) white matter tracts. Mean CRP values significantly declined (t = -5.54, p < 0.0001) over 6 years, and subject-specific slopes (best linear unbiased predictors of slopes) all showed a decline (mean = -0.57, standard deviation = 0.53) for our participant sample. More than 50% of study participants were still in the moderate to high cardiovascular risk range based on CRP values at year 8. After controlling for demographics, vascular risk factors and MRI white matter hyperintensities, larger decreases in CRP values over time were significantly associated with higher fractional anisotropy in the SLF-dorsal (beta = -0.0052, standard error [SE] = 0.003; 95% confidence interval [CI] = -0.0103 to -0.0025, p = 0.04), SLF-temporal (beta = -0.0109, SE = 0.004; 95% CI = -0.0189 to -0.0029, p = 0.008), and uncinate (beta = -0.0067, SE = 0.003; 95% CI = -0.0132 to -0.0001, p = 0.05) fasciculi. Results suggest that in a prospective cohort of older individuals, faster declines in inflammation over time are related to indicators of white matter health, even after accounting for vascular risk factors. (C) 2015 Elsevier Inc. All rights reserved. C1 [Bettcher, Brianne Magouirk; Neuhaus, John] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Boudreau, Robert M.; Rosano, Caterina] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Aizenstein, Howard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Ding, Jingzhong; Kritchevsky, Stephen B.; Liu, Yongmei] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Bettcher, BM (reprint author), Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln,Suite 190,MC 1207, San Francisco, CA 94158 USA. EM bbettcher@memory.ucsf.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Boudreau, Robert/0000-0003-0162-5187 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050, K23 AG042492-01, RO1-AG028288]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging; Alzheimer's Association [NIRP-12-259223] FX This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, K23 AG042492-01 (Brianne Magouirk Bettcher), RO1-AG028288 (Yongmei Liu), and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, as well as an Alzheimer's Association New Investigator Grant (NIRP-12-259223; Brianne Magouirk Bettcher). NR 56 TC 3 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2015 VL 36 IS 2 BP 948 EP 954 DI 10.1016/j.neurobiolaging.2014.11.004 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CF3MZ UT WOS:000352454400040 PM 25554492 ER PT J AU Munn, LL AF Munn, Lance L. TI Mechanobiology of lymphatic contractions SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Lymphatic; Mechanosensor; Mechanobiology; Stretch-activated channel; Shear stress; Nitric oxide ID GUINEA-PIG MESENTERY; ACTIVATED ION CHANNELS; SMOOTH-MUSCLE-CELLS; SPONTANEOUS TRANSIENT DEPOLARIZATIONS; LIGHT-CHAIN PHOSPHORYLATION; NITRIC-OXIDE PRODUCTION; RAT THORACIC-DUCT; ENDOTHELIAL-CELLS; SHEAR-STRESS; IN-VIVO AB The lymphatic system is responsible for controlling tissue fluid pressure by facilitating flow of lymph (i.e. the plasma and cells that enter the lymphatic system). Because lymph contains cells of the immune system, its transport is not only important for fluid homeostasis, but also immune function. Lymph drainage can occur via passive flow or active pumping, and much research has identified the key biochemical and mechanical factors that affect output. Although many studies and reviews have addressed how tissue properties and fluid mechanics (i.e. pressure gradients) affect lymph transport [1-3] there is less known about lymphatic mechanobiology. As opposed to passive mechanical properties, mechanobiology describes the active coupling of mechanical signals and biochemical pathways. Lymphatic vasomotion is the result of a fascinating system affected by mechanical forces exerted by the flowing lymph, including pressure-induced vessel stretch and flow-induced shear stresses. These forces can trigger or modulate biochemical pathways important for controlling the lymphatic contractions. Here, I review the current understanding of lymphatic vessel function, focusing on vessel mechanobiology, and summarize the prospects for a comprehensive understanding that integrates the mechanical and biomechanical control mechanisms in the lymphatic system. (C) 2015 Elsevier Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Munn, LL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM lmunn@mgh.harvard.edu RI Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 FU National Institutes of Health [NIH R01CA149285] FX This work was funded in part by National Institutes of Health Grant NIH R01CA149285. NR 104 TC 6 Z9 6 U1 4 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD FEB PY 2015 VL 38 BP 67 EP 74 DI 10.1016/j.semcdb.2015.01.010 PG 8 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CF4ER UT WOS:000352502000010 PM 25636584 ER PT J AU Pereira, ER Jones, D Jung, K Padera, TP AF Pereira, Ethel R. Jones, Dennis Jung, Keehoon Padera, Timothy P. TI The lymph node microenvironment and its role in the progression of metastatic cancer SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Lymph node; Metastasis; Lymphatic vessels; Chemokine; Clonality; Lymphangiogenesis ID GROWTH-FACTOR-C; PROMOTES TUMOR-METASTASIS; CD8 T-CELLS; NEAR-INFRARED DYE; VEGF-D PROMOTES; BREAST-CANCER; B-CELLS; VASCULATURE REORGANIZATION; MEDIATED IMMUNOSUPPRESSION; CHEMOKINE RECEPTOR-7 AB Lymph nodes are initial sites for cancer metastasis in many solid tumors. However, their role in cancer progression is still not completely understood. Emerging evidence suggests that the lymph node microenvironment provides hospitable soil for the seeding and proliferation of cancer cells. Resident immune and stromal cells in the lymph node express and secrete molecules that may facilitate the survival of cancer cells in this organ. More comprehensive studies are warranted to fully understand the importance of the lymph node in tumor progression. Here, we will review the current knowledge of the role of the lymph node microenvironment in metastatic progression. (C) 2015 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Dept Radiat Oncol, EL Steele Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Padera, TP (reprint author), Edwin L Steele Lab Tumor Biol, 55 Fruit St,Cox Bldg, Boston, MA 02114 USA. EM tpadera@steele.mgh.harvard.edu OI Pereira, Ethel/0000-0003-0562-4536; Padera, Timothy/0000-0002-3453-9384 FU National Institutes of Health [DP2OD008780, R00CA137167, R21AI097745]; National Cancer Institute Federal Share/MGH Proton Beam Income on [C06 CA059267]; UNCF-Merck Science Initiative Postdoctoral Fellowship; Burroughs Wellcome Postdoctoral Enrichment Program Award FX This work was supported by the National Institutes of Health DP2OD008780 (TPP), R00CA137167 (TPP), R21AI097745 (TPP), National Cancer Institute Federal Share/MGH Proton Beam Income on C06 CA059267 (TPP), UNCF-Merck Science Initiative Postdoctoral Fellowship (D.J.) and Burroughs Wellcome Postdoctoral Enrichment Program Award (D.J.). We would like to acknowledge Sonia Pereira for her help with the graphical illustration. NR 108 TC 16 Z9 17 U1 1 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD FEB PY 2015 VL 38 BP 98 EP 105 DI 10.1016/j.semcdb.2015.01.008 PG 8 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CF4ER UT WOS:000352502000014 PM 25620792 ER PT J AU Finley, EP Bollinger, M Noel, PH Amuan, ME Copeland, LA Pugh, JA Dassori, A Palmer, R Bryan, C Pugh, MJV AF Finley, Erin P. Bollinger, Mary Noel, Polly H. Amuan, Megan E. Copeland, Laurel A. Pugh, Jacqueline A. Dassori, Albana Palmer, Raymond Bryan, Craig Pugh, Mary Jo V. TI A National Cohort Study of the Association Between the Polytrauma Clinical Triad and Suicide-Related Behavior Among US Veterans Who Served in Iraq and Afghanistan SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID TRAUMATIC BRAIN-INJURY; POSTTRAUMATIC-STRESS-DISORDER; MENTAL-HEALTH DIAGNOSES; SUBSTANCE USE DISORDERS; DEPLOYED MILITARY PERSONNEL; PSYCHIATRIC DIAGNOSES; COMMUNITY SAMPLE; WAR VETERANS; RISK; IDEATION AB Objectives. We examined the association of posttraumatic stress disorder (PTSD), traumatic brain injury, and chronic pain-the polytrauma clinical triad (PCT)-independently and with other conditions, with suicide-related behavior (SRB) risk among Operation Enduring Freedom (OEF; Afghanistan) and Operation Iraqi Freedom (OIF) veterans. Methods. We used Department of Veterans Affairs (VA) administrative data to identify OEF and OIF veterans receiving VA care in fiscal years 2009-2011; we used International Classification of Diseases, Ninth Revision, Clinical Modification codes to characterize 211 652 cohort members. Descriptive statistics were followed by multinomial logistic regression analyses predicting SRB. Results. Co-occurrence of PCT conditions was associated with significant increase in suicide ideation risk (odds ratio [OR] = 1.9; 95% confidence interval [CI] = 1.5, 2.4) or attempt and ideation (OR = 2.6; 95% CI = 1.5, 4.6), but did not exceed increased risk with PTSD alone (ideation: OR = 2.3; 95% CI = 2.0, 2.6; attempt: OR = 2.0; 95% CI = 1.4, 2.9; ideation and attempt: OR = 1.8; 95% CI = 1.2, 2.8). Ideation risk was significantly elevated when PTSD was comorbid with depression (OR = 4.2; 95% CI = 3.6, 4.8) or substance abuse (OR = 4.7; 95% CI = 3.9, 5.6). Conclusions. Although PCT was a moderate SRB predictor, interactions among PCT conditions, particularly PTSD, and depression or substance abuse had larger risk increases. C1 [Finley, Erin P.; Bollinger, Mary; Noel, Polly H.; Pugh, Jacqueline A.; Dassori, Albana; Pugh, Mary Jo V.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Palmer, Raymond] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Amuan, Megan E.] Edith Nourse Rogers Mem VA Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Copeland, Laurel A.] Hlth Care Syst, Cent Texas Vet, Ctr Appl Hlth Res, Temple, TX USA. [Copeland, Laurel A.] Scott & White Healthcare Syst, Temple, TX USA. [Bryan, Craig] Univ Utah, Natl Ctr Vet Studies, Salt Lake City, UT USA. [Bryan, Craig] Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. RP Finley, EP (reprint author), South Texas Vet Hlth Care Syst, Audie L Murphy Mem Vet Hosp, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM finleye@uthscsa.edu OI Pugh, Jacqueline/0000-0003-4933-141X; Pugh, Mary Jo/0000-0003-4196-7763; Bryan, Craig/0000-0002-9714-0733; Copeland, Laurel/0000-0002-9478-0209; Finley, Erin/0000-0003-4497-7721 FU Department of Veterans Affairs, Office of Research and Development, VA Health Services Research and Development Service [DHI 09-237]; South Texas Veterans Health Care System; National Institute of Mental Health [R25 MH080916-01A2]; Department of Veterans Affairs, Health Services Research and Development Service, Quality Enhancement Research Initiative FX This study was funded by Department of Veterans Affairs, Office of Research and Development, VA Health Services Research and Development Service (DHI 09-237). J. A. Pugh's and A. Dassori's salaries were funded by the South Texas Veterans Health Care System. E. P. Finley is an investigator with the Implementation Research Institute, at the George Warren Brown School of Social Work, Washington University in St Louis, through an award from the National Institute of Mental Health (R25 MH080916-01A2) and the Department of Veterans Affairs, Health Services Research and Development Service, Quality Enhancement Research Initiative. NR 59 TC 11 Z9 11 U1 3 U2 16 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2015 VL 105 IS 2 BP 380 EP 387 DI 10.2105/AJPH.2014.301957 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CE6CD UT WOS:000351922500046 PM 25033126 ER PT J AU Broytman, O Braun, RK Morgan, BJ Pegelow, DF Hsu, PN Mei, LS Koya, AK Eldridge, M Teodorescu, M AF Broytman, Oleg Braun, Rudolf K. Morgan, Barbara J. Pegelow, David F. Hsu, Pei-Ning Mei, Linda S. Koya, Ajay K. Eldridge, Marlowe Teodorescu, Mihaela TI Effects of Chronic Intermittent Hypoxia on Allergen-Induced Airway Inflammation in Rats SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE airway remodeling, immunology; disease models, animal; fibrosis; lung immunology, metabolism, pathology; rats ID OBSTRUCTIVE SLEEP-APNEA; PULMONARY-FIBROSIS; ASTHMATIC-PATIENTS; LUNG INFLAMMATION; INDUCIBLE FACTORS; ACTIVATION; MACROPHAGES; DYSFUNCTION; HIF-1-ALPHA; EXPRESSION AB Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats. Four groups (n = 9-11/group) of ovalbumin (OVA)-sensitized Brown-Norway rats underwent intermittent hypoxia (10% oxygen, 30 cycles/h, 10 h/d) or normoxia for 30 days concurrent with weekly OVA or vehicle challenges. Lung physiology, differential leukocyte counts from bronchoalveolar lavage, and histology (Picro Sirius Red staining for collagen content) were compared between groups 2 days after the last challenge. Gene expression in bronchoalveolar lavage cells was quantified by quantitative PCR. Compared with normoxia, chronic intermittent hypoxia reduced the FEV0.1/FVC ratio (P = 0.005), peak expiratory flow (P = 0.002), and mean midexpiratory flow (P = 0.004), predominantly in medium and large airways; decreased the baseline eosinophil number (P = 0.01) and amplified the effect of OVA on monocyte number (P = 0.02 for the interaction); in proximal airways, increased (P = 0.008), whereas in distal airways it decreased (P = 0.004), collagen density; induced qualitative emphysematous changes in lung periphery; and increased expression of the M2 macrophage marker YM-1 and augmented OVA-induced expression of plasminogen activator inhibitor-1. Chronic intermittent hypoxia alters immune response to allergen toward a more T-H-1-predominant cellular phenotype with collagen deposition and matrix degradation, leading to airflow limitation. These findings highlight the potential of sleep apnea to aggravate airway dysfunction in patients with preexistent asthma. C1 [Broytman, Oleg; Hsu, Pei-Ning; Mei, Linda S.; Koya, Ajay K.; Teodorescu, Mihaela] Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Med Serv, James B Skatrud Pulm Sleep Res Lab, Madison, WI 53792 USA. [Broytman, Oleg; Teodorescu, Mihaela] Univ Wisconsin, Div Allergy Pulm & Crit Care Med, Sch Med & Publ Hlth, Madison, WI USA. [Braun, Rudolf K.; Pegelow, David F.; Eldridge, Marlowe] Univ Wisconsin, John Rankin Pulm Res Lab, Sch Med & Publ Hlth, Madison, WI USA. [Braun, Rudolf K.; Pegelow, David F.; Eldridge, Marlowe] Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, Madison, WI USA. [Morgan, Barbara J.] Univ Wisconsin, Dept Orthoped & Rehabil, Sch Med & Publ Hlth, Madison, WI USA. RP Teodorescu, M (reprint author), B5056 VA Hosp,2500 Overlook Terrace, Madison, WI 53705 USA. EM mt3@medicine.wisc.edu FU Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin FX This work was supported by funding from the Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. NR 50 TC 9 Z9 9 U1 4 U2 8 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD FEB PY 2015 VL 52 IS 2 BP 162 EP 170 DI 10.1165/rcmb.2014-0213OC PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA CF0BK UT WOS:000352207300003 PM 25004109 ER PT J AU Wei, NJ Nathan, DM Wexler, DJ AF Wei, Nancy J. Nathan, David M. Wexler, Deborah J. TI GLYCEMIC CONTROL AFTER HOSPITAL DISCHARGE IN INSULIN-TREATED TYPE 2 DIABETES: A RANDOMIZED PILOT STUDY OF DAILY REMOTE GLUCOSE MONITORING SO ENDOCRINE PRACTICE LA English DT Article ID BLOOD-GLUCOSE; HYPOGLYCEMIA; RISK; INTERVENTION; MEDICATION; TRANSITION; INPATIENT; MELLITUS; OUTCOMES; TRIAL AB Objective: Little is known about glycemic control in type 2 diabetes patients treated with insulin in the high-risk period between hospital discharge and follow-up. We sought to assess the impact of remote glucose monitoring on postdischarge glycemic control and insulin titration. Methods: We randomly assigned 28 hospitalized type 2 diabetes patients who were discharged home on insulin therapy to routine specialty care (RSC) or RSC with daily remote glucose monitoring (RGM). We compared the primary outcome of mean blood glucose and exploratory outcomes of hypoglycemia/hyperglycemia rates, change in hemoglobin A(1c) and glycated albumin, and insulin titration frequency between groups. Results: Mean blood glucose was not significantly different between the treatment arms (144 +/- 34 mg/dL in the RSC group and 172 +/- 41 mg/dL in the RGM group; not significant), nor were there significant differences in any of the other measures of glycemia during the month after discharge. Hypoglycemia (glucometer reading <60 mg/dL) was common, occurring in 46% of subjects, with no difference between groups. In as-treated analysis, insulin dose adjustments (29% with an increase and 43% with decrease in insulin dose) occurred more frequently in the patients who used RGM (average of 2.8 vs. 1.2 dose adjustments; P = .03). Conclusion: In this pilot trial in insulin-treated type 2 diabetes, RGM did not affect glycemic control after hospital discharge; however, the high rate of hypoglycemia in the postdischarge transition period and the higher frequency of insulin titration in patients who used RGM suggest a safety role for such monitoring in the transition from hospital to home. C1 Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Wei, NJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 404, Boston, MA 02114 USA. EM ncwei@mgh.harvard.edu FU NIDDK training grant [T32 DK 007 028]; NIDDK Career Development Award [K23 DK 080 228] FX We thank Dr. Michael Steffes, (Department of Laboratory Medicine and Pathology, University of Minnesota) for his assistance with the glycated albumin measurements. We would like to recognize Khinlei Myint U. and Dr. Joseph Kvedar, at the Partners Center for Connected Health for their continued technical support of our use of the remote monitoring devices and Diabetes Connect web-portal. Dr. Nancy J. Wei was supported by an NIDDK training grant (number T32 DK 007 028). Dr. Deborah J. Wexler was supported by an NIDDK Career Development Award (number K23 DK 080 228), which also supported this project in part. NR 15 TC 1 Z9 1 U1 1 U2 4 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD FEB PY 2015 VL 21 IS 2 BP 115 EP 121 DI 10.4158/EP14134.OR PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CE9GO UT WOS:000352152300002 PM 25148814 ER PT J AU Mccoy, TH Perlis, RH AF Mccoy, Thomas H., Jr. Perlis, Roy H. TI A Tool to Utilize Adverse Effect Profiles to Identify Brain-Active Medications for Repurposing SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE adverse effects; bioinformatics; chemical screening; drug discovery; repurposing ID COMPUTATIONAL PREDICTION; BARRIER; GATIFLOXACIN AB Background: To shorten the time required to bring new treatments to clinics, recent efforts have focused on repurposing existing Food and Drug Administration (FDA)-approved drugs with established safety data for new indications. We hypothesized that adverse effect profiles might aid in prioritizing compounds for investigation in central nervous system (CNS) applications by providing an indication of their abilities to cross the blood-brain barrier. Methods: Data were drawn from an investigation of similarity of adverse effect profiles, utilizing pre- and post-marketing data. A panel of known CNS-active drugs was utilized to estimate aggregate similarity profiles for all other FDA drugs in the database. Permutations were used to test whether similarities for any given drug exceeded that expected under the null hypothesis. To estimate the performance of algorithms using such profiles, manually-curated lists of known CNS-active and -inactive medications were classified using logistic regression. Algorithms with and without this similarity data were compared for prediction of CNS penetrance. Results: Models incorporating adverse effect similarity data exhibited greater discrimination of brain-penetrant and non-penetrant drugs than models without this data. A visualization tool was developed to allow any medication to be evaluated for adverse effect similarity to the CNS panel or a custom panel. Conclusions: Consideration of adverse effect profiles allows in silico prioritization of compounds for follow-up investigation for CNS indications. In concert with chemical screening approaches, this may accelerate repurposing efforts for putative CNS-active medications. C1 [Mccoy, Thomas H., Jr.; Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Expt Drugs & Diagnost, Dept Psychiat, Boston, MA 02114 USA. [Mccoy, Thomas H., Jr.; Perlis, Roy H.] Harvard Univ, Sch Med, Boston, MA USA. RP Perlis, RH (reprint author), Simches Res Bldg,185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@partners.org OI McCoy, Thomas/0000-0002-5624-0439 FU NIMH [MH086026]; Stanley Center for Psychiatric Research at the Broad Institute FX Dr Perlis is supported by NIMH MH086026 and the Stanley Center for Psychiatric Research at the Broad Institute. Dr McCoy is a participant in NIMH 5R25MH094612. NR 13 TC 1 Z9 1 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD FEB PY 2015 VL 18 IS 3 DI 10.1093/ijnp/pyu078 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CF4QQ UT WOS:000352535900015 ER PT J AU D'Amico, AV AF D'Amico, Anthony V. TI Personalizing the Duration of Androgen-Deprivation Therapy Use in the Management of Intermediate-Risk Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RADICAL PROSTATECTOMY; RADIATION-THERAPY; BIOPSY CORES; DISEASE; TRIAL; RADIOTHERAPY; RECURRENCE; PERCENTAGE; MORTALITY; MEN C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 19 TC 4 Z9 4 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 1 PY 2015 VL 33 IS 4 BP 301 EP U151 DI 10.1200/JCO.2014.59.0968 PG 4 WC Oncology SC Oncology GA CF3BP UT WOS:000352422900006 PM 25534385 ER PT J AU Couch, FJ Hart, SN Sharma, P Toland, AE Wang, XS Miron, P Olson, JE Godwin, AK Pankratz, VS Olswold, C Slettedahl, S Hallberg, E Guidugli, L Davila, JI Beckmann, MW Janni, W Rack, B Ekici, AB Slamon, DJ Konstantopoulou, I Fostira, F Vratimos, A Fountzilas, G Pelttari, LM Tapper, WJ Durcan, L Cross, SS Pilarski, R Shapiro, CL Klemp, J Yao, S Garber, J Cox, A Brauch, H Ambrosone, C Nevanlinna, H Yannoukakos, D Slager, SL Vachon, CM Eccles, DM Fasching, PA AF Couch, Fergus J. Hart, Steven N. Sharma, Priyanka Toland, Amanda Ewart Wang, Xianshu Miron, Penelope Olson, Janet E. Godwin, Andrew K. Pankratz, V. Shane Olswold, Curtis Slettedahl, Seth Hallberg, Emily Guidugli, Lucia Davila, Jaime I. Beckmann, Matthias W. Janni, Wolfgang Rack, Brigitte Ekici, Arif B. Slamon, Dennis J. Konstantopoulou, Irene Fostira, Florentia Vratimos, Athanassios Fountzilas, George Pelttari, Liisa M. Tapper, William J. Durcan, Lorraine Cross, Simon S. Pilarski, Robert Shapiro, Charles L. Klemp, Jennifer Yao, Song Garber, Judy Cox, Angela Brauch, Hiltrud Ambrosone, Christine Nevanlinna, Heli Yannoukakos, Drakoulis Slager, Susan L. Vachon, Celine M. Eccles, Diana M. Fasching, Peter A. TI Inherited Mutations in 17 Breast Cancer Susceptibility Genes Among a Large Triple-Negative Breast Cancer Cohort Unselected for Family History of Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BRCA2 MUTATIONS; UNCERTAIN SIGNIFICANCE; NEXT-GENERATION; SEQUENCING DATA; YOUNG-WOMEN; VARIANTS; CLASSIFICATION; PALB2; PREVALENCE; RISK AB Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives. (C) 2014 by American Society of Clinical Oncology C1 [Couch, Fergus J.; Hart, Steven N.; Wang, Xianshu; Olson, Janet E.; Pankratz, V. Shane; Olswold, Curtis; Slettedahl, Seth; Hallberg, Emily; Guidugli, Lucia; Davila, Jaime I.; Slager, Susan L.; Vachon, Celine M.] Mayo Clin, Rochester, MN 55905 USA. [Sharma, Priyanka; Godwin, Andrew K.; Klemp, Jennifer] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Toland, Amanda Ewart; Pilarski, Robert; Shapiro, Charles L.] Ohio State Univ, Columbus, OH 43210 USA. [Miron, Penelope; Garber, Judy] Dana Farber Canc Inst, Boston, MA 02115 USA. [Beckmann, Matthias W.; Ekici, Arif B.; Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, D-91054 Erlangen, Germany. [Janni, Wolfgang] Univ Hosp Ulm, Ulm, Germany. [Rack, Brigitte] Univ Munich, Munich, Germany. [Brauch, Hiltrud] Univ Tubingen, Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] German Canc Consortium, Heidelberg, Germany. [Brauch, Hiltrud] German Canc Res Ctr, Heidelberg, Germany. [Slamon, Dennis J.; Fasching, Peter A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Athens, Greece. [Fountzilas, George] Aristotle Univ Thessaloniki, Papageorgiou Hosp, GR-54006 Thessaloniki, Greece. [Pelttari, Liisa M.; Nevanlinna, Heli] Univ Helsinki, Helsinki, Finland. [Pelttari, Liisa M.; Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Tapper, William J.; Durcan, Lorraine; Eccles, Diana M.] Univ Southampton, Southampton, Hants, England. [Cross, Simon S.; Cox, Angela] Univ Sheffield, Sheffield, S Yorkshire, England. [Yao, Song; Ambrosone, Christine] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. RP Couch, FJ (reprint author), Mayo Clin, Dept Lab Med & Pathol, Stabile Bldg,200 First St SW, Rochester, MN 55905 USA. EM couch.fergus@mayo.edu RI Pilarski, Robert/E-3871-2011; OI Cross, Simon/0000-0003-2044-1754; Cox, Angela/0000-0002-5138-1099; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU National Institutes of Health [CA128978]; Specialized Program of Research Excellence in Breast Cancer [P50 CA116201]; Breast Cancer Research Foundation FX Supported by National Institutes of Health Grant No. CA128978, Specialized Program of Research Excellence in Breast Cancer Grant No. P50 CA116201 to Mayo Clinic, Breast Cancer Research Foundation, and a generous gift from David F. and Margaret T. Grohne Family Foundation. NR 42 TC 92 Z9 95 U1 10 U2 33 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 1 PY 2015 VL 33 IS 4 BP 304 EP U154 DI 10.1200/JCO.2014.57.1414 PG 11 WC Oncology SC Oncology GA CF3BP UT WOS:000352422900007 PM 25452441 ER PT J AU Warren, JL Butler, EN Stevens, J Lathan, CS Noone, AM Ward, KC Harlan, LC AF Warren, Joan L. Butler, Ebonee N. Stevens, Jennifer Lathan, Christopher S. Noone, Anne-Michelle Ward, Kevin C. Harlan, Linda C. TI Receipt of Chemotherapy Among Medicare Patients With Cancer by Type of Supplemental Insurance SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNITED-STATES; BENEFICIARIES; THERAPY; CARE; POPULATION; HOSPITALS; TRENDS AB Purpose Medicare beneficiaries with cancer bear a greater portion of their health care costs, because cancer treatment costs have increased. Beneficiaries have supplemental insurance to reduce out-of-pocket costs; those without supplemental insurance may face barriers to care. This study examines the association between type of supplemental insurance coverage and receipt of chemotherapy among Medicare patients with cancer who, per National Comprehensive Cancer Network treatment guidelines, should generally receive chemotherapy. Patients and Methods This retrospective, observational study included 1,200 Medicare patients diagnosed with incident cancer of the breast (stage IIB to III), colon (stage III), rectum (stage II to III), lung (stage II to IV), or ovary (stage II to IV) from 2000 to 2005. Using the National Cancer Institute Patterns of Care Studies and linked SEER-Medicare data, we determined each Medicare patient's supplemental insurance status (private insurance, dual eligible [ie, Medicare with Medicaid], or no supplemental insurance), consultation with an oncologist, and receipt of chemotherapy. Using adjusted logistic regression, we evaluated the association of type of supplemental insurance with oncologist consultation and receipt of chemotherapy. Results Dual-eligible patients were significantly less likely to receive chemotherapy than were Medicare patients with private insurance. Patients with Medicare only who saw an oncologist had comparable rates of chemotherapy compared with Medicare patients with private insurance. Conclusion Dual-eligible Medicare beneficiaries received recommended cancer chemotherapy less frequently than other Medicare beneficiaries. With the increasing number of Medicaid patients under the Affordable Care Act, there will be a need for patient navigators and sufficient physician reimbursement so that low-income patients with cancer will have access to oncologists and needed treatment. (C) 2014 by American Society of Clinical Oncology C1 [Warren, Joan L.; Noone, Anne-Michelle; Harlan, Linda C.] NCI, Bethesda, MD 20892 USA. [Stevens, Jennifer] Informat Management Serv Inc, Beltsville, MD USA. [Butler, Ebonee N.] Univ N Carolina, Chapel Hill, NC USA. [Lathan, Christopher S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ward, Kevin C.] Emory Univ, Atlanta, GA 30322 USA. RP Warren, JL (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E428, Bethesda, MD 20892 USA. EM joan_warren@nih.gov FU NCI NIH HHS [P50 CA058223] NR 23 TC 7 Z9 7 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 1 PY 2015 VL 33 IS 4 BP 312 EP U191 DI 10.1200/JCO.2014.55.3107 PG 8 WC Oncology SC Oncology GA CF3BP UT WOS:000352422900008 PM 25534387 ER PT J AU Pisansky, TM Hunt, D Gomella, LG Amin, MB Balogh, AG Chinn, DM Seider, MJ Duclos, M Rosenthal, SA Bauman, GS Gore, EM Rotman, MZ Lukka, HR Shipley, WU Dignam, JJ Sandler, HM AF Pisansky, Thomas M. Hunt, Daniel Gomella, Leonard G. Amin, Mahul B. Balogh, Alexander G. Chinn, Daniel M. Seider, Michael J. Duclos, Marie Rosenthal, Seth A. Bauman, Glenn S. Gore, Elizabeth M. Rotman, Marvin Z. Lukka, Himanshu R. Shipley, William U. Dignam, James J. Sandler, Howard M. TI Duration of Androgen Suppression Before Radiotherapy for Localized Prostate Cancer: Radiation Therapy Oncology Group Randomized Clinical Trial 9910 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-III TRIAL; DEPRIVATION THERAPY; HORMONAL-THERAPY; COMPETING RISK; NEOADJUVANT; RTOG; STRATIFICATION; ADJUVANT; MEN AB Purpose To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer. Patients and Methods One thousand five hundred seventy-nine men with intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up. Results There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8-and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio [HR], 0.81; P = .45), respectively, and 10-year overall survival rates were66%(95% CI, 62.0% to 69.9%) and67%(95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8-and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen-based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively. Conclusion Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate-risk prostate cancer. (C) 2014 by American Society of Clinical Oncology C1 [Pisansky, Thomas M.] Mayo Clin, Rochester, MN 55905 USA. [Hunt, Daniel; Dignam, James J.] Radiat Therapy Oncol Grp Stat Ctr, Philadelphia, PA USA. [Gomella, Leonard G.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Amin, Mahul B.; Sandler, Howard M.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Chinn, Daniel M.] John Muir Med Ctr, Concord, CA USA. [Rosenthal, Seth A.] Sutter Med Grp, Sacramento, CA USA. [Seider, Michael J.] Akron City Hosp, Akron, OH USA. [Gore, Elizabeth M.] Zablocki Vet Adm Med Ctr Wood, Milwaukee, WI USA. [Rotman, Marvin Z.] State Univ New York Downstate, Brooklyn Minor Based Community Clin Oncol Program, Brooklyn, NY USA. [Shipley, William U.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dignam, James J.] Univ Chicago, Chicago, IL 60637 USA. [Balogh, Alexander G.] Tom Baker Canc Clin, Calgary, AB, Canada. [Duclos, Marie] McGill Univ, Montreal, PQ, Canada. [Bauman, Glenn S.] London Reg Canc Program, London, ON, Canada. [Lukka, Himanshu R.] McMaster Univ, Hamilton, ON, Canada. RP Pisansky, TM (reprint author), Mayo Clin, Dept Radiat Oncol, 200 First St SW, Rochester, MN 55905 USA. EM pisansky.thomas@mayo.edu FU Radiation Therapy Oncology Group [U10 CA21661]; Community Clinical Oncology Program [U10 CA37422]; National Cancer Institute [U10 CA180822] FX Supported by Radiation Therapy Oncology Group Grant No. U10 CA21661, Community Clinical Oncology Program Grant No. U10 CA37422, and Grant No. U10 CA180822 from the National Cancer Institute. NR 30 TC 15 Z9 15 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 1 PY 2015 VL 33 IS 4 BP 332 EP U195 DI 10.1200/JCO.2014.58.0662 PG 10 WC Oncology SC Oncology GA CF3BP UT WOS:000352422900011 PM 25534388 ER PT J AU Wolff, AC Blackford, AL Visvanathan, K Rugo, HS Moy, B Goldstein, LJ Stockerl-Goldstein, K Neumayer, L Langbaum, TS Theriault, RL Hughes, ME Weeks, JC Karp, JE AF Wolff, Antonio C. Blackford, Amanda L. Visvanathan, Kala Rugo, Hope S. Moy, Beverly Goldstein, Lori J. Stockerl-Goldstein, Keith Neumayer, Leigh Langbaum, Terry S. Theriault, Richard L. Hughes, Melissa E. Weeks, Jane C. Karp, Judith E. TI Risk of Marrow Neoplasms After Adjuvant Breast Cancer Therapy: The National Comprehensive Cancer Network Experience SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MYELODYSPLASTIC SYNDROMES; CHEMOTHERAPY; ADULTS; RADIATION; WOMEN AB Purpose Outcomes for early-stage breast cancer have improved. First-generation adjuvant chemotherapy trials reported a 0.27% 8-year cumulative incidence of myelodysplastic syndrome/acute myelogenous leukemia. Incomplete ascertainment and follow-up may have underestimated subsequent risk of treatment-associated marrow neoplasm (MN). Patients and Methods We examined the MN frequency in 20,063 patients with stage I to III breast cancer treated at US academic centers between 1998 and 2007. Time-to-event analyses were censored at first date of new cancer event, last contact date, or death and considered competing risks. Cumulative incidence, hazard ratios (HRs), and comparisons with Surveillance, Epidemiology, and End Results estimates were obtained. Marrow cytogenetics data were reviewed. Results Fifty patients developed MN (myeloid, n = 42; lymphoid, n = 8) after breast cancer (median follow-up, 5.1 years). Patients who developed MN had similar breast cancer stage distribution, race, and chemotherapy exposure but were older compared with patients who did not develop MN (median age, 59.1 v 53.9 years, respectively; P = .03). Two thirds of patients had complex MN cytogenetics. Risk of MN was significantly increased after surgery plus chemotherapy (HR, 6.8; 95% CI, 1.3 to 36.1) or after all modalities (surgery, chemotherapy, and radiation; HR, 7.6; 95% CI, 1.6 to 35.8), compared with no treatment with chemotherapy. MN rates per 1,000 person-years were 0.16 (surgery), 0.43 (plus radiation), 0.46 (plus chemotherapy), and 0.54 (all three modalities). Cumulative incidence of MN doubled between years 5 and 10 (0.24% to 0.48%); 9% of patients were alive at 10 years. Conclusion In this large early-stage breast cancer cohort, MNrisk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk ofMNmust be balanced against the absolute survival benefit of adjuvant chemotherapy. (C) 2014 by American Society of Clinical Oncology C1 [Wolff, Antonio C.; Blackford, Amanda L.; Visvanathan, Kala; Langbaum, Terry S.; Karp, Judith E.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Rugo, Hope S.] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Moy, Beverly] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Hughes, Melissa E.; Weeks, Jane C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldstein, Lori J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Stockerl-Goldstein, Keith] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA. [Neumayer, Leigh] Univ Utah, Sch Med, Huntsman Canc Ctr, Salt Lake City, UT USA. [Theriault, Richard L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Wolff, AC (reprint author), Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Breast Canc Program, 1650 Orleans St,CRB1-189, Baltimore, MD 21287 USA. EM awolff@jhmi.edu OI Wolff, Antonio/0000-0003-3734-1063 FU National Cancer Institute [CA89393, CA006973, SAC110053] FX Supported in part by National Cancer Institute Grants No. CA89393 to Dana-Farber Cancer Institute, CA006973 to the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and Susan G. Komen for the Cure Grant No. SAC110053 (A.C.W). NR 20 TC 17 Z9 18 U1 1 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 1 PY 2015 VL 33 IS 4 BP 340 EP U196 DI 10.1200/JCO.2013.54.6119 PG 10 WC Oncology SC Oncology GA CF3BP UT WOS:000352422900012 PM 25534386 ER PT J AU Eapen, M Logan, BR Horowitz, MM Zhong, XB Perales, MA Lee, SJ Rocha, V Soiffer, RJ Champlin, RE AF Eapen, Mary Logan, Brent R. Horowitz, Mary M. Zhong, Xiaobo Perales, Miguel-Angel Lee, Stephanie J. Rocha, Vanderson Soiffer, Robert J. Champlin, Richard E. TI Bone Marrow or Peripheral Blood for Reduced-Intensity Conditioning Unrelated Donor Transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VERSUS-HOST-DISEASE; STEM-CELL TRANSPLANTATION; CHRONIC GRAFT; MYCOPHENOLATE-MOFETIL; COMPARING METHOTREXATE; RANDOMIZED-TRIAL; MOBILIZED BLOOD; EUROPEAN GROUP; TACROLIMUS; CYCLOSPORINE AB Purpose There have been no randomized trials that have compared peripheral blood (PB) with bone marrow (BM) grafts in the setting of reduced-intensity conditioning (RIC) transplantations for hematologic malignancy. Because immune modulation plays a significant role in sustaining clinical remission after RIC, we hypothesize that higher graft-versus-host disease (GVHD) associated with PB transplantation may offer a survival advantage. Patients and Methods The primary outcome evaluated was overall survival. Cox regression models were built to study outcomes after transplantation of PB (n = 887) relative to BM (n = 219) for patients with acute myeloid leukemia, myelodysplastic syndrome, or non-Hodgkin lymphoma, the three most common indications for unrelated RIC transplantation. Transplantations were performed in the United States between 2000 and 2008. Conditioning regimens consisted of an alkylating agent and fludarabine, and GVHD prophylaxis involved a calcineurin inhibitor (CNI) with either methotrexate (MTX) or mycophenolate mofetil (MMF). Results After adjusting for age, performance score, donor-recipient HLA-match, disease, and disease status at transplantation (factors associated with overall survival), there were no significant differences in 5-year rates of survival after transplantation of PB compared with BM: 34% versus 38% with CNI-MTX and 27% versus 20% with CNI-MMF GVHD prophylaxis. Conclusion Survival after transplantation of PB and BM are comparable in the setting of nonirradiation RIC regimens for hematologic malignancy. The effect of GVHD prophylaxis on survival merits further evaluation. (C) 2014 by American Society of Clinical Oncology C1 [Eapen, Mary; Logan, Brent R.; Horowitz, Mary M.; Zhong, Xiaobo] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Rocha, Vanderson] Churchill Hosp, Oxford OX3 7LJ, England. [Soiffer, Robert J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Champlin, Richard E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Eapen, M (reprint author), Med Coll Wisconsin, 8701 Watertown Plank Rd,POB 26509, Milwaukee, WI 53226 USA. EM meapen@mcw.edu FU Public Health Service from the National Cancer Institute [U24-CA76518]; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration [HHSH234200637015C]; Bill Young Stem Cell Transplantation program's FX Supported by Public Health Service Grant No. U24-CA76518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases, and by Health Resources and Services Administration Grant No. HHSH234200637015C for the C.W. Bill Young Stem Cell Transplantation program's contract for the Stem Cell Therapeutic Outcomes Database. M.E. is a clinical scholar of the Leukemia and Lymphoma Society. NR 24 TC 11 Z9 12 U1 0 U2 3 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 1 PY 2015 VL 33 IS 4 BP 364 EP U203 DI 10.1200/JCO.2014.57.2446 PG 7 WC Oncology SC Oncology GA CF3BP UT WOS:000352422900015 PM 25534391 ER PT J AU Friedlander, AH AF Friedlander, Arthur H. TI ETHICAL CONCERNS Response SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Letter C1 VA Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA 90073 USA. RP Friedlander, AH (reprint author), VA Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA 90073 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD FEB PY 2015 VL 146 IS 2 BP 75 EP 75 DI 10.1016/j.adaj.2014.12.005 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CE9GM UT WOS:000352152100003 PM 25637203 ER PT J AU Schoettler, M Elisofon, SA Kim, HB Blume, ED Rodig, N Boyer, D Neufeld, EJ Grace, RF AF Schoettler, Michelle Elisofon, Scott A. Kim, Heung Bae Blume, Elizabeth D. Rodig, Nancy Boyer, Debra Neufeld, Ellis J. Grace, Rachael F. TI Treatment and Outcomes of Immune Cytopenias Following Solid Organ Transplant in Children SO PEDIATRIC BLOOD & CANCER LA English DT Article DE autoimmune hemolytic anemia; autoimmune neutropenia; immune thrombocytopenia; solid organ transplant; tacrolimus ID AUTOIMMUNE HEMOLYTIC-ANEMIA; OF-THE-LITERATURE; IDIOPATHIC THROMBOCYTOPENIC PURPURA; CASE SERIES; PEDIATRIC LIVER; TACROLIMUS; RECIPIENTS AB Background. Immune cytopenias are a recognized life-threatening complication following pediatric solid organ transplants (SOT), but treatment responses and overall outcome are not well described. The aimof this studywas to evaluate the demographic characteristics, response to treatments, and outcomes of a cohort of patients who developed immune cytopenias following SOT. Procedure. In this single center retrospective review, patients with immune cytopenias after SOT were identified by electronic medical record (EMR) search and transplant databases from 1995-2012. Results. Of 764 SOT patients, 19 (2.4%) developed immune cytopenias. Incidence varied widely by transplant type from 1.2% (renal) to 23.5% (multivisceral). Autoimmune hemolytic anemia (AIHA) was the most common immune cytopenia. Overall median time from transplant to immune cytopenia was 8m and varied by transplant type from 3m (liver) to 74m (heart). Standard therapies for immune cytopenias were often used and ineffective. The most effective therapy for the immune cytopenia was changing immunosuppression from tacrolimus to another agent. Three of 19 patients died; none directly attributed to the immune cytopenia. Conclusions. Immune cytopenias are not rare after SOT, and patients usually do not respond well to traditional first line therapies. Provided that the risk of organ rejection is otherwise manageable, temporary cessation of tacrolimus could be more widely explored in this challenging clinical context. (C) 2014 Wiley Periodicals, Inc. C1 [Schoettler, Michelle; Neufeld, Ellis J.; Grace, Rachael F.] Dana Farber Boston Childrens Canc & Blood Disorde, Pediat Hematol Oncol, Boston, MA USA. [Elisofon, Scott A.] Boston Childrens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Kim, Heung Bae] Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Blume, Elizabeth D.] Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Rodig, Nancy] Boston Childrens Hosp, Div Nephrol, Boston, MA 02115 USA. [Boyer, Debra] Boston Childrens Hosp, Div Resp Dis, Boston, MA 02115 USA. RP Grace, RF (reprint author), Boston Childrens Hosp, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM rachael.grace@childrens.harvard.edu OI Grace, Fergal/0000-0002-3144-5999 FU NHLBI NIH HHS [K12 HL087164] NR 22 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2015 VL 62 IS 2 BP 214 EP 218 DI 10.1002/pbc.25215 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CF0FN UT WOS:000352218600008 PM 25308853 ER PT J AU Premereur, E Van Dromme, IC Romero, MC Vanduffel, W Janssen, P AF Premereur, Elsie Van Dromme, Ilse C. Romero, Maria C. Vanduffel, Wim Janssen, Peter TI Effective Connectivity of Depth-Structure-Selective Patches in the Lateral Bank of the Macaque Intraparietal Sulcus SO PLOS BIOLOGY LA English DT Article ID POSTERIOR PARIETAL CORTEX; SUPERIOR TEMPORAL AREA; FRONTAL EYE FIELD; 3-DIMENSIONAL SHAPE; INTRACORTICAL MICROSTIMULATION; FUNCTIONAL CONNECTIVITY; CORTICAL CONNECTIONS; VISUAL-CORTEX; CORTICOCORTICAL CONNECTIONS; ELECTRICAL MICROSTIMULATION AB Extrastriate cortical areas are frequently composed of subpopulations of neurons encoding specific features or stimuli, such as color, disparity, or faces, and patches of neurons encoding similar stimulus properties are typically embedded in interconnected networks, such as the attention or face-processing network. The goal of the current study was to examine the effective connectivity of subsectors of neurons in the same cortical area with highly similar neuronal response properties. We first recorded single-and multi-unit activity to identify two neuronal patches in the anterior part of the macaque intraparietal sulcus (IPS) showing the same depth structure selectivity and then employed electrical microstimulation during functional magnetic resonance imaging in these patches to determine the effective connectivity of these patches. The two IPS subsectors we identified-with the same neuronal response properties and in some cases separated by only 3 mm-were effectively connected to remarkably distinct cortical networks in both dorsal and ventral stream in three macaques. Conversely, the differences in effective connectivity could account for the known visual-to-motor gradient within the anterior IPS. These results clarify the role of the anterior IPS as a pivotal brain region where dorsal and ventral visual stream interact during object analysis. Thus, in addition to the anatomical connectivity of cortical areas and the properties of individual neurons in these areas, the effective connectivity provides novel key insights into the widespread functional networks that support behavior. C1 [Premereur, Elsie; Van Dromme, Ilse C.; Romero, Maria C.; Vanduffel, Wim; Janssen, Peter] Katholieke Univ Leuven, Lab Neuro & Psychofysiol, Leuven, Belgium. [Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Premereur, E (reprint author), Katholieke Univ Leuven, Lab Neuro & Psychofysiol, Leuven, Belgium. EM Peter.Janssen@med.kuleuven.be FU geconcerteerde onderzoeksacties [GOA/10/19]; interuniversity attraction poles IUAP [VII/11]; National Science Foundation NSF [BCS-0745436]; Fonds Wetenschappelijk onderzoek FWO [G.0713.09, G.0622.08, G.0831.11]; European Research Council ERC [Stg-260607]; Odysseus grant [G.0007.12]; [PFV/10/008] FX PJ and WV received funding from geconcerteerde onderzoeksacties GOA/10/19; http://www.kuleuven.be/onderzoek/kernprojecten/goa.htm. PJ and WV received funding from interuniversity attraction poles IUAP VII/11; http://www.belspo.be/belspo/fedra/prog.asp?l = nl&COD=p5. PJ and WV received funding from PFV/10/008; WV received funding from National Science Foundation NSF grant BCS-0745436; http://www.nsf.gov/. WV and PJ received funding from Fonds Wetenschappelijk onderzoek FWO grant G.0713.09, G.0622.08, and G.0831.11; http://www.fwo.be/. PJ received funding from European Research Council ERC Stg-260607; http://erc.europa.eu/. PJ and WV received funding from Odysseus grant G.0007.12; http://www.fwo.be/nl/mandaten-financiering/onderzoeksprojecten/odysseusp rogramma/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 12 Z9 12 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD FEB PY 2015 VL 13 IS 2 AR UNSP e1002072 DI 10.1371/journal.pbio.1002072 PG 20 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA CE8GO UT WOS:000352080100019 PM 25689048 ER PT J AU Gonzalez-Ramirez, LR Ahmed, OJ Cash, SS Wayne, CE Kramer, MA AF Gonzalez-Ramirez, Laura R. Ahmed, Omar J. Cash, Sydney S. Wayne, C. Eugene Kramer, Mark A. TI A Biologically Constrained, Mathematical Model of Cortical Wave Propagation Preceding Seizure Termination SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID EXCITATORY NEURONAL NETWORK; TRAVELING-WAVES; GABA(B) RECEPTORS; SPIKING NEURONS; SPIRAL WAVES; SPATIOTEMPORAL DYNAMICS; EPILEPTIFORM DISCHARGES; ELECTROGRAPHIC SEIZURES; SYNAPTIC DEPRESSION; NEOCORTICAL SLICES AB Epilepsy-the condition of recurrent, unprovoked seizures-manifests in brain voltage activity with characteristic spatiotemporal patterns. These patterns include stereotyped semi-rhythmic activity produced by aggregate neuronal populations, and organized spatiotemporal phenomena, including waves. To assess these spatiotemporal patterns, we develop a mathematical model consistent with the observed neuronal population activity and determine analytically the parameter configurations that support traveling wave solutions. We then utilize high-density local field potential data recorded in vivo from human cortex preceding seizure termination from three patients to constrain the model parameters, and propose basic mechanisms that contribute to the observed traveling waves. We conclude that a relatively simple and abstract mathematical model consisting of localized interactions between excitatory cells with slow adaptation captures the quantitative features of wave propagation observed in the human local field potential preceding seizure termination. C1 [Gonzalez-Ramirez, Laura R.; Wayne, C. Eugene; Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Ahmed, Omar J.; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ahmed, Omar J.; Cash, Sydney S.] Harvard Univ, Sch Med, Boston, MA USA. RP Gonzalez-Ramirez, LR (reprint author), Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. EM mak@math.bu.edu FU National Institutes of Health, National Institute of Neurological Disorders and Stroke [R01 NS072023]; National Science Foundation [DMS-1311553]; National Institutes of Health [F32-NS083208] FX LRGR, SSC, and MAK were supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke R01 NS072023; LRGR and CEW were supported by the National Science Foundation DMS-1311553; OJA was supported by the National Institutes of Health F32-NS083208. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 95 TC 9 Z9 9 U1 3 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2015 VL 11 IS 2 AR e1004065 DI 10.1371/journal.pcbi.1004065 PG 34 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CE8GX UT WOS:000352081000026 PM 25689136 ER PT J AU Thormaehlen, AS Schuberth, C Won, HH Blattmann, P Joggerst-Thomalla, B Theiss, S Asselta, R Duga, S Merlini, PA Ardissino, D Lander, ES Gabriel, S Rader, DJ Peloso, GM Pepperkok, R Kathiresan, S Runz, H AF Thormaehlen, Aenne S. Schuberth, Christian Won, Hong-Hee Blattmann, Peter Joggerst-Thomalla, Brigitte Theiss, Susanne Asselta, Rosanna Duga, Stefano Merlini, Pier Angelica Ardissino, Diego Lander, Eric S. Gabriel, Stacey Rader, Daniel J. Peloso, Gina M. Pepperkok, Rainer Kathiresan, Sekar Runz, Heiko TI Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction SO PLOS GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; FAMILIAL HYPERCHOLESTEROLEMIA; ACMG RECOMMENDATIONS; INCIDENTAL FINDINGS; FUNCTIONAL IMPACT; GENETIC-VARIANTS; BLOOD-LIPIDS; MUTATION; PROTEIN; DATABASE AB A fundamental challenge to contemporary genetics is to distinguish rare missense alleles that disrupt protein functions from the majority of alleles neutral on protein activities. High-throughput experimental tools to securely discriminate between disruptive and non-disruptive missense alleles are currently missing. Here we establish a scalable cell-based strategy to profile the biological effects and likely disease relevance of rare missense variants in vitro. We apply this strategy to systematically characterize missense alleles in the low-density lipoprotein receptor (LDLR) gene identified through exome sequencing of 3,235 individuals and exome-chip profiling of 39,186 individuals. Our strategy reliably identifies disruptive missense alleles, and disruptive-allele carriers have higher plasma LDL-cholesterol (LDL-C). Importantly, considering experimental data refined the risk of rare LDLR allele carriers from 4.5-to 25.3-fold for high LDL-C, and from 2.1-to 20-fold for early-onset myocardial infarction. Our study generates proof-of-concept that systematic functional variant profiling may empower rare variant-association studies by orders of magnitude. C1 [Thormaehlen, Aenne S.; Schuberth, Christian; Joggerst-Thomalla, Brigitte; Theiss, Susanne; Runz, Heiko] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany. [Thormaehlen, Aenne S.; Schuberth, Christian; Blattmann, Peter; Joggerst-Thomalla, Brigitte; Pepperkok, Rainer; Runz, Heiko] Heidelberg Univ, EMBL, Mol Med Partnership Unit MMPU, Heidelberg, Germany. [Won, Hong-Hee; Peloso, Gina M.; Kathiresan, Sekar; Runz, Heiko] Massachusetts Gen Hosp, Ctr Human Genet Res CHGR, Boston, MA 02114 USA. [Won, Hong-Hee; Lander, Eric S.; Gabriel, Stacey; Peloso, Gina M.; Kathiresan, Sekar; Runz, Heiko] Broad Inst MIT & Harvard, Cambridge, MA USA. [Won, Hong-Hee; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Won, Hong-Hee] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Blattmann, Peter; Pepperkok, Rainer] European Mol Biol Lab, Cell Biol Biophys Unit, D-69012 Heidelberg, Germany. [Asselta, Rosanna; Duga, Stefano] Humanitas Univ, Milan, Italy. [Merlini, Pier Angelica; Kathiresan, Sekar] Osped Niguarda Ca Granda, Div Cardiol, Milan, Italy. [Ardissino, Diego] Parma Hosp, Dept Cardiol, Parma, Italy. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Thormaehlen, AS (reprint author), Heidelberg Univ, Inst Human Genet, Heidelberg, Germany. EM heiko.runz@merck.com RI Blattmann, Peter/D-2880-2012; OI Blattmann, Peter/0000-0001-9105-6381; Asselta, Rosanna/0000-0001-5351-0619; Duga, Stefano/0000-0003-3457-1410 FU Junior Career Fellowship of the Heidelberg Research Center for Molecular Medicine (HRCMM); Career Development Award from Fondation Leducq [12CDA04]; Transatlantic Networks of Excellence Program from Fondation Leducq [10CVD03]; European Union [A28]; Systems Microscopy Network of Excellence [FP7/2007-2013-258068]; Nationales Genomforschungsnetz-Plus consortium IG-CSG [01GS0865]; Research Scholar Award from the Massachusetts General Hospital (MGH); Donovan Family Foundation; NIH [R01HL107816]; Lung GO Sequencing Project [HL-102923]; WHI Sequencing Project [HL-102924]; Broad GO Sequencing Project [HL-102925]; Seattle GO Sequencing Project [HL-102926]; Heart GO Sequencing Project [HL-103010]; [RFPS-2007-3-644382]; [NHGRI 5U54HG003067-11] FX AST was supported through a Junior Career Fellowship of the Heidelberg Research Center for Molecular Medicine (HRCMM). HR was supported, in part, through Career Development Award 12CDA04 from Fondation Leducq. Support to the study came from the Transatlantic Networks of Excellence Program 10CVD03 from Fondation Leducq to HR, SK and RP, and the project no. A28 of the European Union-funded program INTERREG IV to HR. Support to RP by the Systems Microscopy Network of Excellence (FP7/2007-2013-258068) and Nationales Genomforschungsnetz-Plus consortium IG-CSG (01GS0865) is acknowledged. SK is supported by a Research Scholar Award from the Massachusetts General Hospital (MGH), the Donovan Family Foundation, and NIH R01HL107816. The authors would like to thank Ron Do for help with power calculations and the Advanced Light Microscopy Facility (ALMF) at EMBL for support in image analysis. The Italian ATVB study is acknowledged for recruiting study participants and sharing samples for exome sequencing (supported by grants RFPS-2007-3-644382 and NHGRI 5U54HG003067-11). The authors further thank the CHARGE Lipids Working Group which produced and provided variant calls for comparison generated among others through CHARGE consortium infrastructure (HL-105756), as well as the NHLBI Go Exome Sequencing Project (including its ongoing studies) supported through the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 8 Z9 8 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2015 VL 11 IS 2 AR e1004855 DI 10.1371/journal.pgen.1004855 PG 23 WC Genetics & Heredity SC Genetics & Heredity GA CE8HF UT WOS:000352081800003 PM 25647241 ER PT J AU Kaji, I Iwanaga, T Watanabe, M Guth, PH Engel, E Kaunitz, JD Akiba, Y AF Kaji, Izumi Iwanaga, Toshihiko Watanabe, Masahiko Guth, Paul H. Engel, Eli Kaunitz, Jonathan D. Akiba, Yasutada TI SCFA transport in rat duodenum SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE acetate; monocarboxylate transporter; sodium-coupled monocarboxylate transporter; short-chain fatty acid ID CHAIN FATTY-ACIDS; NA+-COUPLED TRANSPORTER; BICARBONATE SECRETION; ENTEROENDOCRINE CELLS; HEALTHY-SUBJECTS; DISTAL COLON; MONOCARBOXYLATE TRANSPORTERS; GASTROINTESTINAL-TRACT; CELLULAR EXPRESSION; DIGESTIVE-TRACT AB Bacterial or ingested food-derived short-chain fatty acids (SCFAs) are present in the duodenal lumen. Acetate, the most abundant SCFA in the foregut lumen, is absorbed immediately after ingestion, although the mechanism by which this absorption occurs is not fully understood. We investigated the distribution and function of candidate SCFA transporters in rat duodenum. The Na+ -coupled monocarboxylate transporter-1 (SMCT1) was localized to the brush border, whereas the pH-dependent monocarboxylate transporter (MCT) 1 and MCT4 were localized to the duodenocyte basolateral membrane. In Ussing chambered duodenal mucosa, luminal acetate dose-dependently increased short-circuit current (I-sc) in the presence of serosal bumetanide and indomethacin by a luminal Na+ -dependent, ouabain-sensitive mechanism. The Isc response was inhibited dose-dependently by the SMCT1 nonsubstrate inhibitor ibuprofen, consistent with net electrogenic absorption of acetate via SMCT1. Other SCFAs and lactate also increased Isc. Furthermore, duodenal loop perfusion of acetate increased portal venous acetate concentration, inhibited by coperfusion of ibuprofen or a MCT inhibitor. Luminal acetate perfusion increased duodenal HCO3 secretion via capsaicin-sensitive afferent nerve activation and cyclooxygenase activity, consistent with absorption-mediated HCO3- secretion. These results suggest that absorption of luminal SCFA via SMCT1 and MCTs increases duodenal HCO3- secretion. In addition to SCFA sensing via free fatty acid receptors, the presence of rapid duodenal SCFA absorption may be important for the suppression of luminal bacterial colonization and implicated in the generation of functional dyspepsia due to bacterial overgrowth. C1 [Guth, Paul H.; Kaunitz, Jonathan D.; Akiba, Yasutada] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. [Kaji, Izumi; Guth, Paul H.; Kaunitz, Jonathan D.; Akiba, Yasutada] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Kaunitz, Jonathan D.] Univ Calif Los Angeles, Sch Med, Dept Surg, Los Angeles, CA 90024 USA. [Engel, Eli] Univ Calif Los Angeles, Sch Med, Dept Biomath, Los Angeles, CA 90024 USA. [Kaji, Izumi; Iwanaga, Toshihiko; Watanabe, Masahiko] Hokkaido Univ, Grad Sch Med, Dept Anat, Sapporo, Hokkaido, Japan. [Kaji, Izumi; Kaunitz, Jonathan D.; Akiba, Yasutada] Brentwood Biomed Res Inst, Los Angeles, CA USA. RP Kaunitz, JD (reprint author), West Los Angeles VA Med Ctr, Bldg 114,Suite 217,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jake@ucla.edu RI WATANABE, Masahiko/A-4055-2012 FU Department of Veterans Affairs Merit Review Award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK-54221]; NIDDK [P30-DK-0413]; [24-5317] FX This study was supported by a Grant-in-Aid for the Japan Society for the Promotion of Science Fellows to I. Kaji (no. 24-5317), a Department of Veterans Affairs Merit Review Award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01-DK-54221 to J. Kaunitz), and the animal core of the NIDDK (P30-DK-0413 to J. E. Rozengurt). NR 60 TC 7 Z9 7 U1 1 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD FEB 1 PY 2015 VL 308 IS 3 BP G188 EP G197 DI 10.1152/ajpgi.00298.2014 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA CB6PV UT WOS:000349749900004 PM 25394661 ER PT J AU Syngal, S Brand, RE Church, JM Giardiello, FM Hampel, HL Burt, RW AF Syngal, Sapna Brand, Randall E. Church, James M. Giardiello, Francis M. Hampel, Heather L. Burt, Randall W. TI ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Review ID FAMILIAL ADENOMATOUS POLYPOSIS; NONPOLYPOSIS COLORECTAL-CANCER; PEUTZ-JEGHERS-SYNDROME; DIFFUSE GASTRIC-CANCER; MUTYH-ASSOCIATED POLYPOSIS; FUNDIC GLAND POLYPS; LYNCH SYNDROME CARRIERS; MSH2 MUTATION CARRIERS; MISMATCH-REPAIR GENES; MUIR-TORRE-SYNDROME AB This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first-and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH -associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. C1 [Syngal, Sapna] Brigham & Womens Hosp, Boston, MA 02115 USA. [Syngal, Sapna] Dana Farber Canc Inst, Boston, MA 02215 USA. [Syngal, Sapna] Harvard Univ, Sch Med, Boston, MA USA. [Brand, Randall E.] Univ Pittsburgh, Med Ctr, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Church, James M.] Cleveland Clin, Dept Colorectal Surg, Cleveland, OH 44106 USA. [Church, James M.] Cleveland Clin Fdn, Ctr Hereditary Colorectal Neoplasia, Cleveland, OH 44195 USA. [Church, James M.] Cleveland Clin Fdn, Inst Digest Dis, Cleveland, OH 44195 USA. [Giardiello, Francis M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Hampel, Heather L.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Burt, Randall W.] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA. RP Syngal, S (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1124, Boston, MA 02215 USA. EM sapna_syngal@dfci.harvard.edu FU National Cancer Institute [K24-11311] FX Financial support : This study was supported by the National Cancer Institute K24-11311 (to S.S.). NR 362 TC 116 Z9 121 U1 12 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD FEB PY 2015 VL 110 IS 2 BP 223 EP 262 DI 10.1038/ajg.2014.435 PG 40 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CE5ZV UT WOS:000351915900004 PM 25645574 ER PT J AU Bittner, EA Shank, E Woodson, L Martyn, JAJ AF Bittner, Edward A. Shank, Erik Woodson, Lee Martyn, J. A. Jeevendra TI Acute and Perioperative Care of the Burn-injured Patient SO ANESTHESIOLOGY LA English DT Review ID CRITICALLY-ILL PATIENTS; UNCUFFED ENDOTRACHEAL-TUBES; TIDAL-VOLUME VENTILATION; ACUTE LUNG INJURY; INHALATION INJURY; INTRAHOSPITAL TRANSPORT; PRACTICE GUIDELINES; SMOKE-INHALATION; MAJOR BURNS; CONTROLLED ANALGESIA AB Care of burn-injured patients requires knowledge of the pathophysiologic changes affecting virtually all organs from the onset of injury until wounds are healed. Massive airway and/or lung edema can occur rapidly and unpredictably after burn and/or inhalation injury. Hemodynamics in the early phase of severe burn injury is characterized by a reduction in cardiac output and increased systemic and pulmonary vascular resistance. Approximately 2 to 5 days after major burn injury, a hyperdynamic and hypermetabolic state develops. Electrical burns result in morbidity much higher than expected based on burn size alone. Formulae for fluid resuscitation should serve only as guideline; fluids should be titrated to physiologic endpoints. Burn injury is associated basal and procedural pain requiring higher than normal opioid and sedative doses. Operating room concerns for the burn-injured patient include airway abnormalities, impaired lung function, vascular access, deceptively large and rapid blood loss, hypothermia, and altered pharmacology. C1 [Bittner, Edward A.; Shank, Erik; Martyn, J. A. Jeevendra] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA. [Bittner, Edward A.; Shank, Erik; Martyn, J. A. Jeevendra] Shriners Hosp Children, Boston, MA USA. [Woodson, Lee] Univ Texas Med Branch, Dept Anesthesiol, Galveston, TX 77555 USA. [Woodson, Lee] Shriners Hosp Children, Galveston, TX 77550 USA. RP Martyn, JAJ (reprint author), Dept Anesthesiol, 51 Blossom St,Room 206, Boston, MA 02114 USA. EM jmartyn@mgh.harvard.edu OI Woodson, Lee Clinton/0000-0001-5231-2338 FU Shriners Hospital Research Philanthropy, Tampa, Florida; National Institutes of Health, Bethesda, Maryland [P50-GM 2500] FX Supported, in part, by grants from the Shriners Hospital Research Philanthropy, Tampa, Florida, and from the National Institutes of Health, Bethesda, Maryland, P50-GM 2500 Project I (to Dr. Martyn). NR 107 TC 7 Z9 9 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD FEB PY 2015 VL 122 IS 2 BP 448 EP 464 DI 10.1097/ALN.0000000000000559 PG 17 WC Anesthesiology SC Anesthesiology GA CE3NZ UT WOS:000351734900026 PM 25485468 ER PT J AU Lange, RT Panenka, WJ Shewchuk, JR Heran, MKS Brubacher, JR Bioux, S Eckbo, R Shenton, ME Iverson, GL AF Lange, Rael T. Panenka, William J. Shewchuk, Jason R. Heran, Manraj K. S. Brubacher, Jeffrey R. Bioux, Sylvain Eckbo, Ryan Shenton, Martha E. Iverson, Grant L. TI Diffusion Tensor Imaging Findings and Postconcussion Symptom Reporting Six Weeks Following Mild Traumatic Brain Injury SO ARCHIVES OF CLINICAL NEUROPSYCHOLOGY LA English DT Article DE Mild traumatic brain injury; Diffusion tensor imaging; Postconcussion symptoms; Neurocognitive; Biomarkers ID POST-CONCUSSION SYMPTOMS; POSTTRAUMATIC-STRESS-DISORDER; MINOR HEAD-INJURY; GOOD OLD DAYS; WHITE-MATTER; AXONAL INJURY; CORPUS-CALLOSUM; CHRONIC PAIN; BASE RATES; MODERATE AB The purpose of this study is to examine the relation between the microstructural architecture of white matter, as measured by diffusion tensor imaging (DTI), and postconcussion symptom reporting 6-8 weeks following mild traumatic brain injury (MTBI). Participants were 108 patients prospectively recruited from a Level 1 Trauma Center (Vancouver, BC, Canada) following an orthopedic injury [i.e., 36 trauma controls (TCs)] or MTBI (n = 72). DTI of the whole brain was undertaken using a Phillips 3T scanner at 6-8 weeks postinjury. Participants also completed a 5 h neurocognitive test battery and a brief battery of self-report measures (e.g., depression, anxiety, and postconcussion symptoms). The MTBI sample was divided into two groups based on ICD-10 criteria for postconcussional syndrome (PCS): first, PCS-present (n = 20) and second, PCS-absent (n = 52). There were no significant differences across the three groups (i.e., TC, PCS-present, and PCS-absent) for any of the neurocognitive measures (p = .138-.810). For the self-report measures, the PCS-present group reported significantly more anxiety and depression symptoms compared with the PCS-absent and TC groups (p < .001, d = 1.63-1.89, very large effect sizes). For the DTI measures, there were no significant differences in fractional anisotropy, axial diffusivity, radial diffusivity, or mean diffusivity when comparing the PCS-present and PCS-absent groups. However, there were significant differences (p < .05) in MD and RD when comparing the PCS-present and TC groups. There were significant differences in white matter between TC subjects and the PCS-present MTBI group, but not the PCS-absent MTBI group. Within the MTBI group, white-matter changes were not a significant predictor of ICD-10 PCS. C1 [Lange, Rael T.; Iverson, Grant L.] Def & Vet Brain Injury Ctr, Bethesda, MD USA. [Lange, Rael T.] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20814 USA. [Lange, Rael T.; Panenka, William J.; Shewchuk, Jason R.; Heran, Manraj K. S.; Brubacher, Jeffrey R.; Iverson, Grant L.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Shewchuk, Jason R.; Heran, Manraj K. S.; Brubacher, Jeffrey R.] Vancouver Gen Hosp, Vancouver, BC, Canada. [Bioux, Sylvain; Eckbo, Ryan; Shenton, Martha E.] Brigham Womens Hosp, Boston, MA USA. [Bioux, Sylvain; Eckbo, Ryan; Shenton, Martha E.; Iverson, Grant L.] Harvard Univ, Sch Med, Boston, MA USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Brockton, MA USA. [Iverson, Grant L.] Spaulding Rehabil Hosp, Charlestown, MA USA. [Iverson, Grant L.] Red Sox Fdn, Boston, MA USA. [Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. RP Lange, RT (reprint author), Walter Reed Natl Mil Med Ctr, Def & Vet Brain Injury Ctr, Bldg 8,Room 2264,8901 Wisconsin Ave, Bethesda, MD 20814 USA. EM rael.lange@gmail.com FU Canadian Institutes of Health Research [200903MOP-200377-BSB-CAAA-161276] NR 85 TC 12 Z9 12 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0887-6177 EI 1873-5843 J9 ARCH CLIN NEUROPSYCH JI Arch. Clin. Neuropsychol. PD FEB PY 2015 VL 30 IS 1 BP 7 EP 25 DI 10.1093/arclin/acu060 PG 19 WC Psychology, Clinical; Psychology SC Psychology GA CE6BA UT WOS:000351919400002 PM 25416729 ER PT J AU Ivins, BJ Lange, RT Cole, WR Kane, R Schwab, KA Iverson, GL AF Ivins, Brian J. Lange, Rael T. Cole, Wesley R. Kane, Robert Schwab, Karen A. Iverson, Grant L. TI Using Base Rates of Low Scores to Interpret the ANAM4 TBI-MIL Battery Following Mild Traumatic Brain Injury SO ARCHIVES OF CLINICAL NEUROPSYCHOLOGY LA English DT Article DE Mild traumatic brain injury; Cognitive testing; Military; Low scores; Base rates ID HEALTHY OLDER-ADULTS; NEUROPSYCHOLOGICAL TEST-PERFORMANCE; COGNITIVE IMPAIRMENT; MEMORY SCORES; VALIDATION; DIAGNOSIS; CRITERIA; TESTS AB Base rates of low ANAM4 TBI-MIL scores were calculated in a convenience sample of 733 healthy male active duty soldiers using available military reference values for the following cutoffs: <= 2nd percentile (2 SDs), <= 5th percentile, <10th percentile, and <16th percentile (1 SD). Rates of low scores were also calculated in 56 active duty male soldiers who sustained an mTBI an average of 23 days (SD = 36.1) prior. 22.0% of the healthy sample and 51.8% of the mTBI sample had two or more scores below 1 SD (i.e., 16th percentile). 18.8% of the healthy sample and 44.6% of the mTBI sample had one or more scores <= 5th percentile. Rates of low scores in the healthy sample were influenced by cutoffs and race/ethnicity. Importantly, some healthy soldiers obtain at least one low score on ANAM4. These base rate analyses can improve the methodology for interpreting ANAM4 performance in clinical practice and research. C1 [Ivins, Brian J.; Schwab, Karen A.] Def & Vet Brain Injury Ctr, Headquarters, Div Res, Silver Spring, MD 20910 USA. [Ivins, Brian J.; Lange, Rael T.; Cole, Wesley R.] GDIT, Fairfax, VA USA. [Lange, Rael T.; Iverson, Grant L.] Walter Reed Natl Mil Med Ctr, Def & Vet Brain Injury Ctr, Bethesda, MD USA. [Lange, Rael T.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Cole, Wesley R.] Womack Army Med Ctr, Def & Vet Brain Injury Ctr, Ft Bragg, NC USA. [Kane, Robert] Georgetown Univ, Washington, DC USA. [Schwab, Karen A.] ARK Solut Inc, Reston, AR USA. [Iverson, Grant L.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil,Red Sox Fdn, Spaulding Rehabil Hosp,Massachusetts Gen Hosp,Spo, Boston, MA USA. [Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. RP Ivins, BJ (reprint author), Def & Vet Brain Injury Ctr, 1335 East West Highway,Suite 6-100, Silver Spring, MD 20910 USA. EM brian.j.ivins.ctr@mail.mil NR 38 TC 1 Z9 1 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0887-6177 EI 1873-5843 J9 ARCH CLIN NEUROPSYCH JI Arch. Clin. Neuropsychol. PD FEB PY 2015 VL 30 IS 1 BP 26 EP 38 DI 10.1093/arclin/acu072 PG 13 WC Psychology, Clinical; Psychology SC Psychology GA CE6BA UT WOS:000351919400003 PM 25526791 ER PT J AU Pusztaszeri, MP Faquin, WC AF Pusztaszeri, Marc P. Faquin, William C. TI MYB Is a Helpful Diagnostic Marker for Adenoid Cystic Carcinoma in Fine-Needle Aspiration Biopsy SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Letter ID EXPRESSION C1 [Pusztaszeri, Marc P.] Univ Hosp Geneva, Dept Pathol, Geneva, Switzerland. [Faquin, William C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Pusztaszeri, MP (reprint author), Univ Hosp Geneva, Dept Pathol, Geneva, Switzerland. NR 5 TC 2 Z9 2 U1 0 U2 0 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD FEB PY 2015 VL 139 IS 2 BP 157 EP 157 DI 10.5858/arpa.2014-0206-LE PG 1 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA CE6CN UT WOS:000351923700002 PM 25611095 ER PT J AU Dudley, J Tseng, LH Rooper, L Harris, M Haley, L Chen, GL Gocke, CD Eshleman, JR Lin, MT AF Dudley, Jonathan Tseng, Li-Hui Rooper, Lisa Harris, Marco Haley, Lisa Chen, Guoli Gocke, Christopher D. Eshleman, James R. Lin, Ming-Tseh TI Challenges Posed to Pathologists in the Detection of KRAS Mutations in Colorectal Cancers SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID GROWTH-FACTOR RECEPTOR; TARGETED THERAPY; RECTAL-CANCER; EGFR; CETUXIMAB; CARCINOMA; ACCURATE; PCR; MICRODISSECTION; SENSITIVITY AB Context.-Detection of KRAS mutation is mandatory to predict response to anti-epidermal growth factor receptor monoclonal antibodies in patients with metastatic colorectal cancers. Objective.-To demonstrate challenges posed to pathologists in the clinical detection of KRAS mutations in colorectal cancers. Design.-In this retrospective analysis for quality assessment of the pyrosequencing assay, we survey the characteristics of 463 formalin-fixed, paraffin-embedded neoplastic tissues submitted for KRAS mutation detection during a 26-month period. Results.-The KRAS mutation was detected in 39.2% of tumors. This included 2 tumors with complex pyrograms (GGT>GAG at codon 12 and GGC>GTT at codon 13, as resolved by a Pyromaker software program) and 3 tumors with an indeterminate percentage of mutant alleles (defined as 4% to 5% and confirmed by a next-generation sequencing platform). Among the 25 specimens (5.5%) with fewer than 20% tumor cells, 22 were resected after chemotherapy/radiation. Significant depletion of tumor cells was observed in rectal cancers resected after neoadjuvant therapy (31.0%) versus those without previous treatment (0%) (P = .01). We also explore other specimens with low tumor cellularity and potential causes of discrepancy between the estimated tumor cell percentage and detected mutant allele frequency, such as intratumor heterogeneity of KRAS mutation. Conclusions.-Neoadjuvant therapy may deplete tumor cells and confound the molecular diagnosis of KRAS mutations. Accurate detection of specimens with poor tumor cellularity requires the appropriate selection of neoplastic tissues, evaluation of tumor cellularity, use of assays with high sensitivity, and prospective quality assessment. C1 [Dudley, Jonathan; Tseng, Li-Hui; Rooper, Lisa; Harris, Marco; Haley, Lisa; Chen, Guoli; Gocke, Christopher D.; Eshleman, James R.; Lin, Ming-Tseh] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Gocke, Christopher D.; Eshleman, James R.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Dudley, Jonathan] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Tseng, Li-Hui] Natl Taiwan Univ Hosp, Dept Med Genet, Taipei, Taiwan. RP Lin, MT (reprint author), Johns Hopkins Med Inst, Dept Pathol, Div Mol Pathol, 600 N Wolfe St,Pk SB 202, Baltimore, MD 21287 USA. EM mlin36@jhmi.edu OI TSENG, LI-HUI/0000-0002-8308-6772 NR 34 TC 15 Z9 16 U1 1 U2 10 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD FEB PY 2015 VL 139 IS 2 BP 211 EP 218 DI 10.5858/arpa.2013-0649-OA PG 8 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA CE6CN UT WOS:000351923700016 PM 25611103 ER PT J AU Gordon, K Bonfanti, A Pearson, V Markowitz, SN Jackson, ML Small, L AF Gordon, Keith Bonfanti, Angela Pearson, Victoria Markowitz, Samuel N. Jackson, Mary Lou Small, Luke TI Comprehensive vision rehabilitation SO CANADIAN JOURNAL OF OPHTHALMOLOGY-JOURNAL CANADIEN D OPHTALMOLOGIE LA English DT Letter C1 [Gordon, Keith; Bonfanti, Angela; Pearson, Victoria] CNIB, Toronto, ON, Canada. [Markowitz, Samuel N.] Univ Toronto, Fac Med, Dept Ophthalmol & Vis Sci, Low Vis Rehabil Program, Toronto, ON, Canada. [Jackson, Mary Lou] Massachusetts Eye & Ear Infirm, Vis Rehabil Ctr, Harvard Dept Ophthalmol, Boston, MA 02114 USA. [Small, Luke] Armstrong & Small Eye Care Ctr, Winnipeg, MB, Canada. RP Gordon, K (reprint author), CNIB, Toronto, ON, Canada. EM keidtgordon@cnib.ca OI Pearson, Victoria/0000-0001-6150-3101 NR 5 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN OPHTHAL SOC PI OTTAWA PA 1525 CARLING AVE SUITE 610, OTTAWA, ONTARIO K1Z 8R9, CANADA SN 0008-4182 EI 1715-3360 J9 CAN J OPHTHALMOL JI Can. J. Opthalmol.-J. Can. Opthalmol. PD FEB PY 2015 VL 50 IS 1 BP 85 EP 86 DI 10.1016/j.jcjo.2014.11.009 PG 2 WC Ophthalmology SC Ophthalmology GA CE6MP UT WOS:000351951400029 PM 25677290 ER PT J AU Chandra, A Snider, JT Wu, YY Jena, A Goldman, DP AF Chandra, Amitabh Snider, Julia Thornton Wu, Yanyu Jena, Anupam Goldman, Dana P. TI Robot-Assisted Surgery For Kidney Cancer Increased Access To A Procedure That Can Reduce Mortality And Renal Failure SO HEALTH AFFAIRS LA English DT Article ID QUALITY-OF-LIFE; OPEN RADICAL PROSTATECTOMY; OPEN GASTRIC BYPASS; PARTIAL NEPHRECTOMY; PERIOPERATIVE OUTCOMES; HEALTH-CARE; TUMORS; SURVIVAL; COSTS; METAANALYSIS AB Surgeons increasingly use robot-assisted minimally invasive surgery for a variety of medical conditions. For hospitals, the acquisition and maintenance of a robot requires a significant investment, but financial returns are not linked to any improvement in long-term patient outcomes in the current reimbursement environment. Kidney cancer provides a useful case study for evaluating the long-term value that this innovation can provide. Kidney cancer is generally treated through partial or radical nephrectomy, with evidence favoring the former procedure for appropriate patients. We found that robot-assisted surgery increased access to partial nephrectomy and that partial nephrectomy reduced mortality and renal failure. The value of the benefits of robot-assisted minimally invasive surgery to patients, in terms of quality-adjusted life-years gained, outweighed the health care and surgical costs to patients and payers by a ratio of five to one. In addition, we found no evidence that the availability of robot-assisted minimally invasive surgery increased the likelihood that inappropriate patients received partial nephrectomy. C1 [Chandra, Amitabh] Harvard Univ, John F Kennedy Sch Govt, Publ Policy, Cambridge, MA 02138 USA. [Snider, Julia Thornton] Precis Hlth Econ, Los Angeles, CA USA. [Wu, Yanyu] Precis Hlth Econ, Boston, MA USA. [Jena, Anupam] Harvard Univ, Sch Med, Hlth Care Policy & Med, Boston, MA USA. [Jena, Anupam] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jena, Anupam] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Goldman, Dana P.] Univ So Calif, Schaeffer Ctr Hlth Policy & Econ, Los Angeles, CA USA. RP Chandra, A (reprint author), Harvard Univ, John F Kennedy Sch Govt, Publ Policy, Cambridge, MA 02138 USA. EM amitabh_chandra@harvard.edu FU Intuitive Surgical Inc.; Intuitive Surgical FX Funding for this research was provided by Intuitive Surgical Inc. Amitabh Chandra, Anupam B. Jena, and Dana Goldman hold the positions of chief scientific officer, consultant, and partner, respectively, at Precision Health Economics, which receives consulting payments from Intuitive Surgical and other life science companies. The authors thank Jennifer Benner, Janet Hanley, Trieu Lai, and Mark Linthicum for programming and research support. NR 51 TC 3 Z9 3 U1 1 U2 2 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD FEB PY 2015 VL 34 IS 2 BP 220 EP 228 DI 10.1377/hlthaff.2014.0986 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CE3HA UT WOS:000351716100006 PM 25646101 ER PT J AU Ubel, PA Asch, DA AF Ubel, Peter A. Asch, David A. TI Creating Value In Health By Understanding And Overcoming Resistance To De-Innovation SO HEALTH AFFAIRS LA English DT Editorial Material ID CARE; CHALLENGE; GUIDELINE AB As hard as it may be for clinicians to adopt new practices, it is often harder for them to "de-innovate," or give up old practices, even when new evidence reveals that those practices offer little value. In this article we explore recent controversies over screening for breast and prostate cancer and testing for sleep disorders. We show that these controversies are not caused solely by a lack of clinical data on the harms and benefits of these tests but are also influenced by several psychological biases that make it difficult for clinicians to de-innovate. De-innovation could be fostered by making sure that advisory panels and guideline committees include experts who have competing biases; emphasizing evidence over clinical judgment; resisting " indication creep," or the premature extension of innovations into unproven areas; and encouraging clinicians to explicitly consider how their experiences bias their interpretations of clinical evidence. C1 [Ubel, Peter A.] Duke Univ, Fuqua Sch Business, Dept Med, Durham, NC 27706 USA. [Ubel, Peter A.] Duke Univ, Sanford Sch Publ Policy, Durham, NC 27706 USA. [Asch, David A.] Univ Penn, Ctr Hlth Care Innovat, Philadelphia, PA 19104 USA. [Asch, David A.] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Asch, David A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Ubel, PA (reprint author), Duke Univ, Fuqua Sch Business, Dept Med, Durham, NC 27706 USA. EM asch@wharton.upenn.edu FU Health Policy Investigator Award from the Robert Wood Johnson Foundation FX Peter Ubel is supported by a Health Policy Investigator Award from the Robert Wood Johnson Foundation. The opinions expressed are those of the authors and not of the Department of Veterans Affairs. NR 22 TC 13 Z9 13 U1 0 U2 3 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD FEB PY 2015 VL 34 IS 2 BP 239 EP 244 DI 10.1377/hlthaff.2014.0983 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CE3HA UT WOS:000351716100009 PM 25646103 ER PT J AU Whitman, GT Baloh, RW AF Whitman, Gregory T. Baloh, Robert W. TI Seasonality of Benign Paroxysmal Positional Vertigo SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Letter C1 [Whitman, Gregory T.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Baloh, Robert W.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. RP Whitman, GT (reprint author), Massachusetts Eye & Ear Infirm, Balance & Vestibular Ctr, 250 Pond St, Braintree, MA 02184 USA. EM gregory_whitman@meei.harvard.edu FU NCATS NIH HHS [UL1 TR001102] NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD FEB PY 2015 VL 141 IS 2 BP 188 EP 189 DI 10.1001/jamaoto.2014.2941 PG 2 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CE1PI UT WOS:000351583600018 PM 25411771 ER PT J AU Geetha, D Kallenberg, C Stone, JH Salama, AD Appel, GB Duna, G Brunetta, P Jayne, D AF Geetha, Duvuru Kallenberg, Cees Stone, John H. Salama, Alan D. Appel, Gerald B. Duna, George Brunetta, Paul Jayne, David TI Current therapy of granulomatosis with polyangiitis and microscopic polyangiitis: the role of rituximab SO JOURNAL OF NEPHROLOGY LA English DT Review DE Anti-neutrophil cytoplasmic antibody; Renal; Rituximab; Vasculitis ID ANTIBODY-ASSOCIATED VASCULITIS; ANCA-ASSOCIATED VASCULITIS; ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; IDIOPATHIC MEMBRANOUS NEPHROPATHY; DAILY ORAL CYCLOPHOSPHAMIDE; SMALL-VESSEL VASCULITIS; TERM-FOLLOW-UP; WEGENERS-GRANULOMATOSIS; REMISSION-INDUCTION; RANDOMIZED-TRIAL AB Granulomatosis with polyangiitis and microscopic polyangiitis are anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs) that are prone to cycles of remission and relapse. The introduction of cytotoxic therapy has changed the prognosis for these diseases from typically fatal to manageable chronic illnesses with a relapsing course. Despite improvements in outcomes, recurrence of disease and drug-related toxicity continue to produce significant morbidity and mortality. Better understanding of the pathogenesis of AAV and the mechanism of action of cyclophosphamide has led to investigation of therapies that target B cells. Two randomized controlled trials have shown that rituximab is not inferior to cyclophosphamide for induction of remission in severe AAV, with no significant difference in the incidence of overall adverse events in rituximab- versus cyclophosphamide-treated patients. Data from ongoing clinical trials will determine the role of rituximab in the maintenance of remission. C1 [Geetha, Duvuru] Johns Hopkins Univ, Sch Med, Div Nephrol, Johns Hopkins Bayview Med Ctr, Baltimore, MD 21224 USA. [Kallenberg, Cees] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, Groningen, Netherlands. [Stone, John H.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol, Boston, MA 02114 USA. [Salama, Alan D.] UCL, Ctr Nephrol, London, England. [Appel, Gerald B.] Columbia Univ, Coll Phys & Surg, Glomerular Kidney Dis Ctr, New York, NY USA. [Duna, George; Brunetta, Paul] Genentech Inc, San Francisco, CA USA. [Jayne, David] Addenbrookes Hosp, Vasculitis & Lupus Clin, Cambridge, England. RP Geetha, D (reprint author), Johns Hopkins Univ, Sch Med, Div Nephrol, Johns Hopkins Bayview Med Ctr, 301 Mason Lord Dr,Suite 2500, Baltimore, MD 21224 USA. EM gduvura@jhmi.edu FU F Hoffmann-La Roche Ltd. FX Support for third-party writing assistance for this manuscript was provided by F Hoffmann-La Roche Ltd. NR 72 TC 3 Z9 3 U1 1 U2 5 PU WICHTIG EDITORE PI MILAN PA 72/74 VIA FRIULI, 20135 MILAN, ITALY SN 1121-8428 EI 1724-6059 J9 J NEPHROL JI J. Nephrol. PD FEB PY 2015 VL 28 IS 1 BP 17 EP 27 DI 10.1007/s40620-014-0135-3 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA CE5JC UT WOS:000351867300003 PM 25185728 ER PT J AU Nass, SJ Beaupin, LK Demark-Wahnefried, W Fasciano, K Ganz, PA Hayes-Lattin, B Hudson, MM Nevidjon, B Oeffinger, KC Rechis, R Richardson, LC Seibel, NL Smith, AW AF Nass, Sharyl J. Beaupin, Lynda K. Demark-Wahnefried, Wendy Fasciano, Karen Ganz, Patricia A. Hayes-Lattin, Brandon Hudson, Melissa M. Nevidjon, Brenda Oeffinger, Kevin C. Rechis, Ruth Richardson, Lisa C. Seibel, Nita L. Smith, Ashley W. TI Identifying and Addressing theNeeds of Adolescents and Young Adults With Cancer: Summary of an Institute of Medicine Workshop SO ONCOLOGIST LA English DT Article DE Adolescent; Young adult; Cancer survivorship; Psychosocial aspects; Fertility preservation; Adverse effects ID LONG-TERM SURVIVORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; HEALTH-INSURANCE COVERAGE; CAUSE-SPECIFIC MORTALITY; CHILDHOOD-CANCER; BREAST-CANCER; FERTILITY PRESERVATION; HODGKIN LYMPHOMA; PALLIATIVE CARE; PHYSICAL-ACTIVITY AB Cancer is the leading disease-related cause of death in adolescents and young adults (AYAs). This population faces many short-and long-term health and psychosocial consequences of cancer diagnosis and treatment, but many programs for cancer treatment, survivorship care, and psychosocial support do not focus on the specific needs of AYA cancer patients. Recognizing this health care disparity, the National Cancer Policy Forum of the Institute of Medicine convened a public workshop to examine the needs of AYA patients with cancer. Workshop participants identified many gaps and challenges in the care of AYA cancer patients and discussed potential strategies to address these needs. Suggestions included ways to improve access to care for AYAs, to deliver cancer care that better meets the medical and psychosocial needs of AYAs, to develop educational programs for providers who care for AYA cancer survivors, and to enhance the evidence base for AYAs with cancer by facilitating participation in research. C1 [Nass, Sharyl J.] Inst Med, Washington, DC 20001 USA. [Beaupin, Lynda K.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Birmingham Comprehens Canc Ctr, Birmingham, AL USA. [Fasciano, Karen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Med & Publ Hlth, Los Angeles, CA USA. [Hayes-Lattin, Brandon] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Hudson, Melissa M.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Nevidjon, Brenda] Oncol Nursing Soc, Pittsburgh, PA USA. [Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rechis, Ruth] LIVESTRONG Fdn, Austin, TX USA. [Richardson, Lisa C.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Seibel, Nita L.; Smith, Ashley W.] Natl Canc Inst, Bethesda, MD USA. RP Nass, SJ (reprint author), Inst Med, Natl Canc Policy Forum, 500 Fifth St, Washington, DC 20001 USA. EM snass@nas.edu FU LIVESTRONG Foundation; Young Adult Cancer Alliance; IOM's National Cancer Policy Forum FX The responsibility for the content of this article rests with the authors and does not necessarily represent the views of the Institute of Medicine, its committees, its sponsors, or its convening activities and does not represent the official position of the Centers for Disease Control and Prevention or that of the National Cancer Institute. We thank the LIVESTRONG Foundation for generously cosponsoring the IOM workshop and Critical Mass: The Young Adult Cancer Alliance for supporting the workshop. The activities of the IOM's National Cancer Policy Forum are supported by its sponsoring members, which currently include the Centers for Disease Control and Prevention, the National Cancer Institute, the Association of American Cancer Institutes, the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, the American Society of Hematology, the American Society for Radiation Oncology, AstraZeneca, Bristol-Myers Squibb, C-Change, the Cancer Support Community, the CEO Roundtable on Cancer, EMD Serono, Helsinn Group, the LIVESTRONG Foundation, the National Comprehensive Cancer Network, Novartis Oncology, the Oncology Nursing Society, and Sanofi Oncology. We thank the speakers and participants for their contributions to the workshop. We also thank Sarah Bender and Sara Tharakan for assistance with manuscript preparation. NR 89 TC 22 Z9 22 U1 2 U2 10 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD FEB PY 2015 VL 20 IS 2 BP 186 EP 195 DI 10.1634/theoncologist.2014-0265 PG 10 WC Oncology SC Oncology GA CE5ZR UT WOS:000351915500015 PM 25568146 ER PT J AU Mroz, EA Tward, AM Hammon, RJ Ren, Y Rocco, JW AF Mroz, Edmund A. Tward, Aaron M. Hammon, Rebecca J. Ren, Yin Rocco, James W. TI Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas SO PLOS MEDICINE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; CLONAL EVOLUTION; SEQUENCING DATA; DIVERSITY; SURVIVAL; GLIOBLASTOMA; PROGRESSION; MUTATIONS; LANDSCAPE AB Background Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. Methods and Findings Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity's associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed. Conclusions To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types. C1 [Mroz, Edmund A.; Rocco, James W.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Mroz, Edmund A.; Rocco, James W.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Tward, Aaron M.; Hammon, Rebecca J.; Ren, Yin; Rocco, James W.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Tward, Aaron M.; Hammon, Rebecca J.; Ren, Yin; Rocco, James W.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Tward, Aaron M.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Rocco, James W.] Ohio State Univ, Dept Otolaryngol Head & Neck Surg, Columbus, OH 43210 USA. RP Mroz, EA (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. EM James.Rocco@osumc.edu FU National Institute of Dental and Craniofacial Research [R01 DE022087]; Massachusetts Eye and Ear Infirmary Bacardi Biobank Fund FX Funding was provided by the National Institute of Dental and Craniofacial Research (http://www.nidcr.nih.gov/), grant R01 DE022087, and by private donations to the Massachusetts Eye and Ear Infirmary Bacardi Biobank Fund, with JWR as Principal Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 32 Z9 33 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD FEB PY 2015 VL 12 IS 2 AR UNSP e1001786 DI 10.1371/journal.pmed.1001786 PG 27 WC Medicine, General & Internal SC General & Internal Medicine GA CE3GY UT WOS:000351715900005 PM 25668320 ER PT J AU Fahrenbach, AC AF Fahrenbach, Albert C. TI Template-directed nonenzymatic oligonucleotide synthesis: lessons from synthetic chemistry SO PURE AND APPLIED CHEMISTRY LA English DT Article DE IUPAC-SOLVAY International Award for Young Chemists; kinetic template effect; mechanically interlocked molecules; origins of life; RNA replication; supramolecular chemistry ID RNA WORLD; TETRATHIAFULVALENE UNIT; MOLECULAR RECOGNITION; BINDING-SITES; CROWN ETHERS; CYCLOBIS(PARAQUAT-P-PHENYLENE); COMPLEXES; CATENANES; CATALYSIS; SELECTION AB The nonenzymatic synthesis of nucleic acids, in particular, RNA, and the template-directed synthesis of artificial organic molecules, such as macrocycles, catenanes and rotaxanes, have both undergone significant development since the last half of the 20th century. The intersection of these two fields affords insights into how template effects can lead to information copying and storage at the molecular level. Mechanistic examples of model template-directed RNA replication experiments as well as those for totally artificial organic template-directed syntheses will be discussed. The fact that templates typically bind to their reacted products more tightly than their unreacted substrates may be a mechanistic feature necessary to store information in the form of nucleic acids. Understanding the mechanisms of nonenzymatic RNA synthesis is not only essential for testing the RNA world hypothesis in the context of the origin of life on Earth and other planetary bodies, but may one day afford chemists the insights to construct their own artificial molecular replicators. C1 [Fahrenbach, Albert C.] Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, Tokyo 1528551, Japan. [Fahrenbach, Albert C.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. [Fahrenbach, Albert C.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Fahrenbach, AC (reprint author), Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-12-1 Ookayama, Tokyo 1528551, Japan. EM fahrenbach@molbio.mgh.harvard.edu FU NSF Graduate Research Fellowship; Earth-Life Science Institute (ELSI) FX I would like to first of all thank IUPAC for providing me with the opportunity to write this review. A special thank you goes out to my PhD advisor Professor Fraser Stoddart for his constant support and encouragement that he continues to provide past my graduate career. I would like to acknowledge my current advisor, Professor jack Szostak, for his very valuable input, advice and encouragement. Financial support during my PhD was provided by an NSF Graduate Research Fellowship. I would like to thank the Earth-Life Science Institute (ELSI) for the award of a postdoctoral fellowship and Aaron T. Larsen, Nicholas Guttenberg and Nathaniel Virgo for useful discussions. NR 81 TC 2 Z9 2 U1 0 U2 23 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0033-4545 EI 1365-3075 J9 PURE APPL CHEM JI Pure Appl. Chem. PD FEB PY 2015 VL 87 IS 2 BP 205 EP 218 DI 10.1515/pac-2014-1004 PG 14 WC Chemistry, Multidisciplinary SC Chemistry GA CE6KZ UT WOS:000351946600010 ER PT J AU Kessler, LG Barnhart, HX Buckler, AJ Choudhury, KR Kondratovich, MV Toledano, A Guimaraes, AR Filice, R Zhang, Z Sullivan, DC AF Kessler, Larry G. Barnhart, Huiman X. Buckler, Andrew J. Choudhury, Kingshuk Roy Kondratovich, Marina V. Toledano, Alicia Guimaraes, Alexander R. Filice, Ross Zhang, Zheng Sullivan, Daniel C. CA QIBA Terminology Working Grp TI The emerging science of quantitative imaging biomarkers terminology and definitions for scientific studies and regulatory submissions SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Quantitative; terminology; definitions; bias; precision ID ASSESSING AGREEMENT; TUMOR RESPONSE; MEDICINE; PET AB The development and implementation of quantitative imaging biomarkers has been hampered by the inconsistent and often incorrect use of terminology related to these markers. Sponsored by the Radiological Society of North America, an interdisciplinary group of radiologists, statisticians, physicists, and other researchers worked to develop a comprehensive terminology to serve as a foundation for quantitative imaging biomarker claims. Where possible, this working group adapted existing definitions derived from national or international standards bodies rather than invent new definitions for these terms. This terminology also serves as a foundation for the design of studies that evaluate the technical performance of quantitative imaging biomarkers and for studies of algorithms that generate the quantitative imaging biomarkers from clinical scans. This paper provides examples of research studies and quantitative imaging biomarker claims that use terminology consistent with these definitions as well as examples of the rampant confusion in this emerging field. We provide recommendations for appropriate use of quantitative imaging biomarker terminological concepts. It is hoped that this document will assist researchers and regulatory reviewers who examine quantitative imaging biomarkers and will also inform regulatory guidance. More consistent and correct use of terminology could advance regulatory science, improve clinical research, and provide better care for patients who undergo imaging studies. C1 [Kessler, Larry G.] Univ Washington, Seattle, WA 98195 USA. [Barnhart, Huiman X.; Choudhury, Kingshuk Roy; Sullivan, Daniel C.] Duke Univ, Durham, NC USA. [Buckler, Andrew J.] Elucid Bioimaging Inc, Wenham, MA USA. [Kondratovich, Marina V.; Filice, Ross] US FDA, Silver Spring, MD USA. [Toledano, Alicia] Biostat Consulting LLC, Kensington, MD USA. [Guimaraes, Alexander R.] Harvard Massachusetts Gen Hosp, Boston, MA USA. [Zhang, Zheng] Brown Univ, Providence, RI 02912 USA. RP Kessler, LG (reprint author), Univ Washington, Seattle, WA 98195 USA. EM kesslerl@uw.edu OI Buckler, Andrew/0000-0002-0786-4835 FU Radiological Society of North America; NIH/NIBIB [HHSN268201000050C] FX The authors acknowledge and appreciate the Radiological Society of North America and NIH/NIBIB contract # HHSN268201000050C for supporting two workshops and numerous conference calls for the authors' Working Group. We would also like to thank Michael Boss of NIST and Jingjing Ye and Shashi Amur of the FDA for comments on earlier versions of the paper. NR 25 TC 27 Z9 27 U1 5 U2 14 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2015 VL 24 IS 1 SI SI BP 9 EP 26 DI 10.1177/0962280214537333 PG 18 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700002 PM 24919826 ER PT J AU Huang, EP Wang, XF Choudhury, KR McShane, LM Gonen, M Ye, JJ Buckler, AJ Kinahan, PE Reeves, AP Jackson, EF Guimaraes, AR Zahlmann, G AF Huang, Erich P. Wang, Xiao-Feng Choudhury, Kingshuk Roy McShane, Lisa M. Goenen, Mithat Ye, Jingjing Buckler, Andrew J. Kinahan, Paul E. Reeves, Anthony P. Jackson, Edward F. Guimaraes, Alexander R. Zahlmann, Gudrun CA Meta-Anal Working Grp TI Meta-analysis of the technical performance of an imaging procedure: Guidelines and statistical methodology SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE quantitative imaging; imaging biomarkers; technical performance; repeatability; reproducibility; meta-analysis; meta-regression; systematic review ID SEMIAUTOMATED VOLUME MEASUREMENTS; INDIVIDUAL PATIENT DATA; META-REGRESSION; SYSTEMATIC REVIEWS; ASSESSING AGREEMENT; LUNG-CANCER; FDG-PET; PULMONARY NODULES; MALIGNANT-TUMORS; PRISMA STATEMENT AB Medical imaging serves many roles in patient care and the drug approval process, including assessing treatment response and guiding treatment decisions. These roles often involve a quantitative imaging biomarker, an objectively measured characteristic of the underlying anatomic structure or biochemical process derived from medical images. Before a quantitative imaging biomarker is accepted for use in such roles, the imaging procedure to acquire it must undergo evaluation of its technical performance, which entails assessment of performance metrics such as repeatability and reproducibility of the quantitative imaging biomarker. Ideally, this evaluation will involve quantitative summaries of results from multiple studies to overcome limitations due to the typically small sample sizes of technical performance studies and/or to include a broader range of clinical settings and patient populations. This paper is a review of meta-analysis procedures for such an evaluation, including identification of suitable studies, statistical methodology to evaluate and summarize the performance metrics, and complete and transparent reporting of the results. This review addresses challenges typical of meta-analyses of technical performance, particularly small study sizes, which often causes violations of assumptions underlying standard meta-analysis techniques. Alternative approaches to address these difficulties are also presented; simulation studies indicate that they outperform standard techniques when some studies are small. The meta-analysis procedures presented are also applied to actual [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) test-retest repeatability data for illustrative purposes. C1 [Huang, Erich P.; McShane, Lisa M.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Wang, Xiao-Feng] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Choudhury, Kingshuk Roy] Duke Univ, Dept Radiol, Sch Med, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Goenen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Ye, Jingjing] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Buckler, Andrew J.] Elucid Biomed Imaging Inc, Wenham, MA USA. [Kinahan, Paul E.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Reeves, Anthony P.] Cornell Univ, Sch Elect & Comp Engn, Ithaca, NY USA. [Jackson, Edward F.] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [Guimaraes, Alexander R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zahlmann, Gudrun] F Hoffmann La Roche Ltd, Basel, Switzerland. RP Huang, EP (reprint author), NCI, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr,MSC 9735, Bethesda, MD 20892 USA. EM erich.huang@nih.gov OI Jackson, Edward/0000-0002-5958-0076; Buckler, Andrew/0000-0002-0786-4835 FU Radiological Society of North America; NIH/NIBIB [HHSN268201000050C] FX The authors acknowledge and appreciate the Radiological Society of North America and NIH/NIBIB contract # HHSN268201000050C for supporting two workshops and numerous conference calls for the authors' Working Group. The authors would also like to thank Huiman Barnhart and Daniel Sullivan from Duke University and Gene Pennello, Norberto Pantoja-Galicia, Robert Ochs, Shing Chun Benny Lam, and Mary Pastel from the FDA for their expert advice and comments on this manuscript. NR 77 TC 5 Z9 5 U1 1 U2 7 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2015 VL 24 IS 1 SI SI BP 141 EP 174 DI 10.1177/0962280214537394 PG 34 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700006 PM 24872353 ER PT J AU Trivedi, R Gerrity, M Rumsfeld, JS Spertus, JA Sun, HL McDonell, M Doak, M Lucas, L Fihn, SD AF Trivedi, Ranak Gerrity, Martha Rumsfeld, John S. Spertus, John A. Sun, Haili McDonell, Mary Doak, Melanie Lucas, Linda Fihn, Stephan D. TI Angina Symptom Burden Associated with Depression Status Among Veterans with Ischemic Heart Disease SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Angina; Depression; Quality of life; Patient-reported outcomes ID CORONARY-ARTERY-DISEASE; QUALITY-OF-LIFE; CHRONIC STABLE ANGINA; FUNCTIONAL STATUS; MAJOR DEPRESSION; UNSTABLE ANGINA; RISK-FACTOR; MORTALITY; OUTPATIENTS; PHQ-9 AB Angina and depression are common in ischemic heart disease (IHD), but their association remains understudied. This study was conducted in order to evaluate the association of 1 year change in depression with change in patient-reported outcomes of stable angina. Five hundred sixty-nine stable angina patients completed the Seattle Angina Questionnaire and Patient Health Questionnaire (PHQ) at baseline and 1 year. Participants were divided into four groups: not depressed, new onset of depression at 1 year, remitted at 1 year, and persistently depressed. Associations between depression and angina symptoms were evaluated using regression models. Compared to those not depressed, newly depressed participants reported more angina (beta = -11.7, p < 0.001) and physical limitations (beta = -11.8, p < 0.001) and lower treatment satisfaction (beta = -15.03, p < 0.001) and quality of life (beta = -15.4, p < 0.001). Persistently depressed participants reported physical limitations (beta = -7.4, p < 0.05), lower treatment satisfaction (beta = -10.1, p < 0.001), and poorer quality of life (beta = -10.03, p < 0.001). Changes in depression scores and angina outcomes were significantly associated. C1 [Trivedi, Ranak; Sun, Haili; McDonell, Mary] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Gerrity, Martha; Doak, Melanie; Lucas, Linda] Portland VA Med Ctr, Portland, OR USA. [Gerrity, Martha; Doak, Melanie; Lucas, Linda] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Rumsfeld, John S.] VA Eastern Colorado Hlth Care Syst, Denver, CO USA. [Spertus, John A.] Univ Missouri, Dept Med, Kansas City, KS USA. [Fihn, Stephan D.] Univ Washington, Dept Med, Off Analyt & Business Intelligence, Dept Vet Affairs, Seattle, WA USA. [Trivedi, Ranak] Stanford Univ, Ctr Innovat Implementat, VA Palo Alto Hlth Care Syst, Dept Psychiat & Behav Sci, Menlo Pk, CA 94025 USA. RP Trivedi, R (reprint author), Stanford Univ, Ctr Innovat Implementat, VA Palo Alto Hlth Care Syst, Dept Psychiat & Behav Sci, 795 Willow Rd MPD 42,Bldg 324, Menlo Pk, CA 94025 USA. EM ranak.trivedi@va.gov FU Department of Veterans Affairs (VA); Veterans Health Administration, Health Services Research and Development (HSRD) Service [IHI 02-062]; VA HSR&D Career Development Award (CDA) [09-206] FX This work was supported by the Department of Veterans Affairs (VA), Veterans Health Administration, Health Services Research and Development (HSR&D) Service, IHI 02-062. Dr. Trivedi is supported by a VA HSR&D Career Development Award (CDA 09-206). VA Puget Sound Health Care System and the VA Palo Alto Health Care System provided resources to support this research. The views expressed in this manuscript are those of the authors and do not necessarily represent the opinions of the Department of Veterans Affairs. Dr. Trivedi and Dr. Sun 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 25 TC 3 Z9 3 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD FEB PY 2015 VL 49 IS 1 BP 58 EP 65 DI 10.1007/s12160-014-9629-4 PG 8 WC Psychology, Multidisciplinary SC Psychology GA CC0TX UT WOS:000350050800009 PM 25008432 ER PT J AU Bacalladoi, S Favaro, S Trippa, L AF Bacalladoi, Sergio Favaro, Stefano Trippa, Lorenzo TI Looking-backward probabilities for Gibbs-type exchangeable random partitions SO BERNOULLI LA English DT Article DE Bayesian nonparametrics; conditional random partitions; Ewens-Pitman sampling model; Gibbs-type exchangeable random partitions; looking-backward probabilities; species diversity; species sampling problems AB Gibbs-type random probability measures and the exchangeable random partitions they induce represent the subject of a rich and active literature. They provide a probabilistic framework for a wide range of theoretical and applied problems that are typically referred to as species sampling problems. In this paper, we consider the class of looking-backward species sampling problems introduced in Lijoi et al. (Ann. Appl. Probab. 18 (2008) 1519-1547) in Bayesian nonparametrics. Specifically, given some information on the random partition induced by an initial sample from a Gibbs-type random probability measure, we study the conditional distributions of statistics related to the old species, namely those species detected in the initial sample and possibly re-observed in an additional sample. The proposed results contribute to the analysis of conditional properties of Gibbs-type exchangeable random partitions, so far focused mainly on statistics related to those species generated by the additional sample and not already detected in the initial sample. C1 [Bacalladoi, Sergio] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Favaro, Stefano] Univ Torino, Dept Econ & Stat, I-10134 Turin, Italy. [Trippa, Lorenzo] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Trippa, Lorenzo] Dana Faber Canc Inst, Boston, MA 02215 USA. [Favaro, Stefano] Coll Carlo Alberto, I-10024 Moncalieri, Italy. RP Bacalladoi, S (reprint author), Stanford Univ, Dept Stat, Sequoia Hall, Stanford, CA 94305 USA. EM sergio.bacallado@gmail.com; stefano.favaro@unito.it; ltrippa@jimmy.hatvard.edu FU European Research Council (ERC) through StG "N-BNP" [306406] FX The authors are grateful to an Associate Editor and a Referee for valuable remarks and suggestions that have lead to a substantial improvement in the presentation. Stefano Favaro is supported by the European Research Council (ERC) through StG "N-BNP" 306406. NR 22 TC 0 Z9 0 U1 0 U2 1 PU INT STATISTICAL INST PI VOORBURG PA 428 PRINSES BEATRIXLAAN, 2270 AZ VOORBURG, NETHERLANDS SN 1350-7265 EI 1573-9759 J9 BERNOULLI JI Bernoulli PD FEB PY 2015 VL 21 IS 1 BP 1 EP 37 DI 10.3150/13-BEJ559 PG 37 WC Statistics & Probability SC Mathematics GA CD5IB UT WOS:000351120100001 ER PT J AU Derks, S Diosdado, B AF Derks, S. Diosdado, B. TI Personalized cancer medicine: next steps in the genomic era SO CELLULAR ONCOLOGY LA English DT Editorial Material C1 [Derks, S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Derks, S.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Diosdado, B.] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. RP Diosdado, B (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. EM b.diosdado@vumc.nl NR 10 TC 4 Z9 4 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 2211-3428 EI 2211-3436 J9 CELL ONCOL JI Cell. Oncol. PD FEB PY 2015 VL 38 IS 1 BP 1 EP 2 DI 10.1007/s13402-015-0221-0 PG 2 WC Oncology; Cell Biology; Pathology SC Oncology; Cell Biology; Pathology GA CD7YQ UT WOS:000351312400001 PM 25720594 ER PT J AU Steinberg, BA Hellkamp, AS Lokhnygina, Y Patel, MR Breithardt, G Hankey, GJ Becker, RC Singer, DE Halperin, JL Hacke, W Nessel, CC Berkowitz, SD Mahaffey, K Fox, KAA Califf, RM Piccini, JP AF Steinberg, Benjamin A. Hellkamp, Anne S. Lokhnygina, Yuliya Patel, Manesh R. Breithardt, Guenter Hankey, Graeme J. Becker, Richard C. Singer, Daniel E. Halperin, Jonathan L. Hacke, Werner Nessel, Christopher C. Berkowitz, Scott D. Mahaffey, KennethW. Fox, Keith A. A. Califf, Robert M. Piccini, Jonathan P. CA ROCKET-AF Steering Comm Investigat TI Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial SO EUROPEAN HEART JOURNAL LA English DT Article DE Atrial fibrillation; Paroxysmal; Persistent; Anticoagulation; Outcomes ID RADIOFREQUENCY CATHETER ABLATION; VITAMIN-K ANTAGONISM; RHYTHM MANAGEMENT; FOLLOW-UP; ORAL ANTICOAGULATION; EMBOLISM TRIAL; THERAPY; RIVAROXABAN; WARFARIN; PROGRESSION AB Aim Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation. Methods and results Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, P-interaction = 0.6). Conclusion In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF. C1 [Steinberg, Benjamin A.; Hellkamp, Anne S.; Lokhnygina, Yuliya; Patel, Manesh R.; Piccini, Jonathan P.] Duke Clin Res Inst, Durham, NC 27715 USA. [Breithardt, Guenter] Hosp Univ Munster, Dept Cardiovasc Med, Munster, Germany. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia. [Becker, Richard C.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Nessel, Christopher C.] Janssen Res & Dev LLC, Raritan, NJ USA. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Montville, NJ USA. [Mahaffey, KennethW.] Stanford Univ, Sch Med, Stanford, CA USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC USA. RP Steinberg, BA (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM benjamin.steinberg@duke.edu RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Janssen Research & Development LLC, Raritan, NJ; Bayer HealthCare AG, Leverkusen, Germany; National Institutes of Health (NIH T-32 training grant) [5 T32 HL 7101-38] FX This work and the ROCKET-AF trial were supported by Janssen Research & Development LLC, Raritan, NJ; and Bayer HealthCare AG, Leverkusen, Germany. B.A.S. was funded by the National Institutes of Health (NIH T-32 training grant #5 T32 HL 7101-38). Funding to pay the Open Access publication charges for this article was provided by Janssen Research & Development LLC, Raritan, NJ; and Bayer HealthCare AG, Leverkusen, Germany. NR 27 TC 50 Z9 50 U1 0 U2 6 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 1 PY 2015 VL 36 IS 5 BP 288 EP 296 DI 10.1093/eurheartj/ehu359 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE1QZ UT WOS:000351588300015 PM 25209598 ER PT J AU Perez-Rodrigueza, MM Mahon, K Russo, M Ungar, AK Burdick, KE AF Mercedes Perez-Rodrigueza, M. Mahon, Katie Russo, Manuela Ungar, Allison K. Burdick, Katherine E. TI Oxytocin and social cognition in affective and psychotic disorders SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Oxytocin; Schizophrenia; Major depressive disorder; Bipolar disorder; Social cognition ID BORDERLINE PERSONALITY-DISORDER; INTERACTION TRAINING SCIT; FACIAL-AFFECT RECOGNITION; SCHIZOPHRENIA SPECTRUM DISORDERS; ADJUNCTIVE INTRANASAL OXYTOCIN; RANDOMIZED CONTROLLED-TRIAL; VISUAL SCANNING BEHAVIOR; BIPOLAR DISORDER; ATTRIBUTIONAL STYLE; MAJOR DEPRESSION AB Impairments in social cognition are now recognized as core illness features in psychotic and affective disorders. Despite the significant disability caused by social cognitive abnormalities, treatments for this symptom dimension are lacking. Here, we describe the evidence demonstrating abnormalities in social cognition in schizophrenia, major depressive disorder, and bipolar disorder, as well as the neurobiology of social cognition including the role of oxytocin. We then review clinical trials of oxytocin administration in psychotic and affective disorders and the impact of this agent on social cognition. To date, several studies have demonstrated that oxytocin may improve social cognition in schizophrenia; too few studies have been conducted in affective disorders to determine the effect of oxytocin on social cognition in these disorders. Future work is needed to clarify which aspects of social cognition may be improved with oxytocin treatment in psychotic and affective disorders. (C) 2014 Elsevier B.V. and ECNP. All rights reserved. C1 [Mercedes Perez-Rodrigueza, M.; Mahon, Katie; Russo, Manuela; Ungar, Allison K.; Burdick, Katherine E.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Mercedes Perez-Rodrigueza, M.] James J Peters Vet Affairs Med Ctr, Mental Hlth Patient Care Ctr, Bronx, NY 10468 USA. [Mercedes Perez-Rodrigueza, M.] James J Peters Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY 10468 USA. [Mercedes Perez-Rodrigueza, M.] Univ Autonoma Madrid, CIBERSAM, Fdn Jimenez Diaz Hosp, E-28049 Madrid, Spain. RP Perez-Rodrigueza, MM (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, Psychiat Box 1230,One Gustave L Levy Pl, New York, NY 10029 USA. EM mercedes.perez@mssm.edu FU Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment; Medical Research Service of the Veterans Affairs James J Peters VAMC; Department of Veterans Affairs NY/NJ (VISN3) Mental Illness Research, Education, and Clinical Center (MIRECC); Brain and Behavior Research Foundation NARSAD Young Investigator Award; NIMH [R01 MH100125, UL1TR000067] FX This research is supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the Veterans Affairs James J Peters VAMC; the Department of Veterans Affairs NY/NJ (VISN3) Mental Illness Research, Education, and Clinical Center (MIRECC); a Brain and Behavior Research Foundation NARSAD Young Investigator Award to Dr. Perez Rodriguez, and the NIMH (R01 MH100125 to Dr. Burdick, CTSA grant UL1TR000067 awarded to the Mt. Sinai School of Medicine). NR 193 TC 9 Z9 9 U1 9 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD FEB PY 2015 VL 25 IS 2 BP 265 EP 282 PG 18 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CD4DB UT WOS:000351031700013 ER PT J AU Mayeur, C Kolodziej, SA Wang, A Xu, X Lee, A Yu, PB Shen, J Bloch, KD Bloch, DB AF Mayeur, Claire Kolodziej, Starsha A. Wang, Amy Xu, Xin Lee, Arthur Yu, Paul B. Shen, John Bloch, Kenneth D. Bloch, Donald B. TI Oral administration of a bone morphogenetic protein type I receptor inhibitor prevents the development of anemia of inflammation SO HAEMATOLOGICA LA English DT Letter DE anemia of inflammation; BMP inhibitor; hepcidin ID HEPCIDIN EXPRESSION; CHRONIC DISEASE; IRON; RATS C1 [Mayeur, Claire; Kolodziej, Starsha A.; Bloch, Kenneth D.; Bloch, Donald B.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Mayeur, Claire; Kolodziej, Starsha A.; Yu, Paul B.; Bloch, Kenneth D.; Bloch, Donald B.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Amy; Xu, Xin; Lee, Arthur; Shen, John] NCATS, Therapeut Rare & Neglected Dis TRND Program, NIH, Rockville, MD USA. [Yu, Paul B.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bloch, Donald B.] Massachusetts Gen Hosp, Dept Med, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Mayeur, C (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. EM cmayeur@mgh.harvard.edu OI Yu, Paul/0000-0003-2145-4944 FU NIAMS NIH HHS [R01 AR057374]; NIDDK NIH HHS [R01 DK082971, R01DK082971]; NINDS NIH HHS [1X01NS070702] NR 15 TC 10 Z9 11 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD FEB PY 2015 VL 100 IS 2 BP E68 EP E71 DI 10.3324/haematol.2014.111484 PG 4 WC Hematology SC Hematology GA CD7OB UT WOS:000351278900008 PM 25326432 ER PT J AU Dogan, HH Isik, E Vural, E Vehid, H Brezis, M AF Dogan, H. Hanzade Isik, Elif Vural, Ezgi Vehid, Hayriye Brezis, Mayer TI Quality and extent of informed consent for invasive procedures: a pilot study at the institutional level in Turkey SO INTERNATIONAL JOURNAL FOR QUALITY IN HEALTH CARE LA English DT Article DE informed consent; general surgery; quality of health care; Turkey; ethics AB Objective: To assess the quality of informed consent for patients undergoing invasive procedures and to reveal patient preferences for being informed about the potential risks of treatment and alternatives to treatment. Design: This studywas planned as a pilot study. Hospitalized patients' perceptions and expectations about the informed-consent process were explored in a general surgery department. The prepared questionnaire was completed by patients via interview. Setting: Inpatient services of the general surgery department of a large academic hospital in Istanbul, Turkey. Participants: The study population consisted of hospitalized patients in a general surgery department who underwent invasive procedures in March 2013. Main outcome measures: Recognition of consent forms by the patients, rate of patients' recall of risks, rate of patients who were willing to be involved in decision making, and rate of patients who were satisfied with the whole decision-making process were measured. Results: All patients signed consent forms. Most patients did not properly read the consent form since they trusted their physician. Potential exposure to risk seemed to be important for patient expectations. Conclusions: Paternalism seemed to dominate our clinical setting. The informed-consent process was definitely a separate issue from signing the consent forms. We conclude that the informed-consent process should be modified to be more functional and appropriate to human psychology. We suggest that education is necessary for informed consent to promote better quality and safety in health care. C1 [Dogan, H. Hanzade] Istanbul Univ, Dept Med Eth & Hist, Cerrahpasa Med Sch, Istanbul, Turkey. [Isik, Elif] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Vural, Ezgi] Istanbul Univ, Cerrahpasa Med Sch, Istanbul, Turkey. [Vehid, Hayriye] Istanbul Univ, Cerrahpasa Med Sch, Dept Biostat & Med Informat, Istanbul, Turkey. [Vehid, Hayriye] Istanbul Univ, Inst Child Hlth, Istanbul, Turkey. [Brezis, Mayer] Hadassah Hebrew Univ, Med Ctr, Ctr Clin Qual & Safety, Jerusalem, Israel. RP Dogan, HH (reprint author), Istanbul Univ, Dept Med Eth & Hist, Cerrahpasa Med Sch, Istanbul, Turkey. EM hhanzadedogan@gmail.com NR 24 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1353-4505 EI 1464-3677 J9 INT J QUAL HEALTH C JI Int. J. Qual. Health Care PD FEB 1 PY 2015 VL 27 IS 1 BP 46 EP 51 DI 10.1093/intqhc/mzu093 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CE2AI UT WOS:000351614200007 PM 25502322 ER PT J AU Willers, H Hong, TS AF Willers, Henning Hong, Theodore S. TI Towards an Integrated Understanding of Epidermal Growth Factor Receptor Biology for Radiation Therapy: Integrins Enter SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMA; RADIOTHERAPY; TARGETS; NECK; HEAD C1 [Willers, Henning; Hong, Theodore S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Willers, H (reprint author), Massachusetts Gen Hosp, Ctr Canc, Lab Cellular & Mol Radiat Oncol, 149 13th St, Charlestown, MA 02129 USA. EM hwillers@mgh.harvard.edu NR 14 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD FEB PY 2015 VL 107 IS 2 AR dju440 DI 10.1093/jnci/dju440 PG 2 WC Oncology SC Oncology GA CD7TN UT WOS:000351295700016 ER PT J AU Bilello, JA Thurmond, LM Smith, KM Pi, B Rubin, R Wright, SM Taub, F Henry, ME Shelton, RC Papakostas, GI AF Bilello, John A. Thurmond, Linda M. Smith, Katie M. Pi, Bo Rubin, Robert Wright, Suzin M. Taub, Floyd Henry, Michael E. Shelton, Richard C. Papakostas, George I. TI MDDScore: Confirmation of a Blood Test to Aid in the Diagnosis of Major Depressive Disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; NECROSIS-FACTOR RECEPTOR; SERUM PROLACTIN LEVELS; BODY-MASS INDEX; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; MENTAL-HEALTH; HPA AXIS; DSM-IV; OBESITY AB Background: Previously, a biomarker panel was developed for use as an aid to major depressive disorder (MDD) diagnosis; it consisted of 9 biomarkers associated with the neurotrophic, metabolic, inflammatory, and hypothalamic-pituitary-adrenal axis pathways. This panel and associated algorithm produced good clinical sensitivity and specificity (92% and 81%, respectively) in differentiating MDD patients from individuals without MDD. To further validate the panel, we performed a prospective study using a larger set of new prospectively acquired MDD patients and a similarly collected population of nondepressed subjects. The addition of gender and body mass index (BMI) effects to the algorithm was also evaluated. Method: Blood samples were obtained from MDD patients (n = 68) clinically evaluated at multiple sites in 2011 and 2012 using standard psychiatric assessment tools and structured clinical interviews according to DSM-IV criteria. Blood samples (n = 86) from nondepressed subjects were obtained as controls. MDD and nondepressed samples were randomized into independent training (n = 102) and validation sets (n = 52). Analytes in sera were quantified by immunoassay. Results: Training set biomarker data were used to develop a logistic regression model that included gender and BMI in a manner that allowed for their interaction with the biochemical analytes. For the training set, the sensitivity and specificity of the test (with 95% CI) were 93% (0.80-0.98) and 95% (0.85-0.99), respectively. This method (designated the MDDScore) was then applied to the independent validation set and had a sensitivity and specificity of 96% (0.77-0.98) and 86% (0.66-0.95), respectively. The overall accuracy for the training set was 94%; the validation set accuracy was 91%. Conclusion: Examination of a randomized independent set of samples confirms the ability of the previously established biomarker panel to identify persons with MDD; the accuracy was over 90%. The improved model that adds gender and BMI to the previously established panel of 9 biomarkers is robust and simple; it provides the most rigorously tested, objective diagnostic test for MDD to date. (C) Copyright 2015 Physicians Postgraduate Press, Inc. C1 [Bilello, John A.; Thurmond, Linda M.] Ridge Diagnost Inc, Res & Dev, Res Triangle Pk, NC 27709 USA. [Smith, Katie M.; Pi, Bo] Ridge Diagnost, Res & Dev, San Diego, CA USA. [Rubin, Robert] Whittier Coll, Dept Math, Whittier, CA USA. [Wright, Suzin M.; Taub, Floyd] FindCure, Res & Dev, Aurora, CO USA. [Henry, Michael E.; Papakostas, George I.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Shelton, Richard C.] Univ Alabama Birmingham, Sch Med, Dept Psychiat, Birmingham, AL USA. RP Bilello, JA (reprint author), Ridge Diagnost Inc, 2 Davis Dr, Res Triangle Pk, NC 27709 USA. EM jbilello@ridgedx.com FU Ridge Diagnostics Inc. FX This study was supported by Ridge Diagnostics Inc. NR 67 TC 16 Z9 17 U1 4 U2 8 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2015 VL 76 IS 2 BP E199 EP E206 DI 10.4088/JCP.14m09029 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CD3KG UT WOS:000350976600001 PM 25742207 ER PT J AU O'Malley, SS Corbin, WR Leeman, RF DeMartini, KS Fucito, LM Ikomi, J Romano, DM Wu, R Toll, BA Sher, KJ Gueorguieva, R Kranzler, HR AF O'Malley, Stephanie S. Corbin, William R. Leeman, Robert F. DeMartini, Kelly S. Fucito, Lisa M. Ikomi, Jolomi Romano, Denise M. Wu, Ran Toll, Benjamin A. Sher, Kenneth J. Gueorguieva, Ralitza Kranzler, Henry R. TI Reduction of Alcohol Drinking in Young Adults by Naltrexone: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial of Efficacy and Safety SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID EARLY PROBLEM DRINKERS; US COLLEGE-STUDENTS; TARGETED NALTREXONE; HEAVY DRINKING; INTERVENTION; DEPENDENCE; ADOLESCENTS; OUTCOMES AB Objective: Naltrexone, an opioid antagonist, may facilitate reduction in drinking among young adults. We compared the efficacy and safety of naltrexone administered daily plus targeted dosing with placebo to reduce drinking in young adults who engage in heavy drinking. Method: A randomized, double-blind, placebo-controlled study was conducted in an outpatient research center in March 2008-January 2012. Participants were aged 18-25 years and reported >= 4 heavy drinking days in the prior 4 weeks. Interventions included naltrexone 25 mg daily plus 25 mg targeted (at most daily) in anticipation of drinking (n = 61) or daily/targeted placebo (n = 67). All participants received a personalized feedback session and brief counseling every other week. Primary outcomes were percent heavy drinking days and percent days abstinent over the 8-week treatment period. Secondary outcomes included number of drinks per drinking day and percentage of days with estimated blood alcohol concentration (BAC) levels >= 0.08 g/dL. Results: Of 140 randomized patients, 128 began treatment, comprising the evaluable sample. During treatment, percent heavy drinking days (naltrexone: mean = 21.60, SD = 16.05; placebo: mean = 22.90, SD = 13.20) (P = .58) and percent days abstinent (naltrexone: mean = 56.60, SD = 22.52; placebo: mean = 62.50, SD = 15.75) (P = .39) did not differ by group. Naltrexone significantly reduced the number of drinks per drinking day (naltrexone: mean = 4.90, SD = 2.28; placebo: mean = 5.90, SD = 2.51) (P = .009) and percentage of drinking days with estimated BAC >= 0.08 g/dL (naltrexone: mean = 35.4, SD = 28.40; placebo: mean = 45.7, SD = 26.80) (P = .042). There were no serious adverse events. Sleepiness was more common with naltrexone. Conclusions: Naltrexone did not reduce frequency of drinking or heavy drinking days, but reduced secondary measures of drinking intensity. While effects were modest, the risk-benefit ratio favors offering naltrexone to help young adult heavy drinkers reduce the amount of alcohol they drink. (C) Copyright 2015 Physicians Postgraduate Press, Inc. C1 [O'Malley, Stephanie S.; Leeman, Robert F.; DeMartini, Kelly S.; Fucito, Lisa M.; Ikomi, Jolomi; Romano, Denise M.; Wu, Ran; Toll, Benjamin A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [O'Malley, Stephanie S.; Toll, Benjamin A.] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT USA. [Gueorguieva, Ralitza] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Gueorguieva, Ralitza] Yale Univ, Sch Med, New Haven, CT USA. [Corbin, William R.] Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. [Sher, Kenneth J.] Univ Missouri, Dept Psychol, Columbia, MO 65211 USA. [Kranzler, Henry R.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kranzler, Henry R.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP O'Malley, SS (reprint author), Connecticut Mental Hlth Ctr, 34 Pk St, New Haven, CT 06519 USA. EM Stephanie.omalley@yale.edu OI Gueorguieva, Ralitza/0000-0003-0944-5973 FU State of Connecticut, Department of Mental Health and Addictions Services (DMHAS) from National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland [R01 AA016621, K05 AA014715, K24 AA013736, K05 AA01742, K01 AA019694, K23 AA020000] FX The project described was supported by the State of Connecticut, Department of Mental Health and Addictions Services (DMHAS) and grant numbers R01 AA016621 and K05 AA014715 to Dr O'Malley, K24 AA013736 to Dr Kranzler, K05 AA01742 to Dr Sher, K01 AA019694 to Dr Leeman, and K23 AA020000 to Dr Fucito from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland. NR 36 TC 13 Z9 13 U1 1 U2 8 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2015 VL 76 IS 2 BP E207 EP + DI 10.4088/JCP.13m08934 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CD3KG UT WOS:000350976600002 PM 25742208 ER PT J AU Armstrong, EJ AF Armstrong, Ehrin J. TI Does Gender Influence Outcomes After Femoropopliteal Stenting? SO JOURNAL OF ENDOVASCULAR THERAPY LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; PACLITAXEL-ELUTING STENTS; CRITICAL LIMB ISCHEMIA; PERCUTANEOUS INTERVENTION; RISK-FACTORS; PREVALENCE; WOMEN; POPULATION; MEN C1 [Armstrong, Ehrin J.] Denver VA Med Ctr, Cardiol Sect, Denver, CO USA. [Armstrong, Ehrin J.] Univ Colorado, Sch Med, Denver, CO 80202 USA. RP Armstrong, EJ (reprint author), Univ Colorado, Sch Med, Div Cardiol, VA Eastern Colorado Healthcare Syst, 1250 14th St, Denver, CO 80202 USA. EM ehrin.armstrong@gmail.com NR 19 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1526-6028 EI 1545-1550 J9 J ENDOVASC THER JI J. Endovascular Ther. PD FEB PY 2015 VL 22 IS 1 BP 38 EP 40 DI 10.1177/1526602814565774 PG 3 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CD9JE UT WOS:000351413800007 PM 25775678 ER PT J AU Dey-Guha, I Alves, CP Yeh, AC Salony Sole, X Darp, R Ramaswamy, S AF Dey-Guha, Ipsita Alves, Cleidson P. Yeh, Albert C. Salony Sole, Xavier Darp, Revati Ramaswamy, Sridhar TI A Mechanism for Asymmetric Cell Division Resulting in Proliferative Asynchronicity SO MOLECULAR CANCER RESEARCH LA English DT Article ID AKT; ACTIVATION; AKT/PKB; KINASE AB All cancers contain an admixture of rapidly and slowly proliferating cancer cells. This proliferative heterogeneity complicates the diagnosis and treatment of patients with cancer because slow proliferators are hard to eradicate, can be difficult to detect, and may cause disease relapse sometimes years after apparently curative treatment. While clonal selection theory explains the presence and evolution of rapid proliferators within cancer cell populations, the circumstances and molecular details of how slow proliferators are produced is not well understood. Here, a beta 1-integrin/FAK/mTORC2/AKT1-associated signaling pathway is discovered that can be triggered for rapidly proliferating cancer cells to undergo asymmetric cell division and produce slowly proliferating AKT1(low) daughter cells. In addition, evidence indicates that the proliferative output of this signaling cascade involves a proteasome-dependent degradation process mediated by the E3 ubiquitin ligase TTC3. These findings reveal that proliferative heterogeneity within cancer cell populations, in part, is produced through a targetable signaling mechanism, with potential implications for understanding cancer progression, dormancy, and therapeutic resistance. (C) 2015 AACR. C1 [Dey-Guha, Ipsita; Alves, Cleidson P.; Salony; Sole, Xavier; Darp, Revati; Ramaswamy, Sridhar] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Dey-Guha, Ipsita; Alves, Cleidson P.; Yeh, Albert C.; Salony; Sole, Xavier; Ramaswamy, Sridhar] Harvard Univ, Sch Med, Boston, MA USA. [Ramaswamy, Sridhar] Broad Inst Harvard & MIT, Cambridge, MA USA. [Ramaswamy, Sridhar] Harvard Stem Cell Inst, Cambridge, MA USA. [Ramaswamy, Sridhar] Harvard Ludwig Ctr Canc Res, Boston, MA USA. RP Ramaswamy, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, 185 Cambridge St, Boston, MA 02114 USA. EM sridhar@mgh.harvard.edu FU Stand Up to Cancer Innovative Research Grant [SU2C-AACR-IRG0911]; National Cancer Institute; Howard Hughes Medical Institute; CNPq "Ciencia sem Fronteiras"-Brazil [202620/2012-3]; HHMI Medical Student Research Fellowship; Bolsa de Ampliacion de Estudios, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad [BA12/00021] FX S. Ramaswamy is supported by a Stand Up to Cancer Innovative Research Grant (Grant number SU2C-AACR-IRG0911). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. This work is also supported by awards from the National Cancer Institute, Howard Hughes Medical Institute (Physician-Scientist Early Career Award), Susan G. Komen for the Cure, and Prostate Cancer Foundation (to S. Ramaswamy). C.P. Alves is supported by an award from CNPq "Ciencia sem Fronteiras"-Brazil (202620/2012-3). A.C. Yeh was supported by an HHMI Medical Student Research Fellowship (2010-2012). X. Sole is supported by a "Bolsa de Ampliacion de Estudios, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad (BA12/00021)"-Spanish postdoctoral fellowship award. NR 12 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD FEB PY 2015 VL 13 IS 2 BP 223 EP 230 DI 10.1158/1541-7786.MCR-14-0474 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CD6SO UT WOS:000351219800002 PM 25582703 ER PT J AU Muz, B de la Puente, P Azab, F Ghobrial, IM Azab, AK AF Muz, Barbara de la Puente, Pilar Azab, Feda Ghobrial, Irene M. Azab, Abdel Kareem TI Hypoxia Promotes Dissemination and Colonization in New Bone Marrow Niches in Waldenstrom Macroglobulinemia SO MOLECULAR CANCER RESEARCH LA English DT Article ID MULTIPLE-MYELOMA CELLS; ACTIVATED PRODRUG; MICROENVIRONMENT; CXCR4; PROLIFERATION; ANGIOGENESIS; INHIBITION; DISRUPTS; ADHESION; THERAPY AB Waldenstrom macroglobulinemia, a rare and indolent type of non-Hodgkin lymphoma, is characterized by widespread lymphoplasmacytic B cells in the bone marrow. Previous studies have shown that hypoxic conditions play a key role in the dissemination of other hematologic malignancies. In this study, the effect of hypoxia was tested on the progression and spread of Waldenstrom macroglobulinemia. Interestingly, tumor progression correlated with hypoxia levels in Waldenstrom macroglobulinemia cells and other cells in the bone marrow and correlated with the number of circulating tumor cells in vivo. Mechanistic studies demonstrated that hypoxia decreased cell progression and cell cycle, did not induce apoptosis, and reduced the adhesion between Waldenstrom macroglobulinemia cells and bone marrow stroma, through downregulation of E-cadherin expression, thus explaining increased egress of Waldenstrom macroglobulinemia cells to the circulation. Moreover, hypoxia increased the extravasation and homing of Waldenstrom macroglobulinemia cells to new bone marrow niches in vivo, by increased CXCR4/SDF-1-mediated chemotaxis and maintaining the VLA4-mediated adhesion. Re-oxygenation of hypoxic Waldenstrom macroglobulinemia cells enhanced the rate of proliferation and cell cycle progression and restored intercellular adhesion between Waldenstrom macroglobulinemia cells and bone marrow stroma. This study suggests that targeting hypoxic response is a novel strategy to prevent dissemination of Waldenstrom macroglobulinemia. (C) 2014 AACR. C1 [Muz, Barbara; de la Puente, Pilar; Azab, Feda; Azab, Abdel Kareem] Washington Univ, Sch Med, Dept Radiat Oncol, Div Canc Biol, St Louis, MO 63108 USA. [Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Azab, AK (reprint author), Washington Univ, Sch Med, Dept Radiat Oncol, Div Canc Biol, 4511 Forest Pk Ave,Room 3103, St Louis, MO 63108 USA. EM aazab@radonc.wustl.edu FU International Waldenstrom's Macroglobulinemia Foundation FX This study was supported by a grant from the International Waldenstrom's Macroglobulinemia Foundation. NR 26 TC 3 Z9 3 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD FEB PY 2015 VL 13 IS 2 BP 263 EP 272 DI 10.1158/1541-7786.MCR-14-0150 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CD6SO UT WOS:000351219800006 PM 25232031 ER PT J AU Urday, S Kimberly, WT Beslow, LA Vortmeyer, AO Selim, MH Rosand, J Simard, JM Sheth, KN AF Urday, Sebastian Kimberly, W. Taylor Beslow, Lauren A. Vortmeyer, Alexander O. Selim, Magdy H. Rosand, Jonathan Simard, J. Marc Sheth, Kevin N. TI Targeting secondary injury in intracerebral haemorrhage-perihaematomal oedema SO NATURE REVIEWS NEUROLOGY LA English DT Review ID ACTIVATED RECEPTOR-1 EXPRESSION; DECREASED PERIHEMATOMAL EDEMA; INDUCED BRAIN EDEMA; PERIHEMORRHAGIC EDEMA; ENDOTHELIAL-CELLS; HEMATOMA EXPANSION; CEREBRAL EDEMA; IN-VIVO; MOLECULAR PATHOPHYSIOLOGY; MATRIX METALLOPROTEINASES AB Perihaematomal oedema (PHO) is an important pathophysiological marker of secondary injury in intracerebral haemorrhage (ICH). In this Review, we describe a novel method to conceptualize PHO formation within the framework of Starling's principle of movement of fluid across a capillary wall. We consider progression of PHO through three stages, characterized by ionic oedema (stage 1) and progressive vasogenic oedema (stages 2 and 3). In this context, possible modifiers of PHO volume and their value in identifying patients who would benefit from therapies that target secondary injury are discussed; the practicalities of using neuroimaging to measure PHO volume are also considered. We examine whether PHO can be used as a predictor of neurological outcome following ICH, and we provide an overview of emerging therapies. Our discussion emphasizes that PHO has clinical relevance both as a therapeutic target, owing to its augmentation of the mass effect of a haemorrhage, and as a surrogate marker for novel interventions that target secondary injury. C1 [Urday, Sebastian; Beslow, Lauren A.; Sheth, Kevin N.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Vortmeyer, Alexander O.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Kimberly, W. Taylor; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Selim, Magdy H.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Simard, J. Marc] Univ Maryland, Sch Med, Dept Neurosurg, Baltimore, MD 21201 USA. RP Sheth, KN (reprint author), Yale Univ, Sch Med, Dept Neurol, 333 Cedar St, New Haven, CT 06510 USA. EM kevin.sheth@yale.edu FU MD Medical Student Research Fund in Genetics (Yale University School of Medicine); Student Scholarship in Cerebrovascular Disease and Stroke (American Heart Association Stroke Council); National Institute of Neurological Disorders and Stroke (NINDS) [K12-NS049453]; Department of Veterans Affairs (Baltimore) [BX001629]; NINDS [NS060801, NS061808]; National Heart, Lung and Blood Institute [HL082517] FX S.U. is supported by the Leon Rosenberg, MD Medical Student Research Fund in Genetics (Yale University School of Medicine) and a 2014 Student Scholarship in Cerebrovascular Disease and Stroke (American Heart Association Stroke Council). L.A.B. is supported by the National Institute of Neurological Disorders and Stroke (NINDS; K12-NS049453). J.M.S. is supported by grants from the Department of Veterans Affairs (Baltimore; BX001629), the NINDS (NS060801, NS061808), and the National Heart, Lung and Blood Institute (HL082517). NR 108 TC 18 Z9 18 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD FEB PY 2015 VL 11 IS 2 BP 111 EP 122 DI 10.1038/nrneurol.2014.264 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA CE0SC UT WOS:000351514800010 PM 25623787 ER PT J AU Singh, N Bharti, PK Singh, MP Singh, R Yeboah-Antwi, K Desai, M Udhayakumar, V Muniyandi, M Hamer, DH Wylie, BJ AF Singh, Neeru Bharti, Praveen K. Singh, Mrigendra P. Singh, Rajshree Yeboah-Antwi, Kojo Desai, Meghna Udhayakumar, Venkatachalam Muniyandi, Malaisamy Hamer, Davidson H. Wylie, Blair J. TI What is the burden of submicroscopic malaria in pregnancy in central India? SO PATHOGENS AND GLOBAL HEALTH LA English DT Article DE Malaria; Pregnancy; Subpatent infection; Submicroscopic infection; Plasmodium falciparum; Anemia; India; Polymerase chain reaction ID PLASMODIUM-FALCIPARUM INFECTIONS; POLYMERASE-CHAIN-REACTION; LOW-BIRTH-WEIGHT; PLACENTAL MALARIA; DIAGNOSIS; WOMEN; EPIDEMIOLOGY; MICROSCOPY; SUDAN; GHANA AB Background: Conventional microscopy underestimates the burden of malarial infection when compared with molecular diagnosis using polymerase chain reaction (PCR)-based methods. Lower density parasitemias serve as a reservoir for infection. We evaluated the prevalence of submicroscopic infections in an area of unstable malarial transmission in India and determined whether these infections negatively impacted maternal or fetal outcomes. Methods: This cross-sectional study (2007-2008) was undertaken in two districts of Chhattisgarh, recruiting women from both antenatal clinics (ANCs) and delivery units (DUs). For ANC/DU subjects, peripheral/placental blood, respectively, was obtained for conventional microscopy and collected onto filter paper for PCR analysis. Results: There were 3425 pregnant women, including 2477 ANC subjects and 948 DU subjects who had both microscopic and PCR samples available. Polymerase chain reaction detected significantly more Plasmodium infections than traditional light microscopy both from peripheral (3.4 vs 1.2%; OR 2.9, 95% confidence intervals (CIs) 1.9-4.5) and placental (4.2 vs 1.7%; OR 2.5, 95% CIs 1.4-4.8) blood samples. Submicroscopic infections were not associated with anemia or severe maternal anemia among ANC or DU participants and were not associated with low birth weight (LBW) among DU participants. In contrast, microscopically detected infections were associated with severe anemia and LBW. Conclusions: In this area of unstable malarial transmission from India, submicroscopic infections did not identify a set of pregnant women at increased risk for anemia or LBW. Until PCR techniques become much less expensive and available as a point of care test for the field setting, its use will be limited for malarial detection. C1 [Singh, Neeru; Bharti, Praveen K.; Singh, Rajshree; Muniyandi, Malaisamy] Reg Med Res Ctr Tribals, Jabalpur, Madhya Pradesh, India. [Singh, Mrigendra P.] Natl Inst Malaria Res Field Stn, Jabalpur, Madhya Pradesh, India. [Yeboah-Antwi, Kojo; Hamer, Davidson H.] Boston Univ, Ctr Global Hlth & Dev, Boston, MA 02215 USA. [Yeboah-Antwi, Kojo; Hamer, Davidson H.] Boston Univ, Sch Publ Hlth, Dept Global Hlth, Boston, MA 02215 USA. [Desai, Meghna; Udhayakumar, Venkatachalam] Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Ctr Global Hlth, Atlanta, GA USA. [Hamer, Davidson H.] Boston Univ, Sch Med, Dept Med, Infect Dis Sect, Boston, MA 02215 USA. [Wylie, Blair J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Maternal Fetal Med,Dept Obstet & Gynecol, Boston, MA USA. RP Singh, N (reprint author), Reg Med Res Ctr Tribals, Jabalpur, Madhya Pradesh, India. EM neerusingh@gmail.com FU Indo-U.S. Collaborative Network; ICMR; National Institute of Child Health and Development [1 R03 HD52167-01]; National Institutes of Health (NIH) [K23 ES021471] FX This work was supported by the Indo-U.S. Collaborative Network with funding from the ICMR and the National Institute of Child Health and Development (1 R03 HD52167-01). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the ICMR or the National Institute of Health. BJW was supported by the National Institutes of Health (NIH K23 ES021471). NR 36 TC 1 Z9 1 U1 1 U2 7 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 2047-7724 EI 2047-7732 J9 PATHOG GLOB HEALTH JI Pathog. Glob. Health PD FEB PY 2015 VL 109 IS 1 BP 30 EP 38 DI 10.1179/2047773215Y.0000000002 PG 9 WC Public, Environmental & Occupational Health; Parasitology; Tropical Medicine SC Public, Environmental & Occupational Health; Parasitology; Tropical Medicine GA CD5JD UT WOS:000351122900007 PM 25627878 ER PT J AU Winner, M Goff, SL Chabot, JA AF Winner, Megan Goff, Stephanie L. Chabot, John A. TI Neoadjuvant therapy for Non-metastatic Pancreatic Ductal Adenocarcinoma SO SEMINARS IN ONCOLOGY LA English DT Review ID GEMCITABINE-BASED CHEMORADIATION; PHASE-II TRIAL; SINGLE INSTITUTION EXPERIENCE; RANDOMIZED CONTROLLED-TRIAL; PREOPERATIVE CHEMORADIATION; RESECTABLE ADENOCARCINOMA; SURGICAL RESECTION; RADIATION-THERAPY; UNRESECTABLE ADENOCARCINOMA; GASTROINTESTINAL-TRACT AB Treatment of pancreatic cancer is increasingly multimodal, with patients receiving chemotherapy, radiation, and surgical extirpation in hope of long-term cure. There is ongoing debate over the timing, sequence, and necessity of these treatments as they pertain to the spectrum of local-regional disease. Current guidelines support a neoadjuvant strategy in patients with locally advanced and borderline resectable disease. Although there is currently no high-level evidence to recommend neoadjuvant therapy for all patients, there are data to suggest that wider application of neoadjuvant therapy may be beneficial. Random-assignment prospective trials are ongoing. In this review we examine the literature addressing a neoadjuvant approach to potentially resectable, borderline resectable, and locally advanced pancreatic cancer and highlight the outcomes of preoperative emergence of latent metastatic disease, attempted resection rates, margin negative resection rates, and pathologic response to treatment. (C) 2015 Elsevier Inc. All rights reserved. C1 [Winner, Megan; Chabot, John A.] Columbia Univ, Coll Phys & Surg, Dept Surg, New York, NY USA. [Goff, Stephanie L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chabot, John A.] Columbia Univ, Div Gastrointestinal Endocrine Surg, Pancreas Ctr, New York, NY USA. RP Chabot, JA (reprint author), Herbert Irving Pavilion,161 Ft Washington Ave,Roo, New York, NY 10032 USA. EM Jac4@cumc.columbia.edu NR 93 TC 4 Z9 4 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2015 VL 42 IS 1 BP 86 EP 97 DI 10.1053/j.seminoncol.2014.12.008 PG 12 WC Oncology SC Oncology GA CD2YD UT WOS:000350944000009 PM 25726054 ER PT J AU Parikh, PY Lillemoe, KD AF Parikh, Purvi Y. Lillemoe, Keith D. TI Surgical Management of Pancreatic Cancer-Distal Pancreatectomy SO SEMINARS IN ONCOLOGY LA English DT Review ID ANTEGRADE-MODULAR-PANCREATOSPLENECTOMY; RISK-FACTORS; PROGNOSTIC-FACTORS; RESECTION; OUTCOMES; FISTULA; ADENOCARCINOMA; BODY; SURVIVAL; CLOSURE AB Distal pancreatectomy is the standard procedure for tumors located in the body and tail of the pancreas. In the last three decades, significant progress has been made with regard to technical aspects as well as perioperative care so that excellent mortality and morbidity rates can be achieved. Recently, there is growing evidence that distal pancreatectomy may be performed laparoscopically in selected patients, offering the advantages of minimally invasive surgery. Unfortunately, the oncologic outcomes for pancreatic adenocarcinoma remain poor, in part due to the late stage of presentation in most patients. We review the history of distal pancreatectomy, discuss current indications for performing this procedure, compare operative techniques in performing distal pancreatectomy, and review both the early complications seen in patients who have undergone a distal pancreatectomy and the long-term metabolic and oncologic outcomes of these patients. (C) 2015 Published by Elsevier Inc. C1 [Parikh, Purvi Y.] Stony Brook Med, Dept Surg, Stony Brook, NY USA. [Lillemoe, Keith D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Lillemoe, KD (reprint author), 55 Fruit St,WHT506, Boston, MA 02114 USA. EM klillemoe@partners.org NR 55 TC 9 Z9 9 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2015 VL 42 IS 1 BP 110 EP 122 DI 10.1053/j.seminoncol.2014.12.010 PG 13 WC Oncology SC Oncology GA CD2YD UT WOS:000350944000011 PM 25726056 ER PT J AU Brunner, J Singh, AK Rocha, T Havens, J Goralnick, E Sodickson, A AF Brunner, John Singh, Ajay K. Rocha, Tatiana Havens, Joaquim Goralnick, Eric Sodickson, Aaron TI Terrorist Bombings: Foreign Bodies from the Boston Marathon Bombing SO SEMINARS IN ULTRASOUND CT AND MRI LA English DT Article ID BLAST INJURIES AB On April 15, 2013, 2 improvised explosive devices detonated at the 117th Boston Marathon, killing 3 people and injuring 264 others. In this article, the foreign bodies and injuries that presented at 2 of the responding level 1 trauma hospitals in Boston-Brigham and Women's Hospital and Massachusetts General Hospital-are reviewed with a broader discussion of blast injuries and imaging strategies. (C) 2014 Elsevier Inc. All rights reserved. C1 [Brunner, John] Univ So Calif, Dept Radiol, Los Angeles, CA USA. [Brunner, John; Rocha, Tatiana; Sodickson, Aaron] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Singh, Ajay K.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Havens, Joaquim] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Goralnick, Eric] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. RP Brunner, J (reprint author), 348 South San Pedro,Apt 301, Los Angeles, CA 90012 USA. EM jbrunner@med.usc.edu NR 12 TC 3 Z9 3 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0887-2171 EI 1558-5034 J9 SEMIN ULTRASOUND CT JI Semin. Ultrasound CT MRI PD FEB PY 2015 VL 36 IS 1 BP 68 EP 72 DI 10.1053/j.sult.2014.10.006 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CD6FI UT WOS:000351184600009 PM 25639179 ER PT J AU Hanchate, AD Ash, AS Borzecki, A Abdulkerim, H Stolzmann, KL Rosen, AK Fink, AS Pugh, MJV Shokeen, P Shwartz, M AF Hanchate, Amresh D. Ash, Arlene S. Borzecki, Ann Abdulkerim, Hassen Stolzmann, Kelly L. Rosen, Amy K. Fink, Aaron S. Pugh, Mary Jo V. Shokeen, Priti Shwartz, Michael TI How Pooling Fragmented Healthcare Encounter Data Affects Hospital Profiling SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; QUALITY-OF-CARE; SURGICAL QUALITY; ADMINISTRATIVE DATA; 30-DAY MORTALITY; VETERANS; MEDICARE; SYSTEM; PERFORMANCE; OUTCOMES AB Objectives People receiving healthcare from multiple payers (eg, Medicare and the Veterans Health Administration [VA]) have fragmented health records. How the use of more complete data affects hospital profiling has not been examined. Study Design Retrospective cohort study. Methods We examined 30-day mortality following acute myocardial infarction at 104 VA hospitals for veterans 66 years and older from 2006 through 2010 who were also Medicare beneficiaries. Using VA-only data versus combined VA/Medicare data, we calculated 2 risk-standardized mortality rates (RSMRs): 1 based on observed mortality (O/E) and the other from CMS' Hospital Compare program, based on model-predicted mortality (P/E). We also categorized hospital outlier status based on RSMR relative to overall VA mortality: average, better than average, and worse than average. We tested whether hospitals whose patients received more of their care through Medicare would look relatively better when including those data in risk adjustment, rather than including VA data alone. Results Thirty-day mortality was 14.8%. Adding Medicare data caused both RSMR measures to significantly increase in about half the hospitals and decrease in the other half. O/E RSMR increased in 53 hospitals, on average, by 2.2%, and decreased in 51 hospitals by -2.6%. P/E RSMR increased, on average, by 1.2% in 56 hospitals, and decreased in the others by -1.3%. Outlier designation changed for 4 hospitals using O/E measure, but for no hospitals using P/E measure. Conclusions VA hospitals vary in their patients' use of Medicare-covered care and completeness of health records based on VA data alone. Using combined VA/Medicare data provides modestly different hospital profiles compared with those using VA-alone data. C1 [Hanchate, Amresh D.; Abdulkerim, Hassen; Stolzmann, Kelly L.; Rosen, Amy K.; Shokeen, Priti; Shwartz, Michael] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Hanchate, Amresh D.; Borzecki, Ann] Boston Univ, Gen Internal Med Sect, Boston, MA 02118 USA. [Rosen, Amy K.] Boston Univ, Dept Surg, Boston, MA 02118 USA. [Borzecki, Ann] Boston Univ, Sch Med, Dept Hlth Policy & Management, Sch Publ Hlth, Boston, MA 02118 USA. [Shwartz, Michael] Boston Univ, Dept Operat & Technol Management, Sch Management, Boston, MA 02118 USA. [Ash, Arlene S.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Borzecki, Ann] Bedford Vet Affairs Med Ctr, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. [Fink, Aaron S.] Emory Univ, Sch Med, Atlanta, GA USA. [Pugh, Mary Jo V.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Pugh, Mary Jo V.] Univ Texas San Antonio, Hlth Sci Ctr, Dept Epidemiol & Biostat, San Antonio, TX USA. RP Hanchate, AD (reprint author), Boston Univ, Sch Med, Gen Internal Med Sect, 801 Massachusetts Ave, Boston, MA 02118 USA. EM hanchate@bu.edu FU National Center for Advancing Translational Sciences of the NIH [UL1TR000161] FX Veterans Health Administration Health Services Research & Development. The research reported in this publication was supported by the National Center for Advancing Translational Sciences of the NIH under award number UL1TR000161 (Arlene Ash). NR 43 TC 0 Z9 0 U1 4 U2 5 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD FEB PY 2015 VL 21 IS 2 BP 129 EP + PG 21 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CD3GM UT WOS:000350966400006 PM 25880362 ER PT J AU Baheti, AD Tirumani, SH Sewatkar, R Shinagare, AB Hornick, JL Ramaiya, NH Jagannathan, JP AF Baheti, A. D. Tirumani, S. H. Sewatkar, R. Shinagare, A. B. Hornick, J. L. Ramaiya, N. H. Jagannathan, J. P. TI Imaging features of primary and metastatic extremity synovial sarcoma: a single institute experience of 78 patients SO BRITISH JOURNAL OF RADIOLOGY LA English DT Article ID SOFT-TISSUE SARCOMA; PROGNOSTIC-FACTORS; RETROSPECTIVE ANALYSIS; PERITUMORAL EDEMA; MULTICENTER; PATTERNS; CHILDREN; COMMON; SITES; GRADE AB Objective: To study the appearance of primary and metastatic extremity synovial sarcoma (SS) on cross-sectional imaging. Methods: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, the imaging features of 78 patients (42 males and 36 females; mean age, 40 years) with primary and metastatic extremity SS on MRI and multidetector CT were reviewed, with baseline MRI of the primary available in 31 patients. Results: Primary SSs were predominantly well-circumscribed (27/31) and heterogeneously enhancing solid (18/31) or solid-cystic (13/31) tumours. Imaging features visualized included the presence of perilesional oedema (14/31), interfascial (15/31) and intercompartmental extension (7/31), triple sign (11/31), intratumoral haemorrhage (10/31), calcification (6/31), bowl of grapes appearance (5/31) and bone involvement (3/31). Smaller T1 stage tumours (8/31) appeared as heterogeneously enhancing lesions, with some lesions demonstrating interfascial and intercompartmental extension and perilesional oedema. Recurrent/metastatic disease developed in 49/78 (63%) patients. Of these, 20/78 (26%) had metastasis at presentation, while the remaining developed metastatic disease at a median interval of 27 months (range, 3-161 months). Pleuropulmonary metastases (46/78) were the most common sites, with most of the metastases being pleural based. On univariate analysis, larger tumour size, the presence of perilesional oedema, intercompartmental extension, the presence of intralesional haemorrhage and bowl of grapes appearance on MRI were associated with a significantly higher incidence of metastatic disease. Conclusion: Certain imaging features of primary SS predict the risk of development of metastatic disease. Imaging features of T1 stage tumours included heterogeneous enhancement, interfascial extension and perilesional oedema. Pleural-based metastases are commonly seen in SSs. Advances in knowledge: Imaging features of primary SS correlate with metastatic disease. Pleural-based metastases are often present in SSs. C1 [Baheti, A. D.; Tirumani, S. H.; Shinagare, A. B.; Ramaiya, N. H.; Jagannathan, J. P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Baheti, A. D.; Tirumani, S. H.; Sewatkar, R.; Shinagare, A. B.; Ramaiya, N. H.; Jagannathan, J. P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Hornick, J. L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Baheti, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, 44 Binney St, Boston, MA 02115 USA. EM akshaybaheti@gmail.com NR 27 TC 3 Z9 3 U1 0 U2 1 PU BRITISH INST RADIOLOGY PI LONDON PA 36 PORTLAND PLACE, LONDON W1N 4AT, ENGLAND SN 0007-1285 EI 1748-880X J9 BRIT J RADIOL JI Br. J. Radiol. PD FEB PY 2015 VL 88 IS 1046 AR 20140608 DI 10.1259/bjr.20140608 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CD2CN UT WOS:000350881600012 PM 25431890 ER PT J AU Dipoce, J Bernheim, A Spindola-Franco, H AF Dipoce, J. Bernheim, A. Spindola-Franco, H. TI Radiology of cardiac devices and their complications SO BRITISH JOURNAL OF RADIOLOGY LA English DT Review ID INTRAAORTIC BALLOON PUMP; AORTIC-VALVE IMPLANTATION; ACUTE MYOCARDIAL-INFARCTION; RIGHT-VENTRICULAR PERFORATION; PACEMAKER LEAD FRACTURE; PERMANENT PACEMAKER; COMPUTED-TOMOGRAPHY; RADIOGRAPHIC PSEUDOFRACTURE; CARDIOGENIC-SHOCK; RANDOMIZED-TRIAL AB This article familiarizes the reader with several different cardiac devices including pacemakers and implantable cardioverter defibrillators, intra-aortic balloon pumps, ventricular assist devices, valve replacements and repairs, shuntoccluding devices and passive constraint devices. Many cardiac devices are routinely encountered in clinical practice. Other devices are in the early stages of development, but circumstances suggest that they too will become commonly found. The radiologist must be familiar with these devices and their complications. C1 [Dipoce, J.] Hadassah Med Ctr, Dept Radiol, IL-91120 Jerusalem, Israel. [Bernheim, A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Thorac Imaging, Boston, MA 02215 USA. [Spindola-Franco, H.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Radiol, New York, NY USA. RP Bernheim, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Thorac Imaging, Boston, MA 02215 USA. EM abernheim@mgh.harvard.edu NR 94 TC 0 Z9 0 U1 1 U2 5 PU BRITISH INST RADIOLOGY PI LONDON PA 36 PORTLAND PLACE, LONDON W1N 4AT, ENGLAND SN 0007-1285 EI 1748-880X J9 BRIT J RADIOL JI Br. J. Radiol. PD FEB PY 2015 VL 88 IS 1046 AR 20140540 DI 10.1259/bjr.20140540 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CD2CN UT WOS:000350881600007 PM 25411826 ER PT J AU Liu, Y Lear, T Zhao, Y Zhao, J Zou, C Chen, BB Mallampalli, RK AF Liu, Y. Lear, T. Zhao, Y. Zhao, J. Zou, C. Chen, B. B. Mallampalli, R. K. TI F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7 SO CELL DEATH & DISEASE LA English DT Article ID UBIQUITIN LIGASE; CANCER; IDENTIFICATION; INFLAMMATION; STABILITY; MECHANISM; COMPLEX; BINDING; SYSTEM; FAMILY AB Fbxl7, a subunit of the SCF (Skp-Cul1-F-box protein) complex induces mitotic arrest in cells; however, molecular factors that control its cellular abundance remain largely unknown. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18. An FQ motif within Fbxl7 serves as a molecular recognition site for Fbxl18 interaction. Ectopically expressed Fbxl7 induces apoptosis in Hela cells, an effect profoundly accentuated after cellular depletion of Fbxl18 protein or expression of Fbxl7 plasmids encoding mutations at either Lys 109 or within the FQ motif. Ectopic expression of Fbxl18 plasmid-limited apoptosis caused by overexpressed Fbxl7 plasmid. Thus, Fbxl18 regulates apoptosis by mediating ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein Fbxl7 that may impact cellular processes involved in cell cycle progression. C1 [Liu, Y.; Lear, T.; Zhao, Y.; Zhao, J.; Zou, C.; Chen, B. B.; Mallampalli, R. K.] Univ Pittsburgh, Acute Lung Injury Ctr Excellence, Dept Med, Pittsburgh, PA 15213 USA. [Mallampalli, R. K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. RP Mallampalli, RK (reprint author), Univ Pittsburgh, UPMC Montefiore, Dept Med, RK Mallampalli Pulm Allergy & Crit Care Med,NW628, Pittsburgh, PA 15213 USA. EM mallampallirk@upmc.edu OI Lear, Travis/0000-0001-9156-0844 FU United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; United States Department of Veterans Affairs; National Institutes of Health [HL096376, HL097376, HL098174, HL081784, 1UH2HL123502, P01 HL114453, HL116472, HL01916]; American Heart Association Award [12SDG9050005, 12SDG12040330] FX The authors thank Wei Chen and Jin Li for cells. This work was supported in part by the United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development and by a Merit Review award from the United States Department of Veterans Affairs (to RKM). This work was also supported, in part, by National Institutes of Health R01 grants HL096376, HL097376, HL098174, HL081784, 1UH2HL123502 and P01 HL114453 (to RKM), HL116472 (to BBC), HL01916 (to YZ), and American Heart Association Award 12SDG9050005 (to JZ) and 12SDG12040330 (to CZ). NR 29 TC 6 Z9 6 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD FEB PY 2015 VL 6 AR e1630 DI 10.1038/cddis.2014.585 PG 9 WC Cell Biology SC Cell Biology GA CC7VF UT WOS:000350575800004 PM 25654763 ER PT J AU Wildes, R Kayden, S Goralnick, E Niescierenko, M Aschkenasy, M Kemen, KM Vanrooyen, M Biddinger, P Cranmer, H AF Wildes, Ryan Kayden, Stephanie Goralnick, Eric Niescierenko, Michelle Aschkenasy, Miriam Kemen, Katherine M. Vanrooyen, Michael Biddinger, Paul Cranmer, Hilarie TI Sign Me Up: Rules of the Road for Humanitarian Volunteers During the Ebola Outbreak SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Article DE voluntary workers; disease outbreaks; disaster medicine; emergency responders AB The current Ebola outbreak is the worst global public health emergency of our generation, and our global health care community must and will rise to serve those affected. Aid organizations participating in the Ebola response must carefully plan to carry out their responsibility to ensure the health, safety, and security of their responders. At the same time, individual health care workers and their employers must evaluate the ability of an aid organization to protect its workers in the complex environment of this unheralded Ebola outbreak. We present a minimum set of operational standards developed by a consortium of Boston-based hospitals that a professional organization should have in place to ensure the health, safety, and security of its staff in response to the Ebola virus disease outbreak. (Disaster Med Public Health Preparedness. 2014;0:1-2) C1 [Wildes, Ryan] Partners Healthcare Risk & Insurance Serv, Boston, MA USA. [Kayden, Stephanie] Brigham & Womens Hosp, Dept Emergency Med, Div Int Emergency Med & Humanitarian Programs, Boston, MA 02115 USA. [Goralnick, Eric] Brigham & Womens Healthcare, Boston, MA USA. [Niescierenko, Michelle] Boston Childrens Hosp, Global Hlth Program, Boston, MA USA. [Aschkenasy, Miriam; Cranmer, Hilarie] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Kemen, Katherine M.] Partners HealthCare Emergency Preparedness, Boston, MA USA. [Vanrooyen, Michael] Harvard Humanitarian Initiat, Boston, MA USA. Partners Healthcare, Boston, MA USA. [Biddinger, Paul] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cranmer, H (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM hcranmer@partners.org NR 5 TC 3 Z9 3 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1935-7893 EI 1938-744X J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD FEB PY 2015 VL 9 IS 1 BP 88 EP 89 DI 10.1017/dmp.2014.110 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC9DR UT WOS:000350668600020 PM 25343427 ER PT J AU Luo, HBR Mondal, S AF Luo, Hongbo R. Mondal, Subhanjan TI Molecular control of PtdIns(3,4,5)P3 signaling in neutrophils SO EMBO REPORTS LA English DT Review DE innate immunity; inositol phosphate; lipid phosphatase; neutrophils; PtdIns(3,4,5)P3 ID TUMOR-SUPPRESSOR PTEN; INOSITOL HEXAKISPHOSPHATE KINASE; CHRONIC GRANULOMATOUS-DISEASE; PLECKSTRIN HOMOLOGY DOMAINS; PHOSPHATIDYLINOSITOL 3-KINASE; NADPH OXIDASE; IN-VIVO; PHOSPHATASE SHIP; DIPHOSPHOINOSITOL PENTAKISPHOSPHATE; SPONTANEOUS DEATH AB Neutrophils play critical roles in innate immunity and host defense. However, excessive neutrophil accumulation or hyper-responsiveness of neutrophils can be detrimental to the host system. Thus, the response of neutrophils to inflammatory stimuli needs to be tightly controlled. Many cellular processes in neutrophils are mediated by localized formation of an inositol phospholipid, phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3), at the plasma membrane. The PtdIns(3,4,5)P3 signaling pathway is negatively regulated by lipid phosphatases and inositol phosphates, which consequently play a critical role in controlling neutrophil function and would be expected to act as ideal therapeutic targets for enhancing or suppressing innate immune responses. Here, we comprehensively review current understanding about the action of lipid phosphatases and inositol phosphates in the control of neutrophil function in infection and inflammation. C1 [Luo, Hongbo R.; Mondal, Subhanjan] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Luo, Hongbo R.; Mondal, Subhanjan] Childrens Hosp, Dept Lab Med, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Mondal, Subhanjan] Promega Corp, Madison, WI USA. RP Luo, HBR (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM hongbo.luo@childrens.harvard.edu FU NHLBI NIH HHS [R01 HL092020, P01 HL095489]; NIAID NIH HHS [R01 AI103142] NR 181 TC 3 Z9 4 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD FEB PY 2015 VL 16 IS 2 BP 149 EP 163 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CC9MV UT WOS:000350695600007 PM 25576302 ER PT J AU Dobrev, I Furlong, C Cheng, JT Rosowski, JJ AF Dobrev, I. Furlong, C. Cheng, J. T. Rosowski, J. J. TI Optimization of a Lensless Digital Holographic Otoscope System for Transient Measurements of the Human Tympanic Membrane SO EXPERIMENTAL MECHANICS LA English DT Article DE Acoustic-solid interaction; High-speed digital holography; Miniaturization engineering; Otology; Transient response; Tympanic membrane ID STIMULATED ACOUSTIC EMISSIONS; MIDDLE-EAR; STROBOSCOPIC HOLOGRAPHY; VIBRATION; SURFACE; MOTION; INTERFEROMETRY; SOUND; MODEL AB In this paper, we propose a multi-pulsed double exposure (MPDE) acquisition method to quantify in full-field-of-view the transient (i.e., >10 kHz) acoustically induced nanometer scale displacements of the human tympanic membrane (TM or eardrum). The method takes advantage of the geometrical linearity and repeatability of the TM displacements to enable high-speed measurements with a conventional camera (i.e., <20 fps). The MPDE is implemented on a previously developed digital holographic system (DHS) to enhance its measurement capabilities, at a minimum cost, while avoiding constraints imposed by the spatial resolutions and dimensions of high-speed (i.e., >50 kfps) cameras. To our knowledge, there is currently no existing system to provide such capabilities for the study of the human TM. The combination of high temporal (i.e., >50 kHz) and spatial (i.e., >500 k data points) resolutions enables measurements of the temporal and frequency response of all points across the surface of the TM simultaneously. The repeatability and accuracy of the MPDE method are verified against a Laser Doppler Vibrometer (LDV) on both artificial membranes and ex-vivo human TMs that are acoustically excited with a sharp (i.e., <100 mu s duration) click. The measuring capabilities of the DHS, enhanced by the MPDE acquisition method, allow for quantification of spatially dependent motion parameters of the TM, such as modal frequencies, time constants, as well as inferring local material properties. C1 [Dobrev, I.; Furlong, C.] Worcester Polytech Inst, Dept Mech Engn, CHSLT, Worcester, MA 01609 USA. [Furlong, C.; Cheng, J. T.; Rosowski, J. J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Furlong, C.; Cheng, J. T.; Rosowski, J. J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Dobrev, I (reprint author), Worcester Polytech Inst, Dept Mech Engn, CHSLT, Worcester, MA 01609 USA. EM ivo_d@wpi.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD); National Institute of Health (NIH); Massachusetts Eye and Ear Infirmary (MEEI); Mittal Fund; NanoEngineering, Science, and Technology (NEST) program at the Worcester Polytechnic Institute, Mechanical Engineering Department FX The authors should like to acknowledge the help of Michael Ravicz at the Eaton-Peabody Laboratory (EPL) of the Massachusetts Eye and Ear Infirmary (MEEI) and Ellery Harrington and Morteza Khaleghi at the Center for Holographic Studies and Laser micro-mechaTronics (CHSLT) at Worcester Polytechnic Institute. This work has been funded by the National Institute on Deafness and Other Communication Disorders (NIDCD), the National Institute of Health (NIH), the Massachusetts Eye and Ear Infirmary (MEEI), and the Mittal Fund. The authors also gratefully acknowledge the support of the NanoEngineering, Science, and Technology (NEST) program at the Worcester Polytechnic Institute, Mechanical Engineering Department. NR 33 TC 1 Z9 1 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4851 EI 1741-2765 J9 EXP MECH JI Exp. Mech. PD FEB PY 2015 VL 55 IS 2 BP 459 EP 470 DI 10.1007/s11340-014-9945-4 PG 12 WC Materials Science, Multidisciplinary; Mechanics; Materials Science, Characterization & Testing SC Materials Science; Mechanics GA CC8ZB UT WOS:000350656000014 PM 25780271 ER PT J AU Yin, R Wang, M Huang, YY Landi, G Vecchio, D Chiang, LY Hamblin, MR AF Yin, Rui Wang, Min Huang, Ying-Ying Landi, Giacomo Vecchio, Daniela Chiang, Long Y. Hamblin, Michael R. TI Antimicrobial photodynamic inactivation with decacationic functionalized fullerenes: Oxygen-independent photokilling in presence of azide and new mechanistic insights SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Functionalized decacationic [60] fullerenes; Antimicrobial photodynamic inactivation; Reactive oxygen species; Azide radicals; Photoinduced electron transfer; Oxygen-independent photokilling ID GRAM-POSITIVE BACTERIA; IN-VIVO; ANTIBIOTIC-RESISTANCE; INFECTIOUS-DISEASE; ESCHERICHIA-COLI; SURFACE-PROTEINS; CANCER-CELLS; THERAPY; DERIVATIVES; PHOTOINACTIVATION AB Functionalized fullerenes are gaining wide interest for mediating photodynamic therapy (PDT) of diseases such as cancers and infections. We recently reported the synthesis of two new decacationic fullerene monoadducts: C-60[ > M(C3N6+C3)(2)]-(I-)(10)(LC14) and its derivative with a light-harvesting antenna conjugated as a C-60[ > CPAF-(MN6+C3)(2)]-(I-)(10) nanostructure (LC15). We studied the ability of these compounds to mediate PDT of human cancer cells in vitro when excited by UVA light or by white light. Here we report the synthesis of a new fullerene derivative C-60[ > M(C3N6+C3)(2)][ > M(C3N6+C3)\(2)][ > M(C3N6C3)(2)]-(I-)(10) (LC16 derived from LC14), as a malonate bisadduct containing a covalently bound decatertiary amine arm. We investigated the relative abilities of the three compounds to generate singlet oxygen (O-1(2)), hydroxyl radicals (HO center dot), and hydrogen peroxide (H2O2) after excitation by UVA or by white light. We used three different classes of pathogenic microbial cells (Gram-positive bacterium, methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative bacterium Escherichia coli, and fungal yeast Candida albicans). LC15 was the most powerful broad spectrum antimicrobial fullerenyl photosensitizer (FPS) followed by LC16, and LC14 was least powerful. Killing depended on both fullerene monoadduct concentration and light fluence. UVA was five times more effective than white light for killing, but not for generation of ROS and relative absorption was greater in white spectral region. Bacterial killing was not much inhibited by addition of azide anions and in some cases was potentiated. In the absence of oxygen, microbial photokilling was highly potentiated (up to 5 logs) by the addition of azide anions. We conclude that molecular functional addends that encourage a type I electron-transfer mechanism increase the ability of photoactivated fullerene monoadducts to kill microbial cells. Oxygen-independent photokilling is possible with fullerene monoadducts in the presence of azide anions, probably mediated by azidyl radicals. UVA excitation may kill bacteria partly by an electron-transfer mechanism directly into bacteria as well as by ROS. (C) 2014 Elsevier Inc. All rights reserved. C1 [Yin, Rui] Third Mil Med Univ, Southwest Hosp, Dept Dermatol, Chongqing, Peoples R China. [Yin, Rui; Huang, Ying-Ying; Landi, Giacomo; Vecchio, Daniela; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Yin, Rui; Huang, Ying-Ying; Vecchio, Daniela; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Wang, Min; Chiang, Long Y.] Univ Massachusetts, Dept Chem, Lowell, MA USA. [Huang, Ying-Ying] Guangxi Med Univ, Dept Pathol, Nanning, Peoples R China. [Landi, Giacomo] Univ Siena, Dept Mol Med, I-53100 Siena, Italy. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Hamblin, MR (reprint author), BAR414,40 Blossom St, Boston, MA 02114 USA. EM Hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU US NIH [R01CA137108, R01AI050875]; AFOSR [FA9550-09-1-0183, FA9550-09-1-0380]; Chinese National Natural Science Foundation [81172495] FX This work was funded by US NIH Grants R01CA137108 and R01AI050875. The authors at UML also acknowledge support by AFOSR Grants FA9550-09-1-0183 and FA9550-09-1-0380. Rui Yin was supported by Chinese National Natural Science Foundation (Grant 81172495). NR 43 TC 9 Z9 9 U1 7 U2 42 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB PY 2015 VL 79 BP 14 EP 27 DI 10.1016/j.freeradbiomed.2014.10.514 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CC5IS UT WOS:000350392900002 PM 25451642 ER PT J AU Noble, M Mayer-Proschel, M Li, ZB Dong, TF Cui, WC Proschel, C Ambeskovic, I Dietrich, J Han, RL Yang, YM Folts, C Stripay, J Chen, HY Stevens, BM AF Noble, Mark Mayer-Proeschel, Margot Li, Zaibo Dong, Tiefei Cui, Wanchang Proeschel, Christoph Ambeskovic, Ibro Dietrich, Joerg Han, Ruolan Yang, Yin Miranda Folts, Christopher Stripay, Jennifer Chen, Hsing-Yu Stevens, Brett M. TI Redox biology in normal cells and cancer: Restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE Redox; Stem cell; Progenitor cell; Oligodendrocyte/type-2 astrocyte progenitor cell; c-Cbl; Redox/Fyn/c-Cbl pathway; Glioblastoma; Basal-like breast cancer; Tumor initiating cell; Tamoxifen ID GROWTH-FACTOR RECEPTOR; HIGH-DOSE TAMOXIFEN; CENTRAL-NERVOUS-SYSTEM; MULTIFOCAL INFLAMMATORY LEUKOENCEPHALOPATHY; SPINAL-CORD-INJURY; NEGATIVE BREAST-CANCER; METABOTROPIC GLUTAMATE RECEPTORS; INDUCED COGNITIVE IMPAIRMENT; LEVAMISOLE ADJUVANT THERAPY; NUCLEOTIDE EXCHANGE FACTOR AB This review discusses a unique discovery path starting with novel findings on redox regulation of precursor cell and signaling pathway function and identification of a new mechanism by which relatively small changes in redox status can control entire signaling networks that regulate self-renewal, differentiation, and survival. The pathway central to this work, the redox/Fyn/c-Cbl (RFC) pathway, converts small increases in oxidative status to pan-activation of the c-Cbl ubiquitin ligase, which controls multiple receptors and other proteins of central importance in precursor cell and cancer cell function. Integration of work on the RFC pathway with attempts to understand how treatment with systemic chemotherapy causes neurological problems led to the discovery that glioblastomas (GBMs) and basal-like breast cancers (BLBCs) inhibit c-Cbl function through altered utilization of the cytoskeletal regulators Cool-1/beta pix and Cdc42, respectively. Inhibition of these proteins to restore normal c-Cbl function suppresses cancer cell division, increases sensitivity to chemotherapy, disrupts tumor-initiating cell (TIC) activity, in GBMs and BLBCs, controls multiple critical TIC regulators: and also allows targeting of non-TICs. Moreover, these manipulations do not increase chemosensitivity or suppress division of nontransformed cells. Restoration of normal c-Cbl function also allows more effective harnessing of estrogen receptor-alpha (ER alpha)-independent activities of tamoxifen to activate the RFC pathway and target ER alpha-negative cancer cells. Our work thus provides a discovery strategy that reveals mechanisms and therapeutic targets that cannot be deduced by standard genetics analyses, which fail to reveal the metabolic information, isoform shifts, protein activation, protein complexes, and protein degradation critical to our discoveries. (C) 2015 Published by Elsevier Inc. C1 [Noble, Mark; Mayer-Proeschel, Margot; Proeschel, Christoph; Ambeskovic, Ibro; Han, Ruolan; Yang, Yin Miranda; Folts, Christopher; Stripay, Jennifer] Univ Rochester, Med Ctr, Dept Biomed Genet, Rochester, NY 14642 USA. [Noble, Mark; Mayer-Proeschel, Margot; Proeschel, Christoph; Ambeskovic, Ibro; Han, Ruolan; Yang, Yin Miranda; Folts, Christopher; Stripay, Jennifer] Univ Rochester, Med Ctr, Stem Cell & Regenerat Med Inst, Rochester, NY 14642 USA. [Li, Zaibo] Ohio State Univ, Wexner Med Ctr, Dept Pathol, Columbus, OH 43210 USA. [Dong, Tiefei] Univ Michigan Tech Transfer, Ann Arbor, MI 48109 USA. [Cui, Wanchang] Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Dietrich, Joerg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Chen, Hsing-Yu] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Stevens, Brett M.] Univ Colorado, Sch Med, Div Hematol, Aurora, CO 80045 USA. RP Noble, M (reprint author), Univ Rochester, Med Ctr, Dept Biomed Genet, Rochester, NY 14642 USA. EM mark_noble@urmc.rochester.edu; margot_mayer-proschel@urmc.rochester.edu; liz2@upmc.edu; tiefeid@umich.edu; wcui@som.umaryland.edu; Chris_Proschel@urmc.rochester.edu; Ibro_Ambeskovic@URMC.Rochester.edu; joergdietrich@hotmail.com; ruolan.han@gmail.com; yyang607@gmail.com; Christopher_Folts@URMC.Rochester.edu; jennifer_Stripay@URMC.Rochester.edu; hsing-yu_chen@hms.harvard.edu; brett.stevens@ucdenver.edu FU National Institutes of Health [CA131385, ES012708, CO24319, AG030711]; New York State Department of Health and Empire State Stem Cell Board (NYSTEM) [N09G195, C026877]; Komen Foundation for the Cure [BCTR0707697]; Department of Defense [AS073218]; Autism Speaks; Wilmot Cancer Institute FX The research presented in this review was supported by the National Institutes of Health (CA131385, ES012708, CO24319, AG030711), the New York State Department of Health and Empire State Stem Cell Board (NYSTEM) (N09G195, C026877), the Komen Foundation for the Cure (BCTR0707697), the Department of Defense (AS073218), Autism Speaks, and the Wilmot Cancer Institute. The authors contributed to work discussed in this review as follows: redox biology of O-2A/OPCs (M.M.P., I.A., C.F., M.N.); redox/Fyn/c-Cbl pathway (Z.L., T.D., W.C., C.P., M.N.); effects of systemic chemotherapy on the CNS (J.D., R.H., Y.M.Y., M.N.); protection from adverse effects of tamoxifen (H.-Y.C., Y.M.Y., R.H., M.N.); Inhibition of c-Cbl as a therapeutic target in cancer treatment (B.M.S., H.-Y.C., J.S., M.N.). NR 398 TC 4 Z9 4 U1 5 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB PY 2015 VL 79 BP 300 EP 323 DI 10.1016/j.freeradbiomed.2014.10.860 PG 24 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CC5IS UT WOS:000350392900029 PM 25481740 ER PT J AU Matulonis, U Vergote, I Backes, F Martin, LP McMeekin, S Birrer, M Campana, F Xu, Y Egile, C Ghamande, S AF Matulonis, Ursula Vergote, Ignace Backes, Floor Martin, Lainie P. McMeekin, Scott Birrer, Michael Campana, Frank Xu, Yi Egile, Coumaran Ghamande, Sharad TI Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Endometrial cancer; PI3K inhibitors ID ADVANCED SOLID TUMORS; MAMMALIAN TARGET; CLINICAL-TRIALS; CANCER; MUTATIONS; TEMSIROLIMUS; PATHWAY; PIK3CA; PTEN; COMBINATION AB Objective. Patients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma. Methods. This Phase II, multicenter, single-arm, open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma, who had received one or two prior chemotherapy regimens. Patients received pilaralisib 600 mg capsules or 400 mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free suririval (PFS) >6 months and safety. Molecular profiling in archival tumor tissue and circulating tumor DNA were performed to identify molecular markers associated with response or resistance to pilaralisib. Results. 67 patients were enrolled, of which 50 and 17 patients had received one or two prior regimens, respectively. Complete or partial tumor responses occurred in two patients each (ORR 6.0%); three had tumors with normal PTEN expression and PIK3R1 mutations and one had a tumor with PTEN protein deficiency. However, there was no association between molecular alterations and clinical activity. Rate of PFS >6 months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (403%), diarrhea (37.3%) and fatigue (28.4%). The most commonly reported treatment-related grade >= 3 AEs were rash (9.0%), diarrhea (4.5%) and increased alanine aminotransferase (4.5%). Conclusions. Pilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma. (C) 2014 Elsevier Inc. All rights reserved. C1 [Matulonis, Ursula] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vergote, Ignace] European Union, Leuven Canc Inst, Leuven, Belgium. [Backes, Floor] Ohio State Univ, Columbus, OH 43210 USA. [Martin, Lainie P.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [McMeekin, Scott] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Birrer, Michael] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Campana, Frank; Xu, Yi] Sanofi, Cambridge, MA USA. [Egile, Coumaran] Sanofi Oncol, Vitry Sur Seine, France. [Ghamande, Sharad] Georgia Regents Univ, Ctr Canc, Augusta, GA USA. RP Matulonis, U (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM Ursula_Matulonis@dfci.harvard.edu OI Backes, Floor/0000-0002-9225-6913 FU Sanofi; Simone Blagg of MediTech Media - Sanofi FX CE is grateful to the following for their contributions to this study: Christelle Castell (Sanofi, for assistance with sample management and biomarker data analysis), Elisa Francesconi (Sanofi, for assistance with the plasma C peptide and glucose analysis), Sandrine Mace (Sanofi, for assistance with sample management and sequencing data collection), Bin Wu (Sanofi, for assistance with PTEN IHC data analysis), Hui Su (Sanofi, for assistance with PTEN IHC staining), Colette Dib and Edouard Turlotte (Sanofi, for assistance with FFPE tissue processing and DNA preparation), Joonil Jung, Madelyn Light, Wilson Dos-Santos-Bele and Joon Sang Lee (Sanofi, for assistance with NGS data collection), Laurent Debussche (Sanofi, for intellectual contribution), Douglas Laird, Valentina Vysotskaia and Frauke Bentzien (all from Exelixis, for assistance with candidate Sanger and next-generation sequencing data). CE thanks Don Bergstrom, Christoph Lengauer, Rodrigo Ruiz-Soto (all formerly Sanofi) and Joanne Lager (Sanofi) for thoughtful discussions and intellectual contributions. This study was funded by Sanofi. The authors received editorial support from Simone Blagg of MediTech Media, funded by Sanofi. NR 40 TC 15 Z9 16 U1 3 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 246 EP 253 DI 10.1016/j.ygyno.2014.12.019 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500012 PM 25528496 ER PT J AU Rauh-Hain, JA Connor, S Clemmer, J Clark, R Hall, T Growdon, W Goodman, AK Borutall, D Schorge, J del Carmen, M AF Rauh-Hain, J. Alejandro Connor, Sarah Clemmer, Joel Clark, Rachel Hall, Tracilyn Growdon, Whitfield Goodman, A. K. Borutall, David Schorge, John del Carmen, Marcela TI Trends in treatment of uterine serous cancer in the medicare population SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Rauh-Hain, J. Alejandro; Connor, Sarah; Clemmer, Joel; Clark, Rachel; Hall, Tracilyn; Growdon, Whitfield; Goodman, A. K.; Borutall, David; Schorge, John; del Carmen, Marcela] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 396 EP 396 DI 10.1016/j.ygyno.2014.11.028 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500043 ER PT J AU Growdon, W Byron, V DiGloria, C Borger, D Foster, R Winslow, J Sperinde, J Rueda, BR AF Growdon, Whitfield Byron, Virginia DiGloria, Celeste Borger, Darrell Foster, Rosemary Winslow, John Sperinde, Jeffery Rueda, Bo R. TI HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Growdon, Whitfield; Byron, Virginia; DiGloria, Celeste; Borger, Darrell; Foster, Rosemary; Winslow, John; Sperinde, Jeffery; Rueda, Bo R.] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 398 EP 398 DI 10.1016/j.ygyno.2014.11.034 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500049 ER PT J AU Hall, T DiGloria, C Kim, M Zhang, L Foster, R Growdon, W Rueda, B AF Hall, Tracilyn DiGloria, Celeste Kim, Minji Zhang, Ling Foster, Rosemary Growdon, Whitfield Rueda, Bo TI Dual inhibition of PI3K and PARP demonstrates synergistic anti-tumor activity in endometrioid endometrial cancer patient derived xenografts SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Hall, Tracilyn; DiGloria, Celeste; Kim, Minji; Zhang, Ling; Foster, Rosemary; Growdon, Whitfield; Rueda, Bo] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 398 EP 398 DI 10.1016/j.ygyno.2014.11.033 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500048 ER PT J AU Dorton, BJ Elias, KM Growdon, W Horowitz, NS AF Dorton, Benjamin J. Elias, Kevin M. Growdon, Whitfield Horowitz, Neil S. TI Biomarkers in Gynecologic Cancers Red cell distribution width (RDW) as a novel marker for predicting recurrence of high-grade cervical dysplasia or carcinoma in active smokers SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Dorton, Benjamin J.; Elias, Kevin M.; Growdon, Whitfield; Horowitz, Neil S.] Harvard Univ, Massachusetts Gen Hosp, Brigham & Womens Hosp, Cambridge, MA 02138 USA. NR 0 TC 2 Z9 2 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 400 EP 400 DI 10.1016/j.ygyno.2014.11.038 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500053 ER PT J AU Davis, M Rauh-Hain, A Worley, M Berkowitz, R Schorge, J Muto, M Growdon, W Horowitz, N Del Carmen, M AF Davis, M. Rauh-Hain, A. Worley, M. Berkowitz, R. Schorge, J. Muto, M. Growdon, W. Horowitz, N. Del Carmen, M. TI Investigating the impact of body mass index on intraperitoneal chemotherapy outcomes in patients with advanced stage ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Davis, M.; Rauh-Hain, A.; Worley, M.; Berkowitz, R.; Schorge, J.; Muto, M.; Growdon, W.; Horowitz, N.; Del Carmen, M.] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Davis, M.; Rauh-Hain, A.; Worley, M.; Berkowitz, R.; Schorge, J.; Muto, M.; Growdon, W.; Horowitz, N.; Del Carmen, M.] Harvard Univ, Brigham & Womens Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 402 EP 403 DI 10.1016/j.ygyno.2014.11.046 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500061 ER PT J AU Clark, RM Clemmer, JT Melamed, A Rauh-Hain, JA Boruta, D del Carmen, M Goodman, AK Growdon, WB Hall, T Schorge, JO AF Clark, Rachel M. Clemmer, Joel T. Melamed, Alexander Rauh-Hain, Jose A. Boruta, David del Carmen, Marcela Goodman, Anne Kathryn Growdon, Whitfield B. Hall, Tracilyn Schorge, John O. TI Primary debulking surgery in advanced stage ovarian cancer is associated with improved survival SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Clark, Rachel M.; Clemmer, Joel T.; Melamed, Alexander; Rauh-Hain, Jose A.; Boruta, David; del Carmen, Marcela; Goodman, Anne Kathryn; Growdon, Whitfield B.; Hall, Tracilyn; Schorge, John O.] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. OI Melamed, Alexander/0000-0002-0654-0863 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 403 EP 404 DI 10.1016/j.ygyno.2014.11.049 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500064 ER PT J AU Joseph, N Clark, R Lee, M Dizon, DS Growdon, WB AF Joseph, Naima Clark, Rachel Lee, Malinda Dizon, Don S. Growdon, Whitfield B. TI Delay in chemotherapy administration adversely affects overall survival in elderly ovarian cancer patients SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Joseph, Naima; Clark, Rachel; Lee, Malinda; Dizon, Don S.; Growdon, Whitfield B.] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 403 EP 403 DI 10.1016/j.ygyno.2014.11.047 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500062 ER PT J AU Rauh-Hain, JA Foley, OW Winograd, D Andrade, C Clark, RM Vargas, RJ Hinchclifff, EM Esselen, KM Horowitz, NS del Carmen, MG AF Rauh-Hain, J. Alejandro Foley, Olivia W. Winograd, Dina Andrade, Carolina Clark, Rachel M. Vargas, Roberto J. Hinchclifff, Emily M. Esselen, Katherine M. Horowitz, Neil S. del Carmen, Marcela G. TI Clinical characteristics and outcomes of patients with stage I epithelial ovarian cancer compared to fallopian tube cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Rauh-Hain, J. Alejandro; Foley, Olivia W.; Winograd, Dina; Andrade, Carolina; Clark, Rachel M.; Vargas, Roberto J.; Hinchclifff, Emily M.; del Carmen, Marcela G.] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Vargas, Roberto J.; Hinchclifff, Emily M.; Esselen, Katherine M.; Horowitz, Neil S.] Harvard Univ, Brigham & Womens Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 403 EP 403 DI 10.1016/j.ygyno.2014.11.048 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500063 ER PT J AU Rauh-Hain, A Kim, M Zhang, L Foster, R Rueda, B Bhasin, MK Growdon, W AF Rauh-Hain, Alejandro Kim, Minji Zhang, Ling Foster, Rosemary Rueda, Bo Bhasin, Manoj K. Growdon, Whitfield TI Next-generation sequencing demonstrates genomic signature of resistance patterns following phosphatidylinositol 3-kinase (PI3K) inhibition SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Rauh-Hain, Alejandro; Kim, Minji; Zhang, Ling; Foster, Rosemary; Rueda, Bo; Bhasin, Manoj K.; Growdon, Whitfield] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 406 EP 406 DI 10.1016/j.ygyno.2014.11.056 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500071 ER PT J AU Rauh-Hain, JA Gockley, A Clemmer, J Clark, RM Hall, T Growdon, W Goodman, AK Boruta, D Schorge, J del Carman, M AF Rauh-Hain, J. Alejandro Gockley, Allison Clemmer, Joel Clark, Rachel M. Hall, Tracilyn Growdon, Whitfield Goodman, A. K. Boruta, David, II Schorge, John del Carman, Marcela TI The impact of chemotherapy on survival in uterine clear cell carcinoma patients SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 407 EP 408 DI 10.1016/j.ygyno.2014.11.060 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500075 ER PT J AU Vargas, R Rauh-Hain, JA Iafrate, AJ Chung, D Ellisen, L Shannon, K Rodgers, L Oliva, E Schorge, J AF Vargas, Roberto Rauh-Hain, J. Alejandro Iafrate, Anthony John Chung, Daniel Ellisen, Leif Shannon, Kristen Rodgers, Linda Oliva, Esther Schorge, John TI Lynch syndrome screening in endometrial cancer patients with immunohistochemistry: A single center experience SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Vargas, Roberto; Rauh-Hain, J. Alejandro; Iafrate, Anthony John; Chung, Daniel; Ellisen, Leif; Shannon, Kristen; Rodgers, Linda; Oliva, Esther; Schorge, John] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 407 EP 407 DI 10.1016/j.ygyno.2014.11.058 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500073 ER PT J AU Buskwofie, A Rauh-Hain, JA Clemmer, J Clark, RM Hall, T Growdon, WB Goodman, AK Borutall, DM Schorge, JO Del Carmen, MG AF Buskwofie, Ama Rauh-Hain, J. Alejandro Clemmer, Joel Clark, Rachel M. Hall, Tracilyn Growdon, Whitfield B. Goodman, A. K. Borutall, David M. Schorge, John O. Del Carmen, Marcela G. TI Racial disparities and trends in treatment of high-grade endometrial cancer in the medicare population SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Buskwofie, Ama; Rauh-Hain, J. Alejandro; Clemmer, Joel; Clark, Rachel M.; Hall, Tracilyn; Growdon, Whitfield B.; Goodman, A. K.; Borutall, David M.; Schorge, John O.; Del Carmen, Marcela G.] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 409 EP 410 DI 10.1016/j.ygyno.2014.11.066 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500081 ER PT J AU Ghezelayagh, T Growdon, WB AF Ghezelayagh, T. Growdon, W. B. TI The natural history and outcomes of vaginal sarcoma - A Surveillance, Epidemiology, and End Results database analysis SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Ghezelayagh, T.; Growdon, W. B.] Harvard Univ, Massachusetts Gen Hosp, Harvard Sch Publ Hlth, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 409 EP 409 DI 10.1016/j.ygyno.2014.11.064 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500079 ER PT J AU Ngonzi, J Boatin, A Mugyenyi, G Bradford, L Clark, R Wylie, B Goodman, A AF Ngonzi, Joseph Boatin, Adeline Mugyenyi, Godfrey Bradford, Leslie Clark, Rachel Wylie, Blair Goodman, Annekathryn TI Teaching by teleconference: The Massachusetts General Hospital - Ugandan experience SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Ngonzi, Joseph; Boatin, Adeline; Mugyenyi, Godfrey; Bradford, Leslie; Clark, Rachel; Wylie, Blair; Goodman, Annekathryn] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 409 EP 409 DI 10.1016/j.ygyno.2014.11.065 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500080 ER PT J AU Shalowitz, DI Schorge, JO AF Shalowitz, David I. Schorge, John O. TI Anchoring bias in gynecologic oncology SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Shalowitz, David I.; Schorge, John O.] Massachusetts Gen Hosp, Boston, MA 02114 USA. OI Shalowitz, David/0000-0002-5189-4687 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 410 EP 411 DI 10.1016/j.ygyno.2014.11.069 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500084 ER PT J AU Oken, E Baccarelli, AA Gold, DR Kleinman, KP Litonjua, AA De Meo, D Rich-Edwards, JW Rifas-Shiman, SL Sagiv, S Taveras, EM Weiss, ST Belfort, MB Burris, HH Camargo, CA Huh, SY Mantzoros, C Parker, MG Gillman, MW AF Oken, Emily Baccarelli, Andrea A. Gold, Diane R. Kleinman, Ken P. Litonjua, Augusto A. De Meo, Dawn Rich-Edwards, Janet W. Rifas-Shiman, Sheryl L. Sagiv, Sharon Taveras, Elsie M. Weiss, Scott T. Belfort, Mandy B. Burris, Heather H. Camargo, Carlos A., Jr. Huh, Susanna Y. Mantzoros, Christos Parker, Margaret G. Gillman, Matthew W. TI Cohort Profile: Project Viva SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Pregnancy; cohort; obesity; nutrition; childhood ID 3 YEARS POSTPARTUM; GESTATIONAL GLUCOSE-TOLERANCE; FOOD FREQUENCY QUESTIONNAIRE; RANDOMIZED CONTROLLED-TRIAL; SHORT-SLEEP DURATION; LIFE RISK-FACTORS; CHILD COGNITION; BLOOD-PRESSURE; CORD BLOOD; FISH CONSUMPTION AB We established Project Viva to examine prenatal diet and other factors in relation to maternal and child health. We recruited pregnant women at their initial prenatal visit in eastern Massachusetts between 1999 and 2002. Exclusion criteria included multiple gestation, inability to answer questions in English, gestational age >= 22 weeks at recruitment and plans to move away before delivery. We completed in-person visits with mothers during pregnancy in the late first (median 9.9 weeks of gestation) and second (median 27.9 weeks) trimesters. We saw mothers and children in the hospital during the delivery admission and during infancy (median age 6.3 months), early childhood (median 3.2 years) and mid-childhood (median 7.7 years). We collected information from mothers via interviews and questionnaires, performed anthropometric and neurodevelopmental assessments and collected biosamples. We have collected additional information from medical records and from mailed questionnaires sent annually to mothers between in-person visits and to children beginning at age 9 years. From 2341 eligible women, there were 2128 live births; 1279 mother-child pairs provided data at the mid-childhood visit. Primary study outcomes include pregnancy outcomes, maternal mental and cardiometabolic health and child neurodevelopment, asthma/atopy and obesity/cardiometabolic health. Investigators interested in learning more about how to obtain Project Viva data can contact Project_Viva@hphc.org. C1 [Oken, Emily; Kleinman, Ken P.; Rifas-Shiman, Sheryl L.; Gillman, Matthew W.] Harvard Univ, Sch Med, Dept Populat Med, Obes Prevent Program, Boston, MA 02215 USA. [Oken, Emily; Kleinman, Ken P.; Rifas-Shiman, Sheryl L.; Gillman, Matthew W.] Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA. [Baccarelli, Andrea A.; Gold, Diane R.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02215 USA. [Baccarelli, Andrea A.; Rich-Edwards, Janet W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Baccarelli, Andrea A.; Gold, Diane R.; Litonjua, Augusto A.; De Meo, Dawn; Rich-Edwards, Janet W.; Weiss, Scott T.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Rich-Edwards, Janet W.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. [Sagiv, Sharon] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Taveras, Elsie M.; Gillman, Matthew W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02215 USA. [Taveras, Elsie M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Belfort, Mandy B.] Boston Childrens Hosp, Div Newborn Med, Boston, MA USA. [Burris, Heather H.] Beth Israel Deaconess Med Ctr, Dept Neonatol, Boston, MA 02215 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Huh, Susanna Y.] Boston Childrens Hosp, Gastroenterol Hepatol & Nutr, Boston, MA USA. [Mantzoros, Christos] Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. [Parker, Margaret G.] Boston Med Ctr, Div Neonatol, Boston, MA USA. [Parker, Margaret G.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Oken, E (reprint author), Harvard Univ, Sch Med, Dept Populat Med, 133 Brookline Ave, Boston, MA 02215 USA. EM emily_oken@hphc.org OI Baccarelli, Andrea/0000-0002-3436-0640 FU National Institutes of Health [R01 HD 034568, R01 HL 075504, R01 HL 64925, R01 MH 068596, R01 HD 064925, R01 ES 016314, U54 CA155626, R37 HD 034568, R01 AI 102960, R03 DE14004, P30 ES000002]; Centers for Disease Control and Prevention [200-95-0957]; Environmental Protection Agency [RD83479801]; March of Dimes Foundation; Harvard Pilgrim Health Care Foundation; National Institutes of Health. [R21 DK 073739, R21 DK 082661, R01 MD 003963, RC1 HD 063590, R01 HD 034568-0951, R01 ES21447, R01 NR013945, R01 HL111108, K24 HL 068041, K23 HD 044807, T32 DK 081505, K23 DK083817, K24 HD069408, K12 DK094721] FX Project Viva and its team of co-investigators have been funded by grants from the National Institutes of Health (R01 HD 034568, R01 HL 075504, R01 HL 64925, R01 MH 068596, R01 HD 034568, R01 HD 064925, R01 ES 016314, U54 CA155626, R37 HD 034568, R01 AI 102960, R03 DE14004, P30 ES000002, R21 DK 073739, R21 DK 082661, R01 MD 003963, RC1 HD 063590, R01 HD 034568-0951, R01 ES21447, R01 NR013945, R01 HL111108, K24 HL 068041, R01 HL 64925, K23 HD 044807, T32 DK 081505, K23 DK083817, K24 HD069408, K12 DK094721), the Centers for Disease Control and Prevention (200-95-0957), the Environmental Protection Agency (RD83479801), and the March of Dimes Foundation, with additional support from the Harvard Pilgrim Health Care Foundation. NR 66 TC 28 Z9 28 U1 3 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2015 VL 44 IS 1 BP 37 EP 48 DI 10.1093/ije/dyu008 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CD1WC UT WOS:000350864200009 PM 24639442 ER PT J AU Geng, EH Neilands, TB Thiebaut, R Bwana, MB Nash, D Moore, RD Wood, R Zannou, DM Althoff, KN Lim, PL Nachega, JB Easterbrook, PJ Kambugu, A Little, F Nakigozi, G Nakanjako, D Kiggundu, V Li, PCK Bangsberg, DR Fox, MP Prozesky, HW Hunt, PW Davies, MA Reynolds, SJ Egger, M Yiannoutsos, CT Vittinghoff, EV Deeks, SG Martin, JN AF Geng, Elvin H. Neilands, Torsten B. Thiebaut, Rodolphe Bwana, Mwebesa Bosco Nash, Denis Moore, Richard D. Wood, Robin Zannou, Djimon Marcel Althoff, Keri N. Lim, Poh Lian Nachega, Jean B. Easterbrook, Philippa J. Kambugu, Andrew Little, Francesca Nakigozi, Gertrude Nakanjako, Damalie Kiggundu, Valerian Li, Patrick Chung Ki Bangsberg, David R. Fox, Matthew P. Prozesky, Hans W. Hunt, Peter W. Davies, Mary-Ann Reynolds, Steven J. Egger, Matthias Yiannoutsos, Constantin T. Vittinghoff, Eric V. Deeks, Steven G. Martin, Jeffrey N. TI CD4+T cell recovery during suppression of HIV replication: an international comparison of the immunological efficacy of antiretroviral therapy in North America, Asia and Africa SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE HIV; Africa; antiretroviral therapy; CD4+T cell counts; immunological activation ID SUBTYPE-D; INFECTED INDIVIDUALS; VIRAL SUPPRESSION; GENETIC SUBTYPES; COUNT RECOVERY; UGANDA; REDISTRIBUTION; RECOMBINANTS; ACTIVATION; INITIATION AB Background: Even among HIV-infected patients who fully suppress plasma HIV RNA replication on antiretroviral therapy, genetic (e.g. CCL3L1 copy number), viral (e.g. tropism) and environmental (e.g. chronic exposure to microbial antigens) factors influence CD4 recovery. These factors differ markedly around the world and therefore the expected CD4 recovery during HIV RNA suppression may differ globally. Methods: We evaluated HIV-infected adults from North America, West Africa, East Africa, Southern Africa and Asia starting non-nucleoside reverse transcriptase inhibitor-based regimens containing efavirenz or nevirapine, who achieved at least one HIV RNA level <500/mu l in the first year of therapy and observed CD4 changes during HIV RNA suppression. We used a piecewise linear regression to estimate the influence of region of residence on CD4 recovery, adjusting for socio-demographic and clinical characteristics. We observed 28 217 patients from 105 cohorts over 37 825 person-years. Results: After adjustment, patients from East Africa showed diminished CD4 recovery as compared with other regions. Three years after antiretroviral therapy initiation, the mean CD4 count for a prototypical patient with a pre-therapy CD4 count of 150 mu l was 529/mu l [95% confidence interval (Cl): 517-541] in North America, 494/mu l (95% Cl: 429-559) in West Africa, 5150 (95% Cl: 508-522) in Southern Africa, 503/mu l (95% Cl: 478-528) in Asia and 437/mu l (95% Cl: 425-449) in East Africa. Conclusions: CD4 recovery during HIV RNA suppression is diminished in East Africa as compared with other regions of the world, and observed differences are large enough to potentially influence clinical outcomes. Epidemiological analyses on a global scale can identify macroscopic effects unobservable at the clinical, national or individual regional level. C1 [Geng, Elvin H.; Neilands, Torsten B.; Hunt, Peter W.; Vittinghoff, Eric V.; Deeks, Steven G.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94110 USA. [Thiebaut, Rodolphe] Bordeaux Univ, INSERM, U897, Bordeaux, France. [Bwana, Mwebesa Bosco] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Nash, Denis] CUNY, New York, NY 10021 USA. [Moore, Richard D.; Althoff, Keri N.; Reynolds, Steven J.] Johns Hopkins Univ, Baltimore, MD USA. [Wood, Robin; Little, Francesca; Davies, Mary-Ann] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Zannou, Djimon Marcel] Ctr Natl Hosp Univ, Cotonou, Benin. [Lim, Poh Lian] Tan Tock Seng Hosp, Inst Infect Dis, Singapore, Singapore. [Nachega, Jean B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Program Infect Dis, Pittsburgh, PA USA. [Nachega, Jean B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Nachega, Jean B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Nachega, Jean B.] Univ Stellenbosch, Dept Med, Cape Town, South Africa. [Nachega, Jean B.] Univ Stellenbosch, Ctr Infect Dis, Cape Town, South Africa. [Easterbrook, Philippa J.; Kambugu, Andrew; Nakanjako, Damalie] Infect Dis Inst, Kampala, Uganda. [Nakigozi, Gertrude; Kiggundu, Valerian; Reynolds, Steven J.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Li, Patrick Chung Ki] Queen Elizabeth Hosp, Hong Kong, Hong Kong, Peoples R China. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02115 USA. [Fox, Matthew P.] Boston Univ, Ctr Global Hlth & Dev, Boston, MA 02215 USA. [Fox, Matthew P.] Univ Witwatersrand, Fac Hlth Sci, Sch Clin Med, Hlth Econ & Epidemiol Res Off,Dept Internal Med, Johannesburg, South Africa. [Prozesky, Hans W.] Univ Stellenbosch, Dept Med, Div Infect Dis, Cape Town, South Africa. [Prozesky, Hans W.] Tygerberg Acad Hosp, Cape Town, South Africa. [Reynolds, Steven J.] NIAID, Washington, DC USA. [Egger, Matthias] Univ Bern, Bern, Switzerland. [Yiannoutsos, Constantin T.] Indiana Univ, Indianapolis, IN 46204 USA. RP Geng, EH (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, 995 Potrero Ave,Bldg 80,Box 0874, San Francisco, CA 94110 USA. EM genge@php.ucsf.edu OI Prozesky, Hans/0000-0001-9715-3449 FU National Institutes of Health [K23 AI084544, U01 AI069918, U01 AI069919, U01 AI069924, U01 AI069911, U01 AI069907, R01 MH054907, P30 AI027763]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Funding has been provided by the National Institutes of Health [K23 AI084544, U01 AI069918, U01 AI069919, U01 AI069924, U01 AI069911, U01 AI069907, R01 MH054907 and P30 AI027763] and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 38 TC 1 Z9 1 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2015 VL 44 IS 1 BP 251 EP 263 DI 10.1093/ije/dyu271 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CD1WC UT WOS:000350864200033 PM 25859596 ER PT J AU Hyder, JA Hirschberg, RE Nguyen, LL AF Hyder, Joseph A. Hirschberg, Ronald E. Nguyen, Louis L. TI Home Discharge as a Performance Metric for Surgery SO JAMA SURGERY LA English DT Editorial Material C1 [Hyder, Joseph A.] Mayo Clin, Dept Anesthesiol, Div Crit Care Med, Rochester, MN 55905 USA. [Hyder, Joseph A.; Nguyen, Louis L.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Hirschberg, Ronald E.] Massachusetts Gen Hosp, Dept Phys Med & Rehabil Serv, Boston, MA 02114 USA. [Hirschberg, Ronald E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nguyen, Louis L.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Hyder, JA (reprint author), Mayo Clin, Dept Anesthesiol, Div Pulm & Crit Care Med, 200 1st St SW, Rochester, MN 55905 USA. EM hyder.joseph@mayo.edu NR 6 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD FEB PY 2015 VL 150 IS 2 BP 96 EP 97 DI 10.1001/jamasurg.2014.1725 PG 2 WC Surgery SC Surgery GA CC7JF UT WOS:000350542800001 PM 25472699 ER PT J AU Hall, DE Hanusa, BH Stone, RA Ling, BS Arnold, RM AF Hall, Daniel E. Hanusa, Barbara H. Stone, Roslyn A. Ling, Bruce S. Arnold, Robert M. TI Time Required for Institutional Review Board Review at One Veterans Affairs Medical Center SO JAMA SURGERY LA English DT Article ID CLINICAL-TRIALS; MULTICENTER; QUALITY; EVENTS; COSTS AB IMPORTANCE Despite growing concern that institutional review boards (IRBs) impose burdensome delays on research, little is known about the time required for IRB review across different types of research. OBJECTIVE To measure the overall and incremental process times for IRB review as a process of quality improvement. DESIGN, SETTING, AND PARTICIPANTS After developing a detailed process flowchart of the IRB review process, 2 analysts abstracted temporal data from the records pertaining to all 103 protocols newly submitted to the IRB at a large urban Veterans Affairs medical center from June 1, 2009, through May 31, 2011. Disagreements were reviewed with the principal investigator to reach consensus. We then compared the review times across review types using analysis of variance and post hoc Scheffe tests after achieving normally distributed data through logarithmic transformation. MAIN OUTCOMES AND MEASURES Calendar days from initial submission to final approval of research protocols. RESULTS Initial IRB review took 2 to 4 months, with expedited and exempt reviews requiring less time (median [range], 85 [23-631] and 82 [16-437] days, respectively) than full board reviews (median [range], 131 [64-296] days; P = .008). The median time required for credentialing of investigators was 1 day (range, 0-74 days), and review by the research and development committee took a median of 15 days (range, 0-184 days). There were no significant differences in credentialing or research and development times across review types (exempt, expedited, or full board). Of the extreme delays in IRB review, 80.0% were due to investigators' slow responses to requested changes. There were no systematic delays attributable to the information security officer, privacy officer, or IRB chair. CONCLUSIONS AND RELEVANCE Measuring and analyzing review times is a critical first step in establishing a culture and process of continuous quality improvement among IRBs that govern research programs. The review times observed at this IRB are substantially longer than the 60-day target recommended by expert panels. Themethod described here could be applied to other IRBs to begin identifying and improving inefficiencies. C1 [Hall, Daniel E.; Hanusa, Barbara H.; Stone, Roslyn A.; Ling, Bruce S.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. [Hall, Daniel E.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Stone, Roslyn A.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Ling, Bruce S.; Arnold, Robert M.] Univ Pittsburgh, Dept Gen Internal Med, Pittsburgh, PA 15261 USA. RP Hall, DE (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Bldg 30,Univ Dr 151C, Pittsburgh, PA 15240 USA. EM hallde@upmc.edu OI Hall, Daniel/0000-0001-6382-0522 FU US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development [CDA 08-281, SDR 11-399-1] FX This research was supported by grants CDA 08-281 and SDR 11-399-1 from the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development (Dr Hall). NR 14 TC 4 Z9 4 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD FEB PY 2015 VL 150 IS 2 BP 103 EP 109 DI 10.1001/jamasurg.2014.956 PG 7 WC Surgery SC Surgery GA CC7JF UT WOS:000350542800004 PM 25494359 ER PT J AU Buchbinder, D Baker, R Lee, YN Ravell, J Zhang, Y McElwee, J Nugent, D Coonrod, EM Durtschi, JD Augustine, NH Voelkerding, KV Csomos, K Rosen, L Browne, S Walter, JE Notarangelo, LD Hill, HR Kumanovics, A AF Buchbinder, David Baker, Rebecca Lee, Yu Nee Ravell, Juan Zhang, Yu McElwee, Joshua Nugent, Diane Coonrod, Emily M. Durtschi, Jacob D. Augustine, Nancy H. Voelkerding, Karl V. Csomos, Krisztian Rosen, Lindsey Browne, Sarah Walter, Jolan E. Notarangelo, Luigi D. Hill, Harry R. Kumanovics, Attila TI Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE RAG1; RAG deficiency; primary immunodeficiency; severe combined immune deficiency; common variable immunodeficiency disorder; exome sequencing; gene panel ID GRANULOMATOUS-DISEASE; AUTOIMMUNITY; DEFICIENCY; LYMPHOPENIA; CELLS AB Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients. Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients. Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A > G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G > T, p.W522C and (2) c.2689C > T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection. Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments. C1 [Buchbinder, David; Nugent, Diane] UC Irvine, CHOC Childrens Hosp, Pediat Hematol, Orange, CA USA. [Baker, Rebecca; Ravell, Juan; Rosen, Lindsey; Browne, Sarah] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Lee, Yu Nee] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Zhang, Yu] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [McElwee, Joshua] Merck & Co Inc, Merck Res Labs, Boston, MA USA. [Walter, Jolan E.; Notarangelo, Luigi D.] Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Coonrod, Emily M.; Durtschi, Jacob D.; Augustine, Nancy H.; Voelkerding, Karl V.; Hill, Harry R.; Kumanovics, Attila] ARUP Inst Clin & Expt Pathol, Salt Lake City, UT USA. [Augustine, Nancy H.; Voelkerding, Karl V.; Hill, Harry R.; Kumanovics, Attila] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA. [Hill, Harry R.] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT USA. [Hill, Harry R.] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Csomos, Krisztian; Walter, Jolan E.] Harvard Univ, Sch Med, Pediat Allergy & Immunol, Boston, MA USA. [Csomos, Krisztian; Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Buchbinder, David] CHOC Childrens Hosp, Div Hematol, Orange, CA 92868 USA. RP Buchbinder, D (reprint author), CHOC Childrens Hosp, Div Hematol, 1201 La Veta, Orange, CA 92868 USA. EM dbuchbinder@choc.org RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 FU Intramural NIH HHS; NIAID NIH HHS [1K08AI103035-03, 5P01AI076210-04, K08 AI103035, P01 AI076210, U54 AI082973, U54AI082973] NR 22 TC 15 Z9 15 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD FEB PY 2015 VL 35 IS 2 BP 119 EP 124 DI 10.1007/s10875-014-0121-5 PG 6 WC Immunology SC Immunology GA CD2EE UT WOS:000350886300006 PM 25516070 ER PT J AU Stock, C Mathisen, D AF Stock, Cameron Mathisen, Douglas TI THE VATS ADVANTAGE: SEEING IS BELIEVING... AND VICE VERSA Reply SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Letter C1 [Stock, Cameron; Mathisen, Douglas] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Stock, C (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD FEB PY 2015 VL 149 IS 2 BP 647 EP 647 DI 10.1016/j.jtcvs.2014.09.119 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA CC7NA UT WOS:000350553600061 PM 25726890 ER PT J AU Maan, A Heist, EK Ruskin, JN Mansour, M AF Maan, Abhishek Heist, E. Kevin Ruskin, Jeremy N. Mansour, Moussa TI Practical issues in the management of novel oral anticoagulants-cardioversion and ablation SO JOURNAL OF THORACIC DISEASE LA English DT Review DE Novel oral anticoagulants (NOACs); atrial fibrillation (AF); cardioversion; catheter ablation ID NONVALVULAR ATRIAL-FIBRILLATION; ASSAYS LABORATORY RECOMMENDATIONS; THROMBIN INHIBITOR DABIGATRAN; ROCKET AF TRIAL; CATHETER ABLATION; COAGULATION ASSAYS; RADIOFREQUENCY ABLATION; STROKE PREVENTION; COST-EFFECTIVENESS; RENAL IMPAIRMENT AB Recent research and publication of various landmark trials have led to the approval and subsequent use of novel oral anticoagulants (NOACs) in clinical practice. The use of these newer agents for anticoagulation offers several benefits such as greater specificity, relatively rapid onset and offset of action and a predictable pharmacological profile as compared to warfarin. With the increasing use of these agents, several key issues ranging from appropriate selection to management of complications and considerations for concurrent procedures (cardioversion and catheter ablation) have also emerged. The timing of interruption of anticoagulants prior to catheter ablation and re-initiation after the procedure to minimize the peri-procedural thromboembolism risk without increasing the bleeding risk is of key relevance in electrophysiology practice. The use of NOACs in patients undergoing catheter ablation and cardioversion also requires special considerations based on the pharmacological properties of the individual agent and the presence of comorbidities such as renal and or hepatic impairment. In this review we aim to discuss the practical considerations with the use of NOACs in the setting of cardioversion and catheter ablation based on the currently available data. C1 [Maan, Abhishek; Heist, E. Kevin; Ruskin, Jeremy N.; Mansour, Moussa] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Div Electrophysiol, Boston, MA 02114 USA. RP Mansour, M (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. EM mmansour@mgh.harvard.edu FU E. Kevin Heist: Biotronik; Boston Scientific FX E. Kevin Heist: Biotronik (research grant, honoraria), Boston Scientific (research grant, consultant, honoraria), Medtronic (honoraria), Sanofi (consultant), Sorin (consultant, honoraria), St. Jude Medical (research grant, consultant, honoraria); Jeremy N. Ruskin: Astellas/ Cardiome-Consultant (significant); Biosense Webster-Consultant (modest) & Fellowship Support (significant); Boston Scientific-Fellowship Support (significant); CardioFocus-Clinical Oversight Committee (no compensation); CardioInsight-Scientific Advisory Board (modest); CryoCath-Scientific Steering Committee (no compensation); Medtronic-Consultant (modest) & Fellowship Support (significant); Med-IQ-Honoraria (modest); Pfizer-Consultant and Scientific Steering Committee (modest); Portola-Consultant & equity (modest); Sanofi-Consultant (modest), St. Jude Medical-Fellowship Support (significant); Third Rock Ventures-consultant (significant); Moussa Mansour: Biosense-Webster (consultant, research grant), Boston Scientific (research grant), St. Jude (consultant), Cardiofocus (research grant), Endosense (research grant), MC10 (research grant), St. Jude Medical (consultant, research grant), Voyage Medical (research grant). NR 62 TC 6 Z9 6 U1 1 U2 4 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2072-1439 EI 2077-6624 J9 J THORAC DIS JI J. Thorac. Dis. PD FEB PY 2015 VL 7 IS 2 BP 115 EP 131 DI 10.3978/j.issn.2072-1439.2014.11.35 PG 17 WC Respiratory System SC Respiratory System GA CD0AP UT WOS:000350732600001 PM 25713727 ER PT J AU Chenelle, CT Oto, J Sulemanji, D Fisher, DF Kacmarek, RM AF Chenelle, Christopher T. Oto, Jun Sulemanji, Demet Fisher, Daniel F. Kacmarek, Robert M. TI Evaluation of an Automated Endotracheal Tube Cuff Controller During Simulated Mechanical Ventilation SO RESPIRATORY CARE LA English DT Article DE IntelliCuff; endotracheal tube; ETT cuff; cuff pressure; mechanical ventilation; cuff pressure controller ID INTUBATED PATIENTS; PRESSURE; PNEUMONIA; CONSEQUENCES; POSITION; TRACHEA AB BACKGROUND: Maintaining endotracheal tube cuff pressure within a narrow range is an important factor in patient care. The goal of this study was to evaluate the IntelliCuff against the manual technique for maintaining cuff pressure during simulated mechanical ventilation with and without movement. METHODS: The IntelliCuff was compared to the manual technique of a manometer and syringe. Two independent studies were performed during mechanical ventilation: part 1, a 2-h trial incorporating continuous mannikin head movement; and part 2, an 8-h trial using a stationary trachea model. We set cuff pressure to 25 cm H2O, PEEP to 10 cm H2O, and peak inspiratory pressures to 20, 30, and 40 cm H2O. Clinical importance was defined as both statistically significant (P < .05) and clinically significant (pressure change [Delta] > 10%). RESULTS: In part 1, the change in cuff pressure from before to after ventilation was clinically important for the manual technique (P < .001, Delta = 39.6%) but not for the IntelliCuff (P = .02, Delta = 3.5%). In part 2, the change in cuff pressure from before to after ventilation was clinically important for the manual technique (P = .004, Delta = 14.39%) but not for the IntelliCuff (P = .20, Delta = 5.65%). CONCLUSIONS: There was a clinically important drop in manually set cuff pressure during simulated mechanical ventilation in a stationary model and an even larger drop with movement, but this was significantly reduced by the IntelliCuff in both scenarios. Additionally, we observed that cuff pressure varied directly with inspiratory airway pressure for both techniques, leading to elevated average cuff pressures. (C) 2015 Daedalus Enterprises C1 [Chenelle, Christopher T.; Oto, Jun; Sulemanji, Demet; Fisher, Daniel F.; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Oto, Jun; Sulemanji, Demet; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Oto, Jun; Sulemanji, Demet; Kacmarek, Robert M.] Harvard Univ, Sch Med, Boston, MA USA. RP Kacmarek, RM (reprint author), Massachusetts Gen Hosp, Dept Resp Care, Warren Bldg,Room 1225,55 Fruit St, Boston, MA 02114 USA. EM rkacmarek@mgh.harvard.edu OI Chenelle, Christopher/0000-0002-1499-9973 NR 25 TC 3 Z9 3 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD FEB PY 2015 VL 60 IS 2 BP 183 EP 190 DI 10.4187/respcare.03387 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CD2IC UT WOS:000350898900007 PM 25425705 ER PT J AU Fisher, DF Kacmarek, RM AF Fisher, Daniel F. Kacmarek, Robert M. TI Endotracheal Tube Holders and the Prone Position: A Cause for Concern-Reply SO RESPIRATORY CARE LA English DT Letter C1 [Fisher, Daniel F.] Massachusetts Gen Hosp, Resp Care Serv, Boston, MA 02114 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Resp Care Serv, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Sch Med, Boston, MA USA. RP Fisher, DF (reprint author), Massachusetts Gen Hosp, Resp Care Serv, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD FEB PY 2015 VL 60 IS 2 BP E42 EP E42 DI 10.4187/respcare.03980 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CD2IC UT WOS:000350898900030 PM 25634885 ER PT J AU Kiernan, PT Montenigro, PH Solomon, TM McKee, AC AF Kiernan, Patrick T. Montenigro, Philip H. Solomon, Todd M. McKee, Ann C. TI Chronic Traumatic Encephalopathy: A Neurodegenerative Consequence of Repetitive Traumatic Brain Injury SO SEMINARS IN NEUROLOGY LA English DT Article DE chronic traumatic encephalopathy; traumatic brain injury; tauopathy; TDP-43; Alzheimer disease ID CLOSED-HEAD INJURY; RESEARCH DIAGNOSTIC-CRITERIA; FOOTBALL-LEAGUE PLAYER; ALZHEIMERS-DISEASE; AXONAL INJURY; AMYLOID-BETA; MOUSE MODEL; TAU PATHOLOGY; NEUROFIBRILLARY TANGLES; COGNITIVE IMPAIRMENT AB Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that develops as a result of repetitive mild traumatic brain injury. Chronic traumatic encephalopathy is characterized by a unique pattern of accumulation of hyperphosphorylated tau in neurons and astrocytes. The tau abnormalities begin focally and perivascularly at the depths of the cerebral sulci, spread to the superficial layers of the adjacent cortex, and eventually become widespread throughout the medial temporal lobes, diencephalon, and brainstem. Abnormalities in 43 kDa TAR DNA-binding protein are also found in most cases of CTE. To date, CTE can only be diagnosed by postmortem neuropathological examination, although there are many ongoing research studies examining imaging techniques and biomarkers that might prove to have diagnostic utility. Currently, the incidence and prevalence of CTE are unknown, although great strides are being made to better understand the clinical symptoms and signs of CTE. Further research is critically needed to better identify the genetic and environmental risk factors for CTE as well as potential rehabilitation and therapeutic strategies. C1 [Kiernan, Patrick T.; Montenigro, Philip H.; Solomon, Todd M.; McKee, Ann C.] Boston Univ, Chron Traumat Encephalopathy Ctr, Boston, MA 02215 USA. [Montenigro, Philip H.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Solomon, Todd M.; McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Solomon, Todd M.; McKee, Ann C.] Boston Univ, Alzheimers Dis Ctr, Boston, MA 02215 USA. [McKee, Ann C.] VA Boston Healthcare Syst, Jamaica Plain, MA USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol & Lab Sci, Boston, MA 02118 USA. RP McKee, AC (reprint author), VA Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. EM amckee@bu.edu OI Montenigro, Philip/0000-0003-4442-9207 FU National Institute of Neurological Disorders and Stroke [1U01N5086659-01]; Department of Veterans Affairs; Veterans Affairs Biorepository [CSP 501]; Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS); Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence [B6796-C]; National Institute of Aging Boston University Alzheimer's Disease Center [P30AG13846, 0572063345-5]; National Institute of Aging Boston University Framingham Heart Study [R01 (AG1649)]; National Operating Committee on Standards for Athletic Equipment (NOCSAE); Sports Legacy Institute; Andlinger Foundation; WWE (World Wrestling Entertainment); National Football League (NFL) FX The authors gratefully acknowledge the use of the resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA). We also gratefully acknowledge the help of all members of the Chronic Traumatic Encephalopathy Center at Boston University, the Boston VA, as well as the individuals and families whose participation and contributions made this work possible. This work was supported by the National Institute of Neurological Disorders and Stroke (1U01N5086659-01), Department of Veterans Affairs, the Veterans Affairs Biorepository (CSP 501), the Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS), Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B6796-C), the National Institute of Aging Boston University Alzheimer's Disease Center (P30AG13846; supplement 0572063345-5), the National Institute of Aging Boston University Framingham Heart Study R01 (AG1649), the National Operating Committee on Standards for Athletic Equipment (NOCSAE), and the Sports Legacy Institute. This work was also supported by unrestricted gifts from the Andlinger Foundation, the WWE (World Wrestling Entertainment), and the National Football League (NFL). NR 114 TC 5 Z9 5 U1 5 U2 15 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 EI 1098-9021 J9 SEMIN NEUROL JI Semin. Neurol. PD FEB PY 2015 VL 35 IS 1 BP 20 EP 28 DI 10.1055/s-0035-1545080 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CC4AP UT WOS:000350293300005 PM 25714864 ER PT J AU Rao, VR Parko, KL AF Rao, Vikram R. Parko, Karen L. TI Clinical Approach to Posttraumatic Epilepsy SO SEMINARS IN NEUROLOGY LA English DT Article DE traumatic brain injury; epilepsy; posttraumatic epilepsy; seizure; neuromodulation ID TRAUMATIC BRAIN-INJURY; PSYCHOGENIC NONEPILEPTIC SEIZURES; VAGUS NERVE-STIMULATION; TEMPORAL-LOBE EPILEPSY; HEAD-INJURY; REFRACTORY EPILEPSY; CONCUSSIVE CONVULSIONS; NEUROLOGIC EXAMINATION; INTRACTABLE EPILEPSY; AMERICAN-ACADEMY AB Traumatic brain injury (TBI) is one of the most common causes of acquired epilepsy, and posttraumatic epilepsy (PTE) results in significant somatic and psychosocial morbidity. The risk of developing PTE relates directly to TBI severity, but the latency to first seizure can be decades after the inciting trauma. Given this "silent period," much work has focused on identification of molecular and radiographic biomarkers for risk stratification and on development of therapies to prevent epileptogenesis. Clinical management requires vigilant neurologic surveillance and recognition of the heterogeneous endophenotypes associated with PTE. Appropriate treatment of patients who have or are at risk for seizures varies as a function of time after TBI, and the clinician's armamentarium includes an ever-expanding diversity of pharmacological and surgical options. Most recently, neuromodulation with implantable devices has emerged as a promising therapeutic strategy for some patients with refractory PTE. Here, we review the epidemiology, diagnostic considerations, and treatment options for PTE and develop a roadmap for providers encountering this challenging clinical entity. C1 [Rao, Vikram R.; Parko, Karen L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Parko, Karen L.] San Francisco VA Med Ctr, Dept Neurol, San Francisco, CA USA. RP Rao, VR (reprint author), Univ Calif San Francisco, Epilepsy Ctr, 400 Parnassus Ave,8th Floor, San Francisco, CA 94143 USA. EM vikram.rao@ucsf.edu NR 120 TC 4 Z9 4 U1 1 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 EI 1098-9021 J9 SEMIN NEUROL JI Semin. Neurol. PD FEB PY 2015 VL 35 IS 1 BP 57 EP 63 DI 10.1055/s-0035-1544239 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CC4AP UT WOS:000350293300009 PM 25714868 ER PT J AU Jain, S Keys, D Nydam, T Plenter, RJ Edelstein, CL Jani, A AF Jain, Swati Keys, Daniel Nydam, Trevor Plenter, Robert J. Edelstein, Charles L. Jani, Alkesh TI Inhibition of autophagy increases apoptosis during re-warming after cold storage in renal tubular epithelial cells SO TRANSPLANT INTERNATIONAL LA English DT Article DE apoptosis; autophagy; cold storage; re-warming ID KIDNEY-TRANSPLANTATION; INJURY; PRESERVATION; PROTECTS; FAILURE; MICE; RAT; PARTICIPATION; BIOFLAVONOIDS; DEGENERATION AB Prolonged cold storage and re-warming (CS/REW) of kidneys are risk factors for delayed graft function (DGF). Studies in renal tubular epithelial cells (RTECs) have determined apoptosis and autophagy in models of either cold storage (CS) or re-warming alone. The effect of both cold storage and re-warming on apoptosis and autophagy, in RTECS is not known and is relevant to DGF as the kidney is subjected to both CS and re-warming. We hypothesized that CS/REW of RTECs would induce autophagy that protects against apoptosis. In CS/REW, there was increased autophagic flux of RTECs. Autophagy inhibition using an Atg5 siRNA resulted in increased cleaved caspase-3 and increased apoptotic cells (on both morphology and annexin V staining) during CS/REW. The effect of autophagy inhibition on necrosis in RTECs is unknown. There were increased necrosis and caspase-1, a mediator of necrosis, during CS/REW, and the Atg5 siRNA had no effect on necrosis and caspase-1. In a kidney transplant model, there was an increase in LC3 II, a marker of autophagy, in kidneys transplanted after cold storage. In summary, autophagic flux is increased during CS/REW. Autophagy inhibition resulted in increased cleaved caspase-3 and increased apoptosis during CS/REW without an effect on necrosis or caspase-1. In conclusion, autophagy inhibition in RTECs after CS/REW induces apoptotic cell death and may be deleterious as a therapy to decrease DGF. C1 [Jain, Swati; Keys, Daniel; Nydam, Trevor; Plenter, Robert J.; Edelstein, Charles L.; Jani, Alkesh] Univ Colorado, Denver, CO 80202 USA. [Edelstein, Charles L.; Jani, Alkesh] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Edelstein, CL (reprint author), Univ Colorado, Denver Div Renal Dis & Hypertens, 12700 East 19th Ave,C281, Aurora, CO 80045 USA. EM Charles.edelstein@ucdenver.edu FU NIDDK NIH HHS [1 R03 DK96151-01, T32 DK007135] NR 32 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0934-0874 EI 1432-2277 J9 TRANSPL INT JI Transpl. Int. PD FEB PY 2015 VL 28 IS 2 BP 214 EP 223 DI 10.1111/tri.12465 PG 10 WC Surgery; Transplantation SC Surgery; Transplantation GA CD3MQ UT WOS:000350983200012 PM 25270002 ER PT J AU Apolo, AB Hoffman, V Kaag, MG Latini, DM Lee, CT Rosenberg, JE Knowles, M Theodorescu, D Czerniak, BA Efstathiou, JA Albert, ML Sridhar, SS Margulis, V Matin, SF Galsky, MD Hansel, D Kamat, AM Flaig, TW Smith, AB Messing, E Quale, DZ Lotan, Y AF Apolo, Andrea B. Hoffman, Vanessa Kaag, Matthew G. Latini, David M. Lee, Cheryl T. Rosenberg, Jonathan E. Knowles, Margaret Theodorescu, Dan Czerniak, Bogdan A. Efstathiou, Jason A. Albert, Matthew L. Sridhar, Srikala S. Margulis, Vitaly Matin, Surena F. Galsky, Matthew D. Hansel, Donna Kamat, Ashish M. Flaig, Thomas W. Smith, Angela B. Messing, Edward Quale, Diane Zipursky Lotan, Yair TI Summary of the 8th Annual Bladder Cancer Think Tank: Collaborating to move research forward SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Review DE Bladder cancer; BCAN; Think Tank; Targeted therapies; Sexual dysfunction; Gender disparities; Working groups ID TRACT UROTHELIAL CARCINOMA; UPPER URINARY-TRACT; TRANSITIONAL-CELL-CARCINOMA; THERAPY-ONCOLOGY-GROUP; RADICAL CYSTECTOMY; ANDROGEN RECEPTOR; ILEAL NEOBLADDER; SCREENING TRIAL; CLINICAL-TRIAL; LYMPH-NODES AB Objectives: The 8th Annual Bladder Cancer Think Tank (BCAN-TT) brought together a multidisciplinary group of clinicians, researchers, and patient advocates in an effort to advance bladder cancer research. Methods and Materials: With the theme of "Collaborating to Move Research Forward," the meeting included three panel presentations and seven small working groups. Results: The panel presentations and interactive discussions focused on three main areas: gender disparities, sexual dysfunction, and targeting novel pathways in bladder cancer. Small working groups also met to identify projects for the upcoming year, including: (1) improving enrollment and quality of clinical trials; (2) collecting data from multiple institutions for future research; (3) evaluating patterns of care for non-muscle-invasive bladder cancer; (4) improving delivery of care for muscle-invasive disease; (5) improving quality of life for survivors; (6) addressing upper tract disease; and (7) examining the impact of health policy changes on research and treatment of bladder cancer. Conclusions: The goal of the BCAN-TT is to advance the care of patients with bladder cancer and to promote collaborative research throughout the year. The meeting provided ample opportunities for collaboration among clinicians from multiple disciplines, patients and patient advocates, and industry representatives. (C) 2014 Elsevier Inc. All rights reserved. C1 [Apolo, Andrea B.] NCI, Genitourinary Malignancies Branch, Bethesda, MD 20892 USA. [Hoffman, Vanessa; Quale, Diane Zipursky] Bladder Canc Advocacy Network, Bethesda, MD USA. [Kaag, Matthew G.] Penn State Hershey Med Ctr, Dept Urol, Hershey, PA USA. [Latini, David M.] Baylor Coll Med, Dept Urol, Houston, TX 77030 USA. [Lee, Cheryl T.] Univ Michigan Hlth Syst, Dept Urol, Ann Arbor, MI USA. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Knowles, Margaret] Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England. [Theodorescu, Dan] Univ Colorado, Ctr Canc, Denver, CO 80202 USA. [Czerniak, Bogdan A.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Efstathiou, Jason A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Albert, Matthew L.] Inst Pasteur, Dept Immunol, F-75724 Paris, France. [Sridhar, Srikala S.] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Margulis, Vitaly; Lotan, Yair] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Matin, Surena F.; Kamat, Ashish M.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Galsky, Matthew D.] Mt Sinai Hosp, Dept Med Oncol, New York, NY 10029 USA. [Hansel, Donna] Univ Calif La Jolla, Dept Pathol, San Diego, CA USA. [Smith, Angela B.] Univ N Carolina, Dept Urol, Chapel Hill, NC USA. [Messing, Edward] Univ Rochester, Med Ctr, Dept Urol, Rochester, NY 14642 USA. RP Lotan, Y (reprint author), Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. EM yair.lotan@utsouthwestern.edu OI Latini, David/0000-0002-6161-4861; Rosenberg, Jonathan/0000-0003-2637-4249 NR 66 TC 2 Z9 2 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD FEB PY 2015 VL 33 IS 2 BP 53 EP 64 DI 10.1016/j.urolonc.2014.06.013 PG 12 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CD0PV UT WOS:000350777300001 PM 25065704 ER PT J AU Tsai, AC AF Tsai, Alexander C. TI Socioeconomic Gradients in Internalized Stigma Among 4,314 Persons with HIV in Sub-Saharan Africa SO AIDS AND BEHAVIOR LA English DT Article DE Social stigma; Social discrimination; HIV; Africa South of the Sahara; Social class ID AIDS-RELATED STIGMA; ANTIDEPRESSANT MEDICATION TREATMENT; ANTIRETROVIRAL THERAPY CARE; POISSON REGRESSION APPROACH; TO-CHILD TRANSMISSION; RURAL UGANDA; SOUTH-AFRICA; EDUCATIONAL-ATTAINMENT; HIV/AIDS STIGMA; CAPE-TOWN AB The stigma attached to HIV is a major public health problem given its adverse impacts on HIV prevention and on the psychosocial wellbeing of persons with HIV. In this study, I apply a novel method to data from the Demographic and Health Surveys to identify persons with HIV who were aware of their seropositivity at the time of the survey. The pooled dataset includes 4,314 persons with HIV in Cameroon, Ethiopia, Gabon, Kenya, Lesotho, Malawi, Rwanda, Swaziland, Tanzania, Uganda, Zambia, and Zimbabwe. My findings indicate that nearly one-fifth of study participants provided survey responses consistent with internalization of stigmatizing beliefs. Furthermore, in multivariable regression models, striking socioeconomic gradients in internalized stigma were observed. A clear implication of my findings is that the adverse health and psychosocial impacts of HIV stigma are likely concentrated among those with the fewest socioeconomic resources for managing and resisting it. C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Tsai, Alexander C.] Harvard Univ, Sch Med, Boston, MA USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org OI Tsai, Alexander/0000-0001-6397-7917 FU U.S. National Institutes of Health [K23MH096620]; Robert Wood Johnson Health and Society Scholars Program FX I received no specific funding for the conduct of this study. I acknowledge salary support from U.S. National Institutes of Health K23MH096620 and the Robert Wood Johnson Health and Society Scholars Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 101 TC 11 Z9 11 U1 2 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD FEB PY 2015 VL 19 IS 2 BP 270 EP 282 DI 10.1007/s10461-014-0993-7 PG 13 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CC4UL UT WOS:000350349300007 PM 25572833 ER PT J AU Menendez, ME Ring, D AF Menendez, Mariano E. Ring, David TI Factors associated with hospital admission for proximal humerus fracture SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID EMERGENCY-DEPARTMENT SAMPLE; UNITED-STATES; RATES; EPIDEMIOLOGY; INSURANCE; SURGERY; INJURY; AGE AB Background: The number of inpatient admissions for proximal humerus fracture is increasing, but the factors that determine hospitalization are not well documented. We sought to identify predictors of hospital admission among individuals presenting to the emergency department (ED) with a fracture of the proximal humerus. Methods: Using the Nationwide Emergency Department Sample for 2010 and 2011, an estimated 285661 patients were identified and separated into those who were admitted to hospital (19%) and those who were discharged directly home (81%). Multivariable logistic regression modeling was used to identify independent predictors of hospital admission. Results: Factors associated with admission included increasing age and Charlson comorbidity index, ED visit on a weekday, Medicare and Medicaid insurance, open fracture, injury due to motor vehicle crash, polytrauma, urban teaching hospital, and residence in the Northeast. The lowest ratio of hospital admission to home discharge was noted for uninsured patients (0.09). Discussion: Factors unrelated to medical complexity such as insurance status, geographic region, timing of ED visit, and hospital type are associated with inpatient admission for proximal humerus fracture. Interventions to reduce variation in hospital admission and the influence of nonclinical factors merit attention. (C) 2014 Elsevier Inc. All rights reserved. C1 [Menendez, Mariano E.; Ring, David] Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Menendez, ME (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM marianofurrer@gmail.com; dring@mgh.harvard.edu NR 25 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD FEB PY 2015 VL 33 IS 2 BP 155 EP 158 DI 10.1016/j.ajem.2014.10.045 PG 4 WC Emergency Medicine SC Emergency Medicine GA CC6AW UT WOS:000350447900004 PM 25467892 ER PT J AU Edla, S Reisner, AT Liu, JB Convertino, VA Carter, R Reifman, J AF Edla, Shwetha Reisner, Andrew T. Liu, Jianbo Convertino, Victor A. Carter, Robert, III Reifman, Jaques TI Is heart rate variability better than routine vital signs for prehospital identification of major hemorrhage? SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID TRAUMA PATIENTS; LIFESAVING INTERVENTIONS; PERIOD VARIABILITY; RATE COMPLEXITY; COMBAT CASUALTIES; RATE RESPONSE; PREDICTION; MORTALITY; TRANSPORT; CAUTIONS AB Objective: During initial assessment of trauma patients, metrics of heart rate variability (HRV) have been associated with high- risk clinical conditions. Yet, despite numerous studies, the potential of HRV to improve clinical outcomes remains unclear. Our objectivewas to evaluate whether HRV metrics provide additional diagnostic information, beyond routine vital signs, for making a specific clinical assessment: identification of hemorrhaging patients who receive packed red blood cell (PRBC) transfusion. Methods: Adult prehospital trauma patients were analyzed retrospectively, excluding those who lacked a complete set of reliable vital signs and a clean electrocardiogram for computation of HRV metrics. We also excluded patients who did not survive to admission. The primary outcome was hemorrhagic injury plus different PRBC transfusion volumes. We performed multivariate regression analysis using HRV metrics and routine vital signs to test the hypothesis that HRV metrics could improve the diagnosis of hemorrhagic injury plus PRBC transfusion vs routine vital signs alone. Results: As univariate predictors, HRV metrics in a data set of 402 subjects had comparable areas under receiver operating characteristic curves compared with routine vital signs. In multivariate regression models containing routine vital signs, HRV parameters were significant (P<.05) but yielded areas under receiver operating characteristic curves with minimal, nonsignificant improvements (+0.00 to +0.05). Conclusions: A novel diagnostic test should improve diagnostic thinking and allowfor better decision making in a significant fraction of cases. Our findings do not support that HRV metrics add value over routine vital signs in terms of prehospital identification of hemorrhaging patients who receive PRBC transfusion. Published by Elsevier Inc. C1 [Edla, Shwetha; Liu, Jianbo; Reifman, Jaques] US Army, Med Res & Mat Command, Telemed & Adv Technol Res Ctr, Software Applicat Inst,Dept Def Biotechnol High P, Ft Detrick, MD 21702 USA. [Reisner, Andrew T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Convertino, Victor A.; Carter, Robert, III] US Army, Inst Surg Res, Ft Sam Houston, TX 78234 USA. RP Reifman, J (reprint author), US Army, Med Res & Mat Command, Telemed & Adv Technol Res Ctr, ATTN MCMR TT,Software Applicat Inst,Dept Def Biot, 504 Scott St, Ft Detrick, MD 21702 USA. EM jaques.reifman.civ@mail.mil FU US Department of Defense Medical Research and Development Program [D10_I_AR_J6_773]; Combat Casualty Care Research Area Directorate of the US Army Medical Research and Materiel Command, Fort Detrick, MD, USA FX This work was supported by the US Department of Defense Medical Research and Development Program (grant no. D10_I_AR_J6_773) and by the Combat Casualty Care Research Area Directorate of the US Army Medical Research and Materiel Command, Fort Detrick, MD, USA. The study sponsors did not have any role in the study design, data collection, analysis and interpretation of data, report writing, or the decision to submit the article for publication. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army or of the US Department of Defense. This article has been approved for public release with unlimited distribution. NR 42 TC 2 Z9 2 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD FEB PY 2015 VL 33 IS 2 BP 254 EP 261 DI 10.1016/j.ajem.2014.11.046 PG 8 WC Emergency Medicine SC Emergency Medicine GA CC6AW UT WOS:000350447900022 PM 25534122 ER PT J AU Tanner, CM Comella, CL AF Tanner, Caroline M. Comella, Cynthia L. TI When brawn benefits brain: physical activity and Parkinson's disease risk SO BRAIN LA English DT Editorial Material C1 [Tanner, Caroline M.] Univ Calif San Francisco, Parkinsons Dis Res Educ & Clin Ctr, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Tanner, Caroline M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Comella, Cynthia L.] Rush Presbyterian St Lukes Med Ctr, Neurol Sci, Chicago, IL USA. RP Tanner, CM (reprint author), Univ Calif San Francisco, Parkinsons Dis Res Educ & Clin Ctr, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. EM caroline.tanner@ucsf.edu FU NCATS NIH HHS [U54 TR001456]; NINDS NIH HHS [U54 NS065701, R01NS074343, U54NS065701] NR 10 TC 3 Z9 3 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD FEB 1 PY 2015 VL 138 BP 238 EP 239 DI 10.1093/brain/awu351 PN 2 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CC2YA UT WOS:000350209900012 PM 25627233 ER PT J AU Fling, BW Nutt, JG Horak, FB AF Fling, Brett W. Nutt, John G. Horak, Fay B. TI Reply: Does dominant pedunculopontine nucleus exist? SO BRAIN LA English DT Letter ID PARKINSONS-DISEASE; GAIT; CONNECTIVITY; INHIBITION C1 [Fling, Brett W.; Nutt, John G.; Horak, Fay B.] Oregon Hlth & Sci Univ, Dept Neurol, Sch Med, Portland, OR 97239 USA. [Fling, Brett W.; Horak, Fay B.] Portland VA Med Ctr, Portland, OR 97239 USA. RP Fling, BW (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Sch Med, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM fling@ohsu.edu FU NIA NIH HHS [R01 AG006457]; RRD VA [I01 RX001075] NR 15 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD FEB 1 PY 2015 VL 138 AR e324 DI 10.1093/brain/awu226 PN 2 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CC2YA UT WOS:000350209900002 PM 25125613 ER PT J AU Reed, GW Kumar, A Guo, JP Aranki, S Shekar, P Agnihotri, A Maree, AO McLean, DS Rosenfield, K Cannon, CP AF Reed, Grant W. Kumar, Amit Guo, Jianping Aranki, Sary Shekar, Prem Agnihotri, Arvind Maree, Andrew O. McLean, Dalton S. Rosenfield, Kenneth Cannon, Christopher P. TI Point-of-Care Platelet Function Testing Predicts Bleeding in Patients Exposed to Clopidogrel Undergoing Coronary Artery Bypass Grafting: Verify Pre-Op TIMI 45-A Pilot Study SO CLINICAL CARDIOLOGY LA English DT Article ID ST-SEGMENT ELEVATION; ANTIPLATELET THERAPY; THORACIC SURGEONS; CARDIOVASCULAR-ANESTHESIOLOGISTS; PRACTICE GUIDELINES; HEALTHY-VOLUNTEERS; MYOCARDIAL DAMAGE; CARDIAC-SURGERY; INTERVENTION; REACTIVITY AB BackgroundGuidelines recommend delaying coronary artery bypass grafting (CABG) for 5 days after discontinuing clopidogrel. However, platelet function may recover quicker in certain individuals. HypothesisWe hypothesized that perioperative measurement of platelet function with a point-of-care P2Y(12) inhibitor assay could predict bleeding during CABG in patients exposed to clopidogrel. MethodsVerify Pre-Op TIMI 45 was a prospective pilot study of 39 patients on clopidogrel who subsequently underwent CABG. Preoperative on-treatment platelet reactivity was assessed with VerifyNow P2Y(12) Reaction Units (PRU), with higher PRU indicating more reactive platelets. Outcomes were stratified by PRU quartiles, as well as prespecified cutpoints for the lowest quartile (PRU 173), a cutpoint for major bleeding determined by the Youden index using receiver operator curve analysis (PRU 207), and clopidogrel resistance (PRU 230). ResultsPatients in higher PRU quartiles experienced smaller decreases in hemoglobin and hematocrit (P<0.05 for all comparisons), less major bleeding (P=0.021), and less major or minor bleeding (P=0.003). Patients above the PRU 207 and 230 cutpoints had less chest-tube output (P=0.041 and P=0.012, respectively), less major bleeding (P=0.005 and P=0.036, respectively), and less major or minor bleeding (P=0.013 and P<0.001, respectively). By receiver operator curve analysis, preoperative PRU207 discriminated between patients with and without major bleeding during surgery (area under the curve: 0.76, 95% confidence interval: 0.59-0.94, P=0.018). ConclusionsIn this pilot study, we found that point-of-care platelet function assessment could predict bleeding in patients recently exposed to clopidogrel undergoing CABG. C1 [Reed, Grant W.; Guo, Jianping; Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Reed, Grant W.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44195 USA. [Kumar, Amit] Brown Univ, Dept Cardiovasc Med, Providence, RI 02912 USA. [Aranki, Sary; Shekar, Prem] Brigham & Womens Hosp, Div Cardiac Surg, Boson, MA USA. [Agnihotri, Arvind] St Elizabeths Med Ctr, Dept Surg, Brighton, MA USA. [Maree, Andrew O.] St James Hosp, Div Cardiol, Dublin 8, Ireland. [McLean, Dalton S.] LeBauer Cardiol, Greensboro, NC USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Reed, GW (reprint author), Cleveland Clin, Dept Cardiovasc Med, 9500 Euclid Ave,Desk J3-6, Cleveland, OH 44195 USA. EM reedg2@ccf.org FU Accumetrics; Arisaph; AstraZeneca; Boehringer-Ingelheim; Janssen; GlaxoSmithKline; Merck; Takeda; BMS; CSL Behring; Essentialis; Lipimedix; Pfizer; Regeneron; Sanofi FX The study is supported by Accumetrics. Dr. Cannon reports research grants from Accumetrics, Arisaph, AstraZeneca, Boehringer-Ingelheim, and Janssen; grants and personal fees from GlaxoSmithKline, Merck, and Takeda; and consulting fees from BMS, CSL Behring, Essentialis, Lipimedix, Pfizer, Regeneron, and Sanofi. Arvnid Agnihotri - Consultant (proctor) and Advisory Board, Edwards Lifesciences. Andrew O. Maree - Speakers bureau Daichi Sankyo and Boehringer Ingelheim, and Advisory Board, Abbott Vascular. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 29 TC 12 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 EI 1932-8737 J9 CLIN CARDIOL JI Clin. Cardiol. PD FEB PY 2015 VL 38 IS 2 BP 92 EP 98 DI 10.1002/clc.22357 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CC4EA UT WOS:000350302400005 PM 25655085 ER PT J AU Flores-Blanco, PJ Manzano-Fernandez, S Perez-Calvo, JI Pastor-Perez, FJ Ruiz-Ruiz, FJ Carrasco-Sanchez, FJ Morales-Rull, JL Pascual-Figal, D Galisteo-Almeda, L Januzzi, JL AF Flores-Blanco, Pedro J. Manzano-Fernandez, Sergio Perez-Calvo, Juan I. Pastor-Perez, Francisco J. Ruiz-Ruiz, Francisco J. Carrasco-Sanchez, Francisco J. Morales-Rull, Jose L. Pascual-Figal, Domingo Galisteo-Almeda, Luis Januzzi, James L. TI Cystatin C-based CKD-EPI Equations and N-Terminal Pro-B-Type Natriuretic Peptide for Predicting Outcomes in Acutely Decompensated Heart Failure SO CLINICAL CARDIOLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; WORSENING RENAL-FUNCTION; EMERGENCY-DEPARTMENT PRIDE; CHRONIC KIDNEY-DISEASE; IN-HOSPITAL MORTALITY; SERUM CREATININE; CARDIORENAL SYNDROME; ESTIMATING GFR; DIAGNOSIS; MARKER AB BackgroundIn patients with acute decompensated heart failure (ADHF), both natriuretic peptides and renal impairment predict adverse outcomes. Our aim was to evaluate the complementary prognosis role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the newly developed Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations based on cystatin C (CysC) for glomerular filtration rate (GFR) estimation in ADHF patients. HypothesisRenal impairment assessed by CysC-based CKD-EPI equations and natriuretic peptides have complementary prognostic value in ADHF patients. MethodsThe study included 613 consecutive patients presenting with ADHF. At admission, plasma levels of NT-proBNP and CysC were determined. The GFR was estimated using CysC-based CKD-EPI equations. The primary endpoint was death from any cause and heart failure readmission. ResultsDuring the median follow-up of 365 days (interquartile range, 227-441 days), 323 patients (0.65 %patient-year) died or were readmitted for heart failure. After multivariate adjustment, estimated GFR <60 mL/min/1.73m(2) and NT-proBNP >3251pg/mL were independent predictors of adverse outcomes (P < 0.01). The combination of GFR <60 mL/min/1.73m(2) and NT-proBNP >3251pg/mL was associated with the highest risk of adverse outcomes. Furthermore, reclassification analyses demonstrated that use of both NT-proBNP and CysC-based CKD-EPI equations resulted in improving the accuracy for adverse outcomes prediction. ConclusionsIn patients with ADHF, the combination of NT-proBNP with estimated GFR using CysC-based CKD-EPI equations better predicts outcomes than either parameter alone and adds valuable complementary prognosis information to other established risk factors. C1 [Flores-Blanco, Pedro J.; Manzano-Fernandez, Sergio; Pastor-Perez, Francisco J.; Pascual-Figal, Domingo] Univ Murcia, Sch Med, Div Cardiol, Univ Hosp Virgen de la Arrixaca, Murcia 30120, Spain. [Perez-Calvo, Juan I.; Ruiz-Ruiz, Francisco J.] Univ Zaragoza, Sch Med, Clin Univ Hosp Lozano Blesa, Dept Internal Med, Zaragoza, Spain. [Perez-Calvo, Juan I.] Hosp Juan Ramon Jimenez, Inst Hlth Res, Huelva, Spain. [Carrasco-Sanchez, Francisco J.] Hosp Juan Ramon Jimenez, Dept Internal Med, Huelva, Spain. [Morales-Rull, Jose L.] Univ Hosp Arnau de Vilanova, Dept Internal Med, Lerida, Spain. [Galisteo-Almeda, Luis] Hosp Juan Ramon Jimenez, Dept Clin Biochem & Lab, Huelva, Spain. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Manzano-Fernandez, S (reprint author), Univ Murcia, Sch Med, Div Cardiol, Univ Hosp Virgen de la Arrixaca, Carretera Madrid Cartagena S-N, Murcia 30120, Spain. EM sergiosmf13@hotmail.com OI Pascual Figal, Domingo A./0000-0002-4993-9540 NR 40 TC 3 Z9 4 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 EI 1932-8737 J9 CLIN CARDIOL JI Clin. Cardiol. PD FEB PY 2015 VL 38 IS 2 BP 106 EP 113 DI 10.1002/clc.22362 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CC4EA UT WOS:000350302400007 PM 25663560 ER PT J AU Ughi, GJ Verjans, J Fard, AM Wang, H Osborn, E Hara, T Mauskapf, A Jaffer, FA Tearney, GJ AF Ughi, Giovanni J. Verjans, Johan Fard, Ali M. Wang, Hao Osborn, Eric Hara, Tetsuya Mauskapf, Adam Jaffer, Farouc A. Tearney, Guillermo J. TI Dual modality intravascular optical coherence tomography (OCT) and near-infrared fluorescence (NIRF) imaging: a fully automated algorithm for the distance-calibration of NIRF signal intensity for quantitative molecular imaging SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Optical coherence tomography; Optical frequency-domain imaging; Near-infrared fluorescence ID IN-VIVO; VALIDATION; STENTS AB Intravascular optical coherence tomography (IVOCT) is a well-established method for the high-resolution investigation of atherosclerosis in vivo. Intravascular near-infrared fluorescence (NIRF) imaging is a novel technique for the assessment of molecular processes associated with coronary artery disease. Integration of NIRF and IVOCT technology in a single catheter provides the capability to simultaneously obtain co-localized anatomical and molecular information from the artery wall. Since NIRF signal intensity attenuates as a function of imaging catheter distance to the vessel wall, the generation of quantitative NIRF data requires an accurate measurement of the vessel wall in IVOCT images. Given that dual modality, intravascular OCT-NIRF systems acquire data at a very high frame-rate (> 100 frames/s), a high number of images per pullback need to be analyzed, making manual processing of OCT-NIRF data extremely time consuming. To overcome this limitation, we developed an algorithm for the automatic distance-correction of dual-modality OCT-NIRF images. We validated this method by comparing automatic to manual segmentation results in 180 in vivo images from six New Zealand White rabbit atherosclerotic after indocyanine-green injection. A high Dice similarity coefficient was found (0.97 +/- A 0.03) together with an average individual A-line error of 22 A mu m (i.e., approximately twice the axial resolution of IVOCT) and a processing time of 44 ms per image. In a similar manner, the algorithm was validated using 120 IVOCT clinical images from eight different in vivo pullbacks in human coronary arteries. The results suggest that the proposed algorithm enables fully automatic visualization of dual modality OCT-NIRF pullbacks, and provides an accurate and efficient calibration of NIRF data for quantification of the molecular agent in the atherosclerotic vessel wall. C1 [Ughi, Giovanni J.; Fard, Ali M.; Wang, Hao; Jaffer, Farouc A.; Tearney, Guillermo J.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Ughi, Giovanni J.; Verjans, Johan; Fard, Ali M.; Wang, Hao; Osborn, Eric; Hara, Tetsuya; Mauskapf, Adam; Jaffer, Farouc A.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Verjans, Johan; Osborn, Eric; Hara, Tetsuya; Mauskapf, Adam; Jaffer, Farouc A.] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Verjans, Johan; Osborn, Eric; Hara, Tetsuya; Mauskapf, Adam; Jaffer, Farouc A.] Harvard Univ, Sch Med, Div Cardiol, Boston, MA USA. [Verjans, Johan] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands. [Wang, Hao] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Osborn, Eric] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Tearney, Guillermo J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Tearney, Guillermo J.] Harvard Massachusetts Inst Technol Hlth Sci & Tec, Cambridge, MA USA. RP Ughi, GJ (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. EM giovanni.ughi@mgh.harvard.edu; tearney@helix.mgh.harvard.edu OI Ughi, Giovanni J./0000-0003-3354-0698 FU NIH [R01HL093717, R01HL108229]; AHA [13GRNT1760040]; MGH SPARK Award; Bullock-Wellman Fellowship Award/Harvard Medical School and Massachusetts General Hospital; Harvard Catalyst NIH [1UL1 TR001102-01]; Netherlands Organization for Scientific Research [825.12.013]; Merck FX NIH R01HL093717 (GJT-development of imaging system), R01HL108229 (FAJ), AHA Grant-in-Aid 13GRNT1760040 (FAJ), MGH SPARK Award, Bullock-Wellman Fellowship Award/Harvard Medical School and Massachusetts General Hospital (GJU), Harvard Catalyst NIH 1UL1 TR001102-01 (EO), Rubicon Grant 825.12.013/Netherlands Organization for Scientific Research (JV), and Merck (GJT and FAJ). NR 25 TC 14 Z9 15 U1 3 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 EI 1573-0743 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD FEB PY 2015 VL 31 IS 2 BP 259 EP 268 DI 10.1007/s10554-014-0556-z PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CC6MK UT WOS:000350479000006 PM 25341407 ER PT J AU Deniger, A Troller, P Kennelty, KA AF Deniger, Amanda Troller, Peggy Kennelty, Korey A. TI Geriatric Transitional Care and Readmissions Review SO JNP-JOURNAL FOR NURSE PRACTITIONERS LA English DT Review DE 30 days; care coordination; discharge; geriatrics; nurse; nurse practitioner; readmissions; transitional care; transitions AB Geriatric patients are a highly vulnerable population and are at increased risk for hospital admission and readmission. A university hospital implemented the Geriatric Transitional Care program, aimed at improving quality of care and reducing 30-day hospital readmission rates. Enrolled patients received telephone calls, and, if there was high risk for readmission, home visits from a nurse practitioner. Twenty-six (6.6%) inpatient-to-inpatient readmissions occurred, which was a 48% reduction from the hospital-wide readmission rate. Causes of readmissions fell into 6 categories. Transitional care can reduce frequency, serve as a point of contact, and monitor discharge follow-up. C1 [Deniger, Amanda; Troller, Peggy] Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. [Kennelty, Korey A.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Kennelty, Korey A.] Univ Wisconsin, Sch Pharm, Madison, WI 53706 USA. RP Deniger, A (reprint author), Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. EM adeniger@uwhealth.org FU University of Wisconsin Hospital and Clinics FX The authors thank the University of Wisconsin Hospital and Clinics, specifically Dr. Steven Barczi, Dr. Amy Kind, Julie Christofferson, Kathy Scott, Donna Cole, and Maria Brenny-Fitzpatrick, for guidance and support through the development and implementation of the program. NR 4 TC 1 Z9 1 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1555-4155 EI 1878-058X J9 JNP-J NURSE PRACT JI JNP-J. Nurse Pract. PD FEB PY 2015 VL 11 IS 2 BP 248 EP 252 DI 10.1016/j.nurpra.2014.08.014 PG 5 WC Nursing SC Nursing GA CC7IA UT WOS:000350539700022 ER PT J AU Huttner, B Jones, M Madaras-Kelly, K Neuhauser, MM Rubin, MA Goetz, MB Samore, MH AF Huttner, Benedikt Jones, Makoto Madaras-Kelly, Karl Neuhauser, Melinda M. Rubin, Michael A. Goetz, Matthew Bidwell Samore, Matthew H. TI Initiation and termination of antibiotic regimens in Veterans Affairs hospitals SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE antibiotic use; practice variation; infectious diseases ID ANTIBACTERIAL DRUG-USE; CONSUMPTION AB Objectives: To assess rates of starting or stopping antibiotics across different hospitals. Methods: We used barcode medication administration data to measure antibiotic use on acute-care wards in 128 Veterans Affairs medical centres (VAMCs) in 2010. A treatment day (TD) was defined as the administration of any antibiotic on a given day. A treatment period (TP) was defined as an interval of inpatient antimicrobial therapy with gaps of <= 1 day in TDs. The rate of starting antibiotics was calculated for inpatients who had not yet started antibiotics, as the number of start events divided by the 'person-time at risk'. The rate of stopping antibiotics was calculated analogously for inpatients that were on antibiotics. Once individuals had stopped antibiotics they were removed from further analysis. Per-day start and stop rates were also calculated for each day of hospitalization. Results: The hospital mean rate of starting the first TP was 18.1 start events/100 days at risk (range 8.4-25.6/100 days at risk). The mean hospital stopping rate was 21.1 stop events/100 days at risk (range 13.3-29.5/100 days at risk). The ratio of a facility's starting and stopping rates was highly correlated with overall antibiotic use in TDs/1000 patient-days (r(s) = 0.92, P<0.001), while starting and stopping rates individually were only moderately correlated (r(s) = 0.39, P<0.001). Conclusions: VAMCs with similar antibiotic use showed marked differences in their starting and stopping rates of antibiotics. It may be useful to target empirical therapy when starting rates are high and definitive therapy when stopping rates are low. C1 [Huttner, Benedikt; Jones, Makoto; Rubin, Michael A.; Samore, Matthew H.] VA Salt Lake City Hlth Care Syst, IDEAS Ctr, Salt Lake City, UT 84148 USA. [Huttner, Benedikt; Jones, Makoto; Rubin, Michael A.; Samore, Matthew H.] Univ Utah, Div Epidemiol, Salt Lake City, UT 84132 USA. [Madaras-Kelly, Karl] Boise VA Med Ctr, Boise, ID 83702 USA. [Madaras-Kelly, Karl] Idaho State Univ, Coll Pharm, Meridian, ID 83713 USA. [Neuhauser, Melinda M.] Dept Vet Affairs Pharm Benefit Management Serv, Hines, IL USA. [Goetz, Matthew Bidwell] VA Greater LA Healthcare Syst, Los Angeles, CA 90073 USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. RP Huttner, B (reprint author), VA Salt Lake City Hlth Care Syst, 500 Foothill Dr, Salt Lake City, UT 84148 USA. EM makoto.jones@va.gov RI Huttner, Benedikt/M-5616-2014; OI Huttner, Benedikt/0000-0002-1749-9464; Goetz, Matthew/0000-0003-4542-992X FU VA Informatics and Computing Infrastructure [VA HSR HIR 08-204]; Consortium for Healthcare Informatics Research [VA HSR HIR 08-374]; Centers for Disease Control and Prevention's Prevention Epicenters Program [5U01CI000334, 07FED706504]; career development award [CDA 10-030-02]; Geneva University Hospitals, Switzerland FX This work was supported by: the VA Informatics and Computing Infrastructure (grant number VA HSR HIR 08-204); the Consortium for Healthcare Informatics Research (grant number VA HSR HIR 08-374); the Centers for Disease Control and Prevention's Prevention Epicenters Program (grant numbers 5U01CI000334 and 07FED706504); a career development award (CDA 10-030-02 to M. J.); and a fellowship grant from Geneva University Hospitals, Switzerland (to B. H.). NR 11 TC 1 Z9 1 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 EI 1460-2091 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD FEB PY 2015 VL 70 IS 2 BP 598 EP 601 DI 10.1093/jac/dku388 PG 4 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA CC2YR UT WOS:000350211600035 PM 25288680 ER PT J AU Barnes, SM Russell, LM Hostetter, TA Forster, JE Devore, MD Brenner, LA AF Barnes, Sean M. Russell, Leah M. Hostetter, Trisha A. Forster, Jeri E. Devore, Maria D. Brenner, Lisa A. TI Characteristics of Traumatic Brain Injuries Sustained Among Veterans Seeking Homeless Services SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Traumatic brain injuries; homeless; Veterans ID PEOPLE; HEALTH AB This hypothesis-generating research describes the characteristics of traumatic brain injuries (TBIs) sustained among 229 Veterans seeking homeless services. Nearly all participants (83%) had sustained at least one TBI prior to their first episode of homelessness. Among participants with a TBI, assaults, transportation-related accidents, and falls were the most common causes of these injuries. Thirty percent of individuals sustained injuries with severity levels that would be expected to be associated with ongoing TBI-related deficits. Forty-three percent of the Veterans sustained at least one brain injury following their first episode of homelessness. Median lifetime number of TBIs was three. The severity of TBIs was similar among Veterans who sustained injuries before or after their first incident of homelessness. Findings suggest that future research should directly examine the potential bi-directional relationship between TBI and homelessness, as well as the impact of TBI-related deficits on Veterans' ability to benefit from homeless services and/or maintain stable housing. C1 [Barnes, Sean M.; Russell, Leah M.; Hostetter, Trisha A.; Forster, Jeri E.; Devore, Maria D.; Brenner, Lisa A.] Vet Integrated Serv Network 19 Mental Illness Res, Denver, CO USA. RP Barnes, SM (reprint author), Denver VA Med Ctr, MIRECC, 1055 Clermont St, Denver, CO 80220 USA. EM Sean.Barnes2@va.gov FU National Center on Homelessness FX The authors are associated with the Veterans Integrated Service Network 19 Mental Illness Research, Education, and Clinical Center, Denver, CO. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. We wish to thank the National Center on Homelessness for their support of this project. Correspondence should be sent to Sean M. Barnes, Denver VA Medical Center, MIRECC, 1055 Clermont Street, Denver, CO 80220 (e-mail: Sean.Barnes2@va.gov). NR 26 TC 1 Z9 1 U1 0 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2015 VL 26 IS 1 BP 92 EP 105 PG 14 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CC7BO UT WOS:000350522900011 PM 25702730 ER PT J AU Iezzoni, LI Barreto, EA Wint, AJ Hong, CSK Donelan, K AF Iezzoni, Lisa I. Barreto, Esteban A. Wint, Amy J. Hong, Clemens S. K. Donelan, Karen TI Development and Preliminary Testing of the Health in Community Survey SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Social determinants of health; chronic conditions; care coordination; care integration; patient survey ID CENTERED MEDICAL HOME; MULTIPLE CHRONIC CONDITIONS; PRIMARY-CARE; PRACTICE TRANSFORMATION; PATIENT COMPLEXITY; INCOME INEQUALITY; MODEL; DISPARITIES; OUTCOMES; DETERMINANTS AB Objectives. Develop and pilot test the Health in Community Survey (HCS), to collect patients' perceptions of care integration between traditional care providers and community-based services that address social determinants of health. Research design. Interviews of working-age, English- or Spanish-speaking patients with multiple chronic conditions to identify survey domains; cognitive interviews and pilot test of HCS Version 1. Results. Preliminary interview subjects identified diverse care concerns. From these findings, we designed six HCS domains. Cognitive interviews identified problems relating to patients' perceptions about limited function and disability Nearly one-third of pilot test subjects reported they did not definitely have enough resources for food, transportation, doctor and hospital bills, and medications; 41.6% said their clinicians only sometimes or never knew about their resource problems. Conclusions. Although it requires further validation, the HCS offers insights into patients' perceptions of care integration between traditional health care providers and services addressing social determinants of health. C1 [Iezzoni, Lisa I.; Barreto, Esteban A.; Wint, Amy J.; Hong, Clemens S. K.; Donelan, Karen] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Iezzoni, Lisa I.; Barreto, Esteban A.; Wint, Amy J.; Hong, Clemens S. K.; Donelan, Karen] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Iezzoni, Lisa I.; Barreto, Esteban A.; Wint, Amy J.; Hong, Clemens S. K.; Donelan, Karen] Partners Healthcare, Boston, MA USA. [Iezzoni, Lisa I.; Hong, Clemens S. K.; Donelan, Karen] Harvard Univ, Sch Med, Boston, MA USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Stanford St,Room 901B, Boston, MA 02114 USA. EM liezzoni@mgh.harvard.edu NR 43 TC 1 Z9 1 U1 2 U2 5 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2015 VL 26 IS 1 BP 134 EP 153 PG 20 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CC7BO UT WOS:000350522900014 PM 25702733 ER PT J AU Zhi, DG Shendre, A Scherzer, R Irvin, MR Perry, RT Levy, S Arnett, DK Grunfeld, C Shrestha, S AF Zhi, Degui Shendre, Aditi Scherzer, Rebecca Irvin, Marguerite R. Perry, Rodney T. Levy, Shawn Arnett, Donna K. Grunfeld, Carl Shrestha, Sadeep TI Deep sequencing of RYR3 gene identifies rare and common variants associated with increased carotid intima-media thickness (cIMT) in HIV-infected individuals SO JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MICROBIAL TRANSLOCATION; ATHEROSCLEROSIS; PREDICTION; HERITABILITY; ACTIVATION; DISEASE; EVENTS; WOMEN; RISK AB Carotid intima-media thickness (cIMT) is a subclinical measure of atherosclerosis with mounting evidence that higher cIMT confers an increased risk of cardiovascular disease. The ryanodine receptor 3 gene (RYR3) has previously been linked to increased cIMT; however, the causal variants have not yet been localized. Therefore, we sequenced 339 480 bp encompassing 104 exons and 2 kb flanking region of the RYR3 gene in 96 HIV-positive white men from the extremes of the distribution of common cIMT from the Fat Redistribution and Metabolic Changes in HIV infection study (FRAM). We identified 2710 confirmed variants (2414 single-nucleotide polymorphisms (SNPs) and 296 insertion/deletions (indels)), with a mean count of 736 SNPs (ranging from 528 to 1032) and 170 indels (ranging from 128 to 214) distributed in each individual. There were 39 variants in the exons and 15 of these were non-synonymous, of which with only 4 were common variants and the remaining 11 were rare variants, one was a novel SNP. We confirmed that the common variant rs2229116 was significantly associated with cIMT in this design (P<7.9 x 10(-9)), and observed seven other significantly associated SNPs (P<10(-8)). These variants including the private non-synonymous SNPs need to be followed up in a larger sample size and also tested with clinical atherosclerotic outcomes. C1 [Zhi, Degui] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Shendre, Aditi; Irvin, Marguerite R.; Perry, Rodney T.; Arnett, Donna K.; Shrestha, Sadeep] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Scherzer, Rebecca; Grunfeld, Carl] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Scherzer, Rebecca; Grunfeld, Carl] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Levy, Shawn] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. RP Shrestha, S (reprint author), Univ Alabama Birmingham, Dept Epidemiol, 1665 Univ Blvd,RPHB Room 217L, Birmingham, AL 35294 USA. EM sshrestha@uab.edu FU NIH [RO1-DK57508, RO1-HL74814, RO1-HL53359, K23-AI66943, UL1 RR024131, M01-RR00036, M01-RR00051, M01-RR00052, M01-RR00054, M01-RR00083, M01-RR0636, M01-RR00865]; UAB Center for AIDS Research (CFAR) developmental project (NIAID) [P30 AI027767]; Albert L. and Janet A. Schultz Supporting Foundation FX We thank investigators and staff of the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study. The FRAM study was supported by NIH grants RO1-DK57508, -HL74814 and -HL53359, K23-AI66943 and UL1 RR024131; NIH GCRC grants M01-RR00036, -RR00051, -RR00052, -RR00054, -RR00083, -RR0636 and -RR00865; the Albert L. and Janet A. Schultz Supporting Foundation and with resources and the use of facilities of the Veterans Affairs Medical Centers of Atlanta, District of Columbia, New York and San Francisco. Sequencing experiments were conducted at HudsonAlpha Institute for Biotechnology, Huntsville, AL and the genetic sub-study was supported by UAB Center for AIDS Research (CFAR; P30 AI027767) developmental project (NIAID Supplement PI: Shrestha). NR 29 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1434-5161 EI 1435-232X J9 J HUM GENET JI J. Hum. Genet. PD FEB PY 2015 VL 60 IS 2 BP 63 EP 67 DI 10.1038/jhg.2014.104 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CC4WA UT WOS:000350354100002 PM 25500725 ER PT J AU Feng, Y Sassi, S Shen, JK Yang, XQ Gao, Y Osaka, E Zhang, JM Yang, SH Mankin, CYHJ Mankin, HJ Hornicek, FJ Duan, ZF AF Feng, Yong Sassi, Slim Shen, Jacson K. Yang, Xiaoqian Gao, Yan Osaka, Eiji Zhang, Jianming Yang, Shuhua Yang, Cao Mankin, Henry J. Hornicek, Francis J. Duan, Zhenfeng TI Targeting Cdk11 in Osteosarcoma Cells Using the CRISPR-cas9 System SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE osteosarcoma; CRISPR-Cas9; CDK11 ID RNA INTERFERENCE; KINASE-ACTIVITY; BETA-CATENIN; GENE-THERAPY; CANCER-CELLS; INVASION; EXPRESSION; MIGRATION; GROWTH; CRISPR/CAS9 AB Osteosarcoma is the most common type primary malignant tumor of bone. Patients with regional osteosarcoma are routinely treated with surgery and chemotherapy. In addition, many patients with metastatic or recurrent osteosarcoma show poor prognosis with current chemotherapy agents. Therefore, it is important to improve the general condition and the overall survival rate of patients with osteosarcoma by identifying novel therapeutic strategies. Recent studies have revealed that CDK11 is essential in osteosarcoma cell growth and survival by inhibiting CDK11 mRNA expression with RNAi. Here, we apply the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system, a robust and highly efficient novel genome editing tool, to determine the effect of targeting endogenous CDK11 gene at the DNA level in osteosarcoma cell lines. We show that CDK11 can be efficiently silenced by CRISPR-Cas9. Inhibition of CDK11 is associated with decreased cell proliferation and viability, and induces cell death in osteosarcoma cell lines KHOS and U-2OS. Furthermore, the migration and invasion activities are also markedly reduced by CDK11 knockout. These results demonstrate that CRISPR-Cas9 system is a useful tool for the modification of endogenous CDK11 gene expression, and CRISPR-Cas9 targeted CDK11 knockout may be a promising therapeutic regimen for the treatment of osteosarcoma. (C) 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. C1 [Feng, Yong; Shen, Jacson K.; Yang, Xiaoqian; Gao, Yan; Osaka, Eiji; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, Boston, MA 02114 USA. [Feng, Yong; Shen, Jacson K.; Yang, Xiaoqian; Gao, Yan; Osaka, Eiji; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Feng, Yong; Yang, Shuhua; Yang, Cao] Huazhong Univ Sci & Technol, Union Hosp, Dept Orthopaed Surg, Tongji Med Coll, Wuhan, Peoples R China. [Sassi, Slim] Harvard Univ, Ctr Computat & Integrat Biol, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zhang, Jianming] Harvard Univ, Cutaneous Biol Res Ctr, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu FU Sarcoma Foundation of America; National Cancer Institute/National Institutes of Health [UO1 CA 151452-01]; Sarcoma SPORE/NIH; Academic Enrichment MGH Orthopaedics; National Science Foundation China [81101375] FX Grant sponsor: Gattegno and Wechsler; Grant sponsor: Kenneth Stanton; Grant sponsor: Sarcoma Foundation of America; Grant sponsor: National Cancer Institute/National Institutes of Health; Grant number: UO1 CA 151452-01; Grant sponsor: Sarcoma SPORE/NIH; Grant sponsor: Academic Enrichment MGH Orthopaedics; Grant sponsor: National Science Foundation China; Grant number: 81101375. NR 49 TC 12 Z9 13 U1 6 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD FEB PY 2015 VL 33 IS 2 BP 199 EP 207 DI 10.1002/jor.22745 PG 9 WC Orthopedics SC Orthopedics GA CC6JW UT WOS:000350472200006 PM 25348612 ER PT J AU Sundt, TM AF Sundt, Thoralf M. TI Aortic replacement in the setting of bicuspid aortic valve: How big? How much? SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID ASCENDING AORTA; COMPLICATIONS; DISSECTION; DISEASE; RISK; MANAGEMENT; ANEURYSM; OUTCOMES; ROOT AB Despite more than a decade of intense investigation, controversy persists regarding appropriate triggers for aortic replacement in the setting of bicuspid aortic valve. The difficulty is that the data are inescapably imperfect. Although we can count individuals with bicuspid valve who suffer dissection, we have an insufficient understanding of the true denominator of individuals at risk to calculate the probability of dissection for an individual patient. In addition, our own decision-making process is subject to "denominator neglect'' or focus on the fact of the occurrence of the event rather than on the risk of the occurrence. Furthermore, the data are inherently incomplete given the asymmetric nature of outcomes information. Specifically, although we can see those who did or did not dissect among the patients not undergoing surgery, the converse is not true; the tragedy of prophylactic surgery is that one cannot distinguish those who have benefited through prevention of dissection from those who paid the price of surgery but in whom dissection would never have occurred. Finally, we have data for only some of the critical determinants of dissection. Structural failure occurs when stresses exceed strengths. Aortic diameter gives us some insight into stress but we have little information on the material strength of the aorta. Early indications that patients undergoing aortic valve replacement for bicuspid valve had a significant risk of aortic dissection were followed by laboratory data showing histologic, biochemical, and mechanical abnormalities supporting an aggressive approach to resection; however, more recent clinical studies call this into question. C1 [Sundt, Thoralf M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02115 USA. RP Sundt, TM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiac Surg,Edward D Churchill Prof Surg, 55 Fruit St, Boston, MA 02114 USA. EM tsundt@partners.org NR 24 TC 4 Z9 4 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD FEB PY 2015 VL 149 IS 2 SU S BP S6 EP S9 DI 10.1016/j.jtcvs.2014.07.069 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA CC7MI UT WOS:000350551500003 PM 25218534 ER PT J AU Avram, M Ortiz, A AF Avram, Mathew Ortiz, Arisa TI Introduction SO LASERS IN SURGERY AND MEDICINE LA English DT Editorial Material C1 [Avram, Mathew] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Ctr Photomed, Cambridge, MA 02138 USA. [Ortiz, Arisa] Univ Calif San Diego, Dept Dermatol, San Diego, CA 92122 USA. RP Ortiz, A (reprint author), Univ Calif San Diego, Dept Dermatol, 8899 Univ Ctr Ln 350, San Diego, CA 92122 USA. EM arisaortiz@gmail.com NR 0 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2015 VL 47 IS 2 SI SI BP 103 EP 105 DI 10.1002/lsm.22337 PG 3 WC Dermatology; Surgery SC Dermatology; Surgery GA CC7KQ UT WOS:000350546700001 PM 25727551 ER PT J AU Ortiz, AE Anderson, RR Avram, MM AF Ortiz, Arisa E. Anderson, R. Rox Avram, Mathew M. TI 1064 nm Long-Pulsed Nd: YAG Laser Treatment of Basal Cell Carcinoma SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE BCC; laser therapy; laser treatment; nonmelanoma skin cancer; skin cancer ID DYE-LASER; SELECTIVE PHOTOTHERMOLYSIS; RADIATION; SKIN AB Background and ObjectiveStandard surgical and destructive treatments for basal cell carcinoma (BCC) can result in significant morbidity and scarring, stimulating the investigation of alternative non-surgical options. The objective of this study was to determine the safety, clinical, and histological efficacy of pulsed, high-fluence 1064nm Nd:YAG laser therapy for the treatment of BCC on the trunk and extremities. Study Design/Materials and MethodsThis was a prospective, non-randomized, open-label clinical trial. Ten subjects with a biopsy-proven BCC less than 1.5cm in diameter on the trunk or extremities received one treatment with a 10milliseconds pulsed 1064nm Nd:YAG laser. Standard excision was performed 1 month after laser treatment to confirm histologic clearance. ResultsThe laser treatment was quick and well tolerated. There was complete histologic clearance after one treatment in 92% of the BCC tumors, overall. At higher fluences, there was 100% histologic clearance after one treatment. No significant adverse events were seen, including scarring. ConclusionsThe 1064nm long-pulsed Nd:YAG laser may offer a safe alternative for treating BCC off the face. A larger study is highly warranted to confirm these preliminary results. Lasers Surg. Med. 47:106-110, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Ortiz, Arisa E.; Anderson, R. Rox; Avram, Mathew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dermatol Cosmet & Laser Ctr, Boston, MA 02114 USA. [Ortiz, Arisa E.; Anderson, R. Rox; Avram, Mathew M.] Wellman Ctr Photomed, Boston, MA 02114 USA. [Ortiz, Arisa E.] Univ Calif San Diego, San Diego, CA 92122 USA. RP Ortiz, AE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dermatol Cosmet & Laser Ctr, 50 Staniford St,St 250, Boston, MA 02114 USA. EM arisaortiz@gmail.com FU Kythera; Photomedex; MOE Devices; Cytrellis; Living Proof; Seventh Sense; Seven Oaks FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and have disclosed the following: [None reported for Dr. Ortiz. Dr. Avram serves on the medical advisory board and is a paid consultant for Zeltiq. He is also a paid consultant for Kythera, and on the scientific advisory board for Cytrellis. Dr. Anderson is a paid consultant for Photomedex, MOE Devices, Cytrellis, Living Proof, Seventh Sense, and Seven Oaks, unrelated to this study]. NR 19 TC 1 Z9 1 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2015 VL 47 IS 2 SI SI BP 106 EP 110 DI 10.1002/lsm.22310 PG 5 WC Dermatology; Surgery SC Dermatology; Surgery GA CC7KQ UT WOS:000350546700002 PM 25645536 ER PT J AU Xu, LY Kilmer, SL Ross, EV Avram, MM AF Xu, Lisa Y. Kilmer, Suzanne L. Ross, E. Victor Avram, Mathew M. TI Bacterial Infections Following Non-Ablative Fractional Laser Treatment: A Case Series and Discussion SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE bacterial infections; laser complications; non-ablative fractional laser ID ANTIBIOTIC-PROPHYLAXIS; RESURFACING TREATMENT; FIBER LASER; COMPLICATIONS; PHOTOTHERMOLYSIS AB Non-ablative fractional laser procedures have become increasingly popular since their introduction in 2004. The fractional 1,927nm thulium laser is a non-ablative device that penetrates up to 300m in the skin and the 1,550nm erbium:glass laser penetrates up to 1,400m. These procedures are considered minimally invasive with a high safety profile; therefore, infectious complications are exceedingly rare. However, we report five recent cases of bacterial infection with both gram-positive and gram-negative organisms following treatment with the fractional 1550/1927nm laser approximately 1 day to 1 week post-procedure. One patient had a rapidly progressing pustular eruption with symptoms of sepsis. These patients were seen immediately, cultures were obtained and empiric antibiotic therapy was initiated. They recovered without long-term complications. Rapid-onset bacterial infections following non-ablative laser resurfacing with the 1550/1927nm laser have not been previously reported in the literature. The infections can progress quickly and lead to serious sequelae, including systemic illness and severe scarring, if not identified and appropriately treated. We present these cases to highlight the importance of close surveillance and when appropriate, rapid intervention, following non-ablative fractional procedures, especially when patients present with atypical symptoms and signs. Lasers Surg. Med. 47:128-132, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Xu, Lisa Y.] Johns Hopkins Univ, Dept Dermatol, Baltimore, MD 21231 USA. [Kilmer, Suzanne L.] Laser & Skin Surg Ctr Northern Calif, Sacramento, CA 95816 USA. [Ross, E. Victor] Scripps Clin Laser & Cosmet Dermatol, San Diego, CA 92130 USA. [Avram, Mathew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dermatol Laser & Cosmet Ctr, Boston, MA 02114 USA. RP Xu, LY (reprint author), Johns Hopkins Univ, Dept Dermatol, 1550 Orleans St,Suite 207, Baltimore, MD 21231 USA. EM lxu24@jhmi.edu NR 14 TC 2 Z9 2 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2015 VL 47 IS 2 SI SI BP 128 EP 132 DI 10.1002/lsm.22315 PG 5 WC Dermatology; Surgery SC Dermatology; Surgery GA CC7KQ UT WOS:000350546700005 PM 25586939 ER PT J AU Tremaine, AM Avram, MM AF Tremaine, Anne Marie Avram, Mathew M. TI FDA MAUDE Data on Complications With Lasers, Light Sources, and Energy-Based Devices SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE adverse events; alexandrite; cryolipolysis; diode; FDA; focused ultrasound; fractional resurfacing; intense pulsed light; laser hair removal; pulsed dye laser; microwave technology; Nd:YAG; radiofrequency ID PULSED DYE-LASER; INTENSITY FOCUSED ULTRASOUND; SUBCUTANEOUS ADIPOSE-TISSUE; MICROFOCUSED ULTRASOUND; EXPERIENCE DATABASE; SKIN LAXITY; RADIOFREQUENCY; CRYOLIPOLYSIS; REDUCTION; MANUFACTURER AB Background and ObjectiveIt is essential for physicians to be fully informed regarding adverse events and malfunctions associated with medical devices that occur in routine practice. There is limited information on this important issue in the medical literature, and it is mostly based on initial studies and case reports. More advanced knowledge regarding device adverse events is necessary to guide physicians towards providing safe treatments. The FDA requires that manufacturers and device users submit medical device reports (MDRs) for suspected injuries from device use or malfunction. The database of MDRs, entitled Manufacturer and User Facility Device Experience (MAUDE) enables the FDA to monitor device performance and identify potential safety issues. Study Design/Materials and MethodsWe employed the following search strategy to identify reported adverse events. We searched the MAUDE electronic database on the FDA website in December 2013: We collected all reported cases between 1991 and December 2013. The search terms utilized included a comprehensive list of device manufacturers, specific product names, and the wavelengths/technology of the devices used in the field of dermatology. ResultsOur search yielded 1257 MDRs. Forty-five MDRs were excluded due to insufficient data. The data is broken down into the adverse events observed, such as, but not limited to: blistering, burns, scarring, dyschromia, fat loss, and nerve palsy. The MDRs describe the adverse event and attempt to determine if it was related to device malfunction versus operator error. Radiofrequency devices, diode lasers, and intense pulsed light devices were the most commonly reported devices related to injuries. Conclusion1257 MDRs, from a myriad of devices used in dermatology, have been reported to the FDA as of December 2013. Despite the underreporting of adverse events, the MAUDE database is an untapped resource of post-market surveillance of medical devices. The database can offer additional information, which combined with the initial device studies and published case reports from our colleagues, will help raise awareness and improve patient safety. Lasers Surg. Med. 47:133-140, 2015. (c) 2015 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc. C1 [Tremaine, Anne Marie; Avram, Mathew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tremaine, Anne Marie; Avram, Mathew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tremaine, Anne Marie] Laser Skin Care Ctr, Long Beach, CA 90807 USA. RP Tremaine, AM (reprint author), 3918 Long Beach Blvd Suite 200, Long Beach, CA 90807 USA. EM amt1998@gmail.com NR 32 TC 6 Z9 6 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2015 VL 47 IS 2 SI SI BP 133 EP 140 DI 10.1002/lsm.22328 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA CC7KQ UT WOS:000350546700006 PM 25655709 ER PT J AU Gonzalez-Suarez, A Gutierrez-Herrera, E Berjano, E Lozano, JNJ Franco, W AF Gonzalez-Suarez, Ana Gutierrez-Herrera, Enoch Berjano, Enrique Lozano, Joel N. Jimenez Franco, Walfre TI Thermal and Elastic Response of Subcutaneous Tissue With Different Fibrous Septa Architectures to RF Heating: Numerical Study SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE cellulite; fat; fibrous septa; hyperthermia; hypodermis; modeling; radiofrequency heating; skin; tissue mechanics ID BIOLOGICAL TISSUES; RADIOFREQUENCY; SKIN; FAT; FIELDS AB Background and ObjectiveRadiofrequency currents are commonly used in dermatology to treat cutaneous and subcutaneous tissues by heating. The subcutaneous morphology of tissue consists of a fine, collagenous and fibrous septa network enveloping clusters of adipocyte cells. The architecture of this network, namely density and orientation of septa, varies among patients and, furthermore, it correlates with cellulite grading. In this work we study the effect of two clinically relevant fibrous septa architectures on the thermal and elastic response of subcutaneous tissue to the same RF treatment; in particular, we evaluate the thermal damage and thermal stress induced to an intermediate- and a high-density fibrous septa network architecture that correspond to clinical morphologies of 2.5 and 0 cellulite grading, respectively. Study Design/Materials and MethodsWe used the finite element method to assess the electric, thermal and elastic response of a two-dimensional model of skin, subcutaneous tissue and muscle subjected to a relatively long, constant, low-power RF treatment. The subcutaneous tissue is constituted by an interconnected architecture of fibrous septa and fat lobules obtained by processing micro-MRI sagittal images of hypodermis. As comparison criteria for the RF treatment of the two septa architectures, we calculated the accumulated thermal damage that corresponds to 63% loss in cell viability. ResultsElectric currents preferentially circulated through the fibrous septa in the subcutaneous tissue. However, the intensity of the electric field was higher within the fat because it is a poor electric conductor. The power absorption in the fibrous septa relative to that in the fat varied with septum orientation: it was higher in septa with vertical orientation and lower in septa with horizontal orientation. Overall, maximum values of electric field intensity, power absorption and temperature were similar for both fibrous septa architectures. However, the high-density septa architecture (cellulite grade 0) had a more uniform and broader spatial distribution of power absorption, resulting in a larger cross-sectional area of thermal damage (approximate to 1.5 times more). Volumetric strains (expansion and contraction) were small and similar for both network architectures. During the first seconds of RF exposure, the fibrous septa were subjected to thermal expansion regardless of orientation. In the long term, the fibrous septa contracted due to the thermal expansion of fat. Skin and muscle were subjected to significantly higher Von Mises stresses (measure of yield) or distortion energy than the subcutaneous tissue. ConclusionThe distribution of electric currents within subcutaneous tissues depends on tissue morphology. The electric field is more intense in septum oriented along the skin to muscle (top to bottom) direction, creating lines or planes of preferential heating. It follows that the more septum available for preferential heating, the larger the extent of volumetric RF-heating and thermal damage to the subcutaneous tissue. Thermal load alone, imposed by long-exposure to heating up to 50 degrees C, results in small volumetric expansion and contraction in the subcutaneous tissue. The subcutaneous tissue is significantly less prone to non-reversible deformation by a thermal load than the skin and muscle. Lasers Surg. Med. 47:183-195, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Gonzalez-Suarez, Ana; Berjano, Enrique] Univ Politecn Valencia, Dept Elect Engn, Biomed Synergy, Valencia 46022, Spain. [Gutierrez-Herrera, Enoch; Lozano, Joel N. Jimenez; Franco, Walfre] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. RP Franco, W (reprint author), Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. EM wfranco@mgh.harvard.edu FU Plan Nacional de I + D + I del Ministerio de Ciencia e Innovacion [TEC2011-27133-C02-01]; Generalitat Valenciana [VALi+d (ACIF/2011/194), BFPI/2013/003]; United States Air Force Office of Scientific Research FX Contract grant sponsor: Plan Nacional de I + D + I del Ministerio de Ciencia e Innovacion; Contract grant number: TEC2011-27133-C02-01; Contract grant sponsor: Generalitat Valenciana; Contract grant number: VALi+d (ACIF/2011/194), BFPI/2013/003; Contract grant sponsor: United States Air Force Office of Scientific Research. NR 25 TC 3 Z9 3 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2015 VL 47 IS 2 SI SI BP 183 EP 195 DI 10.1002/lsm.22301 PG 13 WC Dermatology; Surgery SC Dermatology; Surgery GA CC7KQ UT WOS:000350546700014 PM 25651998 ER PT J AU Zhu, RY Yue, BS Yang, QR Ma, Y Huang, GQ Guan, M Avram, MM Lu, Z AF Zhu, Rongyi Yue, Baishuang Yang, Qiaorong Ma, Ying Huang, Guiqin Guan, Ming Avram, Mathew M. Lu, Zhong TI The Effect of 595 nm Pulsed Dye Laser on Connective Tissue Growth Factor (CTGF) Expression in Cultured Keloid Fibroblasts SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE connective tissue growth factor; pulsed dye laser; scar; wound healing; keloid fibroblast; culture; keloid ID HYPERTROPHIC STERNOTOMY SCARS; TREATMENT RESPONSE AB ObjectiveTo investigate the effect of pulsed dye laser (PDL 595nm) on the proliferation and expression of connective tissue growth factor (CTGF) in cultured keloid fibroblasts. Materials and MethodsCultured keloid fibroblasts were exposed to pulsed dye laser irradiation at fluences of 6, 8, and 10J/cm(2), with pulse durations of 1.5, 3, and 10ms. The viability of keloid fibroblasts was measured with CCK-8 at 72, 24, and 12 hours prior to irradiation. Subsequently, viability was measured at 12, 24, and 72 hours post-irradiation. Additionally, the fibroblast cell cycle and apoptosis rate were measured by flow cytometry. Finally, keloid fibroblasts underwent real-time polymerase chain reaction (PCR) and Western blot to investigate the CTGF mRNA and protein expression after PDL irradiation. The untreated cultured keloid fibroblasts served as controls. ResultsThe proliferation of keloid fibroblasts was significantly inhibited after PDL irradiation. Both CTGF mRNA and protein expression were significantly down-regulated in 1.5, 3, and 10ms pulse duration groups, in a dose dependent manner (P<0.05). However, there was no statistically significant difference between groups of different pulse duration in 6, 8, and 10J/cm(2) fluence ranges (P>0.05). ConclusionsWithin certain fluence ranges, pulsed dye laser can effectively suppress the growth of keloids and significantly down-regulate CTGF mRNA and CTGF expression. Lasers Surg. Med. 47:203-209, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Zhu, Rongyi; Yue, Baishuang; Yang, Qiaorong; Ma, Ying; Huang, Guiqin; Lu, Zhong] Fudan Univ, Huashan Hosp, Dept Dermatol, Shanghai 200040, Peoples R China. [Zhu, Rongyi] Fudan Univ, Huadong Hosp, Dept Dermatol, Shanghai 200040, Peoples R China. [Yang, Qiaorong] Fudan Univ, Zhongshan Hosp, Dept Dermatol, Shanghai 200032, Peoples R China. [Guan, Ming] Fudan Univ, Huashan Hosp, Dept Lab, Shanghai 200040, Peoples R China. [Avram, Mathew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,MGH Dermatol Laser & Cosmet Ctr, Boston, MA 02114 USA. RP Lu, Z (reprint author), Fudan Univ, Huashan Hosp, Dept Dermatol, Shanghai 200040, Peoples R China. EM luzhong20100806@qq.com FU Shanghai Science and Technology Committee Medical Guidance Programme [10411961100] FX Contract grant sponsor: Shanghai Science and Technology Committee Medical Guidance Programme; Contract grant number: 10411961100. NR 19 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD FEB PY 2015 VL 47 IS 2 SI SI BP 203 EP 209 DI 10.1002/lsm.22334 PG 7 WC Dermatology; Surgery SC Dermatology; Surgery GA CC7KQ UT WOS:000350546700016 PM 25727552 ER PT J AU Liu, YH Li, XY Chen, CY Zhang, HM Kang, JX AF Liu, Ying-Hua Li, Xiang-Yong Chen, Chih-Yu Zhang, Hong-Man Kang, Jing X. TI Omega-3 Fatty Acid Intervention Suppresses Lipopolysaccharide-Induced Inflammation and Weight Loss in Mice SO MARINE DRUGS LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; TOLL-LIKE RECEPTORS; EICOSAPENTAENOIC ACID; TLR4; RECOGNITION; INHIBITION; MODULATION; SEPSIS; LPS AB Bacterial endotoxin lipopolysaccharide (LPS)-induced sepsis is a critical medical condition, characterized by a severe systemic inflammation and rapid loss of muscle mass. Preventive and therapeutic strategies for this complex disease are still lacking. Here, we evaluated the effect of omega-3 (n-3) polyunsaturated fatty acid (PUFA) intervention on LPS-challenged mice with respect to inflammation, body weight and the expression of Toll-like receptor 4 (TLR4) pathway components. LPS administration induced a dramatic loss of body weight within two days. Treatment with n-3 PUFA not only stopped loss of body weight but also gradually reversed it back to baseline levels within one week. Accordingly, the animals treated with n-3 PUFA exhibited markedly lower levels of inflammatory cytokines or markers in plasma and tissues, as well as down-regulation of TLR4 pathway components compared to animals without n-3 PUFA treatment or those treated with omega-6 PUFA. Our data demonstrate that n-3 PUFA intervention can suppress LPS-induced inflammation and weight loss via, at least in part, down-regulation of pro-inflammatory targets of the TLR4 signaling pathway, and highlight the therapeutic potential of n-3 PUFA in the management of sepsis. C1 [Liu, Ying-Hua; Li, Xiang-Yong; Chen, Chih-Yu; Zhang, Hong-Man; Kang, Jing X.] Massachusetts Gen Hosp East, LLMT, Boston, MA 02129 USA. [Liu, Ying-Hua; Li, Xiang-Yong; Chen, Chih-Yu; Zhang, Hong-Man; Kang, Jing X.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Liu, Ying-Hua] Peoples Liberat Army Gen Hosp, Dept Nutr, Beijing 100853, Peoples R China. [Li, Xiang-Yong] Guangdong Med Coll, Inst Biochem & Mol Biol, Zhanjiang 524023, Guangdong, Peoples R China. RP Kang, JX (reprint author), Massachusetts Gen Hosp East, LLMT, Boston, MA 02129 USA. EM liuyinghua77@hotmail.com; xyli75@126.com; cchen45@mgh.harvard.edu; hmzhang9607@sina.com; kang.jing@mgh.harvard.edu FU Sansun Life Sciences; Fortune Education Foundation FX This study was supported by the generous funding from Sansun Life Sciences and the Fortune Education Foundation. The authors are also grateful to Marina Kang for her editorial assistance. NR 24 TC 3 Z9 4 U1 0 U2 10 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-3397 J9 MAR DRUGS JI Mar. Drugs PD FEB PY 2015 VL 13 IS 2 BP 1026 EP 1036 DI 10.3390/md13021026 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CC3AW UT WOS:000350217500021 PM 25689565 ER PT J AU Elliott, G Hong, CB Xing, XY Zhou, X Li, DF Coarfa, C Bell, RJA Maire, CL Ligon, KL Sigaroudinia, M Gascard, P Tlsty, TD Harris, RA Schalkwyk, LC Bilenky, M Mill, J Farnham, PJ Kellis, M Marra, MA Milosavljevic, A Hirst, M Stormo, GD Wang, T Costello, JF AF Elliott, GiNell Hong, Chibo Xing, Xiaoyun Zhou, Xin Li, Daofeng Coarfa, Cristian Bell, Robert J. A. Maire, Cecile L. Ligon, Keith L. Sigaroudinia, Mahvash Gascard, Philippe Tlsty, Thea D. Harris, R. Alan Schalkwyk, Leonard C. Bilenky, Misha Mill, Jonathan Farnham, Peggy J. Kellis, Manolis Marra, Marco A. Milosavljevic, Aleksandar Hirst, Martin Stormo, Gary D. Wang, Ting Costello, Joseph F. TI Intermediate DNA methylation is a conserved signature of genome regulation SO NATURE COMMUNICATIONS LA English DT Article ID GENE-EXPRESSION; CPG ISLAND; CELLS; WIDESPREAD; REGIONS; RESOLUTION; LANDSCAPE; ENHANCERS; SEQUENCE; DATABASE AB The role of intermediate methylation states in DNA is unclear. Here, to comprehensively identify regions of intermediate methylation and their quantitative relationship with gene activity, we apply integrative and comparative epigenomics to 25 human primary cell and tissue samples. We report 18,452 intermediate methylation regions located near 36% of genes and enriched at enhancers, exons and DNase I hypersensitivity sites. Intermediate methylation regions average 57% methylation, are predominantly allele-independent and are conserved across individuals and between mouse and human, suggesting a conserved function. These regions have an intermediate level of active chromatin marks and their associated genes have intermediate transcriptional activity. Exonic intermediate methylation correlates with exon inclusion at a level between that of fully methylated and unmethylated exons, highlighting gene context-dependent functions. We conclude that intermediate DNA methylation is a conserved signature of gene regulation and exon usage. C1 [Elliott, GiNell; Xing, Xiaoyun; Zhou, Xin; Li, Daofeng; Stormo, Gary D.; Wang, Ting] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, Dept Genet, St Louis, MO 63108 USA. [Hong, Chibo; Bell, Robert J. A.; Costello, Joseph F.] Univ Calif San Francisco, Dept Neurosurg, Helen Diller Family Comprehens Canc Ctr, Brain Tumor Res Ctr, San Francisco, CA 94115 USA. [Coarfa, Cristian; Harris, R. Alan; Milosavljevic, Aleksandar] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Bell, Robert J. A.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA. [Maire, Cecile L.; Ligon, Keith L.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Sigaroudinia, Mahvash; Gascard, Philippe; Tlsty, Thea D.] Univ Calif San Francisco, Dept Pathol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94115 USA. [Schalkwyk, Leonard C.] Univ Essex, Sch Biol Sci, Colchester CO4 3SQ, Essex, England. [Bilenky, Misha; Marra, Marco A.; Hirst, Martin] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Mill, Jonathan] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Mill, Jonathan] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England. [Farnham, Peggy J.] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Farnham, Peggy J.] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Kellis, Manolis] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Hirst, Martin] Univ British Columbia, Ctr High Throughput Biol, Vancouver, BC V6T 1Z4, Canada. [Hirst, Martin] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada. RP Wang, T (reprint author), Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, Dept Genet, St Louis, MO 63108 USA. EM twang@genetics.wustl.edu; joseph.costello@ucsf.edu RI Li, Daofeng/E-5386-2011; Mill, Jonathan/B-3276-2010; Hirst, Martin/B-7684-2016; Marra, Marco/B-5987-2008; OI Li, Daofeng/0000-0001-7492-3703; Mill, Jonathan/0000-0003-1115-3224; Schalkwyk, Leonard/0000-0001-7030-5756; Farnham, Peggy/0000-0003-4469-7914 FU NIH Roadmap Epigenomics Program - National Institute on Drug Abuse (NIDA); National Institute of Environmental Health Sciences (NIEHS); NIH [5U01ES017154, R01HG007354, R01HG007175, R01ES024992, R01CA169316]; Chancellor's Graduate Fellowship Program at the Washington University in St Louis; American Cancer Society [RSG-14-049-01-DMC] FX We thank collaborators in the Reference Epigenome Mapping Centers (REMC), the Epigenome Data Analysis and Coordination Center and NCBI who have generated and processed data used in this project. We thank Jufang Chang and Jeff Milbrandt for providing mouse cortical neuron samples. We acknowledge support from the NIH Roadmap Epigenomics Program, sponsored by the National Institute on Drug Abuse (NIDA) and the National Institute of Environmental Health Sciences (NIEHS). We thank Theresa Kadlecek and Arthur Weiss for processing blood samples. J.F.C. and T.W. are supported by NIH grant 5U01ES017154. G.E. is partly supported by the Chancellor's Graduate Fellowship Program at the Washington University in St Louis. T.W. and G.E. are also supported by NIH Grant R01HG007354, R01HG007175, R01ES024992 and American Cancer Society grant RSG-14-049-01-DMC. J.F.C. is also supported by NIH R01CA169316. NR 45 TC 19 Z9 19 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2015 VL 6 AR 6363 DI 10.1038/ncomms7363 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC4BL UT WOS:000350295600002 PM 25691127 ER PT J AU Alexander, BM Galanis, E Yung, WKA Ballman, KV Boyett, JM Cloughesy, TF Degroot, JF Huse, JT Mann, B Mason, W Mellinghoff, IK Mikkelsen, T Mischel, PS O'Neill, BP Prados, MD Sarkaria, JN Tawab-Amiri, A Trippa, L Ye, XB Ligon, KL Berry, DA Wen, PY AF Alexander, Brian M. Galanis, Evanthia Yung, W. K. Alfred Ballman, Karla V. Boyett, James M. Cloughesy, Timothy F. Degroot, John F. Huse, Jason T. Mann, Bhupinder Mason, Warren Mellinghoff, Ingo K. Mikkelsen, Tom Mischel, Paul S. O'Neill, Brian P. Prados, Michael D. Sarkaria, Jann N. Tawab-Amiri, Abdul Trippa, Lorenzo Ye, Xiaobu Ligon, Keith L. Berry, Donald A. Wen, Patrick Y. TI Brain Malignancy Steering Committee clinical trials planning workshop: Report from the Targeted Therapies Working Group SO NEURO-ONCOLOGY LA English DT Article DE adaptive randomization; biomarkers; clinical trials; glioblastoma ID NEWLY-DIAGNOSED GLIOBLASTOMA; PROGRESSION-FREE SURVIVAL; INTEGRATED GENOMIC ANALYSIS; RANDOMIZED PHASE-III; I-SPY 2; ISOCITRATE DEHYDROGENASE; ADAPTIVE RANDOMIZATION; ADJUVANT TEMOZOLOMIDE; MUTATIONAL ANALYSIS; TUMOR SAMPLES AB Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings. Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting. C1 [Alexander, Brian M.; Trippa, Lorenzo; Ligon, Keith L.; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Galanis, Evanthia; Ballman, Karla V.; O'Neill, Brian P.; Sarkaria, Jann N.] Mayo Clin, Rochester, MN USA. [Yung, W. K. Alfred; Degroot, John F.; Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Boyett, James M.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Los Angeles, CA USA. [Huse, Jason T.; Mellinghoff, Ingo K.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Mann, Bhupinder; Tawab-Amiri, Abdul] Natl Canc Inst, Bethesda, MD USA. [Mason, Warren] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Mikkelsen, Tom] Henry Ford Hosp, Detroit, MI 48202 USA. [Mischel, Paul S.] Univ Calif San Diego, San Diego, CA 92103 USA. [Prados, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ye, Xiaobu] Johns Hopkins Univ, Baltimore, MD USA. RP Alexander, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM brian_alexander@dfci.harvard.edu FU Pfizer; Novartis; Genentech; Basilea; Sanofi; Merck; EMD Serono FX WM reports advisory role for Roche, Lilly and Merck. TM reports advisory board role for Roche, Merck, and Celgene. MDP reports advisory board role for Roche and Novartis and clinical and laboratory research support from Pfizer and Novartis. JNS reports research funding from Genentech, Basilea, Sanofi, and Merck. KLL reports consulting fee from EMD Serono. DAB is co-owner of and statistical consultant with Berry Consultants, LLC, a company that designs Bayesian adaptive clinical trials for pharmaceutical and medical device companies and NIH cooperative groups. NR 47 TC 5 Z9 5 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD FEB PY 2015 VL 17 IS 2 BP 180 EP 188 DI 10.1093/neuonc/nou154 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC1XK UT WOS:000350138500003 PM 25165194 ER PT J AU Mak, KS Gainor, JF Niemierko, A Oh, KS Willers, H Choi, NC Loeffler, JS Sequist, LV Shaw, AT Shih, HA AF Mak, Kimberley S. Gainor, Justin F. Niemierko, Andrzej Oh, Kevin S. Willers, Henning Choi, Noah C. Loeffler, Jay S. Sequist, Lecia V. Shaw, Alice T. Shih, Helen A. TI Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases SO NEURO-ONCOLOGY LA English DT Article DE ALK; brain metastases; EGFR; non-small cell lung cancer; radiotherapy ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITORS; K-RAS MUTATIONS; RADIATION-THERAPY; RANDOMIZED-TRIAL; PROGRESSION-FREE; ADENOCARCINOMA; CHEMOTHERAPY; CRIZOTINIB; GEFITINIB AB Background. We determined the impact of genetic alterations in EGFR, ALK, or KRAS on survival after radiotherapy for brain metastases in non-small cell lung cancer (NSCLC). Methods. Of 172 genotyped NSCLC patients treated with radiotherapy for brain metastases in 2005-2012, 54 had cancers with EGFR mutations, 12 had ALK rearrangements, 38 had KRAS mutations, and 68 were wild-type (WT). Overall survival (OS) was determined. Results. Median follow-up was 8.6 months. Median OS was 13.6 months for patients with EGFR mutations and 26.3 months for patients with ALK rearrangements, in contrast to 5.7 months for KRAS-mutant patients and 5.5 months for WT patients (P = .001). On multivariate analysis, adjusting for receipt of targeted therapy after cranial radiotherapy, ALK rearrangements were associated with improved OS (HR, 0.31; 95% CI, 0.13-0.74; P = .008). EGFR mutations were not significantly associated with improved OS on multivariate analysis (HR, 0.71; 95% CI, 0.37-1.38; P = .3). KRAS mutations were also not associated with improved OS (HR, 0.93; 95% CI, 0.59-1.47; P = .8). Receipt of targeted therapy after cranial radiotherapy was independently associated with improved OS (HR, 0.30; 95% CI, 0.17-0.54; P < .001). Receipt of chemotherapy after cranial radiotherapy, number of brain metastases, extra-cranial metastases, age, and performance status were also associated with OS. Conclusions. NSCLC patients with genetic alterations in ALK have improved survival outcomes after radiotherapy for brain metastases compared with EGFR, KRAS, or WT. Subsequent receipt of targeted therapy was associated with additional improvement in OS. C1 [Mak, Kimberley S.] Massachusetts Gen Hosp, Harvard Radiat Oncol Program, Boston, MA 02114 USA. [Gainor, Justin F.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Niemierko, Andrzej; Oh, Kevin S.; Willers, Henning; Choi, Noah C.; Loeffler, Jay S.; Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Sequist, Lecia V.; Shaw, Alice T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Shih, HA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM hshih@partners.org NR 48 TC 18 Z9 18 U1 0 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD FEB PY 2015 VL 17 IS 2 BP 296 EP 302 DI 10.1093/neuonc/nou146 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC1XK UT WOS:000350138500014 PM 25053852 ER PT J AU Rigotti, NA Harrington, KF Richter, K Fellows, JL Sherman, SE Grossman, E Chang, YC Tindle, HA Ylioja, T AF Rigotti, Nancy A. Harrington, Kathleen F. Richter, Kimber Fellows, Jeffrey L. Sherman, Scott E. Grossman, Ellie Chang, Yuchiao Tindle, Hilary A. Ylioja, Thomas CA CHART TI Increasing Prevalence of Electronic Cigarette Use Among Smokers Hospitalized in 5 US Cities, 2010-2013 SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; NICOTINE DELIVERY-SYSTEMS; SMOKING-CESSATION; TOBACCO CONTROL; PROTOCOL; ADULTS; AWARENESS; HEALTH AB Introduction: Little is known about the pattern of electronic cigarette (e-cigarette) use over time or among smokers with medical comorbidity. Methods: We assessed current cigarette smokers' use of e-cigarettes during the 30 days before admission to 9 hospitals in 5 geographically dispersed US cities: Birmingham, AL; Boston, MA; Kansas City, KS; New York, NY; and Portland, OR. Each hospital was conducting a randomized controlled trial as part of the NIH-sponsored Consortium of Hospitals Advancing Research on Tobacco (CHART). We conducted a pooled analysis using multiple logistic regression to examine changes in e-cigarette use over time and to identify correlates of e-cigarette use. Results: Among 4,660 smokers hospitalized between July 2010 and December 2013 (mean age 57 years, 57% male, 71% white, 56% some college, average 14 cigarettes/day), 14% reported using an e-cigarette during the 30 days before admission. The prevalence of e-cigarette use increased from 1.1% in 2010 to 10.3% in 2011, 10.2% in 2012, and 18.4% in 2013; the increase was statistically significant (p < .0001) after adjustment for age, sex, education, and CHART study. Younger, better educated, and heavier smokers were more likely to use e-cigarettes. Smokers who were Hispanic, non-Hispanic black, and who had Medicaid or no insurance were less likely to use e-cigarettes. E-cigarette use also varied by CHART project and by geographic region. Conclusions: E-cigarette use increased substantially from 2010 to 2013 among a large sample of hospitalized adult cigarette smokers. E-cigarette use was more common among heavier smokers and among those who were younger, white, and who had higher socioeconomic status. C1 [Rigotti, Nancy A.; Chang, Yuchiao] Massachusetts Gen Hosp, Dept Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Rigotti, Nancy A.; Chang, Yuchiao] Harvard Univ, Sch Med, Boston, MA USA. [Harrington, Kathleen F.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL USA. [Richter, Kimber] Univ Kansas, Sch Med, Dept Prevent Med & Publ Hlth, Kansas City, KS USA. [Fellows, Jeffrey L.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Sherman, Scott E.; Grossman, Ellie] NYU, Sch Med, Div Gen Internal Med, New York, NY USA. [Tindle, Hilary A.; Ylioja, Thomas] Univ Pittsburgh, Sch Med, Div Gen Med, Pittsburgh, PA USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, 50 Staniford St,S50-9, Boston, MA 02114 USA. EM nrigotti@partners.org OI Sherman, Scott/0000-0003-1752-7303 FU NIH [RC1HL099668, R01HL111821, U01DA031515, U01HL105232, U01HL105229, U01HL105231] FX NIH grants RC1HL099668 (NAR), R01HL111821 (NAR, YC, HAT, and TY), U01DA031515 (KFH), U01HL105232 (KR), U01HL105229 (SES and EG), and U01HL105231 (JLF). NR 15 TC 6 Z9 6 U1 2 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2015 VL 17 IS 2 SI SI BP 236 EP 244 DI 10.1093/ntr/ntu138 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CC1YW UT WOS:000350142300019 PM 25168031 ER PT J AU Burger, E Mendes, ACSC Bani, GMAC Brigagao, MRPL Santos, GB Malaquias, LCC Chavasco, JK Verinaud, LM de Camargo, ZP Hamblin, MR Sperandio, FF AF Burger, Eva Mendes, Ana Carolina S. C. Bani, Giulia M. A. C. Brigagao, Maisa R. P. L. Santos, Gersika B. Malaquias, Luiz Cosme C. Chavasco, Jorge Kleber Verinaud, Liana M. de Camargo, Zoilo P. Hamblin, Michael R. Sperandio, Felipe F. TI Low-level Laser Therapy to the Mouse Femur Enhances the Fungicidal Response of Neutrophils against Paracoccidioides brasiliensis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID MURINE POLYMORPHONUCLEAR NEUTROPHILS; ACTIVATED HUMAN NEUTROPHILS; CELLULAR IMMUNE-RESPONSE; ACUTE LUNG INFLAMMATION; HELIUM-NEON LASER; PULMONARY PARACOCCIDIOIDOMYCOSIS; ANTIFUNGAL ACTIVITY; SUSCEPTIBLE MICE; P-BRASILIENSIS; SYRIAN-HAMSTER AB Neutrophils (PMN) play a central role in host defense against the neglected fungal infection paracoccidioidomycosis (PCM), which is caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb). PCM is of major importance, especially in Latin America, and its treatment relies on the use of antifungal drugs. However, the course of treatment is lengthy, leading to side effects and even development of fungal resistance. The goal of the study was to use low-level laser therapy (LLLT) to stimulate PMN to fight Pb in vivo. Swiss mice with subcutaneous air pouches were inoculated with a virulent strain of Pb or fungal cell wall components (Zymosan), and then received LLLT (780 nm; 50 mW; 12.5 J/cm2; 30 seconds per point, giving a total energy of 0.5 J per point) on alternate days at two points on each hind leg. The aim was to reach the bone marrow in the femur with light. Non-irradiated animals were used as controls. The number and viability of the PMN that migrated to the inoculation site was assessed, as well as their ability to synthesize proteins, produce reactive oxygen species (ROS) and their fungicidal activity. The highly pure PMN populations obtained after 10 days of infection were also subsequently cultured in the presence of Pb for trials of protein production, evaluation of mitochondrial activity, ROS production and quantification of viable fungi growth. PMN from mice that received LLLT were more active metabolically, had higher fungicidal activity against Pb in vivo and also in vitro. The kinetics of neutrophil protein production also correlated with a more activated state. LLLT may be a safe and non-invasive approach to deal with PCM infection. C1 [Burger, Eva; Mendes, Ana Carolina S. C.; Bani, Giulia M. A. C.; Malaquias, Luiz Cosme C.; Chavasco, Jorge Kleber] Fed Univ Alfenas UNIFAL MG, Inst Biomed Sci, Dept Microbiol & Immunol, Alfenas, MG, Brazil. [Brigagao, Maisa R. P. L.; Santos, Gersika B.] Fed Univ Alfenas UNIFAL MG, Inst Biomed Sci, Dept Biochem, Alfenas, MG, Brazil. [Verinaud, Liana M.] State Univ Campinas UNICAMP, Inst Biol, Dept Struct & Funct Biol, Sao Paulo, Brazil. [de Camargo, Zoilo P.] Fed Univ Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, Sao Paulo, SP, Brazil. [Hamblin, Michael R.; Sperandio, Felipe F.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.; Sperandio, Felipe F.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sperandio, Felipe F.] Fed Univ Alfenas UNIFAL MG, Inst Biomed Sci, Dept Pathol & Parasitol, Alfenas, MG, Brazil. RP Burger, E (reprint author), Fed Univ Alfenas UNIFAL MG, Inst Biomed Sci, Dept Microbiol & Immunol, Alfenas, MG, Brazil. EM felipe.fornias@unifal-mg.edu.br FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [486135/2012-8, 304827/2012-6]; Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [CBB-PPM-00119-14]; National Institute of Health (US NIH) [R01AI050875]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [AEX-9765-14-0] FX This study was supported by grants: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq - www.cnpq.br) 486135/2012-8 and 304827/2012-6; and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG - www.fapemig.br) CBB-PPM-00119-14. MRH was supported by National Institute of Health (US NIH - www.nih.gov) grant R01AI050875. FFS was supported by Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES - www.capes.gov.br) grant AEX-9765-14-0. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 4 Z9 4 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2015 VL 9 IS 2 AR UNSP e0003541 DI 10.1371/journal.pntd.0003541 PG 19 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CD3PW UT WOS:000350992500061 PM 25675431 ER PT J AU Bauman, WA Cardozo, CP AF Bauman, William A. Cardozo, Christopher P. TI Osteoporosis in Individuals with Spinal Cord Injury SO PM&R LA English DT Review ID BONE-MINERAL DENSITY; QUANTITATIVE COMPUTED-TOMOGRAPHY; VITAMIN-D DEFICIENCY; PULSED ELECTROMAGNETIC-FIELDS; LOWER-EXTREMITY FRACTURES; LOW-INTENSITY VIBRATION; POSTMENOPAUSAL WOMEN; DISUSE OSTEOPOROSIS; PREVENTS BONE; MUSCLE LOSS AB The pathophysiology, clinical considerations, and relevant experimental findings with regard to osteoporosis in individuals with spinal cord injury (SCI) will be discussed. The bone loss that occurs acutely after more neurologically motor complete SCI is unique for its sublesional skeletal distribution and rate, at certain skeletal sites approaching 1% of bone mineral density per week, and its resistance to currently available treatments. The areas of high bone loss include the distal femur, proximal tibia, and more distal boney sites. Evidence from a study performed in monozygotic twins discordant for SCI indicates that sublesional bone loss in the twin with SCI increases for several decades, strongly suggesting that the heightened net bone loss after SCI may persist for an extended period of time. The increased frequency of fragility fracture after paralysis will be discussed, and a few risk factors for such fractures after SCI will be examined. Because vitamin D deficiency, regardless of disability, is a relevant consideration for bone health, as well as an easily reversible condition, the increased prevalence of and treatment target values for vitamin D in this deficiency state in the SCI population will be reviewed. Pharmacological and mechanical approaches to preserving bone integrity in persons with acute and chronic SCI will be reviewed, with emphasis placed on efficacy and practicality. Emerging osteoanabolic agents that improve functioning of WNT/beta-catenin signaling after paralysis will be introduced as therapeutic interventions that may hold promise. C1 [Bauman, William A.; Cardozo, Christopher P.] James J Peters Vet Affairs Med Ctr, Dept Vet Affairs Rehabil Res & Dev Serv, Natl Ctr Excellence Med Consequences Spinal Cord, Bronx, NY 10468 USA. [Bauman, William A.; Cardozo, Christopher P.] James J Peters VA Med Ctr, Med Serv, Bronx, NY USA. [Bauman, William A.; Cardozo, Christopher P.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Bauman, William A.; Cardozo, Christopher P.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. RP Bauman, WA (reprint author), James J Peters Vet Affairs Med Ctr, Dept Vet Affairs Rehabil Res & Dev Serv, Natl Ctr Excellence Med Consequences Spinal Cord, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM william.bauman@va.gov FU Veterans Affairs Rehabilitation Research and Development Service [B9212C]; James J. Peters VA Medical Center FX Supported by the Veterans Affairs Rehabilitation Research and Development Service (grant no. B9212C) and the James J. Peters VA Medical Center. NR 99 TC 11 Z9 12 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD FEB PY 2015 VL 7 IS 2 BP 188 EP 201 DI 10.1016/j.pmrj.2014.08.948 PG 14 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA CB9ZZ UT WOS:000349995500011 PM 25171878 ER PT J AU Mckay, D Sookman, D Neziroglu, F Wilhelm, S Stein, DJ Kyrios, M Matthews, K Veale, D AF Mckay, Dean Sookman, Debbie Neziroglu, Fugen Wilhelm, Sabine Stein, Dan J. Kyrios, Michael Matthews, Keith Veale, David TI Efficacy of cognitive-behavioral therapy for obsessive-compulsive disorder SO PSYCHIATRY RESEARCH LA English DT Review DE Obsessive-compulsive disorder; Exposure with response prevention; Cognitive therapy; Meta-analysis; Treatment adherence ID COMORBID MAJOR DEPRESSION; OVERVALUED IDEAS SCALE; FOLLOW-UP; INTRUSIONS INVENTORY; RESPONSE PREVENTION; PSYCHOMETRIC VALIDATION; BELIEFS QUESTIONNAIRE; INDIVIDUAL TREATMENT; ANXIETY DISORDERS; PATIENT ADHERENCE AB Cognitive-behavioral therapy (CBT), which encompasses exposure with response prevention (ERP) and cognitive therapy, has demonstrated efficacy in the treatment of obsessive-compulsive disorder (OCD). However, the samples studied (reflecting the heterogeneity of OCD), the interventions examined (reflecting the heterogeneity of CBT), and the definitions of treatment response vary considerably across studies. This review examined the meta-analyses conducted on ERP and cognitive therapy (CT) for OCD. Also examined was the available research on long-term outcome associated with ERP and CT. The available research indicates that ERP is the first line evidence based psychotherapeutic treatment for OCD and that concurrent administration of cognitive therapy that targets specific symptom-related difficulties characteristic of OCD may improve tolerance of distress, symptom-related dysfunctional beliefs, adherence to treatment, and reduce drop out. Recommendations are provided for treatment delivery for OCD in general practice and other service delivery settings. The literature suggests that ERP and CT may be delivered in a wide range of clinical settings. Although the data are not extensive, the available research suggests that treatment gains following ERP are durable. Suggestions for future research to refine therapeutic outcome are also considered. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Mckay, Dean] Fordham Univ, Bronx, NY 10458 USA. [Sookman, Debbie] McGill Univ, Montreal, PQ, Canada. [Neziroglu, Fugen] Biobehav Inst, Great Neck, NY USA. [Wilhelm, Sabine] Harvard Univ, Boston, MA 02115 USA. [Wilhelm, Sabine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stein, Dan J.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Kyrios, Michael] Univ Melbourne, Melbourne, Vic, Australia. [Matthews, Keith] Univ Dundee, Dundee, Scotland. [Veale, David] Kings Coll London, South London & Maudsley NHS Fdn Trust, NIHR Specialist Biomed Res Ctr Mental Hlth, London WC2R 2LS, England. [Veale, David] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. RP Mckay, D (reprint author), Fordham Univ, Bronx, NY 10458 USA. EM mckay@fordham.edu RI Stein, Dan/A-1752-2008; OI Stein, Dan/0000-0001-7218-7810; Matthews, Keith/0000-0002-4478-5888; McKay, Dean/0000-0003-1158-5043 NR 101 TC 12 Z9 12 U1 6 U2 40 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD FEB PY 2015 VL 225 IS 3 BP 236 EP 246 DI 10.1016/j.psychres.2014.11.058 PG 11 WC Psychiatry SC Psychiatry GA CC2NI UT WOS:000350181500002 PM 25613661 ER PT J AU Oh, JY Yu, BH Heo, JY Yoo, I Song, H Jeon, HJ AF Oh, Jae-Young Yu, Bum-Hee Heo, Jung-Yoon Yoo, Ikki Song, Hyemin Jeon, Hong Jin TI Plasma catecholamine levels before and after paroxetine treatment in patients with panic disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Panic disorder; Catecholamine; Paroxetine ID NERVOUS-SYSTEM ACTIVITY; HEART-RATE-VARIABILITY; ATTACK-LIKE EPISODES; BLOOD-BRAIN-BARRIER; PARKINSONS-DISEASE; ANXIETY DISORDERS; CHRONIC-SCHIZOPHRENIA; CEREBRAL-CIRCULATION; SOCIAL PHOBIA; NOREPINEPHRINE AB Catecholamines such as norepinephrine, epinephrine, and dopamine are closely related to the autonomic nervous system, suggesting that panic disorder may involve elevated catecholamine levels. This study investigated basal and posttreatment catecholamine levels in patients with panic disorder. A total of 29 patients with panic disorder and 23 healthy controls participated in the study. Panic disorder patients received paroxetine treatment for 12 weeks after clinical tests and examination had been conducted. We investigated the difference in basal levels of catecholamine and measured the changes in catecholamine levels before and after drug treatment in panic disorder patients. The basal plasma epinephrine (48.87 +/- 6.18 pg/ml) and dopamine (34.87 +/- 3.57 pg/ml) levels of panic disorder patients were significantly higher than those (34.79 +/- 4.72 pg/ml and 20.40 +/- 3.53 pg/ml) of the control group. However, basal plasma norepinephrine levels did not show statistically significant differences between patients and controls. After drug therapy, plasma catecholamine levels were nonsignificantly decreased and norepinephrine levels showed a tendency toward a decrease that did not reach significance. In conclusion, this study suggests the possibility of a baseline increase of plasma catecholamine levels and activation of sympathetic nervous systems in patients with panic disorder which may normalize after treatment with paroxetine. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Oh, Jae-Young; Yu, Bum-Hee; Heo, Jung-Yoon; Yoo, Ikki; Song, Hyemin; Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. [Jeon, Hong Jin] SAIHST, Seoul, South Korea. [Jeon, Hong Jin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. RP Jeon, HJ (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. EM jeonhj@skku.edu FU Samsung Biomedical Research Institute Grant (SBRI) [C-B1-311]; National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0013064]; Samsung Medical Center Clinical Research Development Program (CRDP) [SMO1131461] FX This research was supported by the Samsung Biomedical Research Institute Grant (SBRI) (C-B1-311). This study was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2011-0013064), and the Samsung Medical Center Clinical Research Development Program (CRDP) Grant SMO1131461. NR 45 TC 1 Z9 1 U1 2 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD FEB PY 2015 VL 225 IS 3 BP 471 EP 475 DI 10.1016/j.psychres.2014.11.065 PG 5 WC Psychiatry SC Psychiatry GA CC2NI UT WOS:000350181500037 PM 25529258 ER PT J AU Maguen, S Skopp, NA Zhang, Y Smolenski, DJ AF Maguen, Shira Skopp, Nancy A. Zhang, Ying Smolenski, Derek J. TI Gender differences in suicide and suicide attempts among US Army soldiers SO PSYCHIATRY RESEARCH LA English DT Article DE Suicide; Military personnel; Female; Mental Health; Risk ID MALE VETERANS; RISK-FACTORS; MILITARY PERSONNEL; IDEATION; SERVICE; PERSPECTIVE; POPULATION; STATES; WORK AB In order to best tailor suicide prevention initiatives and programs, it is critical to gain an understanding of how service members' suicide risk factors may differ by gender. We aimed to better understand gender differences in suicide and suicide attempts among soldiers, including demographic, military, mental health, and other risk factors. We also examined risk factors uniquely associated with suicide and suicide attempts. We conducted a retrospective study of 1857 US Army soldiers who died by suicide or attempted suicide between 2008 and 2010 and had a Department of Defense Suicide Event Report. Female and male soldiers had more similarities than differences when examining risk factors associated with suicide. The only gender difference approaching significance was workplace difficulties, which was more strongly associated with suicide for female soldiers, compared to their male counterparts. Among suicide decedents, the most common risk factor was having a failed intimate relationship in the 90 days prior to suicide. Among those who attempted suicide, the most common risk factor was a major psychiatric diagnosis. Better understanding both gender differences and risk factors uniquely associated with suicide has critical prevention and public health implications as we work to better understand preventable mortality in our youngest generation of service members. Published by Elsevier Ireland Ltd. C1 [Maguen, Shira] San Francisco VA Med Ctr, San Francisco, CA USA. [Maguen, Shira] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Skopp, Nancy A.; Zhang, Ying; Smolenski, Derek J.] Natl Ctr Telehlth & Technol, Def Ctr Excellence Psychol Hlth, Joint Base Lewis McChord, Tacoma, WA USA. [Skopp, Nancy A.; Zhang, Ying; Smolenski, Derek J.] Natl Ctr Telehlth & Technol, Def Ctr Traumat Brain Injury, Joint Base Lewis McChord, Tacoma, WA USA. [Skopp, Nancy A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Maguen, S (reprint author), San Francisco VA Med Ctr, PTSD Program 116 P, 4150 Clement St, San Francisco, CA 94121 USA. EM Shira.Maguen@va.gov NR 24 TC 1 Z9 1 U1 4 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD FEB PY 2015 VL 225 IS 3 BP 545 EP 549 DI 10.1016/j.psychres.2014.11.050 PG 5 WC Psychiatry SC Psychiatry GA CC2NI UT WOS:000350181500048 PM 25530416 ER PT J AU Hartmann, AS Thomas, JJ Greenberg, JL Rosenfield, EH Wilhelm, S AF Hartmann, Andrea S. Thomas, Jennifer J. Greenberg, Jennifer L. Rosenfield, Elizabeth H. Wilhelm, Sabine TI Accept, distract, or reframe? An exploratory experimental comparison of strategies for coping with intrusive body image thoughts in anorexia nervosa and body dysmorphic disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Body image; Anorexia nervosa; Body dysmorphic disorder; Acceptance; Cognitive restructuring; Distraction ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; OBSESSIVE-COMPULSIVE DISORDER; QUALITY-OF-LIFE; COMMITMENT THERAPY; EATING-DISORDERS; CLINICAL-TRIAL; RELIABILITY; SUPPRESSION; MANAGEMENT AB Negative body image is the hallmark of anorexia nervosa (AN) and body dysmorphic disorder (BDD). One aspect of body image, appearance-related thoughts, have shown to be a major contributor to relapse, thus further investigation of successful treatment strategies targeting these maladaptive thoughts are warranted. The present study tested an acceptance/mindfulness (AC), a cognitive restructuring (CR), and a distraction strategy with regard to their short-term effectiveness of reducing the frequency of thought occurrence and associated outcomes in participants with AN (n=20), BDD (n=21), and healthy controls (HC; n=22). Although all strategies led to a significant reduction of thought frequency, there was no group x strategy interaction effect in their reduction. Positive affect increased in the BDD group through the AC strategy, but decreased in healthy controls. Acceptance of the thought increased in the CR strategy in AN, whereas that strategy seemed to work least for BDD. Healthy controls showed most acceptance when using distraction. Taken together, the study suggests that all strategies might have their benefits and that it might be worthwhile further investigating differential indication of the strategies with regard to diagnosis and individual factors. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Hartmann, AS (reprint author), Univ Osnabruck, Dept Human Sci, Inst Psychol, Knollstr 15, D-49069 Osnabruck, Germany. RI Barker, E/F-9367-2015 FU Swiss National Science Foundation [PBSKP1_134330/1, PBSKP1_140040] FX The present study was supported by a post-doctoral fellowship awarded to Andrea S. Hartmann by the Swiss National Science Foundation (PBSKP1_134330/1 and PBSKP1_140040). We would like to thank all of the individuals who participated in this study. NR 66 TC 4 Z9 5 U1 8 U2 41 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD FEB PY 2015 VL 225 IS 3 BP 643 EP 650 DI 10.1016/j.psychres.2014.11.031 PG 8 WC Psychiatry SC Psychiatry GA CC2NI UT WOS:000350181500063 PM 25530419 ER PT J AU Hartoonian, N Terrill, AL Of, MLBUOWS Turner, AP Day, MA Alschuler, KN AF Hartoonian, Narineh Terrill, Alexandra L. Beier, Meghan L. Turner, Aaron P. Day, Melissa A. Alschuler, Kevin N. TI Predictors of Anxiety in Multiple Sclerosis SO REHABILITATION PSYCHOLOGY LA English DT Article DE multiple sclerosis; anxiety; depression ID QUALITY-OF-LIFE; NEGATIVE AFFECTIVITY; DEPRESSION SCALE; HOSPITAL ANXIETY; COMORBID ANXIETY; RISK-FACTORS; DISORDERS; SEVERITY; FATIGUE; PREVALENCE AB Purpose/Objectives: The aims of this study were to (1) identify the predictors of symptoms of anxiety, and (2) evaluate the differential association of somatic and nonsomatic symptoms of depression on anxiety over time in persons with multiple sclerosis (MS). Method/Design: Participants were 513 persons with MS who previously enrolled in a study exploring the experience of living with MS and completed a 4-month follow-up survey. The main outcome measure used was the Hospital Anxiety and Depression Scale-Anxiety. Demographic, disease-associated variables (time since onset of MS, Expanded Disability Status Scale Mobility, pain, and fatigue), and Time 1 psychological variables were entered into a hierarchical regression model to examine predictors at baseline for anxiety symptoms at Time 2. Results: A large portion of the sample was White (92%), female (82%), and had relapsing-remitting MS (57%). After adjusting for demographic and disease related variables, anxiety (beta = .001), employment (beta = .07), and nonsomatic depressive symptoms (beta = .10) at baseline significantly predicted anxiety at Time 2, ps < .05. Interactions revealed significant effects for time since onset of MS and somatic symptoms as well as time since onset and nonsomatic symptoms, ps < .05. Nonsomatic symptoms were more linked to anxiety early in the disease and somatic symptoms were more prominently linked to anxiety later in the disease. Conclusions: Findings suggest that nonsomatic symptoms of depression and employment predict anxiety in MS. The relationship between different aspects of depression and anxiety may change over the course of the disease. C1 [Hartoonian, Narineh; Turner, Aaron P.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Hartoonian, Narineh; Turner, Aaron P.] Vet Affairs Multiple Sclerosis Ctr Excellence Wes, Seattle, WA USA. [Hartoonian, Narineh; Terrill, Alexandra L.; Beier, Meghan L.; Turner, Aaron P.; Alschuler, Kevin N.] Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98195 USA. [Day, Melissa A.] Australian Catholic Univ, Sch Psychol, Sydney, NSW 2059, Australia. RP Hartoonian, N (reprint author), Univ Washington, Sch Med, Dept Rehabil Med, VA Puget Sound Hlth Care Syst, S-117-MSCOE,1660 South Columbia Way, Seattle, WA 98108 USA. EM narhart@uw.edu OI Turner, Aaron/0000-0001-6897-8003 FU Department of Education, NIDRR [H133B031129, H133B080025]; National Institutes of Health through the NIH Roadmap for Medical Research [5U01AR052171-03]; National Multiple Sclerosis Society [MB 0008, MB0026] FX Portions of this article were presented at the 16th annual Rehabilitation Psychology Conference in San Antonio, Texas, March 1, 2014. The contents of this article were developed under grants from the Department of Education, NIDRR Grants H133B031129 and H133B080025. However, these contents do not necessarily represent the policy of the Department of Education, and you should not assume endorsement by the Federal Government. In addition, the work reported in this article was supported by a grant from the National Institutes of Health through the NIH Roadmap for Medical Research, Grant 5U01AR052171-03 to University of Washington, Amtmann (PI), and by grants from the National Multiple Sclerosis Society Grant MB 0008 (Dawn Ehde, PI) and MB0026 (Aaron Turner, PI). NR 40 TC 3 Z9 3 U1 0 U2 7 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0090-5550 EI 1939-1544 J9 REHABIL PSYCHOL JI Rehabil. Psychol. PD FEB PY 2015 VL 60 IS 1 BP 91 EP 98 DI 10.1037/rep0000019 PG 8 WC Psychology, Clinical; Rehabilitation SC Psychology; Rehabilitation GA CC4VV UT WOS:000350353600010 PM 25496434 ER PT J AU Sloan, CA Berke, DS Zeichner, A AF Sloan, Colleen A. Berke, Danielle S. Zeichner, Amos TI Bias-motivated Aggression against Men: Gender Expression and Sexual Orientation as Risk Factors for Victimization SO SEX ROLES LA English DT Article DE Aggression; Gender expression Sexual orientation; Social identity theory Exclusively masculine identity ID GAY MEN; LABORATORY AGGRESSION; PHYSICAL AGGRESSION; ROLE STRESS; ATTITUDES; MASCULINITY; PREJUDICE; WOMEN; HETEROSEXUALS; CONFORMITY AB Bias-motivated aggression is an ongoing problem in the United States, and data show that men comprise the majority of both perpetrators and victims of these types of offenses. Although gay men appear to be at particular risk for victimization, theory suggests that aggression of this type may be understood as a way to preserve exclusive masculine identity and in-group status by punishing those men who step outside rigidly constructed gender boundaries, rather than as a reaction to target sexual orientation alone. As such, studies investigating gender non-conformity as it interacts with gay identity are needed to elucidate how both target gender expression and sexuality potentiate risk for victimization. Therefore, the current study examined the influence of men's sexual orientation and gender expression on the perpetration of bias-motivated aggression. One-hundred two undergraduate men in the Southeastern U.S. participated in a bogus reaction-time task, during which they had the option to shock an ostensible opponent as a measure of aggression. Participants were assigned to one of four opponent conditions (masculine, gay man; feminine, gay man; masculine, heterosexual man; feminine heterosexual man), as part of a 2x2 factorial design. It was predicted that the most aggression would occur toward a gay, feminine opponent. Contrarily, findings indicated that most aggression was evinced toward a feminine heterosexual opponent. Results are discussed in terms of heterosexual men's nonconformity and the influence of in-group/out-group dynamics on bias-motivated aggression. C1 [Sloan, Colleen A.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Berke, Danielle S.; Zeichner, Amos] Univ Georgia, Athens, GA 30602 USA. RP Sloan, CA (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA. EM colleen.sloan2@va.gov NR 44 TC 0 Z9 0 U1 2 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-0025 EI 1573-2762 J9 SEX ROLES JI Sex Roles PD FEB PY 2015 VL 72 IS 3-4 BP 140 EP 149 DI 10.1007/s11199-014-0443-z PG 10 WC Psychology, Developmental; Psychology, Social; Women's Studies SC Psychology; Women's Studies GA CC4QE UT WOS:000350337100005 ER PT J AU Lee, AH Mojica, J Thomas, RJ Bianchi, MT AF Lee, Albert H. Mojica, James Thomas, Robert J. Bianchi, Matt T. TI Dissociation of EEG and autonomic sleep physiology SO SLEEP MEDICINE LA English DT Letter C1 [Lee, Albert H.; Bianchi, Matt T.] Massachusetts Gen Hosp, Dept Neurol, Sleep Div, Boston, MA 02114 USA. [Mojica, James] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Thomas, Robert J.; Bianchi, Matt T.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Thomas, Robert J.] Beth Israel Deaconess Med Ctr, Dept Med, Div Pulm Crit Care & Sleep Med, Boston, MA 02215 USA. RP Bianchi, MT (reprint author), Massachusetts Gen Hosp, Wang 7 Neurol,55 Fruit St, Boston, MA 02114 USA. EM mtbianchi@partners.org NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD FEB PY 2015 VL 16 IS 2 BP 308 EP 309 DI 10.1016/j.sleep.2014.10.009 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CC3CP UT WOS:000350222500016 PM 25620197 ER PT J AU Joseph, RM Fricker, Z Keehn, B AF Joseph, Robert M. Fricker, Zachary Keehn, Brandon TI Activation of frontoparietal attention networks by non-predictive gaze and arrow cues SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE gaze; arrow; visual attention; spatial orienting; intention ID COUNTERPREDICTIVE GAZE; SOCIAL ATTENTION; BRAIN IMAGES; EYE GAZE; ROBUST; SHIFTS; OPTIMIZATION; REGISTRATION; PERCEPTION; VOLUNTARY AB Gaze and arrow cues automatically orient visual attention, even when they have no predictive value, but the neural circuitry by which they direct attention is not clear. Recent evidence has indicated that the ventral frontoparietal attention network is primarily engaged by breaches of a viewer's cue-related expectations. Accordingly, we hypothesized that to the extent that non-predictive gaze and arrow cues automatically engender expectations with regard to cue location, they should activate the ventral attention network when they cue attention invalidly. Using event-related fMRI, we found that invalid gaze but not arrow cues activated the ventral attention network, specifically in the area of the right temporal parietal junction (TPJ), as well as nodes along the dorsal attention network associated with a redirection of attention to the correct target location. In additional whole-brain analyses, facilitation of behavioral response time by valid gaze cues was linearly associated with the degree of activation in the right TPJ. We conclude from our findings that gaze direction elicits potent expectations in humans with regard to an actor's intention that engage attention networks if not differently from, at least more robustly than, arrow cues. C1 [Joseph, Robert M.; Fricker, Zachary] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Fricker, Zachary] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Keehn, Brandon] Boston Childrens Hosp, Labs Cognit Neurosci, Div Dev Med, Boston, MA USA. RP Joseph, RM (reprint author), Boston Univ, Sch Med, Dept Anat & Neurobiol, 72 E Concord St,L 816, Boston, MA 02118 USA. EM rmjoseph@bu.edu OI Keehn, Brandon/0000-0001-8796-2250 FU National Institute of Mental Health [K01 MH 073944] FX This research was supported by a National Institute of Mental Health award (K01 MH 073944) to R.M.J. NR 34 TC 2 Z9 2 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD FEB PY 2015 VL 10 IS 2 BP 294 EP 301 DI 10.1093/scan/nsu054 PG 8 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA CC1NV UT WOS:000350108800018 PM 24748545 ER PT J AU Creager, MA Hiatt, WR Hirsch, AT Olin, JW Jaff, MR Cooke, JP Rooke, T Beckman, JA Froehlich, JB AF Creager, Mark A. Hiatt, William R. Hirsch, Alan T. Olin, Jeffrey W. Jaff, Michael R. Cooke, John P. Rooke, Thom Beckman, Joshua A. Froehlich, James B. TI The Society for Vascular Medicine: The first quarter century SO VASCULAR MEDICINE LA English DT Article DE vascular diseases; professional societies; vascular medicine ID FUTURE; STATEMENT; SURGERY; CARE AB The Society for Vascular Medicine was founded in 1989. During the subsequent 25 years, the Society has grown to approximately 500 members and has achieved international recognition while making important contributions to vascular disease education, clinical vascular medicine and biology research, and patient care. In celebration of the Society's 25th anniversary, its past and current presidents reflect on the Society's history, challenges, and achievements, and emphasize the vital role of the SVM in the discipline of vascular medicine. C1 [Creager, Mark A.; Beckman, Joshua A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hiatt, William R.] Univ Colorado, Sch Med, Denver, CO USA. [Hirsch, Alan T.] Univ Minnesota, Minneapolis, MN USA. [Olin, Jeffrey W.] Mt Sinai Med Sch Med, New York, NY USA. [Jaff, Michael R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Cooke, John P.] Houston Methodist Res Inst, Houston, TX USA. [Rooke, Thom] Mayo Clin, Rochester, MN USA. [Froehlich, James B.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Creager, MA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM Mcreager@partners.org OI Cooke, John/0000-0003-0033-9138; Beckman, Joshua/0000-0001-8332-8439 NR 8 TC 3 Z9 3 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD FEB PY 2015 VL 20 IS 1 BP 60 EP 68 DI 10.1177/1358863X14566042 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CC6JY UT WOS:000350472400008 PM 25722420 ER PT J AU Gray, BH Jaff, MR Slovut, DP Bacharach, JM Carman, T Creager, M Halperin, J von Mering, G Kinlay, S AF Gray, Bruce H. Jaff, Michael R. Slovut, David Paul Bacharach, J. Michael Carman, Terry Creager, Mark Halperin, Jonathon von Mering, Gregory Kinlay, Scott TI dThe first 10 years of the American Board of Vascular Medicine SO VASCULAR MEDICINE LA English DT Article DE credentialing; vascular medicine; vascular diseases AB The American Board of Vascular Medicine (ABVM) was conceived through the Society for Vascular Medicine and this year will complete 10 years of certifying physicians who practice vascular medicine and endovascular medicine. The value of certification to our physicians, patients, and field cannot be understated. This paper reviews the highlights of the test development process, quality assurance measures, and management of these high stakes examinations. C1 [Gray, Bruce H.] Greenville Hlth Syst, Greenville, SC 29605 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Slovut, David Paul] Montefiore Med Ctr, New York, NY USA. [Bacharach, J. Michael] North Cent Heart, Sioux Falls, SD USA. [Carman, Terry] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Creager, Mark] Brigham & Womens Hosp, Boston, MA 02115 USA. [Halperin, Jonathon] Mt Sinai Med Ctr, New York, NY 10029 USA. [von Mering, Gregory] Munroe Reg Med Ctr, Ocala, FL USA. [Kinlay, Scott] VA Boston Healthcare Syst, Boston, MA USA. RP Gray, BH (reprint author), Greenville Hlth Syst, Dept Surg, 701 Grove Rd, Greenville, SC 29605 USA. EM bhgray@ghs.org NR 5 TC 3 Z9 3 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD FEB PY 2015 VL 20 IS 1 BP 69 EP 73 DI 10.1177/1358863X14562857 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CC6JY UT WOS:000350472400009 PM 25520319 ER PT J AU Hilty, DM Belitsky, R Cohen, MB Cabaniss, DL Dickstein, LJ Bernstein, CA Kaplan, AS Scheiber, SC Crisp-Han, HD Wrzosek, MI Silberman, EK AF Hilty, Donald M. Belitsky, Richard Cohen, Mitchell B. Cabaniss, Deborah L. Dickstein, Leah J. Bernstein, Carol A. Kaplan, Allan S. Scheiber, Stephen C. Crisp-Han, Holly D. Wrzosek, Marika I. Silberman, Edward K. TI Impact of the Information Age on Residency Training: Communication, Access to Public Information, and Clinical Care SO ACADEMIC PSYCHIATRY LA English DT Editorial Material DE Psychiatry residents; Supervision; Social media; Electronic communication ID PSYCHIATRY AB Access to technology in practice helps physicians manage information, communicate, and research topics; however, those in training receive almost no formal preparation for integrating web-based technologies into practice. One reason for this is that many faculty-aside from junior faculty or those in recent generations-did not grow up using Internet communication, may use it minimally, if at all, in their own practices, and may know little about its forms and varieties. This report presents a case to illustrate how these disparities may play out in the supervisory situation and makes suggestions about helping supervisors integrate technology-awareness into their teaching. C1 [Hilty, Donald M.] Keck Sch Med USC, Los Angeles, CA 90089 USA. [Belitsky, Richard] Yale Univ, Sch Med, New Haven, CT USA. [Cohen, Mitchell B.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Cabaniss, Deborah L.] Columbia Univ, New York, NY USA. [Dickstein, Leah J.] Assoc Women Psychiatrists, Dallas, TX USA. [Bernstein, Carol A.] Amer Psychiat Assoc, Arlington, VA USA. [Kaplan, Allan S.] Univ Toronto, Toronto, ON, Canada. [Scheiber, Stephen C.] Amer Board Psychiat & Neurol, Etobicoke, ON, Canada. [Crisp-Han, Holly D.] Gabbard Ctr, Bellaire, TX USA. [Wrzosek, Marika I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Silberman, Edward K.] Tufts Med Ctr, Boston, MA USA. RP Hilty, DM (reprint author), Keck Sch Med USC, Los Angeles, CA 90089 USA. EM hilty@usc.edu NR 10 TC 4 Z9 4 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD FEB PY 2015 VL 39 IS 1 BP 104 EP 107 DI 10.1007/s40596-014-0196-6 PG 4 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA CB0GV UT WOS:000349304800019 PM 25124878 ER PT J AU Fan, J Teng, X Liu, L Mattaini, KR Looper, RE Vander Heiden, MG Rabinowitz, JD AF Fan, Jing Teng, Xin Liu, Ling Mattaini, Katherine R. Looper, Ryan E. Vander Heiden, Matthew G. Rabinowitz, Joshua D. TI Human Phosphoglycerate Dehydrogenase Produces the Oncometabolite D-2-Hydroxyglutarate SO ACS CHEMICAL BIOLOGY LA English DT Article ID 3-PHOSPHOGLYCERATE DEHYDROGENASE; LIQUID-CHROMATOGRAPHY; METABOLOMIC ANALYSIS; BREAST-CANCER; 2-HYDROXYGLUTARATE; MUTATIONS; ACIDURIA; SERINE; IDH1; FLUX AB Human D-3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the serine biosynthetic pathway, is genomically amplified in tumors including breast cancer and melanoma. In PHGDH-amplified cancer cells, knockdown of PHGDH is not fully rescued by exogenous serine, suggesting possible additional growth-promoting roles for the enzyme. Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite D-2-hydroxyglutarate (D-2HG). Knockdown of PHGDH decreased cellular 2HG by approximately 50% in the PHGDH-amplified breast cancer cell lines MDA-MB-468 (normal concentration 93 mu M) and BT-20 (normal concentration 35 mu M) and overexpression of PHGDH increased cellular 2HG by over 2-fold in non-PHGDH-amplified MDA-MB-231 breast cancer cells, which normally display very low PHGDH expression. The reduced 2HG level in PHGDH knockdown cell lines can be rescued by PHGDH re-expression, but not by a catalytically inactive PHGDH mutant. The initial connection between cancer and D-2HG involved production of high levels of D-2HG by mutant isocitrate dehydrogenase. More recently, however, elevated D-2HG has been observed in breast cancer tumors without isocitrate dehydrogenase mutation. Our results suggest that PHGDH is one source of this d-2HG. C1 [Fan, Jing; Teng, Xin; Liu, Ling; Rabinowitz, Joshua D.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Looper, Ryan E.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Fan, Jing; Teng, Xin; Liu, Ling; Rabinowitz, Joshua D.] Princeton Univ, Dept Chem & Mol Biol, Princeton, NJ 08544 USA. [Rabinowitz, Joshua D.] Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Mattaini, Katherine R.; Vander Heiden, Matthew G.] MIT, Koch Inst, Cambridge, MA 02139 USA. [Mattaini, Katherine R.; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Rabinowitz, JD (reprint author), Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. EM joshr@genomics.princeton.edu OI Looper, Ryan/0000-0003-1626-1363 FU NIH [1R01CA163591, P50GM071508, P30CA14051]; NSF; AACR; Burroughs Wellcome Fund; Howard Hughes Medical Institute (HHMI) international student research fellowship FX We thank K. Olszewski for generously sharing the strep-tagged enzyme and helpful discussions and S. Zhang for help with GC-MS analysis. This work was supported by NIH grants 1R01CA163591 and P50GM071508. We also acknowledge support from NIH P30CA14051, NSF, AACR, and the Burroughs Wellcome Fund. J. Fan was supported by a Howard Hughes Medical Institute (HHMI) international student research fellowship. NR 27 TC 21 Z9 21 U1 0 U2 65 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD FEB PY 2015 VL 10 IS 2 BP 510 EP 516 DI 10.1021/cb500683c PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CB9HN UT WOS:000349942700020 PM 25406093 ER PT J AU Kong, XT Khan, AA Kidambi, PR Deng, S Yetisen, AK Dlubak, B Hiralal, P Montelongo, Y Bowen, J Xavier, S Jiang, K Amaratunga, GAJ Hofmann, S Wilkinson, TD Dai, Q Butt, H AF Kong, Xiang-Tian Khan, Ammar A. Kidambi, Piran R. Deng, Sunan Yetisen, Ali K. Dlubak, Bruno Hiralal, Pritesh Montelongo, Yunuen Bowen, James Xavier, Stephane Jiang, Kyle Amaratunga, Gehan A. J. Hofmann, Stephan Wilkinson, Timothy D. Dai, Qing Butt, Haider TI Graphene-Based Ultrathin Flat Lenses SO ACS PHOTONICS LA English DT Article DE graphene; thin lenses; Fresnel zone plates ID FRESNEL LENS; FABRICATION; LITHOGRAPHY; DIFFRACTION; DESIGN; GROWTH AB Flat lenses when compared to curved surface lenses have the advantages of being aberration free, and they offer a compact design necessary for a myriad of electro-optical applications. In this paper we present flat and ultrathin lenses based on graphene, the world's thinnest known material. Monolayers and multilayers of graphene were fabricated into Fresnel zones to produce Fresnel zone plates, which utilize the reflection and transmission properties of graphene for their operation. The working of the lenses and their performance in the visible and terahertz regimes were analyzed computationally. Experimental measurements I characterize the lens in the visible regime, and a good agreement was obtained with the simulations. principle of atom thick graphene-based lenses, with perspectives for ultracompact integration. were also performed to This work demonstrates the principle of atom thick graphene-based lenses, with perspectives for ultracompact integration. C1 [Kong, Xiang-Tian; Dai, Qing] Natl Ctr Nanosci & Technol, Beijing 100190, Peoples R China. [Khan, Ammar A.; Kidambi, Piran R.; Dlubak, Bruno; Hiralal, Pritesh; Montelongo, Yunuen; Amaratunga, Gehan A. J.; Hofmann, Stephan; Wilkinson, Timothy D.] Univ Cambridge, Elect Engn Div, Dept Engn, Cambridge CB3 0FA, England. [Deng, Sunan; Jiang, Kyle; Butt, Haider] Univ Birmingham, Sch Mech Engn, Birmingham B15 2TT, W Midlands, England. [Yetisen, Ali K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yetisen, Ali K.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Bowen, James] Univ Birmingham, Sch Chem Engn, Birmingham B15 2TT, W Midlands, England. [Hofmann, Stephan] Thales Res & Technol, F-91767 Palaiseau, France. RP Dai, Q (reprint author), Natl Ctr Nanosci & Technol, Beijing 100190, Peoples R China. EM daiq@nanoctr.cn; h.butt@bham.ac.uk RI Kong, Xiang-Tian/G-2410-2014; Bowen, James/B-9874-2011; Montelongo, Yunuen/H-4955-2012; Hofmann, Stephan/D-3906-2012 OI Dlubak, Bruno/0000-0001-5696-8991; Butt, Haider/0000-0003-2434-9525; Kong, Xiang-Tian/0000-0002-8554-0369; Bowen, James/0000-0002-8452-0139; Montelongo, Yunuen/0000-0002-1266-183X; Hofmann, Stephan/0000-0001-6375-1459 FU Lindemann Trust Fellowship; Leverhulme Trust; Bureau of International Cooperation, Chinese Academy of Sciences [121D11KYSB20130013] FX P.R.K. acknowledges the Lindemann Trust Fellowship. H.B. would like to thank The Leverhulme Trust for the research funding. Q.D. is supported by Bureau of International Cooperation, Chinese Academy of Sciences (121D11KYSB20130013). NR 28 TC 15 Z9 15 U1 10 U2 37 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2330-4022 J9 ACS PHOTONICS JI ACS Photonics PD FEB PY 2015 VL 2 IS 2 BP 200 EP 207 DI 10.1021/ph500197j PG 8 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Optics; Physics, Applied; Physics, Condensed Matter SC Science & Technology - Other Topics; Materials Science; Optics; Physics GA CB7NP UT WOS:000349814400006 ER PT J AU Tipps, ME Raybuck, JD Buck, KJ Lattal, KM AF Tipps, Megan E. Raybuck, Jonathan D. Buck, Kari J. Lattal, K. Matthew TI Acute Ethanol Withdrawal Impairs Contextual Learning and Enhances Cued Learning SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Acute Ethanol Withdrawal; Fear Conditioning; Strain Comparison; Hippocampus ID INDUCED MEMORY IMPAIRMENT; QUANTITATIVE TRAIT LOCI; ALCOHOL HANGOVER; C57BL/6 MICE; RAT HIPPOCAMPUS; MOUSE STRAINS; INBRED MICE; DBA/2 MICE; FEAR; TRACE AB BackgroundAlcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure. MethodsWe assess the effects of acute ethanol withdrawal (6hours postinjection with 4g/kg ethanol) on 2 forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post training withdrawal exposure; foreground/background processing; training strength; and nonassociative effects) is also investigated. ResultsAcute ethanol withdrawal during training had a bidirectional effect on fear-conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses. ConclusionsOur results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes. C1 [Tipps, Megan E.; Buck, Kari J.] Portland VA Med Ctr, Portland Alcohol Res Ctr, Portland, OR USA. [Tipps, Megan E.; Raybuck, Jonathan D.; Buck, Kari J.; Lattal, K. Matthew] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. RP Tipps, ME (reprint author), VA Med Ctr, Dept Behav Neurosci, Mail Code L470, Portland, OR 97239 USA. EM metipps@gmail.com FU NIH [F32 AA022011, T32 AA07468, F32 DA031537, T32 DA07262, R01 AA011114, P60 AA10760, R24 AA020245, R01 DA005228, R01 DA025922]; VA; US Department of the Army/DOD-TAT-RC [W81XWH-12-2-0048] FX This work was supported by NIH F32 AA022011 and T32 AA07468 (MET); NIH F32 DA031537 and T32 DA07262 (JDR); NIH R01 AA011114, P60 AA10760, R24 AA020245, R01 DA005228, and the VA (KJB); and NIH R01 DA025922 and US Department of the Army/DOD-TAT-RC:W81XWH-12-2-0048 (KML). NR 50 TC 4 Z9 5 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2015 VL 39 IS 2 BP 282 EP 290 DI 10.1111/acer.12614 PG 9 WC Substance Abuse SC Substance Abuse GA CC1KZ UT WOS:000350100900009 PM 25684050 ER PT J AU Marshall, BDL Shoveller, JA Kahler, CW Koblin, BA Mayer, KH Mimiaga, MJ van den Berg, JJ Zaller, ND Operario, D AF Marshall, Brandon D. L. Shoveller, Jean A. Kahler, Christopher W. Koblin, Beryl A. Mayer, Kenneth H. Mimiaga, Matthew J. van den Berg, Jacob J. Zaller, Nickolas D. Operario, Don TI Heavy Drinking Trajectories Among Men Who Have Sex with Men: A Longitudinal, Group-Based Analysis SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol; Men Who Have Sex With Men; Depression; Substance Use; Educational Attainment ID ALCOHOL-USE; SUBSTANCE USE; EDUCATIONAL-ATTAINMENT; HIV-INFECTION; YOUNG MEN; DRUG-USE; DEVELOPMENTAL TRAJECTORIES; CAGE QUESTIONNAIRE; EPISODIC DRINKING; BINGE DRINKING AB BackgroundHeavy episodic drinking (HED) is associated with sexual risk behavior and HIV seroconversion among men who have sex with men (MSM), yet few studies have examined heavy drinking typologies in this population. MethodsWe analyzed data from 4,075 HIV-uninfected MSM (aged 16 to 88) participating in EXPLORE, a 48-month behavioral intervention trial, to determine the patterns and predictors of HED trajectories. HED was defined as the number of days in which 5 alcohol drinks were consumed in the past 6months. Longitudinal group-based mixture models were used to identify HED trajectories, and multinomial logistic regression was used to determine correlates of membership in each group. ResultsWe identified 5 distinct HED trajectories: nonheavy drinkers (31.9%); infrequent heavy drinkers (i.e., <10 heavy drinking days per 6-month period, 54.3%); regular heavy drinkers (30 to 45 heavy drinking days per 6months, 8.4%); drinkers who increased HED over time (average 33days in the past 6months to 77days at end of follow-up, 3.6%); and very frequent heavy drinkers (>100days per 6months, 1.7%). Intervention arm did not predict drinking trajectory patterns. Younger age, self-identifying as white, lower educational attainment, depressive symptoms, and stimulant use were associated with reporting heavier drinking trajectories. Compared to nonheavy drinkers, participants who increased HED more often experienced a history of childhood sexual abuse (CSA). Over the study period, depressive symptomatology increased significantly among very frequent heavy drinkers. ConclusionsSocioeconomic factors, substance use, depression, and CSA were associated with heavier drinking patterns among MSM. Multicomponent interventions to reduce HED should seek to mitigate the adverse impacts of low educational attainment, depression, and early traumatic life events on the initiation, continuation, or escalation of frequent HED among MSM. C1 [Marshall, Brandon D. L.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Shoveller, Jean A.] Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Kahler, Christopher W.; van den Berg, Jacob J.; Operario, Don] Brown Univ, Sch Publ Hlth, Dept Behav & Social Sci, Providence, RI 02912 USA. [Kahler, Christopher W.] Brown Univ, Alcohol Res Ctr HIV AIDS, Providence, RI 02912 USA. [Koblin, Beryl A.] New York Blood Ctr, New York, NY 10021 USA. [Mayer, Kenneth H.; Mimiaga, Matthew J.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Mayer, Kenneth H.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Mayer, Kenneth H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [van den Berg, Jacob J.; Zaller, Nickolas D.] Miriam Hosp, Div Infect Dis, Providence, RI 02906 USA. RP Marshall, BDL (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 South Main St,Box G-S-121-2, Providence, RI 02912 USA. EM brandon_marshall@brown.edu FU U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U24-AA022000, P01-AA019072]; U.S. National Institute of Allergy and Infectious Diseases (NIAID) through the Lifespan/Tufts/Brown Center for AIDS Research [P30-AI042853]; HIV Prevention Trials Network; NIAID; NIAAA, of the National Institutes of Health, Department of Health and Human Services [N01-AI35176]; Abt Associates Inc. [N01-AI45200]; Fred Hutchinson Cancer Research Center; Denver Public Health; Fenway Community Health Center; Howard Brown Health Center; New York Blood Center; Public Health Foundation Inc.; University of Washington; National Institute of Child Health and Human Development (NICHD); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research of the National Institutes of Health, U.S. Department of Health and Human Services; Family Health International [U01-AI46749, U01-AI48040, U01-AI48016, U01-AI47981, U01-AI47995] FX This work was funded by the U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants U24-AA022000 and P01-AA019072, and in part by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) grant P30-AI042853 through the Lifespan/Tufts/Brown Center for AIDS Research. The EXPLORE study was originally supported by the HIV Prevention Trials Network as study HIVNET 015 and was sponsored by the NIAID and NIAAA, of the National Institutes of Health, Department of Health and Human Services, through: contract N01-AI35176 with Abt Associates Inc.; contract N01-AI45200 with the Fred Hutchinson Cancer Research Center; and subcontracts with the Denver Public Health, the Fenway Community Health Center, the Howard Brown Health Center, the New York Blood Center, the Public Health Foundation Inc., and the University of Washington. This work was additionally sponsored by the National Institute of Child Health and Human Development (NICHD), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Office of AIDS Research of the National Institutes of Health, U.S. Department of Health and Human Services, through: a cooperative agreement with Family Health International (U01-AI46749) with a subsequent subcontract to Abt Associates Inc. with subcontracts to the Howard Brown Health Center and Denver Public Health; cooperative agreement U01-AI48040 to the Fenway Community Health Center; cooperative agreement U01-AI48016 to Columbia University (including a sub-agreement with the New York Blood Center); a cooperative agreement U01-AI47981 to the University of Washington; and cooperative agreement U01-AI47995 to the University of California, San Francisco. NR 49 TC 4 Z9 4 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2015 VL 39 IS 2 BP 380 EP 389 DI 10.1111/acer.12631 PG 10 WC Substance Abuse SC Substance Abuse GA CC1KZ UT WOS:000350100900021 PM 25684055 ER PT J AU Schaefer, PW Pulli, B Copen, WA Hirsch, JA Leslie-Mazwi, T Schwamm, LH Wu, O Gonzalez, RG Yoo, AJ AF Schaefer, P. W. Pulli, B. Copen, W. A. Hirsch, J. A. Leslie-Mazwi, T. Schwamm, L. H. Wu, O. Gonzalez, R. G. Yoo, A. J. TI Combining MRI with NIHSS Thresholds to Predict Outcome in Acute Ischemic Stroke: Value for Patient Selection SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID SCALE SCORE; LESION VOLUMES; THROMBOLYSIS; DIFFUSION; PERFUSION; ALTEPLASE; TRIAL AB BACKGROUND AND PURPOSE: Selecting acute ischemic stroke patients for reperfusion therapy on the basis of a diffusion-perfusion mismatch has not been uniformly proved to predict a beneficial treatment response. In a prior study, we have shown that combining clinical with MR imaging thresholds can predict clinical outcome with high positive predictive value. In this study, we sought to validate this predictive model in a larger patient cohort and evaluate the effects of reperfusion therapy and stroke side. MATERIALS AND METHODS: One hundred twenty-three consecutive patients with anterior circulation acute ischemic stroke underwent MR imaging within 6 hours of stroke onset. DWI and PWI volumes were measured. Lesion volume and NIHSS score thresholds were used in models predicting good 3-month clinical outcome (mRS 0-2). Patients were stratified by treatment and stroke side. RESULTS: Receiver operating characteristic analysis demonstrated 95.6% and 100% specificity for DWI > 70 mL and NIHSS score > 20 to predict poor outcome, and 92.7% and 91.3% specificity for PWI (mean transit time) < 50 mL and NIHSS score < 8 to predict good outcome. Combining clinical and imaging thresholds led to an 88.8% (71/80) positive predictive value with a 65.0% (80/123) prognostic yield. One hundred percent specific thresholds for DWI (103 versus 31 mL) and NIHSS score (20 versus 17) to predict poor outcome were significantly higher in treated (intravenous and/or intra-arterial) versus untreated patients. Prognostic yield was lower in right-versus left-sided strokes for all thresholds (10.4%-20.7% versus 16.9%-40.0%). Patients with right-sided strokes had higher 100% specific DWI (103.1 versus 74.8 mL) thresholds for poor outcome, and the positive predictive value was lower. CONCLUSIONS: Our predictive model is validated in a much larger patient cohort. Outcome may be predicted in up to two-thirds of patients, and thresholds are affected by stroke side and reperfusion therapy. C1 [Schaefer, P. W.; Pulli, B.; Copen, W. A.; Hirsch, J. A.; Leslie-Mazwi, T.; Wu, O.; Gonzalez, R. G.; Yoo, A. J.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Schwamm, L. H.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Schaefer, PW (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neuroradiol Div, 55 Fruit St, Boston, MA 02114 USA. EM pschaefer@partners.org FU National Institutes of Health [R01NS059775, R01NS063925, P50NS051343, P41EB015896] FX Joshua A. Hirsch-UNRELATED: Consultancy: CareFusion, Comments: In > 24 months and < 36 months, I received compensation related to vertebral augmentation; Royalties: CareFusion (as above); Stock/Stock Options: Intratech, Comments: development-stage company for interventional stroke products. Lee H. Schwamm-UNRELATED: Consultancy: Lundbeck, Comments: Member of data safety monitoring board for Desmoteplase In Acute Ischemic Stroke trial three-fourths trials of desmoteplase; Grants/Grants Pending: National Institute of Neurological Disorders and Stroke/Genentech,* Comments: Genentech provides drugs free of charge and some supplemental site payments for the MR WITNESS trial of extended window thrombolysis (Dr Schwamm is the Principal Investigator). Ona Wu-RELATED: Grant: National Institutes of Health,* Comments: R01NS059775, R01NS063925, P50NS051343, P41EB015896; UNRELATED: Consultancy: Penumbra, Comments: provided consultancy regarding digital imaging and communications in medicine servers and clients; Grants/Grants Pending. Genentech,* Comments: Genentech has provided funds to MR WITNESS to help per-subject reimbursement for each site; OTHER RELATIONSHIPS: I have a patent on "Delay-Compensated Calculation of Tissue Blood Flow," US Patent 7,512,435, March 31, 2009, and the patent has been licensed to GE Healthcare, Siemens, Imaging Biometric, and lea Medical. Albert). Yoo-UNRELATED: Grants/Grants Pending Penumbra,* Comments: core imaging lab. *Money paid to the institution. NR 20 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 2015 VL 36 IS 2 BP 259 EP 264 DI 10.3174/ajnr.A4103 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CB5GR UT WOS:000349656000006 PM 25258369 ER PT J AU Deipolyi, AR Hamberg, LM Gonzalez, RG Hirsch, JA Hunter, GJ AF Deipolyi, A. R. Hamberg, L. M. Gonzalez, R. G. Hirsch, J. A. Hunter, G. J. TI Diagnostic Yield of Emergency Department Arch-to-Vertex CT Angiography in Patients with Suspected Acute Stroke SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; PERFUSION; FEASIBILITY; ASSOCIATION AB BACKGROUND AND PURPOSE: Our aim was to investigate how often relevant diagnostic findings in an arch-to-vertex CTA scan, obtained specifically as part of the acute stroke CT protocol, are located in the head, neck, and upper chest regions. MATERIALS AND METHODS: Radiology reports were reviewed in 302 consecutive patients (170 men, 132 women; median ages, 66 and 73 years, respectively) who underwent emergency department investigation of suspected acute stroke between January and July 2010. Diagnostic CTA findings relevant to patient management were recorded for the head, neck, and chest regions individually. Additionally, the contributions to the total CTA scan effective dose were estimated from each of the 3 anatomic regions by using the ImPACT CT Dose Calculator. RESULTS: Of the 302 patients, 161 (54%) had relevant diagnostic findings in the head; 94 (31%), in the neck; and 4 (1%), in the chest. The estimated contributions to the total CIA scan dose from each body region, head, neck, and upper chest, were 14 +/- 2%, 33 +/- 5%, and 53 +/- 6%, respectively. CONCLUSIONS: Most clinically relevant findings are in the head and neck, supporting inclusion of these regions in arch-to-vertex CTA performed specifically in patients with acute stroke in the emergency department. Further studies are required to investigate extending the scan to the upper chest because only 1% of patients in our study had clinically relevant findings in the mediastinum, yet half the CTA effective dose was due to scanning in this region. C1 [Deipolyi, A. R.; Gonzalez, R. G.; Hirsch, J. A.; Hunter, G. J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hamberg, L. M.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Hunter, GJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM gjhunter@partners.org OI Deipolyi, Amy/0000-0003-3144-386X NR 22 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 2015 VL 36 IS 2 BP 265 EP 268 DI 10.3174/ajnr.A4112 PG 4 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CB5GR UT WOS:000349656000007 PM 25258370 ER PT J AU Gaddikeri, S Andre, JB Benjert, J Hippe, DS Anzai, Y AF Gaddikeri, S. Andre, J. B. Benjert, J. Hippe, D. S. Anzai, Y. TI Impact of Model-Based Iterative Reconstruction on Image Quality of Contrast-Enhanced Neck CT SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID FILTERED BACK-PROJECTION; MULTIDETECTOR ROW CT; COMPUTED-TOMOGRAPHY; DOSE REDUCTION; RADIATION-EXPOSURE; HELICAL CT; OPTIMIZATION; STRATEGIES; 64-MDCT; CANCER AB BACKGROUND AND PURPOSE: Improved image quality is clinically desired for contrast-enhanced CT of the neck. We compared 30% adaptive statistical iterative reconstruction and model-based iterative reconstruction algorithms for the assessment of image quality of contrast-enhanced CT of the neck. MATERIALS AND METHODS: Neck contrast-enhanced CT data from 64 consecutive patients were reconstructed retrospectively by using 30% adaptive statistical iterative reconstruction and model-based iterative reconstruction. Objective image quality was assessed by comparing SNR, contrast-to-noise ratio, and background noise at levels 1 (mandible) and 2 (superior mediastinum). Two independent blinded readers subjectively graded the image quality on a scale of 1-5, (grade 5 = excellent image quality without artifacts and grade 1 = nondiagnostic image quality with significant artifacts). The percentage of agreement and disagreement between the 2 readers was assessed. RESULTS: Compared with 30% adaptive statistical iterative reconstruction, model-based iterative reconstruction significantly improved the SNR and contrast-to-noise ratio at levels 1 and 2. Model-based iterative reconstruction also decreased background noise at level] (P = .016), though there was no difference at level 2 (P = .61). Model-based iterative reconstruction was scored higher than 30% adaptive statistical iterative reconstruction by both reviewers at the nasopharynx (P < .001) and oropharynx (P < .001) and for overall image quality (P < .001) and was scored lower at the vocal cords (P < .001) and sternoclavicular junction (P < .001), due to artifacts related to thyroid shielding that were specific for model-based iterative reconstruction. CONCLUSIONS: Model-based iterative reconstruction offers improved subjective and objective image quality as evidenced by a higher SNR and contrast-to-noise ratio and lower background noise within the same dataset for contrast-enhanced neck CT. Model-based iterative reconstruction has the potential to reduce the radiation dose while maintaining the image quality, with a minor downside being prominent artifacts related to thyroid shield use on model-based iterative reconstruction. C1 [Gaddikeri, S.; Andre, J. B.; Anzai, Y.] Univ Washington, Med Ctr, Dept Neuroradiol, Seattle, WA 98195 USA. [Benjert, J.] Univ Washington, Dept Neuroradiol, Seattle, WA 98195 USA. VA Puget Sound, Seattle, WA USA. [Hippe, D. S.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. RP Gaddikeri, S (reprint author), Univ Washington, Med Ctr, Dept Radiol, 1959 NE Pacific St,Box 357115, Seattle, WA 98195 USA. EM sg272@uw.edu OI Andre, Jalal/0000-0002-0896-183X NR 31 TC 5 Z9 5 U1 0 U2 3 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 2015 VL 36 IS 2 BP 391 EP 396 DI 10.3174/ajnr.A4123 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CB5GR UT WOS:000349656000027 PM 25300982 ER PT J AU Le Bas-Bernardet, S Tillou, X Branchereau, J Dilek, N Poirier, N Chatelais, M Charreau, B Minault, D Hervouet, J Renaudin, K Crossan, C Scobie, L Takeuchi, Y Diswall, M Breimer, ME Klar, N Daha, MR Simioni, P Robson, SC Nottle, MB Salvaris, EJ Cowan, PJ d'Apice, AJF Sachs, DH Yamada, K Lagutina, I Duchi, R Perota, A Lazzari, G Galli, C Cozzi, E Soulillou, JP Vanhove, B Blancho, G AF Le Bas-Bernardet, S. Tillou, X. Branchereau, J. Dilek, N. Poirier, N. Chatelais, M. Charreau, B. Minault, D. Hervouet, J. Renaudin, K. Crossan, C. Scobie, L. Takeuchi, Y. Diswall, M. Breimer, M. E. Klar, N. Daha, M. R. Simioni, P. Robson, S. C. Nottle, M. B. Salvaris, E. J. Cowan, P. J. d'Apice, A. J. F. Sachs, D. H. Yamada, K. Lagutina, I. Duchi, R. Perota, A. Lazzari, G. Galli, C. Cozzi, E. Soulillou, J. -P. Vanhove, B. Blancho, G. TI Bortezomib, C1-Inhibitor and Plasma Exchange Do Not Prolong the Survival of Multi-Transgenic GalT-KO Pig Kidney Xenografts in Baboons SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID ALPHA-1,3-GALACTOSYLTRANSFERASE KNOCKOUT PIGS; PORCINE ENDOGENOUS RETROVIRUS; N-GLYCOLYLNEURAMINIC ACID; EX-VIVO MODEL; NUCLEAR TRANSFER; XENOTRANSPLANTATION MODEL; COMPLEMENT ACTIVATION; CARDIAC XENOGRAFTS; RENAL XENOGRAFTS; EARLY REJECTION AB Galactosyl-transferase KO (GalT-KO) pigs represent a potential solution to xenograft rejection, particularly in the context of additional genetic modifications. We have performed life supporting kidney xenotransplantation into baboons utilizing GalT-KO pigs transgenic for human CD55/CD59/CD39/HT. Baboons received tacrolimus, mycophenolate mofetil, corticosteroids and recombinant human C1 inhibitor combined with cyclophosphamide or bortezomib with or without 2-3 plasma exchanges. One baboon received a control GalT-KO xenograft with the latter immunosuppression. All immunosuppressed baboons rejected the xenografts between days 9 and 15 with signs of acute humoral rejection, in contrast to untreated controls (n = 2) that lost their grafts on days 3 and 4. Immunofluorescence analyses showed deposition of IgM, C3, C5b-9 in rejected grafts, without C4d staining, indicating classical complement pathway blockade but alternate pathway activation. Moreover, rejected organs exhibited predominantly monocyte/macrophage infiltration with minimal lymphocyte representation. None of the recipients showed any signs of porcine endogenous retrovirus transmission but some showed evidence of porcine cytomegalovirus (PCMV) replication within the xenografts. Our work indicates that the addition of bortezomib and plasma exchange to the immunosuppressive regimen did not significantly prolong the survival of multi-transgenic GalT-KO renal xenografts. Non-Gal antibodies, the alternative complement pathway, innate mechanisms with monocyte activation and PCMV replication may have contributed to rejection. C1 [Le Bas-Bernardet, S.; Tillou, X.; Branchereau, J.; Dilek, N.; Poirier, N.; Chatelais, M.; Charreau, B.; Minault, D.; Hervouet, J.; Soulillou, J. -P.; Vanhove, B.; Blancho, G.] Univ Nantes, Inst Transplantat Urol Nephrol, INSERM, CHU Nantes,UMRS 1064, Nantes, France. [Dilek, N.; Poirier, N.; Vanhove, B.] Effimune, Nantes, France. [Renaudin, K.] CHU Hotel Dieu, Pathol Lab, Nantes, France. [Crossan, C.; Scobie, L.] Glasgow Caledonian Univ, Dept Biol & Biomed Sci, Glasgow G4 0BA, Lanark, Scotland. [Takeuchi, Y.] UCL, Med Res Council Ctr Med Virol, London, England. [Takeuchi, Y.] UCL, Wohl Virion Ctr, Div Infect & Immun, London, England. [Diswall, M.; Breimer, M. E.] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Surg, Gothenburg, Sweden. [Klar, N.; Daha, M. R.] Univ Med Ctr, Dept Nephrol, Leiden, Netherlands. [Simioni, P.] Univ Padua, Dept Cardiol Thorac & Vasc Sci, Padua, Italy. [Robson, S. C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Gastroenterol & Transplant Inst,Dept Med, Boston, MA 02215 USA. [Nottle, M. B.] Univ Adelaide, Sch Paediat & Reprod Hlth, Robinson Inst, Adelaide, SA, Australia. [Salvaris, E. J.; Cowan, P. J.; d'Apice, A. J. F.] St Vincents Hosp, Immunol Res Ctr, Melbourne, Vic, Australia. [Sachs, D. H.; Yamada, K.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Sachs, D. H.; Yamada, K.] Harvard Univ, Sch Med, Boston, MA USA. [Lagutina, I.; Duchi, R.; Perota, A.; Lazzari, G.; Galli, C.] Avantea, Cremona, Italy. [Galli, C.] Univ Bologna, Dept Vet Med Sci, Ozzano Dell Emilia, Italy. [Cozzi, E.] Padua Hosp, Transplant Immunol Unit, Padua, Italy. [Cozzi, E.] Consortium Res Organ Transplantat, Padua, Italy. RP Blancho, G (reprint author), Univ Nantes, Inst Transplantat Urol Nephrol, INSERM, CHU Nantes,UMRS 1064, Nantes, France. EM gilles.blancho@chu-nantes.fr OI SIMIONI, PAOLO/0000-0002-6744-383X FU European Commission [LSHB-CT-2006-037377]; NIH [5P01AI45897] FX We thank Edwin van Amersfoort (Pharming Technologies BV) for supplying the rhC1-INH, Dr. Franco Caffi (Prosus, Scrl) for the access to pig ovaries, and Paola Turini, Gabriella Crotti and Silvia Colleoni (Avantea) for technical support in cloning pigs for this study. The following reagent was obtained through the NIH Nonhuman Primate Reagent Resource: antiCD38 Ab (OKT10). This work was supported by the European Commission's Sixth Framework Programme, under the priority thematic area Life Sciences, Genomics and Biotechnology for Health, contract No. LSHB-CT-2006-037377, XENOME and by NIH Grant number 5P01AI45897. NR 49 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD FEB PY 2015 VL 15 IS 2 BP 358 EP 370 DI 10.1111/ajt.12988 PG 13 WC Surgery; Transplantation SC Surgery; Transplantation GA CB9UQ UT WOS:000349979100015 PM 25612490 ER PT J AU Mezochow, AK Henry, R Blumberg, EA Kotton, CN AF Mezochow, A. K. Henry, R. Blumberg, E. A. Kotton, C. N. TI Transfusion Transmitted Infections in Solid Organ Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID WEST-NILE-VIRUS; PRIMARY CYTOMEGALOVIRUS-INFECTION; LIVER-TRANSPLANTATION; BLOOD-TRANSFUSION; MULTIVARIATE-ANALYSIS; HEART-TRANSPLANT; RESIDUAL RISK; UNITED-STATES; TRANSMISSION; RECIPIENTS AB While the risk of infectious disease transmission through blood transfusion has been greatly reduced as a result of improved screening methods, transfusion-transmissible infections remain a concern for transplant recipients, especially those receiving multiple transfusions. Although transfusion and transplant recipients are at risk for similar infections, the current reporting requirements for infections transmitted by transfusions and organ transplantation vary greatly and remain distinctly separate with no communication between reporting systems. This article reviews 23 past reports of transfusion-transmitted infections in organ recipients acquired through transfusions. While cytomegalovirus was a major focus of such reports in the 1980s, more recent reports have focused on West Nile virus transmission. Additionally, this article highlights challenges in determining transfusion-transmitted infection risk in transplant recipients related to the current reporting systems. C1 [Mezochow, A. K.; Henry, R.] US Dept HHS, Off Assistant Secretary Hlth, Div Blood & Tissue Safety & Availabil, Washington, DC 20201 USA. [Blumberg, E. A.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kotton, C. N.] Harvard Univ, Sch Med, Dept Med, Div Infect Dis,Massachusetts Gen Hosp, Boston, MA 02138 USA. RP Kotton, CN (reprint author), Harvard Univ, Sch Med, Dept Med, Div Infect Dis,Massachusetts Gen Hosp, Boston, MA 02138 USA. EM CKOTTON@mgh.harvard.edu NR 41 TC 3 Z9 3 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD FEB PY 2015 VL 15 IS 2 BP 547 EP 554 DI 10.1111/ajt.13006 PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA CB9UQ UT WOS:000349979100035 PM 25612502 ER PT J AU Meerwijk, EL Ford, JM Weiss, SJ AF Meerwijk, Esther L. Ford, Judith M. Weiss, Sandra J. TI Resting-state EEG delta power is associated with psychological pain in adults with a history of depression SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Psychological pain; Mental pain; EEG; Depression; Nonlinear measures; Default mode network ID DEFAULT-MODE NETWORK; TRANSCRANIAL MAGNETIC STIMULATION; HEART-RATE-VARIABILITY; ALPHA ASYMMETRY; MENTAL PAIN; MAJOR DEPRESSION; FUNCTIONAL CONNECTIVITY; CONTROLLED-TRIALS; HEALTHY CONTROLS; BRAIN ACTIVITY AB Psychological pain is a prominent symptom of clinical depression. We asked if frontal alpha asymmetry, frontal EEG power, and frontal fractal dimension asymmetry predicted psychological pain in adults with a history of depression. Resting-state frontal EEG (F3/F4) was recorded while participants (N=35) sat upright with their eyes closed. Frontal delta power predicted psychological pain while controlling for depressive symptoms, with participants who exhibited less power experiencing greater psychological pain. Frontal fractal dimension asymmetry, a nonlinear measure of complexity, also predicted psychological pain, such that greater left than right complexity was associated with greater psychological pain. Frontal alpha asymmetry did not contribute unique variance to any regression model of psychological pain. As resting-state delta power is associated with the brain's default mode network, results suggest that the default mode network was less activated during high psychological pain. Findings are consistent with a state of arousal associated with psychological pain. (C) 2015 Elsevier B.V. All rights reserved. C1 [Meerwijk, Esther L.; Weiss, Sandra J.] Univ Calif San Francisco, Dept Community Hlth Syst, San Francisco, CA 94143 USA. [Ford, Judith M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Ford, Judith M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Meerwijk, EL (reprint author), Univ Calif San Francisco, Dept Family Hlth Care Nursing, 2 Koret Way N411Y, San Francisco, CA 94143 USA. EM esther.meerwijk@ucsf.edu FU American Psychiatric Nursing Foundation; Sigma Theta Tau International Honor Society of Nursing, Alpha Eta Chapter; National Institute of Nursing Research [T32 NR07088]; U.S. Department of Veterans Affairs [I01CX000497]; Research Career Scientist award; Robert C & Delphine Wentland Eschbach Endowment FX We thank Gwendolyn van der Linden for her assistance in data management and implementation of the fractal dimension algorithm. Source code of the box-counting algorithm is available from the first author upon request. This study was supported by research grants from the American Psychiatric Nursing Foundation and Sigma Theta Tau International Honor Society of Nursing, Alpha Eta Chapter. Esther Meerwijk received additional support during preparation of this manuscript from the National Institute of Nursing Research Grant No. T32 NR07088. Additional support to Judith Ford during preparation of this manuscript was provided by U.S. Department of Veterans Affairs (I01CX000497) and a Research Career Scientist award. Additional support to Sandra Weiss was provided by the Robert C & Delphine Wentland Eschbach Endowment. Funding organizations were not involved in study design, data collection, analysis, or interpretation, or the decision to submit the article for publication. NR 88 TC 5 Z9 5 U1 4 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 EI 1873-6246 J9 BIOL PSYCHOL JI Biol. Psychol. PD FEB PY 2015 VL 105 BP 106 EP 114 DI 10.1016/j.biopsycho.2015.01.003 PG 9 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA CB8WH UT WOS:000349912100012 PM 25600291 ER PT J AU Hay, RA Roach, BJ Srihari, VH Woods, SW Ford, JM Mathalon, DH AF Hay, Rachel A. Roach, Brian J. Srihari, Vinod H. Woods, Scott W. Ford, Judith M. Mathalon, Daniel H. TI Equivalent mismatch negativity deficits across deviant types in early illness schizophrenia-spectrum patients SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Event related potential; Schizophrenia spectrum; Mismatch negativity; Auditory cortex; MMN ID AUDITORY CHANGE-DETECTION; CLINICAL HIGH-RISK; 1ST-EPISODE PSYCHOSIS; HUMAN BRAIN; FEATURE CONJUNCTIONS; STIMULUS DEVIANCE; SPEECH SOUNDS; 1ST EPISODE; MMN; DURATION AB Neurophysiological abnormalities in auditory deviance processing, as reflected by the mismatch negativity (MMN), have been observed across the course of schizophrenia. Studies in early schizophrenia patients have typically shown varying degrees of MMN amplitude reduction for different deviant types, suggesting that different auditory deviants are uniquely processed and may be differentially affected by duration of illness. To explore this further, we examined the MMN response to 4 auditory deviants (duration, frequency, duration + frequency "double deviant", and intensity) in 24 schizophrenia-spectrum patients early in the illness (ESZ) and 21 healthy controls. ESZ showed significantly reduced MMN relative to healthy controls for all deviant types (p < 0.05), with no significant interaction with deviant type. No correlations with clinical symptoms were present (all ps > 0.05). These findings support the conclusion that neurophysiological mechanisms underlying processing of auditory deviants are compromised early in illness, and these deficiencies are not specific to the type of deviant presented. (C) 2015 Elsevier B.V. All rights reserved. C1 [Ford, Judith M.; Mathalon, Daniel H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hay, Rachel A.; Roach, Brian J.; Ford, Judith M.; Mathalon, Daniel H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Srihari, Vinod H.; Woods, Scott W.] Yale Univ, Sch Med, New Haven, CT USA. RP Mathalon, DH (reprint author), San Francisco VA Med Ctr, Mental Hlth Serv 116D,4150 Clement St, San Francisco, CA 94121 USA. EM daniel.mathalon@ucsf.edu FU National Institute of Mental Health [MH076989, MH058262]; U.S. Department of Veterans Affairs [I01 CX000497] FX This work was supported by the National Institute of Mental Health (MH076989, MH058262) and the U.S. Department of Veterans Affairs (I01 CX000497). NR 88 TC 6 Z9 6 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 EI 1873-6246 J9 BIOL PSYCHOL JI Biol. Psychol. PD FEB PY 2015 VL 105 BP 130 EP 137 DI 10.1016/j.biopsycho.2015.01.004 PG 8 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA CB8WH UT WOS:000349912100015 PM 25603283 ER PT J AU Comoglio, F Sievers, C Paro, R AF Comoglio, Federico Sievers, Cem Paro, Renato TI Sensitive and highly resolved identification of RNA-protein interaction sites in PAR-CLIP data SO BMC BIOINFORMATICS LA English DT Article DE PAR-CLIP; RNA; RNA binding proteins; Bayesian statistics ID BINDING PROTEINS; ARGONAUTE PROTEINS; MICRORNA; DISEASE AB Background: PAR-CLIP is a recently developed Next Generation Sequencing-based method enabling transcriptome-wide identification of interaction sites between RNA and RNA-binding proteins. The PAR-CLIP procedure induces specific base transitions that originate from sites of RNA-protein interactions and can therefore guide the identification of binding sites. However, additional sources of transitions, such as cell type-specific SNPs and sequencing errors, challenge the inference of binding sites and suitable statistical approaches are crucial to control false discovery rates. In addition, a highly resolved delineation of binding sites followed by an extensive downstream analysis is necessary for a comprehensive characterization of the protein binding preferences and the subsequent design of validation experiments. Results: We present a statistical and computational framework for PAR-CLIP data analysis. We developed a sensitive transition-centered algorithm specifically designed to resolve protein binding sites at high resolution in PAR-CLIP data. Our method employes a Bayesian network approach to associate posterior log-odds with the observed transitions, providing an overall quantification of the confidence in RNA-protein interaction. We use published PAR-CLIP data to demonstrate the advantages of our approach, which compares favorably with alternative algorithms. Lastly, by integrating RNA-Seq data we compute conservative experimentally-based false discovery rates of our method and demonstrate the high precision of our strategy. Conclusions: Our method is implemented in the R package wavClusteR 2.0. The package is distributed under the GPL-2 license and is available from BioConductor at http://www.bioconductor.org/packages/devel/bioc/html/wavClusteR.html. C1 [Comoglio, Federico; Sievers, Cem; Paro, Renato] Swiss Fed Inst Technol Zurich, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland. [Sievers, Cem] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sievers, Cem] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Sievers, Cem] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Sievers, Cem] MIT & Harvard, Broad Inst, Cambridge, MA USA. [Paro, Renato] Univ Basel, Fac Sci, CH-4056 Basel, Switzerland. RP Comoglio, F (reprint author), Swiss Fed Inst Technol Zurich, Dept Biosyst Sci & Engn, Mattenstr 26, CH-4058 Basel, Switzerland. EM federico.comoglio@bsse.ethz.ch; csievers@mgh.harvard.edu OI Comoglio, Federico/0000-0002-8970-6610 FU ETH Zurich FX This work was supported by the ETH Zurich. F.C. is a member of the Life Science Zurich Graduate School, PhD program in Systems Biology. We are thankful to Moritz Gerstung and Maurizio Rinaldi for helpful discussion, to Martin Morgan for support with the package implementation, and to Hind Hashwah and Tommy Schlumpf for feedback on the package. NR 22 TC 5 Z9 5 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 1 PY 2015 VL 16 AR 32 DI 10.1186/s12859-015-0470-y PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CB8XD UT WOS:000349914600001 PM 25638391 ER PT J AU Briggs, A Rosenberg, L Buie, JD Rizvi, H Bertagnolli, MM Cho, NL AF Briggs, Alexandra Rosenberg, Laura Buie, Justin D. Rizvi, Hira Bertagnolli, Monica M. Cho, Nancy L. TI Antitumor effects of hyaluronan inhibition in desmoid tumors SO CARCINOGENESIS LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; MESENCHYMAL PROGENITOR CELLS; AGGRESSIVE FIBROMATOSIS; BREAST-CANCER; STEM-CELLS; CD44; 4-METHYLUMBELLIFERONE; MOTILITY; RECEPTOR; GROWTH AB Desmoid tumors (DTs) are rare, mesenchymal tumors that exhibit features of an abundant wound healing process. Previously, we showed that mesenchymal stem cells (MSCs) are constituents of DTs and may contribute to desmoid tumorigenesis via activities associated with wound healing. Hyaluronan (HA) is a long-charged chain of repeating glucuronate and N-acetylglucosamine disaccharides that is synthesized by HA synthases (HAS) and degraded by hyaluronidases (HYAL). HA is secreted into the extracellular matrix by injured stroma and is important for normal tissue repair and neoplastic progression. Here, we investigated the presence of HA in DTs and the antitumor effects of the HA inhibitor, 4-methylumbelliferone (4-MU), on DT-derived mesenchymal cells. By immunohistochemistry and enzyme-linked immunosorbent assay, we found abundant expression of HA in 29/30 DTs as well as > 5-fold increased HA levels in DT-derived cell lines relative to controls. Immunohistochemistry also demonstrated high expression of HAS2 in DTs, and quantitative PCR analysis showed increased HAS2 upregulation in frozen DTs and DT-derived cells. 4-MU treatment of DT-derived cells significantly decreased proliferation as well as HA and HAS2 levels. Fluorescent immunohistochemistry showed that MSCs in DTs coexpressed HA, HAS2, HYAL2, as well as the major HA receptor CD44 and HA coreceptor TLR4. Taken together, our results suggest that paracrine regulation of HA signaling in DTs may contribute to MSC recruitment and tumor proliferation. Future studies investigating the role of HA in tumor-stroma crosstalk and inhibition of HA-MSC interactions as a novel therapeutic target in DTs and other solid tumors are warranted. C1 [Briggs, Alexandra; Buie, Justin D.; Rizvi, Hira; Bertagnolli, Monica M.; Cho, Nancy L.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Rosenberg, Laura] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Cho, NL (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM nlcho@partners.org RI Xia, Bo/P-9380-2016 FU Desmoid Tumor Research Foundation, Inc. FX Desmoid Tumor Research Foundation, Inc. to N.L.C. NR 47 TC 5 Z9 5 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2015 VL 36 IS 2 BP 272 EP 279 DI 10.1093/carcin/bgu324 PG 8 WC Oncology SC Oncology GA CC2ZX UT WOS:000350214900011 PM 25556151 ER PT J AU Freeman, JV Reynolds, K Fang, M Udaltsova, N Steimle, A Pomernacki, NK Borowsky, LH Harrison, TN Singer, DE Go, AS AF Freeman, James V. Reynolds, Kristi Fang, Margaret Udaltsova, Natalia Steimle, Anthony Pomernacki, Niela K. Borowsky, Leila H. Harrison, Teresa N. Singer, Daniel E. Go, Alan S. TI Digoxin and Risk of Death in Adults With Atrial Fibrillation The ATRIA-CVRN Study SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE arrhythmia; atrial fibrillation; digoxin; morbidity; mortality ID GLOMERULAR-FILTRATION-RATE; VENTRICULAR RATE CONTROL; CHRONIC KIDNEY-DISEASE; SINUS RHYTHM; INCREASED MORTALITY; CLINICAL-TRIALS; HEART-FAILURE; MANAGEMENT; OUTCOMES; AFFIRM AB Background-Digoxin remains commonly used for rate control in atrial fibrillation, but limited data exist supporting this practice and some studies have shown an association with adverse outcomes. We examined the independent association between digoxin and risks of death and hospitalization in adults with incident atrial fibrillation and no heart failure. Methods and Results-We performed a retrospective cohort study of 14 787 age, sex, and high-dimensional propensity score-matched adults with incident atrial fibrillation and no previous heart failure or digoxin use in the AnTicoagulation and Risk factors In Atrial fibrillation-Cardiovascular Research Network (ATRIA-CVRN) study within Kaiser Permanente Northern and Southern California. We examined the independent association between newly initiated digoxin and the risks of death and hospitalization using extended Cox regression. During a median 1.17 (interquartile range, 0.49-1.97) years of follow-up among matched patients with atrial fibrillation, incident digoxin use was associated with higher rates of death (8.3 versus 4.9 per 100 person-years; P < 0.001) and hospitalization (60.1 versus 37.2 per 100 person-years; P < 0.001). Incident digoxin use was independently associated with a 71% higher risk of death (hazard ratio, 1.71; 95% confidence interval, 1.52-1.93) and a 63% higher risk of hospitalization (hazard ratio, 1.63; 95% confidence interval, 1.56-1.71). Results were consistent in subgroups of age and sex and when using intent-to-treat or on-treatment analytic approaches. Conclusions-In adults with atrial fibrillation, digoxin use was independently associated with higher risks of death and hospitalization. Given other available rate control options, digoxin should be used with caution in the management of atrial fibrillation. C1 [Freeman, James V.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Reynolds, Kristi; Harrison, Teresa N.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Fang, Margaret; Go, Alan S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Udaltsova, Natalia; Pomernacki, Niela K.; Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [Steimle, Anthony] Kaiser Permanente Santa Clara Med Ctr, Div Cardiol, Santa Clara, CA USA. [Borowsky, Leila H.; Singer, Daniel E.] Massachusetts Gen Hosp, Clin Epidemiol Unit, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Go, Alan S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Go, AS (reprint author), Kaiser Permanente No Calif, Div Res, 2000 Broadway St, Oakland, CA 94612 USA. EM Alan.S.Go@kp.org FU National Heart, Lung, and Blood Institute, United States [1RC2 HL101589, U19 HL91179]; American Heart Association Pharmaceutical Roundtable-Spina Cardiovascular Outcomes Research Center program [0875162N] FX This study was supported by grants 1RC2 HL101589 and U19 HL91179 from the National Heart, Lung, and Blood Institute; National Institutes of Health, United States and grant 0875162N for the American Heart Association Pharmaceutical Roundtable-Spina Cardiovascular Outcomes Research Center program. NR 45 TC 19 Z9 21 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3149 EI 1941-3084 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD FEB PY 2015 VL 8 IS 1 BP 49 EP U77 DI 10.1161/CIRCEP.114.002292 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CB8IU UT WOS:000349873000010 PM 25414270 ER PT J AU Lubitz, SA Ellinor, PT AF Lubitz, Steven A. Ellinor, Patrick T. TI Somatic Mutations and Atrial Fibrillation The End or Just the Beginning? SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Editorial Material DE Editorials; atrial fibrillation; genes; genetics; mutation C1 Massachusetts Gen Hosp, Div Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Broad Inst, Med & Populat Genet Program, Cambridge, MA USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St,4th Floor, Charlestown, MA 02129 USA. EM ellinor@mgh.harvard.edu FU Doris Duke Charitable Foundation [2014105]; NHLBI NIH HHS [2R01HL092577, 1K24HL105780, R01 HL104156, K23HL114724, K24 HL105780, U19 HL065962, K23 HL114724, U01 HL065962, 1R01HL104156, HL065962, R01 HL092577] NR 6 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2015 VL 8 IS 1 BP 2 EP 3 DI 10.1161/CIRCGENETICS.115.000963 PG 2 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA CB8IW UT WOS:000349873200001 PM 25691683 ER PT J AU Jabbari, J Olesen, MS Yuan, L Nielsen, JB Liang, B Macri, V Christophersen, IE Nielsen, N Sajadieh, A Ellinor, PT Grunnet, M Haunso, S Holst, AG Svendsen, JH Jespersen, T AF Jabbari, Javad Olesen, Morten S. Yuan, Lei Nielsen, Jonas B. Liang, Bo Macri, Vincenzo Christophersen, Ingrid E. Nielsen, Nikolaj Sajadieh, Ahmad Ellinor, Patrick T. Grunnet, Morten Haunso, Stig Holst, Anders G. Svendsen, Jesper H. Jespersen, Thomas CA LuCamp TI Common and Rare Variants in SCN10A Modulate the Risk of Atrial Fibrillation SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE atrial fibrillation arrhythmia; electrophysiology; genetic polymorphism; genome-wide association study; genotyping; SCN10A; voltage-gated sodium channel alpha subunit Na(v)1.8 ID LONG-QT SYNDROME; NODAL REENTRANT TACHYCARDIA; GENOME-WIDE ASSOCIATION; PR INTERVAL; ATRIOVENTRICULAR-CONDUCTION; CARDIAC CONDUCTION; BRUGADA-SYNDROME; SODIUM-CHANNELS; NERVOUS-SYSTEM; SCN5A VARIANTS AB Background-Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Na(v)1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r(2)=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. Methods and Results-SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3x10(-5)). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. Conclusions-The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF. C1 [Jabbari, Javad; Olesen, Morten S.; Yuan, Lei; Nielsen, Jonas B.; Liang, Bo; Nielsen, Nikolaj; Grunnet, Morten; Haunso, Stig; Holst, Anders G.; Svendsen, Jesper H.; Jespersen, Thomas] Univ Copenhagen, Danish Natl Res Fdn Ctr Cardiac Arrhythmia DARC, Dept Biomed Sci, Copenhagen, Denmark. [Jabbari, Javad; Olesen, Morten S.; Nielsen, Jonas B.; Haunso, Stig; Holst, Anders G.; Svendsen, Jesper H.] Univ Copenhagen, Rigshosp, Mol Cardiol Lab, Dept Cardiol, DK-2100 Copenhagen, Denmark. [Haunso, Stig; Svendsen, Jesper H.] Univ Copenhagen, Dept Clin Med, Fac Hlth & Med Sci, Copenhagen, Denmark. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Ellinor, Patrick T.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Christophersen, Ingrid E.] Vestre Viken Hosp Trust, Baerum Hosp, Dept Med Res, Rud, Norway. [Sajadieh, Ahmad] Copenhagen Univ Hosp Bispebjerg, Dept Cardiol, Copenhagen, Denmark. [Haunso, Stig] LuCamp, Copenhagen, Denmark. RP Jespersen, T (reprint author), Fac Hlth & Med Sci, Dept Biomed Sci, Heart & Circulatory Res Sect, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. EM thojes@sund.ku.dk OI Christophersen, Ingrid Elisabeth/0000-0002-6141-4712; Svendsen, Jesper Hastrup/0000-0001-8466-8515 FU Research Committee of Rigshospitalet (University of Copenhagen); Danish Heart Foundation; John and Birthe Meyer foundation; Arvid Nilsson Foundation; Novo Nordisk Foundation; Fondsborsvekselerer Henry Hansen's Legat; Director Ib Henriksens Foundation; National Institute of Health [R01HL092577, R01HL104156, K24HL105780]; American Heart Association Established Investigator Award [13EIA14220013] FX This work was supported by the Research Committee of Rigshospitalet (University of Copenhagen), The Danish Heart Foundation, The John and Birthe Meyer foundation, The Arvid Nilsson Foundation, The Novo Nordisk Foundation, Fondsborsvekselerer Henry Hansen's Legat, Director Ib Henriksens Foundation, National Institute of Health grants R01HL092577, R01HL104156, K24HL105780, and an American Heart Association Established Investigator Award 13EIA14220013. NR 47 TC 12 Z9 14 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2015 VL 8 IS 1 BP 64 EP 73 DI 10.1161/HCG.0000000000000022 PG 10 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA CB8IW UT WOS:000349873200010 PM 25691686 ER PT J AU Zilinski, JL Contursi, ME Isaacs, SK Deluca, JR Lewis, GD Weiner, RB Hutter, AM d'Hemecourt, PA Troyanos, C Dyer, KS Baggish, AL AF Zilinski, Jodi L. Contursi, Miranda E. Isaacs, Stephanie K. Deluca, James R. Lewis, Gregory D. Weiner, Rory B. Hutter, Adolph M., Jr. d'Hemecourt, Pierre A. Troyanos, Christopher Dyer, K. Sophia Baggish, Aaron L. TI Myocardial Adaptations to Recreational Marathon Training Among Middle-Aged Men SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE echocardiography; exercise; risk factors ID CARDIAC-HYPERTROPHY; PHYSICAL-ACTIVITY; HEALTHY-ADULTS; UPPER LIMIT; EXERCISE; HEART; ECHOCARDIOGRAPHY; PREVALENCE; RECOMMENDATIONS; PARTICIPANTS AB Background-Myocardial adaptations to exercise have been well documented among competitive athletes. To what degree cardiac remodeling occurs among recreational exercisers is unknown. We sought to evaluate the effect of recreational marathon training on myocardial structure and function comprehensively. Methods and Results-Male runners (n=45; age, 48 +/- 7 years; 64% with >= 1 cardiovascular risk factor) participated in a structured marathon-training program. Echocardiography, cardiopulmonary exercise testing, and laboratory evaluation were performed pre and post training to quantify changes in myocardial structure and function, cardiorespiratory fitness, and traditional cardiac risk parameters. Completion of an 18-week running program (25 +/- 9 miles/wk) led to increased cardiorespiratory fitness (peak oxygen consumption, 44.6 +/- 5.2 versus 46.3 +/- 5.4 mL/kg per minute; P<0.001). In this setting, there was a significant structural cardiac remodeling characterized by dilation of the left ventricle (end-diastolic volume, 156 +/- 26 versus 172 +/- 28 mL, P<0.001), right ventricle (end-diastolic area=27.0 +/- 4.8 versus 28.6 +/- 4.3 cm(2); P=0.02), and left atrium (end-diastolic volume, 65 +/- 19 versus 72 +/- 19; P=0.02). Functional adaptations included increases in both early (E'=12.4 +/- 2.5 versus 13.2 +/- 2.0 cm/s; P=0.007) and late (A'=11.5 +/- 1.9 versus 12.2 +/- 2.1 cm/s; P=0.02) left ventricular diastolic velocities. Myocardial remodeling was accompanied by beneficial changes in cardiovascular risk factors, including body mass index (27.0 +/- 2.7 versus 26.7 +/- 2.6 kg/m2; P<0.001), total cholesterol (199 +/- 33 versus 192 +/- 29 mg/dL; P=0.01), low-density lipoprotein (120 +/- 29 versus 114 +/- 26 mg/dL; P=0.01), and triglycerides (100 +/- 52 versus 85 +/- 36 mg/dL; P=0.02). Conclusions-Among middle-aged men, recreational marathon training is associated with biventricular dilation, enhanced left ventricular diastolic function, and favorable changes in nonmyocardial determinants of cardiovascular risk. Recreational marathon training may, therefore, serve as an effective strategy for decreasing incident cardiovascular disease. C1 [Zilinski, Jodi L.; Contursi, Miranda E.; Isaacs, Stephanie K.; Deluca, James R.; Lewis, Gregory D.; Weiner, Rory B.; Hutter, Adolph M., Jr.; Baggish, Aaron L.] Massachusetts Gen Hosp, Cardiovasc Performance Program, Div Cardiol, Dept Internal Med, Boston, MA 02114 USA. [d'Hemecourt, Pierre A.] Boston Childrens Hosp, Sports Med Div, Boston, MA USA. [d'Hemecourt, Pierre A.; Troyanos, Christopher; Dyer, K. Sophia; Baggish, Aaron L.] Boston Athlet Assoc, Boston, MA USA. [Dyer, K. Sophia] Boston Med Ctr, Dept Emergency Med, Boston, MA USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Cardiovasc Performance Program, Yawkey Suite 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org NR 35 TC 16 Z9 16 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD FEB PY 2015 VL 8 IS 2 AR e002487 DI 10.1161/CIRCIMAGING.114.002487 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CB7VM UT WOS:000349836600008 PM 25673646 ER PT J AU Lam, CT Tse, SH Chan, ST Tam, JK Yuen, JWM AF Lam, C. T. Tse, S. H. Chan, S. T. Tam, J. K. Yuen, J. W. M. TI A survey on the prevalence and utilization characteristics of gua sha in the Hong Kong community SO COMPLEMENTARY THERAPIES IN MEDICINE LA English DT Article DE Gua sha; Survey; Prevalence; Utilization characteristics; Usage ID RANDOMIZED CONTROLLED-TRIAL; HEPATITIS-B; THERAPY; MEDICINE; NECK; PAIN AB Objective: To conduct a community-based survey to describe the demographics, experience, and utilization variables among the users of gua sha living in Hong Kong. Method: A total of 3209 adult respondents were surveyed by using a short Chinese questionnaire. Results: Gua sha was found to have a one-year prevalence of 22.7% and four-week prevalence of 6.6%. The users were seen to be old of age and less educated. The majority believed that gua sha is beneficial to health, practiced in non-regular basis, and mainly employed for treating illnesses. For both mate and female, the top two common illnesses to be treated were the respiratory and pain problems, which accounting for 74% of all users. Other illnesses included nervousness, heat stroke, fever, infection, dizziness, diarrhoea and vomiting, oedema, and constipation. As practiced by most respondents, unidirectional pressured stroking was applied repeatedly on the lubricated skin surface at the back region using various smooth-edged tools typically spoons. Almost all users reported the occurrence of skin blemishing and subsequently faded within 7 days after the gua sha treatment. Conclusion: The general population of Hong Kong was found to have high prevalence of gua sha usage. The utilization characteristics as reported by the users were generally aligned with the current scientific knowledge, in particular the treatment procedures and response. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Lam, C. T.; Tse, S. H.; Tam, J. K.; Yuen, J. W. M.] Hong Kong Polytech Univ, Sch Nursing, Kowloon, Hong Kong, Peoples R China. [Chan, S. T.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. RP Yuen, JWM (reprint author), Hong Kong Polytech Univ, Sch Nursing, Yuk Choi Rd, Kowloon, Hong Kong, Peoples R China. EM john.yuen@polyu.edu.hk RI Chan, Suk-tak/G-5846-2015; Yuen, John Wai-Man/A-4963-2011 OI Yuen, John Wai-Man/0000-0003-1681-233X FU Faculty of Health and Social Sciences, The Hong Kong Polytechnic University [1-99N8, 1-99NA] FX Financial support of the project was provided by the Summer Research Studentship Scheme with grant numbers 1-99N8 and 1-99NA (Faculty of Health and Social Sciences, The Hong Kong Polytechnic University) which awarded to Mr. Chris T Lam in 2012 for conducting the research. NR 28 TC 0 Z9 0 U1 1 U2 5 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0965-2299 EI 1873-6963 J9 COMPLEMENT THER MED JI Complement. Ther. Med. PD FEB PY 2015 VL 23 IS 1 BP 46 EP 54 DI 10.1016/j.ctim.2014.12.002 PG 9 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA CB6II UT WOS:000349730300007 PM 25637152 ER PT J AU Signorovitch, JE Betts, KA Reichmann, WM Thomason, D Galebach, P Wu, EQ Chen, L DeAngelo, DJ AF Signorovitch, James E. Betts, Keith A. Reichmann, William M. Thomason, Darren Galebach, Phil Wu, Eric Q. Chen, Lei DeAngelo, Daniel J. TI One-year and long-term molecular response to nilotinib and dasatinib for newly diagnosed chronic myeloid leukemia: a matching-adjusted indirect comparison SO CURRENT MEDICAL RESEARCH AND OPINION LA English DT Article DE Chronic myeloid leukemia; Dasatinib; Indirect comparison; Long-term molecular response; Nilotinib ID FOLLOW-UP; TASK-FORCE; IMATINIB; TRIALS; METAANALYSIS; PREDICTS; SURVIVAL; THERAPY AB Background: Nilotinib and dasatinib have shown superior rates of molecular response (MR) compared to imatinib for the treatment of newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP). This study indirectly compares MR in patients taking nilotinib 300 mg bid with that in those taking dasatinib 100 mg qd by 12 months and through 48 months. Methods: Patients in ENESTnd were re-weighted to match published baseline characteristics reported for DASISION using a propensity score model. After matching, differences in rates of major MR (MMR, measured as a 3 log reduction on the International Scale [IS]), MR4.0 (4 log reduction on IS), and MR4.5 (4.5 log reduction on IS) relative to imatinib were indirectly compared between nilotinib and dasatinib. Hazard ratios (HRs) were used to indirectly compare MR outcomes between nilotinib and dasatinib through 48 months of follow-up, while rate differences were used to compare progression to AP/BC between nilotinib and dasatinib by 48 months. Results: After matching, rates of MR by 12 months were higher with nilotinib vs dasatinib by 11.7% for MMR (p = 0.045), 8.2% for MR4.0 (p = 0.029), and 8.5% for MR4.5 (p<0.001). Higher rates of MMR (HR = 1.44, p = 0.018) and MR4.0 (HR = 1.58, p = 0.013) achievement were maintained with nilotinib compared to dasatinib through 48 months of follow-up. No statistically significant differences were observed for MR 4.5 through 48 months or progression to AP/BC by 48 months. Limitations: Limitations include comparisons based solely on indirect evidence and HRs for MR4.0 and MR4.5 from the DASISION trial being extracted from cumulative incidence curves. Conclusions: This indirect comparison suggests that nilotinib is associated with higher rates of achieving MMR, MR4.0, and MR4.5 by 12 months compared to dasatinib for the treatment of newly diagnosed CML-CP. In addition, higher rates of MR achievement with nilotinib were also maintained through 48 months of follow-up. C1 [Signorovitch, James E.; Betts, Keith A.; Reichmann, William M.; Thomason, Darren; Galebach, Phil; Wu, Eric Q.] Anal Grp Inc, Boston, MA USA. [Chen, Lei] Novartis Pharmaceut, E Hanover, NJ USA. [DeAngelo, Daniel J.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Signorovitch, JE (reprint author), 111 Huntington Ave,10th Floor, Boston, MA 02199 USA. EM James.Signorovitch@analysisgroup.com OI Betts, Keith/0000-0002-3088-7453 FU Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA FX Research was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. NR 23 TC 1 Z9 1 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0300-7995 EI 1473-4877 J9 CURR MED RES OPIN JI Curr. Med. Res. Opin. PD FEB PY 2015 VL 31 IS 2 BP 315 EP 322 DI 10.1185/03007995.2014.977992 PG 8 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA CB9UW UT WOS:000349979800013 PM 25356603 ER PT J AU Chia, K O'Brien, M Brown, M Lim, E AF Chia, KeeMing O'Brien, Megan Brown, Myles Lim, Elgene TI Targeting the Androgen Receptor in Breast Cancer SO CURRENT ONCOLOGY REPORTS LA English DT Article DE Androgen receptor; Breast cancer; Breast cancer subtype; Androgen receptor-directed therapy ID ADVANCED PROSTATE-CANCER; TAMOXIFEN RESISTANCE; PIK3CA MUTATIONS; PHASE-II; ER-ALPHA; EXPRESSION; THERAPY; BETA; ENDOCRINE; TUMORS AB The androgen receptor (AR) is expressed in the majority of breast cancer and across the three main breast cancer subtypes. Historically, the oncogenic role of AR has best been described in molecular apocrine breast cancers, an estrogen receptor (ER)-/AR+ subtype which has a steroid response signature similar to that in the ER-positive breast cancer. The signalling effect of AR is likely to be different across breast cancer subtypes, and particularly important is its interaction with ER signalling. Despite the high frequency of AR expression in breast cancer, it is still not a standard clinical practice to use AR antagonists as therapy. Older trials of AR-directed therapies in breast cancer have had generally been disappointing. More recently, more potent, next-generation, AR-directed therapies have been developed in the context of prostate cancer. Here, we will review the emerging literature dissecting the role of AR signalling in a context-dependent manner in breast cancer and the renewed interest and wave of clinical trials targeting the AR in breast cancer. C1 [Chia, KeeMing; O'Brien, Megan; Lim, Elgene] Olivia Newton John Canc Res Inst, Heidelberg, Vic, Australia. [Lim, Elgene] Univ Melbourne, Melbourne, Vic, Australia. [Lim, Elgene] La Trobe Univ, Bundoora, Vic, Australia. [O'Brien, Megan; Lim, Elgene] Dana Farber Canc Inst, Boston, MA 02115 USA. [Brown, Myles; Lim, Elgene] Harvard Univ, Boston, MA 02115 USA. RP Lim, E (reprint author), Olivia Newton John Canc Res Inst, Heidelberg, Vic, Australia. EM elgene.lim@onjcri.org.au OI Lim, Elgene/0000-0001-8065-8838; Brown, Myles/0000-0002-8213-1658 FU Breast Cancer Research Foundation; National Breast Cancer Foundation, Australia; Victorian Cancer Agency, Australia; National Health and Medical Research Council, Australia FX Myles Brown has received a grant from the Breast Cancer Research Foundation.; Elgene Lim has received grants from the National Breast Cancer Foundation, Australia, Victorian Cancer Agency, Australia, and the National Health and Medical Research Council, Australia. NR 50 TC 14 Z9 14 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3790 EI 1534-6269 J9 CURR ONCOL REP JI Curr. Oncol. Rep. PD FEB PY 2015 VL 17 IS 2 AR 4 DI 10.1007/s11912-014-0427-8 PG 6 WC Oncology SC Oncology GA CB9KC UT WOS:000349949500004 PM 25665553 ER PT J AU Sonnenberg, A Genta, RM AF Sonnenberg, Amnon Genta, Robert M. TI Prevalence of benign gastric polyps in a large pathology database SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE Epidemiology; Fundic gland polyps; Gastric adenomas; Gastric atrophy; Gastric hyperplastic polyps; Gastric neuroendocrine tumours; Intestinal metaplasia ID PROTON-PUMP INHIBITORS; GASTROESOPHAGEAL-REFLUX DISEASE; HELICOBACTER-PYLORI; ESOPHAGEAL EOSINOPHILIA; SYDNEY SYSTEM; RISK; CLASSIFICATION; GUIDELINES; MANAGEMENT; INFECTION AB Aims: The aim of the study was to utilize a large national histopathology database for the analysis of the clinical epidemiology of gastric polyps. Methods: In a case-control study, 71,575 case subjects with gastric polyps were compared to 741,351 control subjects without gastric polyps. Results: Of all patients, 7.72% harboured fundic gland polyps, 1.79% gastric hyperplastic polyps, 0.09% gastric adenomas, and 0.06% type I neuroendocrine tumours. All types showed a clear-cut age-dependent rise. Reflux disease was significantly more common in patients with fundic gland polyps and significantly less common in patients with gastric adenomas or neuroendocrine tumours. Anaemia was more common in patients with gastric hyperplastic polyps, gastric adenomas, or neuroendocrine tumours. Helicobacter pylon was found significantly less frequently in all subjects with gastric polyps than in controls. Intestinal metaplasia and gastric atrophy were both more common in gastric adenoma and neuroendocrine tumours and less common in fundic gland polyps than in controls. Different polyp types tended to coincide in the same patients. Conclusions: Gastric hyperplastic polyps appeared to mark the beginning of a progression from chronic gastritis to intestinal metaplasia and gastric atrophy, which leads to diminished gastric acid output and increased gastrin secretion. Gastric adenoma and neuroendocrine tumours reflect later stages of this process. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. C1 [Sonnenberg, Amnon; Genta, Robert M.] Miraca Life Sci, Res Inst, Irving, TX USA. [Sonnenberg, Amnon] Portland VA Med Ctr, Portland, OR 97239 USA. [Genta, Robert M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr, P3-GI,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 32 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD FEB PY 2015 VL 47 IS 2 BP 164 EP 169 DI 10.1016/j.dld.2014.10.004 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CB9RY UT WOS:000349971300013 PM 25458775 ER PT J AU Pugh, MJ Parko, K AF Pugh, Mary Jo Parko, Karen TI Research using archival health care data: Let the buyer beware SO EPILEPSIA LA English DT Letter ID NEW-ONSET EPILEPSY; RISK-FACTORS; POPULATION; ADULTS C1 [Pugh, Mary Jo] South Texas Vet Hlth Care Syst, VA Epilepsy Ctr Excellence, San Antonio, TX 78229 USA. [Parko, Karen] San Francisco VA Med Ctr, VA Epilepsy Ctr Excellence, San Francisco, CA USA. RP Pugh, MJ (reprint author), South Texas Vet Hlth Care Syst, VA Epilepsy Ctr Excellence, San Antonio, TX 78229 USA. EM maryjo.pugh2@va.gov OI Pugh, Mary Jo/0000-0003-4196-7763 FU HSRD VA [I01 HX000717] NR 9 TC 1 Z9 1 U1 1 U2 1 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 IS 2 BP 321 EP 322 DI 10.1111/epi.12873 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CC2AH UT WOS:000350146300033 PM 25708477 ER PT J AU Swirski, FK AF Swirski, F. K. TI Inflammation and repair in the ischaemic myocardium SO HAMOSTASEOLOGIE LA English DT Review DE Inflammation; myocardium ID HEART-FAILURE; CARDIAC REPAIR; CELL-DEATH; INFARCTION; MONOCYTES; MICE; ATHEROSCLEROSIS; MACROPHAGES; APOPTOSIS; DIFFERENTIATION AB Shortly after myocardial infarction, various circulating leukocyte subsets accumulate in the heart. Leukocyte recruitment is highly coordinated and relies on cell production in the bone marrow, mobilization to the blood, and chemokine-mediated infiltration to the destination tissue. Neutrophils, which are phagocytic and inflammatory, are among the first leukocytes to accumulate in large numbers. Within a day, neutrophils disappear and are replaced by a subset of monocytes that, further contribute to inflammation and phagocytosis. After a few days, monocyte-derived reparative macrophages accrue, quell inflammation, and foster angiogenesis and tissue remodelling. Studies suggest a well-balanced response comprising these three waves is essential to optimal infarct healing. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. RP Swirski, FK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM fswirski@mgh.harvard.edu NR 50 TC 1 Z9 1 U1 1 U2 6 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0720-9355 J9 HAMOSTASEOLOGIE JI Hamostaseologie PD FEB PY 2015 VL 35 IS 1 BP 34 EP 36 DI 10.5482/HAMO-14-09-0045 PG 3 WC Hematology SC Hematology GA CB8KE UT WOS:000349877700005 PM 25375277 ER PT J AU Speakman, E Paris, R Gioiella, ME Hathaway, J AF Speakman, Elizabeth Paris, Ruth Gioiella, Marie Elena Hathaway, Jeanne TI "I Didn't Fight for My Life to Be Treated Like This!": The Relationship between the Experience of Cancer and Intimate Partner Abuse SO HEALTH & SOCIAL WORK LA English DT Article DE cancer; intimate partner abuse; psychological adjustment; support ID BREAST-CANCER; VIOLENCE; HEALTH; WOMEN AB The current article seeks to further understanding of the high frequency of intimate partner abuse among cancer patients through qualitative analysis of semistructured interviews with 20 women and one man facing cancer and intimate partner abuse concurrently. Participants described a range of abusive and unsupportive behaviors by their intimate partners over the course of cancer treatment, which contributed to their reassessing and making changes in their relationships. Important factors in this process of change appear to be participants' increased focus on their own health, discovery of greater inner strength, and increased social support. Barriers to making changes in their relationships during their cancer treatment also were described. Participants who made significant changes in or left an abusive relationship usually did so after having recovered from cancer treatment. Implications of these findings for social workers in health care are discussed, as are directions for future research. C1 [Speakman, Elizabeth] Cambridge Initiat Domest & Gender Based Violence, Cambridge, MA 02139 USA. [Paris, Ruth] Boston Univ Sch Social Work, Boston, MA USA. [Gioiella, Marie Elena] Massachusetts Gen Hosp, Social Serv Dept, Boston, MA 02114 USA. [Hathaway, Jeanne] Massachusetts Dept Publ Hlth, Injury Surveillance Program, Boston, MA USA. RP Speakman, E (reprint author), Cambridge Initiat Domest & Gender Based Violence, 119 Windsor St, Cambridge, MA 02139 USA. EM espeakman@cambridgema.gov NR 16 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0360-7283 EI 1545-6854 J9 HEALTH SOC WORK JI Health Soc. Work PD FEB PY 2015 VL 40 IS 1 BP 51 EP 58 DI 10.1093/hsw/hlu040 PG 8 WC Social Work SC Social Work GA CC1ZW UT WOS:000350145000007 PM 25665291 ER PT J AU Zeng, X Zou, L Levine, RA Guerrero, JL Handschumacher, MD Sullivan, SM Braithwaite, GJC Stone, JR Solis, J Muratoglu, OK Vlahakes, GJ Hung, J AF Zeng, Xin Zou, Lin Levine, Robert A. Guerrero, J. Luis Handschumacher, Mark D. Sullivan, Suzanne M. Braithwaite, Gavin J. C. Stone, James R. Solis, Jorge Muratoglu, Orhun K. Vlahakes, Gus J. Hung, Judy TI Efficacy of Polymer Injection for Ischemic Mitral Regurgitation Persistent Reduction of Mitral Regurgitation and Attenuation of Left Ventricular Remodeling SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE echocardiography; mitral regurgitation; myocardial infarction; remodeling ID MYOCARDIAL-INFARCTION; PAPILLARY-MUSCLES; REVERSE REMODEL; OVINE MODEL; ANNULOPLASTY; EXPANSION; COMPLEX; WALL AB OBJECTIVES The aim of this study was to examine the chronic effects of polyvinyl-alcohol (PVA) injection on mitral regurgitation (MR) reduction, mitral valve geometry, and left ventricular (LV) remodeling in a chronic ischemic MR sheep model. BACKGROUND Previous studies have demonstrated acute efficacy of PVA hydrogel polymer injection into infarcted myocardium underlying the papillary muscle to relieve MR by papillary muscle repositioning. However, the chronic efficacy of PVA injection in the chronic infarction setting remains unclear. METHODS Sixteen sheep developed chronic MR 8 weeks after induced inferoposterior myocardial infarction. Ten consecutive sheep underwent PVA injection (PVA group) and 6 sheep served as control subjects with saline injection. Epicardial 2-/3-dimensional echocardiography was performed at the baseline, chronic MR (pre-injection), and sacrifice (8 weeks after injection) stages. RESULTS Both groups were comparable at the baseline and chronic MR stages. At sacrifice, MR decreased from moderate to trace or mild (vena contracta: 0.17 +/- 0.08 cm vs. 0.56 +/- 0.10 cm, p < 0.001) in the PVA group but progressed to moderate to severe in the control group. End-systolic and -diastolic volumes remained stable in the PVA group but increased significantly in the control group (both p < 0.05). At sacrifice, compared with the control group, the PVA group had significantly less left ventricular remodeling (end-systolic volume: 41.1 +/- 10.4 ml vs. 55.9 +/- 12.4 ml, p < 0.05), lower MR severity (vena contracta: 0.17 +/- 0.08 cm vs. 0.60 +/- 0.14 cm, p < 0.01), and favorable changes in mitral valve geometry. CONCLUSIONS Polymer injection in a chronic ischemic MR model results in persistent reduction of MR and attenuation of continued left ventricular remodeling over 8 weeks of follow-up. (C) 2015 by the American College of Cardiology Foundation. C1 [Zeng, Xin; Zou, Lin; Levine, Robert A.; Handschumacher, Mark D.; Solis, Jorge; Hung, Judy] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Guerrero, J. Luis; Sullivan, Suzanne M.; Vlahakes, Gus J.] Massachusetts Gen Hosp, Cardiac Surg Div, Boston, MA 02114 USA. [Braithwaite, Gavin J. C.] Cambridge Polymer Inc, Boston, MA USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Muratoglu, Orhun K.] Massachusetts Gen Hosp, Dept Orthoped Surg, Biomat Lab, Boston, MA 02114 USA. RP Hung, J (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Blake 256,55 Fruit St, Boston, MA 02114 USA. EM jhung@mgh.harvard.edu FU National Institutes of Health/NationalHeart, Lung, and Blood Institute [R01 HL092101, R01 HL109506, K24 HL67434]; American Society of Echocardiography; Leducq Foundation [07CVD04]; Biomet; Mako; Depuy FX This work was supported in part by a grant #R01 HL092101 from the National Institutes of Health/NationalHeart, Lung, and Blood Institute(Dr. Hung); the Echo-Investigator Award from the American Society of Echocardiography (Dr. Hung); grants #R01 HL109506 and #K24 HL67434 from National Institutes of Health/National Heart, Lung, and Blood Institute (Dr. Levine); and grant #07CVD04 from the Leducq Foundation (Dr. Levine). Dr. Braithwaite is an employee and shareholder of Cambridge Polymer Inc. Dr. Muratoglu has an equity interest in Cambridge Polymer Inc.; has received royalties from Zimmer, Biomet, Corin, Iconacy, Renovis, Conformis, Aston Medical, Meril Healthcare, Arthrex, Mako, Ceramtec; has received research support from Biomet, Mako, and Depuy; and has received or materials support from Biomet, Orthopaedic Technology Group. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 24 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD FEB PY 2015 VL 8 IS 2 BP 355 EP 363 DI 10.1016/j.jcin.2014.09.016 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CB8VS UT WOS:000349910300024 PM 25596792 ER PT J AU Ali, SS Goddard, AL Luke, JJ Donahue, H Todd, DJ Werchniak, A Vleugels, RA AF Ali, Shirwa Sheik Goddard, Allison L. Luke, Jason J. Donahue, Hilary Todd, Derrick J. Werchniak, Andrew Vleugels, Ruth Ann TI Drug-Associated Dermatomyositis Following Ipilimumab Therapy A Novel Immune-Mediated Adverse Event Associated With Cytotoxic T-Lymphocyte Antigen 4 Blockade SO JAMA DERMATOLOGY LA English DT Article ID NECROSIS-FACTOR; MELANOMA; CANCER AB IMPORTANCE Ipilimumab, a human monoclonal antibody targeted against cytotoxic T-lymphocyte antigen 4, has shown promise in the treatment of metastatic melanoma. However, given its mechanism of action, immune-related adverse effects have been reported with this therapy. Despite increasing reports of immune-related adverse effects related to ipilimumab therapy, dermatomyositis associated with this agent has not previously been reported. OBSERVATIONS We describe a woman undergoing treatment with ipilimumab for metastatic melanoma who developed classic cutaneous findings of dermatomyositis along with proximal muscle weakness and elevated muscle enzymes. CONCLUSIONS AND RELEVANCE This case adds to the expanding literature regarding immune-related adverse events associated with ipilimumab. To our knowledge, drug-induced dermatomyositis from ipilimumab has not previously been reported. Physicians should be aware of these potential immune-related adverse events and consider drug-associated dermatomyositis in the differential diagnosis in patients receiving ipilimumab who present with a cutaneous eruption or muscle weakness. C1 [Ali, Shirwa Sheik] Kings Coll London, Sch Med, London, England. [Goddard, Allison L.; Werchniak, Andrew; Vleugels, Ruth Ann] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Goddard, Allison L.; Werchniak, Andrew] Dana Farber Canc Inst, Ctr Cutaneous Oncol, Boston, MA 02115 USA. [Luke, Jason J.; Donahue, Hilary] Dana Farber Canc Inst, Dept Med Oncol, Melanoma Dis Ctr, Boston, MA 02115 USA. [Todd, Derrick J.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. RP Vleugels, RA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, 221 Longwood Ave, Boston, MA 02115 USA. EM rvleugels@partners.org NR 15 TC 4 Z9 5 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD FEB PY 2015 VL 151 IS 2 BP 195 EP 199 DI 10.1001/jamadermatol.2014.2233 PG 5 WC Dermatology SC Dermatology GA CB6RL UT WOS:000349754200016 ER PT J AU Hemphill, LC AF Hemphill, Linda C. TI The Cholesterol Lowering Atherosclerosis Study (CLAS): What it tells us about niacin/colestipol therapy SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Editorial Material ID CORONARY-ARTERY-DISEASE; QUANTITATIVE ARTERIOGRAPHY; PROGNOSTIC-SIGNIFICANCE; COLESTIPOL-NIACIN; HDL CHOLESTEROL; BYPASS GRAFTS; FOLLOW-UP; PROGRESSION; EVENTS; MORTALITY C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. RP Hemphill, LC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. EM lhemphill@partners.org NR 20 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD FEB PY 2015 VL 9 IS 1 BP 11 EP 13 DI 10.1016/j.jacl.2014.09.010 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC1IB UT WOS:000350093300003 PM 25670355 ER PT J AU Blanch-Hartigan, D Viswanath, K AF Blanch-Hartigan, Danielle Viswanath, Kasisomayajula TI Socioeconomic and Sociodemographic Predictors of Cancer-Related Information Sources Used by Cancer Survivors SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID PHYSICIAN RACE; SEEKING; CARE; DISPARITIES; BEHAVIORS; HEALTH; PATIENT; COMMUNICATION; CONCORDANCE; EXPERIENCES AB With 14 million cancer survivors in the United States, identifying and categorizing their use of sources of cancer-related information is vital for targeting effective communications to this growing population. In addition, recognizing socioeconomic and sociodemographic differences in the use of cancer-related information sources is a potential mechanism for reducing health disparities in survivorship. Fourteen sources of information survivors (N=519) used for cancer-related information were factor-analyzed to create a taxonomy of source use. The association between social determinants and use of these source types was analyzed in regression models. Factor analysis revealed 5 categories of information source use (mass media; Internet and print; support organizations; family and friends; health care providers), and use varied based on sociodemographic and socioeconomic characteristics. Higher education predicted increased use of all source categories except mass media. African American cancer survivors turned to health care providers as a source for cancer-related information less often than did White survivors. Social determinants predicted differences in the type of cancer-related information sources used. Providers and health communicators should target communication platforms based on the demographic profile of specific survivor audiences. C1 [Blanch-Hartigan, Danielle] Bentley Univ, Dept Nat & Appl Sci, Waltham, MA 02452 USA. [Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Viswanath, Kasisomayajula] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Blanch-Hartigan, D (reprint author), Bentley Univ, Dept Nat & Appl Sci, Jennison 100,175 Forest St, Waltham, MA 02452 USA. EM danielleblanch@gmail.com NR 38 TC 2 Z9 2 U1 2 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD FEB 1 PY 2015 VL 20 IS 2 BP 204 EP 210 DI 10.1080/10810730.2014.921742 PG 7 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA CC4QS UT WOS:000350338700010 PM 25495027 ER PT J AU Clerkin, KJ Thomas, SS Haythe, J Schulze, PC Farr, M Takayama, H Jorde, UP Restaino, SW Naka, Y Mancini, DM AF Clerkin, Kevin J. Thomas, Sunu S. Haythe, Jennifer Schulze, P. Christian Farr, Maryjane Takayama, Hiroo Jorde, Ulrich P. Restaino, Susan W. Naka, Yoshifumi Mancini, Donna M. TI Mechanical Circulatory Support as a Bridge to Cardiac Retransplantation: A single center experience SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE mechanical circulatory support; retransplant; waiting list survival; UNOS allocation policy ID SURVIVAL; TRANSPLANTATION; HEART AB BACKGROUND: Cardiac retransplantation is increasing in frequency. Recent data have shown that retransplantation outcomes are now comparable with primary transplantation. The use of mechanical circulatory support (MCS) as a bridge to retransplantation has similar post-retransplant outcomes to those without MCS, but the success of bridging patients to retransplant with MCS has not been well studied. METHODS: From January 2000 to February 2014 at Columbia University Medical Center, 84 patients were listed for retransplantation. Of this cohort, 48 patients underwent retransplantation, 15 were bridged with MCS, 24 died, and 6 clinically improved. A retrospective analysis was performed examining waiting list time, survival to retransplantation, and survival after retransplant. The effect of the United Network of Organ Sharing (UNOS) allocation policy change in 2006 on waiting list time and MCS use was also investigated. RESULTS: Of 48 patients who underwent retransplantation, 11 were bridged with MCS. Overall 1-year survival to retransplantation was 81.3%. There was no significant difference in waiting list survival (p = 0.71) in those with and without MCS. Death from cardiac arrest or multiorgan failure with infection was more frequent in the medically managed group (p = 0.002). After the UNOS 2006 allocation policy change, waiting list time (599 +/- 936 days in Era 1 vs 526 +/- 498 days in Era 2, p = 0.65) and waiting list survival (p = 0.22) between eras were comparable, but there was a trend toward greater use of MCS (p = 0.13). Survival after retransplant was acceptable. CONCLUSION: The use of MCS as a bridge to cardiac retransplantation is a reasonable strategy. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Clerkin, Kevin J.; Haythe, Jennifer; Schulze, P. Christian; Farr, Maryjane; Jorde, Ulrich P.; Restaino, Susan W.; Mancini, Donna M.] Columbia Univ Coll Phys & Surg, Div Cardiol, Dept Med, New York, NY 10032 USA. [Takayama, Hiroo; Naka, Yoshifumi] Columbia Univ Coll Phys & Surg, Div Cardiothorac Surg, Dept Surg, New York, NY 10032 USA. [Thomas, Sunu S.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Mancini, DM (reprint author), Ctr Adv Cardiac Care, Dept Med, Div Cardiol, 622 168th St,PH 1273, New York, NY 10032 USA. EM dmm31@columbia.edu FU Thoratec; HeartWare FX Dr Jorde has received consulting fees from Thoratec and HeartWare, and Dr. Naka has received consulting fees from Thoratec and HeartWare. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. NR 10 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2015 VL 34 IS 2 BP 161 EP 166 DI 10.1016/j.healun.2014.09.033 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA CC1DV UT WOS:000350082300004 PM 25455751 ER PT J AU Gries, CJ Bhadriraju, S Edelman, JD Goss, CH Raghu, G Mulligan, MS AF Gries, Cynthia J. Bhadriraju, Sudha Edelman, Jeffrey D. Goss, Christopher H. Raghu, Ganesh Mulligan, Michael. S. TI Obese patients with idiopathic pulmonary fibrosis have a higher 90-day mortality risk with bilateral lung transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE idiopathic pulmonary fibrosis; body mass index; lung transplantation; obesity; transplant type ID OFFICIAL ADULT LUNG; INTERNATIONAL-SOCIETY; MULTIPLE IMPUTATION; REGISTRY; HEART; SURVIVAL AB BACKGROUND: Obese patients with idiopathic pulmonary fibrosis (IPF) have higher 90-day mortality after lung transplantation. We sought to determine whether body mass index (BMI) differentially modified the effect of transplant procedure type on 90-day mortality in IPF patients. METHODS: We analyzed data from the Organ Procurement and Transplantation Network (OPTN) for all patients with IPF who were transplanted between 2000 and 2010. Post-transplant survival was examined using Kaplan Meier estimates. Multivariable logistic regression modeling was used to determine the difference in 90-day survival. The primary variable of interest was the interaction term between body mass index (BMI) and transplant type. RESULTS: A total of 3,389 (58% single-lung transplant [SLT] and 42% bilateral lung transplant [BLT]) subjects were included. Multivariable logistic regression modeling demonstrated a statistically significant interaction between BIVII and transplant type (p = 0.047). Patients with a BMI > 30 kg/m(2) who received a BLT are 1.71 times (95% CI [1.03 to 2.85], p = 0.038) more likely to die within 90 days than BLT recipients with a BMI of 18.5 to 30 kg/m(2). CONCLUSIONS: Our results suggest that obese patients who receive a BLT may be at higher risk of 90-day mortality compared with patients of normal weight. Further study is needed to obtain more detailed information about comorbidities and other risk factors for early death that are not included in the OPTN database. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Gries, Cynthia J.] Univ Pittsburgh, Med Ctr, Div Allergy Pulm & Crit Care Med, Pittsburgh, PA 15213 USA. [Bhadriraju, Sudha] Univ Pittsburgh, Med Ctr, Dept Internal Med, Pittsburgh, PA 15213 USA. [Edelman, Jeffrey D.] VA Puget Sound Healthcare Syst, Div Pulm & Crit Care Med, Seattle, WA USA. [Goss, Christopher H.; Raghu, Ganesh] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [Mulligan, Michael. S.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. RP Gries, CJ (reprint author), Univ Pittsburgh, Med Ctr, Div Allergy Pulm & Crit Care Med, 628 NW Montefiore,3459 Fifth Ave, Pittsburgh, PA 15213 USA. EM griescj@upmc.edu FU National Institutes of Health (NIH); National Center for Research Resources (NCRR); NIH Roadmap for Medical Research [5KL2RR025015] FX The authors have no conflicts of interest to disclose. This study was supported by the National Center for Research Resources (NCRR) from a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research (5KL2RR025015). NR 18 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2015 VL 34 IS 2 BP 241 EP 246 DI 10.1016/j.healun.2014.09.031 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA CC1DV UT WOS:000350082300015 PM 25447567 ER PT J AU Sisto, R Moleti, A Shera, CA AF Sisto, Renata Moleti, Arturo Shera, Christopher A. TI On the spatial distribution of the reflection sources of different latency components of otoacoustic emissions SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID GENERATION PLACE; THRESHOLDS; COCHLEA AB The experimental observation of long-and short-latency components in both stimulus-frequency and transient-evoked otoacoustic emissions admits a comprehensive explanation within the coherent reflection mechanism, in a linear active transmission-line cochlear model. A local complex reflectivity function associated with roughness was defined and analyzed by varying the tuning factor of the model, systematically showing, for each frequency, a multiple-peak spatial structure, compatible with the observed multiple-latency structure of otoacoustic emissions. Although this spatial pattern and the peak relative intensity changes with the chosen random roughness function, the multiple-peak structure is a reproducible feature of different "digital ears," in good agreement with experimental data. If one computes the predicted transmission delays as a function of frequency and position for each source, one gets a good match to the latency-frequency patterns that are directly computed from synthesized otoacoustic spectra using time-frequency analysis. This result clarifies the role of the spatial distribution of the otoacoustic emission sources, further supporting the interpretation of different-latency otoacoustic components as due to reflection sources localized at different places along the basilar membrane. (C) 2015 Acoustical Society of America. C1 [Sisto, Renata] INAIL Italian Workers Compensat Author Res, Dipartimento Igiene Lavoro, I-00040 Rome, Italy. [Moleti, Arturo] Univ Roma Tor Vergata, Dipartimento Fis, I-00133 Rome, Italy. [Shera, Christopher A.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. [Shera, Christopher A.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Moleti, A (reprint author), Univ Roma Tor Vergata, Dipartimento Fis, Via Ric Sci 1, I-00133 Rome, Italy. EM arturo.moleti@roma2.infn.it RI Moleti, Arturo/P-6812-2016; OI Moleti, Arturo/0000-0002-2465-8849; Renata, Sisto/0000-0002-5086-7003 FU Finalized Project of the Italian Ministry of Health [RF-2009-1470310]; National Institutes of Health [R01 DC003687] FX This work was partly supported by the Finalized Project of the Italian Ministry of Health RF-2009-1470310 and by Grant No. R01 DC003687 (CAS) from the National Institutes of Health. NR 17 TC 12 Z9 12 U1 0 U2 1 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD FEB PY 2015 VL 137 IS 2 BP 768 EP 776 DI 10.1121/1.4906583 PG 9 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA CC0KO UT WOS:000350024600038 PM 25698011 ER PT J AU Mehta, DD Wolfe, PJ AF Mehta, Daryush D. Wolfe, Patrick J. TI Statistical properties of linear prediction analysis underlying the challenge of formant bandwidth estimation SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID VOCAL-TRACT; TRACKING; SPEECH AB Formant bandwidth estimation is often observed to be more challenging than the estimation of formant center frequencies due to the presence of multiple glottal pulses within a period and short closed-phase durations. This study explores inherently different statistical properties between linear prediction (LP)-based estimates of formant frequencies and their corresponding bandwidths that may be explained in part by the statistical bounds on the variances of estimated LP coefficients. A theoretical analysis of the Cramer-Rao bounds on LP estimator variance indicates that the accuracy of bandwidth estimation is approximately twice as low as that of center frequency estimation. Monte Carlo simulations of all-pole vowels with stochastic and mixed-source excitation demonstrate that the distributions of estimated LP coefficients exhibit expectedly different variances for each coefficient. Transforming the LP coefficients to formant parameters results in variances of bandwidth estimates being typically larger than the variances of respective center frequency estimates, depending on vowel type and fundamental frequency. These results provide additional evidence underlying the challenge of formant bandwidth estimation due to inherent statistical properties of LP-based speech analysis. (C) 2015 Acoustical Society of America. C1 [Mehta, Daryush D.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Wolfe, Patrick J.] UCL, Dept Stat Sci, London WC1E 6BT, England. [Wolfe, Patrick J.] UCL, Dept Comp Sci, London WC1E 6BT, England. [Wolfe, Patrick J.] Univ Illinois, Dept Elect & Comp Engn, Urbana, IL 61801 USA. RP Mehta, DD (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. EM mehta.daryush@mgh.harvard.edu FU U.S. Army Research Office under PECASE Award [W911NF-09-1-0555]; U.S. Office of Naval Research [N00014-14-1-0819]; UK EPSRC under Mathematical Sciences Established Career Fellowship [EP/K005413/1]; UK Royal Society under a Wolfson Research Merit Award; European Union [PCIG12-GA-2012-334622]; NIH National Institute on Deafness and Other Communication Disorders [R33 DC011588]; Voice Health Institute FX Work supported in part by the U.S. Army Research Office under PECASE Award W911NF-09-1-0555; by the U.S. Office of Naval Research under Award N00014-14-1-0819; by the UK EPSRC under Mathematical Sciences Established Career Fellowship EP/K005413/1; by the UK Royal Society under a Wolfson Research Merit Award; and by Marie Curie FP7 Integration Grant PCIG12-GA-2012-334622 within the 7th European Union Framework Program. Support also received from a grant from the NIH National Institute on Deafness and Other Communication Disorders (R33 DC011588) and the Voice Health Institute. Manuscript contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The authors thank D. Rudoy (Rudoy, 2010), whose work inspired the current study. NR 31 TC 1 Z9 1 U1 1 U2 2 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD FEB PY 2015 VL 137 IS 2 BP 944 EP 950 DI 10.1121/1.4906840 PG 7 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA CC0KO UT WOS:000350024600053 PM 25698026 ER PT J AU Marcus, BS McAvay, G Gill, TM Fragoso, CAV AF Marcus, Brian S. McAvay, Gail Gill, Thomas M. Fragoso, Carlos A. Vaz TI Respiratory Symptoms, Spirometric Respiratory Impairment, and Respiratory Disease in Middle-Aged and Older Persons SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE spirometry; Z-scores; respiratory impairment; respiratory symptoms ID OBSTRUCTIVE PULMONARY-DISEASE; LUNG-FUNCTION; CHRONIC-BRONCHITIS; PREVALENCE; DYSPNEA; GUIDELINES; MANAGEMENT; VALUES; ADULTS; COPD AB ObjectivesTo evaluate whether a novel definition of spirometric respiratory impairment from the Global Lung Initiative (GLI) is strongly associated with respiratory symptoms and, in turn, frequently establishes symptomatic respiratory disease. DesignCross-sectional. SettingThird National Health and Nutrition Examination Survey. ParticipantsCommunity-dwelling individuals aged 40 to 80 (N=7,115). MeasurementsGLI-defined spirometric respiratory impairment (airflow obstruction and restrictive pattern), dyspnea on exertion (DOE), chronic bronchitis (CB), and wheezing. ResultsPrevalence rates were 12.7% for airflow obstruction, 6.2% for restrictive pattern, 28.6% for DOE, 12.6% for CB, and 12.9% for wheezing. Airflow obstruction was associated with DOE (adjusted odds ratio (aOR)=1.69, 95% confidence interval (CI)=1.42-2.02), CB (aOR=1.92, 95% CI=1.62-2.29), and wheezing (aOR=2.50, 95% CI=2.08-3.00), and restrictive pattern was associated with DOE (aOR=1.75, 95% CI=1.36-2.25), CB (aOR=1.39, 95% CI=1.08-1.78), and wheezing (aOR=1.53, 95% CI=1.15-2.04). Nonetheless, among participants who had airflow obstruction and restrictive pattern, only a minority had DOE (38.6% and 45.5%), CB (23.3% and 15.9%), and wheezing (24.4% and 19.1%), yielding a positive predictive value (PPV) of only 53% for any respiratory symptom in the setting of any spirometric respiratory impairment. In addition, most participants who had DOE (73.0%), CB (67.8%), and wheezing (66.8%) did not have airflow obstruction or restrictive pattern, yielding a PPV of only 26% for any spirometric respiratory impairment in the setting of any respiratory symptom. The results differed only modestly when stratified according to age (40-64 vs 65-80). ConclusionGLI-defined spirometric respiratory impairment increased the likelihood of respiratory symptoms but was nonetheless a poor predictor of respiratory symptoms. Similarly, respiratory symptoms were poor predictors of GLI-defined spirometric respiratory impairment. Hence, a comprehensive assessment is needed when evaluating respiratory symptoms, even in the presence of spirometric respiratory impairment. C1 [Marcus, Brian S.; McAvay, Gail; Gill, Thomas M.; Fragoso, Carlos A. Vaz] Yale Univ, Sch Med, New Haven, CT USA. [Fragoso, Carlos A. Vaz] US Dept Vet Affairs, Clin Epidemiol Res Ctr, West Haven, CT USA. RP Fragoso, CAV (reprint author), VA Connecticut Healthcare Syst, Clin Epidemiol Res Ctr, 950 Campbell Ave,Mailcode 151B, West Haven, CT 06516 USA. EM carlos.fragoso@yale.edu FU Yale Claude D. Pepper Older Americans Independence Center [P30AG021342]; Veterans Administration Merit Award; National Institute on Aging [K07AG043587]; START@Yale Program FX The study was conducted at the Yale Claude D. Pepper Older Americans Independence Center (Grant P30AG021342). Dr. Vaz Fragoso is the recipient of a Veterans Administration Merit Award. Dr. Gill is the recipient of Academic Leadership Award K07AG043587 from the National Institute on Aging. Mr. Brian Marcus is the recipient of support from the START@Yale Program. NR 38 TC 6 Z9 6 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2015 VL 63 IS 2 BP 251 EP 257 DI 10.1111/jgs.13242 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CB8PP UT WOS:000349893300005 PM 25643966 ER PT J AU Jennings, LA Reuben, DB Evertson, LC Serrano, KS Ercoli, L Grill, J Chodosh, J Tan, Z Wenger, NS AF Jennings, Lee A. Reuben, David B. Evertson, Leslie Chang Serrano, Katherine S. Ercoli, Linda Grill, Joshua Chodosh, Joshua Tan, Zaldy Wenger, Neil S. TI Unmet Needs of Caregivers of Individuals Referred to a Dementia Care Program SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE dementia; primary care; caregiver strain ID QUALITY-OF-LIFE; SELF-EFFICACY; ALZHEIMERS-DISEASE; FAMILY CAREGIVERS; BEHAVIORAL-PROBLEMS; MANAGING DEMENTIA; STRAIN INDEX; OLDER-ADULTS; HEALTH; STRESS AB ObjectivesTo characterize caregiver strain, depressive symptoms, and self-efficacy for managing dementia-related problems and the relationship between these and referring provider type. DesignCross-sectional observational cohort. SettingUrban academic medical center. ParticipantsCaregivers of community-dwelling adults with dementia referred to a dementia care management program. MeasurementsCaregivers were surveyed and completed the Patient Health Questionnaire (PHQ-9) about themselves; the Modified Caregiver Strain Index; the Neuropsychiatric Inventory Questionnaire, which measures patient symptom severity and related caregiver distress; and a nine-item caregiver self-efficacy scale developed for the study. ResultsOf 307 patient-caregiver dyads surveyed over a 1-year period, 32% of caregivers reported confidence in managing dementia-related problems, 19% knew how to access community services to help provide care, and 28% agreed that the individual's provider helped them work through dementia care problems. Thirty-eight percent reported high levels of caregiver strain, and 15% reported moderate to severe depressive symptoms. Caregivers of individuals referred by geriatricians more often reported having a healthcare professional to help work through dementia care problems than those referred by internists, family physicians, or other specialists, but self-efficacy did not differ. Low caregiver self-efficacy was associated with higher caregiver strain, more caregiver depressive symptoms, and caring for an individual with more-severe behavioral symptoms. ConclusionMost caregivers perceived inadequate support from the individual's provider in managing dementia-related problems, reported strain, and had low confidence in managing caregiving. New models of care are needed to address the complex care needs of individuals with dementia and their caregivers. C1 [Jennings, Lee A.; Reuben, David B.; Evertson, Leslie Chang; Serrano, Katherine S.; Chodosh, Joshua; Tan, Zaldy] Univ Calif Los Angeles, Multicampus Program Geriatr Med & Gerontol, Los Angeles, CA 90095 USA. [Wenger, Neil S.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Ercoli, Linda] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Grill, Joshua] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Grill, Joshua] Univ Calif Los Angeles, Mary Easton Ctr Alzheimers Dis Res, Los Angeles, CA 90095 USA. [Chodosh, Joshua] Vet Affairs Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. RP Jennings, LA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Geriatr, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. EM lajennings@mednet.ucla.edu OI Chodosh, Joshua/0000-0001-7784-4306 FU Avanir; Bristol-Myers Squibb; Eli Lilly; Genentech; Janssen Alzheimer Immunotherapy; Medivation; Merck; Alzheimer's Disease Cooperative Study; Centers for Medicare and Medicaid Services Centers for Medicare and Medicaid Innovation [CMS-1C1-12-0001, 1C1CMS330982-01-00]; UCLA Claude Pepper Older Americans Independence Center - National Institute on Aging [5P30AG028748]; National Institutes of Health, National Center for Advancing Translational Science FX All authors report no conflict of interest associated with this paper. Dr. Joshua Grill has received grant and research support as a site investigator for clinical trials sponsored by Avanir, Bristol-Myers Squibb, Eli Lilly, Genentech, Janssen Alzheimer Immunotherapy, Medivation, Merck, and the Alzheimer's Disease Cooperative Study.; The project described was supported by Funding Opportunity CMS-1C1-12-0001 from the Centers for Medicare and Medicaid Services (1C1CMS330982-01-00) Centers for Medicare and Medicaid Innovation and the UCLA Claude Pepper Older Americans Independence Center funded by the National Institute on Aging (5P30AG028748) and the National Institutes of Health, National Center for Advancing Translational Science. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Health and Human Services or any of its agencies. NR 44 TC 6 Z9 7 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2015 VL 63 IS 2 BP 282 EP 289 DI 10.1111/jgs.13251 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CB8PP UT WOS:000349893300009 PM 25688604 ER PT J AU Yolin-Raley, DS Dagogo-Jack, I Niell, HB Soiffer, RJ Antin, JH Antin, EP Glotzbecker, BE AF Yolin-Raley, Deborah S. Dagogo-Jack, Ibiayi Niell, Heidi B. Soiffer, Robert J. Antin, Joseph H. Alyea, Edwin P., III Glotzbecker, Brett E. TI The Utility of Routine Chest Radiography in the Initial Evaluation of Adult Patients With Febrile Neutropenia Patients Undergoing HSCT SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID STEM-CELL TRANSPLANTATION; CANCER; FEVER; CHILDREN; INFECTIONS; MANAGEMENT; RADIATION; GUIDELINE; DISEASES; COSTS AB Background: The routine use of chest radiographs (CXRs) in the initial evaluation of asymptomatic patients with febrile neutropenia undergoing hematopoietic stem cell transplant (HSCT) is controversial. Objective: The goal of this study was to document the incidence of pneumonia demonstrated on CXR during an initial febrile neutropenic episode in adult patients undergoing HSCT. Materials and Methods: Clinical records of 1083 adult patients undergoing autologous (n=766), allogeneic (n=269), or umbilical cord blood HSCT (n=48) between October 1, 2009, and December 31, 2012, were retrospectively reviewed. CXRs obtained at the initial febrile neutropenic episode were evaluated for radiologic features of pneumonia. The presence of clinical symptoms, length of stay (LOS), and readmission rates were assessed. Results: A total of 817 (75%) febrile neutropenic episodes were noted. Of the patients with neutropenic fevers, 455 (55%) had CXRs. Of the 76 patients with respiratory symptoms at the time of CXR, 24 (31.6%) had findings suggestive of pneumonia. None of the 379 CXRs performed in the absence of symptoms revealed an infectious process (P=.0001). Moreover, the mean LOS was 23.8 days for patients receiving a CXR compared with 22.2 days (P=.04) in patients without a CXR. Additionally, in patients who had CXRs, 15.7% were readmitted within 30 days compared with 7.4% in those without CXRs (P=.0004). Conclusions: Indiscriminate routine CXR at the time of first neutropenic fever in asymptomatic adults undergoing HSCT is unlikely to reveal an infectious process or change clinical practice, and may be associated with increased LOS and readmission rates. C1 [Yolin-Raley, Deborah S.; Niell, Heidi B.; Soiffer, Robert J.; Antin, Joseph H.; Alyea, Edwin P., III; Glotzbecker, Brett E.] Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA 02115 USA. [Dagogo-Jack, Ibiayi] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. RP Glotzbecker, BE (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM brett_glotzbecker@dfci.harvard.edu NR 25 TC 1 Z9 2 U1 0 U2 4 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD FEB PY 2015 VL 13 IS 2 BP 184 EP 189 PG 6 WC Oncology SC Oncology GA CB7UT UT WOS:000349834400010 PM 25691611 ER PT J AU Ajani, JA D'Amico, TA Almhanna, K Bentrem, DJ Besh, S Chao, J Das, P Denlinger, C Fanta, P Fuchs, CS Gerdes, H Gerdes, H Hayman, JA Hochwald, S Hofstetter, WL Ilson, DH Jaroszewski, D Jasperson, K Keswani, RN Kleinberg, LR Korn, WM Leong, S Lockhart, AC Mulcahy, MF Orringer, MB Posey, JA Poultsides, GA Sasson, AR Scott, WJ Strong, VE Varghese, TK Washington, MK Willett, CG Wright, CD Zelman, D McMillian, N Sundar, H AF Ajani, Jaffer A. D'Amico, Thomas A. Almhanna, Khaldoun Bentrem, David J. Besh, Stephen Chao, Joseph Das, Prajnan Denlinger, Crystal Fanta, Paul Fuchs, Charles S. Gerdes, Hans Glasgow, Robert E. Hayman, James A. Hochwald, Steven Hofstetter, Wayne L. Ilson, David H. Jaroszewski, Dawn Jasperson, Kory Keswani, Rajesh N. Kleinberg, Lawrence R. Korn, W. Michael Leong, Stephen Lockhart, A. Craig Mulcahy, Mary F. Orringer, Mark B. Posey, James A. Poultsides, George A. Sasson, Aaron R. Scott, Walter J. Strong, Vivian E. Varghese, Thomas K., Jr. Washington, Mary Kay Willett, Christopher G. Wright, Cameron D. Zelman, Debra McMillian, Nicole Sundar, Hema TI Esophageal and Esophagogastric Junction Cancers, Version 1.2015 SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID PHASE-II TRIAL; POSITRON-EMISSION-TOMOGRAPHY; SQUAMOUS-CELL CARCINOMA; ARBEITSGEMEINSCHAFT INTERNISTISCHE ONKOLOGIE; RANDOMIZED CONTROLLED-TRIAL; COMBINED-MODALITY THERAPY; DOCETAXEL PLUS CISPLATIN; GASTROESOPHAGEAL JUNCTION; GASTRIC-CANCER; METASTATIC ADENOCARCINOMA AB Esophageal cancer is the sixth most common cause of cancer deaths worldwide. Adenocarcinoma is more common in North America and Western European countries, originating mostly in the lower third of the esophagus, which often involves the esophagogastric junction (EGJ). Recent randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival in patients with resectable cancer. Targeted therapies with trastuzumab and ramucirumab have produced encouraging results in the treatment of advanced or metastatic EGJ adenocarcinomas. Multidisciplinary team management is essential for patients with esophageal and EGJ cancers. This portion of the NCCN Guidelines for Esophageal and EGJ Cancers discusses management of locally advanced adenocarcinoma of the esophagus and EGJ. C1 [Ajani, Jaffer A.; Das, Prajnan; Hofstetter, Wayne L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Almhanna, Khaldoun] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Bentrem, David J.; Keswani, Rajesh N.; Mulcahy, Mary F.] NorthWestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA. [Besh, Stephen] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Chao, Joseph] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Denlinger, Crystal; Scott, Walter J.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Fanta, Paul] UC San Diego Moores Canc Ctr, La Jolla, CA 92093 USA. [Fuchs, Charles S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Gerdes, Hans; Ilson, David H.; Strong, Vivian E.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Glasgow, Robert E.; Jasperson, Kory] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Hayman, James A.; Orringer, Mark B.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Hochwald, Steven] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Kleinberg, Lawrence R.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sidney, BC, Canada. [Korn, W. Michael] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Leong, Stephen] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Lockhart, A. Craig] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Lockhart, A. Craig] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO 63110 USA. [Posey, James A.] Univ Alabama Birmingham, Birmingham, AL 35233 USA. [Poultsides, George A.] Stanford Canc Inst, Stanford, CA USA. [Varghese, Thomas K., Jr.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA USA. [Washington, Mary Kay] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Wright, Cameron D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Ajani, JA (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 129 TC 39 Z9 42 U1 1 U2 8 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD FEB PY 2015 VL 13 IS 2 BP 194 EP 227 PG 34 WC Oncology SC Oncology GA CB7UT UT WOS:000349834400011 PM 25691612 ER PT J AU Nillni, YI Pineles, SL Patton, SC Rouse, MH Sawyer, AT Rasmusson, AM AF Nillni, Yael I. Pineles, Suzanne L. Patton, Samantha C. Rouse, Matthew H. Sawyer, Alice T. Rasmusson, Ann M. TI Menstrual Cycle Effects on Psychological Symptoms in Women With PTSD SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PREMENSTRUAL EXACERBATION; ANXIETY SENSITIVITY; PANIC DISORDER; HEALTHY WOMEN; MOOD CHANGES; ESTROGEN; PHASE; DEPRESSION; EXTINCTION AB The menstrual cycle has been implicated as a sex-specific biological process influencing psychological symptoms across a variety of disorders. Limited research exists regarding the role of the menstrual cycle in psychological symptoms among women with posttraumatic stress disorder (PTSD). The current study examined the severity of a broad range of psychological symptoms in both the early follicular (Days 2-6) and midluteal (6-10 days postlutenizing hormone surge) phases of the menstrual cycle in a sample of trauma-exposed women with and without PTSD (N = 49). In the sample overall, total psychological symptoms (d = 0.63), as well as depression (d = 0.81) and phobic anxiety (d = 0.81) symptoms, specifically, were increased in the early follicular compared to midluteal phase. The impact of menstrual cycle phase on phobic anxiety was modified by a significant PTSD x Menstrual Phase interaction (d = 0.63). Women with PTSD reported more severe phobic anxiety during the early follicular versus midluteal phase, whereas phobic anxiety did not differ across the menstrual cycle in women without PTSD. Thus, the menstrual cycle appears to impact fear-related symptoms in women with PTSD. The clinical implications of the findings and future research directions are discussed. C1 [Nillni, Yael I.; Pineles, Suzanne L.; Patton, Samantha C.; Rasmusson, Ann M.] Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. [Nillni, Yael I.; Pineles, Suzanne L.; Rouse, Matthew H.; Sawyer, Alice T.; Rasmusson, Ann M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Rouse, Matthew H.; Sawyer, Alice T.] Vet Affairs Boston Healthcare Syst, Boston, MA 02130 USA. RP Nillni, YI (reprint author), Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave 116B-3, Boston, MA 02130 USA. EM yael.nillni@va.gov FU VA Career Development Award from the Clinical Sciences R&D Service, Department of Veterans Affairs FX Support for this work was provided by a VA Career Development Award (Principal Investigator: S. L. Pineles) from the Clinical Sciences R&D Service, Department of Veterans Affairs NR 29 TC 3 Z9 3 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-9867 EI 1573-6598 J9 J TRAUMA STRESS JI J. Trauma Stress PD FEB PY 2015 VL 28 IS 1 BP 1 EP 7 DI 10.1002/jts.21984 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CB9XF UT WOS:000349986900001 PM 25613589 ER PT J AU Lippa, SM Fonda, JR Fortier, CB Amick, MA Kenna, A Milberg, WP McGlinchey, RE AF Lippa, Sara M. Fonda, Jennifer R. Fortier, Catherine B. Amick, Melissa A. Kenna, Alexandra Milberg, William P. McGlinchey, Regina E. TI Deployment-Related Psychiatric and Behavioral Conditions and Their Association with Functional Disability in OEF/OIF/OND Veterans SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID TRAUMATIC BRAIN-INJURY; POSTTRAUMATIC-STRESS-DISORDER; PERSISTENT POSTCONCUSSIVE SYMPTOMS; STRUCTURED CLINICAL INTERVIEW; MCGILL PAIN QUESTIONNAIRE; TEST-RETEST RELIABILITY; MENTAL-HEALTH PROBLEMS; SLEEP QUALITY INDEX; IRAQ; AFGHANISTAN AB Understanding the factors that influence veterans' functional outcome after deployment is critical to provide appropriately targeted care. Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) have been related to disability, but other psychiatric and behavioral conditions are not as well examined. We investigated the impact of deployment-related psychiatric and behavioral conditions on disability among 255 OEF/OIF/OND service members and veterans. Structured clinical interviews assessed TBI and the psychiatric conditions of depression, PTSD, anxiety, and substance use. Self-report questionnaires assessed disability and the behavioral conditions of sleep disturbance and pain. Over 90% of participants had a psychiatric and/or behavioral condition, with approximately half presenting with 3 conditions. Exploratory factor analysis revealed 4 clinically relevant psychiatric and behavioral factors which accounted for 76.9% of the variance: (a) depression, PTSD, and military mTBI (deployment trauma factor); (b) pain and sleep (somatic factor); (c) anxiety disorders, other than PTSD (anxiety factor); and (d) substance abuse or dependence (substance use factor). Individuals with the conditions comprising the deployment trauma factor were more likely to be substantially disabled than individuals with depression and PTSD, but no military mTBI, OR = 3.52; 95% CI [1.09, 11.37]. Depression, PTSD, and a history of military mTBI may comprise an especially harmful combination associated with high risk for substantial disability. C1 [Lippa, Sara M.; Fonda, Jennifer R.; Fortier, Catherine B.; Amick, Melissa A.; Kenna, Alexandra; Milberg, William P.; McGlinchey, Regina E.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders TRACTS, Boston, MA 02130 USA. [Lippa, Sara M.; Fonda, Jennifer R.; Fortier, Catherine B.; Amick, Melissa A.; Kenna, Alexandra; Milberg, William P.; McGlinchey, Regina E.] VA Boston Healthcare Syst, GRECC, Boston, MA 02130 USA. [Lippa, Sara M.] Walter Reed Natl Mil Med Ctr, Def & Vet Brain Injury Ctr, Bethesda, MD USA. [Fonda, Jennifer R.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Fortier, Catherine B.; Milberg, William P.; McGlinchey, Regina E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Amick, Melissa A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP McGlinchey, RE (reprint author), VA Boston Healthcare Syst, TRACTS GRECC JP 182, 150 South Huntington Ave, Boston, MA 02130 USA. EM regina_mcglinchey@hms.harvard.edu RI McGlinchey, Regina/R-1971-2016 FU Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development (RR&D) Traumatic Brain Injury Center of Excellence [B6796-C]; VA CSR&D Merit Review Award; NIH NIA [K01AG024898] FX This research was supported by the Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development (RR&D) Traumatic Brain Injury Center of Excellence (B6796-C) and VA CSR&D Merit Review Award to Regina McGlinchey, and NIH NIA K01AG024898 to Catherine Fortier. We would like to thank Wally Musto for his championing of our work among military personnel and his tireless recruitment efforts on our behalf, as well as the entire TRACTS team for their assistance with data collection and management. We would also like to thank Drs. Patricia Dorn and Stuart Hoffman of VA RR&D for their support of our TBI CoE. Lastly, we would like to thank the anonymous reviewers of this manuscript for their thoughtful comments, which substantially strengthened the manuscript. NR 49 TC 13 Z9 13 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-9867 EI 1573-6598 J9 J TRAUMA STRESS JI J. Trauma Stress PD FEB PY 2015 VL 28 IS 1 BP 25 EP 33 DI 10.1002/jts.21979 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CB9XF UT WOS:000349986900004 PM 25703936 ER PT J AU Boasso, AM Steenkamp, MM Nash, WP Larson, JL Litz, BT AF Boasso, Alyssa M. Steenkamp, Maria M. Nash, William P. Larson, Jonathan L. Litz, Brett T. TI The Relationship Between Course of PTSD Symptoms in Deployed US Marines and Degree of Combat Exposure SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; TRAJECTORIES; WAR AB Large cohort studies suggest that most military personnel experience minimal posttraumatic stress disorder (PTSD) symptoms following warzone deployment, an outcome often labeled resilience. Very low symptom levels, however, may be a marker for low exposure, not resilience, which requires relatively high-magnitude or high-frequency stress exposure as a precondition. We used growth mixture modeling (GMM) to examine the longitudinal course of lifetime PTSD symptoms following combat exposure by disaggregating deployed U.S. Marines into upper, middle, and lower tertiles of combat exposure. All factor models fit the data well; Tucker-Lewis Index (TLI) and comparative fit index (CFI) values ranged from .91 to .97. Three distinct trajectories best explained the data within each tertile. The upper tertile comprised True Resilience (73.2%), New-Onset Symptoms (18.3%), and Pre-existing Symptoms (8.5%) trajectories. The middle tertile also comprised True Resilience (74.5%), New-Onset Symptoms (16.1%), and Pre-existing Symptoms (9.4%) trajectories. The lower tertile comprised Artifactual Resilience (86.3%), Pre-existing Symptoms (7.6%), and New-Onset Symptoms (6.1%) trajectories. True Resilience involved a clinically significant symptom increase followed by a return to baseline, whereas Artifactual Resilience involved consistently low symptoms. Conflating artifactual and true resilience may inaccurately create the expectation of persistently low symptoms regardless of warzone exposure. C1 [Boasso, Alyssa M.; Larson, Jonathan L.; Litz, Brett T.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Steenkamp, Maria M.] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Nash, William P.] Boston VA Res Inst Inc, Boston, MA USA. [Litz, Brett T.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Boasso, AM (reprint author), 800 Boylston St, Boston, MA 02199 USA. EM Alyssa.Boasso@gmail.com FU VA Health Service Research and Development [SDR 09-0128]; U.S. Marine Corps and Navy Bureau of Medicine and Surgery FX This study was funded by VA Health Service Research and Development (SDR 09-0128) and by the U.S. Marine Corps and Navy Bureau of Medicine and Surgery. The authors acknowledge the Marine Resiliency Study (MRS) team who made this work possible. NR 15 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-9867 EI 1573-6598 J9 J TRAUMA STRESS JI J. Trauma Stress PD FEB PY 2015 VL 28 IS 1 BP 73 EP 78 DI 10.1002/jts.21988 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CB9XF UT WOS:000349986900011 PM 25630586 ER PT J AU Iverson, KM King, MW Gerber, MR Resick, PA Kimerling, R Street, AE Vogt, D AF Iverson, Katherine M. King, Matthew W. Gerber, Megan R. Resick, Patricia A. Kimerling, Rachel Street, Amy E. Vogt, Dawne TI Accuracy of an Intimate Partner Violence Screening Tool for Female VHA Patients: A Replication and Extension SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID WOMEN VETERANS AB The 4-item Hurt/Insult/Threaten/Scream (HITS) tool accurately detects past-year intimate partner violence (IPV) among female Veterans Health Administration (VHA) patients; however, it lacks a sexual IPV item. This study evaluated the accuracy of an extended HITS (E-HITS), which adds a sexual IPV item, in female VHA patients. A sample of 80 female U.S. veteran VHA patients in New England completed a mail survey (50.0% response rate) that included the 5-item E-HITS and the Revised Conflict Tactics Scales (CTS-2). Women were included if they were in an intimate relationship in the past year. The women averaged 49 years of age and 86.0% of the sample was White. Accuracy of the 4-item HITS was compared to the 5-item E-HITS, using the CTS-2 as the reference. There were 20 women (25.0%) who reported past-year IPV on the CTS-2. The receiver operator characteristic curves demonstrated that the HITS and E-HITS performed nearly identically at their optimal cutoff scores of 6 and 7, respectively. At these cutoff scores, the sensitivity of both tools was .75, 95% CI [.55, .95]. The specificities were similar; .83 for the HITS, 95% CI [.73, .92], and .82 for the E-HITS, 95% CI [.72, .90]. Including a sexual IPV item may be clinically beneficial; it also attains the same accuracy of case identification as the HITS. C1 [Iverson, Katherine M.; King, Matthew W.; Street, Amy E.; Vogt, Dawne] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Iverson, Katherine M.; Street, Amy E.; Vogt, Dawne] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Gerber, Megan R.] VA Boston Healthcare Syst, Womens Hlth Ctr, Boston, MA 02130 USA. [Gerber, Megan R.] Boston Univ, Sch Med, Dept Gen Internal Med, Boston, MA 02118 USA. [Resick, Patricia A.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Kimerling, Rachel] VA Palo Alto Hlth Care Syst, Natl Ctr PTSD, Menlo Pk, CA USA. [Kimerling, Rachel] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA USA. RP Iverson, KM (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave 116B-3, Boston, MA 02130 USA. EM katherine.iverson@va.gov OI Gerber, Megan/0000-0002-8444-5554 FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development (HSR&D) Services as part of Dr. Iverson's HSR&D Career Development Award [CDA 10-029]; Presidential Early Career Award for Scientists and Engineers [USA 14-275] FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development (HSR&D) Services as part of Dr. Iverson's HSR&D Career Development Award (CDA 10-029) and her Presidential Early Career Award for Scientists and Engineers (USA 14-275). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 11 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-9867 EI 1573-6598 J9 J TRAUMA STRESS JI J. Trauma Stress PD FEB PY 2015 VL 28 IS 1 BP 79 EP 82 DI 10.1002/jts.21985 PG 4 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CB9XF UT WOS:000349986900012 PM 25624170 ER PT J AU Ghosh, S Lertwattanarak, R Garduno, JD Galeana, JJ Li, JQ Zamarripa, F Lancaster, JL Mohan, S Hussey, S Musi, N AF Ghosh, Sangeeta Lertwattanarak, Raweewan Garduno, Jose de Jesus Galeana, Joaquin Joya Li, Jinqi Zamarripa, Frank Lancaster, Jack L. Mohan, Sumathy Hussey, Sophie Musi, Nicolas TI Elevated Muscle TLR4 Expression and Metabolic Endotoxemia in Human Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; LPS; TLR4; NF kappa B; JNK; Sarcopenia ID INDUCED INSULIN-RESISTANCE; NF-KAPPA-B; TYPE-2 DIABETIC SUBJECTS; RODENT SKELETAL-MUSCLE; FREE FATTY-ACID; GLUCOSE-TOLERANCE; OXIDATIVE STRESS; ACUTE EXERCISE; INFLAMMATORY MARKERS; ELDERLY SUBJECTS AB Aging is associated with alterations in glucose metabolism and sarcopenia that jointly contribute to a higher risk of developing type 2 diabetes. Because aging is considered as a state of low-grade inflammation, in this study we examined whether older, healthy (lean, community-dwelling) participants have altered signaling flux through toll-like receptor 4 (TLR4), a key mediator of innate and adaptive immune responses. We also examined whether a 4-month aerobic exercise program would have an anti-inflammatory effect by reducing TLR4 expression and signaling. At baseline, muscle TLR4, nuclear factor kappa B p50 and nuclear factor kappa B p65 protein content, and c-Jun N-terminal kinase phosphorylation were significantly elevated in older versus young participants. The plasma concentration of the TLR4 agonist lipopolysaccharide and its binding protein also were significantly elevated in older participants, indicative of metabolic endotoxemia, which is a recently described phenomenon of increased plasma endotoxin level in metabolic disease. These alterations in older participants were accompanied by decreased insulin sensitivity, quadriceps muscle volume, and muscle strength. The exercise training program increased insulin sensitivity, without affecting quadriceps muscle volume or strength. Muscle TLR4, nuclear factor kappa B, and c-Jun N-terminal kinase, and plasma lipopolysaccharide and lipopolysaccharide binding protein were not changed by exercise. In conclusion, insulin resistance and sarcopenia of aging are associated with increased TLR4 expression/signaling, which may be secondary to metabolic endotoxemia. C1 [Ghosh, Sangeeta; Hussey, Sophie; Musi, Nicolas] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Audie L Murphy VA Hosp, San Antonio, TX 78229 USA. [Ghosh, Sangeeta; Hussey, Sophie; Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Ghosh, Sangeeta; Lertwattanarak, Raweewan; Garduno, Jose de Jesus; Galeana, Joaquin Joya; Hussey, Sophie; Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Ctr Hlth Aging, San Antonio, TX 78229 USA. [Li, Jinqi; Zamarripa, Frank; Lancaster, Jack L.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Mohan, Sumathy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP Musi, N (reprint author), South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Audie L Murphy VA Hosp, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM musi@uthscsa.edu FU American Diabetes Association; National Institutes of Health [DK-80157, DK-089229]; San Antonio Nathan Shock Center [AG-013319]; American Federation for Aging Research [AG-030979]; National Institute on Aging; Institutional Ruth L. Kirchstein National research Service Award (NRSA) [T32-HL-04776] FX This study was supported by grants from the American Diabetes Association (N.M.), the National Institutes of Health (DK-80157 and DK-089229 to N.M.), the San Antonio Nathan Shock Center (AG-013319). N.M. was the recipient of a Paul B. Beeson Career Development Award (AG-030979) from the American Federation for Aging Research and the National Institute on Aging. S.G. was supported by an Institutional Ruth L. Kirchstein National research Service Award (NRSA) (T32-HL-04776). NR 75 TC 16 Z9 16 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2015 VL 70 IS 2 BP 232 EP 246 DI 10.1093/gerona/glu067 PG 15 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CC1RR UT WOS:000350121100013 PM 24846769 ER PT J AU Kivekas, I Chao, WC Faquin, W Hollowell, M Silvola, J Rasooly, T Poe, D AF Kivekas, Ilkka Chao, Wei-Chieh Faquin, William Hollowell, Monica Silvola, Juha Rasooly, Tali Poe, Dennis TI Histopathology of Balloon-Dilation Eustachian Tuboplasty SO LARYNGOSCOPE LA English DT Article DE Eustachian tuboplasty; balloon dilation; histopathology; mucosa; inflammation AB Objectives/Hypothesis: Surgical intervention of the Eustachian tube (ET) has become increasingly common in the past decade, and balloon dilation has shown promising results in recent studies. It is unclear how balloon dilation enhances ET function. Our aim was to evaluate histological changes in the ET's mucosal lumen comparing before balloon dilation, immediately after, and postoperatively. Study Design: Case series. Methods: Thirteen patients with bilateral ET dysfunction were enrolled. Biopsies of the ET mucosa were obtained just before balloon dilation; immediately after; and in three cases, 5 to 12 weeks postoperatively. Specimens were retrospectively examined under light microscopy by two pathologists blinded to the clinical information and whether specimens were pre- or postballoon dilation. Results: Preoperative biopsies were characterized by inflammatory changes within the epithelium and submucosal layer. Immediate response to balloon dilation was thinning of the mucosa, shearing of epithelium and crush injury to the submucosa, especially to lymphocytic infiltrates. Postoperative biopsies demonstrated healthy pseudocolumnar epithelium and replacement of lymphocytic infiltrate with a thinner layer of fibrous tissue. Conclusion: Reduction of inflammatory epithelial changes and submucosal inflammatory infiltrate appeared to be the principal result of balloon dilation. The balloon may shear or crush portions of inflamed epithelium but usually spared the basal layer, allowing for rapid healing. Additionally, it appeared to effectively crush lymphocytes and lymphocytic follicles that may become replaced with thinner fibrous scar. Histopathology of the ET undergoing balloon dilation demonstrated effects that could reduce the overall inflammatory burden and may contribute to clinical improvement in ET function. C1 [Kivekas, Ilkka; Chao, Wei-Chieh; Rasooly, Tali; Poe, Dennis] Boston Childrens Hosp, Dept Otolaryngol, Boston, MA 02115 USA. [Hollowell, Monica] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Faquin, William] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Kivekas, Ilkka] Tampere Univ Hosp, Dept Otorhinolaryngol, Tampere, Finland. [Kivekas, Ilkka] Univ Tampere, FIN-33101 Tampere, Finland. [Chao, Wei-Chieh] Chang Gung Univ, Chang Gung Mem Hosp, Dept Otolaryngol, Taoyuan, Taiwan. [Silvola, Juha] Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Otorhinolaryngol, N-0027 Oslo, Norway. RP Poe, D (reprint author), Boston Childrens Hosp, Dept Otol & Laryngol, Dept Otolaryngol & Commun Enhancement, 333 Longwood Ave,Lo 367, Boston, MA 02115 USA. EM dennis.poe@childrens.harvard.edu OI Kivekas, Ilkka/0000-0002-6931-3641 FU Acclarent, Inc. FX D.P. received two speaking honoraria from Acclarent, Inc., and is a coprimary investigator in a pending clinical trial, sponsored by Acclarent, Inc. The authors have no other funding, financial relationships; or conflicts of interest to disclose. NR 10 TC 8 Z9 11 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD FEB PY 2015 VL 125 IS 2 BP 436 EP 441 DI 10.1002/lary.24894 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CB9SS UT WOS:000349973400041 PM 25154612 ER PT J AU Kamani, D Potenza, AS Cernea, CR Kamani, YV Randolph, GW AF Kamani, Dipti Potenza, Andre S. Cernea, Claudio R. Kamani, Yash V. Randolph, Gregory W. TI The Nonrecurrent Laryngeal Nerve: Anatomic and Electrophysiologic Algorithm for Reliable Identification SO LARYNGOSCOPE LA English DT Article DE Nonrecurrent laryngeal nerve; NRLN; IONM; anatomical types of NRLN; inferior thyroid artery; RLN; thyroid surgery; vagal stimulation; intraoperative Identification of Non recurrent laryngeal nerve (NRLN) ID THYROID-SURGERY; ENDOCRINE SURGEONS; RECURRENT; INJURY; PARATHYROIDECTOMY; ASSOCIATION; MULTICENTER; PARALYSIS AB Objectives/Hypothesis: The recurrent laryngeal nerve (RLN) intraoperative monitoring (IONM) provides a new functional dynamic that adds to visual identification of the RLN to optimize its intraoperative management. Intraoperative monitoring has been applied to the initial identification of the RLN. We now apply IONM to the identification of the nonrecurrent laryngeal nerve (NRLN) and provide electrophysiologic and anatomic parameters to facilitate this technique of neural identification for the NRLN, which is at increased risk of injury during thyroid surgery. Study Design: Retrospective. Methods: A study of cases of the NRLN from consecutive thyroid surgeries with IONM was conducted. Preoperative and postoperative laryngoscopy was documented in all cases. Results: Ten right-sided nerves (0.6%) were identified as NRLN. One hundred percent of NRLNs had documented normal preoperative and postoperative laryngeal function. Distal and proximal vagal nerve stimulation points that allowed for the electrophysiologic prediction of a nonrecurrence in all patients were identified. Electrophysiological normative parameters of NRLN were compared to those of the normal right RLN and right vagus nerves. Conclusion: Nonrecurrent laryngeal nerve is present in 0.6% of patients undergoing thyroid surgery. Intraoperative monitoring involving vagal stimulation at the defined distal and proximal points provides reliable electrophysiologic intraoperative verification of the presence of the NRLN. Three anatomical subtypes of right NRLN are noted that enable early identification of the NRLN. In conjunction with detailed knowledge of the NRLN anatomic pathways, they also may be helpful in preventing injury to the NRLN, which has been shown to be at higher risk during thyroid surgery. We provide an anatomic and electrophysiologic algorithm for reliable identification of the NRLN. C1 [Kamani, Dipti; Kamani, Yash V.; Randolph, Gregory W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Thyroid & Parathyroid Surg, Boston, MA USA. [Randolph, Gregory W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol Endocrine Surg Serv, Boston, MA USA. [Potenza, Andre S.; Cernea, Claudio R.] Univ Sao Paulo, Sch Med, Dept Head & Neck Surg, Sao Paulo, Brazil. RP Randolph, GW (reprint author), Massachusetts Eye & Ear Infirm, Div Thyroid & Parathyroid Surg, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Gregory_Randolph@meei.harvard.edu RI Cernea, Claudio/F-5610-2016 FU John and Claire Bertucci Thyroid Research fund FX The John and Claire Bertucci Thyroid Research fund supported this research. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 35 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD FEB PY 2015 VL 125 IS 2 BP 503 EP 508 DI 10.1002/lary.24823 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CB9SS UT WOS:000349973400053 PM 25042210 ER PT J AU Sritharan, N Chase, M Kamani, D Randolph, M Randolph, GW AF Sritharan, Niranjan Chase, Meghan Kamani, Dipti Randolph, Madeline Randolph, Gregory W. TI The Vagus Nerve, Recurrent Laryngeal Nerve, and External Branch of the Superior Laryngeal Nerve Have Unique Latencies Allowing for Intraoperative Documentation of Intact Neural Function During Thyroid Surgery SO LARYNGOSCOPE LA English DT Article DE Intraoperative nerve monitoring; recurrent laryngeal nerve; normal parameters; postoperative glottis and/or recurrent laryngeal nerve function; bilateral vocal cord palsy; complications of thyroid surgery; electrophysiologic parameters ID NEUROMONITORING IONM; PARATHYROID SURGERY; ENDOCRINE SURGEONS; PARALYSIS; INJURY; STIMULATION; MULTICENTER; VAGAL; RISK AB Objectives/Hypothesis: To define normative amplitude and latency of vagus, recurrent laryngeal nerve (RLN), and external branch of superior laryngeal nerve (EBSLN) and to apply them to postoperative neural function documentation. To our knowledge, this is the first study to report electrophysiologic characteristics of all three nerves in a consecutive patient series. Study Design: Prospective. Methods: Quantitative analysis of evoked waveform data was performed on both sides in consecutive patients undergoing thyroid surgery by a single surgeon. Mean values, standard error of mean, and standard deviation were calculated for latency (in milliseconds) and amplitude (in microvolts) of the vagus nerves, RLN, and EBSLN. Pre- and postoperative vocal cord function was normal in all patients. Results: Normative latency analysis showed mean right and left vagal latency of 5.47 ms (+/- 0.73) and 8.14 ms (+/- 0.86), respectively (P<.0001). Pooled RLN latency was 3.96 ms (+/- 0.69), and pooled EBSLN latency was 3.56 ms (+/- 0.49), both significantly shorter than vagal latencies (P<.0001). There was no association between amplitude and latency parameters and tumor-size (> or <5 cm), body mass index (> or <25), age (> or <50 years), gender, or degree of neural dissection. Conclusions: The unique right vagus, left vagus, and RLN latencies are characteristic of the individual nerves and allow identification (through the characteristic waveform latency) of an intact left or right vagus/RLN system. Timed recording of vagal waveform after thyroid lobectomy consequently documents intact ipsilateral vagal-RLN neural circuit and may be placed into the medical record as electrophysiologic documentation of existence of postresection complete neural integrity. C1 [Sritharan, Niranjan; Chase, Meghan; Kamani, Dipti; Randolph, Madeline; Randolph, Gregory W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Thyroid & Parathyroid Surg,Dept Laryngol & Ot, Boston, MA USA. [Randolph, Gregory W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol,Dept Surg, Boston, MA USA. RP Randolph, GW (reprint author), Massachusetts Eye & Ear Infirm, Div Thyroid & Parathyroid Surg, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM gregory_randolph@meei.harvard.edu FU John and Claire Bertucci Thyroid Research fund FX This work was funded by the John and Claire Bertucci Thyroid Research fund. NR 29 TC 14 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD FEB PY 2015 VL 125 IS 2 BP E84 EP E89 DI 10.1002/lary.24781 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CB9SS UT WOS:000349973400007 PM 24945758 ER PT J AU McCormack, C Lo Gullo, R Kalra, M Louissaint, A Stone, J AF McCormack, Carmen Lo Gullo, Roberto Kalra, Mannudeep Louissaint, Abner Stone, James TI Reliability of Body Size Measurements Obtained at Autopsy: Impact on the Pathologic Assessment of the Heart SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [McCormack, Carmen; Lo Gullo, Roberto; Kalra, Mannudeep; Louissaint, Abner; Stone, James] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 17 BP 8A EP 8A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200018 ER PT J AU Sajed, D Stone, J AF Sajed, Dipti Stone, James TI An Autopsy Study of Renal Fat Embolization Associated With Extracorporeal Membrane Oxygenation Placement SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Sajed, Dipti; Stone, James] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 24 BP 10A EP 10A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200025 ER PT J AU Al-Ibraheemi, A Kurek, K Dentino, K Padwa, B Woo, S AF Al-Ibraheemi, Alyaa Kurek, Kyle Dentino, Kelley Padwa, Bonnie Woo, Sook TI Histopathologic Features of Chronic Nonbacterial Sclerosing Osteomyelitis: A Retrospective Review SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Boston Childrens Hosp, Boston, MA USA. Mass Gen Hosp, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 38 BP 14A EP 14A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200039 ER PT J AU Inyang, A Inwards, C Folpe, A Nielsen, GP Rosenberg, A AF Inyang, Alero Inwards, Carrie Folpe, Andrew Nielsen, G. Petur Rosenberg, Andrew TI Primary Pseudomyogenic Hemangioendothelioma of Bone SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Univ Miami, Miami, FL USA. Mayo Clin, Rochester, MN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 64 BP 19A EP 19A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200065 ER PT J AU Wojcik, J Mahadevan, K Nielsen, GP Deshpande, V AF Wojcik, John Mahadevan, Krishnan Nielsen, G. Petur Deshpande, Vikram TI In-Situ Hybridization of MDM2 RNA Is a Useful Adjunct To Immunohistochemistry in the Diagnosis of Atypical Lipomatous Neoplasm/Well-Differentiated Liposarcoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Hosp Univ Penn, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 102 BP 29A EP 29A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200103 ER PT J AU Torous, VF Schnitt, S Garber, J Hacker, M Poles, E Alexander, B Lee, L Collins, L Tung, N AF Torous, Vanda Farahmand Schnitt, Stuart Garber, Judy Hacker, Michele Poles, Emily Alexander, Brian Lee, Larissa Collins, Laura Tung, Nadine TI Prevalence of Androgen Receptor Expression in Triple Negative Breast Cancers According To BRCA1 Mutation Status SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 164 BP 44A EP 44A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200165 ER PT J AU Eng, G Halushka, M Judge, D Semigran, M Stone, J AF Eng, George Halushka, Mare Judge, Daniel Semigran, Mary Stone, James TI Optimization of Serum Free Light Chain Analysis for Rapid and Reliable Subclassification of Cardiac Amyloidosis SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 300 BP 78A EP 78A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200301 ER PT J AU Farhat, N Pei, ZT Krane, J Sadow, P Faquin, W AF Farhat, Nada Pei, Zhengtong Krane, Jeffrey Sadow, Peter Faquin, William TI Cytologic, Histologic and Molecular Features of Primary Thyroid Neoplasms With Signet-Ring Cells SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Barnabas Hlth, Livingston, NJ USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 343 BP 88A EP 88A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200344 ER PT J AU Holmes, B Brauner, E Krane, J Parangi, S Faquin, W AF Holmes, Brittany Brauner, Eran Krane, Jeffrey Parangi, Sareh Faquin, William TI Performance of the Afirma Gene Expression Classifier in Hurthle Cell Thyroid Nodules SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 363 BP 93A EP 93A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200364 ER PT J AU Lee, T Phan, R Nham, P Moatamed, N AF Lee, Thomas Phan, Ryan Nham, Phillipp Moatamed, Neda TI Post Hoc Assessment of B-Cell and T-Cell Gene Rearrangements From Cytology Smears SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 375 BP 96A EP 96A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200376 ER PT J AU Vaickus, L Tambouret, R AF Vaickus, Louis Tambouret, Rosemary TI N:C Ratio Estimation: Just How Accurate Are We? SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Vaickus, Louis; Tambouret, Rosemary] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 424 BP 109A EP 109A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200424 ER PT J AU Mochel, M Piris, A Nose, V Hoang, M AF Mochel, Mark Piris, Adriano Nose, Vania Hoang, Mai TI Loss of Bap1 Expression in Non-Melanoma Skin Cancer in Patients With Germline BAP1 Mutations SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Mochel, Mark; Piris, Adriano; Nose, Vania; Hoang, Mai] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 481 BP 124A EP 124A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200481 ER PT J AU Fox, S Vander Heide, R Law, C Faulkner-Jones, B AF Fox, Sharon Vander Heide, Richard Law, C. Faulkner-Jones, Beverly TI Whole-Slide Images Versus Glass Slides for Pathology Resident Education SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 BIDMC, Boston, MA USA. Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. Kitware Inc, Clifton Pk, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 505 BP 129A EP 129A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200505 ER PT J AU Cipriani, N Dias-Santagata, D Faquin, W Sadow, P AF Cipriani, Nicole Dias-Santagata, Dora Faquin, William Sadow, Peter TI Clear Cell Thyroid Carcinoma: A Clinicopathologic and Molecular Study SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Univ Chicago, Chicago, IL 60637 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 519 BP 133A EP 133A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200519 ER PT J AU Cornejo, K Hutchinson, L St Cyr, M Nose, V Iafrate, AJ Sadow, P AF Cornejo, Kristine Hutchinson, Lloyd St Cyr, Maryann Nose, Vania Iafrate, A. John Sadow, Peter TI MYC Analysis By Fluorescent In Situ Hybridization and Immunohistochemistry in Primary Adrenal Angiosarcoma (PAA) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Univ Massachusetts, Sch Med, Worcester, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 520 BP 133A EP 133A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200520 ER PT J AU Turk, A Asa, S Baloch, Z Du, E Faquin, W Ghossein, R Giordano, T LiVolsi, V Lloyd, R Mete, O Su, H Suster, S Thompson, L Wenig, B AF Turk, Andrew Asa, Sylvia Baloch, Zubair Du, Eugenie Faquin, William Ghossein, Ronald Giordano, Thomas LiVolsi, Virginia Lloyd, Ricardo Mete, Ozgur Su, Henry Suster, Saul Thompson, Lester Wenig, Bruce TI Minimal Extrathyroidal Extension (ETE) and Extranodal Extension (ENE) in Papillary Thyroid Carcinoma: A Consensus Evaluation SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Mt Sinai Beth Israel, New York, NY USA. Columbia Univ, New York, NY USA. Univ Penn, Philadelphia, PA 19104 USA. Toronto Gen Hosp, Toronto, ON, Canada. Univ Michigan, Ann Arbor, MI 48109 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Wisconsin, Madison, WI USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. So Calif Permanente Med Grp, Woodland Hills, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 557 BP 142A EP 142A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200557 ER PT J AU Bledsoe, J Huynh, T Mino-Kenudson, M AF Bledsoe, Jacob Huynh, Tiffany Mino-Kenudson, Mari TI Yap1, a Hippo-Pathway Transcriptional Coactivator, Is Overexpressed in Microsatellite-Stable BRAF Mutant Colorectal Adenocarcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Bledsoe, Jacob; Huynh, Tiffany; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 587 BP 149A EP 149A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200587 ER PT J AU Borowsky, J Setia, N Lauwers, G Brown, I Rosty, C Conrad, R Susman, R AF Borowsky, Jennifer Setia, Namrata Lauwers, Grego Brown, Ian Rosty, Christophe Conrad, Rod Susman, Rachel TI Gastrointestinal Tract Pathology in PTEN Hamartoma Tumour Syndrome: A Review of 43 Cases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Pathol Queensland, Brisbane, Qld, Australia. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Envoi Specialist Pathologists, Brisbane, Qld, Australia. Sullivan Nicolaides Pathol, Brisbane, Qld, Australia. Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 589 BP 149A EP 150A PG 2 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200589 ER PT J AU Cottreau, J Lauwers, G Arnason, T AF Cottreau, Jonathan Lauwers, Gregory Arnason, Thomas TI The Incidence of Epidermoid Metaplasia in 1048 Consecutive Esophageal Tissue Samples and 58 Cases of Esophageal Squamous Neoplasia SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 609 BP 155A EP 155A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200609 ER PT J AU Khor, T Ooi, E Srivastava, A Park, DY Lauwers, G Kumarasinghe, M AF Khor, Tze Ooi, Esther Srivastava, Amitabh Park, Do-Youn Lauwers, Gregory Kumarasinghe, Marian TI HER2 Expression in Dysplasia-Carcinoma Sequence of Barrett Esophagus, and Its Role in the Different Pathways of Carcinogenesis in Barrett Esophagus SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. PathWest Lab Med, Nedlands, WA, Australia. Univ Western Australia, Nedlands, WA 6009, Australia. Brigham & Womens Hosp, Boston, MA 02115 USA. Pusan Natl Univ Hosp, Med Res Inst, Pusan, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 662 BP 168A EP 168A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200662 ER PT J AU Kojima, M Puppa, G Richard, K Basturk, O Frankel, W Vieth, M Lugli, A Sheahan, K Yeh, M Lauwers, G Risio, M Shimazaki, H Iwaya, K Kage, M Akiba, J Ohkura, Y Hortguchi, S Shomori, K Kushima, R Nomura, S Ajioka, Y Adsay, V Ochiai, A AF Kojima, Motohiro Puppa, Giacomo Richard, Kirsch Basturk, Olca Frankel, Wendy Vieth, Michael Lugli, Alessandro Sheahan, Kieran Yeh, Matthew Lauwers, Greg Risio, Mauro Shimazaki, Hideyuki Iwaya, Keichi Kage, Masayoshi Akiba, Jun Ohkura, Yasuo Hortguchi, Shinichiro Shomori, Kohei Kushima, Ryoji Nomura, Shogo Ajioka, Yoichi Adsay, Volkan Ochiai, Atsushi TI Construction of an Objective Pathological Diagnostic System of Blood and Lymphatic Vessel Invasion SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Natl Canc Ctr Hosp East, Chiba, Japan. Hop Cantonal Univ Geneva, Geneva, Switzerland. Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. Klinikum Bayreuth, Bayreuth, Germany. Univ Bern, Bern, Switzerland. St Vincents Univ Hosp, Dublin 4, Ireland. Univ Washington, Sch Med, Seattle, WA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Inst Canc Res & Treatment, Turin, Italy. Natl Def Med Coll, Saitama, Japan. Kurume Univ Scool Med, Fukuoka, Japan. Kyorin Univ, Grad Sch Med, Tokyo, Japan. Tokyo Metropolitan Komagome Hosp, Tokyo, Japan. Sanin Rosai Hosp, Tottori, Japan. Shiga Univ Med Sci Hosp, Shiga, Japan. Niigata Univ, Niigata, Japan. Emory Univ, Sch Med, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 673 BP 171A EP 171A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201011 ER PT J AU Mahadevan, K Arora, K Rivera, M Ting, D Deshpande, V AF Mahadevan, Krishnan Arora, Kshitij Rivera, Miguel Ting, David Deshpande, Vikram TI Human Papilloma Virus in Rectal Adenocarcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Mahadevan, Krishnan; Arora, Kshitij; Rivera, Miguel; Ting, David; Deshpande, Vikram] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 698 BP 177A EP 177A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201036 ER PT J AU Mahadevan, K Ting, D Arora, K Mattia, A Zukerberg, L Lauwers, G Deshpande, V AF Mahadevan, Krishnan Ting, David Arora, Kshitij Mattia, Anthony Zukerberg, Lawrence Lauwers, Gregory Deshpande, Vikram TI LINE-1 Overexpression Is a Hallmark of Gastrointestinal Cancers and Pre-Neoplastic Diseases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Mahadevan, Krishnan; Ting, David; Arora, Kshitij; Mattia, Anthony; Zukerberg, Lawrence; Lauwers, Gregory; Deshpande, Vikram] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 699 BP 177A EP 178A PG 2 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201037 ER PT J AU Rosenbaum, M Bledsoe, J Huynh, T Mino-Kenudson, M AF Rosenbaum, Matthew Bledsoe, Jacob Tiffany Huynh Mino-Kenudson, Mari TI Programmed Cell Death Ligand 1 Expression Is Associated With BRAF Mutation, Microsatellite Instability, Medullary Morphology, and Helps To Characterize Tumor Behavior in Colorectal Carcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Rosenbaum, Matthew; Bledsoe, Jacob; Tiffany Huynh; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 743 BP 188A EP 188A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201081 ER PT J AU Sajed, D MacKenzie, O Arora, K Aryee, M Ting, D Deshpande, V AF Sajed, Dipti MacKenzie, Olivia Arora, Kshitij Aryee, Martin Ting, David Deshpande, Vikram TI LINE-1 RNA In Situ Hybridization: A Novel Application for Assessing Global Methylation Status SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Sajed, Dipti; MacKenzie, Olivia; Arora, Kshitij; Aryee, Martin; Ting, David; Deshpande, Vikram] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 749 BP 189A EP 189A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201087 ER PT J AU Setia, N Lennerz, J Mullen, J Kwak, E Hong, T Park, DY Lauwers, G AF Setia, Namrata Lennerz, Jochen Mullen, John Kwak, Eunice Hong, Theodore Park, Do Youn Lauwers, Gregory TI Western Series of Early Gastric Cancer: Comparison With Eastern Series and Evaluation of Risk Factors for Lymph Node Metastasis SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Pusan Natl Univ Hosp, Pusan, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 762 BP 192A EP 192A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201100 ER PT J AU Setia, N Lennerz, J Srivastava, A Mino-Kenudson, M Lauwers, G AF Setia, Namrata Lennerz, Jochen Srivastava, Amitabh Mino-Kenudson, Mari Lauwers, Gregory TI Test Algorithm for Protein-Expression Based Classification of Gastric Adenocarcinoma Encompassing TCGA and "Mesenchymal" Subtype SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 761 BP 192A EP 192A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201099 ER PT J AU Setia, N Agoston, A Lauwers, G Srivastava, A AF Setia, Namrata Agoston, Agoston Lauwers, Gregory Srivastava, Amitabh TI ARID1A in Gastric Adenocarcinoma: Clincopathologic Features and Association With Expression of p53 and MMR Proteins SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 760 BP 192A EP 192A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201098 ER PT J AU Tse, J Chan, M Zukerberg, L Nazarian, R AF Tse, Julie Chan, May Zukerberg, Lawrence Nazarian, Rosalynn TI Assessment of Melanocyte Density in Anal Mucosa for the Evaluation of Surgical Margins in Primary Anal Melanoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 777 BP 196A EP 196A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201115 ER PT J AU Yang, M Li, ZS Lauwers, G AF Yang, Michelle Li, Zengshan Lauwers, Gregory TI Clinical Significance of Duodenal Mucosa With Normal Villous Architecture and Slightly Increased Intraepithelial Lymphocytes in Pediatric and Adult Populations SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Yang, Michelle; Li, Zengshan; Lauwers, Gregory] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 795 BP 200A EP 200A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201133 ER PT J AU Canete, S Sanchez, D Piris, A Zarza, P Oneto, S Lezcano, C Ayala, G Hoang, M Mihm, M Cubilla, A AF Canete, Sofia Sanchez, Diego Piris, Adriano Zarza, Patricia Oneto, Sabrina Lezcano, Cecilia Ayala, Gustavo Hoang, Mai Mihm, Martin Cubilla, Antonio TI Continuous Spatial Sequences of Lichen Sclerosus (LS), Penile Intraepithelial Neoplasia (PeIN) and Invasive Carcinomas SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Inst Patol & Invest, Asuncion, Paraguay. UNA, Fac Ciencias Med, Asuncion, Paraguay. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Texas Houston, Houston, TX USA. RI Sanchez, Diego/K-2398-2016 OI Sanchez, Diego/0000-0002-9503-1947 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 833 BP 210A EP 210A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201171 ER PT J AU Coulson, H Loda, M O'Donnell, E Sweeney, C Hirsch, M AF Coulson, Hannah Loda, Massimo O'Donnell, Elizabeth Sweeney, Christopher Hirsch, Michelle TI Targeted Next Generation Sequencing of Testicular Germ Cell Tumors SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 848 BP 213A EP 213A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201186 ER PT J AU Coulson, H Dal Cin, P Choueiri, T Hirsch, M AF Coulson, Hannah Dal Cin, Paola Choueiri, Toni Hirsch, Michelle TI Chromophobe Renal Cell Carcinoma - A Simplified and Reproducible Two Tier Approach to Tumor Grading SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 847 BP 213A EP 213A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201185 ER PT J AU Fontugne, J Sanda, M Tomlins, S Wei, J Patil, D Ye, HH Park, K Chipman, J Regan, M Scherr, D Siddiqui, J Chinnaiyan, A Rubin, M Mosquera, JM AF Fontugne, Jacqueline Sanda, Martin Tomlins, Scott Wei, John Patil, Dattatraya Ye, Huihui Park, Kyung Chipman, Jonathan Regan, Meredith Scherr, Douglas Siddiqui, Javed Chinnaiyan, Arul Rubin, Mark Mosquera, Juan Miguel TI Correlation of Urinary T2:ERG Fusion Detection and Tissue ERG Expression: Comprehensive Evaluation of Prostatectomy Specimens From the EDRN Study SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Weill Cornell Med Coll, New York, NY USA. Emory Univ, Sch Med, Atlanta, GA USA. Univ Michigan, Sch Med, Ann Arbor, MI USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RI Patil , Dattatraya /H-5682-2015; Sanda, Martin/B-2023-2015 OI Patil , Dattatraya /0000-0002-8242-9825; NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 876 BP 220A EP 220A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201214 ER PT J AU Huang, Y Bowden, M Loda, M AF Huang, Ying Bowden, Michaela Loda, Massimo TI Multiplex TSA-Plus Fluorescence IHC Combined With Spectral Image Analysis for PI3K Pathway Dysregulation in Prostate Cancer SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Huang, Ying; Bowden, Michaela; Loda, Massimo] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 917 BP 230A EP 230A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201255 ER PT J AU Kao, CS Cornejo, K Ulbright, T Young, R AF Kao, Chia-Sui Cornejo, Kristine Ulbright, Thomas Young, Robert TI Juvenile Granulosa Cell Tumors (JGCT) of the Testis: A Clinicopathologic Study of 68 Cases With Emphasis on Its Wide Morphologic Spectrum SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Indiana Univ Sch Med, Indianapolis, IN 46202 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 925 BP 232A EP 232A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201263 ER PT J AU Kao, CS Cheng, L Ulbright, T Idrees, M AF Kao, Chia-Sui Cheng, Liang Ulbright, Thomas Idrees, Muhammad TI The Utility of SOX9, FOXL2, and SF1 Immunohistochemical (IHC) Stains in the Diagnosis of Testicular Sex Cord-Stromal Tumors (SCST) Compared To Other Commonly Used Markers SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Indiana Univ Sch Med, Indianapolis, IN 46202 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 926 BP 233A EP 233A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201264 ER PT J AU Kehr, E Loda, M Drapkin, R Dal Cin, P Choueiri, T Hirsch, M AF Kehr, Elizabeth Loda, Massimo Drapkin, Ronny Dal Cin, Paola Choueiri, Toni Hirsch, Michelle TI Targeted Next Generation Sequencing of Renal Epithelial Tumors SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 931 BP 234A EP 234A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201269 ER EF