FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Ferraresi, C Bertucci, D Schiavinato, J Reiff, R Araujo, A Panepucci, R Matheucci, E Cunha, AF Arakelian, VM Hamblin, MR Parizotto, N Bagnato, V AF Ferraresi, Cleber Bertucci, Danilo Schiavinato, Josiane Reiff, Rodrigo Araujo, Amelia Panepucci, Rodrigo Matheucci, Euclides, Jr. Cunha, Anderson Ferreira Arakelian, Vivian Maria Hamblin, Michael R. Parizotto, Nivaldo Bagnato, Vanderlei TI Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: Case-control Study with a Pair of Identical Twins SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Biopsy; Creatine Kinase; Low-Level Laser Therapy; Photobiomodulation; Visual Analog Scale ID SKELETAL-MUSCLE; LASER IRRADIATION; DOSE-RESPONSE; EXERCISE; INTENSITY; FATIGUE; MECHANISMS; NM; PHOTOTHERAPY; RESISTANCE AB Objective The aim of this study was to verify how a pair of monozygotic twins would respond to light-emitting diode therapy (LEDT) or placebo combined with a strength-training program during 12 weeks. Design This case-control study enrolled a pair of male monozygotic twins, allocated randomly to LEDT or placebo therapies. Light-emitting diode therapy or placebo was applied from a flexible light-emitting diode array ( = 850 nm, total energy = 75 J, t = 15 seconds) to both quadriceps femoris muscles of each twin immediately after each strength training session (3 times/wk for 12 weeks) consisting of leg press and leg extension exercises with load of 80% and 50% of the 1-repetition maximum test, respectively. Muscle biopsies, magnetic resonance imaging, maximal load, and fatigue resistance tests were conducted before and after the training program to assess gene expression, muscle hypertrophy and performance, respectively. Creatine kinase levels in blood and visual analog scale assessed muscle damage and delayed-onset muscle soreness, respectively, during the training program. Results Compared with placebo, LEDT increased the maximal load in exercise and reduced fatigue, creatine kinase, and visual analog scale. Gene expression analyses showed decreases in markers of inflammation (interleukin 1) and muscle atrophy (myostatin) with LEDT. Protein synthesis (mammalian target of rapamycin) and oxidative stress defense (SOD2 [mitochondrial superoxide dismutase]) were up-regulated with LEDT, together with increases in thigh muscle hypertrophy. Conclusions Light-emitting diode therapy can be useful to reduce muscle damage, pain, and atrophy, as well as to increase muscle mass, recovery, and athletic performance in rehabilitation programs and sports medicine. C1 [Ferraresi, Cleber; Parizotto, Nivaldo] Univ Fed Sao Carlos, Dept Phys Therapy, Lab Electrothermophototherapy, Sao Paulo, Brazil. [Ferraresi, Cleber; Matheucci, Euclides, Jr.; Parizotto, Nivaldo] Univ Fed Sao Carlos, Postgrad Program Biotechnol, Sao Paulo, Brazil. [Ferraresi, Cleber; Bagnato, Vanderlei] Univ Sao Paulo, Phys Inst Sao Carlos, Opt Grp, Sao Paulo, Brazil. [Ferraresi, Cleber; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Bertucci, Danilo] Univ Fed Sao Carlos, Dept Physiol Sci, Sao Carlos, SP, Brazil. [Schiavinato, Josiane; Araujo, Amelia] Univ Sao Paulo, Fac Med, Ribeirao Preto, Brazil. [Schiavinato, Josiane; Araujo, Amelia; Panepucci, Rodrigo] Univ Fed Sao Carlos, Ctr Cell Therapy, Sao Carlos, SP, Brazil. [Schiavinato, Josiane; Araujo, Amelia; Panepucci, Rodrigo] Univ Fed Sao Carlos, Reg Blood Ctr Ribeirao Preto, Sao Carlos, SP, Brazil. [Reiff, Rodrigo] Univ Fed Sao Carlos, Dept Med, Sao Carlos, SP, Brazil. [Cunha, Anderson Ferreira] Univ Fed Sao Carlos, Dept Genet & Evolut, Sao Carlos, SP, Brazil. [Arakelian, Vivian Maria] Univ Sao Paulo, Postgrad Program Bioengn, Sao Carlos, SP, Brazil. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Ferraresi, C (reprint author), Univ Fed Sao Carlos, Rodovia Washington Luis,Km 235, BR-13565905 Sao Paulo, Brazil. RI Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016; USP, CePOF/J-3608-2015 FU FAPESP [2010/07194-7, 2012/05919-0] FX The authors thank Vilmar Baldissera, PhD, for his contribution to set up the strength training program. CF thanks FAPESP for his PhD scholarships (no. 2010/07194-7 and 2012/05919-0). NR 44 TC 1 Z9 1 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD OCT PY 2016 VL 95 IS 10 BP 746 EP 757 DI 10.1097/PHM.0000000000000490 PG 12 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DX5UL UT WOS:000384447800010 PM 27088469 ER PT J AU Cade, BE Chen, H Stilp, AM Gleason, KJ Sofer, T Ancoli-Israel, S Arens, R Bell, GI Below, JE Bjonnes, AC Chun, S Conomos, MP Evans, DS Johnson, WC Frazier-Wood, AC Lane, JM Larkin, EK Loredo, JS Post, WS Ramos, AR Rice, K Rotter, JI Shah, NA Stone, KL Taylor, KD Thornton, TA Tranah, GJ Wang, CL Zee, PC Hanis, CL Sunyaev, SR Patel, SR Laurie, CC Zhu, XF Saxena, R Lin, XH Redline, S AF Cade, Brian E. Chen, Han Stilp, Adrienne M. Gleason, Kevin J. Sofer, Tamar Ancoli-Israel, Sonia Arens, Raanan Bell, Graeme I. Below, Jennifer E. Bjonnes, Andrew C. Chun, Sung Conomos, Matthew P. Evans, Daniel S. Johnson, W. Craig Frazier-Wood, Alexis C. Lane, Jacqueline M. Larkin, Emma K. Loredo, Jose S. Post, Wendy S. Ramos, Alberto R. Rice, Ken Rotter, Jerome I. Shah, Neomi A. Stone, Katie L. Taylor, Kent D. Thornton, Timothy A. Tranah, Gregory J. Wang, Chaolong Zee, Phyllis C. Hanis, Craig L. Sunyaev, Shamil R. Patel, Sanjay R. Laurie, Cathy C. Zhu, Xiaofeng Saxena, Richa Lin, Xihong Redline, Susan TI Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE sleep apnea; hypoxia; genetics; GWAS; Prader-Willi syndrome ID GENOME-WIDE ASSOCIATION; PRADER-WILLI-SYNDROME; DIVERSE BACKGROUNDS; HEALTH; METABOLISM; EXPRESSION; DISEASES; HYPOXIA; LATINOS; GPR83 AB Rationale: Obstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability. Objectives: To define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts. Methods: Genome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, Multi Ethnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration. Measurements and Main Results: Two novel loci were identified at genome-level significance (rs11691765, GPR83, P =1.90 X 10(-8) for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 X 10(-8) for respiratory event duration) and seven additional loci were identified with suggestive significance (P < 5 X 10(-7)). Secondary sex-stratified analyses also identified one significant and several suggestive associations. Multiple loci overlapped genes with biologic plausibility. Conclusions: These are the first genome-level significant findings reported for obstructive sleep apnea-related physiologic traits in any population. These findings identify novel associations in inflammatory, hypoxia signaling, and sleep pathways. C1 [Cade, Brian E.; Gleason, Kevin J.; Lane, Jacqueline M.; Patel, Sanjay R.; Saxena, Richa; Redline, Susan] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA. [Bjonnes, Andrew C.; Chun, Sung; Sunyaev, Shamil R.] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Cade, Brian E.; Lane, Jacqueline M.; Patel, Sanjay R.; Redline, Susan] Harvard Med Sch, Div Sleep Med, Boston, MA USA. [Chun, Sung; Sunyaev, Shamil R.] Harvard Med Sch, Div Med Sci, Boston, MA USA. [Chen, Han; Wang, Chaolong; Lin, Xihong] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Stilp, Adrienne M.; Sofer, Tamar; Conomos, Matthew P.; Johnson, W. Craig; Rice, Ken; Thornton, Timothy A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Ancoli-Israel, Sonia] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Ancoli-Israel, Sonia] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Ancoli-Israel, Sonia] San Diego Ctr Excellence Stress & Mental Hlth, Dept Vet Affairs, San Diego, CA USA. [Arens, Raanan] Childrens Hosp Montefiore, Albert Einstein Coll Med, Div Resp & Sleep Med, Bronx, NY USA. [Bell, Graeme I.] Univ Chicago, Sect Adult & Pediat Endocrinol Diabet & Metab, Chicago, IL 60637 USA. [Below, Jennifer E.; Hanis, Craig L.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Evans, Daniel S.; Stone, Katie L.; Tranah, Gregory J.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Frazier-Wood, Alexis C.] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Lane, Jacqueline M.; Saxena, Richa] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lane, Jacqueline M.; Saxena, Richa] Massachusetts Gen Hosp, Dept Anesthesia Pain & Crit Care Med, Boston, MA 02114 USA. [Lane, Jacqueline M.; Sunyaev, Shamil R.; Saxena, Richa] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Larkin, Emma K.] Vanderbilt Univ, Med Ctr, Dept Med, Div Allergy Pulm & Crit Care, 221 Kirkland Hall, Nashville, TN 37235 USA. [Loredo, Jose S.] Univ Calif San Diego, Sch Med, Dept Med, Div Pulm Crit Care & Sleep Med, La Jolla, CA USA. [Post, Wendy S.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. [Ramos, Alberto R.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Rotter, Jerome I.; Taylor, Kent D.] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Shah, Neomi A.] Montefiore Med Ctr, Dept Med, 111 E 210th St, Bronx, NY 10467 USA. [Wang, Chaolong] Genome Inst Singapore, Singapore, Singapore. [Zee, Phyllis C.] Northwestern Univ, Dept Neurol, Chicago, IL 60611 USA. [Zee, Phyllis C.] Northwestern Univ, Sleep Med Ctr, Chicago, IL 60611 USA. [Patel, Sanjay R.; Redline, Susan] Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, Boston, MA 02215 USA. [Zhu, Xiaofeng] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. RP Cade, BE (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 221 Longwood Ave, Boston, MA 02115 USA. EM bcade@partners.org OI Cade, Brian/0000-0003-1424-0673; Chun, Sung/0000-0003-3440-1913; Chen, Han/0000-0002-9510-4923; Sofer, Tamar/0000-0001-8520-8860 FU National Institutes of Health [T32-HL007901-16, R01-HL113338-04, 5-R01-HL046380-15, 5-KL2-RR024990-05, R01 DK073541, U01 DK085501, R01 AI085014, R01 HL102830]; NHLBI [N01-HC65233, N02-HL-64278]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [N01-HC65235]; Northwestern University [N01-HC65236]; San Diego State University [N01-HC65237]; National Institute of Dental and Craniofacial Research [HHSN268201300005C AM03, MOD03]; National Center for Advancing Translational Sciences (NCATS) CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) DRC grant [DK063491]; NCATS CTSI [UL1TR000124]; NIDDK DRC [DK063491]; Kovler Family Foundation [P30 DK020595]; University of North Carolina [N01-HC-55015, N01-HC-55018]; Baylor College of Medicine [N01-HC-55016]; University of Minnesota [N01-HC-55019]; Johns Hopkins University [N01-HC-55020]; University of Mississippi Medical Center [N01-HC-55021]; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [UL1-TR-001079]; [UL1-TR-000040]; [HL56984] FX Supported by National Institutes of Health grants T32-HL007901-16 and R01-HL113338-04 (B.E.C.). The Sleep Reading Center of Brigham and Women's Hospital has been supported by National Institutes of Health grants 5-R01-HL046380-15 and 5-KL2-RR024990-05. Hispanic Community Health Study/Study of Latinos (HCHS/SOL): baseline examination of HCHS/SOL was performed as a collaborative study supported by contracts from the NHLBI to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following institutes/centers/offices contributed to the first phase of HCHS/SOL through a transfer of kinds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, and National Institutes of Heath Institution-Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and National Institute of Dental and Craniofacial Research contracts (HHSN268201300005C AM03 and MOD03). Provision of genotyping services supported in part by National Center for Advancing Translational Sciences (NCATS) CTSI grant UL1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) DRC grant DK063491. Multi-Ethnic Study of Atherosclerosis (MESA): MESA is conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and Massachusetts Institute of Technology (Boston, MA). Funding support for the Sleep Polysomnography dataset was provided by grant HL56984. Provision of genotyping services supported in part by NCATS CTSI grant UL1TR000124 and NIDDK DRC grant DK063491. Starr County Health Studies (Starr): Starr is supported in part by grants R01 DK073541, U01 DK085501, R01 AI085014, and R01 HL102830 from the National Institutes of Health, and kinds from the University of Texas Health Science Center at Houston. G.I.B. supported in part by grant P30 DK020595 and a gift from the Kovler Family Foundation. The Atherosclerosis Risk in Communities Study is conducted and supported by the NHLBI in collaboration with the University of North Carolina (N01-HC-55015, N01-HC-55018), Baylor College of Medicine (N01-HC-55016), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), and University of Mississippi Medical Center (N01-HC-55021). NR 60 TC 3 Z9 3 U1 5 U2 5 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 OCT 1 PY 2016 VL 194 IS 7 BP 886 EP 897 DI 10.1164/rccm.201512-2431OC PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DX4ZH UT WOS:000384389100017 PM 26977737 ER PT J AU Kao, CS Idrees, MT Young, RH Ulbright, TM AF Kao, Chia-Sui Idrees, Muhammad T. Young, Robert H. Ulbright, Thomas M. TI "Dissecting Gonadoblastoma" of Scully A Morphologic Variant That Often Mimics Germinoma SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE gonadoblastoma; dissecting gonadoblastoma; germinoma; undifferentiated gonadal tissue AB Dr Robert E. Scully, who recognized and defined gonadoblastoma (GB), used the term "dissecting gonadoblastoma" (DGB) to describe variants with either an infiltrative type or diffuse pattern instead of the usual small nested arrangement. These patterns have not been emphasized in the literature. To investigate the features of DGB we examined 50 GBs microscopically and performed immunohistochemistry (IHC) in some. DGB was found in 38 (76%) GBs and was represented by 3 patterns. The most frequent was solid/expansile (n=26), consisting of large coalescent nests of germ cells, often (92%) interrupted by fibrovascular septa, with usually minor numbers of sex cord cells. Less frequent were small anastomosing nests (n=24) and cord-like arrangements (n=22) of germ cells irregularly distributed in a prominent stroma and with mostly inconspicuous sex cord cells. Most DGBs (24) showed >1 pattern and demonstrated the characteristic globular deposits of basement membrane, although these were often subtle. The germ cells in all patterns varied from spermatogonium-like to seminoma-like; OCT3/4 was positive only in the latter (7/7). The sex cord cells were small with dense, oval or angulated nuclei, inconspicuous nucleoli, and positivity for inhibin (9/9, strong), FOXL2 (9/9, strong), SF1 (8/9, strong), SOX9 (9/9, weak and focal), WT1 (5/7, variable), and calretinin (3/7, variable). Granulomas were present in 84% of germinoma foci, 13% of DGB foci, and 8% of classic GB foci. Twenty two of 38 DGBs had associated germinoma; 3 also had embryonal carcinoma, yolk sac tumor, and choriocarcinoma, respectively. Follow-up of 2 cases lacking an invasive tumor showed that both patients were disease free at 13 and 4.8 years after bilateral gonadectomy. We conclude that DGB is commonly seen with classic GB and displays identical IHC features, supporting it as a morphologic variant of GB. It appears likely that cord-like DGB is the earliest phase in a GB developmental continuum that may proceed successively into anastomosing, nested (classic GB), and solid/expansile patterns. DGB often mimics germinoma because of the large size of the nests, pseudoinfiltrative pattern of some cases, and inconspicuous sex cord cells. The presence of sex cord cells (identification aided by IHC for sex cord markers), the heterogenous morphology of the germ cells, and globules of basement membrane are useful differential features. The lack of a granulomatous reaction also favors DGB over germinoma. Mistaking DGB for GB with invasive germinoma may result in more aggressive therapy than warranted. The likely relationship of DGB to the relatively recently described concept of so-called "undifferentiated gonadal tissue" is discussed herein. C1 [Kao, Chia-Sui] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Idrees, Muhammad T.; Ulbright, Thomas M.] Indiana Univ Sch Med, Dept Pathol & Lab Med, Room 4014,350 W 11th St, Indianapolis, IN 46202 USA. [Young, Robert H.] Harvard Med Sch, Massachusetts Gen Hosp, James Homer Wright Pathol Lab, Boston, MA USA. RP Ulbright, TM (reprint author), Indiana Univ Sch Med, Dept Pathol & Lab Med, Room 4014,350 W 11th St, Indianapolis, IN 46202 USA. EM tulbrigh@iupui.edu NR 5 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2016 VL 40 IS 10 BP 1417 EP 1423 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA DX1HX UT WOS:000384118600015 PM 27454939 ER PT J AU Leffert, L Landau, R AF Leffert, Lisa Landau, Ruth TI Integrating the New Thromboprophylaxis Guidelines Into Obstetric Anesthesia Practice SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material ID NEURAXIAL ANESTHESIA; REGIONAL-ANESTHESIA; GENERAL-ANESTHESIA; COMPLICATIONS; PATIENT; RISK C1 [Leffert, Lisa] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Landau, Ruth] Columbia Univ Coll Phys & Surg, Dept Anesthesiol, New York, NY 10032 USA. RP Leffert, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM lleffert@partners.org NR 14 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD OCT PY 2016 VL 123 IS 4 BP 809 EP 811 DI 10.1213/ANE.0000000000001567 PG 3 WC Anesthesiology SC Anesthesiology GA DW8RT UT WOS:000383923900002 PM 27636568 ER PT J AU Mirzakhani, H Bittner, E Eikermann, M Nozari, A AF Mirzakhani, Hooman Bittner, Edward Eikermann, Matthias Nozari, Ala TI Neuromuscular Blockers and Electroconvulsive Therapy: How Much Is Enough? Response SO ANESTHESIA AND ANALGESIA LA English DT Letter ID RAPID TRACHEAL INTUBATION; DOSE ROCURONIUM; SUCCINYLCHOLINE; RECOVERY; ONSET C1 [Mirzakhani, Hooman; Bittner, Edward; Eikermann, Matthias; Nozari, Ala] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA USA. RP Mirzakhani, H (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA USA. EM hoomi@post.harvard.edu OI Mirzakhani, Hooman/0000-0002-2290-4436 NR 14 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD OCT PY 2016 VL 123 IS 4 BP 1060 EP 1061 DI 10.1213/ANE.0000000000001443 PG 2 WC Anesthesiology SC Anesthesiology GA DW8RT UT WOS:000383923900035 PM 27636580 ER PT J AU Merrill, AL Tang, R Plichta, JK Rai, U Coopey, SB McEvoy, MP Hughes, KS Specht, MC Gadd, MA Smith, BL AF Merrill, Andrea L. Tang, Rong Plichta, Jennifer K. Rai, Upahvan Coopey, Suzanne B. McEvoy, Maureen P. Hughes, Kevin S. Specht, Michelle C. Gadd, Michele A. Smith, Barbara L. TI Should New "No Ink On Tumor" Lumpectomy Margin Guidelines be Applied to Ductal Carcinoma In Situ (DCIS)? A Retrospective Review Using Shaved Cavity Margins SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID BREAST-CONSERVING SURGERY; SURGICAL ADJUVANT BREAST; RADIATION-THERAPY; LOCAL RECURRENCE; INTRADUCTAL-CARCINOMA; WIDE EXCISION; 8-YEAR UPDATE; CONSERVATION; CANCER; B-17 AB No consensus exists for clear margins for breast-conserving surgery for pure ductal carcinoma in situ (DCIS). We examined the implications of applying a "no ink on tumor" standard for pure DCIS by correlating clear margin width with rates of residual disease. Lumpectomies with complete shaved cavity margins (SCMs) for pure DCIS at our institution from 2004 to 2007 were reviewed and patients with microinvasive cancer or multifocal disease requiring multiple wires excluded. Rates of residual disease in shaved margins were determined based on margin status of the main lumpectomy specimen using margin widths of "ink on tumor," aecurrency sign1, > 1 to < 2, and aeyen2 mm. Overall, 182 women undergoing lumpectomy for pure DCIS met eligibility criteria. In patients with "ink on tumor" in the main lumpectomy specimen, 88 % had residual disease in the SCMs. Rates of residual disease in SCMs for lumpectomies with margins of < 2 mm (but not on ink) were 52 % compared with 13 % for lumpectomies with margins aeyen2 mm (p < 0.0005). Multivariate analyses confirmed the association of lumpectomy margin width and residual tumor in shaved cavity margins. Odds of residual disease in the SCM for postmenopausal patients were 74 % less than for pre/perimenopausal women (odds ratio 0.26; confidence interval 0.08-0.82). Application of a "no ink on tumor" lumpectomy margin standard to patients with DCIS results in a significant increase in the rates of residual disease in cavity margins compared with use of a aeyen2-mm margin standard. Use of narrower margins may have important implications for use of adjuvant therapy. C1 [Merrill, Andrea L.; Tang, Rong; Plichta, Jennifer K.; Rai, Upahvan; Coopey, Suzanne B.; McEvoy, Maureen P.; Hughes, Kevin S.; Specht, Michelle C.; Gadd, Michele A.; Smith, Barbara L.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Tang, Rong] Cent S Univ, Xiangya Med Sch, Affiliated Tumor Hosp, Div Breast Surg,Hunan Canc Hosp, Changsha, Hunan, Peoples R China. RP Smith, BL (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. EM blsmith1@partners.org NR 34 TC 2 Z9 2 U1 2 U2 2 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 OCT PY 2016 VL 23 IS 11 BP 3453 EP 3458 DI 10.1245/s10434-016-5251-y PG 6 WC Oncology; Surgery SC Oncology; Surgery GA DV4XV UT WOS:000382930000009 PM 27207096 ER PT J AU Mamtani, A Barrio, AV King, TA Van Zee, KJ Plitas, G Pilewskie, M El-Tamer, M Gemignani, ML Heerdt, AS Sclafani, LM Sacchini, V Cody, HS Patil, S Morrow, M AF Mamtani, Anita Barrio, Andrea V. King, Tari A. Van Zee, Kimberly J. Plitas, George Pilewskie, Melissa El-Tamer, Mahmoud Gemignani, Mary L. Heerdt, Alexandra S. Sclafani, Lisa M. Sacchini, Virgilio Cody, Hiram S., III Patil, Sujata Morrow, Monica TI How Often Does Neoadjuvant Chemotherapy Avoid Axillary Dissection in Patients With Histologically Confirmed Nodal Metastases? Results of a Prospective Study SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 69th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 02-05, 2016 CL Boston, MA SP Soc Surg Oncol ID POSITIVE BREAST-CANCER; ACOSOG Z1071 ALLIANCE; SENTINEL LYMPH-NODES; MULTICENTER TRIAL; CLINICAL-TRIAL; BLUE-DYE; BIOPSY; SURGERY; IDENTIFICATION; METAANALYSIS AB In breast cancer patients with nodal metastases at presentation, false-negative rates lower than 10 % have been demonstrated for sentinel node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) when three or more negative sentinel nodes (SLNs) are retrieved. However, the frequency with which axillary dissection (ALND) can be avoided is uncertain. Among 534 prospectively identified consecutive patients with clinical stages 2 and 3 cancer receiving NAC from November 2013 to November 2015, all biopsy-proven node-positive (N+) cases were identified. Patients clinically node-negative after NAC were eligible for SLNB. The indications for ALND were failed mapping, fewer than three SLNs retrieved, and positive SLNs. Of 288 N+ patients, 195 completed surgery, with 132 (68 %) of these patients eligible for SLNB. The median age was 50 years. Of these patients, 73 (55 %) were estrogen receptor-positive (ER+), 21 (16 %) were ER- and human epidermal growth factor receptor-2-positive (HER2+), and 38 (29 %) were triple-negative. In four cases, SLNB was deferred intraoperatively. Among 128 SLNB attempts, three or more SLNs were retrieved in 110 cases (86 %), one or two SLNs were retrieved in 15 cases (12 %), and failed mapping occurred in three cases (2 %). In 66 cases, ALND was indicated: 54 (82 %) for positive SLNs, 9 (14 %) for fewer than three negative SLNs, and 3 (4 %) for failed mapping. Persistent disease was found in 17 % of the patients with fewer than three negative SLNs retrieved. Of the 128 SLNB cases, 62 (48 %) had SLNB alone with three or more SLNs retrieved. Among 195 N+ patients who completed surgery, nodal pathologic complete response (pCR) was achieved for 49 %, with rates ranging from 21 % for ER+/HER2- to 97 % for ER-/HER2+ cases, and was significantly more common than breast pCR in ER+/HER2- and triple-negative cases. Nearly 70 % of the N+ patients were eligible for SLNB after NAC. For 48 %, ALND was avoided, supporting the role of NAC in reducing the need for ALND among patients presenting with nodal metastases. C1 [Mamtani, Anita; Barrio, Andrea V.; Van Zee, Kimberly J.; Plitas, George; Pilewskie, Melissa; El-Tamer, Mahmoud; Gemignani, Mary L.; Heerdt, Alexandra S.; Sclafani, Lisa M.; Sacchini, Virgilio; Cody, Hiram S., III; Morrow, Monica] Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10021 USA. [King, Tari A.] Dana Farber Brigham & Womens Canc Ctr, Dept Breast Surg, Boston, MA USA. [Patil, Sujata] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Morrow, M (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10021 USA. EM morrowm@mskcc.org FU NCI NIH HHS [P30 CA008748] NR 31 TC 2 Z9 2 U1 3 U2 3 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 OCT PY 2016 VL 23 IS 11 BP 3467 EP 3474 DI 10.1245/s10434-016-5246-8 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA DV4XV UT WOS:000382930000011 PM 27160528 ER PT J AU Ahlen, J Ahuja, N Antbacka, R Bagaria, S Blay, JY Bonvalot, S Callegaro, D Canter, RJ Cardona, K Casali, PG Colombo, C Dei Tos, AP De Paoli, A Desai, A Dickson, BC Eilber, FC Fiore, M Fletcher, CD Ford, SJ Gelderblom, HJ Gonzalez, R Grignani, G Grignol, V Gronchi, A Haas, RL Hayes, AJ Hartmann, W Henzler, T Hohenberger, P Italiano, A Jakob, J Jones, RL Judson, I Kane, JM Lahat, G MacNeill, AJ Maestro, R Messiou, C Meeus, P Miceli, R Mullen, JT Nessim, C Pennacchioli, E Pillarisetty, VG Pollock, RE Quagliuolo, V Radaelli, S Raut, CP Rutkowski, P Sandrucci, S Schrage, YM Sicklick, JK Smith, MJ Stacchiotti, S Stoeckle, E Strauss, DC AF Ahlen, Jan Ahuja, Nita Antbacka, Robert Bagaria, Sanjay Blay, Jean-Yves Bonvalot, Sylvie Callegaro, Dario Canter, Robert J. Cardona, Kenneth Casali, Paolo G. Colombo, Chiara Dei Tos, Angelo P. De Paoli, Antonino Desai, Anant Dickson, Brendan C. Eilber, Fritz C. Fiore, Marco Fletcher, Cristopher D. Ford, Samuel J. Gelderblom, Hans J. Gonzalez, Ricardo Grignani, Giovanni Grignol, Valerie Gronchi, Alessandro Haas, Rick L. Hayes, Andrew J. Hartmann, Wolfgang Henzler, Thomas Hohenberger, Peter Italiano, Antoine Jakob, Jens Jones, Robin L. Judson, Ian Kane, John M., III Lahat, Guy MacNeill, Andrea J. Maestro, Roberta Messiou, Christina Meeus, Pierre Miceli, Rosalba Mullen, John T. Nessim, Carolyn Pennacchioli, Elisabetta Pillarisetty, Vinu G. Pollock, Raphael E. Quagliuolo, Vittorio Radaelli, Stefano Raut, Chandrajit P. Rutkowski, Piotr Sandrucci, Sergio Schrage, Yvonne M. Sicklick, Jason K. Smith, Myles J. Stacchiotti, Silvia Stoeckle, Eberhardt Strauss, Dirk C. CA Trans-Atlantic RPS Working Grp TI Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID SOFT-TISSUE SARCOMA; MAIN HISTOLOGICAL SUBTYPES; RESECTION PREDICT PATTERN; PROGNOSTIC-FACTORS; ADJUVANT CHEMOTHERAPY; MULTICENTER ANALYSIS; SURGICAL-MANAGEMENT; COMPUTED-TOMOGRAPHY; SINGLE INSTITUTION; SURVIVAL AB Retroperitoneal soft tissue sarcomas (RPS) are rare tumors. Surgery is the mainstay of curative therapy, but local recurrence is common. No recommendations concerning the best management of recurring disease have been developed so far. Although every effort should be made to optimize the initial approach, recommendations to treat recurring RPS will be helpful to maximize disease control at recurrence. An RPS transatlantic working group was established in 2013. The goals of the group were to share institutional experiences, build large multi-institutional case series, and develop consensus documents on the approach to this difficult disease. The outcome of this document applies to recurrent RPS that is nonvisceral in origin. Included are sarcomas of major veins, undifferentiated pleomorphic sarcoma of psoas, ureteric leiomyosarcoma (LMS). Excluded are desmoids-type fibromatosis, angiomyolipoma, gastrointestinal stromal tumors, sarcomas arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing sarcoma, alveolar/embryonal rhabdomyosarcoma, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma. Recurrent RPS management was evaluated from diagnosis to follow-up. It is a rare and complex malignancy that is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, but some patients may experience prolonged disease control also at recurrence, when the approach is optimized and follows the recommendations contained herein. International collaboration is critical for adding to the present knowledge. A transatlantic prospective registry has been established. C1 [Ahlen, Jan] Karolinska Hosp, Dept Surg, Stockholm, Sweden. [Ahuja, Nita] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Surg, Sch Med, Baltimore, MD USA. [Antbacka, Robert] Univ Utah, Dept Surg, Huntsman Canc Inst, Salt Lake City, UT USA. [Bagaria, Sanjay] Mayo Clin Florida, Dept Surg, Jacksonville, FL USA. [Blay, Jean-Yves] Ctr Leon Berard, Dept Canc Med, Lyon, France. [Bonvalot, Sylvie] Inst Curie, Dept Surg, Paris, France. [Callegaro, Dario; Colombo, Chiara; Fiore, Marco; Gronchi, Alessandro; Radaelli, Stefano] Fdn IRCCS Ist Nazl Tumori, Dept Surg, Milan, Italy. [Canter, Robert J.] Univ Calif Davis, Div Surg Oncol, Dept Surg, Sch Med, Sacramento, CA USA. [Cardona, Kenneth] Emory Univ, Div Surg Oncol, Dept Surg, Winship Canc Inst, Atlanta, GA 30322 USA. [Casali, Paolo G.; Stacchiotti, Silvia] Fdn IRCCS Ist Nazl Tumori, Dept Canc Med, Milan, Italy. [Dei Tos, Angelo P.] Treviso Gen Hosp, Dept Pathol, Treviso, Italy. [De Paoli, Antonino] Ctr Riferimento Oncol, Dept Radiat Oncol, Aviano, Italy. [Desai, Anant] Queen Elizabeth Hosp, Dept Surg, Birmingham, W Midlands, England. [Dickson, Brendan C.] Mt Sinai Hosp, Dept Pathol, Toronto, ON, Canada. [Dickson, Brendan C.] Mt Sinai Hosp, Dept Lab Med, Toronto, ON, Canada. [Eilber, Fritz C.] Univ Calif Los Angeles, Dept Surg, Div Surg Oncol, Los Angeles, CA 90024 USA. [Fletcher, Cristopher D.] Harvard Med Sch, Dept Pathol, Brigham & Womens Hosp, Boston, MA USA. [Ford, Samuel J.] Queen Elizabeth Hosp, Dept Surg, Birmingham, W Midlands, England. [Gelderblom, Hans J.] Leiden Univ, Dept Clin Oncol, Med Ctr, Leiden, Netherlands. [Gonzalez, Ricardo] H Lee Moffitt Canc Ctr & Res Inst, Dept Surg, Tampa, FL USA. [Grignani, Giovanni] Ist Candiolo, Dept Canc Med, Turin, Italy. [Grignol, Valerie; Pollock, Raphael E.] Ohio State Univ, Med Ctr, Dept Surg, Div Surg Oncol, Columbus, OH 43210 USA. [Haas, Rick L.] Netherlands Canc Inst, Dept Radiat Oncol, Amsterdam, Netherlands. [Hayes, Andrew J.] Royal Marsden Hosp NHS Fdn Trust, Dept Surg, London, England. [Hartmann, Wolfgang] Univ Hosp Munster, Dept Pathol, Gerhard Domagk Inst Pathol, Munster, Germany. [Henzler, Thomas] Heidelberg Univ, Inst Clin Radiol & Nucl Med, Univ Med Ctr Mannheim, Mannheim, Germany. [Hohenberger, Peter; Jakob, Jens] Dept Surg Oncol & Thorac Surg, Mannheim, Germany. [Italiano, Antoine] Inst Bergonie, Dept Canc Med, Bordeaux, France. [Jones, Robin L.; Judson, Ian] Royal Marsden Hosp, Dept Canc Med, London, England. [Kane, John M., III] Roswell Pk Canc Inst, Dept Surg Oncol, Buffalo, NY 14263 USA. [Lahat, Guy] Sourasky Med Ctr, Dept Surg, Tel Aviv, Israel. [MacNeill, Andrea J.] Univ British Columbia, Dept Surg, Vancouver Gen Hosp, Vancouver, BC, Canada. [Maestro, Roberta] Ctr Riferimento Oncol, Dept Expt Oncol, Aviano, Italy. [Messiou, Christina] Royal Marsden Hosp NHS Fdn Trust, Dept Radiol, London, England. [Meeus, Pierre] Ctr Leon Berard, Dept Surg, Lyon, France. [Miceli, Rosalba] Fdn IRCCS Ist Nazl Tumori, Dept Biostat, Milan, Italy. [Mullen, John T.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Nessim, Carolyn] Ottawa Hosp, Dept Surg, Ottawa, ON, Canada. [Pennacchioli, Elisabetta] European Inst Oncol, Dept Surg, Milan, Italy. [Pillarisetty, Vinu G.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Quagliuolo, Vittorio] Humanitas Canc Ctr, Dept Surg, Rozzano, Italy. [Raut, Chandrajit P.] Harvard Med Sch, Dept Surg, Div Surg Oncol, Brigham & Womens Hosp, Boston, MA USA. [Rutkowski, Piotr] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Soft Tissue Bone Sarcoma & Melanoma, Warsaw, Poland. [Sandrucci, Sergio] Univ Turin, S Giovanni Battista Hosp, Dept Surg, Turin, Italy. [Schrage, Yvonne M.] Leiden Univ, Dept Surg, Med Ctr, Leiden, Netherlands. [Sicklick, Jason K.] Univ Calif San Diego, Dept Surg, Div Surg Oncol, Moores Canc Ctr, San Diego, CA 92103 USA. [Smith, Myles J.; Strauss, Dirk C.] Royal Marsden Hosp NHS Fdn Trust, Dept Surg, London, England. [Stoeckle, Eberhardt] Inst Bergonie, Dept Surg, Bordeaux, France. RP Gronchi, A (reprint author), Fdn IRCCS Ist Nazl Tumori, Dept Surg, Milan, Italy. EM alessandro.gronchi@istitutotumori.mi.it RI Maestro, Roberta/M-1846-2015; Fiore, Marco/M-6587-2016; OI Maestro, Roberta/0000-0002-6642-5592; Fiore, Marco/0000-0001-8220-424X; Callegaro, Dario/0000-0002-3392-4002 NR 54 TC 0 Z9 0 U1 3 U2 3 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 OCT PY 2016 VL 23 IS 11 BP 3531 EP 3540 DI 10.1245/s10434-016-5336-7 PG 10 WC Oncology; Surgery SC Oncology; Surgery GA DV4XV UT WOS:000382930000020 ER PT J AU Daw, NC Laack, NN McIlvaine, EJ Krailo, M Womer, RB Granowetter, L Grier, HE Marina, NM Bernstein, ML Gebhardt, MC Marcus, KJ Advani, SM Healey, JH Letson, GD Gorlick, RG Randall, RL AF Daw, Najat C. Laack, Nadia N. McIlvaine, Elizabeth J. Krailo, Mark Womer, Richard B. Granowetter, Linda Grier, Holcombe E. Marina, Neyssa M. Bernstein, Mark L. Gebhardt, Mark C. Marcus, Karen J. Advani, Shailesh M. Healey, John H. Letson, George D. Gorlick, Richard G. Randall, R. Lor TI Local Control Modality and Outcome for Ewing Sarcoma of the Femur: A Report From the Children's Oncology Group SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID PROGNOSTIC-FACTORS; STANDARD CHEMOTHERAPY; COMPETING RISK; BONE; TUMOR; FRACTURES; SURVIVORS; FAMILY AB The choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes. The study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression. The median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55-73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61-78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (< 8 vs aeyen8 cm). The findings showed no statistically significant differences in EFS, OS, cumulative incidence of local failure, or cumulative incidence of distant failure according to LC modality (surgery, surgery plus radiation, or radiation). The LC modality did not significantly affect disease outcome for EWS of the femur. Further study of treatment complications and functional outcome may help to define the optimal LC modality. C1 [Daw, Najat C.; Advani, Shailesh M.] Univ Texas MD Anderson Canc Ctr, Div Pediat, Houston, TX 77030 USA. [Laack, Nadia N.] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [McIlvaine, Elizabeth J.; Krailo, Mark] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Womer, Richard B.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Womer, Richard B.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Granowetter, Linda] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Granowetter, Linda] NYU, Langone Med Ctr, New York, NY USA. [Grier, Holcombe E.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat, Boston, MA 02115 USA. [Grier, Holcombe E.; Gebhardt, Mark C.; Marcus, Karen J.] Harvard Med Sch, Boston, MA USA. [Marina, Neyssa M.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Marina, Neyssa M.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Bernstein, Mark L.] IWK Hlth Ctr, Div Pediat Hematol Oncol, Halifax, NS, Canada. [Gebhardt, Mark C.] Childrens Hosp, Dana Farber Canc Inst, Dept Orthoped Surg, Boston, MA 02115 USA. [Marcus, Karen J.] Childrens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Healey, John H.] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA. [Letson, George D.] All Childrens Hosp, H Lee Moffitt Canc Ctr & Res Inst, Dept Surg, Tampa, FL USA. [Gorlick, Richard G.] Montefiore Med Ctr Moses Campus, Sect Pediat Hematol Oncol, Bronx, NY USA. [Randall, R. Lor] Univ Utah, Sch Med, Dept Orthopaed, Huntsman Canc Inst, Salt Lake City, UT USA. RP Daw, NC (reprint author), Univ Texas MD Anderson Canc Ctr, Div Pediat, Houston, TX 77030 USA. EM ndaw@mdanderson.org OI Granowetter MD, Linda/0000-0002-2399-9107 FU National Institute of Health/National Cancer Institute [1K23CA154530]; NCTN Operations Center Grant [U10CA180886]; NCTN Statistics & Data Center Grant [U10CA180899]; National Cancer Institute [U10CA98543, U10CA98413]; WWWW (QuadW) Foundation, Inc. FX This study was supported by National Institute of Health/National Cancer Institute grant 1K23CA154530 and by U10CA180886 (NCTN Operations Center Grant) and U10CA180899 (NCTN Statistics & Data Center Grant), as well as by U10CA98543 (Chair's Grant) and U10CA98413 (Statistics & Data Center Grant) grants from the National Cancer Institute. Additional support for research was provided by a grant from the WWWW (QuadW) Foundation, Inc. (www.QuadW.org). NR 24 TC 0 Z9 0 U1 2 U2 2 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 OCT PY 2016 VL 23 IS 11 BP 3541 EP 3547 DI 10.1245/s10434-016-5269-1 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA DV4XV UT WOS:000382930000021 PM 27216741 ER PT J AU Harms, KL Healy, MA Nghiem, P Sober, AJ Johnson, TM Bichakjian, CK Wong, SL AF Harms, Kelly L. Healy, Mark A. Nghiem, Paul Sober, Arthur J. Johnson, Timothy M. Bichakjian, Christopher K. Wong, Sandra L. TI Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID PATHOLOGICAL NODAL EVALUATION; UNKNOWN PRIMARY ORIGIN; SURVIVAL AB The first consensus Merkel cell carcinoma (MCC) staging system was published in 2010. New information on the clinical course prompts review of MCC staging. A total of 9387 MCC cases from the National Cancer Data Base Participant User File with follow-up and staging data (1998-2012) were analyzed. Prognostic differences based on clinical and pathological staging were evaluated. Survival estimates were compared by disease extent. Sixty-five percent of cases presented with local disease, whereas 26 and 8 % presented with nodal and distant disease. Disease extent at presentation was predictive of 5-year overall survival (OS) with estimates of 51, 35, and 14 % for local, nodal, and distant disease. Tumor burden at the regional nodal basin was predictive of 5-year OS with estimates of 40 and 27 % for clinically occult and clinically detected nodal disease. For local disease, we confirm improved prognosis when the regional nodal basin was negative by pathological compared with clinical staging. We identified 336 cases with clinically detected nodal disease and unknown primary tumor and showed improved prognosis over cases presenting with concurrent primary tumor (OS estimates of 42 vs. 27 %). Analysis of a national dataset of MCC cases validates the predictive value of disease extent at presentation. Separation of clinical and pathological stage groups and regrouping of unknown primary tumors are supported by the analysis. The revised staging system provides more accurate prognostication and has been formally accepted by the AJCC staging committee for inclusion in the 8th edition. C1 [Harms, Kelly L.; Johnson, Timothy M.; Bichakjian, Christopher K.] Univ Michigan Hlth Syst, Dept Dermatol, Ann Arbor, MI 48109 USA. [Harms, Kelly L.; Healy, Mark A.; Johnson, Timothy M.; Bichakjian, Christopher K.; Wong, Sandra L.] Sch Med, Ann Arbor, MI USA. [Healy, Mark A.; Johnson, Timothy M.; Wong, Sandra L.] Univ Michigan Hlth Syst, Dept Surg, Ann Arbor, MI USA. [Healy, Mark A.; Wong, Sandra L.] Univ Michigan, Ctr Healthcare Outcomes & Policy, Ann Arbor, MI 48109 USA. [Nghiem, Paul] Univ Washington, Dept Med Dermatol, Seattle, WA 98195 USA. [Nghiem, Paul] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Nghiem, Paul] Seattle Canc Care Alliance, Seattle, WA USA. [Sober, Arthur J.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Sober, Arthur J.] Harvard Med Sch, Boston, MA USA. [Johnson, Timothy M.] Univ Michigan Hlth Syst, Dept Otolaryngol, Ann Arbor, MI USA. [Wong, Sandra L.] Dartmouth Hitchcock Med Ctr, Dept Surg, Lebanon, NH 03766 USA. [Wong, Sandra L.] Geisel Sch Med Dartmouth, Lebanon, NH USA. RP Harms, KL (reprint author), Univ Michigan Hlth Syst, Dept Dermatol, Ann Arbor, MI 48109 USA.; Harms, KL (reprint author), Sch Med, Ann Arbor, MI USA. EM kharms@med.umich.edu RI Nghiem, Paul/A-9210-2011 OI Nghiem, Paul/0000-0003-2784-963X FU NIH [T32CA009672-24] FX MAH is supported by NIH T32CA009672-24. The data used in the study are from the NCDB PUF. The ACS-CoC has not verified and are not responsible for the analytic/statistical methodology employed or the conclusions drawn by the investigators. NR 19 TC 2 Z9 2 U1 2 U2 3 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 OCT PY 2016 VL 23 IS 11 BP 3564 EP 3571 DI 10.1245/s10434-016-5266-4 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA DV4XV UT WOS:000382930000024 PM 27198511 ER PT J AU Moye, J AF Moye, Jennifer TI Their Time Has Come: Providing Culturally Competent Care to LGBT Older Adults SO CLINICAL GERONTOLOGIST LA English DT Editorial Material C1 [Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Moye, Jennifer] Harvard Med Sch, Boston, MA 02115 USA. RP Moye, J (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA.; Moye, J (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM Jennifer.moye@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X NR 9 TC 0 Z9 0 U1 2 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PD OCT-DEC PY 2016 VL 39 IS 5 BP 363 EP 365 DI 10.1080/07317115.2016.1203584 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DX0QI UT WOS:000384068700001 ER PT J AU Galovski, TE Harik, JM Blain, LM Farmer, C Turner, D Houle, T AF Galovski, Tara E. Harik, Juliette M. Blain, Leah M. Farmer, Courtney Turner, Dana Houle, Tim TI Identifying Patterns and Predictors of PTSD and Depressive Symptom Change During Cognitive Processing Therapy SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE Posttraumatic stress disorder; Treatment outcome; Cognitive processing therapy; Avoidant personality disorder ID POSTTRAUMATIC-STRESS-DISORDER; FEMALE RAPE VICTIMS; PROLONGED EXPOSURE; PERSONALITY-DISORDERS; VETERANS; SCALE AB This study sought to identify specific trajectories of posttraumatic stress disorder (PTSD) and depression symptom change (and the relationship thereof) within a variable length course of cognitive processing therapy (CPT). Clinical characteristics, including initial severity of PTSD and depressive symptoms and characterological features consistent with personality disorder diagnoses, were examined as potential predictors of treatment response trajectory. Male and female interpersonal violence survivors (N = 69) with PTSD were treated with a modified form of CPT wherein treatment end was dictated by individual course of recovery (4-18 sessions). Latent class growth analysis and Bayesian information criteria revealed three distinct groups based on change patterns (partial responders, consistent responders, and initial responders). Baseline PTSD and depressive symptoms and characterological features were associated with patterns of change. Findings provide evidence for variability in efficiency of response to PTSD treatment and highlight the need for continued assessment of progress to inform the course of therapy. C1 [Galovski, Tara E.] VA Boston Healthcare Syst, Natl Ctr PTSD Womens Hlth Sci Div, 150 South Huntington Ave 116B-3, Boston, MA 02130 USA. [Harik, Juliette M.] Vet Affairs Med Ctr, Natl Ctr PTSD Execut Div, White River Jct, VT USA. [Blain, Leah M.] VA Maryland Healthcare Syst, Baltimore, MD USA. [Farmer, Courtney] Univ Missouri, St Louis, MO 63121 USA. [Turner, Dana; Houle, Tim] Wake Forest Univ, Winston Salem, NC 27109 USA. RP Galovski, TE (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD Womens Hlth Sci Div, 150 South Huntington Ave 116B-3, Boston, MA 02130 USA. EM Tara.Galovski@va.gov; juliette.harik@va.gov; leahblain@gmail.com; courtneyfarmer@gmail.com; daturner@wakehealth.edu; thoule@wakehealth.edu FU National Institute of Mental Health/NIH [1R34-MH-074937] FX This study was funded by the National Institute of Mental Health/NIH (1R34-MH-074937). NR 30 TC 0 Z9 0 U1 10 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 EI 1573-2819 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD OCT PY 2016 VL 40 IS 5 BP 617 EP 626 DI 10.1007/s10608-016-9770-4 PG 10 WC Psychology, Clinical SC Psychology GA DX2NV UT WOS:000384208100003 ER PT J AU Zhang, YC Tessier, SN Storey, KB AF Zhang, Yichi Tessier, Shannon N. Storey, Kenneth B. TI Inhibition of skeletal muscle atrophy during torpor in ground squirrels occurs through downregulation of MyoG and inactivation of Foxo4 SO CRYOBIOLOGY LA English DT Article DE Ictidomys tridecemlineatus; Muscle remodeling; Foxo4; Immunoblotting; MAFbx; Ubiquitin ligase ID FORKHEAD TRANSCRIPTION FACTOR; PROTEIN-KINASE-B; RAL-BINDING PROTEIN-1; UBIQUITIN LIGASES; GENE-EXPRESSION; FACTOR AFX; MAMMALIAN HIBERNATION; NEURAL ACTIVITY; CELL-SURVIVAL; ACTIVATION AB Foxo4 and MyoG proteins regulate the transcription of numerous genes, including the E3 ubiquitin ligases MAFbx and MuRF1, which are activated in skeletal muscle under atrophy-inducing conditions. In the thirteen-lined ground squirrel, there is little muscle wasting that occurs during hibernation, a process characterized by bouts of torpor and arousal, despite virtual inactivity. Consequently, we were interested in studying the regulatory role of Foxo4 and MyoG on ubiquitin ligases throughout torpor-arousal cycles. Findings indicate that MAFbx and MuRF1 decreased during early torpor (ET) by 42% and 40%, respectively, relative to euthermic control (EC), although MuRF1 expression subsequently increased at late torpor (LT). The expression pattern of MyoG most closely resembled that of MAFbx, with levels decreasing during LT. In addition, the phosphorylation of Foxo4 at Thr-451 showed an initial increase during EN, followed by a decline throughout the remainder of the torpor-arousal cycle, suggesting Foxo4 inhibition. This trend was mirrored by inhibition of the Ras-Ral pathway, as the Ras and Ral proteins were decreased by 77% and 41% respectively, at ET. Foxo4 phosphorylation at 5197 was depressed during entrance and torpor, suggesting Foxo4 nuclear localization, and possibly regulating the increase in MuRF1 levels at LT. These findings indicate that signaling pathways involved in regulating muscle atrophy, such as MyoG and Foxo4 through the Ras-Ral pathway, contribute to important muscle-specific changes during hibernation. Therefore, this data provides novel insight into the molecular mechanisms regulating muscle remodeling in a hibernator model. (C) 2016 Elsevier Inc. All rights reserved. C1 [Zhang, Yichi; Storey, Kenneth B.] Carleton Univ, Inst Biochem, 1125 Colonel By Dr, Ottawa, ON K1S 5B6, Canada. [Zhang, Yichi; Storey, Kenneth B.] Carleton Univ, Dept Biol, 1125 Colonel By Dr, Ottawa, ON K1S 5B6, Canada. [Tessier, Shannon N.] Massachusetts Gen Hosp, Dept Surg, 114 16th St, Charlestown, MA 02129 USA. [Tessier, Shannon N.] Massachusetts Gen Hosp, Ctr Engn Med, 114 16th St, Charlestown, MA 02129 USA. [Tessier, Shannon N.] Harvard Med Sch, 114 16th St, Charlestown, MA 02129 USA. RP Storey, KB (reprint author), Carleton Univ, Inst Biochem, 1125 Colonel By Dr, Ottawa, ON K1S 5B6, Canada.; Storey, KB (reprint author), Carleton Univ, Dept Biol, 1125 Colonel By Dr, Ottawa, ON K1S 5B6, Canada. EM kenneth.storey@carleton.ca OI Storey, Kenneth/0000-0002-7363-1853 FU Discovery grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada [6793]; Queen Elizabeth II Graduate Scholarship in Science and Technology FX This work was supported by a Discovery grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada (#6793). KBS holds the Canada Research Chair in Molecular Physiology; YZ is a Master's Student funded by a Queen Elizabeth II Graduate Scholarship in Science and Technology; SNT held a NSERC Postdoctoral Fellowship. NR 62 TC 1 Z9 1 U1 5 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0011-2240 EI 1090-2392 J9 CRYOBIOLOGY JI Cryobiology PD OCT PY 2016 VL 73 IS 2 BP 112 EP 119 DI 10.1016/j.cryobiol.2016.08.013 PG 8 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA DX4ZC UT WOS:000384388600002 PM 27593478 ER PT J AU Liu, J Tanrikut, C Wright, DL Lee, GY Toner, M Biggers, JD Toth, TL AF Liu, Jie Tanrikut, Cigdem Wright, Diane L. Lee, Gloria Y. Toner, Mehmet Biggers, John D. Toth, Thomas L. TI Cryopreservation of human spermatozoa with minimal non-permeable cryoprotectant SO CRYOBIOLOGY LA English DT Article DE Sperm cryopreservation; Sugars; Silica micro-capillary; Cryoprotectant ID HUMAN SPERM; PHASE-TRANSITIONS; BORON-NITRIDE; VITRIFICATION; TREHALOSE; SUCROSE; PARAMETERS; POLYIMIDE; MEMBRANES; BEHAVIOR AB Cryopreservation of human spermatozoa is a commonly used technique in assisted reproduction, however freezing low concentrations of sperm while maintaining adequate post-thaw motility remains a challenge. In an effort to optimize post-thaw motility yields, low volumes of human sperm were frozen in polyimide-coated fused silica micro-capillaries using 0.065 M, 0.125 M, 0.25 M, or 0.5 M trehalose as the only cryoprotectant. Micro-capillaries were either initially incubated in liquid nitrogen vapor before plunging into liquid nitrogen, or directly plunged into liquid nitrogen. Post thaw sperm counts and motility were estimated. Spermatozoa that were initially incubated in liquid nitrogen vapor had greater post thaw motility than those plunged immediately into liquid nitrogen independent of trehalose concentration. The protective effect of 0.125 M D-glucose, 3-O-methyl-D-glucopyranose, trehalose, sucrose, raffinose, or stachyose were evaluated individually. Trehalose and sucrose were the most effective cryoprotectants, recovering 69.0% and 68.9% of initial sperm motility, respectively. (C) 2016 Elsevier Inc. All rights reserved. C1 [Liu, Jie; Lee, Gloria Y.; Toner, Mehmet; Biggers, John D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Liu, Jie; Tanrikut, Cigdem; Wright, Diane L.; Lee, Gloria Y.; Toner, Mehmet; Biggers, John D.; Toth, Thomas L.] Harvard Med Sch, Boston, MA 02114 USA. [Tanrikut, Cigdem] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Wright, Diane L.; Toth, Thomas L.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Biggers, John D.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Liu, Jie; Lee, Gloria Y.; Toner, Mehmet; Biggers, John D.] Shriners Hosp Children, Boston, MA 02114 USA. RP Biggers, JD (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.; Biggers, JD; Toth, TL (reprint author), Harvard Med Sch, Boston, MA 02114 USA.; Toth, TL (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. EM John_Biggers@hms.harvard.edu; TLTOTH@mgh.harvard.edu FU R24 grant from National Institute of Health [5R24OD016985] FX The authors acknowledge all members of the Andrology laboratory team at the Massachusetts General Hospital Fertility Center, specifically Maria Thatcher, as well as the preliminary research efforts of Joseph McQuaid, MD, and Yahir Santiago-Lastra, MD; a special thank you is extended to all study participants for allowing research use of their semen samples. This study was supported by a R24 grant from the National Institute of Health (5R24OD016985). NR 29 TC 0 Z9 0 U1 10 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0011-2240 EI 1090-2392 J9 CRYOBIOLOGY JI Cryobiology PD OCT PY 2016 VL 73 IS 2 BP 162 EP 167 DI 10.1016/j.cryobiol.2016.08.004 PG 6 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA DX4ZC UT WOS:000384388600009 PM 27498216 ER PT J AU Nissim, S Weeks, O Talbot, JC Hedgepeth, JW Wucherpfennig, J Schatzman-Bone, S Swinburne, I Cortes, M Alexa, K Megason, S North, TE Amacher, SL Goessling, W AF Nissim, Sahar Weeks, Olivia Talbot, Jared C. Hedgepeth, John W. Wucherpfennig, Julia Schatzman-Bone, Stephanie Swinburne, Ian Cortes, Mauricio Alexa, Kristen Megason, Sean North, Trista E. Amacher, Sharon L. Goessling, Wolfram TI Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Nuclear receptor; Endoderm development; Hepatopancreas progenitors; Exocrine pancreas; Liver ID FETOPROTEIN TRANSCRIPTION FACTOR; FACTOR FTF GENE; EXOCRINE PANCREAS; DIGESTIVE-SYSTEM; TARGET GENE; ZEBRAFISH; EXPRESSION; SPECIFICATION; DIFFERENTIATION; MORPHOGENESIS AB The stepwise progression of common endoderm progenitors into differentiated liver and pancreas organs is regulated by a dynamic array of signals that are not well understood. The nuclear receptor subfamily 5, group A, member 2 gene nr5a2, also known as Liver receptor homolog-1 (Lrh-1) is expressed in several tissues including the developing liver and pancreas. Here, we interrogate the role of Nr5a2 at multiple developmental stages using genetic and chemical approaches and uncover novel pleiotropic requirements during zebrafish liver and pancreas development. Zygotic loss of nr5a2 in a targeted genetic null mutant disrupted the development of the exocrine pancreas and liver, while leaving the endocrine pancreas intact. Loss of nr5a2 abrogated exocrine pancreas markers such as trypsin, while pancreas progenitors marked by ptf1a or pdx1 remained unaffected, suggesting a role for Nr5a2 in regulating pancreatic acinar cell differentiation. In the developing liver, Nr5a2 regulates hepatic progenitor outgrowth and differentiation, as nr5a2 mutants exhibited reduced hepatoblast markers hnf4 alpha and prox1 as well as differentiated hepatocyte marker fabp10a. Through the first in vivo use of Nr5a2 chemical antagonist Cpd3, the iterative requirement for Nr5a2 for exocrine pancreas and liver differentiation was temporally elucidated: chemical inhibition of Nr5a2 function during hepatopancreas progenitor specification was sufficient to disrupt exocrine pancreas formation and enhance the size of the embryonic liver, suggesting that Nr5a2 regulates hepatic vs. pancreatic progenitor fate choice. Chemical inhibition of Nr5a2 at a later time during pancreas and liver differentiation was sufficient to block the formation of mature acinar cells and hepatocytes. These findings define critical iterative and pleiotropic roles for Nr5a2 at distinct stages of pancreas and liver organogenesis, and provide novel perspectives for interpreting the role of Nr5a2 in disease. (C) 2016 Elsevier Inc. All rights reserved. C1 [Nissim, Sahar; Goessling, Wolfram] Harvard Med Sch, Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Nissim, Sahar; Weeks, Olivia; Hedgepeth, John W.; Wucherpfennig, Julia; Schatzman-Bone, Stephanie; Alexa, Kristen; Goessling, Wolfram] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Nissim, Sahar; Goessling, Wolfram] Dana Farber Canc Inst, Boston, MA 02115 USA. [Talbot, Jared C.; Amacher, Sharon L.] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA. [Talbot, Jared C.; Amacher, Sharon L.] Ohio State Univ, Dept Biol Chem & Pharmacol, Columbus, OH 43210 USA. [Swinburne, Ian; Megason, Sean] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Cortes, Mauricio; North, Trista E.] Harvard Med Sch, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [North, Trista E.; Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Goessling, Wolfram] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Goessling, W (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. EM wgoessling@partners.org FU NIH [K08 DK105326, T32 GM007226]; National Pancreas Foundation [108244]; Harvard Digestive Diseases Center [P30 DK034854]; Anna Fuller Fund; Pelotonia Postoctoral Fellowship; Harvard Stem Cell Institute; Burroughs Wellcome Fund Career Award for Medical Scientists; NINDS [T32 NS077984]; [R01DK090311]; [R24OD017870]; [R01GM088041] FX We thank Chad Walesky from the Goessling Laboratory for providing the hnf4 alpha probe. We also extend our gratitude to Eric Ortlund at Emory University for helpful discussions, and staff of the Beth Israel Deaconess Medical Center, Ohio State University, and Brigham and Women's Hospital zebrafish facilities for zebra fish husbandry. This work was supported by the NIH K08 DK105326 (S.N.), NIH T32 GM007226 (O.W.), R01DK090311, R24OD017870 (W.G.), R01GM088041 (S.L.A.), NINDS T32 NS077984 (J.C.T.), the National Pancreas Foundation (Grant no. 108244) (S.N.), the Harvard Digestive Diseases Center (P30 DK034854; S.N., W.G.) and the Anna Fuller Fund (W.G.). J.C.T. is a recipient of a Pelotonia Postoctoral Fellowship. O.W. is the recipient of a Sternlicht Director's Fund Award for Graduate Students in Diabetes Research at the Harvard Stem Cell Institute. S.N. is a recipient of the Burroughs Wellcome Fund Career Award for Medical Scientists. W.G. is a Pew Scholar in the Biomedical Sciences. There are no conflicts of interest to report. NR 62 TC 1 Z9 1 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 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD OCT 1 PY 2016 VL 418 IS 1 BP 108 EP 123 DI 10.1016/j.ydbio.2016.07.019 PG 16 WC Developmental Biology SC Developmental Biology GA DX5BD UT WOS:000384393900011 PM 27474396 ER PT J AU Vavricka, SR Vadasz, N Stotz, M Lehmann, R Studerus, D Greuter, T Frei, P Zeitz, J Scharl, M Misselwitz, B Pohl, D Fried, M Tutuian, R Fasano, A Schoepfer, AM Rogler, G Biedermann, L AF Vavricka, Stephan R. Vadasz, Nina Stotz, Matthias Lehmann, Romina Studerus, Diana Greuter, Thomas Frei, Pascal Zeitz, Jonas Scharl, Michael Misselwitz, Benjamin Pohl, Daniel Fried, Michael Tutuian, Radu Fasano, Alessio Schoepfer, Alain M. Rogler, Gerhard Biedermann, Luc TI Celiac disease diagnosis still significantly delayed - Doctor's but not patients' delay responsive for the increased total delay in women SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE Celiac disease; Diagnostic delay; Doctors' delay; Gender; Irritable bowel syndrome; Patients' delay ID QUALITY-OF-LIFE; UNITED-STATES; PREVALENCE; RISK; MORTALITY; MANAGEMENT AB Background: There is insufficient data on diagnostic delay and associated factors in celiac disease (CeD) as well as on its potential impact on the course of disease. Methods: Specifically taking its two components - patients' and doctors' delay - into account, we performed a large systematic patient survey study among unselected CeD patients in Switzerland. Results: We found a mean/median total diagnostic delay of 87/24 months (IQR 5-96), with a range from 0 up to 780 months and roughly equal fractions of patients' and doctors' delay. Both mean/median total (93.1/24 vs. 60.2/12, p < 0.001) and doctors' (41.8/3 vs. 23.9/2, p < 0.001) diagnostic delay were significantly higher in female vs. male patients, whereas patients' delay was similar, regardless of preceding irritable bowel syndrome diagnosis. Patients with a diagnostic delay shorter than 2 years were significantly less often in need of steroids and/or immunosuppressants, substitution for any nutritional deficiency but more often free of symptoms 6 and 12 months after diagnosis. Conclusions: There is a substantial diagnostic delay in CeD, which is associated with a worse clinical outcome and significantly longer in female patients. This increased diagnostic delay in women is due to doctors' but not patients' delay and cannot be explained by antecedent IBS prior to establishing the CeD diagnosis. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. C1 [Vavricka, Stephan R.; Vadasz, Nina; Stotz, Matthias; Lehmann, Romina] Triemli Hosp Zurich, Div Gastroenterol & Hepatol, Zurich, Switzerland. [Studerus, Diana] IG Zoliakie, Basel, Switzerland. [Greuter, Thomas; Zeitz, Jonas; Scharl, Michael; Misselwitz, Benjamin; Pohl, Daniel; Fried, Michael; Rogler, Gerhard; Biedermann, Luc] Univ Zurich Hosp, Div Gastroenterol & Hepatol, Raemistr 100, CH-8006 Zurich, Switzerland. [Frei, Pascal] Gastroenterol Bethanien, Div Gastroenterol & Hepatol, Zurich, Switzerland. [Tutuian, Radu] Spital Tiefenau, Div Gastroenterol & Hepatol, Bern, Switzerland. [Fasano, Alessio] MassGen Hosp Children, Pediat Gastroenterol & Nutr, Boston, MA USA. [Schoepfer, Alain M.] Univ Hosp Lausanne CHUV, Div Gastroenterol & Hepatol, Lausanne, Switzerland. RP Biedermann, L (reprint author), Univ Zurich Hosp, Div Gastroenterol & Hepatol, Raemistr 100, CH-8006 Zurich, Switzerland. EM luc.biedermann@usz.ch RI Misselwitz, Benjamin/L-7193-2016 OI Misselwitz, Benjamin/0000-0002-8719-5175 NR 37 TC 2 Z9 2 U1 6 U2 6 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 OCT PY 2016 VL 48 IS 10 BP 1148 EP 1154 DI 10.1016/j.dld.2016.06.016 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DW9YD UT WOS:000384017800007 PM 27401607 ER PT J AU Le, NT Michels, FAS Song, MY Zhang, XH Bernstein, AM Giovannucci, EL Fuchs, CS Ogino, S Chan, AT Sinha, R Willett, WC Wu, KN AF Ngoan Tran Le Michels, Fernanda Alessandra Silva Song, Mingyang Zhang, Xuehong Bernstein, Adam M. Giovannucci, Edward L. Fuchs, Charles S. Ogino, Shuji Chan, Andrew T. Sinha, Rashmi Willett, Walter C. Wu, Kana TI A Prospective Analysis of Meat Mutagens and Colorectal Cancer in the Nurses' Health Study and Health Professionals Follow-up Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; DIETARY HETEROCYCLIC AMINES; NATIONAL DEATH INDEX; COLON-CANCER; MULTIETHNIC COHORT; RED MEAT; COOKING METHODS; RISK FINDINGS; HEME IRON; CONSUMPTION AB BACKGROUND: Heterocyclic amines (HCAs) in cooked meats may play a role in colorectal cancer (CRC) development. OBJECTIVES: We aimed to prospectively examine the association between estimated intakes of HCAs and meat-derived mutagenicity (MDM) in two cohorts of health professionals, the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS). METHODS: In 29,615 men and 65,875 women, intake of the HCAs 2-amino-3,8-dimethylimidazo(4,5-j) quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP), 2-amino-3,4,8-trimethylimidazo(4,5-f) quinoxaline (DiMeIQx), and MDM was estimated using a 1996 cooking questionnaire, the 1994 food frequency questionnaire, and an online database. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and to adjust for potential confounders. Estimates for both cohorts were pooled using random-effects meta-analysis. RESULTS: Between 1996 and 2010, 418 male and 790 female CRC cases were identified. Meat mutagen intake was not statistically significantly associated with risk of CRC [highest vs. lowest quintile, pooled HR (95% CI) for MeIQx: 1.12 (0.93, 1.34), p for trend 0.23; PhIP: 1.10 (0.90, 1.33), p for trend 0.35; MDM: 1.03 (0.86, 1.24), p for trend 0.75] or subtypes of CRC defined by tumor location (proximal or distal colon, or rectum). When analyzed by source of meat, PhIP from red but not from white meat was nonsignificantly positively associated with CRC and significantly positively associated with proximal cancers [HR (95% CI) per standard deviation increase of log-transformed intake: PhIP red meat: CRC: 1.06 (0.99, 1.12), proximal: 1.11 (1.02, 1.21); PhIP white meat: CRC: 0.99 (0.94, 1.04), proximal: 1.00 (0.93, 1.09)]. CONCLUSIONS: Estimated intakes of meat mutagens were not significantly associated with CRC risk over 14 years of follow-up in the NHS and HPFS cohorts. Results for PhIP from red but not from white meat warrant further investigation. C1 [Ngoan Tran Le] Hanoi Med Univ, Dept Occupat Hlth, Hanoi, Vietnam. [Ngoan Tran Le; Michels, Fernanda Alessandra Silva; Song, Mingyang; Giovannucci, Edward L.; Willett, Walter C.; Wu, Kana] Harvard TH Chan Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. [Song, Mingyang; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Song, Mingyang; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Song, Mingyang; Zhang, Xuehong; Giovannucci, Edward L.; Fuchs, Charles S.; Ogino, Shuji; Chan, Andrew T.; Willett, Walter C.] Harvard Med Sch, Boston, MA USA. [Song, Mingyang; Giovannucci, Edward L.; Ogino, Shuji; Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Zhang, Xuehong; Giovannucci, Edward L.; Ogino, Shuji; Chan, Andrew T.; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Bernstein, Adam M.] Rally Hlth, San Francisco, CA USA. [Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA. [Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Le, NT (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM letngoan@hmu.edu.vn FU National Institutes of Health [UM1 CA167552, UM1 CA186107, P50 CA127003, R35 CA197735, P01 CA87969, P01 CA 55075]; Union for International Cancer Control (UICC) American Cancer Society Beginning Investigators Fellowship - American Cancer Society; UICC Yamagiwa-Yoshida Memorial International Cancer Study Grant FX This work was supported by federal grants (National Institutes of Health): UM1 CA167552, UM1 CA186107, P50 CA127003, R35 CA197735, P01 CA87969, and P01 CA 55075. This work has also been supported by a Union for International Cancer Control (UICC) American Cancer Society Beginning Investigators Fellowship funded by the American Cancer Society and by a UICC Yamagiwa-Yoshida Memorial International Cancer Study Grant to N.T.L. NR 64 TC 2 Z9 2 U1 9 U2 9 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD OCT PY 2016 VL 124 IS 10 BP 1529 EP 1536 DI 10.1289/EHP238 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DX4EQ UT WOS:000384334400015 PM 27105317 ER PT J AU Bottcher, A Dommerich, S Sander, S Olze, H Stromberger, C Coordes, A Jowett, N Knopke, S AF Boettcher, Arne Dommerich, Steffen Sander, Steffen Olze, Heidi Stromberger, Carmen Coordes, Annekatrin Jowett, Nate Knopke, Steffen TI Nodal yield of neck dissections and influence on outcome in laryngectomized patients SO EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY LA English DT Article DE Total laryngectomy; HNSCC; Neck dissection; Nodal yield; Survival outcome ID SQUAMOUS-CELL CARCINOMA; LYMPH-NODES; PHARYNGOCUTANEOUS FISTULA; CANCER-PATIENTS; SELECTIVE NECK; NUMBER; HEAD; SURVIVAL; LYMPHADENECTOMY; RESECTION AB The appropriate extent of neck dissection (ND) in head and neck squamous cell carcinoma (SCC) continues to be investigated. This study aimed to determine whether the extent of ND as measured by nodal yield (NY) is a prognostic factor in patients undergoing primary total laryngectomy (TL) for advanced laryngeal SCC. A retrospective review at a tertiary referral centre identified 54 patients who underwent TL with elective (n = 39, cN0) or therapeutic (n = 15, cN+) ND with curative intent between 2002 and 2014. Survival analysis was obtained via regression analysis, calculated for overall (OS) and disease-free survival (DFS). Stage-independent 5-year OS was 32.1 %. Mean NY was 18.67 (standard deviation 9.898; range 0-45). The rate of cervical lymph node metastasis on pathology (pN+) was 27.8 %. Uni- and multivariate regression analysis detected no association between NY and OS or DFS (P aeyen 0.05). Advantages in OS and DFS were seen among patients without cervical lymph node metastasis (pN0) in comparison to those with pN+ necks (OS: hazard ratio [HR] 0.179; 95 % confidence interval [CI] 0.046-0.693; P = 0.013, and DFS: HR 0.190; 95 % CI 0.061-0.590; P = 0.004). ND resulted in pathologic upstaging of the neck in seven patients and downgrading in eight; increasing NY was not associated with an increased probability of a change in nodal stage. No significant association was found between NY and OS or DFS in patients undergoing TL with ND as primary therapy for advanced laryngeal SCC. C1 [Boettcher, Arne; Olze, Heidi; Knopke, Steffen] Charite Univ Med Ctr Berlin, Dept Otorhinolaryngol Head & Neck Surg, Campus Virchow Klinikum, Augustenburger Pl 1, D-13353 Berlin, Germany. [Dommerich, Steffen; Olze, Heidi] Charite Univ Med Ctr Berlin, Dept Otorhinolaryngol Head & Neck Surg, Campus Charite Mitte, Berlin, Germany. [Sander, Steffen] Charite Univ Med Ctr Berlin, CCCC, Clin Canc Registry, Campus Charite Mitte, Berlin, Germany. [Stromberger, Carmen] Charite Univ Med Ctr Berlin, Dept Radiooncol, Campus Virchow Klinikum, Berlin, Germany. [Coordes, Annekatrin] Charite Univ Med Ctr Berlin, Dept Otorhinolaryngol Head & Neck Surg, Campus Benjamin Franklin, Berlin, Germany. [Jowett, Nate] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Jowett, Nate] Harvard Med Sch, Boston, MA USA. RP Bottcher, A (reprint author), Charite Univ Med Ctr Berlin, Dept Otorhinolaryngol Head & Neck Surg, Campus Virchow Klinikum, Augustenburger Pl 1, D-13353 Berlin, Germany. EM arne.boettcher@charite.de NR 23 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0937-4477 EI 1434-4726 J9 EUR ARCH OTO-RHINO-L JI Eur. Arch. Oto-Rhino-Laryn. PD OCT PY 2016 VL 273 IS 10 BP 3321 EP 3329 DI 10.1007/s00405-016-3928-2 PG 9 WC Otorhinolaryngology SC Otorhinolaryngology GA DV5DJ UT WOS:000382945900062 PM 26874731 ER PT J AU Amin, N Allebrandt, KV van der Spek, A Muller-Myhsok, B Hek, K Teder-Laving, M Hayward, C Esko, T van Mill, JG Mbarek, H Watson, NF Melville, SA Del Greco, FM Byrne, EM Oole, E Kolcic, I Chen, TH Evans, DS Coresh, J Vogelzangs, N Karjalainen, J Willemsen, G Gharib, SA Zgaga, L Mihailov, E Stone, KL Campbell, H Brouwer, RW Demirkan, A Isaacs, A Dogas, Z Marciante, KD Campbell, S Borovecki, F Luik, AI Li, M Hottenga, JJ Huffman, JE van den Hout, MCGN Cummings, SR Aulchenko, YS Gehrman, PR Uitterlinden, AG Wichmann, HE Muller-Nurasyid, M Fehrmann, RSN Montgomery, GW Hofman, A Kao, WHL Oostra, BA Wright, AF Vink, JM Wilson, JF Pramstaller, PP Hicks, AA Polasek, O Punjabi, NM Redline, S Psaty, BM Heath, AC Merrow, M Tranah, GJ Gottlieb, DJ Boomsma, DI Martin, NG Rudan, I Tiemeier, H van IJcken, WFJ Penninx, BW Metspalu, A Meitinger, T Franke, L Roenneberg, T van Duijn, CM AF Amin, Najaf Allebrandt, Karla V. van der Spek, Ashley Mueller-Myhsok, Bertram Hek, Karin Teder-Laving, Maris Hayward, Caroline Esko, Tonu van Mill, Josine G. Mbarek, Hamdi Watson, Nathaniel F. Melville, Scott A. Del Greco, Fabiola M. Byrne, Enda M. Oole, Edwin Kolcic, Ivana Chen, Ting-hsu Evans, Daniel S. Coresh, Josef Vogelzangs, Nicole Karjalainen, Juha Willemsen, Gonneke Gharib, Sina A. Zgaga, Lina Mihailov, Evelin Stone, Katie L. Campbell, Harry Brouwer, Rutger Ww Demirkan, Ayse Isaacs, Aaron Dogas, Zoran Marciante, Kristin D. Campbell, Susan Borovecki, Fran Luik, Annemarie I. Li, Man Hottenga, Jouke Jan Huffman, Jennifer E. van den Hout, Mirjam C. G. N. Cummings, Steven R. Aulchenko, Yuru S. Gehrman, Philip R. Uitterlinden, Andre G. Wichmann, Heinz-Erich Muller-Nurasyid, Martina Fehrmann, Rudolf S. N. Montgomery, Grant W. Hofman, Albert Kao, Wen Hong Linda Oostra, Ben A. Wright, Alan F. Vink, Jacqueline M. Wilson, James F. Pramstaller, Peter P. Hicks, Andrew A. Polasek, Ozren Punjabi, Naresh M. Redline, Susan Psaty, Bruce M. Heath, Andrew C. Merrow, Martha Tranah, Gregory J. Gottlieb, Daniel J. Boomsma, Dorret I. Martin, Nicholas G. Rudan, Igor Tiemeier, Henning van IJcken, Wilfred F. J. Penninx, Brenda W. Metspalu, Andres Meitinger, Thomas Franke, Lude Roenneberg, Till van Duijn, Cornelia M. TI Genetic variants in RBFOX3 are associated with sleep latency SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; LINKAGE ANALYSIS; ONSET INSOMNIA; RECORDED SLEEP; CANDIDATE-GENE; SELF-REPORT; EXPRESSION; FAMILY; DETERMINANTS; IMPUTATION AB Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values = 5.77 x 10(-08), 6.59 x 10(-08) and 9.17 x 10(-08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values = 1.5 x 10(-02), 7.0 x 10(-03) and 2.5 x 10(-03); combined meta-analysis P-values = 5.5 x 10(-07), 5.4 x 10(-07) and 1.0 x 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value = 1.4 x 10(-316)) and the central nervous system (P-value = 7.5 x 10(-321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9x10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency. C1 [Amin, Najaf; van der Spek, Ashley; Demirkan, Ayse; Isaacs, Aaron; Aulchenko, Yuru S.; Oostra, Ben A.] Erasmus Univ, Med Ctr, Dept Epidemiol, Unit Genet Epidemiol, Wytemaweg 80, Rotterdam, Netherlands. [Allebrandt, Karla V.; Roenneberg, Till] Univ Munich, Inst Med Psychol, Munich, Germany. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, Munich, Germany. [Hek, Karin; Luik, Annemarie I.; Tiemeier, Henning] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Hek, Karin; Tiemeier, Henning] Erasmus MC, Dept Psychiat, Rotterdam, Netherlands. [Teder-Laving, Maris; Esko, Tonu; Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Teder-Laving, Maris; Esko, Tonu; Mihailov, Evelin; Metspalu, Andres] Estonian Bioctr, Tartu, Estonia. [Hayward, Caroline; Campbell, Susan; Huffman, Jennifer E.; Wright, Alan F.; Wilson, James F.] Univ Edinburgh, IGMM, Human Genet Unit, MRC, Edinburgh, Midlothian, Scotland. [van Mill, Josine G.; Vogelzangs, Nicole; Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Psychiat, Amsterdam, Netherlands. [Mbarek, Hamdi; Willemsen, Gonneke; Hottenga, Jouke Jan; Vink, Jacqueline M.; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Watson, Nathaniel F.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Watson, Nathaniel F.; Gharib, Sina A.] Univ Washington, Med Sleep Ctr, Seattle, WA 98195 USA. [Melville, Scott A.; Gharib, Sina A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Del Greco, Fabiola M.; Hicks, Andrew A.] European Acad Bolzano, Ctr Biomed, Bolzano, Italy. [Del Greco, Fabiola M.; Hicks, Andrew A.] Univ Lubeck, Lubeck, Germany. [Byrne, Enda M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Byrne, Enda M.; Montgomery, Grant W.] Queensland Inst Med Res, Brisbane, Qld, Australia. [Oole, Edwin; Brouwer, Rutger Ww; van den Hout, Mirjam C. G. N.; van IJcken, Wilfred F. J.] Erasmus MC, Ctr Biom, Rotterdam, Netherlands. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Sch Med, Split, Croatia. [Chen, Ting-hsu] Boston Univ, VA Boston Healthcare Syst, Boston, MA 02215 USA. [Evans, Daniel S.; Stone, Katie L.; Cummings, Steven R.; Tranah, Gregory J.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Coresh, Josef] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Coresh, Josef] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Karjalainen, Juha; Fehrmann, Rudolf S. N.; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Gharib, Sina A.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Seattle, WA USA. [Campbell, Harry; Wilson, James F.; Rudan, Igor] Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Dogas, Zoran] Univ Split, Sch Med, Dept Neurosci, Split, Croatia. [Dogas, Zoran] Univ Split, Sch Med, Sleep Med Ctr, Split, Croatia. [Marciante, Kristin D.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Borovecki, Fran] Univ Zagreb, Fac Med, Ctr Funct Genom, Zagreb, Croatia. [Borovecki, Fran] Univ Zagreb, Fac Med, Dept Neurol, Zagreb, Croatia. [Li, Man; Kao, Wen Hong Linda] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gehrman, Philip R.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Netherlands Consortium Hlth Ageing & Natl Genom I, Leiden, Netherlands. [Wichmann, Heinz-Erich; Muller-Nurasyid, Martina] German Res Ctr Environm Hlth, Helmholtz Zentrum Munich, 31Institute Epidemiol, Neuherberg, Germany. [Wichmann, Heinz-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, Heinz-Erich] Klinikum Grosshadern, Munich, Germany. [Wichmann, Heinz-Erich] Tech Univ Munich, Inst Med Stat & Epidemiol, Munich, Germany. [Muller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Muller-Nurasyid, Martina] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Muller-Nurasyid, Martina] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Polasek, Ozren] Univ Split, Sch Med, Ctr Global Hlth, Split, Croatia. [Punjabi, Naresh M.] Johns Hopkins Univ, Dept Pulm Med & Epidemiol, Baltimore, MD USA. [Redline, Susan; Gottlieb, Daniel J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Redline, Susan] Harvard Med Sch, Beth Deaconess Med Ctr, Boston, MA USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Heath, Andrew C.] Washington Univ, Dept Psychiat, St Louis, MO USA. [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. [Tiemeier, Henning] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Munich, Germany. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. RP Amin, N (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Unit Genet Epidemiol, Wytemaweg 80, Rotterdam, Netherlands. EM n.amin@erasmusmc.nl RI Franke, Lude/P-7036-2016; Karjalainen, Juha/P-8624-2016; Fehrmann, Rudolf/E-2551-2011; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Dogas, Zoran/E-3269-2017; Hicks, Andrew/E-9518-2017; OI Franke, Lude/0000-0002-5159-8802; Fehrmann, Rudolf/0000-0002-7516-315X; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Hicks, Andrew/0000-0001-6320-0411; Mbarek, Hamdi/0000-0002-1108-0371; Luik, Annemarie I/0000-0001-7517-197X FU FP6 programme EUCLOCK; Dutch Science Foundation (the NWO); Hersenstichting Nederland; Rosalind Franklin Fellowships of the University of Groningen; Estonian Government; European Union through the European Regional Development Fund in the frame of Centre of Excellence in Genomics; Geestkracht programme of the Dutch Scientific Organization (ZON-MW); Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health; EUROSPAN (European Special Populations Research Network) through the European Commission FP6 STRP grant; Chief Scientist Office of the Scottish Government; Royal Society; Centre for Medical Systems Biology [CMSB1, CMSB2]; Netherlands Genomics Initiative (NGI); Netherlands Organization for Scientific Research (NWO-VENI) [916.10.135]; Netherlands Genomics Initiative [92519031]; European Community's Health Seventh Framework Programme (FP7) [259867]; FP7 Projects ECOGENE; BBMRI; ENGAGE; OPENGENE; Medical Research Council, Erasmus University, Erasmus MC; ALBAN FX We thank all the participants and staff of all the studies for their co-operation and contribution. We are grateful to all participants and their relatives, general practitioners and neurologists for their contributions and to P Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and P Snijders for his help in data collection for the ERF study. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database, and Karol Estrada and Maksim V Struchalin for their support in creation and analysis of imputed data for the Rotterdam Study. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Fernando Rivadeneira, Dr Tobias A Knoch, Anis Abuseiris, Luc V de Zeeuw and Rob de Graaf for their help in creating GRIMP, and BigGRID, MediGRID and Services@MediGRID/D-Grid. We acknowledge the invaluable contributions of the recruitment team from the Croatian Centre for Global Health, University of Split, the administrative teams in Croatia and Edinburgh and the people of Split. Our work was supported by the FP6 programme EUCLOCK, the Dutch Science Foundation (the NWO), the Hersenstichting Nederland, the Rosalind Franklin Fellowships of the University of Groningen, targeted Financing from the Estonian Government, the European Union through the European Regional Development Fund in the frame of Centre of Excellence in Genomics, FP7 Projects ECOGENE, BBMRI, ENGAGE and OPENGENE, the Geestkracht programme of the Dutch Scientific Organization (ZON-MW) and matching funds from participating universities and mental health care organizations, the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, the EUROSPAN (European Special Populations Research Network) through the European Commission FP6 STRP grant, the Chief Scientist Office of the Scottish Government, the Royal Society, the Medical Research Council, Erasmus University, Erasmus MC, the Centre for Medical Systems Biology (CMSB1 and CMSB2) and the Netherlands Genomics Initiative (NGI) and ALBAN. We acknowledge the High Performance Computing Center of University of Tartu, for space and facilities to conduct part of the EGCUT analysis. We also acknowledge the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), The Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports of the Netherlands, the European Commission (DG XII) and the Municipality of Rotterdam. This study was supported by grants from the Netherlands Organization for Scientific Research (NWO-VENI grant 916.10.135 to LF) and a Horizon Breakthrough grant from the Netherlands Genomics Initiative (grant 92519031 to LF). The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867. Study-specific acknowledgments and the ethical statement are provided in the Supplementary text. NR 60 TC 3 Z9 3 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD OCT PY 2016 VL 24 IS 10 BP 1488 EP 1495 DI 10.1038/ejhg.2016.31 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DX0WV UT WOS:000384088000016 PM 27142678 ER PT J AU Kim, AR Sankaran, VG AF Kim, Ah Ram Sankaran, Vijay G. TI Development of autologous blood cell therapies SO EXPERIMENTAL HEMATOLOGY LA English DT Review ID PLURIPOTENT STEM-CELLS; HEMATOPOIETIC STEM/PROGENITOR CELLS; LARGE-SCALE PRODUCTION; ZINC-FINGER NUCLEASES; HUMAN ERYTHROID-CELLS; EX-VIVO EXPANSION; IN-VITRO; HUMAN MEGAKARYOCYTES; GENE-THERAPY; PLATELET TRANSFUSION AB Allogeneic hematopoietic stem cell transplantation and blood cell transfusions are performed commonly in patients with a variety of blood disorders. Unfortunately, these donor-derived cell therapies are constrained due to limited supplies, infectious risk factors, a lack of appropriately matched donors, and the risk of immunologic complications from such products. The use of autologous cell therapies has been proposed to overcome these shortcomings. One can derive such therapies directly from hematopoietic stem and progenitor cells of individuals, which can then be manipulated ex vivo to produce the desired modifications or differentiated to produce a particular target population. Alternatively, pluripotent stem cells, which have a theoretically unlimited self-renewal capacity and an ability to differentiate into any desired cell type, can be used as an autologous starting source for such manipulation and differentiation approaches. Such cell products can also be used as a delivery vehicle for therapeutics. In this review, we highlight recent advances and discuss ongoing challenges for the in vitro generation of autologous hematopoietic cells that can be used for cell therapy. Copyright (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. C1 [Kim, Ah Ram; Sankaran, Vijay G.] Harvard Med Sch, Dana Farber Canc Inst, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Kim, Ah Ram; Sankaran, Vijay G.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Kim, Ah Ram; Sankaran, Vijay G.] MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kim, Ah Ram; Sankaran, Vijay G.] Harvard Univ, Cambridge, MA 02138 USA. RP Sankaran, VG (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. EM sankaran@broadinsitute.org FU National Institutes of Health [R01 DK103794, R33 HL120791] FX This work was funded by the National Institutes of Health (Grants R01 DK103794 and R33 HL120791 to V.G.S.). NR 96 TC 2 Z9 2 U1 14 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD OCT PY 2016 VL 44 IS 10 BP 887 EP 894 DI 10.1016/j.exphem.2016.06.005 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DX3MB UT WOS:000384276100001 PM 27345108 ER PT J AU Liddicoat, BJ Hartner, JC Piskol, R Ramaswami, G Chalk, AM Kingsley, PD Sankaran, VG Wall, M Purton, LE Seeburg, PH Palis, J Orkin, SH Lu, J Li, JB Walkley, CR AF Liddicoat, Brian J. Hartner, Jochen C. Piskol, Robert Ramaswami, Gokul Chalk, Alistair M. Kingsley, Paul D. Sankaran, Vijay G. Wall, Meaghan Purton, Louise E. Seeburg, Peter H. Palis, James Orkin, Stuart H. Lu, Jun Li, Jin Billy Walkley, Carl R. TI Adenosine-to-inosine RNA editing by ADAR1 is essential for normal murine erythropoiesis SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID ENZYME ADAR1; ERYTHROID-DIFFERENTIATION; EXPRESSION PROFILES; SEQUENCING DATA; GENE-REGULATION; NULL MUTATION; MICE; DEAMINASE; MOUSE; INTERFERON AB Adenosine deaminases that act on RNA (ADARs) convert adenosine residues to inosine in double stranded RNA. In vivo, ADAR1 is essential for the maintenance of hematopoietic stem/progenitors. Whether other hematopoietic cell types also require ADAR1 has not been assessed. Using erythroid- and myeloid-restricted deletion of Adar1, we demonstrate that ADAR1 is dispensable for myelopoiesis but is essential for normal erythropoiesis. Adar1-deficient erythroid cells display a profound activation of innate immune signaling and high levels of cell death. No changes in microRNA levels were found in ADAR1-deficient erythroid cells. Using an editing-deficient allele, we demonstrate that RNA editing is the essential function of ADAR1 during erythropoiesis. Mapping of adenosine-to-inosine editing in purified erythroid cells identified clusters of hyperedited adenosines located in long 3'-untranslated regions of erythroid-specific transcripts and these are ADAR1-specific editing events. ADAR1-mediated RNA editing is essential for normal erythropoiesis. Copyright (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. C1 [Liddicoat, Brian J.; Chalk, Alistair M.; Purton, Louise E.; Walkley, Carl R.] St Vincents Inst Med Res, Fitzroy, Vic, Australia. [Liddicoat, Brian J.; Chalk, Alistair M.; Purton, Louise E.; Walkley, Carl R.] Univ Melbourne, St Vincents Hosp, Dept Med, Fitzroy, Vic, Australia. [Hartner, Jochen C.] Taconic Biosci, Cologne, Germany. [Hartner, Jochen C.; Sankaran, Vijay G.; Orkin, Stuart H.] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Oncol, Childrens Hosp Boston,Harvard Stem Cell Inst,Dept, Boston, MA USA. [Hartner, Jochen C.; Sankaran, Vijay G.; Orkin, Stuart H.] Harvard Med Sch, Harvard Stem Cell Inst, Childrens Hosp Boston, Stem Cell Program, Boston, MA USA. [Piskol, Robert; Ramaswami, Gokul; Li, Jin Billy] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Kingsley, Paul D.; Palis, James] Univ Rochester, Med Ctr, Dept Pediat, Ctr Pediat Biomed Res, Rochester, NY 14642 USA. [Wall, Meaghan] St Vincents Hosp, Victorian Canc Cytogenet Serv, Fitzroy, Vic, Australia. [Seeburg, Peter H.] Max Planck Inst Med Res, Dept Mol Neurobiol, Heidelberg, Germany. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA USA. [Lu, Jun] Yale Univ, Dept Genet, New Haven, CT USA. [Lu, Jun] Yale Univ, Yale Stem Cell Ctr, New Haven, CT USA. RP Walkley, CR (reprint author), St Vincents Inst, 9 Princes St, Fitzroy, Vic 3065, Australia. EM cwalkley@svi.edu.au OI Chalk, Alistair/0000-0002-9630-6236 FU Leukaemia Foundation; National Health and Medical Research Council (NHMRC) [APP1021216, APP559016, 1003339]; German Academic Exchange Service; Stanford Dean's Fellowship; Stanford Genome National Institutes of Health Grant [R01GM102484]; Ellison Medical Foundation; Stanford University Department of Genetics; National Institutes of Health [R01HL116364]; Victorian State Government OIS Program FX The authors thank M. Smyth for Ifnar-/- and Ifngr-/-; the SVH BioResources Centre; and the SVI Flow Cytometry Core Facility (M. Thomson). This work was supported by grants from the Leukaemia Foundation (C.R.W.); the Leukaemia Foundation (doctoral scholarship to B.J.L.); the National Health and Medical Research Council (NHMRC Project Grant APP1021216, NHMRC Career Development Award APP559016 to C.R.W.; NHMRC Research Fellowship Grant #1003339 to L.E.P.); the German Academic Exchange Service (postdoctoral fellowship); a Stanford Dean's Fellowship to R.P.; Stanford Genome National Institutes of Health Grant R01GM102484, the Ellison Medical Foundation; Stanford University Department of Genetics (J.B.L.); National Institutes of Health (Grant R01HL116364 to J.P.); and the Victorian State Government OIS Program (to St. Vincent's Institute). S.H.O. is an investigator at the Howard Hughes Medical Institute. C.R.W. was the Leukaemia Foundation Phillip Desbrow Senior Research Fellow. NR 63 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD OCT PY 2016 VL 44 IS 10 BP 947 EP 963 DI 10.1016/j.exphem.2016.06.250 PG 17 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DX3MB UT WOS:000384276100010 PM 27373493 ER PT J AU McGuire, JF Orr, SP Essoe, JKY McCracken, JT Storch, EA Piacentini, J AF McGuire, Joseph F. Orr, Scott P. Essoe, Joey K. -Y. McCracken, James T. Storch, Eric A. Piacentini, John TI Extinction learning in childhood anxiety disorders, obsessive compulsive disorder and post-traumatic stress disorder: implications for treatment SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE Conditioning; extinction; threat; fear; anxiety disorders; obsessive compulsive disorder; post-traumatic stress disorder; adolescence; inhibitory learning; exposure therapy ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; EXPOSURE THERAPY; FEAR EXTINCTION; D-CYCLOSERINE; UNCONDITIONAL STIMULUS; DEVELOPMENTAL ASPECTS; DEPRESSIVE-DISORDERS; RESPONSE PREVENTION; UNPLEASANT SOUND AB Introduction: Threat conditioning and extinction play an important role in anxiety disorders, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). Although these conditions commonly affect children, threat conditioning and extinction have been primarily studied in adults. However, differences in phenomenology and neural architecture prohibit the generalization of adult findings to youth.Areas covered: A comprehensive literature search using PubMed and PsycInfo was conducted to identify studies that have used differential conditioning tasks to examine threat acquisition and extinction in youth. The information obtained from this review helps to clarify the influence of these processes on the etiology and treatment of youth with OCD, PTSD and other anxiety disorders. Thirty studies of threat conditioning and extinction were identifiedExpert commentary: Youth with anxiety disorders, OCD, and PTSD have largely comparable threat acquisition relative to unaffected controls, with some distinctions noted for youth with PTSD or youth who have suffered maltreatment. However, impaired extinction was consistently observed across youth with these disorders and appears to be consistent with deficiencies in inhibitory learning. Incorporating strategies to improve inhibitory learning may improve extinction learning within extinction-based treatments like cognitive behavioral therapy (CBT). Strategies to improve inhibitory learning in CBT are discussed. C1 [McGuire, Joseph F.; McCracken, James T.; Piacentini, John] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 760 Westwood Plaza,48-228B, Los Angeles, CA 90095 USA. [Orr, Scott P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Orr, Scott P.] Harvard Med Sch, Boston, MA 02114 USA. [Essoe, Joey K. -Y.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Storch, Eric A.] Univ S Florida, Dept Pediat, Tampa, FL USA. [Storch, Eric A.] Univ S Florida, Dept Psychiat, Tampa, FL USA. [Storch, Eric A.] Univ S Florida, Dept Behav Neurosci, Tampa, FL USA. [Storch, Eric A.] Univ S Florida, Dept Hlth Policy & Management, Tampa, FL USA. [Storch, Eric A.] Rogers Behav Hlth, Tampa Bay, FL USA. [Storch, Eric A.] Johns Hopkins Med, All Childrens Hosp, St Petersburg, FL USA. RP McGuire, JF (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 760 Westwood Plaza,48-228B, Los Angeles, CA 90095 USA. EM jfmcguire@mednet.ucla.edu FU Tourette Association of American; National Institutes of Mental Health (NIMH) [T32MH073517]; National Institutes of Health/National Institute of Mental Health (NIH/NIMH) [1R21MH101567]; Department of Defense; Department of Veterans Affairs; National Institute of Health [T32MH073517]; Seaside Therapeutics; Roche; Otsuka; National Institute of Mental Health [R01MH093381]; CDC; Agency for Healthcare Research and Quality; IOCDF; All Children's Hospital Research Foundation; Ortho-McNeil Scientific Affairs; All Children's Hospital Guild Endowed Chair; National Institute of Mental Health (NIMH) [T32MH073517]; Tourette Syndrome Association (TSA); Pfizer; Pettit Family Foundation FX JF McGuire receives grant support from the Tourette Association of American and the National Institutes of Mental Health (NIMH) through T32MH073517. The views expressed within this article represent those of the authors, were not influenced by this funding source, and are not intended to represent the position of NIMH. SP Orr receives grant support from the National Institutes of Health/National Institute of Mental Health (NIH/NIMH) in part through 1R21MH101567, Department of Defense, and Department of Veterans Affairs. JT McCracken receives support from the National Institute of Health in part through T32MH073517, Seaside Therapeutics, Roche, and Otsuka. He has served as a consultant to BioMarin and PharmaNet. EA Storch receives grant support from the National Institute of Mental Health in part through R01MH093381, CDC, Agency for Healthcare Research and Quality, IOCDF, All Children's Hospital Research Foundation, and Ortho-McNeil Scientific Affairs. He receives textbook honorarium from Springer publishers, American Psychological Association, Lawrence Erlbaum, Elsevier, and Wiley-Blackwell. He is a consultant for RuiJin Hospital and Rogers Memorial Hospital, and is on the Speaker's Bureau and Scientific Advisory Board for the IOCDF. He receives research support from the All Children's Hospital Guild Endowed Chair. J Piacentini receives support for his work from National Institute of Mental Health (NIMH) in part through T32MH073517, Tourette Syndrome Association (TSA), Pfizer and the Pettit Family Foundation; book royalties from Oxford University Press and Guilford Publications, and speaking honoraria from the Tourette Association of America, International OCD Foundation (IOCDF), and Trichotillomania Learning Center. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 91 TC 0 Z9 0 U1 17 U2 17 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD OCT PY 2016 VL 16 IS 10 BP 1155 EP 1174 DI 10.1080/14737175.2016.1199276 PG 20 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DX2KW UT WOS:000384199400006 PM 27275519 ER PT J AU Chebib, I Rosenberg, AE Fletcher, CDM Rosenthal, DI Hornicek, FJ Nielsen, GP AF Chebib, Ivan Rosenberg, Andrew E. Fletcher, Christopher D. M. Rosenthal, Daniel I. Hornicek, Francis J. Nielsen, G. Petur TI Primary intra-articular sarcoma: a clinicopathological study of 15 cases SO HISTOPATHOLOGY LA English DT Article DE chondrosarcoma; extraskeletal; intra-articular; joint; myxoid; synovial sarcoma ID EXTRASKELETAL MYXOID CHONDROSARCOMA; MYXOINFLAMMATORY FIBROBLASTIC SARCOMA; MALIGNANT FIBROUS HISTIOCYTOMA; SOFT-TISSUE TUMORS; OF-THE-LITERATURE; GIANT-CELL TUMOR; SYNOVIAL SARCOMA; KNEE-JOINT; TEMPOROMANDIBULAR-JOINT; EPITHELIOID SARCOMA AB AimsTo assess the clinical and histopathological spectrum of primary intra-articular sarcomas. Methods and resultsFifteen patients were identified as having primary intra-articular sarcomas and the clinical and pathological features were evaluated. There were nine males and six females who ranged in age from 16 to 84 (mean 44) years. All tumours originated in the knee joint. The pathological diagnoses included: five synovial sarcoma, three extraskeletal myxoid chondrosarcomas, two high-grade myxofibrosarcoma (one conventional, one epithelioid), two undifferentiated pleomorphic sarcoma (one with giant cells) and one each myxoinflammatory fibroblastic sarcoma, conventional hyaline chondrosarcoma, and high-grade myofibroblastic sarcoma. All tumours were treated by segmental resection or amputation. Adjuvant therapy was given in selected cases. Follow-up ranged from 11 to 150 months. Of patients with follow-up, two died of disease; one developed pulmonary metastases after 6 years and was then lost to follow-up. Nine patients were alive and free of disease 12-150 months after diagnosis. ConclusionsPrimary sarcomas of the joints are very rare and most frequently affect the knee. Our experience indicates that synovial sarcoma and extraskeletal myxoid chondrosarcoma are the most common intra-articular sarcomas. C1 [Chebib, Ivan; Nielsen, G. Petur] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Chebib, Ivan; Fletcher, Christopher D. M.; Rosenthal, Daniel I.; Hornicek, Francis J.; Nielsen, G. Petur] Harvard Med Sch, Boston, MA 02114 USA. [Rosenberg, Andrew E.] Univ Miami Hosp, Dept Pathol, Miami, FL USA. [Fletcher, Christopher D. M.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Hornicek, Francis J.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. RP Chebib, I (reprint author), Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA.; Chebib, I (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM ichebib@partners.org NR 50 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD OCT PY 2016 VL 69 IS 4 BP 614 EP 623 DI 10.1111/his.12978 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA DW4IE UT WOS:000383605600010 PM 27028835 ER PT J AU McKelvie, PA Climent, F Krings, G Hasserjian, RP Abramson, JS Pilch, BZ Harris, NL Ferry, JA Zukerberg, LR Sohani, AR AF McKelvie, Penelope A. Climent, Fina Krings, Gregor Hasserjian, Robert P. Abramson, Jeremy S. Pilch, Ben Z. Harris, Nancy Lee Ferry, Judith A. Zukerberg, Lawrence R. Sohani, Aliyah R. TI Small-cell predominant extranodal NK/T cell lymphoma, nasal type: clinicopathological analysis of a series of cases diagnosed in a Western population SO HISTOPATHOLOGY LA English DT Article DE chronic active EBV infection; chronic rhinosinusitis; EBERin-situ hybridization; Epstein-Barr virus; extranodal NK; T cell lymphoma; nasal type ID NATURAL-KILLER-CELL; BARR-VIRUS DISEASE; NEOPLASMS; INFECTION; SINONASAL; DISTINCT AB AimsExtranodal NK/T cell lymphoma, nasal type (ENKTCL) is usually composed of medium- to large-sized lymphoid cells showing prominent angiotrophism and tumour cell necrosis. We report 13 cases composed predominantly of small lymphocytes diagnosed in the United States and Western Europe. Methods and resultsPatients included seven females and six males aged 17-75 years. Ten presented with sinonasal and three with buccal disease. Nine had stage IE/IIE and four had stage IV disease. In five of seven patients with multiple biopsies at different time-intervals, the lymphoma was misinterpreted as representing chronic inflammation on an earlier biopsy. In all cases morphology showed a dense infiltrate of small lymphoid cells with minimal cytological atypia. Necrosis, angioinvasion and angiodestruction were each seen in 17%, 22% and 17% of biopsies. Median Ki67 was 5%. Four patients died of lymphoma 4-16 months after diagnosis, including three of four patients with stage IV disease; seven (54%) are alive with no evidence of disease at a median of 39 months; one patient with stage IV disease is alive at 10 months and one recurred at 17 months. ConclusionsIn sinonasal biopsies with predominantly small lymphocytic infiltrates with admixed chronic inflammation, focal hypercellularity, focal surface ulceration or microscopic bone invasion by small lymphoid cells should alert pathologists to the possibility of small-cell predominant ENKTCL. Awareness of the full histological spectrum of ENKTCL, particularly in non-endemic areas, is important in avoiding a delay in diagnosis and ensuring timely initiation of therapy. C1 [McKelvie, Penelope A.; Hasserjian, Robert P.; Pilch, Ben Z.; Harris, Nancy Lee; Ferry, Judith A.; Zukerberg, Lawrence R.; Sohani, Aliyah R.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [McKelvie, Penelope A.; Hasserjian, Robert P.; Pilch, Ben Z.; Harris, Nancy Lee; Ferry, Judith A.; Zukerberg, Lawrence R.; Sohani, Aliyah R.] Harvard Med Sch, Dept Pathol, Boston, MA USA. [McKelvie, Penelope A.] St Vincents Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [Climent, Fina] Univ Hosp Bellvitge, IDIBELL, Dept Pathol, Barcelona, Spain. [Krings, Gregor] Univ Calif San Francisco, Sch Med, Dept Pathol, San Francisco, CA 94143 USA. [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA USA. [Abramson, Jeremy S.] Harvard Med Sch, Dept Med, Boston, MA USA. RP Sohani, AR (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN 219, Boston, MA 02114 USA. EM arsohani@mgh.harvard.edu NR 24 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD OCT PY 2016 VL 69 IS 4 BP 667 EP 679 DI 10.1111/his.12990 PG 13 WC Cell Biology; Pathology SC Cell Biology; Pathology GA DW4IE UT WOS:000383605600015 PM 27144366 ER PT J AU Jabra-Rizk, MA Kong, EF Tsui, C Nguyen, MH Clancy, CJ Fidel, PL Noverr, M AF Jabra-Rizk, Mary Ann Kong, Eric F. Tsui, Christina Hong Nguyen, M. Clancy, Cornelius J. Fidel, Paul L., Jr. Noverr, Mairi TI Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework SO INFECTION AND IMMUNITY LA English DT Review ID VULVO-VAGINAL CANDIDIASIS; SECRETED ASPARTYL PROTEINASE; INTRAVENOUS CHALLENGE MODEL; INVASIVE FUNGAL-INFECTIONS; INTRAORAL DENTURE SYSTEM; T-CELLS; OROPHARYNGEAL CANDIDIASIS; IMMUNODEFICIENT MICE; ORAL CANDIDIASIS; BLOOD-STREAM AB Historically, the nature and extent of host damage by a microbe were considered highly dependent on virulence attributes of the microbe. However, it has become clear that disease is a complex outcome which can arise because of pathogen-mediated damage, host-mediated damage, or both, with active participation from the host microbiota. This awareness led to the formulation of the damage response framework (DRF), a revolutionary concept that defined microbial virulence as a function of host immunity. The DRF outlines six classifications of host damage outcomes based on the microbe and the strength of the immune response. In this review, we revisit this concept from the perspective of Candida albicans, a microbial pathogen uniquely adapted to its human host. This fungus commonly colonizes various anatomical sites without causing notable damage. However, depending on environmental conditions, a diverse array of diseases may occur, ranging from mucosal to invasive systemic infections resulting in microbe-mediated and/or host-mediated damage. Remarkably, C. albicans infections can fit into all six DRF classifications, depending on the anatomical site and associated host immune response. Here, we highlight some of these diverse and site-specific diseases and how they fit the DRF classifications, and we describe the animal models available to uncover pathogenic mechanisms and related host immune responses. C1 [Jabra-Rizk, Mary Ann; Kong, Eric F.; Tsui, Christina] Univ Maryland, Sch Dent, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA. [Jabra-Rizk, Mary Ann; Kong, Eric F.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Kong, Eric F.] Univ Maryland, Grad Program Life Sci, Mol Microbiol & Immunol Program, Baltimore, MD 21201 USA. [Hong Nguyen, M.; Clancy, Cornelius J.] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Infect Dis Sect, Pittsburgh, PA USA. [Fidel, Paul L., Jr.; Noverr, Mairi] Louisiana State Univ, Sch Dent, Hlth Sci Ctr, Ctr Excellence Oral & Craniofacial Biol, New Orleans, LA 70119 USA. RP Jabra-Rizk, MA (reprint author), Univ Maryland, Sch Dent, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA.; Jabra-Rizk, MA (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM mrizk@umaryland.edu FU HHS \ National Institutes of Health (NIH) [DE14424, DE022069, AI116025] FX This work, including the efforts of Mary Ann Jabra-Rizk, was funded by HHS vertical bar National Institutes of Health (NIH) (DE14424). This work, including the efforts of Mairi C. Noverr, was funded by HHS vertical bar National Institutes of Health (NIH) (DE022069 and AI116025). NR 166 TC 2 Z9 2 U1 8 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2016 VL 84 IS 10 BP 2724 EP 2739 DI 10.1128/IAI.00469-16 PG 16 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DX0TK UT WOS:000384077800001 PM 27430274 ER PT J AU Yamaguchi, T Movila, A Kataoka, S Wisitrasameewong, W Torruella, MR Murakoshi, M Murakami, S Kawai, T AF Yamaguchi, Tsuguno Movila, Alexandru Kataoka, Shinsuke Wisitrasameewong, Wichaya Torruella, Montserrat Ruiz Murakoshi, Michiaki Murakami, Shinya Kawai, Toshihisa TI Proinflammatory M1 Macrophages Inhibit RANKL-Induced Osteoclastogenesis SO INFECTION AND IMMUNITY LA English DT Article ID ALVEOLAR BONE-RESORPTION; IMMUNE-SYSTEM; CELL-DEATH; POLARIZATION; ACTIVATION; INFLAMMATION; EXPRESSION; DIFFERENTIATION; PERIODONTITIS; APOPTOSIS AB In response to a defined panel of stimuli, immature macrophages can be classified into two major phenotypes: proinflammatory (M1) and anti-inflammatory (M2). Although both phenotypes have been implicated in several chronic inflammatory diseases, their direct role in bone resorption remains unclear. The present study investigated the possible effects of M1 and M2 macrophages on RANKL-induced osteoclastogenesis. In osteoclastogenesis assays using RAW264.7 cells or bone marrow cells as osteoclast precursors, addition of M1 macrophages significantly suppressed RANKL-induced osteoclastogenesis compared to nonstimulated conditions (M0), addition of M2 macrophages, or no macrophage addition (P < 0.05), suggesting that M1 macrophages can downregulate osteoclastogenesis. This effect was maintained when direct contact between M1 and osteoclast precursors was interrupted by cell culture insertion, indicating engagement of soluble factors released from M1. M1 macrophages developed from interferon gamma (IFN-gamma) knockout (IFN-gamma-KO) mice lost the ability to downregulate osteoclastogenesis. Antibody-based neutralization of interleukin-12 (IL-12), but not IL-10, produced by M1 macrophages also abrogated M1-mediated downregulation of osteoclastogenesis. Real-time PCR analyses showed that IFN-gamma suppressed gene expression of NFATc1, a master regulator of osteoclastogenesis, whereas IL-12 increased the apoptosis of osteoclasts, suggesting molecular mechanisms underlying the possible roles of IFN-gamma or IL-12 in M1-mediated inhibition of osteoclastogenesis. These findings were confirmed in an in vivo ligature-induced mouse periodontitis model in which adoptive transfer of M1 macrophages showed a significantly lower level of bone loss and less tartrate-resistant acid phosphatase (TRAP)-positive cell induction than M0 or M2 macrophage transfer. In conclusion, by its secretion of IFN-gamma and IL-12, M1, but not M0 or M2, was demonstrated to inhibit osteoclastogenesis. C1 [Yamaguchi, Tsuguno; Movila, Alexandru; Wisitrasameewong, Wichaya; Torruella, Montserrat Ruiz; Kawai, Toshihisa] Forsyth Inst, Cambridge, MA 02142 USA. [Yamaguchi, Tsuguno; Kataoka, Shinsuke; Murakoshi, Michiaki] LION Corp, Res & Dev Headquarters, Kanagawa, Japan. [Wisitrasameewong, Wichaya; Kawai, Toshihisa] Harvard Sch Dent Med, Boston, MA 02115 USA. [Murakami, Shinya] Osaka Univ, Grad Sch Dent, Dept Periodontol, Suita, Osaka, Japan. RP Kawai, T (reprint author), Forsyth Inst, Cambridge, MA 02142 USA.; Kawai, T (reprint author), Harvard Sch Dent Med, Boston, MA 02115 USA. EM tkawai@forsyth.org FU HHS \ NIH \ National Institute of Dental and Craniofacial Research (NIDCR) [DE-018499, DE-019917, T32 DE 7327-12] FX This work, including the efforts of Toshihisa Kawai, was funded by HHS vertical bar NIH vertical bar National Institute of Dental and Craniofacial Research (NIDCR) (DE-018499 and DE-019917). This work, including the efforts of Alexandru Movila, was funded by HHS vertical bar NIH vertical bar National Institute of Dental and Craniofacial Research (NIDCR) (T32 DE 7327-12). NR 41 TC 1 Z9 1 U1 6 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2016 VL 84 IS 10 BP 2802 EP 2812 DI 10.1128/IAI.00461-16 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DX0TK UT WOS:000384077800008 PM 27456834 ER PT J AU Hersh, C Wentland, C Sally, S de Stadler, M Hardy, S Fracchia, MS Liu, B Hartnick, C AF Hersh, Cheryl Wentland, Carissa Sally, Sarah de Stadler, Marie Hardy, Steven Fracchia, M. Shannon Liu, Bob Hartnick, Christopher TI Radiation exposure from videofluoroscopic swallow studies in children with a type 1 laryngeal cleft and pharyngeal dysphagia: A retrospective review SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Review DE Radiation exposure; Dysphagia; Videofluoroscopic swallow study; Laryngeal cleft; Radiation dose; Modified barium swallow; Aspiration ID MANAGEMENT ALGORITHM; DIAGNOSIS; REPAIR; EXPERIENCE AB Introduction: Radiation exposure is recognized as having long term consequences, resulting in increased risks over the lifetime. Children, in particular, have a projected lifetime risk of cancer, which should be reduced if within our capacity. The objective of this study is to quantify the amount of ionizing radiation in care for children being treated for aspiration secondary to a type 1 laryngeal cleft. With this baseline data, strategies can be developed to create best practice pathways to maintain quality of care while minimizing radiation exposure. Methods: Retrospective review of 78 children seen in a tertiary pediatric aerodigestive center over a 5 year period from 2008 to 2013 for management of a type 1 laryngeal cleft. The number of video fluoroscopic swallow studies (VFSS) per child was quantified, as was the mean effective dose of radiation exposure. The 78 children reviewed were of mean age 19.9 mo (range 4 mo-12 years). All children were evaluated at the aerodigestive center with clinical symptomatology and subsequent diagnosis of a type 1 laryngeal cleft. Aspiration was assessed via VFSS and exposure data collected. Imaging exams where dose parameters were not available were excluded. Results: The mean number of VFSS each child received during the total course of treatment was 3.24 studies (range 1-10). The average effective radiation dose per pediatric VFSS was 0.16 mSv (range: 0.03 mSv-0.59 mSv) per study. Clinical significance was determined by comparison to a pediatric CXR. At our facility a CXR yields an effective radiation dose of 0.017 mSv. Therefore, a patient receives an equivalent total of 30.6 CXR over the course of management. Conclusions: Radiation exposure has known detrimental effects particularly in pediatric patients. The total ionizing radiation from VFSS exams over the course of management of aspiration has heretofore not been reported in peer reviewed literature. With this study's data in mind, future developments are indicated to create innovative clinical pathways and limit radiation exposure. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Hersh, Cheryl; Sally, Sarah; de Stadler, Marie] Massachusetts Gen Hosp, Dept Speech Language & Swallowing Disorders, 275 Cambridge St POB 3, Boston, MA 02114 USA. [Wentland, Carissa; Hartnick, Christopher] Massachusetts Eye & Ear Infirm, Pediat Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Hardy, Steven] Massachusetts Gen Hosp, Pediat Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. [Fracchia, M. Shannon] Massachusetts Gen Hosp, Pediat Pulm Div, 275 Cambridge St POB 5, Boston, MA 02114 USA. [Liu, Bob] Massachusetts Gen Hosp, Dept Imaging, 55 Fruit St, Boston, MA 02114 USA. [de Stadler, Marie] Univ Missouri Heath Syst, Dept Rehabil Serv, Columbia, MO 65201 USA. RP Hartnick, C (reprint author), Massachusetts Eye & Ear Infirm, Pediat Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM cjhersh@partners.org; Carissa_Wentland@MEELHARVARD.EDU; ssally2@partners.org; destadlerm@health.missouri.edu; shardy2@mgh.harvard.edu; mfracchia@mgh.harvard.edu; Bliu7@mgh.harvard.edu; christopher_hartnick@meei.harvard.edu OI Liu, Bob/0000-0001-6221-1047 NR 29 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD OCT PY 2016 VL 89 BP 92 EP 96 DI 10.1016/j.ijporl.2016.07.032 PG 5 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DW8VL UT WOS:000383933500018 PM 27619036 ER PT J AU Simonsen, CZ Schmitz, ML Madsen, MH Mikkelsen, IK Chandra, RV Leslie-Mazwi, T Andersen, G AF Simonsen, Claus Z. Schmitz, Marie L. Madsen, Mette H. Mikkelsen, Irene K. Chandra, Ronil V. Leslie-Mazwi, Thabele Andersen, Grethe TI Early neurological deterioration after thrombolysis: Clinical and imaging predictors SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article DE Acute cerebral infarction; emergency treatment of stroke; magnetic resonance imaging; perfusion-weighted imaging; thrombolysis ID ACUTE ISCHEMIC-STROKE; ACUTE MINOR STROKE; INTRAVENOUS THROMBOLYSIS; RANDOMIZED-TRIAL; ALTEPLASE; THERAPY; IMPROVEMENT; OUTCOMES; ASPIRIN; RISK AB Background National Institutes of Health Stroke Scale is the most common scale used in stroke patients. An increase of four points or more within 24h signifies early neurological deterioration. We aimed to establish how often early neurological deterioration occurs in a cohort selected by magnetic resonance imaging and which factors predicted early neurological deterioration. Methods In this single-center study, we collected epidemiological, imaging and outcome data on 569 consecutive patients undergoing reperfusion therapy after magnetic resonance imaging selection. Results Of these, 33 (5.8%) experienced early neurological deterioration. Seven were due to a symptomatic intracerebral hemorrhage, 23 were caused by extension of ischemia on follow-up imaging and three were due to progression on the basis of small vessel disease. Early neurological deterioration was predicted by a larger perfusion lesion, higher blood glucose and presence of large vessel disease. Penumbra occurred in 34% of patients but only 9% of patients with penumbra experienced early neurological deterioration, thus eroding the value of penumbra as an imaging marker. Early neurological deterioration was a poor prognostic sign. Odds ratio for disability or death was 14.9 (95% confidence interval: 6.5-34.0). Conclusion Early neurological deterioration is rare. It originates mainly from ischemic infarct growth rather than from hemorrhage. Concern should be highest in patients with elevated blood glucose, larger perfusion lesions and large vessel disease. Prior aspirin use increases risk of symptomatic intracerebral hemorrhage. C1 [Simonsen, Claus Z.; Schmitz, Marie L.; Andersen, Grethe] Aarhus Univ Hosp, Dept Neurol, Norrebrogade 44, DK-8000 Aarhus C, Denmark. [Madsen, Mette H.] Aarhus Univ Hosp, Dept Neuroradiol, Aarhus, Denmark. [Mikkelsen, Irene K.] Aarhus Univ Hosp, Ctr Functionally Integrat Neurosci, Aarhus, Denmark. [Chandra, Ronil V.] Monash Univ, Monash Hlth, Intervent Neuroradiol, Melbourne, Vic, Australia. [Leslie-Mazwi, Thabele] Massachusetts Gen Hosp, Neuroendovasc Serv, Boston, MA USA. RP Simonsen, CZ (reprint author), Aarhus Univ Hosp, Dept Neurol, Norrebrogade 44, DK-8000 Aarhus C, Denmark. EM clasim@rm.dk NR 22 TC 1 Z9 1 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD OCT PY 2016 VL 11 IS 7 BP 776 EP 782 DI 10.1177/1747493016650454 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DV5IJ UT WOS:000382960200013 PM 27188241 ER PT J AU Adhi, M Bonini, MA Louzada, RN Kuehlewein, L de Carlo, TE Baumal, CR Witkin, AJ Sadda, SR Sarraf, D Reichel, E Duker, JS Waheed, NK AF Adhi, Mehreen Bonini Filho, Marco A. Louzada, Ricardo N. Kuehlewein, Laura de Carlo, Talisa E. Baumal, Caroline R. Witkin, Andre J. Sadda, Srinivas R. Sarraf, David Reichel, Elias Duker, Jay S. Waheed, Nadia K. TI Retinal Capillary Network and Foveal Avascular Zone in Eyes with Vein Occlusion and Fellow Eyes Analyzed With Optical Coherence Tomography Angiography SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE retinal vein occlusion; optical coherence tomography angiography; foveal avascular zone; perifoveal retinal capillary plexus; vascular perfusion ID ACUTE MIDDLE MACULOPATHY; FLUORESCEIN ANGIOGRAPHY; MICROANGIOGRAPHY; ISCHEMIA; SPECTRUM AB PURPOSE. To evaluate the perifoveolar retinal capillary network at different depths and to quantify the foveal avascular zone (FAZ) in eyes with retinal vein occlusion (RVO) compared with their fellow eyes and healthy controls using spectral-domain optical coherence tomography angiography (SD-OCTA). METHODS. We prospectively recruited 23 patients with RVO including 15 eyes with central RVO (CRVO) and 8 eyes with branch RVO (BRVO), their fellow eyes, and 8 age-matched healthy controls (8 eyes) for imaging on prototype OCTA software within RTVue-XR Avanti. The 3 x 3 mm and 6 x 6 mm en face angiograms of superficial and deep retinal capillary plexuses were segmented. Perifoveolar retinal capillary network was analyzed and FAZ was quantified. RESULTS. Decrease in vascular perfusion at the deep plexus was observed in all eyes with CRVO (8/8, 100%) and BRVO (6/6, 100%) without cystoid macular edema, and in 8 of 15 (53%) and 2 of 8 (25%) of the fellow eyes, respectively. Vascular tortuosity was observed in 13 of 15 (87%) CRVO and 5 of 8 (63%) BRVO eyes. Collaterals were seen in 10 of 15 (67%) CRVO and 5 of 8 (63%) BRVO eyes. Mean FAZ area was larger in eyes with RVO than their fellow eyes (1.13 +/- 0.25 mm(2) versus 0.58 +/- 0.28 mm(2); P = 0.007) and controls (1.13 +/- 0.25 mm(2) versus 0.30 +/- 0.09 mm(2); P < 0.0001), and in fellow eyes of RVO patients when compared to controls (0.58 +/- 0.28 mm(2) versus 0.30 +/- 0.09 mm(2); P = 0.01). CONCLUSIONS. Spectral-domain OCTA reveals abnormalities at different levels of perifoveolar retinal capillary network and is able to quantify the FAZ in RVO. Longitudinal studies may be considered to evaluate the clinical utility of OCTA in RVO and other retinal vascular diseases. C1 [Adhi, Mehreen; Bonini Filho, Marco A.; Louzada, Ricardo N.; de Carlo, Talisa E.; Baumal, Caroline R.; Witkin, Andre J.; Reichel, Elias; Duker, Jay S.; Waheed, Nadia K.] Tufts Univ, Sch Med, New England Eye Ctr, Boston, MA 02111 USA. [Adhi, Mehreen; de Carlo, Talisa E.] MIT, Dept Elect Engn, Cambridge, MA 02139 USA. [Adhi, Mehreen; de Carlo, Talisa E.] MIT, Dept Comp Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Adhi, Mehreen; de Carlo, Talisa E.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Bonini Filho, Marco A.; Louzada, Ricardo N.] Minist Educ Brazil, CAPES Fdn, Brasilia, DF, Brazil. [Louzada, Ricardo N.] Univ Fed Goias, Ophthalm Ctr Reference CEROF, Goiania, Go, Brazil. [Kuehlewein, Laura; Sadda, Srinivas R.; Sarraf, David] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Kuehlewein, Laura; Sadda, Srinivas R.] Doheny Eye Inst, 1355 San Pablo St, Los Angeles, CA 90033 USA. [Sarraf, David] Stein Eye Inst, Los Angeles, CA USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. RP Waheed, NK (reprint author), Tufts Med Ctr, New England Eye Ctr, 800 Washington St, Boston, MA 02111 USA. EM nadiakwaheed@gmail.com FU Massachusetts Lions Club Research Fund; CAPES Foundation, Ministry of Education of Brazil, Brasilia, DF, Brazil FX Supported by Massachusetts Lions Club Research Fund and the CAPES Foundation (MABF, RNL), Ministry of Education of Brazil, Brasilia, DF, Brazil. NR 29 TC 0 Z9 0 U1 5 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2016 VL 57 IS 9 BP OCT486 EP OCT494 DI 10.1167/iovs.15-18907 PG 9 WC Ophthalmology SC Ophthalmology GA DW9MY UT WOS:000383985400050 PM 27442342 ER PT J AU Mallery, RM Poolman, P Thurtell, MJ Wang, JK Garvin, MK Ledolter, J Kardon, RH AF Mallery, Robert M. Poolman, Pieter Thurtell, Matthew J. Wang, Jui-Kai Garvin, Mona K. Ledolter, Johannes Kardon, Randy H. TI The Pattern of Visual Fixation Eccentricity and Instability in Optic Neuropathy and Its Spatial Relationship to Retinal Ganglion Cell Layer Thickness SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE fixation; OCT; optic neuropathy; ganglion cell ID RECEPTIVE-FIELD DENSITY; MACULAR DEGENERATION; EYE-MOVEMENTS; COHERENCE TOMOGRAPHY; CENTRAL SCOTOMAS; STARGARDT-DISEASE; LOCI; GLAUCOMA; SENSITIVITY; SEARCH AB PURPOSE. The purpose of this study was to assess whether clinically useful measures of fixation instability and eccentricity can be derived from retinal tracking data obtained during optical coherence tomography (OCT) in patients with optic neuropathy (ON) and to develop a method for relating fixation to the retinal ganglion cell complex (GCC) thickness. METHODS. Twenty-nine patients with ON underwent macular volume OCT with 30 seconds of confocal scanning laser ophthalmoscope (cSLO)-based eye tracking during fixation. Kernel density estimation quantified fixation instability and fixation eccentricity from the distribution of fixation points on the retina. Preferred ganglion cell layer loci (PGCL) and their relationship to the GCC thickness map were derived, accounting for radial displacement of retinal ganglion cell soma from their corresponding cones. RESULTS. Fixation instability was increased in ON eyes (0.21 deg(2)) compared with normal eyes (0.06982 deg(2); P < 0.001), and fixation eccentricity was increased in ON eyes (0.48 degrees) compared with normal eyes (0.24 degrees; P = 0.03). Fixation instability and eccentricity each correlated moderately with logMAR acuity and were highly predictive of central visual field loss. Twenty-six of 35 ON eyes had PGCL skewed toward local maxima of the GCC thickness map. Patients with bilateral dense central scotomas had PGCL in homonymous retinal locations with respect to the fovea. CONCLUSIONS. Fixation instability and eccentricity measures obtained during cSLO-OCT assess the function of perifoveal retinal elements and predict central visual field loss in patients with ON. A model relating fixation to the GCC thickness map offers a method to assess the structure-function relationship between fixation and areas of preserved GCC in patients with ON. C1 [Mallery, Robert M.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Mallery, Robert M.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Mallery, Robert M.; Thurtell, Matthew J.; Kardon, Randy H.] Univ Iowa Hosp & Clin, Dept Ophthalmol & Visual Sci, Iowa City, IA 52242 USA. [Poolman, Pieter; Thurtell, Matthew J.; Wang, Jui-Kai; Garvin, Mona K.; Ledolter, Johannes; Kardon, Randy H.] Iowa City VA Ctr Prevent & Treatment Visual Loss, Iowa City, IA USA. [Wang, Jui-Kai; Garvin, Mona K.] Univ Iowa, Dept Elect & Comp Engn, Iowa City, IA 52242 USA. RP Mallery, RM (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM robert_mallery@meei.harvard.edu FU Iowa City VA Center for the Prevention and Treatment of Visual Loss Grant, Rehabilitation Research & Development (RR&D), VA Office of Research and Development [C9251-C]; Department of Defense [W81XWH-10-1-0736]; Viragh Foundation FX Supported by Iowa City VA Center for the Prevention and Treatment of Visual Loss Grant C9251-C, Rehabilitation Research & Development (RR&D), VA Office of Research and Development; Department of Defense Grant W81XWH-10-1-0736, (Objective Methods to Test Visual Dysfunction in the Presence of Cognitive Impairment); and the Viragh Foundation through collaboration with Elliot Frohman, MD, PhD, and Teresa Frohman, PA (Department of Neurology and Neurotherapeutics, University of Texas Soutwestern Medical Center). NR 25 TC 0 Z9 0 U1 3 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2016 VL 57 IS 9 BP OCT429 EP OCT437 DI 10.1167/iovs.15-18916 PG 9 WC Ophthalmology SC Ophthalmology GA DW9MY UT WOS:000383985400044 ER PT J AU Chen, P Steinman, MA AF Chen, Pei Steinman, Michael A. TI Perception of primary care physicians on the impact of comprehensive geriatric assessment: what is the next step? SO ISRAEL JOURNAL OF HEALTH POLICY RESEARCH LA English DT Editorial Material DE Comprehensive geriatric assessment; Primary care; Consultative medicine; Medical education ID INCREASE ADHERENCE; RANDOMIZED-TRIAL; RECOMMENDATIONS; INTERVENTION AB Older adults are at high risk of developing multimorbidity, and the high levels of clinical and psychosocial complexity in this population pose special challenges for primary care physicians (PCPs). As a way to improve the care for the older adults, a number of health systems have developed programs to provide comprehensive geriatric assessment (CGA), which generally refers to an intensive interprofessional evaluation and management of geriatric syndromes with the goals of maximizing health in aging. Sternberg and Bentur examined the impact of CGA as perceived by PCPs, the PCPs attitude toward CGA, and their satisfaction with CGA. In this commentary, we seek to provide additional context to the current state of outpatient consultative CGA and how it relates to the findings in the study by Sternberg and Bentur. The knowledge gained from this study begs for future investigations, especially in the areas of PCPs' understanding of outpatient consultative CGA, the perceived benefit in health outcomes and actual health outcomes, perceived needs in geriatric consultation, preference in management of complex geriatric syndromes, and interests in continuing education in geriatrics. Insight into these factors could allow for improvement of the current outpatient consultative CGA model and allow for adaption of the model to local needs. C1 [Chen, Pei; Steinman, Michael A.] Univ Calif San Francisco, Div Geriatr, Dept Med, 3333 Calif St,Suite 380, San Francisco, CA 94143 USA. [Steinman, Michael A.] San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. RP Chen, P (reprint author), Univ Calif San Francisco, Div Geriatr, Dept Med, 3333 Calif St,Suite 380, San Francisco, CA 94143 USA. EM pei.chen@ucsf.edu FU Geriatric Workforce Enhancement Program, a Health Resources and Service Administration grant [U1QHP28727]; National Institutes of Health [K24AG049057, P30AG044281] FX Pei Chen is funded by the Geriatric Workforce Enhancement Program, a Health Resources and Service Administration grant (U1QHP28727). Michael A. Steinman is funded by the National Institutes of Health (K24AG049057 and P30AG044281). NR 15 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-4015 J9 ISR J HEALTH POLICY JI Isr. J. Health Policy Res. PD OCT 1 PY 2016 VL 5 AR 46 DI 10.1186/s13584-016-0106-3 PG 4 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DX6PT UT WOS:000384506300001 PM 27733902 ER PT J AU Bassett, IV Coleman, SM Giddy, J Bogart, LM Chaisson, CE Ross, D Jacobsen, MM Robine, M Govender, T Freedberg, KA Katz, JN Walensky, RP Losina, E AF Bassett, Ingrid V. Coleman, Sharon M. Giddy, Janet Bogart, Laura M. Chaisson, Christine E. Ross, Douglas Jacobsen, Margo M. Robine, Marion Govender, Tessa Freedberg, Kenneth A. Katz, Jeffrey N. Walensky, Rochelle P. Losina, Elena TI Sizanani: A Randomized Trial of Health System Navigators to Improve Linkage to HIV and TB Care in South Africa SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE health system navigator; linkage to HIV care; HIV/TB co-infection; South Africa ID SUB-SAHARAN AFRICA; ANTIRETROVIRAL THERAPY; FOLLOW-UP; INFECTED PERSONS; INITIATION; INTERVENTION; METAANALYSIS; ENGAGEMENT; MORTALITY; PROGRAMS AB Background: A fraction of HIV-diagnosed individuals promptly initiate antiretroviral therapy (ART). We evaluated the efficacy of health system navigators for improving linkage to HIV and tuberculosis (TB) care among newly diagnosed HIV-infected outpatients in Durban, South Africa. Methods: We conducted a randomized controlled trial (Sizanani Trial, NCT01188941) among adults (>= 18 years) at 4 sites. Participants underwent TB screening and randomization into a health system navigator intervention or usual care. Intervention participants had an in-person interview at enrollment and received phone calls and text messages over 4 months. We assessed 9-month outcomes via medical records and the National Population Registry. Primary outcome was completion of at least 3 months of ART or 6 months of TB treatment for coinfected participants. Results: Four thousand nine hundred three participants were enrolled and randomized; 1899 (39%) were HIV-infected, with 1146 (60%) ART-eligible and 523 (28%) TB coinfected at baseline. In the intervention, 212 (39% of outcome-eligible) reached primary outcome compared to 197 (42%) in usual care (RR 0.93, 95% CI: 0.80 to 1.08). One hundred thirty-one (14%) HIV-infected intervention participants died compared to 119 (13%) in usual care; death rates did not differ between arms (RR 1.06, 95% CI: 0.84 to 1.34). In the as-treated analysis, participants reached for >= 5 navigator calls were more likely to achieve study outcome. Conclusions: similar to 40% of ART-eligible participants in both study arms reached the primary outcome 9 months after HIV diagnosis. Low rates of engagement in care, high death rates, and lack of navigator efficacy highlight the urgency of identifying more effective strategies for improving HIV and TB care outcomes. C1 [Bassett, Ingrid V.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bassett, Ingrid V.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Bassett, Ingrid V.; Jacobsen, Margo M.; Robine, Marion; Freedberg, Kenneth A.; Walensky, Rochelle P.; Losina, Elena] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Bassett, Ingrid V.; Bogart, Laura M.; Freedberg, Kenneth A.; Walensky, Rochelle P.; Losina, Elena] Harvard Med Sch, Boston, MA USA. [Bassett, Ingrid V.; Bogart, Laura M.; Freedberg, Kenneth A.; Walensky, Rochelle P.; Losina, Elena] Harvard Univ, Ctr AIDS Res, Boston, MA 02115 USA. [Coleman, Sharon M.; Chaisson, Christine E.] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Giddy, Janet; Govender, Tessa] McCord Hosp, Durban, South Africa. [Bogart, Laura M.] Boston Childrens Hosp, Dept Med, Div Gen Pediat, Boston, MA USA. [Ross, Douglas] St Marys Hosp, Durban, South Africa. [Freedberg, Kenneth A.; Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Freedberg, Kenneth A.; Katz, Jeffrey N.] Harvard Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Div Rheumatol, 75 Francis St, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Bassett, IV (reprint author), Massachusetts Gen Hosp, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM ibassett@partners.org FU US National Institute of Mental Health [R01 MH090326]; Harvard University Center for AIDS Research [P30 AI060354]; National Institutes of Health [R01 AI058736, R01 AI093269] FX The trial was funded by the US National Institute of Mental Health R01 MH090326 (IVB). It was supported by the Harvard University Center for AIDS Research P30 AI060354 (IVB) and the National Institutes of Health R01 AI058736 (KAF) and R01 AI093269 (RPW). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the US National Institute of Mental Health. NR 33 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2016 VL 73 IS 2 BP 154 EP 160 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DX1EW UT WOS:000384109800010 PM 27632145 ER PT J AU Jotwani, V Scherzer, R Estrella, MM Jacobson, LP Witt, MD Palella, F Macatangay, B Bennett, M Parikh, CR Ix, JH Shlipak, M AF Jotwani, Vasantha Scherzer, Rebecca Estrella, Michelle M. Jacobson, Lisa P. Witt, Mallory D. Palella, Frank Macatangay, Bernard Bennett, Michael Parikh, Chirag R. Ix, Joachim H. Shlipak, Michael TI Cumulative Tenofovir Disoproxil Fumarate Exposure is Associated With Biomarkers of Tubular Injury and Fibrosis in HIV-Infected Men SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE tenofovir disoproxil fumarate; kidney; biomarker; nephrotoxicity ID GLOMERULAR-FILTRATION-RATE; KIDNEY INJURY; PLASMA-CONCENTRATIONS; ANTIRETROVIRAL-NAIVE; MOLECULE-1 KIM-1; FUNCTION DECLINE; RENAL TOXICITY; URINARY; PHARMACOKINETICS; NECROSIS AB Tenofovir disoproxil fumarate (TDF) can cause kidney damage, but current clinical tests are insensitive for detecting toxicity. Among 884 HIV-infected men enrolled in the Multicenter AIDS Cohort Study, we measured urine biomarkers specific for tubular damage (interleukin-18, kidney injury molecule-1, procollagen type III N-terminal propeptide) and albuminuria. In adjusted analyses, each year of TDF exposure was independently associated with 3.3% higher interleukin-18 (95% CI: 0.8% to 5.8%), 3.4% higher kidney injury molecule-1 (1.1% to 5.7%), and 3.1% higher procollagen type III N-terminal propeptide (0.8% to 5.5%), but not with albuminuria (2.8%; 20.6% to 6.2%). Biomarkers of tubular damage may be more sensitive than albuminuria for detecting toxicity from TDF and other medications. C1 [Jotwani, Vasantha; Scherzer, Rebecca; Shlipak, Michael] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Jotwani, Vasantha; Scherzer, Rebecca; Shlipak, Michael] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Estrella, Michelle M.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Jacobson, Lisa P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Witt, Mallory D.] Harbor UCLA Med Ctr, Dept Med, Div HIV Med, Torrance, CA 90509 USA. [Witt, Mallory D.] Harbor UCLA, Los Angeles Biomed Res Inst, Torrance, CA USA. [Palella, Frank] Northwestern Univ, Dept Med, Div Infect Dis, Chicago, IL 60611 USA. [Macatangay, Bernard] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA USA. [Bennett, Michael] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, Dept Med, Cincinnati, OH 45229 USA. [Parikh, Chirag R.] Yale Univ, Dept Med, Nephrol Sect, New Haven, CT 06520 USA. [Parikh, Chirag R.] Yale Univ, Dept Med, Program Appl Translat Res, New Haven, CT 06520 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol Hypertens, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Dept Med, Nephrol Sect, San Diego, CA USA. RP Jotwani, V (reprint author), San Francisco VA Med Ctr, 4150 Clement St Box 111A1, San Francisco, CA USA. EM vasantha.jotwani@ucsf.edu FU Veterans Affairs Medical Center, San Francisco, CA [5 F32 DK103451-02]; National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); National Heart, Lung, and Blood Institute (NHLBI); National Institute on Deafness and Communication Disorders (NIDCD); [1 R01 AG034853-01A2] FX The MACS Kidney Study is funded by grant 1 R01 AG034853-01A2 (PI, Shlipak), which was administered by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs Medical Center, San Francisco, CA, and by grant 5 F32 DK103451-02 (PI, Jotwani), which was administered by the University of California, San Francisco. Data in this article were collected by the Multicenter AIDS Cohort Study (MACS) with centers at Baltimore (U01-AI35042): The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick (PI), Jay Bream, Todd Brown, Barbara Crain, Adrian Dobs, Richard Elion, Richard Elion, Michelle Estrella, Lisette Johnson-Hill, Sean Leng, Anne Monroe, Cynthia Munro, Michael W. Plankey, Wendy Post, Ned Sacktor, Jennifer Schrack, Chloe Thio; Chicago (U01-AI35039): Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: Steven M. Wolinsky (PI), John P. Phair, Sheila Badri, Dana Gabuzda, Frank J. Palella, Jr., Sudhir Penugonda, Susheel Reddy, Matthew Stephens, Linda Teplin; Los Angeles (U01-AI35040): University of California, UCLA Schools of Public Health and Medicine: Roger Detels (PI), Otoniel Martinez-Maza (Co-PI), Aaron Aronow, Peter Anton, Robert Bolan, Elizabeth Breen, Anthony Butch, Shehnaz Hussain, Beth Jamieson, Eric N. Miller, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, Zuo Feng Zhang; Pittsburgh (U01-AI35041): University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (PI), Lawrence A. Kingsley (Co-PI), James T. Becker, Phalguni Gupta, Kenneth Ho, Susan Koletar, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, Ronald D. Stall; Data Coordinating Center (UM1-AI35043): The Johns Hopkins University Bloomberg School of Public Health: Lisa P. Jacobson (PI), Gypsyamber D'Souza (Co-PI), Alison, Abraham, Keri Althoff, Jennifer Deal, Priya Duggal, Sabina Haberlen, Alvaro Muoz, Derek Ng, Janet Schollenberger, Eric C. Seaberg, Sol Su, Pamela Surkan. Institute of Allergy and Infectious Diseases: Robin E. Huebner; National Cancer Institute: Geraldina Dominguez. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR001079 (JHU ICTR) from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), Johns Hopkins ICTR, or NCATS. The MACS website is located at http://www.statepi.jhsph.edu/macs/macs.html. NR 52 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2016 VL 73 IS 2 BP 177 EP 181 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DX1EW UT WOS:000384109800013 PM 27088295 ER PT J AU Sudfeld, CR Lei, QH Chinyanga, Y Tumbare, E Khan, N Dapaah-Siakwan, F Sebaka, A Sibiya, J van Widenfelt, E Shapiro, RL Makhema, J Fawzi, WW Powis, KM AF Sudfeld, Christopher R. Lei, Quanhong Chinyanga, Yvonne Tumbare, Esther Khan, Nealia Dapaah-Siakwan, Fredrick Sebaka, Abia Sibiya, Jacinta van Widenfelt, Erik Shapiro, Roger L. Makhema, Joseph Fawzi, Wafaie W. Powis, Kathleen M. TI Linear Growth Faltering Among HIV-Exposed Uninfected Children SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; child; malnutrition; stunting; birth weight; infant ID MIDDLE-INCOME COUNTRIES; PROSPECTIVE COHORT; FEEDING PRACTICES; INFECTED MOTHERS; INFANTS; MORTALITY; WOMEN; BOTSWANA; ZAMBIA; BORN AB Background: HIV-exposed uninfected (HEU) children experience increased mortality compared with their HIV-unexposed uninfected (HUU) peers. It is unclear whether HEU children are also at increased risk for undernutrition, a modifiable risk factor for mortality. Methods: We conducted a cross-sectional, population-based survey of children,5 years of age in 5 health districts in Botswana. Linear mixed-effects models were used to assess continuous outcomes, and generalized estimating equations were used to estimate relative risks of stunting, wasting, and underweight between HEU (n = 396) and HUU (n = 1109) children. Secondary analyses examined potential mediation by low birth weight. Results: The association between maternal HIV exposure and child stunting varied significantly by child age (P < 0.01). HEU children <1 and >= 2 years of age had 1.85 [95% confidence interval (CI): 1.03 to 3.31; P = 0.04] and 1.41 (95% CI: 1.06 to 1.88; P = 0.02) times the risk of stunting compared with HUU children after multivariate adjustment, respectively. During the period of 1-2 years of age, when breastfeeding cessation occurred among HUU children, HUU children had increased risk of stunting compared with HEU children who were predominantly formula fed (relative risk: 1.56; 95% CI: 1.05 to 2.32; P = 0.03). A mediation analysis estimated that 67% of the excess risk of stunting among HEU children >= 2 years was attributable to low birth weight (P = 0.02). There was no difference in risk of wasting or underweight. Conclusion: HEU children are at increased risk of stunting compared with their HUU peers; however, interventions to increase birth weight may significantly ameliorate this excess risk. Interventions to support optimal growth during weaning are needed for all breast-fed children. C1 [Sudfeld, Christopher R.; Fawzi, Wafaie W.] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Lei, Quanhong] TransMedics, Andover, MA USA. [Chinyanga, Yvonne] Botswana Minist Hlth, Div Nutr & Food Control, Gaborone, Botswana. [Tumbare, Esther; Sebaka, Abia; Sibiya, Jacinta] Elizabeth Glaser Pediat AIDS Fdn, Dept Neonatol, Masero, Lesotho. [Khan, Nealia; Shapiro, Roger L.; Powis, Kathleen M.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Dapaah-Siakwan, Fredrick] Univ Miami, Holtz Childrens Hosp, Miami, FL USA. [van Widenfelt, Erik; Shapiro, Roger L.; Makhema, Joseph; Powis, Kathleen M.] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. [Powis, Kathleen M.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Powis, Kathleen M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP Powis, KM (reprint author), 125 Nashua St,Off 8426, Boston, MA 02114 USA. EM kpowis@mgh.harvard.edu FU Centers for Disease Control and Prevention; National Institute of Child Health and Human Development [K23HD070774] FX Supported by the Centers for Disease Control and Prevention. K.M.P. received salary support from the National Institute of Child Health and Human Development (K23HD070774). NR 36 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2016 VL 73 IS 2 BP 182 EP 189 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DX1EW UT WOS:000384109800014 PM 27116046 ER PT J AU Herrin, M Tate, JP Akgun, KM Butt, AA Crothers, K Freiberg, MS Gibert, CL Leaf, DA Rimland, D Rodriguez-Barradas, MC Ruser, CB Herold, KC Justice, AC AF Herrin, Melissa Tate, Janet P. Akgun, Kathleen M. Butt, Adeel A. Crothers, Kristina Freiberg, Matthew S. Gibert, Cynthia L. Leaf, David A. Rimland, David Rodriguez-Barradas, Maria C. Ruser, Chris B. Herold, Kevan C. Justice, Amy C. TI Weight Gain and Incident Diabetes Among HIV-Infected Veterans Initiating Antiretroviral Therapy Compared With Uninfected Individuals SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE diabetes; HIV; weight gain; obesity; veterans; inflammation ID INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; RISK-FACTORS; BODY-MASS; OBESITY; MELLITUS; COHORT; HAART; INFLAMMATION AB Background: The health implications of weight gain after antiretroviral therapy (ART) for HIV infection are not well characterized and may differ from weight gain among uninfected individuals. We use data from the Veterans Aging Cohort Study to determine whether weight gain after ART has a similar association with incident type 2 diabetes mellitus (DM) as weight gained among HIV-uninfected (uninfected) individuals. Methods: We explored associations of weight gain and incident diabetes (A1c >= 6.5%), in the Veterans Aging Cohort Study, a national observational study of HIV-infected (HIV+) individuals demographically matched 1: 2 to uninfected controls. From 2000 to 2011, weight change was assessed in the year following ART initiation for HIV+ individuals and date of first available body mass index for uninfected individuals. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for baseline body mass index using Cox regression. Results: HIV+ individuals had lower prevalence of DM at baseline (12% HIV+, 23% uninfected) and lower incident diabetes (5% HIV +, 11% uninfected). The association of weight gain with risk of DM was linear for HIV+ and uninfected but the slope of the association was steeper for HIV+. For each 5 pounds of weight gained, HIV+ had 14% increased risk of DM (HR, 1.14; 95% CI: 1.10 to 1.17) and uninfected individuals had 8% increased risk (HR, 1.08; 95% CI: 1.07 to 1.10) (P < 0.01 for interaction). Conclusions: Weight gained in the first year after ART initiation is associated with greater risk of DM than that among uninfected individuals. HIV+ individuals initiating ART who are not underweight should avoid substantial weight gain. C1 [Herrin, Melissa; Tate, Janet P.; Ruser, Chris B.; Justice, Amy C.] VA Connecticut Healthcare Syst, Internal Med, West Haven, CT USA. [Herrin, Melissa; Tate, Janet P.; Ruser, Chris B.] Yale Univ, Sch Med, Internal Med, New Haven, CT USA. [Akgun, Kathleen M.] VA Connecticut Healthcare Syst, Dept Internal Med & Gen Internal Med, West Haven, CT USA. [Akgun, Kathleen M.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Butt, Adeel A.] Univ Pittsburgh, Sch Med, Infect Dis, Doha, Qatar. [Butt, Adeel A.; Freiberg, Matthew S.] VA Pittsburgh Healthcare Syst, Infect Dis, Pittsburgh, PA USA. [Butt, Adeel A.] Hamad Med Corp, Doha, Qatar. [Crothers, Kristina] Univ Washington, Sch Med, Pulm & Crit Care Med, Seattle, WA USA. [Freiberg, Matthew S.] Vanderbilt Univ, Sch Med, Cardiovasc Med, Nashville, TN 37212 USA. [Gibert, Cynthia L.] George Washington Univ, Sch Med & Hlth Sci, Internal Med Infect Dis, Washington, DC 20052 USA. [Gibert, Cynthia L.] Vet Affairs Med Ctr, Med Serv Infect Dis, Internal Med Infect Dis, 50 Irving St NW, Washington, DC 20422 USA. [Leaf, David A.] VA Greater Los Angeles Healthcare Syst, Infect Dis, Los Angeles, CA USA. [Leaf, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Infect Dis, Los Angeles, CA 90095 USA. [Rimland, David] VA Med Ctr, Infect Dis, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Infect Dis, Atlanta, GA USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey Vet Affairs VA Med Ctr, Infect Dis Sect, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Herold, Kevan C.] Yale Univ, Sch Med, Yale Diabet Ctr, Immunol,Endocrinol, New Haven, CT USA. [Justice, Amy C.] Yale Univ, Sch Med & Publ Hlth, Internal Med, New Haven, CT USA. RP Justice, AC (reprint author), Vet Affairs Med Ctr, West Haven 950 Campbell Ave,Bldg 35a Room 2-212, West Haven, CT 06516 USA. EM amy.justice2@va.gov OI Crothers, Kristina/0000-0001-9702-0371 FU National Institutes of Health: AHRQ [R01-HS018372]; National Institute on Alcohol Abuse and Alcoholism [U24-AA020794, U01-AA020790, U01-A020795, U01-AA020799, U24-AA022001, U24 AA022007, U10 AA013566-completed]; National Heart and Lung Blood Institute [R01-HL095136, R01-HL090342]; National Institute of Allergy and Infectious Disease [U01-A1069918]; National Institute on Drug Abuse [R01DA035616]; Veterans Health Administration Office of Research and Development [VA REA 08-266]; VA IRR Merit Award; VISN1 CDA [V1CDA2012-20] FX Supported by National Institutes of Health: AHRQ (R01-HS018372), National Institute on Alcohol Abuse and Alcoholism (U24-AA020794, U01-AA020790, U01-A020795, U01-AA020799, U24-AA022001, U24 AA022007, and U10 AA013566-completed), National Heart and Lung Blood Institute (R01-HL095136; R01-HL090342), National Institute of Allergy and Infectious Disease (U01-A1069918), National Institute on Drug Abuse (R01DA035616), and the Veterans Health Administration Office of Research and Development (VA REA 08-266, VA IRR Merit Award; VISN1 CDA (V1CDA2012-20)). NR 44 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2016 VL 73 IS 2 BP 228 EP 236 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DX1EW UT WOS:000384109800020 PM 27171741 ER PT J AU Vartoukian, SR Moazzez, RV Paster, BJ Dewhirst, FE Wade, WG AF Vartoukian, S. R. Moazzez, R. V. Paster, B. J. Dewhirst, F. E. Wade, W. G. TI First Cultivation of Health-Associated Tannerella sp HOT-286 (BU063) SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE culture; microbiome; periodontitis; isolation; dental plaque; bacteriology ID UNCULTURED MICROORGANISMS; PERIODONTAL HEALTH; BACTERIA; DISEASE; SIDEROPHORES; PHYLOTYPE; FORSYTHIA; PLAQUE AB Despite significant advances in recent years in culture-independent molecular microbiology methods, the detailed study of individual bacterial species still relies on having pure cultures in the laboratory. Yet, more than a third of the approximately 700 bacterial taxa found in the human oral cavity are as yet uncultivated in vitro. One such taxon, Tannerella sp. HOT-286 (phylotype BU063), is the focus of much interest since it is associated with periodontal health, while Tannerella forsythia, its closest phylogenetic neighbor, is strongly associated with periodontal disease. HOT-286, however, has remained uncultivated despite the efforts of several research groups, spanning over a decade. The aim of this study was to cultivate Tannerella sp. HOT-286. A heavily diluted sample of subgingival plaque was inoculated onto culture plates supplemented with siderophores (pyoverdines-Fe complex or desferricoprogen) or a neat plaque suspension. After 8 d of anaerobic incubation, microcolonies and colonies showing satellitism were passaged onto fresh culture plates cross-streaked with potential helper strains or onto cellulose-acetate membranes placed over lawn cultures of helper strains. Subcultured colonies were identified by 16S rRNA gene sequencing, and purity was confirmed by sequencing 20 clones per library prepared from a single colony. Three colonies of interest (derived from pyoverdines- and plaque-supplemented plates) were identified as Tannerella sp. HOT-286. The isolates were found to be incapable of independent growth, requiring helpers such as Propionibacterium acnes and Prevotella intermedia for stimulation, with best growth on membranes over helper lawns. A representative isolate was subjected to phenotypic characterization and found to produce a range of glycosidic and proteolytic enzymes. Further comparison of this novel periodontal health-associated taxon with T. forsythia will be valuable in investigating virulence factors of the latter and possible health benefits of the former. C1 [Vartoukian, S. R.; Wade, W. G.] Queen Mary Univ London, Barts & London Sch Med & Dent, London, England. [Moazzez, R. V.] Kings Coll London, Inst Dent, London, England. [Paster, B. J.; Dewhirst, F. E.; Wade, W. G.] Forsyth Inst, Cambridge, MA USA. [Paster, B. J.; Dewhirst, F. E.] Harvard Sch Dent Med, Boston, MA USA. RP Wade, WG (reprint author), Queen Mary Univ London, Blizard Inst, Ctr Immunobiol, 4 Newark St, London E1 2AT, England. EM w.wade@qmul.ac.uk FU National Institute of Dental and Craniofacial Research of the National Institutes of Health [R37DE016937, R01DE 024468] FX Research reported in this publication was supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health under awards R37DE016937 and R01DE 024468. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors wish to thank Dr. J. Aldridge Taylor for collecting the subgingival plaque sample used in this study. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 32 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD OCT PY 2016 VL 95 IS 11 BP 1308 EP 1313 DI 10.1177/0022034516651078 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DX5XU UT WOS:000384456800014 PM 27193146 ER PT J AU Lanier-Bohan, EM Heath, SL AF Lanier-Bohan, Elaine M. Heath, Susan L. TI Patient and Caregiver Perspectives of Preoperative Teaching for Deep Brain Stimulation Surgery SO JOURNAL OF NEUROSCIENCE NURSING LA English DT Article DE deep brain stimulation; dystonia; essential tremor; Parkinson disease; preoperative teaching ID PRIMARY HEADACHE DISORDERS; SUBTHALAMIC NUCLEUS; PSYCHOEDUCATIONAL INTERVENTIONS; PARKINSON-DISEASE; METAANALYSIS; OUTCOMES; NEUROMODULATION; NEUROSTIMULATION; MECHANISMS; HISTORY AB Deep brain stimulation (DBS) has developed into an important therapy for Parkinson disease, essential tremor, and dystonia with more nurses in varied settings often preparing patients and families for this type of surgery. This exploratory study sought to obtain patient and caregiver perspectives of the current DBS teaching for Parkinson disease, essential tremor, and dystonia; to improve the teaching; and to standardize the education. Using survey methodology, 41 patients with movement disorder and 32 caregivers completed surveys about the preoperative instructions they received. Data analysis calculated frequencies for response rate, demographic information, multiple-choice questions, and Likert scale responses. Fill-in questions were summarized. Results overall showed that, because of the teaching, two thirds of patients and nearly two thirds of caregivers felt fully prepared for the DBS surgery. Patients' and caregivers' suggested recommendations for nurses and surgeons included requests for specific information such as attention to delivery of the education, more individualized care during the education, attention to pain during and after procedure, and postdischarge follow-up. The study identified unmet patient and caregiver needs, resulted in changes in practice, and serves as a guide toward standardization of educational approach and/or content. C1 [Lanier-Bohan, Elaine M.; Heath, Susan L.] San Francisco VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, San Francisco, CA 94121 USA. [Lanier-Bohan, Elaine M.] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. RP Lanier-Bohan, EM (reprint author), San Francisco VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, San Francisco, CA 94121 USA.; Lanier-Bohan, EM (reprint author), Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. EM elainelb1949@gmail.com NR 29 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0888-0395 EI 1945-2810 J9 J NEUROSCI NURS JI J. Neurosci. Nurs. PD OCT PY 2016 VL 48 IS 5 BP 247 EP 255 DI 10.1097/JNN.0000000000000221 PG 9 WC Clinical Neurology; Nursing SC Neurosciences & Neurology; Nursing GA DX4BT UT WOS:000384324600005 PM 27579958 ER PT J AU Small, A Gist, D Souza, D Dalton, J Magny-Normilus, C David, D AF Small, Alison Gist, Diana Souza, Danielle Dalton, Joanne Magny-Normilus, Cherlie David, Daniel TI Using Kotter's Change Model for Implementing Bedside Handoff: A Quality Improvement Project SO JOURNAL OF NURSING CARE QUALITY LA English DT Article ID IMPROVING PATIENT SAFETY; SHIFT HANDOFFS; HEALTH-CARE; MNEMONICS C1 [Small, Alison; Gist, Diana; Souza, Danielle] Beth Israel Deaconess Med Ctr, Dept Nursing, Deaconness Rd, Boston, MA 02215 USA. [Dalton, Joanne; Magny-Normilus, Cherlie] Regis Coll, Sch Nursing, Weston, MA USA. [David, Daniel] San Francisco VA Med Ctr, Palliat & Extended Care Serv, San Francisco, CA USA. RP Small, A (reprint author), Beth Israel Deaconess Med Ctr, Dept Nursing, Deaconness Rd, Boston, MA 02215 USA. EM asmall@bidmc.harvard.edu NR 35 TC 0 Z9 0 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1057-3631 EI 1550-5065 J9 J NURS CARE QUAL JI J. Nurs. Care Qual. PD OCT-DEC PY 2016 VL 31 IS 4 BP 304 EP 309 DI 10.1097/NCQ.0000000000000212 PG 6 WC Nursing SC Nursing GA DX1NW UT WOS:000384135100003 PM 27500693 ER PT J AU Nelson, S Cloonan, L Kanakis, AS Fitzpatrick, KM Shideler, KI Perilla, AS Furie, KL Rost, NS AF Nelson, Sarah Cloonan, Lisa Kanakis, Allison S. Fitzpatrick, Kaitlin M. Shideler, Kelsey I. Perilla, Adriana S. Furie, Karen L. Rost, Natalia S. TI Antecedent Aspirin Use Is Associated with Less Severe Symptoms on Admission for Ischemic Stroke SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Brain infarction; aspirin; glucose; atrial fibrillation; blood pressure ID NONVALVULAR ATRIAL-FIBRILLATION; WHITE-MATTER LESIONS; LOW-DOSE ASPIRIN; ACETYLSALICYLIC-ACID; CEREBRAL-ISCHEMIA; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; ANTIPLATELET AGENTS; PLATELET ACTIVATION; PRIMARY PREVENTION AB Background: Aspirin is known to reduce stroke risk; however, its role in reducing severity of ischemic syndrome is not clear. We sought to investigate the relationship between antecedent aspirin use and stroke severity in patients presenting with acute ischemic stroke (AIS). Methods: We retrospectively analyzed a prospectively collected database of consecutive AIS patients presenting to our center. Clinical characteristics (including antecedent aspirin use), imaging findings, and laboratory data were assessed in association with presenting stroke severity, as measured by the National Institutes of Health Stroke Scale (NIHSS). Logistic regression models were used to determine univariate and multivariate predictors of baseline NIHSS. Results: Of the 610 AIS patients with admission brain magnetic resonance imaging available for volumetric analysis of acute infarct size, 241 (39.5%) used aspirin prior to stroke onset. Antecedent aspirin use (P = .0005), history of atrial fibrillation (P < .0001), acute infarct volume (P < .0001), initial systolic blood pressure (P = .041), admission glucose level (P = .0027), and stroke subtype (P < .0001) were associated with presenting stroke severity in univariate analysis. Antecedent aspirin use (P < .0001), history of atrial fibrillation (P < .0002), acute infarct volume (P < .0001), systolic blood pressure (P = .038), and glucose level (P = .0095) remained independent predictors of NIHSS in multivariable analysis. Conclusions: Antecedent aspirin use was independently associated with milder presenting stroke severity, even after accounting for acute infarct volume. While the underlying biology of this apparent protective relationship requires further study, patients at high risk of stroke may benefit from routine aspirin use. C1 [Nelson, Sarah; Cloonan, Lisa; Kanakis, Allison S.; Fitzpatrick, Kaitlin M.; Shideler, Kelsey I.; Perilla, Adriana S.; Rost, Natalia S.] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Furie, Karen L.] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Neurol, Providence, RI 02903 USA. RP Nelson, S (reprint author), 55 Fruit St, Boston, MA 02114 USA. EM senelson13@gmail.com FU NIH-NINDS [R01NS082285, R01NS086905] FX Dr. Rost is in part supported by NIH-NINDS (R01NS082285 and R01NS086905). NR 55 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD OCT PY 2016 VL 25 IS 10 BP 2519 EP 2525 DI 10.1016/j.jstrokecerebrovasdis.2016.06.032 PG 7 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DX0AS UT WOS:000384024500040 PM 27444522 ER PT J AU Ozaki, M Kang, YL Tan, YS Pavlov, VI Liu, BH Boyle, DC Kushak, RI Skjoedt, MO Grabowski, EF Taira, Y Stahl, GL AF Ozaki, Masayuki Kang, Yulin Tan, Ying Siow Pavlov, Vasile I. Liu, Bohan Boyle, Daniel C. Kushak, Rafail I. Skjoedt, Mikkel-Ole Grabowski, Eric F. Taira, Yasuhiko Stahl, Gregory L. TI Human mannose-binding lectin inhibitor prevents Shiga toxin-induced renal injury SO KIDNEY INTERNATIONAL LA English DT Article DE antibody; complement activation; deposition; fibrin; lectin pathway ID HEMOLYTIC-UREMIC SYNDROME; ALTERNATIVE COMPLEMENT PATHWAY; ESCHERICHIA-COLI O157-H7; TISSUE FACTOR; ARTERIAL THROMBOGENESIS; MYOCARDIAL INJURY; OXIDATIVE STRESS; IGA NEPHROPATHY; MURINE MODEL; STEC-HUS AB Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coil (STEC HUS) is a worldwide endemic problem, and its pathophysiology is not fully elucidated. Here we tested whether the mannose-binding lectin (MBL2), an initiating factor of lectin complement pathway activation, plays a crucial role in STEC HUS. Using novel human MBL2-expressing mice (MBL2 KI) that lack murine Mbls (MBL2(+/+)Mbl1(-/-)Mbl2(-/-), a novel STEC HUS model consisted of an intraperitoneal injection with Shiga toxin-2 (Stx-2) with or without anti-MBL2 antibody (3F8, intraperitoneal). Stx-2 induced weight loss, anemia, and thrombocytopenia and increased serum creatinine, free serum hemoglobin, and cystatin C levels, but a significantly decreased glomerular filtration rate compared with control/sham mice. Immunohistochemical staining revealed renal C3d deposition and fibrin deposition in glomeruli in Stx-2-injected mice. Treatment with 3F8 completely inhibited serum MBL2 levels and significantly attenuated Stx-2 induced-renal injury, free serum hemoglobin levels, renal C3d, and fibrin deposition and preserved the glomerular filtration rate. Thus, MBL2 inhibition significantly protected against complement activation and renal injury induced by Stx-2. This novel mouse model can be used to study the role of complement, particularly lectin pathway-mediated complement activation, in Stx-2-induced renal injury. C1 [Ozaki, Masayuki; Kang, Yulin; Tan, Ying Siow; Pavlov, Vasile I.; Skjoedt, Mikkel-Ole; Stahl, Gregory L.] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, Boston, MA USA. [Ozaki, Masayuki; Taira, Yasuhiko] St Marianna Univ, Dept Emergency & Crit Care Med, Sch Med, Kawasaki, Kanagawa, Japan. [Liu, Bohan; Boyle, Daniel C.; Kushak, Rafail I.; Grabowski, Eric F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pediat, Cardiovasc Thrombosis Lab, Boston, MA USA. [Skjoedt, Mikkel-Ole] Rigshosp, Univ Copenhagen Hosp, Dept Clin Immunol, Copenhagen, Denmark. [Skjoedt, Mikkel-Ole] Rigshosp, Univ Copenhagen Hosp, Tissue Typing Lab, Copenhagen, Denmark. RP Stahl, GL (reprint author), Harvard Inst Med, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, HIM 845A,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM gstahl@partners.org OI Skjodt, Mikkel-Ole/0000-0003-1306-6482 FU National Institutes of Health [AI089781, HL056086] FX This work was supported by grants National Institutes of Health AI089781 and HL056086. The authors acknowledge the expert technical assistance of Margaret Morrissey during the course of these studies. NR 66 TC 2 Z9 2 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD OCT PY 2016 VL 90 IS 4 BP 774 EP 782 DI 10.1016/j.kint.2016.05.011 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DX4ZE UT WOS:000384388800013 PM 27378476 ER PT J AU Taber, DJ Gebregziabher, M Hunt, KJ Srinivas, T Chavin, KD Baliga, PK Egede, LE AF Taber, David J. Gebregziabher, Mulugeta Hunt, Kelly J. Srinivas, Titte Chavin, Kenneth D. Baliga, Prabhakar K. Egede, Leonard E. TI Twenty years of evolving trends in racial disparities for adult kidney transplant recipients SO KIDNEY INTERNATIONAL LA English DT Article DE African American; graft loss; kidney transplant; racial disparities ID RENAL-ALLOGRAFT SURVIVAL; DELAYED GRAFT FUNCTION; AFRICAN-AMERICAN; ETHNIC DISPARITIES; PATIENT SURVIVAL; RECEIVING SIROLIMUS; STEROID WITHDRAWAL; ORGAN TRANSPLANT; UNITED-STATES; OUTCOMES AB Disparities in outcomes for African American (AA) kidney transplant recipients have persisted for 40 years without a comprehensive analysis of evolving trends in the risks associated with this disparity. Here we analyzed U.S. transplant registry data, which included adult Caucasian or AA solitary kidney recipients undergoing transplantation between 1990 and 2009 comprising 202,085 transplantations. During this 20-year period, the estimated rate of 5-year graft loss decreased from 27.6% to 12.8%. Notable trends in baseline characteristics that significantly differed by race over time included the following: increased prevalence of diabetes from 2001 to 2009 in AAs (5-year slope difference: 3.4%), longer time on the waiting list (76.5 more days per 5 years in AAs), fewer living donors in AAs from 2003 to 2009 (5-year slope difference: -3.36%), more circulatory death donors in AAs from 2000-09 (5-year slope difference: 1.78%), and a slower decline in delayed graft function in AAs (5-year slope difference: 0.85%). The absolute risk difference between AAs and Caucasians for 5-year graft loss significantly declined over time (-0.92% decrease per 5 years), whereas the relative risk difference actually significantly increased (3.4% increase per 5 years). These results provide a mixed picture of both promising and concerning trends in disparities for AA kidney transplant recipients. Thus, although the disparity for graft loss has significantly improved, equity is still far off, and other disparities, including living donation rates and delayed graft function rates, have widened during this time. C1 [Taber, David J.; Chavin, Kenneth D.; Baliga, Prabhakar K.] Med Univ South Carolina, Div Transplant Surg, Coll Med, Charleston, SC USA. [Taber, David J.] Ralph H Johnson VAMC, Dept Pharm Serv, Charleston, SC USA. [Gebregziabher, Mulugeta; Hunt, Kelly J.] Med Univ South Carolina, Dept Publ Hlth Sci, Coll Med, Charleston, SC USA. [Srinivas, Titte] Med Univ South Carolina, Div Transplant Nephrol, Coll Med, Charleston, SC USA. [Egede, Leonard E.] Ralph H Johnson VAMC, Vet Affairs HSR&D Hlth Equ & Rural Outreach Innov, Charleston, SC USA. RP Taber, DJ (reprint author), Med Univ South Carolina, Div Transplant Surg, 96 Jonathan Lucas St,MSC 611, Charleston, SC 29425 USA. EM taberd@musc.edu OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [K23DK099440] FX Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number K23DK099440. NR 44 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD OCT PY 2016 VL 90 IS 4 BP 878 EP 887 DI 10.1016/j.kint.2016.06.029 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DX4ZE UT WOS:000384388800024 PM 27555121 ER PT J AU Hirsch, JA Chandra, RV AF Hirsch, Joshua A. Chandra, Ronil V. TI Resurrection of evidence for vertebroplasty? SO LANCET LA English DT Editorial Material ID NEUROINTERVENTIONAL SURGERY; PERCUTANEOUS VERTEBROPLASTY; VERTEBRAL AUGMENTATION; RANDOMIZED-TRIAL; FRACTURES; SOCIETY; SPINE C1 [Hirsch, Joshua A.] Massachusetts Gen Hosp, Neuroendovasc Program, Boston, MA 02114 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, NeuroIntervent Spine Serv, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Med Sch, Boston, MA 02115 USA. [Chandra, Ronil V.] Monash Hlth, Monash Imaging, Diagnost & Intervent Neuroradiol, Melbourne, Vic, Australia. [Chandra, Ronil V.] Monash Univ, Dept Med, Melbourne, Vic, Australia. [Chandra, Ronil V.] Monash Univ, Dept Surg, Melbourne, Vic, Australia. RP Hirsch, JA (reprint author), Massachusetts Gen Hosp, Neuroendovasc Program, Boston, MA 02114 USA.; Hirsch, JA (reprint author), Massachusetts Gen Hosp, NeuroIntervent Spine Serv, Boston, MA 02114 USA.; Hirsch, JA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM jahirsch@mgh.harvard.edu NR 14 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 1 PY 2016 VL 388 IS 10052 BP 1356 EP 1357 DI 10.1016/S0140-6736(16)31356-3 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DX5FD UT WOS:000384404300009 PM 27544375 ER PT J AU Schaller, SJ Anstey, M Blobner, M Edrich, T Grabitz, SD Gradwohl-Matis, I Heim, M Houle, T Kurth, T Latronico, N Lee, J Meyer, MJ Peponis, T Talmor, D Velmahos, GC Waak, K Walz, JM Zafonte, R Eikermann, M AF Schaller, Stefan J. Anstey, Matthew Blobner, Manfred Edrich, Thomas Grabitz, Stephanie D. Gradwohl-Matis, Ilse Heim, Markus Houle, Timothy Kurth, Tobias Latronico, Nicola Lee, Jarone Meyer, Matthew J. Peponis, Thomas Talmor, Daniel Velmahos, George C. Waak, Karen Walz, J. Matthias Zafonte, Ross Eikermann, Matthias CA Int Early SOMS-Guided Mobilization TI Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial SO LANCET LA English DT Article ID ACUTE RESPIRATORY-FAILURE; LENGTH-OF-STAY; CRITICALLY-ILL PATIENTS; OPTIMAL MOBILITY SCORE; CRITICAL ILLNESS; NEUROMUSCULAR WEAKNESS; PREDICTS MORTALITY; PHYSICAL MEDICINE; ACQUIRED WEAKNESS; DISTRESS-SYNDROME AB Background Immobilisation predicts adverse outcomes in patients in the surgical intensive care unit (SICU). Attempts to mobilise critically ill patients early after surgery are frequently restricted, but we tested whether early mobilisation leads to improved mobility, decreased SICU length of stay, and increased functional independence of patients at hospital discharge. Methods We did a multicentre, international, parallel-group, assessor-blinded, randomised controlled trial in SICUs of five university hospitals in Austria (n = 1), Germany (n = 1), and the USA (n = 3). Eligible patients (aged 18 years or older, who had been mechanically ventilated for <48 h, and were expected to require mechanical ventilation for >= 24 h) were randomly assigned (1:1) by use of a stratified block randomisation via restricted web platform to standard of care (control) or early, goal-directed mobilisation using an inter-professional approach of closed-loop communication and the SICU optimal mobilisation score (SOMS) algorithm (intervention), which describes patients' mobilisation capacity on a numerical rating scale ranging from 0 (no mobilisation) to 4 (ambulation). We had three main outcomes hierarchically tested in a prespecified order: the mean SOMS level patients achieved during their SICU stay (primary outcome), and patient's length of stay on SICU and the mini-modified functional independence measure score (mmFIM) at hospital discharge (both secondary outcomes). This trial is registered with ClinicalTrials.gov (NCT01363102). Findings Between July 1, 2011, and Nov 4, 2015, we randomly assigned 200 patients to receive standard treatment (control; n = 96) or intervention (n = 104). Intention-to-treat analysis showed that the intervention improved the mobilisation level (mean achieved SOMS 2.2 [ SD 1.0] in intervention group vs 1.5 [0.8] in control group, p < 0.0001), decreased SICU length of stay (mean 7 days [SD 5-12] in intervention group vs 10 days [6-15] in control group, p = 0.0054), and improved functional mobility at hospital discharge (mmFIM score 8 [4-8] in intervention group vs 5 [2-8] in control group, p = 0.0002). More adverse events were reported in the intervention group (25 cases [2.8%]) than in the control group (ten cases [0.8%]); no serious adverse events were observed. Before hospital discharge 25 patients died (17 [16%] in the intervention group, eight [8%] in the control group). 3 months after hospital discharge 36 patients died (21 [22%] in the intervention group, 15 [17%] in the control group). Interpretation Early, goal-directed mobilisation improved patient mobilisation throughout SICU admission, shortened patient length of stay in the SICU, and improved patients' functional mobility at hospital discharge. C1 [Schaller, Stefan J.; Blobner, Manfred; Heim, Markus] Tech Univ Munich, Klinikum Rechts Isar, Klin Anaesthesiol, Munich, Germany. [Anstey, Matthew] Sir Charles Gairdner Hosp, Dept Intens Care, Nedlands, WA, Australia. [Edrich, Thomas] Klinikum Landkreis Erding, Dept Anesthesiol & Crit Care, Erding, Germany. [Edrich, Thomas; Gradwohl-Matis, Ilse] Paracelsus Med Univ, Univ Klinikum Salzburg, Univ Klin Anasthesiol Perioperat Med & Allgemeine, Salzburg, Austria. [Grabitz, Stephanie D.; Houle, Timothy; Meyer, Matthew J.; Peponis, Thomas; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Lee, Jarone; Velmahos, George C.] Massachusetts Gen Hosp, Dept Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Lee, Jarone; Velmahos, George C.; Zafonte, Ross] Harvard Med Sch, Boston, MA USA. [Kurth, Tobias] Charite, Berlin, Germany. [Latronico, Nicola] Univ Brescia, Spedali Civili Univ Hosp, Dept Anesthesia Crit Care & Emergency, Brescia, Italy. [Lee, Jarone] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Waak, Karen] Massachusetts Gen Hosp, Dept Phys Therapy, Boston, MA 02114 USA. [Talmor, Daniel] Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Beth Israel Deaconess Med, Boston, MA USA. [Walz, J. Matthias] Univ Massachusetts, Med Ctr, Dept Anesthesiol & Perioperat Med, Worcester, MA USA. [Zafonte, Ross] Brigham & Womens Hosp, Massachusetts Gen Hosp, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, 75 Francis St, Boston, MA 02115 USA. [Eikermann, Matthias] Univ Duisburg Essen, Klin Anaesthesiol & Intens Med, Essen, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM meikermann@partners.org RI Kurth, Tobias/A-9243-2012 OI Kurth, Tobias/0000-0001-7169-2620 FU Beth Israel; Massachusetts General Hospital; Universitdtsklinikum Salzburg; Klinikum rechts der Isar der TUM; University of Massachusetts Medical Center FX We thank Jeff and Judy Buzen for their generous support of this trial. Support was provided solely from institutional or departmental sources of participating study centres (Beth Israel, Massachusetts General Hospital, Universitdtsklinikum Salzburg, Klinikum rechts der Isar der TUM, University of Massachusetts Medical Center), and by an unrestricted grant of Jeff and Judy Buzen to ME. NR 57 TC 11 Z9 12 U1 12 U2 12 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 OCT 1 PY 2016 VL 388 IS 10052 BP 1377 EP 1388 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DX5FD UT WOS:000384404300032 PM 27707496 ER PT J AU Porter, C Tompkins, RG Finnerty, CC Sidossis, LS Suman, OE Herndon, DN AF Porter, Craig Tompkins, Ronald G. Finnerty, Celeste C. Sidossis, Labros S. Suman, Oscar E. Herndon, David N. TI The metabolic stress response to burn trauma: current understanding and therapies SO LANCET LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; GROWTH-HORMONE TREATMENT; MUSCLE PROTEIN-SYNTHESIS; WHITE ADIPOSE-TISSUE; PEDIATRIC-PATIENTS; SKELETAL-MUSCLE; CLINICAL-TRIAL; INSULIN SENSITIVITY; ENERGY-EXPENDITURE; INJURED PATIENTS AB Major burns provoke a profound stress response, which is unrivalled in terms of its magnitude and duration. Evidence suggests that the pathophysiological stress response to severe burn trauma persists for several years after injury. Thus, there is a pressing need for novel strategies that mitigate this response and restore normal metabolic function in patients with burns. This is the first in a Series of three papers about the care of people with burns. In this paper, we review the current knowledge of the stress response to burn trauma, with a focus on hypermetabolism, muscle wasting, and stress-induced diabetes. We highlight recent developments and important knowledge gaps that need to be pursued to develop novel therapeutic strategies to improve outcomes in burn survivors. C1 [Porter, Craig; Finnerty, Celeste C.; Suman, Oscar E.; Herndon, David N.] Univ Texas Med Branch, Dept Surg, Galveston, TX 77550 USA. [Porter, Craig; Finnerty, Celeste C.; Suman, Oscar E.; Herndon, David N.] Shriners Hosp Children, Galveston, TX 77550 USA. [Tompkins, Ronald G.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Sidossis, Labros S.] Rutgers State Univ, Dept Kinesiol & Hlth, New Brunswick, NJ USA. [Sidossis, Labros S.] Univ Med & Dent New Jersey, Dept Med, New Brunswick, NJ USA. RP Porter, C (reprint author), Univ Texas Med Branch, Dept Surg, Galveston, TX 77550 USA.; Porter, C (reprint author), Shriners Hosp Children, Galveston, TX 77550 USA. EM cr2porte@utmb.edu NR 82 TC 0 Z9 0 U1 8 U2 8 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 OCT 1 PY 2016 VL 388 IS 10052 BP 1417 EP 1426 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DX5FD UT WOS:000384404300036 PM 27707498 ER PT J AU Sullivan, DR Forsberg, CW Ganzini, L Au, DH Gould, MK Provenzale, D Lyons, KS Slatore, CG AF Sullivan, D. R. Forsberg, C. W. Ganzini, L. Au, D. H. Gould, M. K. Provenzale, D. Lyons, K. S. Slatore, C. G. TI Depression symptom trends and health domains among lung cancer patients in the CanCORS study SO LUNG CANCER LA English DT Article DE Lung cancer; Depression symptoms; Risk factors; Health domains; Quality of life; Survival ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIALS; CARE OUTCOMES RESEARCH; EARLY PALLIATIVE CARE; OLDER-ADULTS; MAJOR DEPRESSION; PSYCHOLOGICAL DISTRESS; AFRICAN-AMERICANS; SOCIAL SUPPORT; BREAST-CANCER AB Objectives: Among lung cancer patients depression symptoms are common and impact outcomes. The aims of this study were to determine risk factors that contribute to persistent or new onset depression symptoms during lung cancer treatment, and examine interactions between depression symptoms and health domains that influence mortality. Materials and methods: Prospective observational study in five healthcare systems and 15 Veterans Affairs medical centers. Patients in the Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium with lung cancer were eligible. The 8-item Center for Epidemiologic Studies Depression (CES-D) scale was administered at baseline and follow-up. Scores >= 4 indicated elevated depressive symptoms. Health domains were measured using validated instruments. We applied logistic regression and Cox proportional hazards modeling to explore the association between depression symptoms, health domains, and mortality. Results: Of 1790 participants, 38% had depression symptoms at baseline and among those still alive, 31% at follow-up. Risk factors for depression symptoms at follow-up included younger age (OR=2.81), female sex (OR = 1.59), low income (OR = 1.45), not being married (OR = 1.74) and current smoking status (OR = 1.80); high school education was associated with reduced odds of depression symptoms at follow-up, compared with lesser educational attainment (OR=0.74) (all p values <0.05). Patients with depression symptoms had worse health-related quality of life, vitality, cancer-specific symptoms, and social support than patients without depression symptoms (all p < 0.001). The association between depression symptoms and increased mortality is greater among patients with more lung cancer symptoms (p = 0.008) or less social support (p = 0.04). Conclusions: Patient risk factors for depression symptoms at follow-up were identified and these subgroups should be targeted for enhanced surveillance. Patients with depression symptoms suffer across all health domains; however, only more lung cancer symptoms or less social support are associated with worse mortality among these patients. These potentially modifiable health domains suggest targets for possible intervention in future studies. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Sullivan, D. R.; Slatore, C. G.] Oregon Hlth & Sci Univ, Dept Med, Div Pulm & Crit Care Med, Portland, OR 97201 USA. [Sullivan, D. R.; Forsberg, C. W.; Ganzini, L.; Slatore, C. G.] Vet Affairs Portland Hlth Care Syst, Hlth Serv Res & Dev, Portland, OR USA. [Ganzini, L.] Oregon Hlth & Sci Univ, Dept Psychiat, Div Geriatr Psychiat, Portland, OR 97201 USA. [Au, D. H.] Univ Washington, Hlth Serv Res & Dev Serv, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Au, D. H.] Univ Washington, Dept Med, Seattle, WA USA. [Gould, M. K.] Kaiser Permanente Southern Calif, Dept Res & Evaluat, Pasadena, CA USA. [Gould, M. K.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Provenzale, D.] Durham VA Med Ctr, VA Cooperat Studies Program Epidemiol Ctr Durham, Durham, NC USA. [Provenzale, D.] Duke Univ, Durham, NC USA. [Lyons, K. S.] Oregon Hlth & Sci Univ, Sch Nursing, Portland, OR 97201 USA. [Slatore, C. G.] Vet Affairs Portland Hlth Care Syst, Sect Pulm & Crit Care Med, Portland, OR USA. RP Sullivan, DR (reprint author), Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, UHN67, Portland, OR 97239 USA. EM sullivad@ohsu.edu OI Sullivan, Donald/0000-0003-3266-3389 FU American Lung Association [SB-164388-N]; National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) [5KL2TR000152-08]; National Center for Research Resources through the OHSU Oregon Clinical & Translational Research Institute (OCTRI) [UL1TR000128]; National Cancer Institute (NCI) of the NIH [K07CA190706]; VA HSR&D Career Development Award [CDA 09-025, CDP 11-227]; National Cancer Institute (NCI) [U01 CA093344, U01 CA093332, U01 CA093324, U01 CA093348, U01 CA093329, U01 CA093339, U01 CA 093326]; Department of Veteran's Affairs grant [VA HSRD CRS-02-164] FX This work was supported by a generous grant from the American Lung Association (SB-164388-N; PI: Slatore). DR Sullivan was supported by 5KL2TR000152-08 funded through the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) and National Center for Research Resources through the OHSU Oregon Clinical & Translational Research Institute (OCTRI)UL1TR000128 and National Cancer Institute (NCI) of the NIH under Award Number K07CA190706. CG Slatore was supported by VA HSR&D Career Development Award (CDA 09-025 and CDP 11-227). Drs. Sullivan, Ganzini, and Slatore are supported by resources from the Portland VA Portland Health Care System, Oregon. The work of the CanCORS consortium was supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01 CA093344) and the NCI supported Primary Data Collection and Research Centers (Dana-Farber Cancer Institute/Cancer Research Network U01 CA093332, Harvard Medical School/Northern California Cancer Center U01 CA093324, RAND/UCLA U01 CA093348, University of Alabama at Birmingham U01 CA093329, University of Iowa U01 CA093339, University of North Carolina U01 CA 093326) and by a Department of Veteran's Affairs grant to the Durham VA Medical Center VA HSRD CRS-02-164). The Department of Veterans Affairs did not have a role in the conduct of the study, in the collection, management, analysis, interpretation of data, or in the preparation of the manuscript. 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. DRS, CWF, LG, DHA, DP, KSL, CGS declare no potential conflicts of interest including relevant financial interests, activities, relationships, and affiliations. MKG receives honoraria from UpToDate. NR 85 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD OCT PY 2016 VL 100 BP 102 EP 109 DI 10.1016/j.lungcan.2016.08.008 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DW8YQ UT WOS:000383941800016 PM 27597288 ER PT J AU Mayer, JE Swetter, SM Miller, DR Sober, AJ Johnson, TM Geller, AC AF Mayer, Jonathan E. Swetter, Susan M. Miller, Donald R. Sober, Arthur J. Johnson, Timothy M. Geller, Alan C. TI Association of nevus count with prevention attitudes and behaviors before melanoma diagnosis SO MELANOMA RESEARCH LA English DT Article DE atypical moles; early detection; melanoma; moles; nevi; physician skin examination; prevention; risk factors; skin self-examinations ID CUTANEOUS MALIGNANT-MELANOMA; RISK-FACTORS; MELANOCYTIC NEVI; IDENTIFYING INDIVIDUALS; POPULATION; PEOPLE AB Although melanoma risk factors are commonly known to healthcare professionals, the extent to which the at-risk public is either aware of these factors or perceives their risk accordingly has rarely been studied. We sought to investigate whether the presence of known melanoma risk factors, such as high total nevus and atypical nevus counts, was associated with increased prevention attitudes and behaviors, such as skin self-examinations and physician skin examinations. This was a retrospective study of 566 individuals recently diagnosed with melanoma in two large academic centers. Most prevention attitudes and behaviors did not vary on the basis of total nevi or atypical nevi counts. However, younger patients (<60 years) with many total nevi (>50) were more likely than those with fewer nevi (<20) to believe that they were at-risk for melanoma (42 vs. 23%; P<0.05), and more likely to state that they had been instructed on the signs of melanoma (36 vs. 21%; P<0.05). Patient and health provider recognition of the impact of nevus count on melanoma risk presents a unique and mostly untapped opportunity for earlier detection. C1 [Mayer, Jonathan E.] Johns Hopkins Univ, Sch Med, Dept Med, Johns Hopkins Bayview Med Ctr, Baltimore, MD 21205 USA. [Swetter, Susan M.] Stanford Univ, Med Ctr, Dept Dermatol, Stanford, CA 94305 USA. [Swetter, Susan M.] Inst Canc Res, Stanford, CA USA. [Swetter, Susan M.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Miller, Donald R.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Sober, Arthur J.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Sober, Arthur J.] Harvard Med Sch, Dept Dermatol, Boston, MA USA. [Geller, Alan C.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Johnson, Timothy M.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. RP Geller, AC (reprint author), Kresge Rm 718,677 Huntington Ave, Boston, MA 02115 USA. EM ageller@hsph.harvard.edu FU Merck and Company Inc. FX This study was supported by Merck and Company Inc. The sponsor played no role in the design or conduct of the study; in the collection, analysis, or interpretation of data; or in the preparation, writing, or decision to submit the article. NR 19 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0960-8931 EI 1473-5636 J9 MELANOMA RES JI Melanoma Res. PD OCT PY 2016 VL 26 IS 5 BP 513 EP 516 DI 10.1097/CMR.0000000000000279 PG 4 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA DX5WH UT WOS:000384452900012 PM 27387129 ER PT J AU Bird, GH Mazzola, E Opoku-Nsiah, K Lammert, MA Godes, M Neuberg, DS Walensky, LD AF Bird, Gregory H. Mazzola, Emanuele Opoku-Nsiah, Kwadwo Lammert, Margaret A. Godes, Marina Neuberg, Donna S. Walensky, Loren D. TI Biophysical determinants for cellular uptake of hydrocarbon-stapled peptide helices SO NATURE CHEMICAL BIOLOGY LA English DT Article ID BH3 HELIX; PROAPOPTOTIC ACTIVITY; BIMBH3 HELIX; P53 PEPTIDE; SURVIVAL; BAX; INHIBITION; ACTIVATION; PROTEINS; LEUKEMIA AB Hydrocarbon-stapled peptides are a class of bioactive alpha-helical ligands developed to dissect and target protein interactions. While there is consensus that stapled peptides can be effective chemical tools for investigating protein regulation, their broader utility for therapeutic modulation of intracellular interactions remains an active area of study. In particular, the design principles for generating cell-permeable stapled peptides are empiric, yet consistent intracellular access is essential to in vivo application. Here, we used an unbiased statistical approach to determine which biophysical parameters dictate the uptake of stapled-peptide libraries. We found that staple placement at the amphipathic boundary combined with optimal hydrophobic and helical content are the key drivers of cellular uptake, whereas excess hydrophobicity and positive charge at isolated amino acid positions can trigger membrane lysis at elevated peptide dosing. Our results provide a design roadmap for maximizing the potential to generate cell-permeable stapled peptides with on-mechanism cellular activity. C1 [Bird, Gregory H.; Opoku-Nsiah, Kwadwo; Lammert, Margaret A.; Godes, Marina; Walensky, Loren D.] Dana Farber Canc Inst, Linde Program Canc Chem Biol, Dept Pediat Oncol, Boston, MA 02115 USA. [Mazzola, Emanuele; Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Linde Program Canc Chem Biol, Dept Pediat Oncol, Boston, MA 02115 USA. EM loren_walensky@dfci.harvard.edu FU NIH grants [1R35CA197583, 1R21CA209358]; Leukemia and Lymphoma Society (LLS) Marshall A. Lichtman Specialized Center of Research project grant; William Lawrence and Blanche Hughes Foundation; Todd J. Schwartz Memorial Fund; Wolpoff Family Foundation; LLS Scholar Award; Dana-Farber/Harvard Cancer Center Support grant [5P30CA006516] FX We thank E. Smith for graphics support, S. Rudnicki of the Institute of Chemistry and Cell Biology-Longwood for assistance with IXM screening and analysis, and J. Opferman of St. Jude Children's Research Hospital for the BCL-XL-reconstituted p185+Arf-/-Mcl-1-deleted B-ALL cells. This research was supported by NIH grants 1R35CA197583 and 1R21CA209358, a Leukemia and Lymphoma Society (LLS) Marshall A. Lichtman Specialized Center of Research project grant, the William Lawrence and Blanche Hughes Foundation, the Todd J. Schwartz Memorial Fund, the Wolpoff Family Foundation, and an LLS Scholar Award to L.D.W.E.M. and D.S.N. are supported in part by the Dana-Farber/Harvard Cancer Center Support grant 5P30CA006516. NR 38 TC 5 Z9 5 U1 19 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2016 VL 12 IS 10 BP 845 EP + DI 10.1038/NCHEMBIO.2153 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX3BU UT WOS:000384248600017 PM 27547919 ER PT J AU Zhang, TH Kwiatkowski, N Olson, CM Dixon-Clarke, SE Abraham, BJ Greifenberg, AK Ficarro, SB Elkins, JM Liang, YK Hannett, NM Manz, T Hao, MF Bartkowiak, B Greenleaf, AL Marto, JA Geyer, M Bullock, AN Young, RA Gray, NS AF Zhang, Tinghu Kwiatkowski, Nicholas Olson, Calla M. Dixon-Clarke, Sarah E. Abraham, Brian J. Greifenberg, Ann K. Ficarro, Scott B. Elkins, Jonathan M. Liang, Yanke Hannett, Nancy M. Manz, Theresa Hao, Mingfeng Bartkowiak, Bartlomiej Greenleaf, Arno L. Marto, Jarrod A. Geyer, Matthias Bullock, Alex N. Young, Richard A. Gray, Nathanael S. TI Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors SO NATURE CHEMICAL BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; ACUTE LYMPHOBLASTIC-LEUKEMIA; C-TERMINAL DOMAIN; SUPER-ENHANCERS; P-TEFB; TRANSCRIPTION; KINASE; PHOSPHORYLATION; EXPRESSION; COMPLEX AB Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities. C1 [Zhang, Tinghu; Kwiatkowski, Nicholas; Olson, Calla M.; Ficarro, Scott B.; Liang, Yanke; Manz, Theresa; Hao, Mingfeng; Marto, Jarrod A.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhang, Tinghu; Kwiatkowski, Nicholas; Olson, Calla M.; Ficarro, Scott B.; Liang, Yanke; Hao, Mingfeng; Marto, Jarrod A.; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kwiatkowski, Nicholas; Abraham, Brian J.; Hannett, Nancy M.; Young, Richard A.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Dixon-Clarke, Sarah E.; Elkins, Jonathan M.; Bullock, Alex N.] Univ Oxford, Struct Genom Consortium, Oxford, England. [Greifenberg, Ann K.; Geyer, Matthias] Univ Bonn, Inst Innate Immun, Dept Struct Immunol, Bonn, Germany. [Greifenberg, Ann K.; Geyer, Matthias] Ctr Adv European Studies & Res, Bonn, Germany. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Manz, Theresa] Univ Saarland, Dept Pharm, Pharmaceut & Med Chem, Saarbrucken, Germany. [Bartkowiak, Bartlomiej; Greenleaf, Arno L.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Gray, NS (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Young, RA (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Young, RA (reprint author), MIT, Dept Biol, Cambridge, MA 02139 USA. EM young@wi.mit.edu; Nathanael_Gray@dfci.harvard.edu OI Elkins, Jon/0000-0003-2858-8929 FU National Institutes of Health [HG002668, CA109901, 5 R01 CA179483-02 C]; Koch Institute and Dana-Farber/Harvard Cancer Center Bridge Grant; DFG [GE 976/9-1]; Hope Funds for Cancer Research Grillo-Marxuach Family Fellowship; NDM Prize Studentship; Medical Research Council; AbbVie; Bayer; Boehringer Ingelheim; Genome Canada through Ontario Genomics Institute Grant [OGI-055]; GlaxoSmithKline; Janssen; Lilly Canada; Novartis Research Foundation; Ontario Ministry of Economic Development and Innovation; Pfizer; Takeda; Wellcome Trust [092809/Z/10/Z] FX We thank R. George, K. Wong, P. Hammerman, J. Bradner and members of the Gray and Young laboratories for helpful discussions. We thank P. Wisniewski and C. Zollo from the Whitehead FACS facility for help with FACS instruments. We thank J. Love, T. Volkert, and S. Gupta from the Whitehead Genome Core for help with genomics experiments. The authors would like to thank Diamond Light Source for beamtime (proposal mx8421), and the staff of Beamline I03 for assistance with data collection. We thank W. Massefski from the Dana-Farber NMR lab for help in collecting NMR data for the manuscript. M.G. is a member of the DFG excellence cluster ImmunoSensation. This work was supported by the National Institutes of Health (HG002668 and CA109901 to R.A.Y. and 5 R01 CA179483-02 C to N.S.G.), the Koch Institute and Dana-Farber/Harvard Cancer Center Bridge Grant (N.K., N.S.G., R.A.Y.), the DFG (GE 976/9-1 to M.G.), the Hope Funds for Cancer Research Grillo-Marxuach Family Fellowship (B.J.A.), and a NDM Prize Studentship, funded in part by the Medical Research Council (S.E.D.-C.). The SGC is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer, Boehringer Ingelheim, Genome Canada through Ontario Genomics Institute Grant OGI-055, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and Wellcome Trust Grant 092809/Z/10/Z. NR 58 TC 6 Z9 6 U1 21 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2016 VL 12 IS 10 BP 876 EP + DI 10.1038/nchembio.2166 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX3BU UT WOS:000384248600021 PM 27571479 ER PT J AU Jia, TZ Fahrenbach, AC Kamat, NP Adamala, KP Szostak, JW AF Jia, Tony Z. Fahrenbach, Albert C. Kamat, Neha P. Adamala, Katarzyna P. Szostak, Jack W. TI Oligoarginine peptides slow strand annealing and assist non-enzymatic RNA replication SO NATURE CHEMISTRY LA English DT Article ID AMINO-ACIDS; LIQUID DROPLETS; DNA; ARGININE; BINDING; SYSTEM; POLYMERIZATION; PRECURSORS; MODEL; THERMODYNAMICS AB The non-enzymatic replication of RNA is thought to have been a critical process required for the origin of life. One unsolved difficulty with non-enzymatic RNA replication is that template-directed copying of RNA results in a double-stranded product. After strand separation, rapid strand reannealing outcompetes slow non-enzymatic template copying, which renders multiple rounds of RNA replication impossible. Here we show that oligoarginine peptides slow the annealing of complementary oligoribonucleotides by up to several thousand-fold; however, short primers and activated monomers can still bind to template strands, and template-directed primer extension can still occur, all within a phase-separated condensed state, or coacervate. Furthermore, we show that within this phase, partial template copying occurs even in the presence of full-length complementary strands. This method to enable further rounds of replication suggests one mechanism by which short non-coded peptides could have enhanced early cellular fitness, and potentially explains how longer coded peptides, that is, proteins, came to prominence in modern biology. C1 [Jia, Tony Z.; Fahrenbach, Albert C.; Kamat, Neha P.; Adamala, Katarzyna P.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA. [Jia, Tony Z.; Fahrenbach, Albert C.; Kamat, Neha P.; Adamala, Katarzyna P.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA. [Jia, Tony Z.; Szostak, Jack W.] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. [Fahrenbach, Albert C.; Szostak, Jack W.] Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-12-1-IE-1 Ookayama, Tokyo 1528550, Japan. [Szostak, Jack W.] Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA. [Adamala, Katarzyna P.] MIT, Dept Biol Engn, MIT Media Lab, Cambridge, MA 02139 USA. [Adamala, Katarzyna P.] MIT, Dept Brain & Cognit Sci, MIT Media Lab, Cambridge, MA 02139 USA. [Adamala, Katarzyna P.] MIT, McGovern Inst, Cambridge, MA 02139 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA.; Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA.; Szostak, JW (reprint author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA.; Szostak, JW (reprint author), Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-12-1-IE-1 Ookayama, Tokyo 1528550, Japan.; Szostak, JW (reprint author), Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM szostak@molbio.mgh.harvard.edu OI Adamala, Kate/0000-0003-1066-7207 FU Earth-Life Science Institute at the Tokyo Institute of Technology; NASA; Simons Foundation [290363]; NASA [NNX15AL18G] FX We thank A. E. Engelhart, C. Hentrich, B. D. Heuberger, A. T. Larsen, T. J. Olsen, N. Prywes, R. Saganty, L. Zhou and all other members of the Szostak Lab for helpful discussions and critical reading of the manuscript. We also thank G. Ruvkun and E. Rubin for their support and very helpful advice. J.W.S. is an Investigator of the Howard Hughes Medical Institute. A.C.F. is supported by a Research Fellowship from the Earth-Life Science Institute at the Tokyo Institute of Technology. N.P.K. is supported by an appointment to the National Aeronautics and Space Administration (NASA) Postdoctoral Program, administered by Oak Ridge Associated Universities through a contract with NASA. This work was supported by grants from the Simons Foundation (290363) and NASA (NNX15AL18G) to J.W.S. NR 58 TC 3 Z9 3 U1 30 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1755-4330 EI 1755-4349 J9 NAT CHEM JI Nat. Chem. PD OCT PY 2016 VL 8 IS 10 BP 915 EP 921 DI 10.1038/NCHEM.2551 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA DX5IA UT WOS:000384413000009 PM 27657866 ER PT J AU Ruderfer, DM Hamamsy, T Lek, M Karczewski, KJ Kavanagh, D Samocha, KE Daly, MJ MacArthur, DG Fromer, M Purcell, SM AF Ruderfer, Douglas M. Hamamsy, Tymor Lek, Monkol Karczewski, Konrad J. Kavanagh, David Samocha, Kaitlin E. Daly, Mark J. MacArthur, Daniel G. Fromer, Menachem Purcell, Shaun M. CA Exome Aggregation Consortium TI Patterns of genic intolerance of rare copy number variation in 59,898 human exomes SO NATURE GENETICS LA English DT Article ID HUMAN GENOME; STRUCTURAL VARIATION; HUMAN-DISEASE; SCHIZOPHRENIA; IDENTIFICATION; VARIANTS; SEQUENCE; BURDEN; MAP AB Copy number variation (CNV) affecting protein-coding genes contributes substantially to human diversity and disease. Here we characterized the rates and properties of rare genic CNVs (<0.5% frequency) in exome sequencing data from nearly 60,000 individuals in the Exome Aggregation Consortium (ExAC) database. On average, individuals possessed 0.81 deleted and 1.75 duplicated genes, and most (70%) carried at least one rare genic CNV. For every gene, we empirically estimated an index of relative intolerance to CNVs that demonstrated moderate correlation with measures of genic constraint based on single-nucleotide variation (SNV) and was independently correlated with measures of evolutionary conservation. For individuals with schizophrenia, genes affected by CNVs were more intolerant than in controls. The ExAC CNV data constitute a critical component of an integrated database spanning the spectrum of human genetic variation, aiding in the interpretation of personal genomes as well as population-based disease studies. These data are freely available for download and visualization online. C1 [Ruderfer, Douglas M.; Hamamsy, Tymor; Kavanagh, David; Fromer, Menachem; Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Ruderfer, Douglas M.; Kavanagh, David; Fromer, Menachem; Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Ruderfer, Douglas M.; Lek, Monkol; Karczewski, Konrad J.; Samocha, Kaitlin E.; Daly, Mark J.; MacArthur, Daniel G.; Fromer, Menachem; Purcell, Shaun M.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Lek, Monkol; Karczewski, Konrad J.; Samocha, Kaitlin E.; Daly, Mark J.; MacArthur, Daniel G.; Fromer, Menachem; Purcell, Shaun M.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Purcell, Shaun M.] Brigham & Womens Hosp, Harvard Med Sch, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. RP Ruderfer, DM; Purcell, SM (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA.; Ruderfer, DM; Purcell, SM (reprint author), Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA.; Ruderfer, DM; Purcell, SM (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Purcell, SM (reprint author), Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Analyt & Translat Genet Unit, Boston, MA 02114 USA.; Purcell, SM (reprint author), Brigham & Womens Hosp, Harvard Med Sch, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. EM douglas.ruderfer@mssm.edu; shaun.purcell@mssm.edu OI Ruderfer, Douglas/0000-0002-2365-386X; Ware, James/0000-0002-6110-5880 FU Institute for Genomics and Multiscale Biology; NIH [R01-HG005827, R01-MH099126] FX We would like to acknowledge E. Ruder and K. Shakir for their help in running XHMM at the large scale required for over 60,000 samples. Work at the Icahn School of Medicine at Mount Sinai was supported by the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing) and NIH grants R01-HG005827 and R01-MH099126 (to S.M.P.). NR 35 TC 3 Z9 3 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2016 VL 48 IS 10 BP 1107 EP 1111 DI 10.1038/ng.3638 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA DX5AG UT WOS:000384391600005 PM 27533299 ER PT J AU Gao, RL Davis, A McDonald, TO Sei, E Shi, XQ Wang, Y Tsai, PC Casasent, A Waters, J Zhang, H Meric-Bernstam, F Michor, F Navin, NE AF Gao, Ruli Davis, Alexander McDonald, Thomas O. Sei, Emi Shi, Xiuqing Wang, Yong Tsai, Pei-Ching Casasent, Anna Waters, Jill Zhang, Hong Meric-Bernstam, Funda Michor, Franziska Navin, Nicholas E. TI Punctuated copy number evolution and clonal stasis in triple-negative breast cancer SO NATURE GENETICS LA English DT Article ID TUMOR EVOLUTION; NEXT-GENERATION; SINGLE; CARCINOGENESIS; REARRANGEMENT; CHEMOTHERAPY; INSTABILITY; DIVERSITY; CELLS; MODEL AB Aneuploidy is a hallmark of breast cancer; however, knowledge of how these complex genomic rearrangements evolve during tumorigenesis is limited. In this study, we developed a highly multiplexed single-nucleus sequencing method to investigate copy number evolution in patients with triple-negative breast cancer. We sequenced 1,000 single cells from tumors in 12 patients and identified 1-3 major clonal subpopulations in each tumor that shared a common evolutionary lineage. For each tumor, we also identified a minor subpopulation of non-clonal cells that were classified as metastable, pseudodiploid or chromazemic. Phylogenetic analysis and mathematical modeling suggest that these data are unlikely to be explained by the gradual accumulation of copy number events over time. In contrast, our data challenge the paradigm of gradual evolution, showing. that the majority of copy number aberrations are acquired at the earliest stages of tumor evolution, in short punctuated bursts, followed by stable clonal expansions that form the tumor mass. C1 [Gao, Ruli; Davis, Alexander; Sei, Emi; Wang, Yong; Tsai, Pei-Ching; Casasent, Anna; Waters, Jill; Navin, Nicholas E.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Davis, Alexander; Casasent, Anna; Navin, Nicholas E.] Univ Texas MD Anderson Canc Ctr, Grad Sch Biomed Sci, Houston, TX 77030 USA. [McDonald, Thomas O.; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [McDonald, Thomas O.; Michor, Franziska] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Shi, Xiuqing] Chinese Acad Med Sci, Peking Union Med Coll, Dept Med Oncol, Canc Hosp & Inst, Beijing, Peoples R China. [Zhang, Hong] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Meric-Bernstam, Funda] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Navin, Nicholas E.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. RP Navin, NE (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA.; Navin, NE (reprint author), Univ Texas MD Anderson Canc Ctr, Grad Sch Biomed Sci, Houston, TX 77030 USA.; Navin, NE (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. EM nnavin@mdanderson.org OI Casasent, Anna/0000-0002-7857-179X FU Lefkofsky Family Foundation; NCI [1RO1CA169244-01]; American Cancer Society [129098-RSG-16-092-01-TBG]; Moonshot Knowledge Gap Award; Center for Genetics and Genomics; NIH [CA016672, UL1TR000371]; Rosalie B. Hite Fellowship; Center for Genetics and Genomics Postdoctoral Fellowship; Nellie B. Connally Breast Cancer Research Endowment; Susan Komen [SAC10006]; CPRIT [RP110584]; M.D. Anderson Cancer Center Support grant (NIH/NCI) [P30CA016672]; Dana-Farber Cancer Institute Physical Science Oncology Center [U54CA193461-01] FX We thank M. Edgerton, J. Kendall, M. Wigler and J. Hicks for their support and discussions. We are also very grateful to the patients with breast cancer at M.D. Anderson for generously donating their tumor tissues to our research studies. This work was supported by a grant from the Lefkofsky Family Foundation. N.E.N. is a Nadia's Gift Foundation Damon Runyon-Rachleff Innovator (DRR-25-13). This work is also supported by grants to N.E.N. from the NCI (1RO1CA169244-01) and the American Cancer Society (129098-RSG-16-092-01-TBG). N.E.N. is a T.C. Hsu Endowed Scholar, an AAAS Wachtel Scholar and an Andrew Sabin Family Fellow. The study is also supported by the Moonshot Knowledge Gap Award and the Center for Genetics and Genomics. This study was supported by the M.D. Anderson Sequencing Core Facility grant (CA016672) and the Flow Cytometry Facility grant (CA016672) from the NIH. Additional funding support includes the Rosalie B. Hite Fellowship (A.C.); a Center for Genetics and Genomics Postdoctoral Fellowship (R.G.); NIH UL1TR000371 (F.M.-B.); the Nellie B. Connally Breast Cancer Research Endowment (F.M.-B.), Susan Komen SAC10006 (F.M.-B.), CPRIT RP110584 (F.M.-B.) and the M.D. Anderson Cancer Center Support grant (NIH/NCI P30CA016672). F.M. gratefully acknowledges support from the Dana-Farber Cancer Institute Physical Science Oncology Center (U54CA193461-01). NR 38 TC 15 Z9 15 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2016 VL 48 IS 10 BP 1119 EP 1130 DI 10.1038/ng.3641 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DX5AG UT WOS:000384391600007 PM 27526321 ER PT J AU Guo, HY Ahmed, M Zhang, F Yao, CQ Li, SD Liang, Y Hua, JJ Soares, F Sun, YF Langstein, J Li, YC Poon, C Bailey, SD Desai, K Fei, T Li, QY Sendorek, DH Fraser, M Prensner, JR Pugh, TJ Pomerantz, M Bristow, RG Lupien, M Feng, FY Boutros, PC Freedman, ML Walsh, MJ He, HSHS AF Guo, Haiyang Ahmed, Musaddeque Zhang, Fan Yao, Cindy Q. Li, SiDe Liang, Yi Hua, Junjie Soares, Fraser Sun, Yifei Langstein, Jens Li, Yuchen Poon, Christine Bailey, Swneke D. Desai, Kinjal Fei, Teng Li, Qiyuan Sendorek, Dorota H. Fraser, Michael Prensner, John R. Pugh, Trevor J. Pomerantz, Mark Bristow, Robert G. Lupien, Mathieu Feng, Felix Y. Boutros, Paul C. Freedman, Matthew L. Walsh, Martin J. He, Housheng Hansen TI Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer SO NATURE GENETICS LA English DT Article ID HUMAN CELL-TYPES; CHROMATIN INTERACTIONS; SUSCEPTIBILITY LOCI; RANGE INTERACTION; HUMAN GENOME; EXPRESSION; TRANSCRIPTION; ANNOTATION; 8Q24; PROGRESSION AB Long noncoding RNAs (IncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the IncRNA transcriptome with genomic data and SNP data from prostate cancer genome-wide association studies (GWAS), we identified 45 candidate IncRNAs associated with risk to prostate cancer. We further evaluated the mechanism underlying the top hit, PCAT1, and found that a risk-associated variant at rs7463708 increases binding of ONECUT2, a novel androgen receptor (AR)-interacting transcription factor, at a distal enhancer that loops to the PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment. In addition, PCAT1 interacts with AR and LSD1 and is required for their recruitment to the enhancers of GNMT and DHCR24, two androgen late-response genes implicated in prostate cancer development and progression. PCAT1 promotes prostate cancer cell proliferation and tumor growth in vitro and in vivo. These findings suggest that modulating IncRNA expression is an important mechanism for risk-associated SNPs in promoting prostate transformation. C1 [Guo, Haiyang; Ahmed, Musaddeque; Liang, Yi; Hua, Junjie; Soares, Fraser; Langstein, Jens; Li, Yuchen; Poon, Christine; Bailey, Swneke D.; Fraser, Michael; Pugh, Trevor J.; Bristow, Robert G.; Lupien, Mathieu; He, Housheng Hansen] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Zhang, Fan; Li, SiDe; Sun, Yifei; Walsh, Martin J.] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA. [Yao, Cindy Q.; Sendorek, Dorota H.; Lupien, Mathieu; Boutros, Paul C.] Ontario Inst Canc Res, Toronto, ON, Canada. [Hua, Junjie; Bristow, Robert G.; Lupien, Mathieu; Boutros, Paul C.; He, Housheng Hansen] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Langstein, Jens] German Canc Res Ctr, Heidelberg, Germany. [Desai, Kinjal] Norris Cotton Canc Ctr, Dartmouth Med Sch, Dept Genet, Lebanon, NH USA. [Fei, Teng; Pomerantz, Mark; Freedman, Matthew L.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Dept Med Oncol, Boston, MA 02115 USA. [Li, Qiyuan] Xiamen Univ, Coll Med, Xiamen, Peoples R China. [Prensner, John R.] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI USA. [Feng, Felix Y.] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA. [Feng, Felix Y.] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. [Feng, Felix Y.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Feng, Felix Y.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Boutros, Paul C.] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada. [Freedman, Matthew L.] Eli & Edythe L Broad Inst, Cambridge, MA USA. [Walsh, Martin J.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Prensner, John R.] Boston Childrens Hosp, Dept Pediat, Boston, MA USA. RP He, HSHS (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada.; He, HSHS (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. EM hansenhe@uhnresearch.ca FU Princess Margaret Cancer Foundation; Canada Foundation for Innovation; Ontario Research Fund [CFI32372, CFI32383]; NSERC discovery grant [498706]; WICC Ontario 20th Anniversary Prostate Cancer Innovation Grant of the CCS [703800]; CIHR transitional operating grant [142246]; Prostate Cancer Canada [RS2014-01, RS2014-04, RS2016-1022]; ICS-IG Maud Menten New Principal Investigator Prize [ICS-145381]; OMIR Early Researcher Award; OICR; CIHR; Canadian Cancer Society Research Scientist Award; Terry Fox Research Institute New Investigator Award; CIHR New Investigator Award; Prostate Cancer Foundation (Challenge Award); NIH [R01CA193910, 5RO1CA154903, 5RO1HL103967]; CIHR Graduate Student Fellowship; CIHR Postdoctoral Fellowship FX We thank M. Brown, X.S. Liu, D. Borges-Rivera and R.A. Young for discussion, as well as the Princess Margaret Genomic Centre for high-throughput sequencing support. The work was supported by the Princess Margaret Cancer Foundation (to H.H.H., M.L., T.J.P. and R.G.B.), the Canada Foundation for Innovation and the Ontario Research Fund (CFI32372 to H.H.H. and CFI32383 to T.J.P.), NSERC discovery grant (498706 to H.H.H.), the WICC Ontario 20th Anniversary Prostate Cancer Innovation Grant of the CCS (703800 to H.H.H.), and a CIHR transitional operating grant (142246 to H.H.H.) and Movember Rising Star awards from Prostate Cancer Canada (RS2014-01 to P.C.B., RS2014-04 to M.L. and RS2016-1022 to H.H.H.). H.H.H. holds an ICS-IG Maud Menten New Principal Investigator Prize (ICS-145381) and an OMIR Early Researcher Award. M.L. holds a young investigator award from the OICR and a new investigator salary award from the CIHR. R.G.B. is a recipient of a Canadian Cancer Society Research Scientist Award. P.C.B. is supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award. M.L.F. is supported by the Prostate Cancer Foundation (Challenge Award) and an NIH grant (R01CA193910). J.H. is a CIHR Graduate Student Fellowship recipient. S.D.B. is a CIHR Postdoctoral Fellowship recipient. M.J.W. is supported by grants 5RO1CA154903 and 5RO1HL103967 from the NIH. We acknowledge the ENCODE Consortium and the ENCODE production laboratories that generated the data sets provided by the ENCODE Data Coordination Center used in the manuscript. The results shown here are in whole or part based upon data generated by the TCGA Research Network. NR 59 TC 3 Z9 3 U1 16 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2016 VL 48 IS 10 BP 1142 EP 1150 DI 10.1038/ng.3637 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DX5AG UT WOS:000384391600009 PM 27526323 ER PT J AU Surendran, P Drenos, F Young, R Warren, H Cook, JP Manning, AK Grarup, N Sim, X Barnes, DR Witkowska, K Staley, JR Tragante, V Tukiainen, T Yaghootkar, H Masca, N Freitag, DF Ferreira, T Giannakopoulou, O Tinker, A Harakalova, M Mihailov, E Liu, C Kraja, AT Nielsen, SF Rasheed, A Samue, M Zhao, W Bonnycastle, LL Jackson, AU Narisu, N Swift, AJ Southam, L Marten, J Huyghe, JR Stancakova, A Fava, C Ohlsson, T Matchan, A Stirrups, KE Bork-Jensen, J Gjesing, AP Kontto, J Perola, M Shaw-Hawkins, S Havulinna, AS Zhang, H Donnelly, LA Groves, CJ Rayner, NW Neville, MJ Robertson, NR Yiorkas, AM Herzig, KH Kajantie, E Zhang, W Willems, SM Lannfelt, L Malerba, G Soranzo, N Trabetti, E Verweij, N Evangelou, E Moayyeri, A Vergnaud, AC Nelson, CP Poveda, A Varga, TV Caslake, M de Craen, AJM Trompet, S Luan, J Scott, RA Harris, SE Liewald, DCM Marioni, R Menni, C Farmaki, AE Hallmans, G Renstrom, F Huffman, JE Hassinen, M Burgess, S Vasan, RS Felix, JF Uria-Nickelsen, M Malarstign, A Reilly, DF Hoek, M Vogt, TF Lin, HH Lieb, W Traylor, M Markus, HS Highland, HM Justice, AE Marouli, E Lindstrom, J Uusitupa, M Komulainen, P Lakka, TA Rauramaa, R Polasek, O Rudan, I Rolandsson, O Franks, PW Dedoussis, G Spector, TD Jousilahti, P Mannisto, S Deary, IJ Starr, JM Langenberg, C Wareham, NJ Brown, MJ Dominiczak, AF Connell, JM Jukema, JW Sattar, N Ford, I Packard, CJ Esko, T Magi, R Metspalu, A de Boer, RA van der Meer, P van der Harst, P Gambaro, G Ingelsson, E Lind, L de Bakker, PIW Numans, ME Brandslund, I Christensen, C Petersen, ERB Korpi-Hyovalti, E Oksa, H Chambers, JC Kooner, JS Blakemore, AIF Franks, S Jarvelin, MR Husemoen, LL Linneberg, A Skaaby, T Thuesen, B Karpe, F Tuomilehto, J Doney, ASF Morris, AD Palmer, CNA Holmen, OL Hveem, K Willer, CJ Tuomi, T Groop, L Karajamaki, A Palotie, A Ripatti, S Salomaa, V Alam, DS Majmnder, AAS Di Angelantonio, E Chowdhury, R McCarthy, MI Poulter, N Stanton, AV Sever, P Amouyel, P Arveiler, D Blankenberg, S Ferrieres, J Kee, F Kuulasmaa, K Muller-Nurasyid, M Veronesi, G Virtamo, J Deloukas, P Elliott, P Zeggini, E Kathiresan, S Melander, O Kuusisto, J Laakso, M Padmanabhan, S Porteous, DJ Hayward, C Scotland, G Collins, FS Mohlke, KL Hansen, T Pedersen, O Boehnke, M Stringham, HM Frossard, P Newton-Cheh, C Tobin, MD Nordestgaard, BG Caulfield, MJ Mahajan, A Morris, AP Tomaszewski, M Samani, NJ Saleheen, D Asselbergs, FW Lindgren, CM Danesh, J Wain, LV Butterworth, AS Howson, JMM Munroe, PB AF Surendran, Praveen Drenos, Fotios Young, Robin Warren, Helen Cook, James P. Manning, Alisa K. Grarup, Niels Sim, Xueling Barnes, Daniel R. Witkowska, Kate Staley, James R. Tragante, Vinicius Tukiainen, Taru Yaghootkar, Hanieh Masca, Nicholas Freitag, Daniel F. Ferreira, Teresa Giannakopoulou, Olga Tinker, Andrew Harakalova, Magdalena Mihailov, Evelin Liu, Chunyu Kraja, Aldi T. Nielsen, Sune Fallgaard Rasheed, Asif Samue, Maria Zhao, Wei Bonnycastle, Lori L. Jackson, Anne U. Narisu, Narisu Swift, Amy J. Southam, Lorraine Marten, Jonathan Huyghe, Jeroen R. Stancakova, Alena Fava, Cristiano Ohlsson, Therese Matchan, Angela Stirrups, Kathleen E. Bork-Jensen, Jette Gjesing, Anette P. Kontto, Jukka Perola, Markus Shaw-Hawkins, Susan Havulinna, Aki S. Zhang, He Donnelly, Louise A. Groves, Christopher J. Rayner, N. William Neville, Matt J. Robertson, Neil R. Yiorkas, Andrianos M. Herzig, Karl-Heinz Kajantie, Eero Zhang, Weihua Willems, Sara M. Lannfelt, Lars Malerba, Giovanni Soranzo, Nicole Trabetti, Elisabetta Verweij, Niek Evangelou, Evangelos Moayyeri, Alireza Vergnaud, Anne-Claire Nelson, Christopher P. Poveda, Alaitz Varga, Tibor V. Caslake, Muriel de Craen, Anton J. M. Trompet, Stella Luan, Jian'an Scott, Robert A. Harris, Sarah E. Liewald, David C. M. Marioni, Riccardo Menni, Cristina Farmaki, Aliki-Eleni Hallmans, Goran Renstrom, Frida Huffman, Jennifer E. Hassinen, Maija Burgess, Stephen Vasan, Ramachandran S. Felix, Janine F. Uria-Nickelsen, Maria Malarstign, Anders Reilly, Dermot F. Hoek, Maarten Vogt, Thomas F. Lin, Honghuang Lieb, Wolfgang Traylor, Matthew Markus, Hugh S. Highland, Heather M. Justice, Anne E. Marouli, Eirini Lindstrom, Jaana Uusitupa, Matti Komulainen, Pirjo Lakka, Timo A. Rauramaa, Rainer Polasek, Ozren Rudan, Igor Rolandsson, Olov Franks, Paul W. Dedoussis, George Spector, Timothy D. Jousilahti, Pekka Mannisto, Satu Deary, Ian J. Starr, John M. Langenberg, Claudia Wareham, Nick J. Brown, Morris J. Dominiczak, Anna F. Connell, John M. Jukema, J. Wouter Sattar, Naveed Ford, Ian Packard, Chris J. Esko, Tonu Magi, Reedik Metspalu, Andres de Boer, Rudolf A. van der Meer, Peter van der Harst, Pim Gambaro, Giovanni Ingelsson, Erik Lind, Lars de Bakker, Paul I. W. Numans, Mattijs E. Brandslund, Ivan Christensen, Cramer Petersen, Eva R. B. Korpi-Hyovalti, Eeva Oksa, Heikki Chambers, John C. Kooner, Jaspal S. Blakemore, Alexandra I. F. Franks, Steve Jarvelin, Marjo-Riitta Husemoen, Lise L. Linneberg, Allan Skaaby, Tea Thuesen, Betina Karpe, Fredrik Tuomilehto, Jaakko Doney, Alex S. F. Morris, Andrew D. Palmer, Colin N. A. Holmen, Oddgeir Lingaas Hveem, Kristian Willer, Cristen J. Tuomi, Tiinamaija Groop, Leif Karajamaki, AnneMari Palotie, Aarno Ripatti, Samuli Salomaa, Veikko Alam, Dewan S. Majmnder, Abdulla Al Shafi Di Angelantonio, Emanuele Chowdhury, Rajiv McCarthy, Mark I. Poulter, Neil Stanton, Alice V. Sever, Peter Amouyel, Philippe Arveiler, Dominique Blankenberg, Stefan Ferrieres, Jean Kee, Frank Kuulasmaa, Kari Muller-Nurasyid, Martina Veronesi, Giovanni Virtamo, Jarmo Deloukas, Panos Elliott, Paul Zeggini, Eleftheria Kathiresan, Sekar Melander, Olle Kuusisto, Johanna Laakso, Markku Padmanabhan, Sandosh Porteous, David J. Hayward, Caroline Scotland, Generation Collins, Francis S. Mohlke, Karen L. Hansen, Torben Pedersen, Oluf Boehnke, Michael Stringham, Heather M. Frossard, Philippe Newton-Cheh, Christopher Tobin, Martin D. Nordestgaard, Borge Gronne Caulfield, Mark J. Mahajan, Anubha Morris, Andrew P. Tomaszewski, Maciej Samani, Nilesh J. Saleheen, Danish Asselbergs, Folkert W. Lindgren, Cecilia M. Danesh, John Wain, Louise V. Butterworth, Adam S. Howson, Joanna M. M. Munroe, Patricia B. CA CHARGE Heart Failure Consortiumm EchoGen Consortiumm Metastroke Consortiumm Giant Consortiumm EPIC-InterAct Consortium Lifelines Cohort Study Wellcome Trust Case Control Consor Understanding Soc Sci Grp EPIC-CVD Consortium CHARGE Exome Chip Blood Pressure C T2D-GENES Consortium GoT2DGenes Consortium ExomeBP Consortium CHD Exome Consortium TI Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENE-CENTRIC ARRAY; CARDIOVASCULAR-DISEASE; AGING RESEARCH; PLASMA-LEVELS; RISK-FACTORS; LOCI; CHARGE; HEART; IDENTIFICATION AB High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low frequency and common genetic variants in up to 192,763 individuals and used similar to 155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention. C1 [Surendran, Praveen; Young, Robin; Barnes, Daniel R.; Staley, James R.; Freitag, Daniel F.; Burgess, Stephen; Di Angelantonio, Emanuele; Chowdhury, Rajiv; Saleheen, Danish; Danesh, John; Butterworth, Adam S.; Howson, Joanna M. M.] Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England. [Drenos, Fotios] Univ Bristol, Sch Social & Community Med, Med Res Council Integrat Epidemiol Unit, Oakfield House, Bristol, Avon, England. [Drenos, Fotios] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Warren, Helen; Witkowska, Kate; Shaw-Hawkins, Susan; Brown, Morris J.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England. [Warren, Helen; Witkowska, Kate; Tinker, Andrew; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Natl Inst Hlth Res, Barts Cardiovasc Biomed Res Unit, London, England. 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[Danesh, John; Munroe, Patricia B.] Wellcome Trust Sanger Inst, Hinxton, England. RP Howson, JMM (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.; Howson, JMM (reprint author), Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England.; Howson, JMM (reprint author), Queen Mary Univ London, Natl Inst Hlth Res, Barts Cardiovasc Biomed Res Unit, London, England.; Howson, JMM; Munroe, PB (reprint author), Wellcome Trust Sanger Inst, Hinxton, England. EM jmmh2@medschl.cam.ac.uk; p.b.munroe@qmul.ac.uk RI Palmer, Colin/C-7053-2008; Deloukas, Panos/B-2922-2013; Padmanabhan, Sandosh/S-3963-2016; Verweij, Niek/A-4499-2017; Grarup, Niels/K-2807-2015; Lieb, Wolfgang/C-1990-2012; Polasek, Ozren/B-6002-2011; OI Evangelou, Evangelos/0000-0002-5488-2999; Kontto, Jukka/0000-0003-3899-9852; Burgess, Stephen/0000-0001-5365-8760; Linneberg, Allan/0000-0002-0994-0184; Wain, Louise/0000-0003-4951-1867; Palmer, Colin/0000-0002-6415-6560; Deloukas, Panos/0000-0001-9251-070X; Varga, Tibor/0000-0002-2383-699X; Grarup, Niels/0000-0001-5526-1070; Polasek, Ozren/0000-0002-5765-1862; Traylor, Matthew/0000-0001-6624-8621; Skaaby, Tea/0000-0003-0031-5726; Kuulasmaa, Kari/0000-0003-2165-1411; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Tuomi, Tiinamaija/0000-0002-8306-6202 FU British Heart Foundation [RG/14/5/30893, RG/15/15/31742]; Chief Scientist Office [CZD/16/6/4]; Medical Research Council [MC_UU_12013/5, G0600237, G0601966, G0700931, MC_PC_U127561128, MC_UU_12015/1, MR/K006584/1, MR/K026992/1, MR/L01341X/1]; NHLBI NIH HHS [R01 HL127564]; NIDDK NIH HHS [P30 DK020595, U01 DK062370] NR 43 TC 8 Z9 8 U1 25 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2016 VL 48 IS 10 BP 1151 EP 1161 DI 10.1038/ng.3654 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DX5AG UT WOS:000384391600010 PM 27618447 ER PT J AU Liu, CY Kraja, AT Smith, JA Brody, JA Franceschini, N Bis, JC Rice, K Morrison, AC Lu, YC Weiss, S Guo, XQ Palmas, W Martin, LW Chen, YDI Surendran, P Drenos, F Cook, JP Auer, PL Chu, AY Giri, A Zhao, W Jakobsdottir, J Lin, LA Stafford, JM Amin, N Mei, H Yao, J Voorman, A Larson, MG Grove, ML Smith, AV Hwang, SJ Chen, H Huan, T Kosova, G Stitziel, NO Kathiresan, S Samani, N Schunkert, H Deloukas, P Li, M Fuchsberger, C Pattaro, C Gorski, M Kooperberg, C Papanicolaou, GJ Rossouw, JE Paul, JD Kardia, SLR Bouchard, C Raffe, LF Uitterlinden, AG Franco, OH Vasan, RS O'Donnell, CJ Taylor, KD Liu, K Bottinger, EP Gottesman, O Daw, EW Giulianini, F Ganesh, S Salfati, E Harris, TB Launer, LJ Dorr, M Felix, SB Rettig, R Volzke, H Kim, E Lee, WJ Lee, IT Sheu, WHH Tsosie, KS Edwards, DRV Liu, YM Correa, A Weir, DR Volker, U Ridker, PM Boerwinkle, E Gudnason, V Reiner, AP van Duijn, CM Boreckill, IB Edwards, TL Chakravarti, A Rotter, JI Psaty, BM Loos, RJF Fornage, M Ehret, GB Newton-Cheh, C Levy, D Chasman, DI AF Liu, Chunyu Kraja, Aldi T. Smith, Jennifer A. Brody, Jennifer A. Franceschini, Nora Bis, Joshua C. Rice, Kenneth Morrison, Alanna C. Lu, Yingchang Weiss, Stefan Guo, Xiuqing Palmas, Walter Martin, Lisa W. Chen, Yii-Der Ida Surendran, Praveen Drenos, Fotios Cook, James P. Auer, Paul L. Chu, Audrey Y. Giri, Ayush Zhao, Wei Jakobsdottir, Johanna Lin, Li-An Stafford, Jeanette M. Amin, Najaf Mei, Hao Yao, Jie Voorman, Arend Larson, Martin G. Grove, Megan L. Smith, Albert V. Hwang, Shih-Jen Chen, Han Huan, Tiamdao Kosova, Gulum Stitziel, Nathan O. Kathiresan, Sekar Samani, Nilesh Schunkert, Heribert Deloukas, Panos Li, Man Fuchsberger, Christian Pattaro, Cristian Gorski, Mathias Kooperberg, Charles Papanicolaou, George J. Rossouw, Jacques E. Paul, Jessica D. Kardia, Sharon L. R. Bouchard, Claude Raffe, Leslie F. Uitterlinden, Andre G. Franco, Oscar H. Vasan, Ramachandran S. O'Donnell, Christopher J. Taylor, Kent D. Liu, Kiang Bottinger, Erwin P. Gottesman, Omri Daw, E. Warwick Giulianini, Franco Ganesh, Santhi Salfati, Elias Harris, Tamara B. Launer, Lenore J. Dorr, Marcus Felix, Stephan B. Rettig, Rainer Volzke, Henry Kim, Eric Lee, Wen-Jane Lee, I-Te Sheu, Wayne H-H Tsosie, Krystal S. Edwards, Digna R. Velez Liu, Yongmei Correa, Adolfo Weir, David R. Volker, Uwe Ridker, Paul M. Boerwinkle, Eric Gudnason, Vilmundur Reiner, Alexander P. van Duijn, Cornelia M. Boreckill, Ingrid B. Edwards, Todd L. Chakravarti, Aravinda Rotter, Jerome I. Psaty, Bruce M. Loos, Ruth J. F. Fornage, Myriam Ehret, Georg B. Newton-Cheh, Christopher Levy, Daniel Chasman, Daniel I. CA CHD Exome Consortium ExomeBP Consortium GOT2Dgenes Consortium T2D-Genes Consortium Myocardial Infarction Genetics CAR CKDGen Consortium TI Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; LIPOPROTEIN-LIPASE GENE; NATRIURETIC PEPTIDE RECEPTOR; SUSCEPTIBILITY LOCI; MONOGENIC FORMS; CENTRIC ARRAY; HYPERTENSION; DISEASE; EXPRESSION; RISK AB Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk. C1 [Liu, Chunyu; Chu, Audrey Y.; Larson, Martin G.; Hwang, Shih-Jen; Huan, Tiamdao; Vasan, Ramachandran S.; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Liu, Chunyu; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Liu, Chunyu; Chu, Audrey Y.; Hwang, Shih-Jen; Huan, Tiamdao; Levy, Daniel] NHLBI, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA. [Kraja, Aldi T.; Daw, E. Warwick; Boreckill, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. [Kraja, Aldi T.; Daw, E. Warwick; Boreckill, Ingrid B.] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO USA. [Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Brody, Jennifer A.; Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Franceschini, Nora] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Morrison, Alanna C.; Grove, Megan L.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA. [Lu, Yingchang; Bottinger, Erwin P.; Gottesman, Omri; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Weiss, Stefan; Dorr, Marcus; Felix, Stephan B.; Rettig, Rainer; Volzke, Henry; Volker, Uwe] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany. [Weiss, Stefan; Volker, Uwe] Univ Med, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Weiss, Stefan; Correa, Adolfo; Volker, Uwe] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. [Guo, Xiuqing; Chen, Yii-Der Ida; Yao, Jie; Taylor, Kent D.; Kim, Eric; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Guo, Xiuqing; Chen, Yii-Der Ida; Yao, Jie; Taylor, Kent D.; Kim, Eric; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Palmas, Walter] Columbia Univ, Med Ctr, Div Gen Med, New York, NY USA. [Martin, Lisa W.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Surendran, Praveen] Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England. [Drenos, Fotios] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Drenos, Fotios] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Oakfield House, Bristol, Avon, England. [Cook, James P.] Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England. [Cook, James P.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Auer, Paul L.] Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA. [Chu, Audrey Y.; Giulianini, Franco; Ridker, Paul M.; Levy, Daniel] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Giri, Ayush; Tsosie, Krystal S.; Edwards, Digna R. Velez; Edwards, Todd L.] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Vanderbilt Epidemiol Ctr,Med Ctr, Nashville, TN USA. [Jakobsdottir, Johanna; Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Lin, Li-An; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Stafford, Jeanette M.] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Amin, Najaf; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Mei, Hao] Univ Mississippi, Med Ctr, Dept Data Sci, Sch Populat Hlth, Jackson, MS 39216 USA. [Voorman, Arend] Bill & Melinda Gates Fdn, Seattle, WA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Smith, Albert V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Chen, Han] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kosova, Gulum] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kosova, Gulum; Kathiresan, Sekar; Newton-Cheh, Christopher] Broad Inst MIT & Harvard, Program Med & Populat Genet, Boston, MA USA. [Stitziel, Nathan O.] Washington Univ, Dept Med, Sch Med, Div Cardiol, St Louis, MO USA. [Stitziel, Nathan O.] Washington Univ, Dept Genet, Sch Med, St Louis, MO USA. [Samani, Nilesh] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany. [Schunkert, Heribert] DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia. [Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Li, Man] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Fuchsberger, Christian; Pattaro, Cristian] European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy. [Fuchsberger, Christian; Pattaro, Cristian] Univ Lubeck, Lubeck, Germany. [Gorski, Mathias] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, Regensburg, Germany. [Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Papanicolaou, George J.; Rossouw, Jacques E.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Paul, Jessica D.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA. [Bouchard, Claude] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Raffe, Leslie F.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Uitterlinden, Andre G.; Franco, Oscar H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Boston Vet Adm Healthcare, Cardiol Sect, Dept Med, Boston, MA USA. [O'Donnell, Christopher J.] Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. [O'Donnell, Christopher J.] Harvard Med Sch, Dept Med, Boston, MA USA. [Liu, Kiang] Northwestern Univ, Sch Med, Chicago, IL 60611 USA. [Ganesh, Santhi] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Ganesh, Santhi] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Salfati, Elias] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Harris, Tamara B.; Chakravarti, Aravinda; Ehret, Georg B.] NIA, Lab Epidemiol Demog & Biometry, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Launer, Lenore J.] NIA, Neuroepidemiol Sect, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Dorr, Marcus] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, Greifswald, Germany. [Volzke, Henry] DZD German Ctr Diabet Res, Site Greifswald, Greifswald, Germany. [Volzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Lee, Wen-Jane] Taichung Vet Gen Hosp, Dept Med Res, Taichung, Taiwan. [Lee, I-Te; Sheu, Wayne H-H] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrinol & Metab, Taichung, Taiwan. [Sheu, Wayne H-H] Natl Yang Ming Univ, Sch Med, Taipei, Taiwan. [Lee, I-Te] Chung Shan Med Univ, Sch Med, Taichung, Taiwan. [Sheu, Wayne H-H] Natl Chung Hsing Univ, Inst Med Technol, Taichung, Taiwan. [Sheu, Wayne H-H] Natl Def Med Ctr, Sch Med, Taipei, Taiwan. [Edwards, Digna R. Velez] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Liu, Yongmei] Wake Forest Baptist Med Ctr, Epidemiol & Prevent Ctr Genom & Personalized Med, Winston Salem, NC USA. [Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Ridker, Paul M.; Chasman, Daniel I.] Harvard Med Sch, Boston, MA USA. [Reiner, Alexander P.; Psaty, Bruce M.; Chasman, Daniel I.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Edwards, Todd L.] Vanderbilt Univ, Med Ctr, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Ehret, Georg B.] Univ Hosp Geneva, Cardiol, Geneva, Switzerland. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Liu, C; Levy, D (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA.; Liu, C (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.; Liu, C; Levy, D (reprint author), NHLBI, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA.; Chasman, DI (reprint author), Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.; Chasman, DI (reprint author), Harvard Med Sch, Boston, MA USA. EM chunyu.liu@nih.gov; levyd@nhlbi.nih.gov; dchasman@research.bwh.harvard.edu RI Deloukas, Panos/B-2922-2013; Lin, LiAn/C-5819-2017; Bouchard, Claude/A-7637-2009; OI Deloukas, Panos/0000-0001-9251-070X; Lin, LiAn/0000-0003-2731-1346; Chen, Han/0000-0002-9510-4923; Smith, Jennifer/0000-0002-3575-5468 FU British Heart Foundation [RG/14/5/30893]; Medical Research Council [MC_UU_12013/5]; NHGRI NIH HHS [U01 HG004603, U01 HG004729]; NHLBI NIH HHS [R01 HL120393, HHSN268200800007C, HHSN268200900041C, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C, HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268201300046C, N01 HC025195, N01 HC085079, N01 HC095159, N01HC55222, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, R01 HL068986, R01 HL080295, R01 HL084099, R01 HL087652, R01 HL093029, R01 HL103612, R01 HL105756, R01 HL117078, R21 HL121429, RC2 HL102419, T32 HL007208, U01 HL130114]; NIA NIH HHS [HHSN271201200022C, N01AG12100, R01 AG023629]; NIGMS NIH HHS [RC2 GM092618]; NIH HHS [S10 OD020069] NR 74 TC 6 Z9 6 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2016 VL 48 IS 10 BP 1162 EP 1170 DI 10.1038/ng.3660 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DX5AG UT WOS:000384391600011 PM 27618448 ER PT J AU Ehret, GB Ferreira, T Chasman, DI Jackson, AU Schmidt, EM Johnson, T Thorleifsson, G Luan, J Donnelly, LA Kanoni, S Petersen, AK Pihurl, V Strawbridge, RJ Shungin, D Hughes, MF Meirelles, O Kaakinen, M Bouatia-Naji, N Kristiansson, K Shah, S Kleber, ME Guo, XQ Lyytikainen, LP Fava, C Eriksson, N Nolte, IM Magnusson, PK Salfati, EL Rallidis, LS Theusch, E Smith, AJP Folkersen, L Witkowska, K Pers, TH Joehanes, R Kim, SK Lataniotis, L Jansen, R Johnson, AD Warren, H Kim, YJ Zhao, W Wu, Y Tayo, BO Bochud, M Absher, D Adair, LS Amin, N Arkingl, DE Axelsson, T Baldassarre, D Balkau, B Bandinelli, S Barnes, MR Barroso, I Bevan, S Bis, JC Bjornsdottir, G Boehnke, M Boerwinkle, E Bonnycastle, LL Boomsma, DI Bornstein, SR Brown, MJ Burnier, M Cabrera, CP Chambers, JC Chang, IS Cheng, CY Chines, PS Chung, RH Collins, FS Connell, JM Doring, A Dallongeville, J Danesh, J de Faire, U Delgado, G Dominiczak, AF Doney, ASF Drenos, F Edkins, S Eicher, JD Elosua, R Enroth, S Erdmann, J Eriksson, P Esko, T Evangelou, E Evans, A Fai, T Farra, M Felixl, JF Ferrieres, J Ferrucci, L Fornage, M Forrester, T Franceschinil, N Franco, OH Franco-Cereceda, A Fraser, RM Ganesh, SK Gao, H Gertow, K Gianfagna, F Gigante, B Giulianini, F Goe, A Goodall, AH Goodarzi, M Gorski, M Grassler, J Groves, CJ Gudnason, V Gyllensten, U Hallmans, G Hartikainen, AL Hassinen, M Havulinna, AS Hayward, C Hercberg, S Herzig, KH Hicks, AA Hingorani, AD Hirschhorn, JN Hofmanl, A Holmen, J Holmen, OL Hottenga, JJ Howard, P Hsiung, CA Hunt, SC Ikram, MA Illig, T Iribarren, C Jensen, RA Kahonen, M Kang, HM Kathiresan, S Keating, BJ Khaw, KT Kim, YK Kim, E Kivimaki, M Klopp, N Kolovou, G Komulainen, P Kooner, JS Kosova, G Krauss, RM Kuh, D Kutalik, Z Kuusisto, J Kvaloy, K Lakka, TA Lee, NR Lee, IT Lee, WJ Levy, D Li, X Liang, KW Lin, H Lin, L Lindstrom, J Lobbens, S Mannisto, S Muller, G Muller-Nurasyid, M Mach, F Markus, HS Marouli, E McCarthy, MI McKenzie, CA Meneton, P Menni, C Metspalu, A Mijatovic, V Moilanen, L Montasser, ME Morris, AD Morrison, AC Mulas, A Nagaraja, R Narisu, N Nikus, K O'Donnell, CJ O'Reilly, PF Ong, KK Paccaud, F Palmer, CD Parsa, A Pedersen, NL Penninx, BW Perola, M Peters, A Poulter, N Pramstaller, PP Psaty, BM Quertermous, T Rao, DC Rasheed, A Rayner, NW Renstrom, F Rettig, R Rice, KM Roberts, R Rose, LM Rossouw, J Samani, NJ Sanna, S Saramies, J Schunkert, H Sebert, S Sheu, WHH Shin, YA Sim, X Smit, JH Smith, AV Sosa, MX Spector, TD Stancakova, A Stanton, AV Stirrups, KE Stringham, HM Sundstrom, J Swift, AJ Syvanen, AC Tai, ES Tanaka, T Tarasov, KV Teumer, A Thorsteinsdottir, U Tobin, MD Tremoli, E Uitterlinden, AG Uusitupa, M Vaez, A Vaidya, D van Duijn, CM van Iperen, EPA Vasan, RS Verwoert, GC Virtamo, J Vitart, V Voight, BF Vollenweider, P Wagner, A Wain, LV Wareham, NJ Watldns, H Weder, AB Westra, HJ Wilks, R Wilsgaard, T Wilson, JF Wong, TY Yang, TP Yao, J Yengo, L Zhang, W Zhao, JH Zhu, X Bovet, P Cooper, RS Mohlke, KL Saleheen, D Lee, JY Elliott, P Gierman, HJ Willer, CJ Franke, L Hovingh, GK Taylor, KD Dedoussis, G Sever, P Wong, A Lind, L Assimes, TL Njolstad, I Schwarz, PEH Langenberg, C Snieder, H Caulfield, MJ Melander, E Laakso, M Saltevo, J Rauramaa, R Tuomilehto, J Ingelsson, E Lehtimaki, T Hveem, K Palmas, W Marz, W Kumar, M Salomaa, V Chen, YDI Rotter, JI Froguel, P Jarvelin, MR Lakatta, EG Kuulasmaa, K Franks, PW Hamsten, A Wichmann, HE Palmer, CNA Stefansson, K Ridker, PM Loos, RJF Chalcravarti, A Deloukas, P Morris, AP Newton-Cheh, C Munroe, PB AF Ehret, Georg B. Ferreira, Teresa Chasman, Daniel I. Jackson, Anne U. Schmidt, Ellen M. Johnson, Toby Thorleifsson, Gudmar Luan, Jian'an Donnelly, Louise A. Kanoni, Stavroula Petersen, Ann -Kristin Pihurl, Vasyl Strawbridge, Rona J. Shungin, Dmitry Hughes, Maria F. Meirelles, Osorio Kaakinen, Marika Bouatia-Naji, Nabila Kristiansson, Kati Shah, Sonia Kleber, Marcus E. Guo, Xiuqing Lyytikainen, Leo-Pekka Fava, Cristiano Eriksson, Nidas Nolte, Ilja M. Magnusson, Patrik K. Salfati, Elias L. Rallidis, Loukianos S. Theusch, Elizabeth Smith, Andrew J. P. Folkersen, Lasse Witkowska, Kate Pers, Tune H. Joehanes, Roby Kim, Stuart K. Lataniotis, Lazaros Jansen, Rick Johnson, Andrew D. Warren, Helen Kim, Young Jin Zhao, Wei Wu, Ying Tayo, Bamidele O. Bochud, Murielle Absher, Devin Adair, Linda S. Amin, Najaf Arkingl, Dan E. Axelsson, Tomas Baldassarre, Damian Balkau, Beverley Bandinelli, Stefania Barnes, Michael R. Barroso, Ines Bevan, Stephen Bis, Joshua C. Bjornsdottir, Gyda Boehnke, Michael Boerwinkle, Eric Bonnycastle, Lori L. Boomsma, Dorret I. Bornstein, Stefan R. Brown, Morris J. Burnier, Michel Cabrera, Claudia P. Chambers, John C. Chang, I-Shou Cheng, Ching-Yu Chines, Peter S. Chung, Ren-Hua Collins, Francis S. Connell, John M. Doring, Angela Dallongeville, Jean Danesh, John de Faire, Ulf Delgado, Graciela Dominiczak, Anna F. Doney, Alex S. F. Drenos, Fotios Edkins, Sarah Eicher, John D. Elosua, Roberto Enroth, Stefan Erdmann, Jeanette Eriksson, Per Esko, Tonu Evangelou, Evangelos Evans, Alun Fai, Tove Farra, Martin Felixl, Janine F. Ferrieres, Jean Ferrucci, Luigi Fornage, Myriam Forrester, Terrence Franceschinil, Nora Franco, Oscar H. Franco-Cereceda, Anders Fraser, Ross M. Ganesh, Santhi K. Gao, He Gertow, Karl Gianfagna, Francesco Gigante, Bruna Giulianini, Franco Goe, Anuj Goodall, Alison H. Goodarzi, Mark Gorski, Mathias Grassler, Jurgen Groves, Christopher J. Gudnason, Vilmundur Gyllensten, Ulf Hallmans, Goran Hartikainen, Anna-Liisa Hassinen, Maija Havulinna, Aki S. Hayward, Caroline Hercberg, Serge Herzig, Karl-Heinz Hicks, Andrew A. Hingorani, Aroon D. Hirschhorn, Joel N. Hofmanl, Albert Holmen, Jostein Holmen, Oddgeir Lingaas Hottenga, Jouke-Jan Howard, Phil Hsiung, Chao A. Hunt, Steven C. Ikram, M. Arfan Illig, Thomas Iribarren, Carlos Jensen, Richard A. Kahonen, Mika Kang, Hyun Min Kathiresan, Sekar Keating, Brendan J. Khaw, Kay-Tee Kim, Yun Kyoung Kim, Eric Kivimaki, Mika Klopp, Norman Kolovou, Genovefa Komulainen, Pirjo Kooner, Jaspal S. Kosova, Gulum Krauss, Ronald M. Kuh, Diana Kutalik, Zoltan Kuusisto, Johanna Kvaloy, Kirsti Lakka, Timo A. Lee, Nanette R. Lee, I-Te Lee, Wen-Jane Levy, Daniel Li, Xiaohui Liang, Kae-Woei Lin, Honghuang Lin, Li Lindstrom, Jaana Lobbens, Stephane Mannisto, Satu Muller, Gabriele Muller-Nurasyid, Martina Mach, Francois Markus, Hugh S. Marouli, Eirini McCarthy, Mark I. McKenzie, Colin A. Meneton, Pierre Menni, Cristina Metspalu, Andres Mijatovic, Vladan Moilanen, Leena Montasser, May E. Morris, Andrew D. Morrison, Alanna C. Mulas, Antonella Nagaraja, Ramaiah Narisu, Narisu Nikus, Kjell O'Donnell, Christopher J. O'Reilly, Paul F. Ong, Ken K. Paccaud, Fred Palmer, Cameron D. Parsa, Afshin Pedersen, Nancy L. Penninx, Brenda W. Perola, Markus Peters, Annette Poulter, Neil Pramstaller, Peter P. Psaty, Bruce M. Quertermous, Thomas Rao, Dabeeru C. Rasheed, Asif Rayner, N. William Renstrom, Frida Rettig, Rainer Rice, Kenneth M. Roberts, Robert Rose, Lynda M. Rossouw, Jacques Samani, Nilesh J. Sanna, Serena Saramies, Jouko Schunkert, Heribert Sebert, Sylvain Sheu, Wayne H-H Shin, Young-Ah Sim, Xueling Smit, Johannes H. Smith, Albert V. Sosa, Maria X. Spector, Tim D. Stancakova, Alena Stanton, Alice V. Stirrups, Kathleen E. Stringham, Heather M. Sundstrom, Johan Swift, Amy J. Syvanen, Ann-Christine Tai, E-Shyong Tanaka, Toshiko Tarasov, Kirill V. Teumer, Alexander Thorsteinsdottir, Unnur Tobin, Martin D. Tremoli, Elena Uitterlinden, Andre G. Uusitupa, Matti Vaez, Ahmad Vaidya, Dhananjay van Duijn, Cornelia M. van Iperen, Erik P. A. Vasan, Ramachandran S. Verwoert, Germaine C. Virtamo, Jarmo Vitart, Veronique Voight, Benjamin F. Vollenweider, Peter Wagner, Aline Wain, Louise V. Wareham, Nicholas J. Watldns, Hugh Weder, Alan B. Westra, Harm Jan Wilks, Rainford Wilsgaard, Tom Wilson, James F. Wong, Tien Y. Yang, Tsun-Po Yao, Jie Yengo, Loic Zhang, Weihua Zhao, Jing Hua Zhu, Xiaofeng Bovet, Pascal Cooper, Richard S. Mohlke, Karen L. Saleheen, Danish Lee, Jong-Young Elliott, Paul Gierman, Hinco J. Willer, Cristen J. Franke, Lude Hovingh, G. Kees Taylor, Kent D. Dedoussis, George Sever, Peter Wong, Andrew Lind, Lars Assimes, Themistocles L. Njolstad, Inger Schwarz, Peter E. H. Langenberg, Claudia Snieder, Harold Caulfield, Mark J. Melander, E. Laakso, Markku Saltevo, Juha Rauramaa, Rainer Tuomilehto, Jaakko Ingelsson, Erik Lehtimaki, Terho Hveem, Kristian Palmas, Walter Marz, Winfried Kumar, Meena Salomaa, Veikko Chen, Yii-Der I. Rotter, Jerome I. Froguel, Philippe Jarvelin, Marjo-Riitta Lakatta, Edward G. Kuulasmaa, Kari Franks, Paul W. Hamsten, Anders Wichmann, H-Erich Palmer, Colin N. A. Stefansson, Kari Ridker, Paul M. Loos, Ruth J. F. Chalcravarti, Aravinda Deloukas, Panos Morris, Andrew P. Newton-Cheh, Christopher Munroe, Patricia B. CA CHARGE-EchoGen Consortium CHARGE-HF Consortium Wellcome Trust Case Control Consor TI The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ARTERIAL-HYPERTENSION; COMMON VARIANTS; CELL-TYPES; LOCI; TRAITS; CHROMATIN; SUSCEPTIBILITY; METAANALYSIS; BIOLOGY AB To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation. C1 [Ehret, Georg B.; Pihurl, Vasyl; Arkingl, Dan E.; Sosa, Maria X.; Chalcravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Ehret, Georg B.; Lin, Li; Mach, Francois] Univ Hosp Geneva, Dept Med, Cardiol, Geneva, Switzerland. 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[Kooner, Jaspal S.] MRC Unit Lifelong Hlth & Ageing UCL, London, England. [Krauss, Ronald M.] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kuh, Diana; Wong, Andrew] Swiss Inst Bioinformat, Lausanne, Switzerland. [Kutalik, Zoltan] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Kutalik, Zoltan] Kuopio Univ Hosp, Kuopio, Finland. [Kutalik, Zoltan] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland. [Lakka, Timo A.] Off Populat Studies Fdn Inc, Cebu, Philippines. [Lakka, Timo A.; Sebert, Sylvain; Rauramaa, Rainer] Univ San Carlos, Dept Anthropol Sociol & Hist, Cebu, Philippines. [Lee, Nanette R.] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrine & Metab, Taichung, Taiwan. [Lee, Nanette R.] Natl Yang Ming Univ, Sch Med, Taipei, Taiwan. [Lee, I-Te; Sheu, Wayne H-H] Taichung Vet Gen Hosp, Dept Med Res, Taichung, Taiwan. 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[Schunkert, Heribert] Munich Heart Alliance, Munich, Germany. [Schunkert, Heribert] Univ Oulu, Ctr Lifecourse Hlth Res, Oulu, Finland. [Sebert, Sylvain; Jarvelin, Marjo-Riitta] Natl Def Med Ctr, Coll Med, Taipei, Taiwan. Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. Natl Univ Hlth Syst, Singapore, Singapore. [Sim, Xueling; Tai, E-Shyong] Univ Eastern Finland, Kuopio, Finland. [Sim, Xueling; Tai, E-Shyong] Kuopio Univ Hosp, Kuopio, Finland. [Stancakova, Alena] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin, Ireland. [Stanton, Alice V.] Univ Cambridge, Dept Haematol, Cambridge, England. [Stirrups, Kathleen E.] Natl Univ Singapore, Dept Med, Singapore, Singapore. [Stirrups, Kathleen E.] Natl Univ Hlth Syst, Singapore, Singapore. [Tai, E-Shyong] NIA, Intramural Res Program, Lab Cardiovasc Sci, US Natl Inst Hlth, Baltimore, MD 21224 USA. [Tarasov, Kirill V.; Lakatta, Edward G.] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Teumer, Alexander] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Tobin, Martin D.; Wain, Louise V.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, Kuopio, Finland. [Uusitupa, Matti] Isfahan Univ Med Sci, Res Inst Primordial Prevent Noncommunicable Dis, Esfahan, Iran. [Vaez, Ahmad] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Vaidya, Dhananjay] NGI Erasmus Med Ctr, Ctr Med Syst Biol CMSB 12, Rotterdam, Netherlands. [van Duijn, Cornelia M.] Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands. [van Iperen, Erik P. A.] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. [van Iperen, Erik P. A.] Boston Univ, Dept Med, Sect Prevent Med, Sch Med, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol, Boston, MA 02215 USA. 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[Palmas, Walter] Columbia Univ, Dept Med, New York, NY USA. [Marz, Winfried] Synlab Acad, Synlab Serv, Mannheim, Germany. [Marz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Franks, Paul W.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Wichmann, H-Erich] Tech Univ Munich, Inst Med Stat & Epidemiol, Munich, Germany. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth Dev Inst, New York, NY 10029 USA. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England. RP Munroe, PB (reprint author), Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England.; Munroe, PB (reprint author), Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England.; Newton-Cheh, C (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.; Newton-Cheh, C (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA.; Newton-Cheh, C (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM cnewtoncheh@mgh.harvard.edu; p.b.munroe@qmul.ac.uk RI Magnusson, Patrik/C-4458-2017; Yengo, Loic/D-2692-2017; Hicks, Andrew/E-9518-2017; BOUATIA-NAJI, NABILA/D-5863-2013; Assimes, Themistocles/D-9696-2015; Johnson, Andrew/G-6520-2013; Franke, Lude/P-7036-2016; Wong, Andrew/M-8899-2016; Shah, Sonia/N-7547-2013; Bovet, Pascal/F-4477-2011; Palmer, Colin/C-7053-2008; Peters, Annette/A-6117-2011; Vollenweider, Peter/Q-4603-2016; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013 OI Evangelou, Evangelos/0000-0002-5488-2999; Vaidya, Dhananjay/0000-0002-7164-1601; Folkersen, Lasse/0000-0003-0708-9530; Tai, E Shyong/0000-0003-2929-8966; Smith, Andrew/0000-0003-1141-2978; Peters, Annette/0000-0001-6645-0985; Wain, Louise/0000-0003-4951-1867; Yengo, Loic/0000-0002-4272-9305; Hicks, Andrew/0000-0001-6320-0411; Gianfagna, Francesco/0000-0003-4615-0816; Enroth, Stefan/0000-0002-5056-9137; Bevan, Steve/0000-0003-0490-6830; Kumari, Meena/0000-0001-9716-1035; Kuulasmaa, Kari/0000-0003-2165-1411; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Assimes, Themistocles/0000-0003-2349-0009; Franke, Lude/0000-0002-5159-8802; Wong, Andrew/0000-0003-2079-4779; Shah, Sonia/0000-0001-5860-4526; Bovet, Pascal/0000-0002-0242-4259; Palmer, Colin/0000-0002-6415-6560; Vollenweider, Peter/0000-0002-0765-896X; Deloukas, Panos/0000-0001-9251-070X; FU British Heart Foundation [RG/13/2/30098, RG/14/5/30893, RG/10/12/28456]; Medical Research Council [G0401527, G0600237, G0601261, G1000143, MC_PC_U127561128, MC_UU_12013/5, MC_UU_12015/1, MC_UU_12019/1, MR/K006584/1, MR/K013351/1, MR/L01341X/1]; NCATS NIH HHS [UL1 TR000124]; NHLBI NIH HHS [R01 HL086694, R01 HL113933, R01 HL122684, T32 HL007208, T32 HL098049]; NIA NIH HHS [R01 AG025941]; NICHD NIH HHS [P2C HD050924]; NIDDK NIH HHS [P30 DK063491, U01 DK062370] NR 40 TC 9 Z9 9 U1 29 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2016 VL 48 IS 10 BP 1171 EP 1184 DI 10.1038/ng.3667 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DX5AG UT WOS:000384391600012 PM 27618452 ER PT J AU McCarthy, S Das, S Kretzschmar, W Delaneau, O Wood, AR Teumer, A Kang, HM Fuchsberger, C Danecek, P Sharp, K Luo, Y Sidorel, C Kwong, A Timpson, N Koskinen, S Vrieze, S Scott, LJ Zhang, H Mahajan, A Veldink, J Peters, U Pato, C van Duijn, CM Gillies, CE Gandin, I Mezzavilla, M Gilly, A Cocca, M Traglia, M Angius, A Barrett, JC Boomsma, D Branham, K Breen, G Brummett, CM Busonero, F Campbell, H Chan, A Che, S Chew, E Collins, FS Corbin, LJ Smith, GD Dedoussis, G Dorr, M Farmaki, AE Ferrucci, L Forer, L Fraser, RM Gabriel, S Levy, S Groop, L Harrison, T Hattersley, A Holmen, OL Hveem, K Kretzler, M Lee, JC McGue, M Meitinger, T Melzer, D Min, JL Mohlke, KL Vincent, JB Nauck, M Nickerson, D Palotie, A Pato, M Pirastu, N McInnis, M Richards, JB Sala, C Salomaa, V Schlessinger, D Schoenherr, S Slagboom, PE Small, K Spector, T Stambolian, D Tuke, M Tuomilehto, J van den Berg, LH Van Rheenen, W Volker, U Wijmenga, C Toniolo, D Zeggini, E Gasparini, P Sampson, MG Wilson, JF Frayling, T de Bakker, PIW Swertz, MA McCarroll, S Kooperberg, C Dekker, A Altshuler, D Willer, C Iacono, W Ripatti, S Soranzo, N Walter, K Swaroop, A Cucca, F Anderson, CA Myers, RM Boehnke, M McCarthy, MI Durbin, R Abecasis, G Marchini, J AF McCarthy, Shane Das, Sayantan Kretzschmar, Warren Delaneau, Olivier Wood, Andrew R. Teumer, Alexander Kang, Hyun Min Fuchsberger, Christian Danecek, Petr Sharp, Kevin Luo, Yang Sidorel, Carlo Kwong, Alan Timpson, Nicholas Koskinen, Seppo Vrieze, Scott Scott, Laura J. Zhang, He Mahajan, Anubha Veldink, Jan Peters, Ulrike Pato, Carlos van Duijn, Cornelia M. Gillies, Christopher E. Gandin, Ilaria Mezzavilla, Massimo Gilly, Arthur Cocca, Massimiliano Traglia, Michela Angius, Andrea Barrett, Jeffrey C. Boomsma, Dorrett Branham, Kari Breen, Gerome Brummett, Chad M. Busonero, Fabio Campbell, Harry Chan, Andrew Che, Sai Chew, Emily Collins, Francis S. Corbin, Laura J. Smith, George Davey Dedoussis, George Dorr, Marcus Farmaki, Aliki-Eleni Ferrucci, Luigi Forer, Lukas Fraser, Ross M. Gabriel, Stacey Levy, Shawn Groop, Leif Harrison, Tabitha Hattersley, Andrew Holmen, Oddgeir L. Hveem, Kristian Kretzler, Matthias Lee, James C. McGue, Matt Meitinger, Thomas Melzer, David Min, Josine L. Mohlke, Karen L. Vincent, John B. Nauck, Matthias Nickerson, Deborah Palotie, Aarno Pato, Michele Pirastu, Nicola McInnis, Melvin Richards, J. Brent Sala, Cinzia Salomaa, Veikko Schlessinger, David Schoenherr, Sebastian Slagboom, P. Eline Small, Kerrin Spector, Timothy Stambolian, Dwight Tuke, Marcus Tuomilehto, Jaakko van den Berg, Leonard H. Van Rheenen, Wouter Volker, Uwe Wijmenga, Cisca Toniolo, Daniela Zeggini, Eleftheria Gasparini, Paolo Sampson, Matthew G. Wilson, James F. Frayling, Timothy de Bakker, Paul I. W. Swertz, Morris A. McCarroll, Steven Kooperberg, Charles Dekker, Annelot Altshuler, David Willer, Cristen Iacono, William Ripatti, Samuli Soranzo, Nicole Walter, Klaudia Swaroop, Anand Cucca, Francesco Anderson, Carl A. Myers, Richard M. Boehnke, Michael McCarthy, Mark I. Durbin, Richard Abecasis, Goncalo Marchini, Jonathan CA Haplotype Reference Consortium TI A reference panel of 64,976 haplotypes for genotype imputation SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; RARE VARIANTS; POPULATION; SEQUENCE AB We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently. C1 [McCarthy, Shane; Luo, Yang; Gilly, Arthur; Barrett, Jeffrey C.; Zeggini, Eleftheria; Soranzo, Nicole; Walter, Klaudia; Anderson, Carl A.; Durbin, Richard] Wellcome Trust Sanger Inst, Human Genet, Hinxton, England. [Das, Sayantan; Kang, Hyun Min; Fuchsberger, Christian; Kwong, Alan; Scott, Laura J.; Che, Sai; Boehnke, Michael; Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Das, Sayantan; Kang, Hyun Min; Fuchsberger, Christian; Kwong, Alan; Scott, Laura J.; Che, Sai; Abecasis, Goncalo] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Kretzschmar, Warren; Mahajan, Anubha; McCarthy, Mark I.; Marchini, Jonathan] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Delaneau, Olivier] Univ Geneva, Genet & Dev, Geneva, Switzerland. [Wood, Andrew R.; Tuke, Marcus; Frayling, Timothy] Univ Exeter, Sch Med, Inst Biomed Sci, Genet Complex Traits, Exeter, Devon, England. [Teumer, Alexander] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Teumer, Alexander; Nauck, Matthias] DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Danecek, Petr] Wellcome Trust Sanger Inst, Vertebrate Resequencing Informat, Hinxton, England. [Sharp, Kevin; Marchini, Jonathan] Univ Oxford, Dept Stat, Oxford, MS USA. [Sidorel, Carlo; Angius, Andrea; Busonero, Fabio; Cucca, Francesco] CNR, IRGB, Sardinia, Italy. [Timpson, Nicholas; Corbin, Laura J.; Smith, George Davey; Min, Josine L.] Univ Bristol, MRC, Integrat Epidemiol Unit, Oakfield Grove, England. [Koskinen, Seppo; Salomaa, Veikko] THL, Helsinki, Finland. [Vrieze, Scott] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Vrieze, Scott] Univ Colorado, Dept Psychol & Neurosurg, Boulder, CO 80309 USA. [Zhang, He; Willer, Cristen] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Veldink, Jan; van den Berg, Leonard H.; Van Rheenen, Wouter; Dekker, Annelot] Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands. [Peters, Ulrike; Harrison, Tabitha; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA. [Peters, Ulrike] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Pato, Carlos; Pato, Michele] SUNY Downstate, Dept Psychiat, Brooklyn, NY USA. [van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Gillies, Christopher E.; Sampson, Matthew G.] Univ Michigan, Sch Med, Dept Pediat Nephrol, Ann Arbor, MI USA. [Gandin, Ilaria; Cocca, Massimiliano; Pirastu, Nicola; Gasparini, Paolo] Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy. [Mezzavilla, Massimo] IRCCS Burlo Garofolo, Genet Med, Trieste, Italy. [Mezzavilla, Massimo; Gasparini, Paolo] Dept Expt Genet, Doha, Qatar. [Traglia, Michela; Sala, Cinzia; Toniolo, Daniela] San Raffaele Res Inst, Genet & Cell Biol, Milan, Italy. [Boomsma, Dorrett] Vrije Univ Amsterdam, Dept Biol Psychol, Netherlands Twin Register, Amsterdam, Netherlands. [Branham, Kari] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Breen, Gerome] Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC, Social Genet & Dev Psychiat Ctr, London, England. [Breen, Gerome] Kings Coll London, Inst Psychiat Psychol & Neurosci, NIHR Biomed Res Ctr Mental Hlth, London, England. [Breen, Gerome] South London Maudsley Hosp, London, ON, Canada. [Brummett, Chad M.; Fraser, Ross M.] Univ Michigan, Dept Anesthesiol, Ann Arbor, MI 48109 USA. [Campbell, Harry; Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Chan, Andrew; Boehnke, Michael] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew; Boehnke, Michael] Harvard Med Sch, Boston, MA USA. [Chan, Andrew] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Che, Sai; Kretzler, Matthias; Willer, Cristen] Univ Michigan, Dept Computat Med, Ann Arbor, MI USA. [Che, Sai; Kretzler, Matthias; Willer, Cristen] Univ Michigan, Dept Bioinformat, Ann Arbor, MI 48109 USA. [Chew, Emily] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Collins, Francis S.] US Natl Inst Hlth, Med Genom & Metab Genet Branch, NHGRI, Bethesda, MD USA. [Dedoussis, George; Farmaki, Aliki-Eleni] Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece. [Dorr, Marcus] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Dorr, Marcus; Nauck, Matthias; Volker, Uwe] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Ferrucci, Luigi] Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria. [Gabriel, Stacey; Palotie, Aarno; Altshuler, David] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Levy, Shawn; Myers, Richard M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Groop, Leif] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Groop, Leif] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland. [Groop, Leif] Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland. [Hattersley, Andrew] Univ Exeter, Sch Med, Inst Biomed & Clin Res, Exeter, Devon, England. [Holmen, Oddgeir L.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Hunt Res Ctr, Levanger, Norway. [Kretzler, Matthias] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Lee, James C.] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Lee, James C.] Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, Dept Med, Cambridge, England. [McGue, Matt; Iacono, William] Univ Minnesota, Dept Psychol, Minneapolis, MN USA. [Meitinger, Thomas] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Meitinger, Thomas] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany. [Melzer, David] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Epidemiol & Publ Hlth, Exeter, Devon, England. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Vincent, John B.] Ctr Addict & Mental Hlth, Mol Neuropsychiat & Dev Lab, Toronto, ON, Canada. [Vincent, John B.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Vincent, John B.] Univ Toronto, Inst Med Sci, Toronto, ON, Canada. [Nickerson, Deborah] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Palotie, Aarno] FIMM, Inst Mol Med, Helsinki, Finland. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Palotie, Aarno; Altshuler, David] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McInnis, Melvin] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Richards, J. Brent] McGill Univ, Dept Med, Montreal, PQ, Canada. [Richards, J. Brent] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Richards, J. Brent; Small, Kerrin; Spector, Timothy] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Schlessinger, David] US Natl Inst Hlth, Natl Inst Aging, Baltimore, MD USA. [Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Mol Epidemiol Sect, Leiden, Netherlands. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman, Kuwait. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia. [Volker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Wijmenga, Cisca; Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Wilson, James F.] Univ Edinburgh, Western Gen Hosp, MRC, Human Genet Unit,Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Genet, Utrecht, Netherlands. [Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, Groningen, Netherlands. [McCarroll, Steven] Harvard Med Sch, Dept Genet, Boston, MA USA. [McCarroll, Steven] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Altshuler, David] Harvard Med Sch, Dept Med, Boston, MA USA. [Altshuler, David] MIT, Dept Biol, Cambridge, MA USA. [Altshuler, David] Vertex Pharmaceut, Boston, MA USA. [Ripatti, Samuli] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Soranzo, Nicole] Univ Cambridge, Dept Hematol, Cambridge, England. [Soranzo, Nicole] Univ Cambridge, NIHR Blood & Transplant Unit BTRU Donor Hlth Geno, Cambridge, England. [Swaroop, Anand] US Natl Inst Hlth, Neurobiol Neurodegenerat & Repair Lab, NEI, Bethesda, MD USA. [McCarthy, Mark I.] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, MS USA. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford, England. RP Abecasis, G (reprint author), Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.; Abecasis, G (reprint author), Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.; Marchini, J (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.; Marchini, J (reprint author), Univ Oxford, Dept Stat, Oxford, MS USA. EM rd@sanger.ac.uk; marchini@stats.ox.ac.uk RI Wijmenga, Cisca/D-2173-2009; Fox, Laura /C-6249-2016; Slagboom, P. Eline/R-4790-2016; Davey Smith, George/A-7407-2013; OI Slagboom, P. Eline/0000-0002-2875-4723; Davey Smith, George/0000-0002-1407-8314; Hattersley, Andrew/0000-0001-5620-473X; Brummett, Chad/0000-0003-0974-7242; Swaroop, Anand/0000-0002-1975-1141; McCarthy, Shane/0000-0002-2715-4187; Small, Kerrin/0000-0003-4566-0005; Timpson, Nicholas/0000-0002-7141-9189 FU ERC [617306]; Wellcome Trust [WT097307, WT090851] FX We are grateful to all participants of all the studies that have contributed data to the HRC. J.M. acknowledges support from the ERC (grant 617306). W.K. acknowledges support from the Wellcome Trust (grant WT097307). S. McCarthy and R.D. acknowledge support from Wellcome Trust grant WT090851. A full list of acknowledgments for the cohorts is given in the Supplementary Note. NR 21 TC 11 Z9 11 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2016 VL 48 IS 10 BP 1279 EP 1283 DI 10.1038/ng.3643 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA DX5AG UT WOS:000384391600025 PM 27548312 ER PT J AU Kim, JH Hu, Y Tang, YQ Kim, J Hughes, VA Le Nours, J Marquez, EA Purcell, AW Wan, Q Sugita, M Rossjohn, J Winau, F AF Kim, Ji Hyung Hu, Yu Tang Yongqing Kim, Jessica Hughes, Victoria A. Le Nours, Jerome Marquez, Elsa A. Purcell, Anthony W. Wan, Qi Sugita, Masahiko Rossjohn, Jamie Winau, Florian TI CD1a on Langerhans cells controls inflammatory skin disease SO NATURE IMMUNOLOGY LA English DT Article ID ALLERGIC CONTACT-DERMATITIS; T-CELLS; ANTIGEN PRESENTATION; PEPTIDE REPERTOIRE; DENDRITIC CELLS; URUSHIOL; ALPHA; RECOGNITION; PSORIASIS; LIPIDS AB CD1a is a lipid-presenting molecule that is abundantly expressed on Langerhans cells. However, the in vivo role of CD1a has remained unclear, principally because CD1a is lacking in mice. Through the use of mice with transgenic expression of CD1a, we found that the plant-derived lipid urushiol triggered CD1a-dependent skin inflammation driven by CD4(+) helper T cells that produced the cytokines IL-17 and IL-22 (T(H)17 cells). Human subjects with poison-ivy dermatitis had a similar cytokine signature following CD1a-mediated recognition of urushiol. Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a mouse model and in patients with psoriasis, CD1a amplified inflammatory responses that were mediated by TH17 cells that reacted to self lipid antigens. Treatment with blocking antibodies to CD1a alleviated skin inflammation. Thus, we propose CD1a as a potential therapeutic target in inflammatory skin diseases. C1 [Kim, Ji Hyung; Hu, Yu; Kim, Jessica; Wan, Qi; Winau, Florian] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Tang Yongqing; Hughes, Victoria A.; Le Nours, Jerome; Marquez, Elsa A.; Purcell, Anthony W.; Rossjohn, Jamie] Monash Univ, Biomed Discovery Inst, Infect & Immun Program, Clayton, Vic, Australia. [Tang Yongqing; Hughes, Victoria A.; Le Nours, Jerome; Marquez, Elsa A.; Rossjohn, Jamie] Monash Univ, Biomed Discovery Inst, Dept Biochem & Mol Biol, Clayton, Vic, Australia. [Sugita, Masahiko] Monash Univ, Australian Res Council Ctr Excellence Adv Mol Imm, Clayton, Vic, Australia. [Rossjohn, Jamie] Kyoto Univ, Inst Virus Res, Lab Cell Regulat, Kyoto, Japan. [Kim, Ji Hyung; Hu, Yu] Cardiff Univ, Inst Infect & Immun, Sch Med, Cardiff, S Glam, Wales. RP Winau, F (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Rossjohn, J (reprint author), Monash Univ, Biomed Discovery Inst, Infect & Immun Program, Clayton, Vic, Australia.; Rossjohn, J (reprint author), Monash Univ, Biomed Discovery Inst, Dept Biochem & Mol Biol, Clayton, Vic, Australia.; Rossjohn, J (reprint author), Kyoto Univ, Inst Virus Res, Lab Cell Regulat, Kyoto, Japan. EM jamie.rossjohn@monash.edu; florian.winau@childrens.harvard.edu OI Hu, Yu/0000-0002-9511-9383 FU National Research Foundation of Korea [2012R1A6A3A03040248]; AMOREPACIFIC Research Scholar Program; National Health and Medical Research Council of Australia; Australian Research Council; US National Institutes of Health [R01 AI083426] FX We thank M. Brenner (Brigham and Women's Hospital, Boston) for anti-CD1a; B. Moody and T.-Y. Cheng (Brigham and Women's Hospital, Boston) for K562 cells and advice on human T cell assays; A. Del Grosso (Food and Drug Administration) for natural urushiols; U. von Andrian and J. Ordovas-Montanes for advice on the preparation of skin tissue; the US National Institutes of Health (NIH) tetramer facility for CD1a monomers; and the staff at the Australian synchrotron for assistance with data collection. Supported by the National Research Foundation of Korea (2012R1A6A3A03040248 to J.H.K.), the AMOREPACIFIC Research Scholar Program (to J.H.K.), National Health and Medical Research Council of Australia (J.R. and A.W.P.), the Australian Research Council (J.R.) and the US National Institutes of Health (R01 AI083426 to F.W.). NR 43 TC 1 Z9 1 U1 15 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2016 VL 17 IS 10 BP 1159 EP + DI 10.1038/ni.3523 PG 10 WC Immunology SC Immunology GA DX3VD UT WOS:000384302900007 PM 27548435 ER PT J AU Oliver, LC Welch, L Frank, AL Lemen, RA Mutti, L AF Oliver, L. Christine Welch, Laura Frank, Arthur L. Lemen, Richard A. Mutti, Luciano TI New standard for assessing asbestos exposure and its consequences? SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Letter ID MESOTHELIOMA; BURDEN C1 [Oliver, L. Christine] Occupat Hlth Initiat Inc, Harvard Med Sch, Massachusetts Gen Hosp, 1101 Beacon St,Ste 8 East, Brookline, MA 02446 USA. [Welch, Laura] Ctr Construct Res & Training, Washington, DC USA. [Frank, Arthur L.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Lemen, Richard A.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Mutti, Luciano] Univ Salford, Salford, Greater Manches, England. RP Oliver, LC (reprint author), Occupat Hlth Initiat Inc, Harvard Med Sch, Massachusetts Gen Hosp, 1101 Beacon St,Ste 8 East, Brookline, MA 02446 USA. EM coliver@ohiinc.com NR 4 TC 0 Z9 0 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD OCT PY 2016 VL 73 IS 10 DI 10.1136/oemed-2016-103693 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX0TV UT WOS:000384079100012 ER PT J AU Fawzi, MCS Ng, L Kanyanganzi, F Kirk, C Bizimana, J Cyamatare, F Mushashi, C Kim, T Kayiteshonga, Y Binagwaho, A Betancourt, TS AF Fawzi, Mary C. Smith Ng, Lauren Kanyanganzi, Fredrick Kirk, Catherine Bizimana, Justin Cyamatare, Felix Mushashi, Christina Kim, Taehoon Kayiteshonga, Yvonne Binagwaho, Agnes Betancourt, Theresa S. TI Mental Health and Antiretroviral Adherence Among Youth Living With HIV in Rwanda SO PEDIATRICS LA English DT Article ID COMMUNITY-BASED ACCOMPANIMENT; INFECTED CHILDREN; DEPRESSION SCALE; RURAL RWANDA; THERAPY; PREDICTORS; OUTCOMES; ADULTS; CARE; DECENTRALIZATION AB BACKGROUND AND OBJECTIVES: In Rwanda, significant progress has been made in advancing access to antiretroviral therapy (ART) among youth. As availability of ART increases, adherence is critical for preventing poor clinical outcomes and transmission of HIV. The goals of the study are to (1) describe ART adherence and mental health problems among youth living with HIV aged 10 to 17; and (2) examine the association between these factors among this population in rural Rwanda. METHODS: A cross-sectional analysis was conducted that examined the association of mental health status and ART adherence among youth (n = 193). ART adherence, mental health status, and related variables were examined based on caregiver and youth report. Nonadherence was defined as ever missing or refusing a dose of ART within the past month. Multivariate modeling was performed to examine the association between mental health status and ART adherence. RESULTS: Approximately 37% of youth missed or refused ART in the past month. In addition, a high level of depressive symptoms (26%) and attempt to hurt or kill oneself (12%) was observed in this population of youth living with HIV in Rwanda. In multivariate analysis, nonadherence was significantly associated with some mental health outcomes, including conduct problems (odds ratio 2.90, 95% confidence interval 1.55-5.43) and depression (odds ratio 1.02, 95% confidence interval 1.01-1.04), according to caregiver report. A marginally significant association was observed for youth report of depressive symptoms. CONCLUSIONS: The findings suggest that mental health should be considered among the factors related to ART nonadherence in HIV services for youth, particularly for mental health outcomes, such as conduct problems and depression. C1 [Fawzi, Mary C. Smith; Kim, Taehoon; Binagwaho, Agnes] Harvard Med Sch, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. [Ng, Lauren] Massachusetts Gen Hosp, Div Global Psychiat, Boston, MA USA. [Kanyanganzi, Fredrick; Cyamatare, Felix; Mushashi, Christina] Partners Hlth Rwanda Inshuti Mu Buzima PIH IMB, Rwinkwavu, Rwanda. [Kirk, Catherine; Betancourt, Theresa S.] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Bizimana, Justin; Kayiteshonga, Yvonne] Govt Rwanda, Minist Hlth, Kigali, Rwanda. [Binagwaho, Agnes] Dartmouth Coll, Hanover, NH 03755 USA. [Binagwaho, Agnes] Univ Global Hlth Equ, Kigali, Rwanda. RP Fawzi, MCS (reprint author), Harvard Med Sch, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. EM mary_smith-fawzi@hms.harvard.edu FU National Institutes of Health [P30 AI060354] FX This study was supported by a grant funded by the National Institutes of Health and awarded to Harvard University Center for AIDS Research, grant P30 AI060354. Funded by the National Institutes of Health (NIH). NR 48 TC 1 Z9 1 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD OCT PY 2016 VL 138 IS 4 AR e20153235 DI 10.1542/peds.2015-3235 PG 9 WC Pediatrics SC Pediatrics GA DX3ZT UT WOS:000384317700004 ER PT J AU Goff, SL Mazor, KM Pekow, PS White, KO Priya, A Lagu, T Guhn-Knight, H Murphy, L Budway, YY Lindenauer, PK AF Goff, Sarah L. Mazor, Kathleen M. Pekow, Penelope S. White, Katharine O. Priya, Aruna Lagu, Tara Guhn-Knight, Haley Murphy, Lorna Budway, Yara Youssef Lindenauer, Peter K. TI Patient Navigators and Parent Use of Quality Data: A Randomized Trial SO PEDIATRICS LA English DT Article ID PLAN PERFORMANCE INFORMATION; ONLINE HEALTH INFORMATION; NEWEST VITAL SIGN; MEDICAID BENEFICIARIES; CONSUMER CHOICE; PRIMARY-CARE; OF-CARE; LITERACY; ACTIVATION; IMPROVEMENT AB BACKGROUND: Consumers rarely use publicly reported health care quality data. Despite known barriers to use, few studies have explored the effectiveness of strategies to overcome barriers in vulnerable populations. METHODS: This randomized controlled trial tested the impact of a patient navigator intervention to increase consumer use of publicly reported quality data. Patients attending an urban prenatal clinic serving a vulnerable population enrolled between May 2013 and January 2015. The intervention consisted of 2 in-person sessions in which women learned about quality performance and viewed scores for local practices on the Massachusetts Health Quality Partners Web site. Women in both the intervention and control arms received a pamphlet about health care quality. Primary study outcomes were mean clinical quality and patient experience scores of the practices women selected (range 1-4 stars). RESULTS: Nearly all (726/746; 97.3%) women completed the study, 59.7% were Hispanic, and 65.1% had a high school education or less. In both unadjusted and adjusted models, women in the intervention group chose practices with modestly higher mean clinical quality (3.2 vs 3.0 stars; P = .001) and patient experience (3.0 vs 2.9 stars; P = .05) scores. When asked to rate what factors mattered the most in their decision, few cited quality scores. CONCLUSIONS: An intervention to reduce barriers to using publicly reported health care quality data had a modest effect on patient choice. These findings suggest that factors other than performance on common publicly reported quality metrics have a stronger influence on which pediatric practices women choose. C1 [Goff, Sarah L.; Lagu, Tara; Guhn-Knight, Haley; Lindenauer, Peter K.] Tufts Univ, Sch Med, Baystate Med Ctr, Ctr Qual Care Res, 759 Chestnut St, Springfield, MA 01199 USA. [Goff, Sarah L.; Lagu, Tara; Guhn-Knight, Haley; Lindenauer, Peter K.] Tufts Univ, Sch Med, Baystate Med Ctr, Dept Med, 759 Chestnut St, Springfield, MA 01199 USA. [Mazor, Kathleen M.] Meyers Primary Care Inst, Worcester, MA USA. [Pekow, Penelope S.; Priya, Aruna] Baystate Med Ctr, Ctr Qual Care Res, Springfield, MA USA. [White, Katharine O.] Boston Univ, Boston Med Ctr, Dept Obstet & Gynecol, Boston, MA 02215 USA. [Murphy, Lorna] Renal Transplant Associates New England, Springfield, MA USA. [Budway, Yara Youssef] Massachusetts Gen Hosp, Phys Analyt & Business Intelligence, Boston, MA 02114 USA. RP Goff, SL (reprint author), Tufts Univ, Sch Med, Baystate Med Ctr, Ctr Qual Care Res, 759 Chestnut St, Springfield, MA 01199 USA.; Goff, SL (reprint author), Tufts Univ, Sch Med, Baystate Med Ctr, Dept Med, 759 Chestnut St, Springfield, MA 01199 USA. EM sarah.goffmd@baystatehealth.org FU Agency for Healthcare Research and Quality [5R21HS021864-02]; National Institute of Child Health and Human Development of the National Institutes of Health (NIH) [K23K23HD080870]; National Heart, Lung, and Blood Institute of the NIH [K01HL114745]; National Institutes of Health (NIH) FX Funded by a grant from the Agency for Healthcare Research and Quality (grant 5R21HS021864-02). Dr Goff is supported by the National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award K23K23HD080870. Dr Lagu is supported by the National Heart, Lung, and Blood Institute of the NIH under award K01HL114745. The funding agencies had no role in any aspect of study design, implementation, analyses, or manuscript review or approval. Funded by the National Institutes of Health (NIH). NR 39 TC 1 Z9 1 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD OCT PY 2016 VL 138 IS 4 AR e20161140 DI 10.1542/peds.2016-1140 PG 11 WC Pediatrics SC Pediatrics GA DX3ZT UT WOS:000384317700035 ER PT J AU Chinsongkram, B Chaikeeree, N Saengsirisuwan, V Horak, FB Boonsinsukh, R AF Chinsongkram, Butsara Chaikeeree, Nithinun Saengsirisuwan, Vitoon Horak, Fay B. Boonsinsukh, Rumpa TI Responsiveness of the Balance Evaluation Systems Test (BESTest) in People With Subacute Stroke SO PHYSICAL THERAPY LA English DT Article ID QUALITY-OF-LIFE; POSTURAL ASSESSMENT SCALE; MENTAL-STATE-EXAMINATION; PSYCHOMETRIC PROPERTIES; STANDING BALANCE; MINI-BESTEST; COMMUNITY BALANCE; MOBILITY SCALE; SHORT-FORM; RELIABILITY AB Background. The reliability and convergent validity of the Balance Evaluation Systems Test (BESTest) in people with subacute stroke have been established, but its responsiveness to rehabilitation has not been examined. Objective. The study objective was to compare the responsiveness of the BESTest with those of other clinical balance tools in people with subacute stroke. Design. This was a prospective cohort study. Methods. Forty-nine people with subacute stroke (mean age=57.8 years, SD=11.8) participated in this study. Five balance measures-the BESTest, the Mini-BESTest, the Berg Balance Scale, the Postural Assessment Scale for Stroke Patients, and the Community Balance and Mobility Scale (CB&M)-were used to measure balance performance before and after rehabilitation or before discharge from the hospital, whichever came first. The internal responsiveness of each balance measure was classified with the standardized response mean (SRM); changes in Berg Balance Scale scores of greater than 7 were used as the external standard for determining the external responsiveness. Analysis of the receiver operating characteristic curve was used to determine the accuracy and cutoff scores for identifying participants with balance improvement. Results. Participants received 13.7 days (SD=9.3, range=5-44) of physical therapy rehabilitation. The internal responsiveness of all balance measures, except for the CB&M, was high (SRM=0.9-1.2). The BESTest had a higher SRM than the Mini-BESTest and the CB&M, indicating that the BESTest was more sensitive for detecting balance changes than the Mini-BESTest and the CB&M. In addition, compared with other balance measures, the BESTest had no floor, ceiling, or responsive ceiling effects. The results also indicated that the percentage of participants with no change in scores after rehabilitation was smaller with the BESTest than with the Mini-BESTest and the CB&M. With regard to the external responsiveness, the BESTest had higher accuracy, sensitivity, specificity, and posttest accuracy than the Postural Assessment Scale for Stroke Patients and the CB&M for identifying participants with balance improvement. Changes in BESTest scores of 10% or more indicated changes in balance performance. Limitations. A limitation of this study was the difference in the time periods between the first and the second assessments across participants. Conclusions. The BESTest was the most sensitive scale for assessing balance recovery in participants with subacute stroke because of its high internal and external responsiveness and lack of floor and ceiling effects. C1 [Chinsongkram, Butsara] Rangsit Univ, Fac Phys Therapy, Pathum Thani, Thailand. [Chaikeeree, Nithinun; Boonsinsukh, Rumpa] Srinakharinwirot Univ, Fac Hlth Sci, Div Phys Therapy, 63 Moo 7, Nakhonnayok, Thailand. [Saengsirisuwan, Vitoon] Mahidol Univ, Fac Sci, Dept Physiol, Bangkok, Thailand. [Horak, Fay B.] Oregon Hlth & Sci Univ, Balance Disorders Lab, Dept Neurol, Beaverton, OR USA. [Horak, Fay B.] Portland VA Med Ctr, Portland, OR USA. RP Boonsinsukh, R (reprint author), Srinakharinwirot Univ, Fac Hlth Sci, Div Phys Therapy, 63 Moo 7, Nakhonnayok, Thailand. EM rumpa@swu.ac.th FU Thailand Research Fund; Office of the Higher Education Commission, Srinakharinwirot University [RSA5580002]; NIH and VA Merit Award [AG006457, 1075] FX This project was supported by the Thailand Research Fund, the Office of the Higher Education Commission, Srinakharinwirot University (grant no. RSA5580002), and by NIH and VA Merit Award 1075 (grant no. AG006457). NR 46 TC 1 Z9 1 U1 14 U2 14 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 EI 1538-6724 J9 PHYS THER JI Phys. Ther. PD OCT PY 2016 VL 96 IS 10 BP 1638 EP 1647 DI 10.2522/ptj.20150621 PG 10 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA DX5AA UT WOS:000384391000016 PM 27103226 ER PT J AU Hazlett, EA Blair, NJ Fernandez, N Mascitelli, K Perez-Rodriguez, MM New, AS Goetz, RR Goodman, M AF Hazlett, Erin A. Blair, Nicholas J. Fernandez, Nicolas Mascitelli, Kathryn Perez-Rodriguez, M. Mercedes New, Antonia S. Goetz, Raymond R. Goodman, Marianne TI Startle amplitude during unpleasant pictures is greater in veterans with a history of multiple-suicide attempts and predicts a future suicide attempt SO PSYCHOPHYSIOLOGY LA English DT Article DE Suicide; Affective startle modulation; Amygdala; Columbia Suicide Severity Rating Scale; Emotion; Veteran ID BORDERLINE PERSONALITY-DISORDER; FEAR-POTENTIATED STARTLE; AFFECT-MODULATED STARTLE; INTERNALIZING PSYCHOPATHOLOGY; EMOTION REGULATION; AMYGDALA; SCALE; DEPRESSION; BEHAVIOR; REFLEX AB Recent studies demonstrate that veterans exhibit higher suicide risk compared with the general U.S. population. A prior suicide attempt is a well-documented predictor of suicide death. Despite increased attention to clinical risk factors of suicide and efforts to develop psychosocial interventions to reduce suicide risk, the underlying biological factors that confer this risk are not well understood. This study examined affect-modulated startle (AMS) during a series of intermixed unpleasant, neutral, and pleasant pictures in a sample of 108 demographically-matched veterans at low (passive ideators: n=26) and high risk (active ideators: n=29; single attempters: n=28; and multiple attempters: n=25) for suicide based on the Columbia Suicide Severity Rating Scale. An exploratory aim involved a longitudinal component in a subset of the high-risk sample that went on to participate in a randomized 6-month clinical trial. We investigated whether baseline AMS predicts a subsequent suicide attempt at 12-month follow-up. Compared with the other three groups, multiple attempters showed greater startle potentiation during unpleasant pictures and deficient overall startle habituation from early to later trials. The groups did not differ in startle during neutral or pleasant pictures, or self-reported picture valence. Greater startle during unpleasant pictures was associated with greater emotion dysregulation as measured by the Difficulties in Emotion Regulation Scale and a future suicide attempt assessed prospectively at 12-month follow-up. These findings suggest that startle potentiation during unpleasant pictures in multiple-suicide attempters is a promising psychophysiological biomarker of suicide risk and underscore the clinical importance of targeting emotion dysregulation in the treatment of patients at-risk for suicide. C1 [Hazlett, Erin A.; Perez-Rodriguez, M. Mercedes; New, Antonia S.; Goodman, Marianne] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Hazlett, Erin A.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Hazlett, Erin A.; Blair, Nicholas J.; Fernandez, Nicolas; Mascitelli, Kathryn; Goodman, Marianne] James J Peters Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr MIRECC VISN So, Bronx, NY USA. [Hazlett, Erin A.; Blair, Nicholas J.; Fernandez, Nicolas; Mascitelli, Kathryn] James J Peters Vet Affairs Med Ctr, Res & Dev, Bronx, NY USA. [Goetz, Raymond R.] New York State Psychiat Inst & Hosp, Div Clin Phenomenol, New York, NY 10032 USA. [Goetz, Raymond R.] Columbia Univ, Coll Phys & Surg, New York, NY USA. RP Hazlett, EA (reprint author), James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, 130 West Kingsbridge Rd,Room 6A-44, Bronx, NY 10468 USA. EM erin.hazlett@mssm.edu FU Department of Defense [W81XWH0910722]; VA Merit Award [I01CX00026]; VISN 2 South Mental Illness, Research, Education, and Clinical Center (MIRECC) at the JJPVAMC FX This research was supported by a grant from the Department of Defense (W81XWH0910722-supplement to EAH and MG; MPIs), a VA Merit Award (I01CX00026 to EAH), and the VISN 2 South Mental Illness, Research, Education, and Clinical Center (MIRECC) at the JJPVAMC. NR 50 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD OCT PY 2016 VL 53 IS 10 BP 1524 EP 1534 DI 10.1111/psyp.12698 PG 11 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DX5WK UT WOS:000384453200007 PM 27378071 ER PT J AU Painter, JM Gray, K McGinn, MM Mostoufi, S Hoerster, KD AF Painter, Janelle M. Gray, Kristen McGinn, Meghan M. Mostoufi, Sheeva Hoerster, Katherine D. TI The relationships of posttraumatic stress disorder and depression symptoms with health-related quality of life and the role of social support among Veterans SO QUALITY OF LIFE RESEARCH LA English DT Article DE PTSD; Depression; Health-related quality of life; Physical health; Mental health; Social support ID MENTAL-HEALTH; ANXIETY DISORDERS; PHYSICAL-ACTIVITY; CLINICAL-SAMPLE; VALIDITY; PTSD; ASSOCIATIONS; METAANALYSIS; INDIVIDUALS; COMORBIDITY AB The presence of posttraumatic stress disorder (PTSD) or depression symptoms is associated with poor quality of life. Social support buffers against developing symptoms of PTSD and depression and is associated with greater quality of life. We examined the relationships between PTSD and depression symptom severity with physical (PCS) and mental (MCS) health-related quality of life (HRQoL), and whether social support moderated these relationships. Randomly selected Veterans with at least one Primary Care or PTSD Clinical Team visit received a mailed survey including self-report measures of health and wellness. Among the 717 respondents, we examined the association between symptom severity and HRQoL using linear regression. We included interaction terms between symptom severity and social support to examine whether social support moderated these associations. Social support did not moderate the association between symptom severity and mental HRQoL. Higher PTSD and depression symptom severity were associated with lower MCS scores, whereas higher social support was associated with higher MCS scores. When examining physical HRQoL, social support moderated the association with PTSD and depression symptom severity. Among individuals with high social support, there was a negative association between symptom severity and PCS scores, whereas there was no association among those with low social support. Although there are contexts in which social support is helpful, in some cases it may interfere with HRQoL among those with mental health conditions. Thus, it is important to educate support providers about behaviors that enhance the benefits and minimize the costs of social support. C1 [Painter, Janelle M.; McGinn, Meghan M.; Mostoufi, Sheeva] VA Puget Sound Hlth Care Syst, Mental Hlth Serv, Seattle Div, 1660 S Columbian Way S-116, Seattle, WA 98108 USA. [Painter, Janelle M.] Univ Calif Berkeley, Dept Psychol, 3210 Tolman Hall, Berkeley, CA 94720 USA. [Gray, Kristen; Hoerster, Katherine D.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Serv, Seattle Div, Seattle, WA USA. [Gray, Kristen] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [McGinn, Meghan M.; Hoerster, Katherine D.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Painter, JM (reprint author), VA Puget Sound Hlth Care Syst, Mental Hlth Serv, Seattle Div, 1660 S Columbian Way S-116, Seattle, WA 98108 USA.; Painter, JM (reprint author), Univ Calif Berkeley, Dept Psychol, 3210 Tolman Hall, Berkeley, CA 94720 USA. EM janelle.painter@va.gov FU VA Puget Sound, Seattle Division Mental Illness Research Education and Clinical Center; VA Puget Sound, Seattle Division Health Services Research and Development Center of Excellence; VA Career Development Award [HSRD CDA 12-263] FX This material is the result of work supported by resources from VA Puget Sound Healthcare System. Funding for the study was provided by the VA Puget Sound, Seattle Division Mental Illness Research Education and Clinical Center and the VA Puget Sound, Seattle Division Health Services Research and Development Center of Excellence. Dr. Hoerster is supported by a VA Career Development Award (HSR&D CDA 12-263). NR 56 TC 0 Z9 0 U1 16 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2016 VL 25 IS 10 BP 2657 EP 2667 DI 10.1007/s11136-016-1295-5 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DV5TQ UT WOS:000382993000023 PM 27085339 ER PT J AU Rodrigo-Troyano, A Suarez-Cuartin, G Peiro, M Barril, S Castillo, D Sanchez-Reus, F Plaza, V Restrepo, MI Chalmers, JD Sibila, O AF Rodrigo-Troyano, Ana Suarez-Cuartin, Guillermo Peiro, Meritxell Barril, Silvia Castillo, Diego Sanchez-Reus, Ferran Plaza, Vicente Restrepo, Marcos I. Chalmers, James D. Sibila, Oriol TI Pseudomonas aeruginosa resistance patterns and clinical outcomes in hospitalized exacerbations of COPD SO RESPIROLOGY LA English DT Article DE COPD; exacerbation; Pseudomonas aeruginosa ID OBSTRUCTIVE PULMONARY-DISEASE; RISK-FACTORS; CYSTIC-FIBROSIS; ANTIMICROBIAL RESISTANCE; ANTIBIOTIC-RESISTANCE; MULTIDRUG-RESISTANCE; BACTERIAL-INFECTIONS; MORTALITY; AIRWAY; BRONCHIECTASIS AB Background and objectiveAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) due to Pseudomonas aeruginosa (PA) are associated with worse outcomes. PA antibiotic resistance is important to determine treatment and may influence clinical outcomes. The aim was to study clinical characteristics and outcomes in patients with AECOPD associated with PA based on their antibiotic resistance. MethodsThis was a prospective observational study including all patients with AECOPD and positive PA sputum culture admitted in a respiratory ward in a tertiary hospital in Barcelona during 2013-2014. PA was defined as resistant (PA-R) when the antibiogram showed 1 resistance. ResultsFour hundred one patients with AECOPD were evaluated. Of them, 54 (13%) had a positive PA sputum culture. Eighty-two per cent were men, median age was 77 (SD 7) years old and FEV1 was less than 36% (SD 17) of predicted value. PA-R was isolated in 35 patients (66%), and PA-sensitive (PA-S) was isolated in 18 (34%) patients. No differences were found in demographics, lung function and comorbidities among groups. PA-R patients were more likely exposed to prior oral corticosteroids (77% vs 44%, P=0.03) and antibiotics (77% vs 31%, P=0.01), respectively. AECOPD patients associated with PA-S were more likely to die at 30 days (odds ratio 13.53, 95% confidence interval: 1.14-69.56, P=0.03) and 90 days (odds ratio 7.09, 95% confidence interval: 1.33-37.89, P=0.02), respectively. ConclusionPseudomonas aeruginosa-resistant affects patients with severe AECOPD and previous use of corticosteroids and antibiotics. The presence of PA-S is associated with higher mortality. These results may suggest increased virulence in PA-S strains causing acute infections. Pseudomonas aeruginosa (PA) plays an important role in AECOPD. However, the impact of PA resistance patterns on clinical outcomes is not clear. Our study demonstrates that the presence of PA-sensitive is associated with higher mortality. C1 [Rodrigo-Troyano, Ana; Suarez-Cuartin, Guillermo; Peiro, Meritxell; Barril, Silvia; Castillo, Diego; Plaza, Vicente; Sibila, Oriol] Autonomous Univ Barcelona UAB, Hosp Santa Creu & St Pau, Resp Dept, Barcelona, Spain. [Rodrigo-Troyano, Ana; Suarez-Cuartin, Guillermo; Peiro, Meritxell; Barril, Silvia; Castillo, Diego; Sanchez-Reus, Ferran; Plaza, Vicente; Sibila, Oriol] Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain. [Sanchez-Reus, Ferran] Hosp Santa Creu & Sant Pau, Dept Microbiol, Barcelona, Spain. [Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Chalmers, James D.] Univ Dundee, Tayside Resp Res Grp, Dundee, Scotland. RP Sibila, O (reprint author), Hosp Santa Creu & Sant Pau, Serv Pneumol, C St Antoni M Claret 167, Barcelona 08025, Spain. EM osibila@santpau.cat NR 40 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD OCT PY 2016 VL 21 IS 7 BP 1235 EP 1242 DI 10.1111/resp.12825 PG 8 WC Respiratory System SC Respiratory System GA DX5RQ UT WOS:000384439800014 PM 27325555 ER PT J AU Wray, SH AF Wray, Shirley H. TI Acute Visual Loss SO SEMINARS IN NEUROLOGY LA English DT Review DE ocular stroke ID RETINAL ARTERY-OCCLUSION; TRANSIENT MONOCULAR BLINDNESS; SUSAC-SYNDROME; CAROTID-ARTERY; PLAQUES; MICROANGIOPATHY; DISEASE; BRAIN AB Acute visual loss is a frightening experience, a common ophthalmic emergency, and a diagnostic challenge. In this review, the author focusses on the diagnosis of transient monocular blindness and visual loss due to infarction of the retina and/or the optic nerve -the ocular parallel of cerebral stroke. C1 [Wray, Shirley H.] Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. RP Wray, SH (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. EM wray@helix.mgh.harvard.edu NR 32 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2016 VL 36 IS 5 BP 425 EP 432 DI 10.1055/s-0036-1585452 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DX0PD UT WOS:000384064600005 PM 27704497 ER PT J AU Leng, Y Blackwell, T Stone, KL Hoang, TD Redline, S Yaffe, K AF Leng, Yue Blackwell, Terri Stone, Katie L. Hoang, Tina D. Redline, Susan Yaffe, Kristine TI Periodic Limb Movements in Sleep are Associated with Greater Cognitive Decline in Older Men without Dementia SO SLEEP LA English DT Article DE cognition; cognitive decline; periodic limb movements; PLMS; polysomnography ID OSTEOPOROTIC FRACTURES; PARKINSONS-DISEASE; EXECUTIVE FUNCTION; LEG MOVEMENTS; MROS; DISORDER; RISK AB Study Objectives: To examine the association between periodic limb movements in sleep (PLMS) and change in selected aspects of cognition in community-dwelling older men. Methods: We studied 2,636 older men without dementia who underwent in-home polysomnography with measurement of the periodic limb movement index (PLMI) and periodic limb movement arousal index (PLMAI) using piezoelectric sensors. Random-effects models and logistic regression were used to examine the association between PLMI, PLMAI, and 3- to 4-y change in cognition. Results: After multivariable adjustment, men with a high PLMI had greater decline on the Trail Making Test - Part B (P trend = 0.02); those with a PLMI >= 30 were 48% more likely (odds ratio = 1.48, 95% confidence interval = 1.05-2.07) to experience the development of significant cognitive impairment (>= 1 SD above mean change). Further adjustment for sleep efficiency, nocturnal hypoxemia, or dopaminergic medication use and analysis among men without Parkinson disease (n = 2,607) showed similar findings. No significant association was found for PLMAI or for Modified Mini-Mental State Examination scores. Conclusions: Among older men without dementia, higher PLMS frequency was associated with greater decline in cognition, particularly in executive function. C1 [Leng, Yue] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Blackwell, Terri; Stone, Katie L.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Hoang, Tina D.] Northern Calif Inst Res & Educ, San Francisco, CA USA. [Redline, Susan] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Redline, Susan] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco VA Med Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco VA Med Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Box 181,4150 Clement St, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu FU National Institutes of Health; National Institute on Aging (NIA); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128]; National Heart, Lung, and Blood Institute (NHLBI) [R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, R01 HL070839]; K24 grant [AG031155]; NIH; PCORU; Jazz Pharmaceuticals FX This was not an industry supported study. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Heart, Lung, and Blood Institute (NHLBI) provides funding for the MrOS Sleep ancillary study "Outcomes of Sleep Disorders in Older Men" under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839. Dr Yaffe received funding from K24 grant AG031155. The funding sources had no role in the design and conduction of the study; collection, management, analysis, and interpretation of the data; the decision to submit the manuscript for publication; preparation or approval of the manuscript. Terri Blackwell, Dr. Yaffe, Dr. Redline, and Dr. Stone have received grant support from the NIH grant and supporting agencies as listed above. Dr. Redline's institution receives grant support from NIH and PCORU and has received grant funding from Jazz Pharmaceuticals. The other authors have indicated no financial conflicts of interest. Analysis was performed at California Pacific Medical Center, Research Institute. NR 27 TC 0 Z9 0 U1 3 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD OCT 1 PY 2016 VL 39 IS 10 BP 1807 EP 1810 DI 10.5665/sleep.6158 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DX4ET UT WOS:000384334700005 PM 27568800 ER PT J AU Perlis, ML Grandner, MA Chakravorty, S Bernert, RA Brown, GK Thase, ME AF Perlis, Michael L. Grandner, Michael A. Chakravorty, Subhajit Bernert, Rebecca A. Brown, Gregory K. Thase, Michael E. TI Suicide and sleep: Is it a bad thing to be awake when reason sleeps? SO SLEEP MEDICINE REVIEWS LA English DT Review DE Sleep disturbance; Suicide; Circadian patterning; Hypofrontality; Executive function ID HOSPITALIZED DEPRESSED-PATIENTS; NEUROBEHAVIORAL PERFORMANCE; COGNITIVE PERFORMANCE; CIRCADIAN-RHYTHMS; HEALTHY CONTROLS; DEPRIVATION; TIME; MODULATION; IDEATION; INSOMNIA AB Suicide is the second leading cause of death, worldwide, for those between the ages of 24 and 44 y old. In 2013, more than 41,000 suicides occurred in the United States. These statistics underscore the need to 1) understand why people die by suicide and 2) identify risk factors that are potentially modifiable. While it has been posited that sleep disturbance may represent one such factor, systematic research in this arena did not begin until the 2000s. Since that time, sleep disturbance has been reliably identified as a risk factor for suicidal ideation, suicide attempts, and suicide. While insomnia, nightmares, and other sleep disorders have each been found to contribute to the risk for suicidal ideation and behavior, it is also possible that these factors share some common variance. One possibility is that sleep disturbance results in being awake at night, and being awake at night also confers risk. The hypothesis proffered here is that being awake when one is not biologically prepared to be so results in "hypofrontality" and diminished executive function, and that this represents a common pathway to suicidal ideation and behavior. Such a proposition is highly testable under a variety of possible protocols. The current review summarizes the extant literature on suicide rates by time-of-day, and discusses circadian, psychosocial, and neurocognitive explanations of risk. Such a focus promises to enhance our understanding of how sleep disturbance may confer risk, allows for the identification of future lines of research, and further justifies the need for interventions that promote good sleep continuity among at-risk individuals. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Perlis, Michael L.; Chakravorty, Subhajit] Univ Penn, Behav Sleep Med Program, Dept Psychiat, Philadelphia, PA 19104 USA. [Perlis, Michael L.] Univ Penn, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA. [Perlis, Michael L.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Grandner, Michael A.] Univ Arizona, Dept Psychiat, Tucson, AZ 85721 USA. [Chakravorty, Subhajit] Philadelphia Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. [Bernert, Rebecca A.] Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA 94305 USA. [Brown, Gregory K.] Univ Penn, Ctr Prevent Suicide, Dept Psychiat, Philadelphia, PA 19104 USA. [Thase, Michael E.] Univ Penn, Mood & Anxiety Disorders Treatment & Res Program, Dept Psychiat, Philadelphia, PA 19104 USA. RP Perlis, ML (reprint author), Univ Penn, Dept Psychiat, Upenn Behav Sleep Med Program, 3535 Market St,Suite 670, Philadelphia, PA 19104 USA. EM mperlis@upenn.edu FU [R01AG041783]; [R01AT003332]; [R01MH077900]; [R21ES022931]; [K23HL110216]; [R01MH086572]; [NCC-958]; [IK2CX000855]; [R01MH082794]; [R01NR004281] FX The empirical work regarding the circadian patterning of suicide has been ongoing since 2013 and includes the efforts and talents of a larger group of investigators than those that contributed to the present theoretical review including: David Dinges, Mathias Basner, Ruben Gur, David Roalf, Knashawn Morales, Phil Gehrman, and Ninad Chaudhary. The following are in receipt of grants as follows: Michael Perlis (R01AG041783, R01AT003332, R01MH077900); Michael Grandner (R21ES022931, K23HL110216); Gregory Brown (R01MH086572); Mathias Basner (National Space Biomedical Research Institute through NASA NCC-958); Subhajit Chakravorty (IK2CX000855); Michael Thase (R01MH082794); and David Dinges (R01NR004281). NR 50 TC 2 Z9 2 U1 9 U2 9 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1087-0792 EI 1532-2955 J9 SLEEP MED REV JI Sleep Med. Rev. PD OCT PY 2016 VL 29 BP 101 EP 107 DI 10.1016/j.smrv.2015.10.003 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV5ZN UT WOS:000383009300009 PM 26706755 ER PT J AU Ochoa-Escudero, M Juliano, AF AF Ochoa-Escudero, Martin Juliano, Amy F. TI Unilateral hypoplasia with contralateral hypertrophy of anterior belly of digastric muscle: a case report SO SURGICAL AND RADIOLOGIC ANATOMY LA English DT Article DE Anterior belly; Digastric muscle; Hypoplasia; Hypertrophy AB Anomalies of the anterior belly of the digastric muscle (DM) are uncommon. We present a case of hypoplasia of the anterior belly of the left DM with hypertrophy of the anterior belly of the contralateral DM. The importance of recognizing this finding is to differentiate hypoplasia of the anterior belly of the DM from denervation atrophy, and not to confuse contralateral hypertrophy with a submental mass or lymphadenopathy. In denervation atrophy of the anterior belly of the DM, associated atrophy of the ipsilateral mylohyoid muscle is present. Hypertrophy of the anterior belly of the contralateral DM can be differentiated from a submental mass or lymphadenopathy by recognizing its isodensity on computed tomography and isointensity on magnetic resonance imaging to other muscles, without abnormal contrast enhancement. C1 [Ochoa-Escudero, Martin] Hosp Pablo Tobon Uribe, Neuroradiol Sect, Dept Radiol, Calle 78B 69-240, Medellin, Colombia. [Juliano, Amy F.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Juliano, Amy F.] Harvard Med Sch, Boston, MA USA. RP Ochoa-Escudero, M (reprint author), Hosp Pablo Tobon Uribe, Neuroradiol Sect, Dept Radiol, Calle 78B 69-240, Medellin, Colombia. EM martin127d@gmail.com NR 10 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 0930-1038 EI 1279-8517 J9 SURG RADIOL ANAT JI Surg. Radiol. Anat. PD OCT PY 2016 VL 38 IS 8 BP 973 EP 974 DI 10.1007/s00276-016-1630-0 PG 2 WC Anatomy & Morphology; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Anatomy & Morphology; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA DX5WL UT WOS:000384453300013 PM 26820886 ER PT J AU Keung, EZ Fairweather, M Raut, CP AF Keung, Emily Z. Fairweather, Mark Raut, Chandrajit P. TI Surgical Management of Metastatic Disease SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Soft tissue sarcoma; Metastatic sarcoma; Liver metastasis; Pulmonary metastasis; Metastasectomy ID SOFT-TISSUE SARCOMA; SINGLE-CENTER EXPERIENCE; BODY RADIATION-THERAPY; LONG-TERM SURVIVAL; PHASE I/II TRIAL; PULMONARY METASTASECTOMY; LIVER METASTASES; HEPATIC METASTASES; PROGNOSTIC-FACTORS; TREATMENT PATTERNS AB Sarcomas are rare cancers of mesenchymal cell origin that include many histologic subtypes and molecularly distinct entities. For primary resectable sarcoma, surgery is the mainstay of treatment. Despite treatment, approximately 50% of patients with soft tissue sarcoma are diagnosed with or develop distant metastases, significantly affecting their survival. Although systemic therapy with conventional chemotherapy remains the primary treatment modality for those with metastatic sarcoma, increased survival has been achieved in select patients who receive multi modality therapy, including surgery, for their metastatic disease. This article provides an overview of the literature on surgical management of pulmonary and hepatic sarcoma metastases. C1 [Keung, Emily Z.; Fairweather, Mark; Raut, Chandrajit P.] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Raut, Chandrajit P.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 450 Brookline Ave, Boston, MA 02115 USA. RP Raut, CP (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM craut@bwh.harvard.edu NR 73 TC 0 Z9 0 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 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD OCT PY 2016 VL 96 IS 5 BP 1175 EP + DI 10.1016/j.suc.2016.05.010 PG 19 WC Surgery SC Surgery GA DW4TY UT WOS:000383637100018 PM 27542649 ER PT J AU Scheel, JR Peacock, S Orem, J Bugeza, S Muyinda, Z Porter, PL Wood, WC Comis, RL Lehman, CD AF Scheel, John R. Peacock, Sue Orem, Jackson Bugeza, Samuel Muyinda, Zeridah Porter, Peggy L. Wood, William C. Comis, Robert L. Lehman, Constance D. TI Improving Breast Ultrasound Interpretation in Uganda Using a Condensed Breast Imaging Reporting and Data System SO ACADEMIC RADIOLOGY LA English DT Article DE Breast ultrasound; capacity building; resource-limited countries; Uganda; interpretive performance; education; BI-BADS ID SCREENING OBSTETRIC ULTRASOUND; BI-RADS; CANCER; VARIABILITY; SONOGRAPHY; SURVIVAL; BENIGN AB Rationale and Objectives: This study aimed to determine whether a 2-day educational course using a condensed Breast Imaging Reporting and Data System (condensed BI-BADS) improved the accuracy of Ugandan healthcare workers interpreting breast ultrasound. Materials and Methods: The target audience of this intervention was Ugandan healthcare workers involved in performing, interpreting, or acting on the results of breast ultrasound. The educational course consisted of a pretest knowledge assessment, a series of lectures on breast imaging interpretation and standardized reporting using a condensed BI-BADS, and a posttest knowledge assessment. Participants interpreted 53 different ultrasound test cases by selecting the finding type, descriptors for masses, and recommendations. We compared the percent correct on the pretest and posttest based on occupation and training level. Results: Sixty-one Ugandan healthcare workers participated in this study, including 13 radiologists, 13 other physicians, 12 technologists, and 23 midlevel providers. Most groups improved in identifying the finding type (P < 0.05). All occupations showed improved use of descriptive terms for the shape and internal echogenicity of masses (P < 0.05). Most groups showed significant improvement in recommendations for normal and benign findings with a corresponding reduction in biopsy recommendations. Conclusions: Targeted breast ultrasound education using a condensed BI-BADS improved the interpretive performance of healthcare workers and was particularly successful in reducing the frequency of unnecessary biopsies for normal and benign findings. Multimodal educational efforts to improve accuracy and management of breast ultrasound findings may augment breast cancer early detection efforts in resource-limited settings. C1 [Scheel, John R.] Univ Washington, Seattle Canc Care Alliance, Dept Radiol, 825 Eastlake Ave East,G2-600, Seattle, WA 98109 USA. [Peacock, Sue] Univ Washington, Harborview Med Ctr, Dept Med, Div Gen Internal Med, Seattle, WA 98104 USA. [Orem, Jackson] Uganda Canc Inst, Kampala, Uganda. [Bugeza, Samuel] Mulago Hosp, Dept Radiol, Kampala, Uganda. [Muyinda, Zeridah] Assoc Radiologists Uganda, Mulago Hosp, Dept Radiol, Kampala, Uganda. [Porter, Peggy L.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Wood, William C.] Winship Canc Inst, Atlanta, GA USA. [Comis, Robert L.] ECOG ACRIN Canc Res Grp, Philadelphia, PA USA. [Lehman, Constance D.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Scheel, JR (reprint author), Univ Washington, Seattle Canc Care Alliance, Dept Radiol, 825 Eastlake Ave East,G2-600, Seattle, WA 98109 USA. EM jrs4yg@uw.edu OI Scheel, John/0000-0002-0998-0098 NR 22 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD OCT PY 2016 VL 23 IS 10 BP 1271 EP 1277 DI 10.1016/j.acra.2016.05.018 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DX0FA UT WOS:000384036000010 PM 27325412 ER PT J AU Liachko, NF Saxton, AD McMillan, PJ Strovas, TJ Currey, HN Taylor, LM Wheeler, JM Oblak, AL Ghetti, B Montine, TJ Keene, CD Raskind, MA Bird, TD Kraemer, BC AF Liachko, Nicole F. Saxton, Aleen D. McMillan, Pamela J. Strovas, Timothy J. Currey, Heather N. Taylor, Laura M. Wheeler, Jeanna M. Oblak, Adrian L. Ghetti, Bernardino Montine, Thomas J. Keene, C. Dirk Raskind, Murray A. Bird, Thomas D. Kraemer, Brian C. TI The phosphatase calcineurin regulates pathological TDP-43 phosphorylation SO ACTA NEUROPATHOLOGICA LA English DT Article DE Calcineurin; TDP-43; TARDBP; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; FK506; Tacrolimus; pTDP ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; DEPENDENT PROTEIN PHOSPHATASE; ALZHEIMERS ASSOCIATION GUIDELINES; TAR-DNA-BINDING; CAENORHABDITIS-ELEGANS; NEUROPATHOLOGIC ASSESSMENT; CYTOPLASMIC INCLUSIONS; NATIONAL INSTITUTE; DISEASE AB Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90 % of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date, several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together, these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences. C1 [Liachko, Nicole F.; Saxton, Aleen D.; McMillan, Pamela J.; Strovas, Timothy J.; Currey, Heather N.; Wheeler, Jeanna M.; Bird, Thomas D.; Kraemer, Brian C.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Liachko, Nicole F.; Taylor, Laura M.; Kraemer, Brian C.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98104 USA. [McMillan, Pamela J.; Raskind, Murray A.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ Ctr, Seattle, WA 98108 USA. [McMillan, Pamela J.; Raskind, Murray A.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Clin Ctr, Seattle, WA 98108 USA. [McMillan, Pamela J.; Raskind, Murray A.; Kraemer, Brian C.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Oblak, Adrian L.; Ghetti, Bernardino] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Montine, Thomas J.; Keene, C. Dirk; Kraemer, Brian C.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Bird, Thomas D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Bird, Thomas D.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98104 USA. [Montine, Thomas J.] Stanford Univ, Sch Med, Dept Pathol, Palo Alto, CA 94305 USA. RP Kraemer, BC (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA.; Kraemer, BC (reprint author), Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98104 USA.; Kraemer, BC (reprint author), Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA.; Kraemer, BC (reprint author), Univ Washington, Dept Pathol, Seattle, WA 98195 USA. EM kraemerb@u.washington.edu FU NIH Office of Research Infrastructure Programs [P40 OD010440]; Department of Veterans Affairs [I01BX002619, I01BX007080]; National Institutes of Health [R01NS064131, P50AG05136] FX We thank the reviewers for helpful comments and suggestions. We thank Michael Gitcho for constructive discussion about calcineurin and TDP-43. We thank Elaine Loomis, John Kushleika, Kaili Chickering, Susan Danner, and Samantha Rice for outstanding technical assistance and Allison Beller for outstanding administrative support. We thank Virginia Lee and Manuela Neumann for antibodies and the Developmental Studies Hybridoma Bank (NICHD) for the beta-tubulin antibody E7. We thank WormBase (WS251) for C. elegans genetic information. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), and other strains were provided by the National Bioresource Project (Japan). This work was supported by Grants from the Department of Veterans Affairs [Merit Review Grant #I01BX002619 to B. K., Career Development Award 2 #I01BX007080 to N. L.] and National Institutes of Health [R01NS064131 to B. K and P50AG05136 for T. J. M. and C. D. K. for the UW ADRC for A. L. O and B. G.]. NR 62 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD OCT PY 2016 VL 132 IS 4 BP 545 EP 561 DI 10.1007/s00401-016-1600-y PG 17 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DW2HL UT WOS:000383463400006 PM 27473149 ER PT J AU Dang, BN Westbrook, RA Hartman, CM Giordano, TP AF Dang, Bich N. Westbrook, Robert A. Hartman, Christine M. Giordano, Thomas P. TI Retaining HIV Patients in Care: The Role of Initial Patient Care Experiences SO AIDS AND BEHAVIOR LA English DT Article DE Patient satisfaction; Patient experience; HIV infection; Retention in care; Prospective studies ID SELF-EFFICACY SCALE; SOCIAL SUPPORT; SATISFACTION; VALIDATION; PREDICTORS; ADHERENCE; QUALITY AB Cross-sectional studies have shown an association between better patient experiences and health outcomes. However, the direction of causality remains unclear. Our prospective study seeks to determine whether better initial patient experiences predict subsequent retention in HIV care. We enrolled patients new to an HIV clinic in Houston, Texas, from August 26, 2013 to November 18, 2013. The patients' overall experience with the HIV provider was based on six items; overall experience with the HIV clinic was based on five items. We measured subsequent retention over the first 6 months and entire first year of HIV care. Analyses included 140 patients. Sixty-one percent were non-Hispanic black, 41 % were diagnosed with HIV within the last 3 months, and 36 % had a CD4 cell count < 200. Thirty three percent were totally satisfied with their initial HIV provider experience and 32 % were totally satisfied with their initial HIV clinic experience. Retention was 68 % over the first 6 months and 51 % over the first year. Satisfaction with the HIV provider at the initial visit significantly predicted 6-month retention in care (aOR = 3.56, p = 0.006). Similar results were found for satisfaction with the HIV clinic (aOR = 4.67, p = 0.002). Neither of the patient experience measures at the initial visit predicted 12-month retention. Patients with better initial care experiences have significantly greater retention in HIV care. The effect of better initial care experiences was limited in duration. Consistently improving patient care experiences, not only at baseline but also on subsequent visits, may be a way to increase retention in HIV care. C1 [Dang, Bich N.; Hartman, Christine M.; Giordano, Thomas P.] VA Ctr Innovat Qual Effectiveness & Safety IQuESt, Houston, TX 77030 USA. [Dang, Bich N.; Hartman, Christine M.; Giordano, Thomas P.] Michael E DeBakey Vet Affairs Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. [Dang, Bich N.; Hartman, Christine M.; Giordano, Thomas P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Dang, Bich N.; Giordano, Thomas P.] Harris Hlth Syst, Houston, TX 77030 USA. [Westbrook, Robert A.] Rice Univ, Jesse H Jones Grad Sch Business, Houston, TX USA. RP Dang, BN (reprint author), VA Ctr Innovat Qual Effectiveness & Safety IQuESt, Houston, TX 77030 USA.; Dang, BN (reprint author), Michael E DeBakey Vet Affairs Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA.; Dang, BN (reprint author), Baylor Coll Med, Dept Med, Houston, TX 77030 USA.; Dang, BN (reprint author), Harris Hlth Syst, Houston, TX 77030 USA. EM bndang@bcm.edu FU National Institutes of Health [P30AI036211]; supplemental funds to the District of Columbia Developmental Center for AIDS Research [5P30AI087714] FX We thank Drs. Daniel M. Musher and Richard L. Street for their critical review of an earlier draft of this manuscript. This study was supported by a supplement to the National Institutes of Health-funded Baylor College of Medicine-University of Texas Houston Center for AIDS Research (Grant Number P30AI036211), supplemental funds to the District of Columbia Developmental Center for AIDS Research (Grant Number 5P30AI087714), the facilities and resources of the Houston VA Center for Innovations in Quality, Effectiveness and Safety (HFP90-020), and the facilities and resources of Harris Health System. NR 29 TC 1 Z9 1 U1 0 U2 0 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 OCT PY 2016 VL 20 IS 10 BP 2477 EP 2487 DI 10.1007/s10461-016-1340-y PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DV7GG UT WOS:000383103800028 PM 26910339 ER PT J AU Weisbord, SD Palevsky, PM AF Weisbord, Steven D. Palevsky, Paul M. TI Prevention of Contrast-Associated Acute Kidney Injury: What Should We Do? SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIALS; INDUCED NEPHROPATHY; ISO-OSMOLAR; METAANALYSIS; MEDIA; NEPHROTOXICITY; ANGIOGRAPHY; IODIXANOL; CORONARY; OUTCOMES C1 [Weisbord, Steven D.; Palevsky, Paul M.] Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Palevsky, PM (reprint author), VA Pittsburgh Healthcare Syst, Rm 7E123,111F-U,Univ Dr, Pittsburgh, PA 15240 USA. EM palevsky@pitt.edu OI Palevsky, Paul/0000-0002-7334-5400 NR 17 TC 1 Z9 1 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD OCT PY 2016 VL 68 IS 4 BP 518 EP 521 DI 10.1053/j.ajkd.2016.05.005 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA DW8GF UT WOS:000383892200012 PM 27233380 ER PT J AU Jotwani, V Scherzer, R Estrella, MM Jacobson, LP Witt, MD Palella, FJ Macatangay, B Bennett, M Parikh, CR Ix, JH Shlipak, MG AF Jotwani, Vasantha Scherzer, Rebecca Estrella, Michelle M. Jacobson, Lisa P. Witt, Mallory D. Palella, Frank J., Jr. Macatangay, Bernard Bennett, Michael Parikh, Chirag R. Ix, Joachim H. Shlipak, Michael G. TI HIV Infection, Tenofovir, and Urine alpha(1)-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Tenofovir disoproxil fumarate (TDF); nephrotoxicity; HIV infection; proximal tubular dysfunction; tubular toxicity; biomarker; urine alpha(1)-microglobulin (A1M); kidney damage; antiretroviral (ARV) medication; Multicenter AIDS Cohort Study (MACS) ID CHRONIC KIDNEY-DISEASE; LOW-MOLECULAR-WEIGHT; DISOPROXIL FUMARATE; PROTEASE INHIBITORS; GLOMERULAR FUNCTION; FUNCTION DECLINE; P-GLYCOPROTEIN; APOL1 GENOTYPE; RENAL-FUNCTION; RISK-FACTORS AB Background: Tenofovir disoproxil fumarate (TDF) can cause proximal tubular damage and chronic kidney disease in human immunodeficiency virus (HIV)-infected individuals. Urine alpha(1)-microglobulin (A1M), a low-molecular-weight protein indicative of proximal tubular dysfunction, may enable earlier detection of TDF-associated tubular toxicity. Study Design: Cross-sectional. Setting & Participants: 883 HIV-infected and 350 -uninfectedmen enrolled in the Multicenter AIDS Cohort Study. Predictors: HIV infection and TDF exposure. Outcome: Urine A1M level. Results: Urine A1M was detectable in 737 (83%) HIV-infected and 202 (58%) -uninfected men (P < 0.001). Among HIV-infected participants, 573 (65%) were current TDF users and 112 (13%) were past TDF users. After multivariable adjustment including demographics, traditional kidney disease risk factors, and estimated glomerular filtration rate, HIV infection was associated with 136% (95% CI, 104%-173%) higher urine A1M levels and 1.5-fold (95% CI, 1.3- to 1.6-fold) prevalence of detectable A1M. When participants were stratified by TDF exposure, HIV infection was associated with higher adjusted A1M levels, by 164% (95% CI, 127%-208%) among current users, 124% (95% CI, 78%-183%) among past users, and 76% (95% CI, 45%-115%) among never users. Among HIV-infected participants, each year of cumulative TDF exposure was associated with 7.6% (95% CI, 5.4%-9.9%) higher A1M levels in fully adjusted models, a 4-fold effect size relative to advancing age (1.8% [95% CI, 0.9%-2.7%] per year). Each year since TDF treatment discontinuation was associated with 4.9% (95% CI, 29.4%-20.2%) lower A1M levels among past users. Limitations: Results may not be generalizable to women. Conclusions: HIV-infected men had higher urine A1M levels compared with HIV-uninfected men. Among HIV-infected men, cumulative TDF exposure was associated with incrementally higher A1M levels, whereas time since TDF treatment discontinuation was associated with progressively lower A1M levels. Urine A1M appears to be a promising biomarker for detecting and monitoring TDF-associated tubular toxicity. (C) 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Jotwani, Vasantha; Scherzer, Rebecca; Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Jotwani, Vasantha; Scherzer, Rebecca] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Estrella, Michelle M.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Jacobson, Lisa P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Witt, Mallory D.] Harbor UCLA Med Ctr, Dept Med, Div HIV Med, Torrance, CA 90509 USA. [Witt, Mallory D.] Harbor UCLA, Los Angeles Biomed Res Inst, Torrance, CA USA. [Palella, Frank J., Jr.] Northwestern Univ, Dept Med, Div Infect Dis, Chicago, IL 60611 USA. [Macatangay, Bernard] Univ Pittsburgh, Div Infect Dis, Dept Med, Pittsburgh, PA USA. [Bennett, Michael] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, Cincinnati, OH 45229 USA. [Parikh, Chirag R.] Yale Univ, Dept Med, Nephrol Sect, New Haven, CT 06520 USA. [Parikh, Chirag R.] Yale Univ, Program Appl Translat Res, New Haven, CT USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol Hypertens, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Kidney Hlth Res Collaborat, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Jotwani, V (reprint author), San Francisco VA Med Ctr, 4150 Clement St,Box 111A1, San Francisco, CA 94121 USA. EM vasantha.jotwani@ucsf.edu FU National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute on Drug Abuse; National Institute of Mental Health; National Heart, Lung and Blood Institute; National Institute on Deafness and Communication Disorders; National Center for Advancing Translational Sciences a component of the National Institutes of Health (NIH) [UL1-TR001079]; NIH Roadmap for Medical Research; [R01-AG034853-01A2] FX Support: MACS Kidney Study is funded by grant R01-AG034853-01A2 (Principal Investigator [PI], Dr Shlipak), which was administered by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs Medical Center, San Francisco, CA. Data in this manuscript were collected by the MACS with centers at Baltimore (U01-AI35042): The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick (PI), Jay Bream, Todd Brown, Barbara Crain, Adrian Dobs, Richard Elion, Michelle Estrella, Lisette Johnson-Hill, Sean Leng, Anne Monroe, Cynthia Munro, Michael W. Plankey, Wendy Post, Ned Sacktor, Jennifer Schrack, Chloe Thio; Chicago (U01-AI35039): Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: Steven M. Wolinsky (PI), John P. Phair, Sheila Badri, Dana Gabuzda, Frank J. Palella Jr, Sudhir Penugonda, Susheel Reddy, Matthew Stephens, Linda Teplin; Los Angeles (U01-AI35040): University of California, UCLA Schools of Public Health and Medicine: Roger Detels (PI), Otoniel Martinez-Maza (Co-PI), Aaron Aronow, Peter Anton, Robert Bolan, Elizabeth Breen, Anthony Butch, Shehnaz Hussain, Beth Jamieson, Eric N. Miller, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, Zuo Feng Zhang; Pittsburgh (U01-AI35041): University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (PI), Lawrence A. Kingsley (Co-PI), James T. Becker, Phalguni Gupta, Kenneth Ho, Susan Koletar, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, Ronald D. Stall; Data Coordinating Center (UM1-AI35043): The Johns Hopkins University Bloomberg School of Public Health: Lisa P. Jacobson (PI), Gypsyamber D'Souza (Co-PI), Alison Abraham, Keri Althoff, Jennifer Deal, Priya Duggal, Sabina Haberlen, Alvaro Muoz, Derek Ng, Janet Schollenberger, Eric C. Seaberg, Sol Su, Pamela Surkan. Institute of Allergy and Infectious Diseases: Robin E. Huebner; National Cancer Institute: Geraldina Dominguez. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases, with additional co-funding from the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute of Mental Health. Targeted supplemental funding for specific projects was also provided by the National Heart, Lung and Blood Institute, and the National Institute on Deafness and Communication Disorders. MACS data collection is also supported by UL1-TR001079 (Johns Hopkins University Institute for Clinical and Translational Research) from the National Center for Advancing Translational Sciences a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the NIH, Johns Hopkins Institute for Clinical and Translational Research, or the National Center for Advancing Translational Sciences. The funders of this study had no role in study design; collection, analysis or interpretation of data; manuscript preparation; or the decision to submit the report for publication. The MACS website is located at https://statepi.jhsph.edu/macs/macs.html NR 52 TC 0 Z9 0 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 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD OCT PY 2016 VL 68 IS 4 BP 571 EP 581 DI 10.1053/j.ajkd.2016.03.430 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DW8GF UT WOS:000383892200018 PM 27287300 ER PT J AU Yuan, GY Jones, GB Vasdev, N Liang, SH AF Yuan, Gengyang Jones, Graham B. Vasdev, Neil Liang, Steven H. TI Radiosynthesis and preliminary PET evaluation of F-18-labeled 2-(1-(3-fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)b enzonitrile for imaging AMPA receptors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE AMPA receptor; Positron emission tomography; Fluorine-18; Radiotracer; Perampanel ID POSITRON-EMISSION-TOMOGRAPHY; ANTAGONIST; PERAMPANEL; RADIOFLUORINATION; EPILEPSY; SEIZURES; ACID; DRUG; DISCOVERY; DISEASE AB To prompt the development of F-18-labeled positron emission tomography (PET) tracers for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, we have prepared F-18-labeled 2-(1-(3fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([F-18] 8). The radiosynthesis was achieved by a one-pot two-step method that utilized a spirocyclic hypervalent iodine(III) mediated radiofluorination to prepare the F-18-labeled 1-bromo-3-fluorobenzene ([F-18] 15) intermediate with (KF)-F-18. A subsequent copper(I) iodide mediated coupling reaction was carried out with 2-(2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile (10) to [F-18] 8 in 10 +/- 2% uncorrected radiochemical yield relative to starting F-18-fluoride with > 99% radiochemical purity and 29.6 +/- 7.4 Gbq/lmol specific activity at the time of injection. PET imaging studies with the title radiotracer in normal mice demonstrated good brain uptake (peak standardized uptake value (SUV) = 2.3 +/- 0.1) and warrants further in vivo validation. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Yuan, Gengyang; Jones, Graham B.] Northeastern Univ, Dept Chem & Chem Biol, 360 Huntington Ave, Boston, MA 02115 USA. [Yuan, Gengyang; Vasdev, Neil; Liang, Steven H.] Massachusetts Gen Hosp, Gordon Ctr Med Imaging, 55 Fruit St, Boston, MA 02114 USA. [Yuan, Gengyang; Vasdev, Neil; Liang, Steven H.] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, 55 Fruit St, Boston, MA 02114 USA. [Yuan, Gengyang; Vasdev, Neil; Liang, Steven H.] Harvard Med Sch, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. RP Vasdev, N; Liang, SH (reprint author), Massachusetts Gen Hosp, Gordon Ctr Med Imaging, 55 Fruit St, Boston, MA 02114 USA.; Vasdev, N; Liang, SH (reprint author), Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, 55 Fruit St, Boston, MA 02114 USA.; Vasdev, N; Liang, SH (reprint author), Harvard Med Sch, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM vasdev.neil@mgh.harvard.edu; liang.steven@mgh.harvard.edu FU NIH career development award from the National Institute on Drug Abuse United States [DA038000]; Department of Chemistry & Chemical Biology, Northeastern University FX We would like to thank the staff at the radiochemistry program, Gordon Center for Medical Imaging, Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, MA, and Department of Chemistry & Chemical Biology, Northeastern University for their generous support. We also thank Drs. Lee Collier, Benjamin H. Rotstein and Chongzhao Ran, Mr. Jian Yang and Ms. Jing Yang for their helpful discussions. S.H.L. is a recipient of NIH career development award from the National Institute on Drug Abuse (DA038000) United States. NR 38 TC 0 Z9 0 U1 8 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 1 PY 2016 VL 26 IS 19 BP 4857 EP 4860 DI 10.1016/j.bmcl.2016.07.078 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DW0UW UT WOS:000383359400059 PM 27546294 ER PT J AU Ferreira, AR Palha, A Correia, L Filipe, P Rodrigues, V Costa, L Miranda, A Andre, R Fernandes, J Gouveia, J Passos-Coelho, JL Moreira, A Brito, M Ribeiro, J Metzger, O Lin, NU Vaz-Luis, I AF Ferreira, Arlindo R. Palha, Ana Correia, Lurdes Filipe, Pedro Rodrigues, Vasco Costa, Luis Miranda, Ana Andre, Rosario Fernandes, Joao Gouveia, Joaquim Passos-Coelho, Jose Luis Moreira, Antonio Brito, Margarida Ribeiro, Joana Metzger-Filho, Otto Lin, Nancy U. Vaz-Luis, Ines TI Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: A multi-institutional Portuguese cohort study SO BREAST LA English DT Article DE Chemotherapy; Stage I; Breast cancer ID FOLLOW-UP; NATURAL-HISTORY; CARCINOMA; SURVIVAL; WOMEN; CYCLOPHOSPHAMIDE; TRASTUZUMAB; DOXORUBICIN; DOCETAXEL; MORTALITY AB Background: A contemporary US study showed an increase in the use of chemotherapy in the last decade for some patients with stage-I breast cancer; with a rise in more intensive regimens, and declining use of anthracyclines. Nevertheless, there is still uncertainty on the absolute benefit of chemotherapy for these patients and the optimal regimen. In this study we compare those findings with the patterns of care among a Portuguese cohort of stage-I breast cancers. Methods: Retrospective cohort study of patients with stage-I breast cancer diagnosed from 2006 to 2008 at four Portuguese institutions. The use and type of chemotherapy was evaluated. Results: Among patients with stage I Ill breast cancer 39.4% (n = 682) had stage I disease. Of the 595 eligible patients, 22.4% were treated with chemotherapy, 33.9% aged <55 years vs. 12.7% aged >65 years (p < 0.001). Thirteen percent of patients with hormone receptor (HR)+/HER2- tumors, 52.7% of patients with HER2+ and 66.0% of patients with HR-/HER2- received chemotherapy (p < 0.001). In addition, we found inter-institutional variability, with the use of chemotherapy ranging from 0.0% to 43.4% (p < 0.001). Eighty-five percent of patients treated with chemotherapy received less-intensive regimens with anthracycline-based regimens, such as doxorubicin and cyclophosphamide, being the most frequently used, while docetaxel and cyclophosphamide was only used in 1.5% of cases. Conclusions: Overall, almost one-quarter of patients received chemotherapy with institutional variability. When treated, mostly less-intensive associations including anthracyclines were used, which contrasts with contemporary US practice. This study highlights the need for health-services research to understand local practices and tailor quality improvement interventions. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ferreira, Arlindo R.; Costa, Luis] Univ Lisbon, Inst Mol Med, Fac Med, Lisbon, Portugal. [Ferreira, Arlindo R.; Palha, Ana; Correia, Lurdes; Filipe, Pedro; Rodrigues, Vasco; Costa, Luis] Hosp Santa Maria, Ctr Hosp Lisboa Norte, Lisbon, Portugal. [Miranda, Ana; Andre, Rosario] Registo Oncol Reg Sul, Lisbon, Portugal. [Fernandes, Joao; Gouveia, Joaquim] Hosp CUF Lisboa, Lisbon, Portugal. [Passos-Coelho, Jose Luis] Hosp Luz, Lisbon, Portugal. [Moreira, Antonio; Brito, Margarida] Inst Portugues Oncol FG Lisboa, Lisbon, Portugal. [Ribeiro, Joana] Fundacao Champalimaud, Lisbon, Portugal. [Metzger-Filho, Otto; Lin, Nancy U.; Vaz-Luis, Ines] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ferreira, AR (reprint author), Hosp Santa Maria, Serv Oncol, Av Prof Egas Moniz, P-1649039 Lisbon, Portugal. EM ajrsferreira@medicina.ulisboa.pt OI Ferreira, Arlindo/0000-0002-1567-9322 FU Fundacao para a Ciencia e a Tecnologia (FCT) [HMSP-ICS/0004/201, HMSP-ICJ/0007/2013] FX Fundacao para a Ciencia e a Tecnologia (FCT) grants HMSP-ICS/0004/201 to IVL and HMSP-ICJ/0007/2013 to ARF. NR 19 TC 0 Z9 0 U1 2 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 EI 1532-3080 J9 BREAST JI Breast PD OCT PY 2016 VL 29 BP 68 EP 73 DI 10.1016/j.breast.2016.07.004 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DW7HO UT WOS:000383822000011 ER PT J AU Hernandez-Blanquisett, A Touya, D Strasser-Weippl, K Ruiz, R St Louis, J Goss, P AF Hernandez-Blanquisett, Abraham Touya, Diego Strasser-Weippl, Kathrin Ruiz, Rossana St Louis, Jessica Goss, Paul TI Current and emerging therapies of HER2-positive metastatic breast cancer SO BREAST LA English DT Review DE Breast cancer; Metastatic; HER2; Biomarkers; Targeted therapy; Endocrine therapy ID CIRCULATING TUMOR-CELLS; PHASE-II TRIAL; LAPATINIB PLUS CAPECITABINE; IN-SITU HYBRIDIZATION; TRASTUZUMAB RESISTANCE; 1ST-LINE TREATMENT; ADJUVANT TRASTUZUMAB; DOUBLE-BLIND; TANESPIMYCIN 17-AAG; GENE AMPLIFICATION AB The HER2 receptor as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is overexpressed in 15-20% of all breast cancers and traditionally represents adverse biology and a guarded prognosis, particularly in HER2 positive metastatic breast cancer (MBC). Trastuzumab and newer anti-HER2 targeting agents have significantly improved the clinical outcomes of patients with HER2 positive MBC. The development of new techniques has led to discovery of promising biomarkers that can lead to more precise selection of patients for anti-HER2 therapies. This paper summarizes these new biomarkers, useful in selecting patients for treatment with new and emerging therapies for HER2 positive MBC. Emerging next generation sequencing techniques have truly changed the landscape of HER2 positive MBC. Deployment of multiple anti-HER2 therapies in combination is a strategy which has yielded additive or even synergistic effects and has led to markedly improved patient outcomes in HER2+ MBC. In the future, in order to further improve the treatment of these patients and to reduce toxicities, we need to improve our understanding of HER2-dependent pathways and their function, and to develop further treatment combinations while optimizing selection of patients by identifying new biomarkers. The results of prospective studies using CTCs, cDNA and other promising new biomarkers are awaited with great interest. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Hernandez-Blanquisett, Abraham; Ruiz, Rossana; St Louis, Jessica; Goss, Paul] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Cambridge, MA 02138 USA. [Touya, Diego] Univ Republica, Hosp Clin, Dept Oncol, Montevideo, Uruguay. [Strasser-Weippl, Kathrin] Wilhelminen Hosp, Ctr Oncol Hematol & Palliat Care, Vienna, Austria. RP Goss, P (reprint author), Massachusetts Gen Hosp, Ctr Canc, Avon Breast Canc Ctr Excellence, 55 Fruit St,Lawrence House,LRH-302, Boston, MA 02114 USA. EM pgoss@partners.org OI Ruiz, Rossana/0000-0001-5199-6686 FU Avon Foundation, NY FX PEG and KSW led the writing of this manuscript. AH, DT, KSW, RM, JS and PEG contributed to the literature review, analysis of data and writing of the manuscript. All authors approved of the final version of the manuscript. DT, RM, JS and PEG received partial support from the Avon Foundation, NY. NR 95 TC 2 Z9 2 U1 13 U2 15 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 EI 1532-3080 J9 BREAST JI Breast PD OCT PY 2016 VL 29 BP 170 EP 177 DI 10.1016/j.breast.2016.07.026 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DW7HO UT WOS:000383822000028 PM 27526299 ER PT J AU Husain, A Hu, N Sadow, PM Nucera, C AF Husain, Amjad Hu, Nina Sadow, Peter M. Nucera, Carmelo TI Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF(v600E) SO CANCER LETTERS LA English DT Article DE Anaplastic thyroid cancer; Cachexia; Cytokines; Angiogenesis; Inflammation; BRAF(V600E) ID ENDOTHELIAL GROWTH-FACTOR; ORTHOTOPIC MOUSE MODEL; BRAF V600E MUTATION; CANCER CACHEXIA; DISTANT METASTASIS; NUDE-MICE; CELL-LINE; PHASE-II; TUMOR; CYTOKINES AB Cachexia is the result of complex metabolic alterations which cause morbidity and mortality in patients with advanced cancers including undifferentiated (anaplastic) thyroid carcinoma (ATC). ATC is a lethal disease with limited therapeutic options and unclear etiology for cachexia. We hypothesize that the BRAF(V600E) oncoprotein triggers microvascular endothelial cell tubule formation (in vitro angiogenesis) by means of factors which play a crucial role in angiogenic switch, inflammation/immune response and cachexia. We use human ATC cells and applied multiplex ELISA assay to screen for and measure angiogenic/cachectic and pro-inflammatory factors in the ATC-derived secretome. We find that vemurafenib anti-BRAF(V600E) therapy significantly reduces secreted VEGFA, VEGFC and IL6 protein levels compared to vehicle treated ATC cells. As a result, the secretome from vemurafenib-treated ATC cells inhibits microvascular endothelial cell-related in vitro angiogenesis. Furthermore, ATC clinical samples express VEGFA, VEGFC and IL6 proteins. Our results suggest that angiogenic/cachectic and pro-inflammatory/immune response factors could play a crucial role in BRAF(V600E)-positive human ATC aggressiveness. Understanding the extent to which,microenvironment-associated angiogenic factors participate in cachexia and cancer metabolism in advanced thyroid cancers will reveal new biomarkers and foster novel therapeutic approaches. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Husain, Amjad; Nucera, Carmelo] Harvard Med Sch, Vasc Biol Res Ctr, BIDMC, Boston, MA 02115 USA. [Hu, Nina] Harvard Med Sch, Lab Human Thyroid Canc Preclin & Translat Res, Div Canc Biol & Angiogenesis, CRI,Canc Ctr,Dept Pathol,Beth Israel Deaconess Me, Boston, MA USA. [Sadow, Peter M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. RP Nucera, C (reprint author), Harvard Med Sch, Vasc Biol Res Ctr, BIDMC, Boston, MA 02115 USA. EM cnucera@bidmc.harvard.edu FU National Cancer Institute/National Institutes of Health [1R21CA165039-01A1, 1R01CA181183-01A1]; American Thyroid Association (ATA); ThyCa:Thyroid Cancer Survivors Association Inc. for Thyroid Cancer Research; BIDMC/CAO Grant (Boston, MA) FX Carmelo Nucera was awarded grants by the National Cancer Institute/National Institutes of Health (1R21CA165039-01A1 and 1R01CA181183-01A1), the American Thyroid Association (ATA) and ThyCa:Thyroid Cancer Survivors Association Inc. for Thyroid Cancer Research. Carmelo Nucera was also a recipient of the BIDMC/CAO Grant (Boston, MA) and Guido Berlucchi the "Young Investigator" research award (Brescia, Italy). NR 66 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD OCT 1 PY 2016 VL 380 IS 2 BP 577 EP 585 DI 10.1016/j.canlet.2015.07.012 PG 9 WC Oncology SC Oncology GA DV9ZI UT WOS:000383300300025 PM 26189429 ER PT J AU Khandelwal, A Sholl, LM Araki, T Ramaiya, NH Hatabu, H Nishino, M AF Khandelwal, A. Sholl, L. M. Araki, T. Ramaiya, N. H. Hatabu, H. Nishino, M. TI Patterns of metastasis and recurrence in thymic epithelial tumours: longitudinal imaging review in correlation with histological subtypes SO CLINICAL RADIOLOGY LA English DT Review ID HEALTH-ORGANIZATION CLASSIFICATION; STANDARD OUTCOME MEASURES; CLINICOPATHOLOGICAL CORRELATION; THYMOMA; CT; PROGNOSIS; MALIGNANCIES; MULTICENTER; CARCINOMA; FEATURES AB AIM: To determine the patterns of metastasis and recurrence in thymic epithelial tumours based on longitudinal imaging studies, and to correlate the patterns with World Health Organization (WHO) histological classifications. MATERIALS AND METHODS: Seventy-seven patients with histopathologically confirmed thymomas (n = 62) and thymic carcinomas (n = 15) who were followed with cross-sectional follow-up imaging after surgery were retrospectively studied. All cross-sectional imaging studies during the disease course were reviewed to identify metastasis or recurrence. The sites of involvement and the time of involvement measured from surgery were recorded. RESULTS: Metastasis or recurrence was noted in 24 (31%) of the 77 patients. Patients with metastasis or recurrence were significantly younger than those without (median age: 46 versus 60, respectively; p = 0.0005), and more commonly had thymic carcinomas than thymomas (p = 0.002). The most common site of involvement was the pleura (17/24), followed by the lung (9/24), and thoracic nodes (9/24). Abdominopelvic involvement was noted in 12 patients, most frequently in the liver (n = 8). Lung metastasis was more common in thymic carcinomas than thymomas (p = 0.0005). Time from surgery to the development of metastasis or recurrence was shortest in thymic carcinoma, followed by high-risk thymomas, and was longest in low-risk thymoma (median time in months: 25.1, 68.8, and not reached, respectively; p = 0.0015). CONCLUSIONS: The patterns of metastasis and recurrence of thymic epithelial tumours differ significantly across histological subgroups, with thymic carcinomas more commonly having metastasis with shorter length of time after surgery. The knowledge of different patterns of tumour spread may contribute to further understanding of the biological and clinical behaviours of these tumours. (C) 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. C1 [Khandelwal, A.; Araki, T.; Ramaiya, N. H.; Hatabu, H.; Nishino, M.] Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA. [Khandelwal, A.; Sholl, L. M.; Araki, T.; Ramaiya, N. H.; Hatabu, H.; Nishino, M.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Sholl, L. M.] Brigham & Womens Hosp, Dept Pathol, 450 Brookline Ave, Boston, MA 02215 USA. RP Nishino, M (reprint author), Dana Farber Canc Inst, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA.; Nishino, M (reprint author), Brigham & Womens Hosp, 450 Brookline Ave, Boston, MA 02215 USA. EM Mizuki_Nishino@DFCI.HARVARD.EDU FU NCI [1K23CA157631] FX M.N. was supported by grant no. 1K23CA157631 (NCI). NR 42 TC 1 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0009-9260 EI 1365-229X J9 CLIN RADIOL JI Clin. Radiol. PD OCT PY 2016 VL 71 IS 10 BP 1010 EP 1017 DI 10.1016/j.crad.2016.05.007 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW0TD UT WOS:000383354600009 PM 27267746 ER PT J AU Troxel, AB Asch, DA Volpp, KG AF Troxel, Andrea B. Asch, David A. Volpp, Kevin G. TI Statistical issues in pragmatic trials of behavioral economic interventions SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT 8th Annual Symposium on Statistical Issues in Clinical Trials CY APR, 2015 CL Univ Penn, Philadelphia, PA HO Univ Penn DE Effectiveness; generalizability; innovation; opt-out consent ID CONVERTING ENZYME-INHIBITORS; ACUTE MYOCARDIAL-INFARCTION; ACUTE CORONARY SYNDROMES; BLOOD-PRESSURE CONTROL; LONG-TERM ADHERENCE; ELDERLY PATIENTS; STATIN THERAPY; BETA-BLOCKERS; DISCONTINUATION; PERSISTENCE AB Background: Randomized clinical trials provide gold-standard evidence for the efficacy of interventions, but have limitations, including highly selected populations that make inference on effectiveness difficult and a lack of ability to adapt and change midstream. Methods: We propose two innovations for pragmatic trial design. Results: Evidence-based evolutionary testing, a framework that allows adaptation of interventions and rapid-cycle innovation, preserves the power of randomization while acknowledging the need for adaptation and learning. An opt-out consent framework increases the fraction of the target population who participate in trials, but may lead to dampening of effect sizes. Conclusion: Pragmatic trials offer numerous advantages in the evaluation of behavioral interventions in health. Statistical innovations, including evidence-based evolutionary testing and opt-out framing of consent and enrollment processes, can enhance the power of pragmatic trials and lead to more rapid progress. C1 [Troxel, Andrea B.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, 622 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Asch, David A.; Volpp, Kevin G.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Asch, David A.; Volpp, Kevin G.] US Dept Vet Affairs, Philadelphia, PA USA. RP Troxel, AB (reprint author), Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, 622 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM atroxel@mail.med.upenn.edu OI Troxel, Andrea/0000-0002-1393-3075 FU NCI NIH HHS [P30 CA016520]; NIA NIH HHS [P30 AG034546] NR 28 TC 0 Z9 0 U1 5 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2016 VL 13 IS 5 BP 478 EP 483 DI 10.1177/1740774516654862 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DW1GZ UT WOS:000383392600003 PM 27365015 ER PT J AU Berg, HE Ballard, ED Luckenbaugh, DA Nugent, AC Ionescu, DF Zarate, CA AF Berg, Hannah E. Ballard, Elizabeth D. Luckenbaugh, David A. Nugent, Allison C. Ionescu, Dawn F. Zarate, Carlos A., Jr. TI Recognition of emotional facial expressions in anxious and nonanxious depression SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID STAR-ASTERISK-D; MAJOR DEPRESSION; TRAIT ANXIETY; DISORDER; IDENTIFICATION; OUTPATIENTS; PERCEPTION; BIASES; MOOD AB Background: Anxiety and depression have each been independently associated with impairments in emotional face recognition. However, little is known about the nature of these impairments when anxiety and depression co-occur. Methods: This post-hoc analysis evaluated the relationship between anxiety status and performance on the Emotional Expression Multimorph Task within a clinical sample of individuals with major depressive disorder (MDD). Results: Participants with anxious depression (n = 14) and nonanxious depression (n = 14) completed the Emotional Expression Multimorph Task. Those with anxious depression required greater intensity of emotion to identify both happy (p = .01) and sad (p = .04) facial expressions than those with nonanxious depression. Severity of anxiety also correlated with greater intensity of emotion required to detect sad faces. Contrary to prediction, hypervigilance to angry and fearful facial expressions was not observed in anxious depression. Limitations: The present study did not include an anxiety-only group for comparison, and did not assess state anxiety at time of administration. In addition, the extent to which the experimental task correlates with social functioning is not fully understood. Conclusions: These findings suggest a diminished sensitivity to happy and sad facial expressions specific to anxious depression, but not a hypervigilance toward threatening facial expressions. Further research on the nature of emotion recognition in anxiety and depression may inform improved clinical interventions. Published by Elsevier Inc. C1 [Berg, Hannah E.; Ballard, Elizabeth D.; Luckenbaugh, David A.; Nugent, Allison C.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Ionescu, Dawn F.] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Ionescu, Dawn F.] Harvard Med Sch, Boston, MA USA. RP Ballard, ED (reprint author), Bldg 10,CRC Room 7-3345,10 Ctr Dr,MSC 1282, Bethesda, MD 20892 USA. EM Elizabeth.Ballard@nih.gov RI Ionescu, Dawn/K-5675-2015; OI Berg, Hannah/0000-0002-8283-0133 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health IRP-NIMH-NIH; NCT [00,088,699]; ZIA [MH002927]; NARSAD; Brain and Behavior Mood Disorders Research Award FX Funding for this work was supported in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health IRP-NIMH-NIH; NCT#00,088,699; ZIA MH002927), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain and Behavior Mood Disorders Research Award to Dr. Zarate. These funding sources had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 27 TC 0 Z9 0 U1 11 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD OCT PY 2016 VL 70 BP 1 EP 8 DI 10.1016/j.comppsych.2016.06.007 PG 8 WC Psychiatry SC Psychiatry GA DW8SJ UT WOS:000383925500001 PM 27624417 ER PT J AU Lonial, S Kaufman, J Reece, D Mateos, MV Laubach, J Richardson, P AF Lonial, Sagar Kaufman, Jonathan Reece, Donna Mateos, Maria-Victoria Laubach, Jacob Richardson, Paul TI Update on elotuzumab, a novel anti-SLAMF7 monoclonal antibody for the treatment of multiple myeloma SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Article DE SLAMF7; CS1; elotuzumab; empliciti; IgG1; monoclonal antibody; multiple myeloma ID OPEN-LABEL; DOSE-ESCALATION; SERUM-PROTEIN; DEXAMETHASONE; LENALIDOMIDE; BORTEZOMIB; THERAPY; PHASE-2; CANCER; MULTICENTER AB Introduction: In 2015, 4 new drugs were approved for the treatment of patients with multiple myeloma who experience drug resistance and relapsing disease, offering potential for improved patient outcomes. Given the mortality, morbidity, and projected rise in the incidence of multiple myeloma, more effective, novel therapies and treatment combinations are needed for patients at each stage of the disease. Areas covered: Here, the authors examine published data regarding the development and clinical investigation of elotuzumab, a SLAMF7-targeted monoclonal antibody, for treatment of patients with multiple myeloma. The clinical efficacy, safety, and tolerability of elotuzumab treatment are summarized. Expert opinion: Elotuzumab, a first-in-class immunostimulatory monoclonal antibody, is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1-3 prior therapies. Elotuzumab has the potential for use in patients in the upfront setting, in combination with other backbone regimens, as well as maintenance therapy. Trials demonstrate clinical benefit of adding elotuzumab to conventional lenalidomide and dexamethasone therapy, without additive toxicity. Data suggest that elotuzumab may provide clinical benefit in combination with proteasome inhibitors. Elotuzumab combination therapy is currently under further evaluation in the relapsed/refractory and newly diagnosed settings. C1 [Lonial, Sagar; Kaufman, Jonathan] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Reece, Donna] Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Mateos, Maria-Victoria] Complejo Asistencial Univ Salamanca IBSAL, Haematol Dept, Salamanca, Spain. [Laubach, Jacob; Richardson, Paul] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, 450 Brookline Ave,Mayer 232, Boston, MA 02115 USA. RP Richardson, P (reprint author), Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, 450 Brookline Ave,Mayer 232, Boston, MA 02115 USA. EM Paul_Richardson@dfci.harvard.edu FU Bristol-Myers Squibb FX This review was supported by Bristol-Myers Squibb. Under the direction of the authors, medical writing and editorial assistance was provided by Gwendolyn Wood, PhD, of Caudex, New York, USA, and was funded by Bristol-Myers Squibb. NR 63 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1471-2598 EI 1744-7682 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD OCT PY 2016 VL 16 IS 10 BP 1291 EP 1301 DI 10.1080/14712598.2016.1221920 PG 11 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA DW7GG UT WOS:000383818600010 PM 27533882 ER PT J AU Chrastil, ER Sherrill, KR Hasselmo, ME Stern, CE AF Chrastil, Elizabeth R. Sherrill, Katherine R. Hasselmo, Michael E. Stern, Chantal E. TI Which way and how far? Tracking of translation and rotation information for human path integration SO HUMAN BRAIN MAPPING LA English DT Article DE functional magnetic resonance imaging; navigation; hippocampus; retrosplenial cortex; parahippocampus; working memory ID HUMAN SPATIAL NAVIGATION; MEDIAL TEMPORAL-LOBE; HEAD-DIRECTION CELLS; FREELY MOVING RATS; LONG-TERM-MEMORY; ENTORHINAL CORTEX; RETROSPLENIAL CORTEX; PARIETAL CORTEX; PARAHIPPOCAMPAL CORTEX; DECISION-MAKING AB Path integration, the constant updating of the navigator's knowledge of position and orientation during movement, requires both visuospatial knowledge and memory. This study aimed to develop a systems-level understanding of human path integration by examining the basic building blocks of path integration in humans. To achieve this goal, we used functional imaging to examine the neural mechanisms that support the tracking and memory of translational and rotational components of human path integration. Critically, and in contrast to previous studies, we examined movement in translation and rotation tasks with no defined end-point or goal. Navigators accumulated translational and rotational information during virtual self-motion. Activity in hippocampus, retrosplenial cortex (RSC), and parahippocampal cortex (PHC) increased during both translation and rotation encoding, suggesting that these regions track self-motion information during path integration. These results address current questions regarding distance coding in the human brain. By implementing a modified delayed match to sample paradigm, we also examined the encoding and maintenance of path integration signals in working memory. Hippocampus, PHC, and RSC were recruited during successful encoding and maintenance of path integration information, with RSC selective for tasks that required processing heading rotation changes. These data indicate distinct working memory mechanisms for translation and rotation, which are essential for updating neural representations of current location. The results provide evidence that hippocampus, PHC, and RSC flexibly track task-relevant translation and rotation signals for path integration and could form the hub of a more distributed network supporting spatial navigation. Hum Brain Mapp 37:3636-3655, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Chrastil, Elizabeth R.; Sherrill, Katherine R.; Hasselmo, Michael E.; Stern, Chantal E.] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Chrastil, Elizabeth R.; Sherrill, Katherine R.; Hasselmo, Michael E.; Stern, Chantal E.] Boston Univ, Ctr Memory & Brain, 2 Cummington Mall, Boston, MA 02215 USA. [Chrastil, Elizabeth R.; Sherrill, Katherine R.; Stern, Chantal E.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Chrastil, ER (reprint author), Boston Univ, Ctr Memory & Brain, 2 Cummington Mall, Boston, MA 02215 USA. EM chrastil@bu.edu OI Hasselmo, Michael/0000-0002-9925-6377; Chrastil, Elizabeth/0000-0003-2544-0152 FU Office of Naval Research [MURI N00014-10-1-0936]; Athinoula A. Martinos Center for Biomedical Imaging (Charlestown, MA), NIH [NCRR P41RR14075] FX Contract grant sponsor: Office of Naval Research; Contract grant number: MURI N00014-10-1-0936; Contract grant sponsor: Athinoula A. Martinos Center for Biomedical Imaging (Charlestown, MA), NIH; Contract grant number: NCRR P41RR14075 NR 118 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD OCT PY 2016 VL 37 IS 10 BP 3636 EP 3655 DI 10.1002/hbm.23265 PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DW7WU UT WOS:000383864500019 PM 27238897 ER PT J AU Kurokawa, K Takahashi, K Lee, BL AF Kurokawa, Kenji Takahashi, Kazue Lee, Bok Luel TI The staphylococcal surface-glycopolymer wall teichoic acid (WTA) is crucial for complement activation and immunological defense against Staphylococcus aureus infection SO IMMUNOBIOLOGY LA English DT Article; Proceedings Paper CT 26th International Complement Workshop (ICW) CY SEP 04-08, 2016 CL Kanazawa, JAPAN DE MBL; Complement; Staphylococcus aureus; Wall teichoic acid; Classical pathway; Opsonophagocytosis ID MANNOSE-BINDING LECTIN; GRAM-POSITIVE BACTERIA; FORMYL-PEPTIDE RECEPTORS; TOLL-LIKE RECEPTORS; INNATE IMMUNITY; LIPOTEICHOIC ACID; HOST-DEFENSE; MEDIATED OPSONOPHAGOCYTOSIS; RECOGNITION; PROTEIN AB Staphylococcus aureus is a Gram-positive bacterial pathogen that is decorated by glycopolymers, including wall teichoic acid (WTA), peptidoglycan, lipoteichoic acid, and capsular polysaccharides. These bacterial surface glycopolymers are recognized by serum antibodies and a variety of pattern recognition molecules, including mannose-binding lectin (MBL). Recently, we demonstrated that human serum MBL senses staphylococcal WTA. Whereas MBL in infants who have not yet fully developed adaptive immunity binds to S. aureus WTA and activates complement serum, MBL in adults who have fully developed adaptive immunity cannot bind to WTA because of an inhibitory effect of serum anti-WTA IgG. Furthermore, we showed that human anti-WTA IgGs purified from pooled adult serum IgGs triggered activation of classical complement-dependent opsonophagocytosis against S. aureus. Because the epitopes of WTA that are recognized by anti-WTA IgG and MBL have not been determined, we constructed several S. aureus mutants with altered WTA glycosylation. Our intensive biochemical studies provide evidence that the beta-GlcNAc residues of WTA are required for the induction of anti-WTA IgG-mediated opsonophagocytosis and that both beta- and alpha-GIcNAc residues are required for MBL-mediated complement activation. The molecular interactions of other S. aureus cell wall components and host recognition proteins are also discussed. In summary, in this review, we discuss the biological importance of S. aureus cell surface glycopolymers in complement activation and host defense responses. (C) 2016 Elsevier GmbH. All rights reserved. C1 [Kurokawa, Kenji] Nagasaki Int Univ, Fac Pharmaceut Sci, Sasebo, Nagasaki, Japan. [Takahashi, Kazue] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Lee, Bok Luel] Pusan Natl Univ, Coll Pharm, Busan 46241, South Korea. RP Lee, BL (reprint author), Pusan Natl Univ, Coll Pharm, Global Res Lab Insect Symbiosis, Busan 46241, South Korea. EM brlee@pusan.ac.kr NR 94 TC 0 Z9 0 U1 11 U2 11 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD OCT PY 2016 VL 221 IS 10 SI SI BP 1091 EP 1101 DI 10.1016/j.imbio.2016.06.003 PG 11 WC Immunology SC Immunology GA DV3ER UT WOS:000382804300008 PM 27424796 ER PT J AU Atkinson, JP Wagner, EK Raychaudhuri, S Villalonga, MB Java, A Triebwasser, MP Daly, MJ Seddon, JM AF Atkinson, John P. Wagner, Erin K. Raychaudhuri, Soumya Villalonga, Mercedes B. Java, Anuja Triebwasser, Michael P. Daly, Mark J. Seddon, Johanna M. TI Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD SO IMMUNOBIOLOGY LA English DT Meeting Abstract C1 [Atkinson, John P.; Triebwasser, Michael P.] Washington Univ, Sch Med, Dept Med, Div Rheumatol, St Louis, MO 63110 USA. [Wagner, Erin K.; Villalonga, Mercedes B.; Seddon, Johanna M.] Tufts Med Ctr, Ophthalm Epidemiol & Genet Serv, New England Eye Ctr, Boston, MA USA. [Wagner, Erin K.; Seddon, Johanna M.] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. [Raychaudhuri, Soumya; Daly, Mark J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Raychaudhuri, Soumya; Daly, Mark J.] Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Univ Manchester, Fac Med & Human Sci, Manchester M13 9PL, Lancs, England. [Java, Anuja] Washington Univ, Sch Med, Dept Internal Med, Barnes Jewish Hosp,Div Nephrol, St Louis, MO 63110 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Seddon, Johanna M.] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD OCT PY 2016 VL 221 IS 10 SI SI MA 163 BP 1205 EP 1206 DI 10.1016/j.imbio.2016.06.178 PG 2 WC Immunology SC Immunology GA DV3ER UT WOS:000382804300175 ER PT J AU Li, JY Yu, LB Shen, ZJ Li, YS Chen, BB Wei, W Chen, XH Wang, QY Tong, FJ Lou, HH Chu, M Wei, LL AF Li, Jinyuan Yu, Libo Shen, Zhenji Li, Yushu Chen, Beibei Wei, Wei Chen, Xiaohang Wang, Qingyi Tong, Fangjia Lou, Huihuang Chu, Ming Wei, Lanlan TI miR-34a and its novel target, NLRC5, are associated with HPV16 persistence SO INFECTION GENETICS AND EVOLUTION LA English DT Article DE Human papillomavirus type 16, persistent infection; Cervical cancer; miR-34a; NLRC5; p65 ID NF-KAPPA-B; HUMAN-PAPILLOMAVIRUS; HEPATOCELLULAR-CARCINOMA; IMMUNE-RESPONSE; DISEASE PROGRESSION; CERVICAL LESIONS; VIRUS-INFECTION; RECEPTOR NLRC5; CANCER; EXPRESSION AB Persistent infection with human papillomavirus (HPV), particularly type 16, is causally associated with cervical cancer and its precursors. The role of miRNAs in HPV16 persistence currently remains unclear. Preliminary analysis of miRNA profile demonstrated that HPV16 infection caused a striking downregulation of miR-34a. Through bioinformatics analysis and dual-luciferase assay with site-directed mutagenesis strategy, NLRC5, a negative regulator of NF-kappa B signaling, was identified to be a novel interactor of miR-34a. Transfection of miR-34a mimic strikingly downregulated NLRC5 in the HPV16-positive cervical cells, which might result in the nuclear accumulation of NF-kappa B p65. However, transfection of miR-34a inhibitor exhibited an opposite effect. The antagonistic expressions of NLRC5 and miR-34a were also observed in keratinocytes harboring HPV16 genome as well as in human cervical samples with persistent infection of HPV16. Our data uncover a previously unknown connection among HPV16 persistence, miR-34a and its interactor NLRC5. (C) 2016 Published by Elsevier B.V. C1 [Li, Jinyuan; Shen, Zhenji; Chen, Xiaohang; Tong, Fangjia; Lou, Huihuang; Wei, Lanlan] Harbin Med Univ, Dept Microbiol, Immun & Infect, Pathogen Biol Key Lab Heilongjiang Prov, Harbin 150081, Heilongjiang, Peoples R China. [Yu, Libo; Chen, Beibei] Harbin Med Univ, Affiliated Hosp 3, Dept Gynaecol, Harbin 150001, Heilongjiang, Peoples R China. [Li, Yushu; Chu, Ming] Harbin Med Univ, Affiliated Hosp 1, Dept Neurosurg, Harbin 150001, Heilongjiang, Peoples R China. [Wei, Wei] Jiamusi Univ, Affiliated Hosp 1, Dept Orthoped Surg, Jiamusi 154002, Heilongjiang, Peoples R China. [Wang, Qingyi] Harvard Med Sch, Ctr Computat & Integrat Biol, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wei, LL (reprint author), Harbin Med Univ, Dept Microbiol, Immun & Infect, Pathogen Biol Key Lab Heilongjiang Prov, Harbin 150081, Heilongjiang, Peoples R China. EM weilanlan_1119@163.com FU Natural Science Foundation of Heilongjiang Province [12531275, D201208] FX This study was supported by the Natural Science Foundation of Heilongjiang Province (12531275 and D201208). We grateful thank Michelle A. Ozbun (Molecular Genetics and Microbiology, University of New Mexico) for providing HPV16 construct. We also acknowledge Yanzhen Bi (Hubei Key Laboratory of Animal Embryo Engineering and Molecular Breeding, Hubei Academy of Agricultural Science) for the pMiSensor dual-luciferase reporter plasmid. NR 43 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 EI 1567-7257 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD OCT PY 2016 VL 44 BP 293 EP 299 DI 10.1016/j.meegid.2016.07.013 PG 7 WC Infectious Diseases SC Infectious Diseases GA DW0ZA UT WOS:000383371100040 PM 27423514 ER PT J AU Pedrelli, P Collado, A Shapero, BG Brill, C MacPherson, L AF Pedrelli, Paola Collado, Anahi Shapero, Benjamin G. Brill, Charlotte MacPherson, Laura TI Different pathways explain alcohol-related problems in female and male college students SO JOURNAL OF AMERICAN COLLEGE HEALTH LA English DT Article DE Alcohol-related problems; binge drinking; coping motives; depression; gender ID MAJOR DEPRESSIVE DISORDER; SUBSTANCE USE BEHAVIORS; DRINKING MOTIVES; NEGATIVE CONSEQUENCES; UNIVERSITY-STUDENTS; PRELIMINARY VALIDATION; EMERGING ADULTHOOD; GENDER-DIFFERENCES; BINGE THRESHOLD; FRESHMEN DRINK AB Objectives: Comprehensive models elucidating the intricate associations of depressive symptoms, coping motives, alcohol use, alcohol-related problems (ARPs), and gender among young adults have been scarcely examined. This study investigated relationships among these variables and the effect of gender on these pathways. Methods: College students (N = 163; 49.7% female) completed self-report measures on alcohol consumption, depressive symptoms, coping motives, and ARPs. Results: Structural equation modeling showed that the association between depressive symptoms and ARPs was mediated by coping motives in both females and males. However, frequency of heavy alcohol use mediated the association between depressive symptoms and ARPs in females but not in males. Conclusions: Different models explain the association between depressive symptoms and ARPs in male and female college students. Prevention programs aimed at reducing ARPs should focus on increasing alcohol screening among students with depressive symptoms, teaching coping skills, and emphasizing moderation in alcohol consumption. C1 [Pedrelli, Paola; Shapero, Benjamin G.] Massachusetts Gen Hosp, Depress Clin Res Program, Boston, MA 02114 USA. [Collado, Anahi; MacPherson, Laura] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Brill, Charlotte] Seattle Univ, Dept Psychol, Seattle, WA 98122 USA. RP Pedrelli, P (reprint author), Depress Clin Res Program, One Bowdoin Sq, Boston, MA 02114 USA. EM ppedrelli@partners.org FU National Institute on Alcohol Abuse and Alcohol [5K23AA020064]; Alcoholic Beverage Medical Research Foundation/The Foundation for Alcohol Research grant; National Institutes of Health [R21AA01768] FX This research was supported by National Institute on Alcohol Abuse and Alcohol grant 5K23AA020064, Alcoholic Beverage Medical Research Foundation/The Foundation for Alcohol Research grant to P.P., and National Institutes of Health grant R21AA01768 (Principal Investigator: Lejuez). NR 70 TC 0 Z9 0 U1 16 U2 16 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0744-8481 EI 1940-3208 J9 J AM COLL HEALTH JI J. Am. Coll. Health PD OCT PY 2016 VL 64 IS 7 BP 535 EP 544 DI 10.1080/07448481.2016.1191016 PG 10 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA DW2BF UT WOS:000383447200004 PM 27219280 ER PT J AU Khanna, AR Yanamadala, V Coumans, JV AF Khanna, Arjun R. Yanamadala, Vijay Coumans, Jean-Valery TI Effect of intraoperative navigation on operative time in 1-level lumbar fusion surgery SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Intraoperative spinal navigation; Lumbar fusion; Operative time; Pedicle screw placement ID PEDICLE SCREW PLACEMENT; INSERTION; ARM AB The use of intraoperative image guided navigation (NAV) in spine surgery is increasing. NAV is purported to improve the accuracy of pedicle screw placement but has been criticized for potentially increasing surgical cost, a component of which may be prolongation of total operative time due to time required for setup and intra-operative imaging and registration. In this study, we examine the effect of the introduction of 0-Arm conical CT spinal navigation on surgical duration. We retrospectively analyzed consecutive freehand (FH) (n = 63) and NAV (n = 70) 1-level lumbar transpedicular instrumentation cases at a single institution by a single surgeon. We recorded setup and procedure time for each case. NAV was associated with significantly shorter total operative time for 1-level lumbar fusions compared to FH (4:30 +/- 0:42 hours vs. 4:53 +/- 0:39 hours, p = 0.0013). This shortening of total operative time was realized despite a trend toward slightly longer setup times with NAV. We also found a significant decrease in operative length over time in NAV but not FH cases, indicative of a "learning curve" associated with NAV. The use of NAV in 1-level lumbar transpedicular instrumentation surgery is associated with significantly shorter total operative time compared to the FH technique, and its efficiency improves over time. These data should factor into cost-effectiveness analyses of the use of NAV for these cases. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Khanna, Arjun R.; Yanamadala, Vijay; Coumans, Jean-Valery] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St, Boston, MA 02114 USA. RP Coumans, JV (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St, Boston, MA 02114 USA. EM jcoumans@partners.org NR 9 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD OCT PY 2016 VL 32 BP 72 EP 76 DI 10.1016/j.jocn.2016.02.033 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DW3EN UT WOS:000383525000014 PM 27364319 ER PT J AU Lin, JJ Shaw, AT AF Lin, Jessica J. Shaw, Alice T. TI Differential Sensitivity to Crizotinib: Does EML4-ALK Fusion Variant Matter? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CELL LUNG-CANCER; ANAPLASTIC LYMPHOMA KINASE; GROWTH-FACTOR RECEPTOR; ALK; CHEMOTHERAPY; MUTATIONS; SURVIVAL; GEFITINIB; ERLOTINIB; EXON-19 C1 [Lin, Jessica J.; Shaw, Alice T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Lin, JJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 24 TC 1 Z9 1 U1 3 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 OCT 1 PY 2016 VL 34 IS 28 BP 3363 EP + DI 10.1200/JCO.2016.68.5891 PG 4 WC Oncology SC Oncology GA DW9CR UT WOS:000383953100002 PM 27458283 ER PT J AU Mayer, EL Burstein, HJ AF Mayer, Erica L. Burstein, Harold J. TI Chemotherapy for Triple-Negative Breast Cancer: Is More Better? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PATHOLOGICAL COMPLETE RESPONSE; NEOADJUVANT CISPLATIN; DOSE-DENSE; FOLLOW-UP; TRIAL; CYCLOPHOSPHAMIDE; BEVACIZUMAB; CARBOPLATIN; DOXORUBICIN; BENEFIT C1 [Mayer, Erica L.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. RP Mayer, EL (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. NR 20 TC 0 Z9 0 U1 10 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 1 PY 2016 VL 34 IS 28 BP 3369 EP + DI 10.1200/JCO.2016.68.4068 PG 4 WC Oncology SC Oncology GA DW9CR UT WOS:000383953100004 PM 27551109 ER PT J AU Bradbury, AR Patrick-Miller, L Schwartz, LA Egleston, BL Henry-Moss, D Domchek, SM Daly, MB Tuchman, L Moore, C Rauch, PK Shorter, R Karpink, K Sands, CB AF Bradbury, Angela R. Patrick-Miller, Linda Schwartz, Lisa A. Egleston, Brian L. Henry-Moss, Dare Domchek, Susan M. Daly, Mary B. Tuchman, Lisa Moore, Cynthia Rauch, Paula K. Shorter, Rebecca Karpink, Kelsey Sands, Colleen Burke TI Psychosocial Adjustment and Perceived Risk Among Adolescent Girls From Families With BRCA1/2 or Breast Cancer History SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PSYCHOLOGICAL DISTRESS; PHYSICAL-ACTIVITY; ASSESSMENT DEVICE; DEPRESSION SCALE; HOSPITAL ANXIETY; PARENTAL CANCER; YOUNG-ADULTS; EVENT SCALE; CHILDREN; HEALTH AB Purpose To evaluate the impact of breast cancer family history and maternal BRCA1/2 mutation on the psychosocial adjustment and perceived risk in girls age 11 to 19 years old. Materials and Methods Girls age 11 to 19 years old with one or more relatives with breast cancer or a familial BRCA1/2 mutation (breast cancer family history [BCFH] positive, n = 208; n = 69 with BRCA1/2-positive mother), peers (BCFH negative, n = 112), and their mothers completed assessments of psychosocial adjustment, breast cancer-specific distress, and perceived risk of breast cancer. Results General psychosocial adjustment did not differ significantly between BCFH-positive and BCFH-negative girls, either by self-report or mother report, except for higher self-esteem among BCFH-positive girls (P = .01). BCFH-positive girls had higher breast cancer-specific distress than BCFH-negative girls (P < .001), but girls from BRCA1/2-positive families did not differ from other BCFH-positive peers. BCFH-positive girls were more likely to report themselves at increased self-risk for breast cancer in adulthood than BCFH-negative peers (74% v 33%, respectively; P <= .001). Girls from BRCA1/2-positive families were more likely than other BCFH-positive and BCFH-negative peers to report themselves at increased risk (P < .001). In all groups, perceived risk of breast cancer was associated with older age. Higher breast cancer-specific distress among adolescent girls was associated with higher self-perceived risk of breast cancer and higher maternal breast cancer-specific distress. Conclusion Adolescent girls from BRCA1/2-positive and breast cancer families have higher self-esteem and do not have poorer psychosocial adjustment than peers. However, they do experience greater breast cancer-specific distress and perceived risk of breast cancer, particularly among older girls. Understanding the impact is important to optimize responses to growing up in families at familial and genetic risk for breast cancer, particularly given the debate over the genetic testing of children for cancer susceptibility in adulthood. (C) 2016 by American Society of Clinical Oncology. C1 [Bradbury, Angela R.; Schwartz, Lisa A.; Henry-Moss, Dare; Domchek, Susan M.; Shorter, Rebecca; Karpink, Kelsey; Sands, Colleen Burke] Univ Penn, Perelman Sch Med, 3 West Perelman Ctr,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Schwartz, Lisa A.] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Egleston, Brian L.; Daly, Mary B.] Temple Univ Hlth Syst, Fox Chase Canc Ctr, Philadelphia, PA USA. [Domchek, Susan M.] Univ Penn, Abramson Canc Ctr, Basser Res Ctr BRCA, Philadelphia, PA 19104 USA. [Patrick-Miller, Linda] Univ Chicago, Chicago, IL 60637 USA. [Tuchman, Lisa] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Moore, Cynthia; Rauch, Paula K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bradbury, AR (reprint author), Univ Penn, Perelman Sch Med, 3 West Perelman Ctr,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM angela.bradbury@uphs.upenn.edu OI HENRY-MOSS, DARE/0000-0002-4088-0028 FU Basser Research Center for BRCA in the Abramson Cancer Center at the University of Pennsylvania; Fox Chase Cancer Center Keystone Program in Personalized Risk; National Institutes of Health/National Center for Advancing Translational Sciences Grant [UL1TR000003] FX Supported by The Basser Research Center for BRCA in the Abramson Cancer Center at the University of Pennsylvania and the Fox Chase Cancer Center Keystone Program in Personalized Risk. Recruitment through Pediatric Research Consortium was supported by National Institutes of Health/National Center for Advancing Translational Sciences Grant No. UL1TR000003. NR 57 TC 0 Z9 0 U1 7 U2 7 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 OCT 1 PY 2016 VL 34 IS 28 BP 3409 EP + DI 10.1200/JCO.2015.66.3450 PG 10 WC Oncology SC Oncology GA DW9CR UT WOS:000383953100010 PM 27551110 ER PT J AU Wright, AA Bohlke, K Armstrong, DK Bookman, MA Cliby, WA Coleman, RL Dizon, DS Kash, JJ Meyer, LA Moore, KN Olawaiye, AB Oldham, J Salani, R Sparacio, D Tew, WP Vergote, I Edelson, MI AF Wright, Alexi A. Bohlke, Kari Armstrong, Deborah K. Bookman, Michael A. Cliby, William A. Coleman, Robert L. Dizon, Don S. Kash, Joseph J. Meyer, Larissa A. Moore, Kathleen N. Olawaiye, Alexander B. Oldham, Jessica Salani, Ritu Sparacio, Dee Tew, William P. Vergote, Ignace Edelson, Mitchell I. TI Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADVANCED EPITHELIAL OVARIAN; PRIMARY DEBULKING SURGERY; PHASE-III TRIAL; STAGE-III; PERITONEAL CANCER; INTRAPERITONEAL CISPLATIN; SUBOPTIMAL CYTOREDUCTION; FALLOPIAN-TUBE; OPEN-LABEL; RANDOMIZED-TRIAL AB Purpose To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. Methods The Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an Expert Panel and conducted a systematic review of the literature. Results Four phase III clinical trials form the primary evidence base for the recommendations. The published studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvant chemotherapy and interval cytoreduction are noninferior to primary cytoreduction and adjuvant chemotherapy with respect to overall and progression-free survival and are associated with less perioperative morbidity and mortality. Recommendations All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluation should include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to < 1 cm of residual disease (ideally to no visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primary cytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemotherapy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a high likelihood of achieving cytoreduction to < 1 cm (ideally to no visible disease) with acceptable morbidity. Before neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian, fallopian tube, or peritoneal cancer. Additional information is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki. (C) 2016 Society of Gynecologic Oncology and American Society of Clinical Oncology C1 [Wright, Alexi A.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Dizon, Don S.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Bohlke, Kari] Amer Soc Clin Oncol, Alexandria, VA USA. [Armstrong, Deborah K.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Bookman, Michael A.] US Oncol Res, Tucson, AZ USA. [Bookman, Michael A.] Arizona Oncol, Tucson, AZ USA. [Cliby, William A.] Mayo Clin, Rochester, MN USA. [Coleman, Robert L.; Meyer, Larissa A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kash, Joseph J.] Edward Canc Ctr, Naperville, IL USA. [Oldham, Jessica] Soc Gynecol Oncol, Chicago, IL USA. [Moore, Kathleen N.] Univ Oklahoma, Stephenson Oklahoma Canc Ctr, Oklahoma City, OK USA. [Olawaiye, Alexander B.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Edelson, Mitchell I.] Jefferson Hlth, Abington Hosp, Hanjani Inst Gynecol Oncol, Abington, PA USA. [Salani, Ritu] Ohio State Univ, Columbus, OH 43210 USA. [Tew, William P.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Vergote, Ignace] Leuven Canc Inst, Leuven, Belgium. RP Edelson, MI (reprint author), Hanjani Inst Gynecol Oncol, 1200 Old York Rd, Abington, PA 19001 USA. EM Mitchell.Edelson@jefferson.edu FU National Institutes of Health/National Cancer Institute (NIH/NCI) Cancer Center Support Grant [P30 CA008748]; NIH/NCI [K07 CA166210] FX W.P.T. received support through the National Institutes of Health/National Cancer Institute (NIH/NCI) Cancer Center Support Grant P30 CA008748, and A.A.W. received support from the NIH/NCI K07 CA166210 award. NR 55 TC 9 Z9 9 U1 4 U2 4 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 OCT 1 PY 2016 VL 34 IS 28 BP 3460 EP + DI 10.1200/JCO.2016.68.6907 PG 16 WC Oncology SC Oncology GA DW9CR UT WOS:000383953100016 PM 27502591 ER PT J AU Nishino, M AF Nishino, Mizuki TI Pseudoprogression and Measurement Variability SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CELL LUNG-CANCER; TUMOR MEASUREMENTS; RESPONSE CRITERIA; IMMUNOTHERAPY; SCANS C1 [Nishino, Mizuki] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Nishino, Mizuki] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nishino, M (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.; Nishino, M (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM mizuki_nishino@dfci.harvard.edu NR 10 TC 1 Z9 1 U1 3 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 OCT 1 PY 2016 VL 34 IS 28 BP 3480 EP + DI 10.1200/JCO.2016.67.6759 PG 3 WC Oncology SC Oncology GA DW9CR UT WOS:000383953100019 PM 27458299 ER PT J AU Hodi, FS Wolchok, JD AF Hodi, F. Stephen Wolchok, Jedd D. TI Pseudoprogression and Measurement Variability Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID RESPONSE CRITERIA C1 [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM stephen_hodi@dfci.harvard.edu NR 4 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 OCT 1 PY 2016 VL 34 IS 28 BP 3481 EP + DI 10.1200/JCO.2016.69.1097 PG 2 WC Oncology SC Oncology GA DW9CR UT WOS:000383953100020 PM 27458281 ER PT J AU Sagara, Y Freedman, RA Mallory, MA Wong, SM Barry, WT Golshan, M AF Sagara, Yasuaki Freedman, Rachel A. Mallory, Melissa Anne Wong, Stephanie M. Barry, William T. Golshan, Mehra TI Dangers of Excluding Margin Status From a Ductal Carcinoma In Situ Prognostic Score Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID BREAST; SURGERY; COHORT; INDEX C1 [Sagara, Yasuaki; Mallory, Melissa Anne; Golshan, Mehra] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Sagara, Yasuaki; Wong, Stephanie M.] Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Freedman, Rachel A.; Barry, William T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wong, Stephanie M.] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. RP Sagara, Y (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.; Sagara, Y (reprint author), Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. NR 11 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 OCT 1 PY 2016 VL 34 IS 28 BP 3485 EP + DI 10.1200/JCO.2016.68.7723 PG 3 WC Oncology SC Oncology GA DW9CR UT WOS:000383953100024 PM 27458285 ER PT J AU Lash, DB Jolliff, J Munoz, A Heidari, A AF Lash, D. Benjamin Jolliff, J. Munoz, A. Heidari, A. TI Cross-reactivity between voriconazole, fluconazole and itraconazole SO JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS LA English DT Article DE allergy; fluconazole; voriconazole; itraconazole ID FIXED DRUG ERUPTION AB What is known and objectiveHypersensitivity to triazoles is a rare occurrence and cross-reactivity between agents is unknown. We present a successful voriconazole challenge in a patient allergic to fluconazole and itraconazole. Case summaryA 41-year-old immunocompetent male with coccidioidomycosis developed fever, eosinophilia and maculopapular rash from fluconazole. Switching to itraconazole resulted in worsening of the rash and skin sloughing over 25% of his body. He was given an oral-graded challenge of voriconazole which he tolerated without incident. What is new and conclusionThis is the first report of a lack of cross-reactivity between itraconazole and voriconazole. A 41 year old immunocompetent male with coccidioidomycosis developed fever, eosinophilia, and maculopapular rash from fluconazole. Switching to itraconazole resulted in worsening of the rash and skin sloughing over 25% of his body, while an oral-graded-challenge of voriconazole was tolerated without incident. This is the first report of a lack of cross-reactivity between itraconazole and voriconazole. C1 [Lash, D. Benjamin] Western Univ Hlth Sci, Pomona, CA 91766 USA. [Lash, D. Benjamin] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Jolliff, J.] Kern Med, Dept Pharm, Bakersfield, CA USA. [Munoz, A.; Heidari, A.] Kern Med, Dept Med, Bakersfield, CA USA. RP Lash, DB (reprint author), Western Univ Hlth Sci, Coll Pharm, 309 E Second St, Pomona, CA 91766 USA. EM DLash@WesternU.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-4727 EI 1365-2710 J9 J CLIN PHARM THER JI J. Clin. Pharm. Ther. PD OCT PY 2016 VL 41 IS 5 BP 566 EP 567 DI 10.1111/jcpt.12417 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW0YD UT WOS:000383368300018 ER PT J AU Eliades, P Tsao, H AF Eliades, Philip Tsao, Hensin TI New Insights into the Molecular Distinction of Dysplastic Nevi and Common Melanocytic Nevi-Highlighting the Keratinocyte-Melanocyte Relationship SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID LESIONS; SENESCENCE; PATHWAYS AB Mitsui et al. approach the problem of differentiating dysplastic nevi from common melanocytic nevi through a molecular lens. Whereas most of the literature on this topic shines the spotlight toward melanocytes, the focus of this paper is shifted to the tumor microenvironment. Using microarrays, reverse transcriptase-PCR, and immunohistochemistry, their results emphasize the role of keratinocyte dysplasia within dysplastic nevi. C1 [Eliades, Philip; Tsao, Hensin] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. [Eliades, Philip; Tsao, Hensin] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA USA. [Eliades, Philip] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. EM htsao@mgh.harvard.edu NR 11 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2016 VL 136 IS 10 BP 1933 EP 1935 DI 10.1016/j.jid.2016.01.008 PG 3 WC Dermatology SC Dermatology GA DW4NX UT WOS:000383621100005 PM 27664709 ER PT J AU Fehnel, KP Duggins-Warf, M Zurakowski, D McKee-Proctor, M Majumder, R Raber, M Han, XZ Smith, ER AF Fehnel, Katie Pricola Duggins-Warf, Micah Zurakowski, David McKee-Proctor, Maxwell Majumder, Rajarshi Raber, Michael Han, Xuezhe Smith, Edward R. TI Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Article DE pilocytic astrocytoma; basic fibroblast growth factor; bFGF; tissue inhibitor of metalloproteinase 3; TIMP3; urinary biomarkers; oncology ID FIBROBLAST-GROWTH-FACTOR; OLIGODENDROCYTE DEVELOPMENT; MATRIX METALLOPROTEINASES; ANGIOGENIC FACTORS; BRAIN-TUMORS; MEDULLOBLASTOMA; EXPRESSION; CANCER; IDENTIFICATION; LOCALIZATION AB OBJECTIVE The authors report the use of urinary biomarkers as a novel, noninvasive technique to detect juvenile pilocytic astrocytomas (JPAs), capable of distinguishing JPAs from other CNS diseases, including other brain tumors. Preliminary screening of an array of tumors implicated proteases (including matrix metalloproteinases [MMPs]) and their inhibitors (tissue inhibitors of metalloproteinase [TIMPs]) as well as growth factors (including basic fibroblast growth factor [bFGF]) as candidate biomarkers. These data led the authors to hypothesize that tissue inhibitor of metalloproteinase 3 (TIMP3) and bFGF would represent high-probability candidates as JPA-specific biomarkers. METHODS Urine was collected from 107 patients, which included children with JPA (n = 21), medulloblastoma (n = 17), glioblastoma (n = 9), arteriovenous malformations (n = 25), moyamoya (n = 14), and age- and sex-matched controls (n = 21). Biomarker levels were quantified with enzyme-linked immunosorbent assay, tumor tissue expression was confirmed with immunohistochemical analysis, and longitudinal biomarker expression was correlated with imaging. Results were subjected to univariate and multivariate statistical analyses. RESULTS Using optimal urinary cutoff values of bFGF > 1.0 pg/mu g and TIMP3 > 3.5 pg/mu g, multiplexing bFGF and TIMP3 predicts JPA presence with 98% accuracy. Multiplexing bFGF and MMP13 distinguishes JPA from other brain tumor subtypes with up to 98% accuracy. Urinary biomarker expression correlated with both tumor immunohistochemistry and in vitro tumor levels. Urinary bFGF and TIMP3 decrease following successful tumor treatment and correlate with changes in tumor size. CONCLUSIONS This study identifies 2 urinary biomarkers bFGF and TIMP3 that successfully detect one of the most common pediatric brain tumors with high accuracy. These data highlight potential benefits of urinary biomarkers and support their utility as diagnostic tools in the treatment of children with JPA. C1 [Fehnel, Katie Pricola; Duggins-Warf, Micah; McKee-Proctor, Maxwell; Majumder, Rajarshi; Raber, Michael; Han, Xuezhe; Smith, Edward R.] Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA. [Fehnel, Katie Pricola; Duggins-Warf, Micah; McKee-Proctor, Maxwell; Majumder, Rajarshi; Raber, Michael; Han, Xuezhe; Smith, Edward R.] Boston Childrens Hosp, Dept Neurosurg, Boston, MA USA. [Zurakowski, David] Boston Childrens Hosp, Dept Surg, Boston, MA USA. [Fehnel, Katie Pricola] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Smith, ER (reprint author), Harvard Med Sch, Boston Childrens Hosp, Vasc Biol Program, 300 Longwood Ave, Boston, MA 02115 USA. EM edward.smith@childrens.harvard.edu FU Voices Against Brain Cancer; Christopher Fellows Brain Tumor Research Fund; Neurosurgery Research and Education Foundation; AANS/CNS Section of Pediatric Neurological Surgery Research Fellowship FX We would like to thank Kristen Johnson for preparation of the article and Marsha Moses, PhD, for her review of this manuscript and for all of her research support. This study was funded by Voices Against Brain Cancer and the Christopher Fellows Brain Tumor Research Fund (Dr. Smith), and the Neurosurgery Research and Education Foundation and AANS/CNS Section of Pediatric Neurological Surgery Research Fellowship (Dr. Pricola Fehnel). NR 37 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD OCT PY 2016 VL 18 IS 4 BP 396 EP 407 PG 12 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA DW8XJ UT WOS:000383938500003 ER PT J AU Rucevic, M Kourjian, G Boucau, J Blatnik, R Bertran, WG Berberich, MJ Walker, BD Riemer, AB Le Gall, S AF Rucevic, Marijana Kourjian, Georgio Boucau, Julie Blatnik, Renata Bertran, Wilfredo Garcia Berberich, Matthew J. Walker, Bruce D. Riemer, Angelika B. Le Gall, Sylvie TI Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses SO JOURNAL OF VIROLOGY LA English DT Article ID HLA; EPITOPES; RECOGNITION; LIGANDOME; REPERTOIRE; MONOCYTES; DISCOVERY; INFECTION; LEUKEMIA; DESIGN AB Despite the critical role of epitope presentation for immune recognition, we still lack a comprehensive definition of HIV peptides presented by HIV-infected cells. Here we identified 107 major histocompatibility complex (MHC)-bound HIV peptides directly from the surface of live HIV-transfected 293T cells, HIV-infected B cells, and primary CD4 T cells expressing a variety of HLAs. The majority of peptides were 8 to 12 amino acids (aa) long and mostly derived from Gag and Pol. The analysis of the total MHC-peptidome and of HLA-A02-bound peptides identified new noncanonical HIV peptides of up to 16 aa that could not be predicted by HLA anchor scanning and revealed an heterogeneous surface peptidome. Nested sets of surface HIV peptides included optimal and extended HIV epitopes and peptides partly overlapping or distinct from known epitopes, revealing new immune responses in HIV-infected persons. Surprisingly, in all three cell types, a majority of Gag peptides derived from p15 rather than from the most immunogenic p24. The cytosolic degradation of peptide precursors in corresponding cells confirmed the generation of identified surface-nested peptides. Cytosolic degradation revealed peptides commonly produced in all cell types and displayed by various HLAs, peptides commonly produced in all cell types and selectively displayed by specific HLAs, and peptides produced in only one cell type. Importantly, we identified areas of proteins leading to common presentations of noncanonical peptides by several cell types with distinct HLAs. These peptides may benefit the design of immunogens, focusing T cell responses on relevant markers of HIV infection in the context of HLA diversity. IMPORTANCE The recognition of HIV-infected cells by immune T cells relies on the presentation of HIV-derived peptides by diverse HLA molecules at the surface of cells. The landscape of HIV peptides displayed by HIV-infected cells is not well defined. Considering the diversity of HLA molecules in the human population, it is critical for vaccine design to identify HIV peptides that may be displayed despite the HLA diversity. We identified 107 HIV peptides directly from the surface of three cell types infected with HIV. They corresponded to nested sets of HIV peptides of canonical and novel noncanonical lengths not predictable by the presence of HLA anchors. Importantly, we identified areas of HIV proteins leading to presentation of noncanonical peptides by several cell types with distinct HLAs. Including such peptides in vaccine immunogen may help to focus immune responses on common markers of HIV infection in the context of HLA diversity. C1 [Rucevic, Marijana; Kourjian, Georgio; Boucau, Julie; Bertran, Wilfredo Garcia; Berberich, Matthew J.; Walker, Bruce D.; Le Gall, Sylvie] Harvard Med Sch, Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA 02115 USA. [Blatnik, Renata; Riemer, Angelika B.] German Canc Res Ctr, Immunotherapy & Prevent, Heidelberg, Germany. [Blatnik, Renata; Riemer, Angelika B.] German Ctr Infect Res DZIF, Mol Vaccine Design, Heidelberg, Germany. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Le Gall, S (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA 02115 USA. EM sylvie_legall@hms.harvard.edu FU HHS \ NIH \ NIH Office of the Director (OD) [AI084753, AI084106, AI11249] FX This work, including the efforts of Sylvie Le Gall, was funded by HHS vertical bar NIH vertical bar NIH Office of the Director (OD) (AI084753, AI084106, and AI11249). NR 47 TC 0 Z9 0 U1 5 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD OCT PY 2016 VL 90 IS 19 BP 8605 EP 8620 DI 10.1128/JVI.00599-16 PG 16 WC Virology SC Virology GA DW6LH UT WOS:000383761900020 PM 27440904 ER PT J AU Donius, LR Cheng, YX Choi, J Sun, ZYJ Hanson, M Zhang, M Gierahn, TM Marquez, S Uduman, M Kleinstein, SH Irvine, D Love, JC Reinherz, EL Kim, M AF Donius, Luke R. Cheng, Yuxing Choi, Jaewon Sun, Zhen-Yu J. Hanson, Melissa Zhang, Michael Gierahn, Todd M. Marquez, Susanna Uduman, Mohammed Kleinstein, Steven H. Irvine, Darrell Love, J. Christopher Reinherz, Ellis L. Kim, Mikyung TI Generation of Long-Lived Bone Marrow Plasma Cells Secreting Antibodies Specific for the HIV-1 gp41 Membrane-Proximal External Region in the Absence of Polyreactivity SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; HUMAN MONOCLONAL-ANTIBODIES; COMPLEMENTARITY-DETERMINING REGION; B-CELLS; STRUCTURAL BASIS; 2F5-LIKE ANTIBODIES; MATURATION PATHWAY; EPITOPE-SCAFFOLDS; SEQUENCING DATA AB An effective preventive vaccine is highly sought after in order to stem the current HIV-1 pandemic. Both conservation of contiguous gp41 membrane-proximal external region (MPER) amino acid sequences across HIV-1 clades and the ability of anti-MPER broadly neutralizing antibodies (BNAbs) to block viral hemifusion/fusion establish the MPER as a prime vaccination target. In earlier studies, we described the development of an MPER vaccine formulation that takes advantage of liposomes to array the MPER on a lipid bilayer surface, paralleling its native configuration on the virus membrane while also incorporating molecular adjuvant and CD4 T cell epitope cargo. Here we demonstrate that several immunizations with MPER/liposomes induce high levels of bone marrow long-lived plasma cell (LLPC) antibody production. Single-cell immunoglobulin gene retrieval analysis shows that these plasma cells are derived from a germ line repertoire of B cells with a diverse representation of immunoglobulin genes, exhibiting antigen-driven positive selection. Characterization of LLPC recombinant monoclonal antibodies (rMAbs) indicates that antigen recognition is achieved through convergence on a common epitopic focus by utilizing various complementarity-determining region H3 (CDRH3) lengths. Importantly, the vast majority of rMAbs produced from these cells lack polyreactivity yet manifest antigen specificity in the context of lipids, shaping MPER-specific paratopes through selective pressure. Taken together, these findings demonstrate that the MPER is a vaccine target with minimal risk of generating off-target autoimmunity. IMPORTANCE A useful vaccine must generate desired long-term, antigen-specific antibody responses devoid of polyreactivity or autoreactivity. The common polyreactive features of some HIV-1 BNAbs have raised concern about elicitation of anti-MPER antibodies. Utilizing single-LLPC repertoire analysis and biophysical characterization of anti-MPER rMAbs, we show that their fine specificities require a structural fitness of the antibody combining site involving heavy and light chain variable domains shaped by somatic hypermutation and affinity maturation of B cells in the germinal center. Perhaps more importantly, our results demonstrate that the majority of MPER-specific antibodies are not inherently polyspecific and/or autoreactive, suggesting that polyreactivity of MPER-specific antibodies is separable from their antigen specificity. C1 [Donius, Luke R.; Cheng, Yuxing; Choi, Jaewon; Reinherz, Ellis L.; Kim, Mikyung] Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Donius, Luke R.; Cheng, Yuxing; Choi, Jaewon; Reinherz, Ellis L.; Kim, Mikyung] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sun, Zhen-Yu J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Hanson, Melissa; Zhang, Michael; Irvine, Darrell] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Hanson, Melissa; Zhang, Michael; Irvine, Darrell] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Marquez, Susanna; Uduman, Mohammed; Kleinstein, Steven H.] Yale Sch Med, Dept Pathol, New Haven, CT USA. [Kleinstein, Steven H.] Yale Univ, Yale Sch Med, Dept Immunol, New Haven, CT USA. [Kleinstein, Steven H.] Yale Univ, Interdept Program Computat Biol & Bioinformat, New Haven, CT USA. [Gierahn, Todd M.; Irvine, Darrell; Love, J. Christopher] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Irvine, Darrell] Howard Hughes Med Inst, Chevy Chase, MD USA. [Kim, Mikyung] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Cheng, Yuxing] Pfizer, Cambridge, MA USA. [Choi, Jaewon] Bristol Myers Squibb Co, Devens, MA USA. [Hanson, Melissa] Inst Pasteur, Paris, France. [Zhang, Michael] Univ Maryland, Baltimore, MD 21201 USA. RP Kim, M (reprint author), Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA.; Kim, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Kim, M (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. EM mikyung_kim@dfci.harvard.edu FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI091693, AI104739]; Howard Hughes Medical Institute (HHMI); Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation) [OPP1108179] FX This work, including the efforts of Luke R. Donius, Yuxing Cheng, Jaewon Choi, Zhen-Yu J. Sun, Melissa Hanson, Michael Zhang, Darrell Irvine, Ellis L. Reinherz, and Mikyung Kim, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI091693). This work, including the efforts of Susanna Marquez, Mohammed Uduman, and Steven H. Kleinstein, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI104739). This work, including the efforts of Melissa Hanson, Michael Zhang, and Darrell Irvine, was funded by Howard Hughes Medical Institute (HHMI). This work, including the efforts of Luke R. Donius, Yuxing Cheng, Jaewon Choi, Zhen-Yu J. Sun, Melissa Hanson, Michael Zhang, Darrell Irvine, Ellis L. Reinherz, and Mikyung Kim, was funded by Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation) (OPP1108179). NR 75 TC 1 Z9 1 U1 6 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD OCT PY 2016 VL 90 IS 19 BP 8875 EP 8890 DI 10.1128/JVI.01089-16 PG 16 WC Virology SC Virology GA DW6LH UT WOS:000383761900041 PM 27466419 ER PT J AU Polnaszek, B Gilmore-Bykovskyi, A Hovanes, M Roiland, R Ferguson, P Brown, R Kind, AJH AF Polnaszek, Brock Gilmore-Bykovskyi, Andrea Hovanes, Melissa Roiland, Rachel Ferguson, Patrick Brown, Roger Kind, Amy J. H. TI Overcoming the Challenges of Unstructured Data in Multisite, Electronic Medical Record-based Abstraction SO MEDICAL CARE LA English DT Article DE unstructured data; medical record abstraction; communication documents ID INTERRATER RELIABILITY; HIGH AGREEMENT; DISCHARGE SUMMARIES; HOSPITAL DISCHARGE; LOW KAPPA; CARE; QUALITY; INFORMATION; CONCORDANCE; PHYSICIANS AB Background: Unstructured data encountered during retrospective electronic medical record (EMR) abstraction has routinely been identified as challenging to reliably abstract, as these data are often recorded as free text, without limitations to format or structure. There is increased interest in reliably abstracting this type of data given its prominent role in care coordination and communication, yet limited methodological guidance exists. Objectives: As standard abstraction approaches resulted in substandard data reliability for unstructured data elements collected as part of a multisite, retrospective EMR study of hospital discharge communication quality, our goal was to develop, apply and examine the utility of a phase-based approach to reliably abstract unstructured data. This approach is examined using the specific example of discharge communication for warfarin management. Research Design: We adopted a "fit-for-use" framework to guide the development and evaluation of abstraction methods using a 4-step, phase-based approach including (1) team building; (2) identification of challenges; (3) adaptation of abstraction methods; and (4) systematic data quality monitoring. Measures: Unstructured data elements were the focus of this study, including elements communicating steps in warfarin management (eg, warfarin initiation) and medical follow-up (eg, timeframe for follow-up). Results: After implementation of the phase-based approach, interrater reliability for all unstructured data elements demonstrated kappa's of >= 0.89-an average increase of +0.25 for each unstructured data element. Conclusions: As compared with standard abstraction methodologies, this phase-based approach was more time intensive, but did markedly increase abstraction reliability for unstructured data elements within multisite EMR documentation. C1 [Polnaszek, Brock; Gilmore-Bykovskyi, Andrea; Hovanes, Melissa; Kind, Amy J. H.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Div Geriatr, Madison, WI USA. [Polnaszek, Brock; Roiland, Rachel; Kind, Amy J. H.] William S Middleton Hosp, US Dept Vet Affairs, GRECC, Madison, WI 53705 USA. [Gilmore-Bykovskyi, Andrea; Brown, Roger] Univ Wisconsin, Sch Nursing, Madison, WI USA. [Ferguson, Patrick] Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI USA. RP Kind, AJH (reprint author), William S Middleton Hosp, US Dept Vet Affairs, GRECC, Madison, WI 53705 USA. EM ajk@medicine.wisc.edu FU National Institute on Aging Paul B. Beeson Patient-Oriented Research Career Development Award [K23AG034551]; American Federation for Aging Research; John A. Hartford Foundation; Atlantic Philanthropies; Starr Foundation; Madison VA Geriatric Research, Education and Clinical Center [2013-19]; University of Wisconsin School of Medicine and Public Health's Health Innovation Program; Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research; Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health [1UL1RR025011] FX Supported by National Institute on Aging Paul B. Beeson Patient-Oriented Research Career Development Award (K23AG034551 [PI Kind]), in partnership with the American Federation for Aging Research, the John A. Hartford Foundation, the Atlantic Philanthropies, and the Starr Foundation and the Madison VA Geriatric Research, Education and Clinical Center (GRECC-Manuscript #2013-19). Additional support was provided by the University of Wisconsin School of Medicine and Public Health's Health Innovation Program; the Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research; and the Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health (1UL1RR025011). NR 39 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD OCT PY 2016 VL 54 IS 10 BP E65 EP E72 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DW9RO UT WOS:000383999900001 PM 27624585 ER PT J AU Sellgren, CM Kegel, ME Bergen, SE Ekman, CJ Olsson, S Larsson, M Vawter, MP Backlund, L Sullivan, PF Sklar, P Smoller, JW Magnusson, PKE Hultman, CM Walther-Jallow, L Svensson, CI Lichtenstein, P Schalling, M Engberg, G Erhardt, S Landen, M AF Sellgren, C. M. Kegel, M. E. Bergen, S. E. Ekman, C. J. Olsson, S. Larsson, M. Vawter, M. P. Backlund, L. Sullivan, P. F. Sklar, P. Smoller, J. W. Magnusson, P. K. E. Hultman, C. M. Walther-Jallow, L. Svensson, C. I. Lichtenstein, P. Schalling, M. Engberg, G. Erhardt, S. Landen, M. TI A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder SO MOLECULAR PSYCHIATRY LA English DT Article ID ELEVATED LEVELS; SCHIZOPHRENIA; BRAIN; INTERLEUKIN-1-BETA; TRANSCRIPTION; FLEXIBILITY; ACTIVATION; EXPRESSION; DOPAMINE; FAMILIES AB Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1 beta and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder. C1 [Sellgren, C. M.; Bergen, S. E.; Magnusson, P. K. E.; Hultman, C. M.; Lichtenstein, P.; Landen, M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Sellgren, C. M.; Kegel, M. E.; Olsson, S.; Larsson, M.; Svensson, C. I.; Engberg, G.; Erhardt, S.] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Ekman, C. J.] Karolinska Inst, Sect Psychiat, Dept Clin Neurosci, Stockholm, Sweden. [Vawter, M. P.] Univ Calif Irvine, Sch Med, Funct Genom Lab, Dept Psychiat & Human Behav, Irvine, CA USA. [Backlund, L.; Schalling, M.] Karolinska Inst, Neurogenet Unit, Dept Mol Med & Surg, Stockholm, Sweden. [Backlund, L.; Schalling, M.] Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden. [Sullivan, P. F.] Univ N Carolina, Dept Genet & Psychiat, Chapel Hill, NC USA. [Sklar, P.] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Dept Psychiat, New York, NY USA. [Smoller, J. W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet, Res, Boston, MA 02114 USA. [Smoller, J. W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Smoller, J. W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Walther-Jallow, L.] Karolinska Univ, Huddinge Hosp, Karolinska Inst, Ctr Infect Med,Dept Med, Stockholm, Sweden. [Landen, M.] Univ Gothenburg, Inst Neurosci & Physiol, SE-41345 Gothenburg, Sweden. RP Landen, M (reprint author), Univ Gothenburg, Inst Neurosci & Physiol, SE-41345 Gothenburg, Sweden. EM mikael.landen@neuro.gu.se RI Magnusson, Patrik/C-4458-2017 FU Swedish Medical Research Council [K2014-62X-14647-12-51, K2010-61P-21568-01-4, 2009-3068, 2011-4789, 2009-7053, 2013-2838, 2011-4807, 2013-6652]; Swedish foundation for Strategic Research [KF10-0039]; Swedish Brain foundation; Petrus och Augusta Hedlunds Stiftelse; Ahlen-stiftelsen; AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science; Stockholm County Council; Karolinska Institutet [ALF 20100305]; Broad Institute FX We thank the patients who contributed to this study. We also thank clinical collaborators and facilitators for help with recruitment of participants. We are grateful to Pascal Borgstrom for assistance with the cognitive assessment and to Emil Rhenberg for statistical support. This work was supported by grants from the Swedish Medical Research Council (to Landen: K2014-62X-14647-12-51 and K2010-61P-21568-01-4; to Engberg: 2009-3068 and 2011-4789; to Erhardt: 2009-7053 and 2013-2838; to Schalling: 2011-4807 and 2013-6652; and to Svensson: 2009-3068), the Swedish foundation for Strategic Research (KF10-0039), the Swedish Brain foundation, Petrus och Augusta Hedlunds Stiftelse, Ahlen-stiftelsen, the AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science, the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet (ALF 20100305 and KID) and the Broad Institute. NR 49 TC 5 Z9 5 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD OCT PY 2016 VL 21 IS 10 BP 1342 EP 1350 DI 10.1038/mp.2015.186 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DX1KT UT WOS:000384127000004 PM 26666201 ER PT J AU Kessler, RC van Loo, HM Wardenaar, KJ Bossarte, RM Brenner, LA Cai, T Ebert, DD Hwang, I Li, J de Jonge, P Nierenberg, AA Petukhova, MV Rosellini, AJ Sampson, NA Schoevers, RA Wilcox, MA Zaslavsky, AM AF Kessler, R. C. van Loo, H. M. Wardenaar, K. J. Bossarte, R. M. Brenner, L. A. Cai, T. Ebert, D. D. Hwang, I. Li, J. de Jonge, P. Nierenberg, A. A. Petukhova, M. V. Rosellini, A. J. Sampson, N. A. Schoevers, R. A. Wilcox, M. A. Zaslavsky, A. M. TI Testing a machine-learning algorithm to predict the persistence and severity of major depressive disorder from baseline self-reports SO MOLECULAR PSYCHIATRY LA English DT Article ID RECURSIVE PARTITIONING ANALYSIS; LONG-TERM COURSE; ANTIDEPRESSANT RESPONSE; RISK; REMISSION; SUBTYPES; MODELS; HETEROGENEITY; RATIONALE; CLINICIAN AB Heterogeneity of major depressive disorder (MDD) illness course complicates clinical decision-making. Although efforts to use symptom profiles or biomarkers to develop clinically useful prognostic subtypes have had limited success, a recent report showed that machine-learning (ML) models developed from self-reports about incident episode characteristics and comorbidities among respondents with lifetime MDD in the World Health Organization World Mental Health (WMH) Surveys predicted MDD persistence, chronicity and severity with good accuracy. We report results of model validation in an independent prospective national household sample of 1056 respondents with lifetime MDD at baseline. The WMH ML models were applied to these baseline data to generate predicted outcome scores that were compared with observed scores assessed 10-12 years after baseline. ML model prediction accuracy was also compared with that of conventional logistic regression models. Area under the receiver operating characteristic curve based on ML (0.63 for high chronicity and 0.71-0.76 for the other prospective outcomes) was consistently higher than for the logistic models (0.62-0.70) despite the latter models including more predictors. A total of 34.6-38.1% of respondents with subsequent high persistence chronicity and 40.8-55.8% with the severity indicators were in the top 20% of the baseline ML-predicted risk distribution, while only 0.9% of respondents with subsequent hospitalizations and 1.5% with suicide attempts were in the lowest 20% of the ML-predicted risk distribution. These results confirm that clinically useful MDD risk-stratification models can be generated from baseline patient self-reports and that ML methods improve on conventional methods in developing such models. C1 [Kessler, R. C.; Ebert, D. D.; Hwang, I.; Petukhova, M. V.; Rosellini, A. J.; Sampson, N. A.; Zaslavsky, A. M.] Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. [van Loo, H. M.; Wardenaar, K. J.; de Jonge, P.; Schoevers, R. A.] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regula, Groningen, Netherlands. [Bossarte, R. M.] Dept Vet Affairs, Off Publ Hlth, Washington, DC USA. [Brenner, L. A.] Univ Colorado, Dept Phys Med & Rehabil, Anschutz Med Campus, Aurora, CO USA. [Brenner, L. A.] Univ Colorado, Dept Psychiat, Anschutz Med Campus, Aurora, CO USA. [Brenner, L. A.] Univ Colorado, Dept Neurol, Anschutz Med Campus, Aurora, CO USA. [Brenner, L. A.] Rocky Mt Mental Illness Res Educ & Clin Ctr, Denver, CO USA. [Cai, T.; Li, J.] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ebert, D. D.] Univ Erlangen Nurnberg, Dept Psychol Clin Psychol & Psychotherapy, Erlangen, Germany. [Nierenberg, A. A.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Nierenberg, A. A.] Harvard Med Sch, Depress Clin & Res Program, Boston, MA USA. [Nierenberg, A. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wilcox, M. A.] Janssen Res & Dev LLC, Epidemiol, Titusville, NJ USA. RP Kessler, RC (reprint author), Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM Kessler@hcp.med.harvard.edu RI Wardenaar, Klaas/E-2985-2013 FU VICI grant from Netherlands Organization for Scientific Research (NWO-ZonMW) [91812607]; National Institute of Mental Health (NIMH) [R01MH46376]; National Institute on Drug Abuse (NIDA) [R01DA012058]; NIMH grants [R01MH070884, U01MH060220]; Substance Abuse and Mental Health Services Administration (SAMHSA); Robert Wood Johnson Foundation (RWJF) [044780]; John W. Alden Trust; NIMH [R01MH070884]; John D and Catherine T MacArthur Foundation; Pfizer Foundation; US Public Health Service [R13MH066849, R01MH069864, R01DA016558]; Fogarty International Center (FIRCA) [R03TW006481]; Pan American Health Organization; Eli Lilly and Company; Ortho-McNeil Pharmaceutical; GlaxoSmithKline; Bristol-Myers Squibb FX PdJ was supported by a VICI grant (no: 91812607) from the Netherlands Organization for Scientific Research (NWO-ZonMW). The NCS data collection was supported by the National Institute of Mental Health (NIMH; R01MH46376). The NCS-2 data collection was supported by the National Institute on Drug Abuse (NIDA; R01DA012058). Data analysis for this paper was additionally supported by NIMH grants R01MH070884 and U01MH060220, with supplemental support from the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044780) and the John W. Alden Trust. The NCS-2 is carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork and consultation on data analysis. These activities were supported by the NIMH (R01MH070884), the John D and Catherine T MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13MH066849, R01MH069864 and R01DA016558), the Fogarty International Center (FIRCA R03TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical, GlaxoSmithKline and Bristol-Myers Squibb. NR 51 TC 2 Z9 2 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD OCT PY 2016 VL 21 IS 10 BP 1366 EP 1371 DI 10.1038/mp.2015.198 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DX1KT UT WOS:000384127000007 PM 26728563 ER PT J AU Fava, M Johe, K Ereshefsky, L Gertsik, LG English, BA Bilello, JA Thurmond, LM Johnstone, J Dickerson, BC Makris, N Hoeppner, BB Flynn, M Mischoulon, D Kinrys, G Freeman, MP AF Fava, M. Johe, K. Ereshefsky, L. Gertsik, L. G. English, B. A. Bilello, J. A. Thurmond, L. M. Johnstone, J. Dickerson, B. C. Makris, N. Hoeppner, B. B. Flynn, M. Mischoulon, D. Kinrys, G. Freeman, M. P. TI A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients SO MOLECULAR PSYCHIATRY LA English DT Article ID TREATMENT-RESISTANT DEPRESSION; ANTIDEPRESSANT DRUGS; DISORDERS; DEFINITION; EFFICACY AB We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n = 6) or placebo (n = 2), the second cohort 40 mg b.i.d. (n = 6) or placebo (n = 2), and the third cohort 40 mg t.i.d. (n = 6) or placebo (n = 2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (+/- 3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4-20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions-Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort. C1 [Fava, M.; Hoeppner, B. B.; Flynn, M.; Mischoulon, D.; Kinrys, G.; Freeman, M. P.] Massachusetts Gen Hosp, Clin Trials & Network Inst, Boston, MA 02114 USA. [Fava, M.; Hoeppner, B. B.; Mischoulon, D.; Kinrys, G.; Freeman, M. P.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Johe, K.] Neuralstem Inc, Germantown, MD USA. [Ereshefsky, L.; English, B. A.] Los Angeles Early Phase Unit, PAREXEL Int, Los Angeles, CA USA. [Gertsik, L. G.] Calif Clin Trials Med Grp, Glendale, CA USA. [Bilello, J. A.; Thurmond, L. M.] Ridge Diagnost, Res Triangle Pk, NC USA. [Johnstone, J.] Q Metrx Inc, Glendale, CA USA. [Dickerson, B. C.; Makris, N.] Massachusetts Gen Hosp, Ctr Morphometr Anal, Boston, MA 02114 USA. RP Fava, M (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Clin Trials Network & Inst, Dept Psychiat, 55 Fruit St,Bulfinch 351, Boston, MA 02114 USA. EM mfava@mgh.harvard.edu FU Neuralstem FX The study was supported by Neuralstem. NR 24 TC 3 Z9 3 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD OCT PY 2016 VL 21 IS 10 BP 1372 EP 1380 DI 10.1038/mp.2015.178 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DX1KT UT WOS:000384127000008 PM 26643541 ER PT J AU Antman, EM Loscalzo, J AF Antman, Elliott M. Loscalzo, Joseph TI Precision medicine in cardiology SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID AMERICAN-HEART-ASSOCIATION; BLOOD-PRESSURE; BIG-DATA; CARDIOVASCULAR-DISEASE; SCIENTIFIC STATEMENT; NETWORK MEDICINE; GENOMIC MEDICINE; CLINICAL-TRIALS; MYOCARDIAL-INFARCTION; NEPRILYSIN INHIBITION AB The cardiovascular research and clinical communities are ideally positioned to address the epidemic of noncommunicable causes of death, as well as advance our understanding of human health and disease, through the development and implementation of precision medicine. New tools will be needed for describing the cardiovascular health status of individuals and populations, including 'omic' data, exposome and social determinants of health, the microbiome, behaviours and motivations, patient-generated data, and the array of data in electronic medical records. Cardiovascular specialists can build on their experience and use precision medicine to facilitate discovery science and improve the efficiency of clinical research, with the goal of providing more precise information to improve the health of individuals and populations. Overcoming the barriers to implementing precision medicine will require addressing a range of technical and sociopolitical issues. Health care under precision medicine will become a more integrated, dynamic system, in which patients are no longer a passive entity on whom measurements are made, but instead are central stakeholders who contribute data and participate actively in shared decision-making. Many traditionally defined diseases have common mechanisms; therefore, elimination of a siloed approach to medicine will ultimately pave the path to the creation of a universal precision medicine environment. C1 [Antman, Elliott M.] Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,Off Level One, Boston, MA 02115 USA. [Loscalzo, Joseph] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. RP Antman, EM (reprint author), Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,Off Level One, Boston, MA 02115 USA. EM eantman@rics.bwh.harvard.edu NR 138 TC 5 Z9 5 U1 21 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD OCT PY 2016 VL 13 IS 10 BP 591 EP 602 DI 10.1038/nrcardio.2016.101 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DW9SJ UT WOS:000384002700006 PM 27356875 ER PT J AU Santos, A Rivas, E Rodriguez-Roisin, R Sanchez, M Ruiz-Cabello, J Arismendi, E Venegas, JG AF Santos, Arnoldo Rivas, Eva Rodriguez-Roisin, Roberto Sanchez, Marcelo Ruiz-Cabello, Jesus Arismendi, Ebymar Venegas, Jose G. TI Lung Tissue Volume is Elevated in Obesity and Reduced by Bariatric Surgery SO OBESITY SURGERY LA English DT Article DE Bariatric surgery; Lung tissue volume; Obesity; Pulmonary hemodynamics; Thoracic computed tomography ID MORBIDLY OBESE; COMPUTED-TOMOGRAPHY; RESPIRATORY-FUNCTION; WEIGHT-LOSS; CT; EMPHYSEMA; INFLAMMATION; ATELECTASIS; IMPROVES AB Bariatric surgery (BS) in severely obese subjects causes a significant reduction of body weight with lung function improvement. We have shown that abnormalities in pulmonary gas exchange in morbidly obese subjects are substantially improved with BS. These abnormalities were thought to be related to reduced lung volumes as well as to abnormal endothelial function induced by low-grade chronic inflammation linked to perivascular adipose tissue (PVAT). In this study, we used computed tomography (CT) to assess whether BS also caused measurable structural changes in the lung tissue volume (Vtiss) and cross-sectional vessel analysis, hypothesizing that these measures could be related to the previously reported lung functional changes. This is a post hoc analysis of a previous reported prospective study. Pulmonary vessels and lung volumes, including Vtiss, were quantified in thoracic CT scans. We compared findings in 12 obese women before and after BS and in 8 healthy lean women. Vtiss was significantly elevated in obese subjects before BS compared to control subjects and systematically reduced after BS (by 8 %); other CT lung volumes or vascular areas were not affected in a consistent manner. No relationship was observed between BS-induced individual changes in Vtiss and pulmonary vessel area. Vtiss is elevated in morbidly obese subjects, compared to lean individuals of similar body height, and is systematically reduced by BS. These effects do not appear related to vascular changes but may be caused by elevated extravascular lung water, due to low-grade inflammation, and/or hypertrophic PVAT in severe obesity. C1 [Santos, Arnoldo; Venegas, Jose G.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Santos, Arnoldo; Venegas, Jose G.] Harvard Med Sch, Boston, MA 02115 USA. [Santos, Arnoldo; Ruiz-Cabello, Jesus] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid, Spain. [Santos, Arnoldo; Rodriguez-Roisin, Roberto; Ruiz-Cabello, Jesus; Arismendi, Ebymar] CIBER Enfermedades Resp CIBERES, Madrid, Spain. [Rivas, Eva] Hosp Clin Barcelona, Serv Anestesiol, Barcelona, Spain. [Rivas, Eva; Rodriguez-Roisin, Roberto; Arismendi, Ebymar] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain. [Rivas, Eva; Rodriguez-Roisin, Roberto; Arismendi, Ebymar] FCRB, Barcelona, Spain. [Rodriguez-Roisin, Roberto] Hosp Clin Barcelona, Inst Clin Resp, Serv Pneumol, Barcelona, Spain. [Sanchez, Marcelo] Hosp Clin Barcelona, CDI, Barcelona, Spain. [Ruiz-Cabello, Jesus] Univ Complutense Madrid, Madrid, Spain. RP Venegas, JG (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA.; Rodriguez-Roisin, R (reprint author), CIBER Enfermedades Resp CIBERES, Madrid, Spain.; Rodriguez-Roisin, R (reprint author), Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.; Rodriguez-Roisin, R (reprint author), FCRB, Barcelona, Spain.; Rodriguez-Roisin, R (reprint author), Hosp Clin Barcelona, Inst Clin Resp, Serv Pneumol, Barcelona, Spain. EM rororo@clinic.ub.es; Jvenegas@alum.mit.edu RI Ruiz-Cabello, Jesus/A-9570-2012 OI Ruiz-Cabello, Jesus/0000-0001-8681-5056 FU Spanish Ministry of Economy and Competitiveness (MINECO); Pro CNIC Foundation; Severo Ochoa Center of Excellence (MINECO award) [SEV-2015-0505] FX The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). NR 27 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 EI 1708-0428 J9 OBES SURG JI Obes. Surg. PD OCT PY 2016 VL 26 IS 10 BP 2475 EP 2482 DI 10.1007/s11695-016-2137-9 PG 8 WC Surgery SC Surgery GA DW0MY UT WOS:000383335700028 PM 27000884 ER PT J AU Pollak, KI Tulsky, JA Bravender, T Ostbye, T Lyna, P Dolor, RJ Coffman, CJ Bilheimer, A Lin, PH Farrell, D Bodner, ME Alexander, SC AF Pollak, Kathryn I. Tulsky, James A. Bravender, Terrill Ostbye, Truls Lyna, Pauline Dolor, Rowena J. Coffman, Cynthia J. Bilheimer, Alicia Lin, Pao-Hwa Farrell, David Bodner, Michael E. Alexander, Stewart C. TI Teaching primary care physicians the 5 A's for discussing weight with overweight and obese adolescents SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Physicians; Motivational interviewing; Adolescents; Obesity ID COMMUNICATION; ADULTHOOD; RISK; CHAT AB Objective: We developed an online intervention to teach physicians both MI (addressed in outcomes paper) and the 5 A's (Ask, Advise, Assess, Assist, and Arrange) when discussing weight with overweight/obese adolescents. Methods: We audio recorded 527 encounters between adolescents and physicians and coded the 5 A's during weight/BMI discussions. Half of physicians were randomized to receive a tailored, intervention that included their own audio-recorded clips. To examine arm differences, we used multilevel linear mixed-effects models for sum of 5 A's and generalized estimating equations (GEE) models with a logit link for each of the A's separately. Results: Intervention arm physicians used more A's than control physicians (estimated difference = 0.6; 95% CI(0.2,1.0); p = 0.001). Intervention physicians used Assess (p = 0.004), Assist (p = 0.001) and Arrange (p = 0.02) more when compared to control arm physicians. Conclusion: An online intervention increased physicians' use of the 5 A's when discussing weight with overweight adolescents. These results are promising as the online intervention improved performance for the three A's that are infrequently used (Assess, Assist, and Arrange) yet have the most impact. Practice implications: A tailored online program can increase physicians' use of the 5 A's behavioral counseling approach in clinical practice with adolescents. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Pollak, Kathryn I.; Ostbye, Truls; Lyna, Pauline; Bilheimer, Alicia] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC 27710 USA. [Pollak, Kathryn I.; Ostbye, Truls] Duke Sch Med, Dept Community & Family Med, Durham, NC USA. [Tulsky, James A.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Bravender, Terrill] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Dolor, Rowena J.; Lin, Pao-Hwa] Duke Univ Med, Dept Med, Durham, NC USA. [Coffman, Cynthia J.] Durham VA Med Ctr, Hlth Serv Res & Dev Serv, Durham, NC USA. [Coffman, Cynthia J.] Duke Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Farrell, David] People Designs Inc, Durham, NC USA. [Bodner, Michael E.] Trinity Western Univ, Sch Human Kinet, Langley, BC, Canada. [Alexander, Stewart C.] Purdue Univ, Dept Consumer Sci, Lafayette, IN USA. RP Pollak, KI (reprint author), Duke Canc Inst, Canc Control & Populat Sci, Durham, NC 27710 USA. EM kathryn.pollak@duke.edu FU [R01HL092403] FX This work was supported by grants R01HL092403. Clinical Trial Registration: NCT01040975; clinicaltrials.gov. The study sponsor did not have a role in the study design; collection, analysis and interpretation of data; writing the report; and the decision to submit the report for publication. NR 18 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD OCT PY 2016 VL 99 IS 10 BP 1620 EP 1625 DI 10.1016/j.pec.2016.05.007 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA DW0VQ UT WOS:000383361500011 PM 27228899 ER PT J AU Seitz, HH Gibson, L Skubisz, C Forquer, H Mello, S Schapira, MM Armstrong, K Cappella, JN AF Seitz, Holli H. Gibson, Laura Skubisz, Christine Forquer, Heather Mello, Susan Schapira, Marilyn M. Armstrong, Katrina Cappella, Joseph N. TI Effects of a risk-based online mammography intervention on accuracy of perceived risk and mammography intentions SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Risk communication; Communication intervention; Decision aid; Mammography; Perceived risk; Numeracy ID BREAST-CANCER RISK; DECISION AID; HEALTH; PREDICTORS; NUMERACY; WOMEN; GUIDELINES; BEHAVIOR AB Objective: This experiment tested the effects of an individualized risk-based online mammography decision intervention. The intervention employs exemplification theory and the Elaboration Likelihood Model of persuasion to improve the match between breast cancer risk and mammography intentions. Methods: 2918 women ages 35-49 were stratified into two levels of 10-year breast cancer risk (<1.5%; >= 1.5%) then randomly assigned to one of eight conditions: two comparison conditions and six risk-based intervention conditions that varied according to a 2 (amount of content: brief vs. extended) x 3 (format: expository vs. untailored exemplar [example case] vs. tailored exemplar) design. Outcomes included mammography intentions and accuracy of perceived breast cancer risk. Results: Risk-based intervention conditions improved the match between objective risk estimates and perceived risk, especially for high-numeracy women with a 10-year breast cancer risk <= 1.5%. For women with a risk <= 1.5%, exemplars improved accuracy of perceived risk and all risk-based interventions increased intentions to wait until age 50 to screen. Conclusion: A risk-based mammography intervention improved accuracy of perceived risk and the match between objective risk estimates and mammography intentions. Practice implications: Interventions could be applied in online or clinical settings to help women understand risk and make mammography decisions. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Seitz, Holli H.; Gibson, Laura; Skubisz, Christine; Forquer, Heather; Mello, Susan; Cappella, Joseph N.] Univ Penn, Annenberg Sch Commun, 3620 Walnut St, Philadelphia, PA 19104 USA. [Schapira, Marilyn M.; Armstrong, Katrina] Univ Penn, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Schapira, Marilyn M.] Crescenz VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Skubisz, Christine] Emerson Coll, Sch Commun, 120 Boylston St, Boston, MA 02116 USA. [Mello, Susan] Northeastern Univ, Dept Commun Studies, 360 Huntington Ave, Boston, MA 02115 USA. [Armstrong, Katrina] Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA. RP Seitz, HH (reprint author), Univ Penn, Annenberg Sch Commun, 3620 Walnut St, Philadelphia, PA 19104 USA. EM hollihseitz@gmail.com; lgibson@asc.upenn.edu; christine_skubisz@emerson.edu; heather.forquer@gmail.com; s.mello@northeastern.edu; mschap@mail.med.upenn.edu; karmstrong6@mgh.harvard.edu; jcappella@asc.upenn.edu FU National Cancer Institute [1U54CA163313] FX This project was made possible by Penn Center for Innovation in Personalized Breast Cancer Screening (PCIPS) Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) Grant 1U54CA163313 from the National Cancer Institute. Contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. The National Cancer Institute was not involved in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. NR 29 TC 0 Z9 0 U1 12 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD OCT PY 2016 VL 99 IS 10 BP 1647 EP 1656 DI 10.1016/j.pec.2016.05.005 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA DW0VQ UT WOS:000383361500015 PM 27178707 ER PT J AU Egeler, RM Katewa, S Leenen, PJM Beverley, P Collin, M Ginhoux, F Arceci, RJ Rollins, BJ AF Egeler, R. Maarten Katewa, Satyendra Leenen, Pieter J. M. Beverley, Peter Collin, Matthew Ginhoux, Florent Arceci, Robert J. Rollins, Barrett J. CA Steering Comm Nikolas Symposium TI Langerhans cell histiocytosis is a neoplasm and consequently its recurrence is a relapse: In memory of Bob Arceci SO PEDIATRIC BLOOD & CANCER LA English DT Review DE Langerhans cell histiocytosis; LCH; neoplasm ID ERDHEIM-CHESTER DISEASE; BRAF MUTATIONS; DENDRITIC CELLS; HIGH PREVALENCE; ABUNDANT EXPRESSION; CANCER GENOME; RAS ONCOGENES; LUNG-CANCER; HUMAN-SKIN; T-CELLS AB Langerhans cell histiocytosis (LCH) remains a poorly understood disorder with heterogeneous clinical presentations characterized by focal or disseminated lesions that contain excessive CD1a+ langerin+ cells with dendritic cell features known as LCH cells. Two of the major questions investigated over the past century have been (i) the origin of LCH cells and (ii) whether LCH is primarily an immune dysregulatory disorder or a neoplasm. Current opinion is that LCH cells are likely to arise from hematopoietic precursor cells, although the stage of derailment and site of transformation remain unclear and may vary in patients with different extent of disease. Over the years, evidence has provided the view that LCH is a neoplasm. The demonstration of clonality of LCH cells, insufficient evidence alone for neoplasia, is now bolstered by finding driver somatic mutations in BRAF in up to 55% of patients with LCH, and activation of the RAS-RAF-MEK-ERK (where MEK and ERK are mitogen-activated protein kinase and extracellular signal-regulated kinase, respectively) pathway in nearly 100% of patients with LCH. Herein, we review the evidence that recurrent genetic abnormalities characterized by activating oncogenic mutations should satisfy prerequisites for LCH to be called a neoplasm. As a consequence, recurrent episodes of LCH should be considered relapsed disease rather than disease reactivation. Mapping the complete genetic landscape of this intriguing disease will provide additional support for the conclusion that LCH is a neoplasm and is likely to provide more potential opportunities for molecularly targeted therapies. C1 [Egeler, R. Maarten] Univ Toronto, Hosp Sick Children, Dept Paediat, Div Haematol Oncol, Toronto, ON, Canada. [Katewa, Satyendra] Soni Manipal Hosp, Dept Pediat Hematol Oncol & BMT, Main Sikar Rd,Sect 5, Jaipur, Rajasthan, India. [Leenen, Pieter J. M.] Erasmus MC, Dept Immunol, Rotterdam, Netherlands. [Collin, Matthew] Newcastle Univ, Inst Cellular Med, Dept Haematol Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Ginhoux, Florent] Agcy Sci Technol & Res, Singapore Immunol Network SIgN, Singapore 138648, Singapore. [Arceci, Robert J.] Univ Arizona, Dept Child Hlth, Coll Med Phoenix, Ron Matricaria Inst Mol Med, Phoenix, AZ USA. [Rollins, Barrett J.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Med Oncol, Boston, MA USA. [Rollins, Barrett J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. RP Egeler, RM (reprint author), Univ Toronto, Hosp Sick Children, Dept Paediat, Div Haematol Oncol, Toronto, ON, Canada.; Egeler, RM (reprint author), Hosp Sick Children, Dept Paediat, Div Haematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM maarten.egeler@sickkids.ca FU Medical Research Council [G1100085] NR 101 TC 2 Z9 2 U1 2 U2 2 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 OCT PY 2016 VL 63 IS 10 BP 1704 EP 1712 DI 10.1002/pbc.26104 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DW0ZE UT WOS:000383371500004 PM 27314817 ER PT J AU Cash, T McIlvaine, E Krailo, MD Lessnick, SL Lawlor, ER Laack, N Sorger, J Marina, N Grier, HE Granowetter, L Womer, RB DuBois, SG AF Cash, Thomas McIlvaine, Elizabeth Krailo, Mark D. Lessnick, Stephen L. Lawlor, Elizabeth R. Laack, Nadia Sorger, Joel Marina, Neyssa Grier, Holcombe E. Granowetter, Linda Womer, Richard B. DuBois, Steven G. TI Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE extraosseous; extraskeletal Ewing sarcoma; gene expression; gene profiling; prognosis; soft-tissue Ewing sarcoma ID ERYTHROCYTE SEDIMENTATION-RATE; ROUND-CELL SARCOMAS; PROGNOSTIC-FACTORS; PEDIATRIC-ONCOLOGY; SINGLE INSTITUTION; FRENCH-SOCIETY; GENE FUSION; TUMORS; CANCER; BONE AB BackgroundThe prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES. MethodsPatients had localized ES and were treated on two consecutive protocols using five-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event-free survival (EFS) was estimated using the Kaplan-Meier method, compared using the log-rank test, and modeled using Cox multivariate regression. ResultsPatients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors >8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50-0.95; P = 0.02). Among patients with EES, age 18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS. ConclusionClinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site. C1 [Cash, Thomas] Emory Univ, Dept Pediat, Childrens Healthcare Atlanta, Hlth Sci Res Bldg,Brumley Bridge,3rd Floor,W-350, Atlanta, GA 30322 USA. [McIlvaine, Elizabeth; Krailo, Mark D.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Lessnick, Stephen L.] Ohio State Univ, Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Disorders, Columbus, OH 43210 USA. [Lessnick, Stephen L.] Ohio State Univ, Div Hematol Oncol & BMT, Columbus, OH 43210 USA. [Lawlor, Elizabeth R.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Laack, Nadia] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Sorger, Joel] Cincinnati Childrens Hosp Med Ctr, Dept Orthoped, Cincinnati, OH 45229 USA. [Marina, Neyssa] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Marina, Neyssa] Lucille Packard Childrens Hosp Stanford, Palo Alto, CA USA. [Grier, Holcombe E.] Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat, Boston, MA USA. [Grier, Holcombe E.] Harvard Med Sch, Boston, MA USA. [Granowetter, Linda] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Granowetter, Linda] NYU, Langone Med Ctr, New York, NY USA. [Womer, Richard B.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Womer, Richard B.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [DuBois, Steven G.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA USA. [DuBois, Steven G.] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA. RP Cash, T (reprint author), Emory Univ, Dept Pediat, Childrens Healthcare Atlanta, Hlth Sci Res Bldg,Brumley Bridge,3rd Floor,W-350, Atlanta, GA 30322 USA. EM Thomas.Cash@choa.org OI Granowetter MD, Linda/0000-0002-2399-9107 FU NickCurrey Fund; NIH/NCI [U10CA98543] FX Grant sponsor: NickCurrey Fund; Grant sponsor: NIH/NCI; Grant number: U10CA98543. NR 42 TC 0 Z9 0 U1 3 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 OCT PY 2016 VL 63 IS 10 BP 1771 EP 1779 DI 10.1002/pbc.26096 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DW0ZE UT WOS:000383371500012 PM 27297500 ER PT J AU Xie, WL Drouin, S Nakabayashi, M Pomerantz, M Lee, GSM Kantoff, PW Sharifi, N AF Xie, Wanling Drouin, Sarah Nakabayashi, Mari Pomerantz, Mark Lee, Gwo-Shu Mary Kantoff, Philip W. Sharifi, Nima TI A Genetic Variation of SOD2 Does Not Determine Duration of Response to Androgen Deprivation Therapy for Prostate Cancer SO PROSTATE LA English DT Article DE prostate cancer; MnSOD2 ID MANGANESE SUPEROXIDE-DISMUTASE; DIMORPHISM; RISK AB BACKGROUNDSilencing SOD2 expression upregulates androgen receptor (AR) signaling and expression of SOD2 is downregulated in CRPC, compared with untreated tumors. The decreased SOD2 activity could lead to AR gain-of-function and the development of castration-resistance. METHODSWe genotyped SOD2-rs4880 in a cohort of 753 prostate cancer patients receiving androgen deprivation therapy (ADT) between 1996 and 2010. The rs4880 encodes Ala16Val in SOD2 and the Val variant has been demonstrated to be functionally less efficient than the Ala variant. We assessed the impact of SOD2-rs4880 variants on the time to progression (TTP) and overall survival (OS) on ADT using multivariable Cox regression. RESULTSFour hundred thirty-two out of 753 (57%) had metastases at the time of ADT initiation. Overall, median TTP on ADT was 18.4 (95%CI: 15.8, 20.9) months and median overall survival (OS) from ADT initiation was 6.3 (95%CI: 5.8, 6.8) years. In unadjusted and adjusted analyses, there was no association between SOD-rs4880 and TTP or OS on ADT (P>0.05). Results were similarly negative among patients with and without metastatic disease at ADT initiation. CONCLUSIONSOur result suggests that a functional genetic variant in SOD2 does not determine the efficacy of ADT for prostate cancer. It is possible that the drastic downregulation of SOD2 in advanced prostate cancer cells may have overridden any influence of the genetic variation of SOD2. This study suggests the need for careful consideration about timing if the application of SOD2 mimetics for prostate cancer therapy is considered. Prostate 76:1338-1341, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Xie, Wanling] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Xie, Wanling; Drouin, Sarah; Nakabayashi, Mari; Pomerantz, Mark; Lee, Gwo-Shu Mary; Kantoff, Philip W.] Harvard Med Sch, Boston, MA USA. [Drouin, Sarah; Nakabayashi, Mari; Pomerantz, Mark; Lee, Gwo-Shu Mary; Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Drouin, Sarah] Interne Paris, Urol, Paris, France. [Kantoff, Philip W.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Sharifi, Nima] Cleveland Clin, Dept Canc Biol, 9500 Euclid Ave, Cleveland, OH 44106 USA. RP Kantoff, PW (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.; Sharifi, N (reprint author), Cleveland Clin, Dept Canc Biol, 9500 Euclid Ave, Cleveland, OH 44106 USA. EM kantoff@mskcc.org; sharifn@ccf.org FU Dana-Farber Prostate Cancer SPORE [P50CA090381]; Prostate Cancer Foundation; National Cancer Institute [R01CA168899, R01CA172382, R01CA190289] FX Grant sponsor: Dana-Farber Prostate Cancer SPORE; Grant number: P50CA090381; Grant sponsor: Prostate Cancer Foundation Challenge Award; Grant sponsor: National Cancer Institute; Grant numbers: R01CA168899; R01CA172382; R01CA190289. NR 10 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD OCT 1 PY 2016 VL 76 IS 14 BP 1338 EP 1341 DI 10.1002/pros.23220 PG 4 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA DW2MJ UT WOS:000383476200009 PM 27325180 ER PT J AU Kitajima, S Thummalapalli, R Barbie, DA AF Kitajima, Shunsuke Thummalapalli, Rohit Barbie, David A. TI Inflammation as a driver and vulnerability of KRAS mediated oncogenesis SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE KRAS; Inflammation; NF-kappa B; STAT3; Cytokines; Autophagy ID PANCREATIC DUCTAL ADENOCARCINOMA; MOUSE COLON TUMORS; CELL LUNG-CANCER; PROMOTES T-CELL; COLORECTAL-CANCER; CHECKPOINT BLOCKADE; BOWEL-DISEASE; PD-1 BLOCKADE; TUMORIGENESIS; PROGRESSION AB While important strides have been made in cancer therapy by targeting certain oncogenes, KRAS, the most common among them, remains refractory to this approach. In recent years, a deeper understanding of the critical importance of inflammation in promoting KRAS-driven oncogenesis has emerged, and applies across the different contexts of lung, pancreatic, and colorectal tumorigenesis. Here we review why these tissue types are particularly prone to developing KRAS mutations, and how inflammation conspires with KRAS signaling to fuel carcinogenesis. We discuss multiple lines of evidence that have established NF-kappa B, STAT3, and certain cytokines as key transducers of these signals, and data to suggest that targeting these pathways has significant clinical potential. Furthermore, recent work has begun to uncover how inflammatory signaling interacts with other KRAS regulated survival pathways such as autophagy and MAPK signaling, and that co-targeting these multiple nodes may be required to achieve real benefit. In addition, the impact of KRAS associated inflammatory signaling on the greater tumor microenvironment has also become apparent, and taking advantage of this inflammation by incorporating approaches that harness T cell anti-tumor responses represents another promising therapeutic strategy. Finally, we highlight the likelihood that the genomic complexity of KRAS mutant tumors will ultimately require tailored application of these therapeutic approaches, and that targeting inflammation early in the course of tumor development could have the greatest impact on eradicating this deadly disease. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kitajima, Shunsuke; Thummalapalli, Rohit; Barbie, David A.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Thummalapalli, Rohit] Harvard Med Sch, Div Hlth Sci & Technol, 25 Shattuck St, Boston, MA 02115 USA. RP Barbie, DA (reprint author), 450 Brookline Ave,D819, Boston, MA 02215 USA. EM shunsuke_kitajima@dfci.harvard.edu; rohit_thummalapalli@hms.harvard.edu; dbarbie@partners.org FU strategic young researcher overseas visits program for accelerating brain circulation [NCI-R01 CA190394-01, NCI-K08 CA138918-01A1]; Gloria T. Maheu Fund for Lung Cancer Research FX This work was supported by the strategic young researcher overseas visits program for accelerating brain circulation (S.K.), NCI-R01 CA190394-01 (D.B.), NCI-K08 CA138918-01A1 (D.B.), and the Gloria T. Maheu Fund for Lung Cancer Research (D.B.). NR 76 TC 1 Z9 1 U1 13 U2 13 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 OCT PY 2016 VL 58 BP 127 EP 135 DI 10.1016/j.semcdb.2016.06.009 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DV9TD UT WOS:000383284000015 PM 27297136 ER PT J AU Bowles, DW Deutsch, E Raben, D AF Bowles, Daniel W. Deutsch, Eric Raben, David TI Successes and Failures of Combined Modality Therapies in Head and Neck Cancer SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR RECEPTOR; LOCALLY ADVANCED HEAD; MODULATED RADIATION-THERAPY; PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR; RANDOMIZED PHASE-II; INDUCTION CHEMOTHERAPY; HUMAN-PAPILLOMAVIRUS; FACTOR-BETA; IN-VIVO AB The paradigms for treating head and neck squamous cell carcinoma are changing as new subgroups are defined. The technical successes of improved radiation therapy are many; however, the success of novel combined therapies are few. With the emergence of human papillomavirus and the development of immunooncology agents, such as checkpoint inhibitors, are we ready to reevaluate how we use radiation and chemotherapy for locally advanced and metastatic disease-will we remain the fire or become the fire starter? (C) 2016 Published by Elsevier Inc. C1 [Bowles, Daniel W.] Univ Colorado, Sch Med, Div Med Oncol, Aurora, CO USA. [Bowles, Daniel W.] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO USA. [Deutsch, Eric] Univ Paris Saclay, Univ Paris 11, Dept Radiotherapy, INSERM Mol Radiotherapy 1030, St Aubin, France. [Raben, David] Univ Colorado, Sch Med, Dept Radiat Oncol, Aurora, CO USA. RP Raben, D (reprint author), Univ Colorado Hlth, Dept Radiat Oncol, Mail Stop F706,1665 Aurora Court,Suite 1032, Aurora, CO 80045 USA. EM david.raben@ucdenver.edu NR 86 TC 0 Z9 0 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 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD OCT PY 2016 VL 26 IS 4 BP 299 EP 306 DI 10.1016/j.semradonc.2016.05.004 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DW4UY UT WOS:000383639700006 PM 27619251 ER PT J AU Itchaki, G Brown, JR AF Itchaki, Gilad Brown, Jennifer R. TI The potential of venetoclax (ABT-199) in chronic lymphocytic leukemia SO THERAPEUTIC ADVANCES IN HEMATOLOGY LA English DT Review DE ABT-199; B-cell chronic lymphocytic leukemia; venetoclax ID EFFICIENTLY INDUCES APOPTOSIS; MEDIATED TREATMENT RESISTANCE; KINASE INHIBITOR IBRUTINIB; B-CELL MALIGNANCIES; LYMPHOID MALIGNANCIES; ANTITUMOR-ACTIVITY; BH3 MIMETICS; BCL-2 INHIBITION; MCL-1 EXPRESSION; TARGETING BCL2 AB Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN. We further strive to contextualize VEN in the current CLL treatment landscape and discuss potential mechanisms of resistance. C1 [Brown, Jennifer R.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Itchaki, Gilad] Beilinson Med Ctr, Rabin Med Ctr, Petah Tiqwa, Israel. RP Brown, JR (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jennifer_brown@dfci.harvard.edu NR 93 TC 1 Z9 1 U1 8 U2 8 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2040-6207 EI 2040-6215 J9 THER ADV HEMATOL JI Ther. Adv. Hematol. PD OCT PY 2016 VL 7 IS 5 BP 270 EP 287 DI 10.1177/2040620716655350 PG 18 WC Hematology SC Hematology GA DW4YC UT WOS:000383647900003 PM 27695617 ER PT J AU Patel, TR Shahin, AJ Bhat, J Welling, DB Moberly, AC AF Patel, Tirth R. Shahin, Antoine J. Bhat, Jyoti Welling, D. Bradley Moberly, Aaron C. TI Cortical Auditory Evoked Potentials to Evaluate Cochlear Implant Candidacy in an Ear With Long-standing Hearing Loss: A Case Report SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE auditory evoked potentials; cochlear implants; speech perception ID SPEECH-PERCEPTION; CHILDREN; USERS; SOUND AB Objectives: We describe a novel use of cortical auditory evoked potentials in the preoperative workup to determine ear candidacy for cochlear implantation. Methods: A 71-year-old male was evaluated who had a long-deafened right ear, had never worn a hearing aid in that ear, and relied heavily on use of a left-sided hearing aid. Electroencephalographic testing was performed using free field auditory stimulation of each ear independently with pure tones at 1000 and 2000 Hz at approximately 10 dB above pure-tone thresholds for each frequency and for each ear. Results: Mature cortical potentials were identified through auditory stimulation of the long-deafened ear. The patient underwent successful implantation of that ear. He experienced progressively improving aided pure-tone thresholds and binaural speech recognition benefit (AzBio score of 74%). Conclusions: Findings suggest that use of cortical auditory evoked potentials may serve a preoperative role in ear selection prior to cochlear implantation. C1 [Patel, Tirth R.; Bhat, Jyoti; Moberly, Aaron C.] Ohio State Univ, Wexner Med Ctr, 915 Olentangy River Rd,Suite 4000, Columbus, OH 43212 USA. [Shahin, Antoine J.] Univ Calif Davis, Ctr Mind & Brain, Davis, CA 95616 USA. [Welling, D. Bradley] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Moberly, AC (reprint author), Ohio State Univ, Wexner Med Ctr, 915 Olentangy River Rd,Suite 4000, Columbus, OH 43212 USA. EM Aaron.Moberly@osumc.edu FU NIDCD [R03-DC011168] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Work described in this manuscript was supported by R03-DC011168 from NIDCD awarded to Antoine J. Shahin. NR 15 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD OCT PY 2016 VL 125 IS 10 BP 858 EP 861 DI 10.1177/0003489416656647 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA DV9ED UT WOS:000383241900011 PM 27357975 ER PT J AU Debrey, SM Leehey, MA Klepitskaya, O Filley, CM Shah, RC Kluger, B Berry-Kravis, E Spector, E Tassone, F Hall, DA AF Debrey, Sarah M. Leehey, Maureen A. Klepitskaya, Olga Filley, Christopher M. Shah, Raj C. Kluger, Benzi Berry-Kravis, Elizabeth Spector, Elaine Tassone, Flora Hall, Deborah A. TI Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series SO CEREBELLUM LA English DT Article DE Fragile X-associated tremor/ataxia syndrome; Trinucleotide repeat expansion; Ataxia; Parkinsonism; Movement disorders ID TREMOR/ATAXIA SYNDROME FXTAS; COMORBIDITY SURVEY REPLICATION; FMR1 MESSENGER-RNA; PREMUTATION CARRIERS; CGG-REPEAT; ALZHEIMERS-DISEASE; PARKINSON-DISEASE; NEEDS POPULATION; EXPANDED ALLELES; RATING-SCALE AB Considerable research has focused on patients with trinucleotide (CGG) repeat expansions in the fragile X mental retardation 1 (FMR1) gene that fall within either the full mutation (> 200 repeats) or premutation range (55-200 repeats). Recent interest in individuals with gray zone expansions (41-54 CGG repeats) has grown due to reported phenotypes that are similar to those observed in premutation carriers, including neurological, molecular, and cognitive signs. The purpose of this manuscript is to describe a series of adults with FMR1 alleles in the gray zone presenting with movement disorders or memory loss. Gray zone carriers ascertained in large FMR1 screening studies were identified and their clinical phenotypes studied. Thirty-one gray zone allele carriers were included, with mean age of symptom onset of 53 years in patients with movement disorders and 57 years in those with memory loss. Four patients were chosen for illustrative case reports and had the following diagnoses: early-onset Parkinson disease (PD), atypical parkinsonism, dementia, and atypical essential tremor. Some gray zone carriers presenting with parkinsonism had typical features, including bradykinesia, rigidity, and a positive response to dopaminergic medication. These patients had a higher prevalence of peripheral neuropathy and psychiatric complaints than would be expected. The patients seen in memory clinics had standard presentations of cognitive impairment with no apparent differences. Further studies are necessary to determine the associations between FMR1 expansions in the gray zone and various phenotypes of neurological dysfunction. C1 [Debrey, Sarah M.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Leehey, Maureen A.; Klepitskaya, Olga; Filley, Christopher M.; Kluger, Benzi] Univ Colorado, Sch Med, Dept Neurol, Aurora, CO USA. [Filley, Christopher M.; Kluger, Benzi] Univ Colorado, Sch Med, Dept Psychiat, Aurora, CO USA. [Filley, Christopher M.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Shah, Raj C.] Rush Univ, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth] Rush Univ, Dept Pediat, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth] Rush Univ, Dept Biochem, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth; Hall, Deborah A.] Rush Univ, Dept Neurol Sci, 1725 West Harrison St,Suite 755, Chicago, IL 60612 USA. [Spector, Elaine] Univ Colorado Denver, Dept Pediat, Childrens Hosp Colorado, Denver Genet DNA Diagnost Lab, Aurora, CO USA. [Tassone, Flora] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95616 USA. [Tassone, Flora] Univ Calif Davis, Med Ctr, MIND Inst, Sacramento, CA 95817 USA. RP Hall, DA (reprint author), Rush Univ, Dept Neurol Sci, 1725 West Harrison St,Suite 755, Chicago, IL 60612 USA. EM Deborah_A_Hall@rush.edu FU [R01NS052487] FX This work was funded by R01NS052487 (DAH). We thank the patients who participated in these studies. NR 66 TC 1 Z9 1 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD OCT PY 2016 VL 15 IS 5 SI SI BP 623 EP 631 DI 10.1007/s12311-016-0809-6 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DV4XL UT WOS:000382928900011 PM 27372099 ER PT J AU Donahue, GS Lindgren, V Galea, VP Madanat, R Muratoglu, O Malchau, H AF Donahue, Gabrielle S. Lindgren, Viktor Galea, Vincent P. Madanat, Rami Muratoglu, Orhun Malchau, Henrik TI Are Females at Greater Risk for Revision Surgery After Hip Resurfacing Arthroplasty With the Articular Surface Replacement Prosthesis? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID COMPLICATION RATES DIFFER; NATIONAL JOINT REGISTRY; METAL-ION LEVELS; FAILURE; PATIENT; NICKEL; THA; RELEASE; ALLERGY; GENDER AB Female patients undergoing hip resurfacing arthroplasties may be at greater risk of revision surgery than males, but it is unclear whether this is related to sex or other factors. We focused our analysis on data from a prospective multicenter cohort study monitoring the ASR(TM) hip resurfacing arthroplasty prosthesis on the potential association of sex on patient-reported outcome measures (PROMs), metal ion levels, revision surgery, and presence of adverse local tissue reaction. As thousands of patients with the ASR(TM) prosthesis are still undergoing followup it is critical to optimize the protocol for monitoring these patients. We wished (1) to assess the associations between sex and implant survival, and adverse local tissue reaction; and (2) to report the differences between sexes in metal ion levels and patient-reported outcome measures. One thousand two hundred fifty-two patients (1390 hips) who underwent hip resurfacing arthroplasty with implantation of the ASR(TM) prosthesis from April 2003 to July 2010 were eligible for enrollment in a multicenter followup study of the ASR(TM) Hip Resurfacing System after the voluntary recall of this device was initiated by DePuy in 2010. Nine hundred seventy patients (1098 hips) were enrolled at a mean of 7 years after surgery, with a mean followup of 2 years (range, 1-3.5 years). Nine hundred fifty-eight patients (1084 hips) met the inclusion criteria: ability to provide informed consent, complete PROMs, and continued routine followup. A subset of patients (150 patients, 171 hips), who all were from one center, with annual metal artifact reduction sequence MRI were analyzed. Ninety-three percent of patients from this center had routine MRI performed. The EuroQoL (EQ-5D), Harris hip score (HHS), University of California Los Angeles (UCLA) activity score, VAS pain, radiographs, patient and surgery details, and blood cobalt and chromium levels were obtained. Cox regression analysis was conducted to identify factors associated with implant survival, using any revision as the end point, and presence of adverse local tissue reaction. In patients who had unilateral surgery, the only variable found to be associated with revision surgery was HHS (hazard ratio [HR], 0.96; 95% CI, 0.94-0.97; p < 0.001). In patients who had bilateral surgery, only HHS (HR, 0.93; 95% CI, 0.90-0.97; p < 0.001) and cobalt level (HR, 1.02; 95% CI, 1.01-1.03; p < 0.001) were associated with risk for revision. In patients with metal artifact reduction sequence MRI, the only variable found to be associated with presence of adverse local tissue reaction was cobalt level (HR, 1.06; 95% CI, 1.02-1.10; p = 0.001). Cobalt and chromium concentrations were greater in female patients than in male patients (cobalt, median 1.89 versus median 1.12 parts per billion [ppb], p < 0.001; chromium, median 2.03 versus median 1.17 ppb, p < 0.001). Slight differences were observed between males and females in HHS (males median 96 versus females median 94, p < 0.001) and UCLA scores (median 8 versus median 6, p < 0.001); however, there was no difference between sexes for VAS pain (median 0.5 versus median 0.5, p = 0.405). Differences were identified between males and females in the distribution of EQ-5D scores, yet the medians were the same (median 1.0 versus median 1.0, p < 0.001). Male and female patients who had hip resurfacing arthroplasty with implantation of the ASR(TM) prosthesis should be followed with equal vigilance as both are at similar risk of revision surgery and adverse local tissue reaction. Metal ion levels and HHS should be obtained at followup to monitor for risk of revision and as a screening tool for MRI. Further research is necessary to evaluate if these relationships persist in patients with other metal-on-metal prostheses. Level II, therapeutic study. C1 [Donahue, Gabrielle S.; Lindgren, Viktor; Galea, Vincent P.; Madanat, Rami] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Lindgren, Viktor] Karolinska Inst, Sect Orthopaed, Dept Mol Med & Surg, Stockholm, Sweden. [Muratoglu, Orhun; Malchau, Henrik] Massachusetts Gen Hosp, 55 Fruit St,GRJ 1231, Boston, MA 02114 USA. RP Malchau, H (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRJ 1231, Boston, MA 02114 USA. EM hmalchau@mgh.harvard.edu FU Biomet (Warsaw, IN, USA); Smith & Nephew (London, UK); Zimmer Inc (Warsaw, IN, USA); Mako Surgical Corp (Ft Lauderdale, FL, USA); Mako Surgical Corp.; DePuy Synthes (Warsaw, IN, USA); Zimmer Inc; Biomet; Corin (Cirencester, UK); Iconacy (Warsaw, IN, USA); Renovis (Redlands, CA, USA); Conformis (Burlington, MA, USA); Aston Medical (Saint-Etienne, France); Meril Healthcare (Vapi, Gujarat, India); Arthex (Naples, FL, USA); Mako Surgical Corp; Cambridge Polymer Group (Boston, MA, USA); Orthopedic Technology Group (Boston, MA, USA); Corin; RSA Biomedical (Umea, Sweden) FX One of the authors (HM) has received research support funding from Biomet (Warsaw, IN, USA), Smith & Nephew (London, UK), Zimmer Inc (Warsaw, IN, USA), and Mako Surgical Corp (Ft Lauderdale, FL, USA). One of the authors (OM) has received research support funding from Mako Surgical Corp. The institution of one or more authors (RM, VG, GSD, CRB, OM, HM) has received, during the study period, funding from DePuy Synthes (Warsaw, IN, USA).; One of the authors (OM), or a member of his immediate family, has or may receive payments or benefits, during the study period, an amount of USD 10,000 to USD 100,000, from Zimmer Inc, Biomet, Corin (Cirencester, UK), Iconacy (Warsaw, IN, USA), Renovis (Redlands, CA, USA), Conformis (Burlington, MA, USA), Aston Medical (Saint-Etienne, France), Meril Healthcare (Vapi, Gujarat, India), Arthex (Naples, FL, USA), Mako Surgical Corp, Cambridge Polymer Group (Boston, MA, USA), and Orthopedic Technology Group (Boston, MA, USA).; One of the authors (HM), or a member of his immediate family, has or may receive payments or benefits, during the study period, an amount of USD 10,000 to USD 100,000, from Zimmer Inc, Biomet, Corin, and RSA Biomedical (Umea, Sweden). NR 36 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD OCT PY 2016 VL 474 IS 10 BP 2257 EP 2265 DI 10.1007/s11999-016-4860-x PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DV4YC UT WOS:000382930700033 PM 27121872 ER PT J AU Mundinger, TO Taborsky, GJ AF Mundinger, Thomas O. Taborsky, Gerald J., Jr. TI Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation SO DIABETOLOGIA LA English DT Review DE Autoimmunity; Diabetes; Glucagon; Human; Insulin-induced hypoglycaemia; Islet; Neuropathy; Neurotrophins; Review; Rodent; Sympathetic nerves ID INSULIN-INDUCED HYPOGLYCEMIA; P75 NEUROTROPHIN RECEPTOR; VESICULAR MONOAMINE TRANSPORTER; PERIPHERAL-NERVE REGENERATION; INCREASED GLUCAGON-SECRETION; PANCREATIC BETA-CELLS; MITOCHONDRIAL BIOENERGETICS; AUTONOMIC NEUROPATHY; NEURITE OUTGROWTH; IMPAIRED GLUCAGON AB This review outlines the current state of knowledge regarding a unique neural defect of the pancreatic islet in autoimmune diabetes, one that we have termed early sympathetic islet neuropathy (eSIN). We begin with the findings that a majority of islet sympathetic nerves are lost near the onset of type 1, but not type 2, diabetes and that this nerve loss is restricted to the islet. We discuss later work demonstrating that while the loss of islet sympathetic nerves and the loss of islet beta cells in type 1 diabetes both require infiltration of the islet by lymphocytes, their respective mechanisms of tissue destruction differ. Uniquely, eSIN requires the activation of a specific neurotrophin receptor and we propose two possible pathways for activation of this receptor during the immune attack on the islet. We also outline what is known about the functional consequences of eSIN, focusing on impairment of sympathetically mediated glucagon secretion and its application to the clinical problem of insulin-induced hypoglycaemia. Finally, we offer our view on the important remaining questions regarding this unique neural defect. C1 [Mundinger, Thomas O.; Taborsky, Gerald J., Jr.] Univ Washington, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA 98105 USA. [Mundinger, Thomas O.; Taborsky, Gerald J., Jr.] Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. RP Mundinger, TO (reprint author), Univ Washington, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA 98105 USA. EM mundin@u.washington.edu FU NIH [P30-DK-017047]; Biomedical Laboratory R&D Service of the US Department of Veterans Affairs; US National Institute of Health [R01-DK-050154] FX The studies to determine basal islet expression of BDNF and NGF were performed in part at the Cell Function Analysis Core of the University of Washington's Diabetes Research Center, which is supported by NIH grant no. P30-DK-017047. This work was supported by a Merit Review from the Biomedical Laboratory R&D Service of the US Department of Veterans Affairs and by US National Institute of Health grant no. R01-DK-050154. NR 83 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2016 VL 59 IS 10 BP 2058 EP 2067 DI 10.1007/s00125-016-4026-0 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DV7NI UT WOS:000383122800003 PM 27342407 ER PT J AU Fall, T Salihovic, S Brandmaier, S Nowak, C Ganna, A Gustafsson, S Broeckling, CD Prenni, JE Kastenmuller, G Peters, A Magnusson, PK Wang-Sattler, R Giedraitis, V Berne, C Gieger, C Pedersen, NL Ingelsson, E Lind, L AF Fall, Tove Salihovic, Samira Brandmaier, Stefan Nowak, Christoph Ganna, Andrea Gustafsson, Stefan Broeckling, Corey D. Prenni, Jessica E. Kastenmueller, Gabi Peters, Annette Magnusson, Patrik K. Wang-Sattler, Rui Giedraitis, Vilmantas Berne, Christian Gieger, Christian Pedersen, Nancy L. Ingelsson, Erik Lind, Lars TI Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes SO DIABETOLOGIA LA English DT Article DE Genetic; Metabolomics; Prediction; Type 2 diabetes ID GENOME-WIDE; LOCI; MELLITUS; INSIGHTS; GLUCOSE; RISK; PREDICTION; BIOLOGY; LIPIDS; KORA AB Aims/hypothesis Identification of novel biomarkers for type 2 diabetes and their genetic determinants could lead to improved understanding of causal pathways and improve risk prediction. Methods In this study, we used data from non-targeted metabolomics performed using liquid chromatography coupled with tandem mass spectrometry in three Swedish cohorts (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1138; Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS], n = 970; TwinGene, n = 1630). Metabolites associated with impaired fasting glucose (IFG) and/or prevalent type 2 diabetes were assessed for associations with incident type 2 diabetes in the three cohorts followed by replication attempts in the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort (n = 855). Assessment of the association of metabolite-regulating genetic variants with type 2 diabetes was done using data from a meta-analysis of genome-wide association studies. Results Out of 5961 investigated metabolic features, 1120 were associated with prevalent type 2 diabetes and IFG and 70 were annotated to metabolites and replicated in the three cohorts. Fifteen metabolites were associated with incident type 2 diabetes in the four cohorts combined (358 events) following adjustment for age, sex, BMI, waist circumference and fasting glucose. Novel findings included associations of higher values of the bile acid deoxycholic acid and monoacylglyceride 18:2 and lower concentrations of cortisol with type 2 diabetes risk. However, adding metabolites to an existing risk score improved model fit only marginally. A genetic variant within the CYP7A1 locus, encoding the rate-limiting enzyme in bile acid synthesis, was found to be associated with lower concentrations of deoxycholic acid, higher concentrations of LDL-cholesterol and lower type 2 diabetes risk. Variants in or near SGPP1, GCKR and FADS1/2 were associated with diabetes-associated phospholipids and type 2 diabetes. Conclusions/interpretation We found evidence that the metabolism of bile acids and phospholipids shares some common genetic origin with type 2 diabetes. Access to research materials Metabolomics data have been deposited in the Metabolights database, with accession numbers MTBLS93 (TwinGene), MTBLS124 (ULSAM) and MTBLS90 (PIVUS). C1 [Fall, Tove; Salihovic, Samira; Nowak, Christoph; Ganna, Andrea; Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol, Box 1115, S-75141 Uppsala, Sweden. [Fall, Tove; Salihovic, Samira; Nowak, Christoph; Ganna, Andrea; Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, Uppsala, Sweden. [Brandmaier, Stefan; Wang-Sattler, Rui; Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Brandmaier, Stefan; Peters, Annette; Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Ganna, Andrea] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Ganna, Andrea] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ganna, Andrea] Harvard Med Sch, Boston, MA USA. [Ganna, Andrea; Magnusson, Patrik K.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Broeckling, Corey D.; Prenni, Jessica E.] Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA. [Prenni, Jessica E.] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Kastenmueller, Gabi] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Bioinformat & Syst Biol, Neuherberg, Germany. [Peters, Annette] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Peters, Annette; Wang-Sattler, Rui; Gieger, Christian] German Ctr Diabet Res DZD, Munich, Germany. [Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Berne, Christian; Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Ingelsson, Erik] Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA. RP Fall, T (reprint author), Uppsala Univ, Dept Med Sci, Mol Epidemiol, Box 1115, S-75141 Uppsala, Sweden.; Fall, T (reprint author), Uppsala Univ, Sci Life Lab, Uppsala, Sweden. EM tove.fall@medsci.uu.se RI Peters, Annette/A-6117-2011; Magnusson, Patrik/C-4458-2017; OI Gieger, Christian/0000-0001-6986-9554; Prenni, Jessica/0000-0002-0337-8450; Wang-Sattler, Rui/0000-0002-8794-8229; Ganna, Andrea/0000-0002-8147-240X; Peters, Annette/0000-0001-6645-0985 FU Swedish Research Council (VR) [2012-1397]; Swedish Heart-Lung Foundation [20140422]; Swedish Diabetes Foundation (Diabetesfonden) [2013-024]; Knut och Alice Wallenberg Foundation; European Research Council (ERC Starting Grant); Family Ernfors Foundation; Uppsala University; Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF); State of Bavaria; Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; EU [HEALTH-2009-2.2.1-3/242114, HEALTH-2013-2.4.2-1/602936]; BMBF FX This study was supported by the Swedish Research Council (VR; grant no. 2012-1397), the Swedish Heart-Lung Foundation (20140422), the Swedish Diabetes Foundation (Diabetesfonden; grant no. 2013-024), the Knut och Alice Wallenberg Foundation, the European Research Council (ERC Starting Grant), the Family Ernfors Foundation and Uppsala University. Genotyping was performed by the SNP&SEQ Technology Platform in Uppsala. The computations were partly performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX.; The KORA study was initiated and financed by the Helmholtz Zentrum Munchen - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. Part of this project was supported by EU FP7 grants HEALTH-2009-2.2.1-3/242114 (Project OPTiMiSE) and HEALTH-2013-2.4.2-1/602936 (Project CarTarDis) and by a grant from the BMBF to the German Center for Diabetes Research (DZD e. V.). NR 42 TC 0 Z9 0 U1 21 U2 22 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2016 VL 59 IS 10 BP 2114 EP 2124 DI 10.1007/s00125-016-4041-1 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DV7NI UT WOS:000383122800010 PM 27406814 ER PT J AU Meier, DT Entrup, L Templin, AT Hogan, MF Mellati, M Zraika, S Hull, RL Kahn, SE AF Meier, Daniel T. Entrup, Leon Templin, Andrew T. Hogan, Meghan F. Mellati, Mahnaz Zraika, Sakeneh Hull, Rebecca L. Kahn, Steven E. TI The S20G substitution in hIAPP is more amyloidogenic and cytotoxic than wild-type hIAPP in mouse islets SO DIABETOLOGIA LA English DT Article DE Amylin; Amyloid; Beta cell; Insulin secretion; Islet; Islet amyloid polypeptide; Toxicity; Type 2 diabetes ID BETA-CELL APOPTOSIS; AMYLIN GENE; POLYPEPTIDE; MUTATION; JAPANESE AB Aims/hypothesis The S20G human islet amyloid polypeptide (hIAPP) substitution is associated with an earlier onset of type 2 diabetes in humans. Studies of synthetic S20G hIAPP in cell-free systems and immortalised beta cells have suggested that this may be due to increased hIAPP amyloidogenicity and cytotoxicity. Thus, using primary islets from mice with endogenous S20G hIAPP expression, we sought to determine whether the S20G gene mutation leads to increased amyloid-induced toxicity, beta cell loss and reduced beta cell function. Methods Islets from mice in which mouse Iapp was replaced with human wild-type or S20G hIAPP were isolated and cultured in vitro under amyloid-forming conditions. Levels of insulin and hIAPP mRNA and protein, amyloid deposition and beta cell apoptosis and area, as well as glucose-stimulated insulin and hIAPP secretion, were quantified. Results Islets expressing S20G hIAPP cultured in 16.7 mmol/l glucose demonstrated increased amyloid deposition and beta cell apoptosis, reduced beta cell area, decreased insulin content and diminished glucose-stimulated insulin secretion, compared with islets expressing wild-type hIAPP. Amyloid deposition and beta cell apoptosis were also increased when S20G islets were cultured in 11.1 mmol/l glucose (the concentration that is thought to be physiological for mouse islets). Conclusions/interpretation S20G hIAPP reduces beta cell number and function, thereby possibly explaining the earlier onset of type 2 diabetes in individuals carrying this gene mutation. C1 [Meier, Daniel T.; Entrup, Leon; Templin, Andrew T.; Hogan, Meghan F.; Mellati, Mahnaz; Zraika, Sakeneh; Hull, Rebecca L.; Kahn, Steven E.] VA Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. [Meier, Daniel T.; Entrup, Leon; Templin, Andrew T.; Hogan, Meghan F.; Mellati, Mahnaz; Zraika, Sakeneh; Hull, Rebecca L.; Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. RP Kahn, SE (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA.; Kahn, SE (reprint author), Univ Washington, Seattle, WA 98195 USA. EM skahn@uw.edu OI Kahn, Steven/0000-0001-7307-9002 FU Department of Veterans Affairs [BX001060]; NIH [DK-017047, DK-007247, DK-080945, DK-088082, DK-098506, DK-107022, HL-007028]; Swiss National Foundation Fellowship; Dick and Julia McAbee Endowed Fellowship in Diabetes from the University of Washington; American Diabetes Association Mentor-Based Fellowship FX This work was supported by the Department of Veterans Affairs grant BX001060 and NIH grants DK-017047, DK-007247, DK-080945, DK-088082, DK-098506, DK-107022 and HL-007028. DTM was supported by a Swiss National Foundation Fellowship and the Dick and Julia McAbee Endowed Fellowship in Diabetes from the University of Washington. ATT was supported by an American Diabetes Association Mentor-Based Fellowship. NR 17 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2016 VL 59 IS 10 BP 2166 EP 2171 DI 10.1007/s00125-016-4045-x PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DV7NI UT WOS:000383122800015 PM 27393137 ER PT J AU Rogus-Pulia, NM Larson, C Mittal, BB Pierce, M Zecker, S Kennelty, K Kind, A Connor, NP AF Rogus-Pulia, Nicole M. Larson, Charles Mittal, Bharat B. Pierce, Marge Zecker, Steven Kennelty, Korey Kind, Amy Connor, Nadine P. TI Effects of Change in Tongue Pressure and Salivary Flow Rate on Swallow Efficiency Following Chemoradiation Treatment for Head and Neck Cancer SO DYSPHAGIA LA English DT Article DE Deglutition; Deglutition disorders; Tongue strength; Saliva; Hyposalivation; Head and neck cancer; Chemoradiation ID NASOPHARYNGEAL CARCINOMA; RANDOMIZED-TRIAL; ORAL-CANCER; DRY MOUTH; XEROSTOMIA; RADIOTHERAPY; STRENGTH; PERFORMANCE; PERCEPTION; RADIATION AB Patients treated with chemoradiation for head and neck cancer frequently develop dysphagia. Tissue damage to the oral tongue causing weakness along with decreases in saliva production may contribute to dysphagia. Yet, effects of these variables on swallowing-related measures are unclear. The purpose of this study was (1) to determine effects of chemoradiation on tongue pressures, as a surrogate for strength, and salivary flow rates and (2) to elucidate relationships among tongue pressures, saliva production, and swallowing efficiency by bolus type. Twenty-one patients with head and neck cancer treated with chemoradiation were assessed before and after treatment and matched with 21 healthy control participants who did not receive chemoradiation. Each participant was given a questionnaire to rate dysphagia symptoms. Videofluoroscopic Evaluation of Swallowing (VFES) was used to determine swallowing efficiency; the Saxon test measured salivary flow rate; and the Iowa Oral Performance Instrument (IOPI) was used for oral tongue maximum and endurance measures. Results revealed significantly lower tongue endurance measures for patients post-treatment as compared to controls (p = .012). Salivary flow rates also were lower compared to pre-treatment (p = .000) and controls (p = .000). Simple linear regression analyses showed that change in salivary flow rate was predictive of change in swallow efficiency measures from pre- to post-treatment for 1 mL thin liquid (p = .017), 3 mL nectar-thick liquid (p = .026), and 3 mL standard barium pudding (p = .011) boluses. Based on these findings, it appears that chemoradiation treatment affects tongue endurance and salivary flow rate, and these changes may impact swallow efficiency. These factors should be considered when planning treatment for dysphagia. C1 [Rogus-Pulia, Nicole M.; Kennelty, Korey; Kind, Amy] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, 2500 Overlook Terrace,Madison GRECC 11G, Madison, WI 53705 USA. [Rogus-Pulia, Nicole M.; Kind, Amy] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA. [Larson, Charles; Zecker, Steven] Northwestern Univ, Dept Commun Sci & Disorders, Frances Searle Bldg, Evanston, IL 60208 USA. [Mittal, Bharat B.] Northwestern Univ, Dept Radiat Oncol, Feinberg Sch Med, Chicago, IL 60611 USA. [Pierce, Marge] Northwestern Mem Hosp, Radiat Oncol, Chicago, IL 60611 USA. [Kennelty, Korey] Univ Wisconsin, Sch Pharm, Madison, WI 53706 USA. [Connor, Nadine P.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Madison, WI 53706 USA. [Connor, Nadine P.] Univ Wisconsin, Dept Commun Sci & Disorders, Madison, WI 53706 USA. RP Rogus-Pulia, NM (reprint author), William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, 2500 Overlook Terrace,Madison GRECC 11G, Madison, WI 53705 USA.; Rogus-Pulia, NM (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA. EM npulia@wisc.edu FU NIA NIH HHS [K23 AG034551] NR 50 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-051X EI 1432-0460 J9 DYSPHAGIA JI Dysphagia PD OCT PY 2016 VL 31 IS 5 BP 687 EP 696 DI 10.1007/s00455-016-9733-7 PG 10 WC Otorhinolaryngology SC Otorhinolaryngology GA DV4ZB UT WOS:000382933400012 PM 27492408 ER PT J AU Konwinski, RR Singh, A Soto, J AF Konwinski, Ryan R. Singh, Ajay Soto, Jorge TI Imaging of lower extremity trauma from Boston Marathon bombing SO EMERGENCY RADIOLOGY LA English DT Article DE Boston Marathon bombing; Blast injury; Shrapnel; Explosion; Fracture ID INJURIES; EXPERIENCE; RADIOLOGY; ISRAEL AB The goal of this study is to describe the imaging features of lower extremity blast injuries in patients encountered in the radiology departments from the Boston Marathon bombings. A total of 115 patients presented to four acute care hospitals on April 15, 2013, 43 of whom presented with lower extremity injuries and were included in this study. The imaging findings of primary, secondary, tertiary, and quaternary blast injuries were evaluated. Forty-one of 43 patients sustained secondary blast injuries to the lower extremities with 31 patients (70 %) having retained shrapnel, seven patients (16 %) having soft tissue lacerations without retained shrapnel, and ten patients (23 %) having lower extremity amputation (7 % double amputees). Eight of these patients (20 %) had lower extremity fractures, and five patients (12 %) had vascular injuries. Two of the 43 patients (5 %) had only tertiary injuries, and five of 43 patients (12 %) were noted to have lower extremity burns, consistent with quaternary blast injury. No primary blast injury occurred in the lower extremities. A vast majority of lower extremity injuries were from secondary blast injury, most commonly from retained shrapnel in 70 % of patients and 23 % of patients sustaining lower extremity amputation. Retained shrapnel in the lower extremity was most commonly ball bearings and pressure cooker fragments, and most injuries affected the leg, followed by the thigh and foot. C1 [Konwinski, Ryan R.; Singh, Ajay] Massachusetts Gen Hosp, Div Emergency Radiol, Dept Radiol, 2 Avery St,32H, Boston, MA 02141 USA. [Soto, Jorge] Boston Med Ctr, Dept Radiol, Boston, MA 02118 USA. RP Singh, A (reprint author), Massachusetts Gen Hosp, Div Emergency Radiol, Dept Radiol, 2 Avery St,32H, Boston, MA 02141 USA. EM mghpartners@yahoo.com NR 12 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1070-3004 EI 1438-1435 J9 EMERG RADIOL JI Emerg. Radiol. PD OCT PY 2016 VL 23 IS 5 BP 433 EP 437 DI 10.1007/s10140-016-1414-1 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DV9FL UT WOS:000383245600002 PM 27272899 ER PT J AU Ramalingam, V Bates, DDB Buch, K Uyeda, J Zhao, KM Storer, LA Roberts, MB Lebedis, CA Soto, JA Anderson, SW AF Ramalingam, Vijay Bates, David D. B. Buch, Karen Uyeda, Jennifer Zhao, Kathy M. Storer, Lindsey A. Roberts, Marisa B. Lebedis, Christina A. Soto, Jorge A. Anderson, Stephan W. TI Diagnosing acute appendicitis using a nonoral contrast CT protocol in patients with a BMI of less than 25 SO EMERGENCY RADIOLOGY LA English DT Article DE Appendicitis; Acute abdomen; Oral contrast; CT; Emergency radiology; Protocols ID NONTRAUMATIC ABDOMINAL-PAIN; ORAL CONTRAST; COMPUTED-TOMOGRAPHY; UNITED-STATES; TIME; EPIDEMIOLOGY AB The objective of this study was to compare the accuracy for the diagnosis of appendicitis in patients presenting to the emergency department (ED) with acute, nontraumatic abdominal pain and a body mass index (BMI) of less than 25 before and after the implementation of a nonoral contrast computed tomography (CT) protocol with intravenous contrast. The IRB approved this HIPAA-compliant retrospective study; informed consent was waived. This study included 736 adult patients with a BMI of less than 25 presenting to our ED with acute, nontraumatic abdominal pain over two distinct 6-month time periods. An oral and intravenous contrast-enhanced protocol was utilized in the first cohort (group A), and an intravenous contrast-enhanced protocol without oral contrast was utilized in the second cohort (group B). Three abdominal fellowship-trained readers retrospectively reviewed all CT studies and electronic medical records, including surgical/pathology reports that served as reference standards. Group A consisted of 359 patients; 41 patients had surgically proven appendicitis. The sensitivity and specificity of the readers for diagnosing appendicitis in group A ranged from 95.2-100 and 98.1-99.5 %, respectively. Group B consisted of 372 patients; 39 had surgically proven appendicitis. The sensitivity and specificity of the readers in group B ranged from 92.0-100 and 98.6-100 %, respectively. There were no statistically significant differences in sensitivity or specificity for CT scans performed in groups A and B. In patients with a BMI of less than 25, an intravenous contrast-enhanced CT protocol without oral contrast demonstrates similar accuracy to an intravenous contrast-enhanced protocol with oral contrast for diagnosing acute appendicitis. C1 [Ramalingam, Vijay; Bates, David D. B.; Lebedis, Christina A.; Soto, Jorge A.; Anderson, Stephan W.] Boston Univ, Dept Radiol, Med Ctr, 820 Harrison Ave,FGH Bldg,3rd Floor, Boston, MA 02118 USA. [Buch, Karen] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Uyeda, Jennifer] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Zhao, Kathy M.] McMaster Univ, Dept Radiol, Hamilton, ON, Canada. [Storer, Lindsey A.] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. [Roberts, Marisa B.] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USA. RP Bates, DDB (reprint author), Boston Univ, Dept Radiol, Med Ctr, 820 Harrison Ave,FGH Bldg,3rd Floor, Boston, MA 02118 USA. EM David.Bates@bmc.org OI Buch, Karen/0000-0001-9579-8921 NR 23 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1070-3004 EI 1438-1435 J9 EMERG RADIOL JI Emerg. Radiol. PD OCT PY 2016 VL 23 IS 5 BP 455 EP 462 DI 10.1007/s10140-016-1421-2 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DV9FL UT WOS:000383245600006 PM 27392572 ER PT J AU Bind, MAC Coull, BA Baccarelli, A Tarantini, L Cantone, L Vokonas, P Schwartz, J AF Bind, Marie-Abele C. Coull, Brent A. Baccarelli, Andrea Tarantini, Letizia Cantone, Laura Vokonas, Pantel Schwartz, Joel TI Distributional changes in gene-specific methylation associated with temperature SO ENVIRONMENTAL RESEARCH LA English DT Article DE Quantile regression; Temperature; DNA methylation; Susceptibility ID C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; LONGITUDINAL DATA; DNA METHYLATION; AIR-TEMPERATURE; TISSUE FACTOR; INFLAMMATION; COAGULATION; RESPONSES; CORONARY AB Temperature has been related to mean differences in DNA methylation. However, heterogeneity in these associations may exist across the distribution of methylation outcomes. This study examined whether the association between three-week averaged of temperature and methylation differs across quantiles of the methylation distributions in nine candidate genes. We measured gene-specific blood methylation repeatedly in 777 elderly men participating in the Normative Aging Study (1999-2010). We fit quantile regressions for longitudinal data to investigate whether the associations of temperature on methylation (expressed as %5mC) varied across the distribution of the methylation outcomes. We observed heterogeneity in the associations of temperature across percentiles of methylation in F3, TLR-2, CRAT, iNOS, and ICAM-1 genes. For instance, an increase in three-week temperature exposure was associated with a longer left-tail of the F3 methylation distribution. A 5 degrees C increase in temperature was associated with a 0.15%5mC (95% confidence interval (CI): -0.27, -0.04) decrease on the 20th quantile of F3 methylation, but was not significantly related to the 80th quantile of this distribution (Estimate:0.06%5mC, 95%Cl: -0.22, 0.35). Individuals with low values of F3, TLR-2, CRAT, and iNOS methylation, as well as a high value of IGAM-1 methylation, may be more susceptible to temperature effects on systemic inflammation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bind, Marie-Abele C.] Harvard Univ, Dept Stat, Fac Arts & Sci, Cambridge, MA 02138 USA. [Coull, Brent A.] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Baccarelli, Andrea; Schwartz, Joel] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Tarantini, Letizia; Cantone, Laura] Univ Milan, Dept Clin Sci & Community Hlth, Ctr Mol & Genet Epidemiol, Milan, Italy. [Tarantini, Letizia; Cantone, Laura] Fdn Ca Granda, IRCCS Osped Maggiore Policlin, Milan, Italy. [Vokonas, Pantel] Boston Univ, Sch Med, VA Boston Healthcare Syst, VA Normat Aging Study, Boston, MA 02118 USA. [Vokonas, Pantel] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Bind, MAC (reprint author), Harvard Univ, Dept Stat, Fac Arts & Sci, Cambridge, MA 02138 USA. OI Cantone, Laura/0000-0003-3660-129X FU Ziff Fund at the Harvard University Center for the Environment, U.S. EPA [RD-827353, RD-832416]; NIEHS [RO1-ES015172, 2RO1-ES015172, R21 AG0H0027, ES014663, ES00002]; Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs FX This work was supported by the Ziff Fund at the Harvard University Center for the Environment, the following U.S. EPA grants RD-827353 and RD-832416; NIEHS grants RO1-ES015172, 2RO1-ES015172, R21 AG0H0027, ES014663, ES00002. The Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts. NR 28 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 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD OCT PY 2016 VL 150 BP 38 EP 46 DI 10.1016/j.envres.2016.05.034 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DV4NU UT WOS:000382903100006 PM 27236570 ER PT J AU John, T Walter, JE Schuetz, C Chen, K Abraham, RS Bonfim, C Boyce, TG Joshi, AY Kang, E Carvalho, BTC Mahajerin, A Nugent, D Puthenveetil, G Soni, A Su, HL Cowan, MJ Notarangelo, L Buchbinder, D AF John, Tami Walter, Jolan E. Schuetz, Catherina Chen, Karin Abraham, Roshini S. Bonfim, Carmem Boyce, Thomas G. Joshi, Avni Y. Kang, Elizabeth Costa Carvalho, Beatriz Tavares Mahajerin, Arash Nugent, Diane Puthenveetil, Geetha Soni, Amit Su, Helen Cowan, Morton J. Notarangelo, Luigi Buchbinder, David TI Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE RAG deficiency; primary immunodeficiency; immune dysregulation; autoimmunity; bone marrow transplantation ID POOR GRAFT FUNCTION; MUTATIONS AB The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency. C1 [John, Tami] CHOC Childrens Hosp, Div Hematol Oncol, 1201 W La Veta Ave, Orange, CA 92868 USA. [Walter, Jolan E.] MassGen Hosp Children, Div Immunol, 55 Fruit St, Boston, MA 02114 USA. [Schuetz, Catherina] Univ Med Ctr Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. [Chen, Karin] Univ Utah, Sch Med, Dept Pediat, Div Allergy Immunol & Rheumatol, 81 Mario Capecchi Dr, Salt Lake City, UT USA. [Abraham, Roshini S.; Joshi, Avni Y.] Mayo Clin, Allergy & Immunol, 200 First St SW, Rochester, MN 55905 USA. [Bonfim, Carmem] Univ Fed Parana, Bone Marrow Transplantat Unit, Rua XV Novembro 1299, BR-80060000 Curitiba, Parana, Brazil. [Boyce, Thomas G.] Vanderbilt Univ, Dept Pediat, Sch Med, Nashville, TN 37232 USA. [Kang, Elizabeth; Su, Helen] NIAID, NIH, Bldg 10CRC,Room 5-3940,10 Ctr Dr,MSC 1456, Bethesda, MD 20892 USA. [Costa Carvalho, Beatriz Tavares] Univ Fed Sao Paulo, Disciplina Alergia Imunol Clin & Reumatol, Sao Paulo, Brazil. [Mahajerin, Arash; Nugent, Diane; Puthenveetil, Geetha; Soni, Amit; Buchbinder, David] CHOC Childrens Hosp, Div Hematol, 1201 W La Veta Ave, Orange, CA 92868 USA. [Cowan, Morton J.] Univ Calif San Francisco, Dept Pediat, Box 1278, San Francisco, CA 94143 USA. [Notarangelo, Luigi] Childrens Hosp Boston, Div Immunol, Karp Bldg,Room 10217,1 Blackfan Circle, Boston, MA 02115 USA. RP John, T (reprint author), CHOC Childrens Hosp, Div Hematol Oncol, 1201 W La Veta Ave, Orange, CA 92868 USA. EM tamidjohn@gmail.com; JEWALTER@partners.org; catharina.schuetz@uniklinik-ulm.de; karin.chen@hsc.utah.edu; Abraham.Roshini@mayo.edu; carmembonfim@gmail.com; Thomas.Boyce@mayo.edu; Joshi.Avni@mayo.edu; ekang@niaid.nih.gov; beacarvalho@terra.com.br; amaharein@choc.org; dnugent@choc.org; gputhenveetil@choc.org; asoni@choc.org; HSU@niaid.nih.gov; Mort.Cowan@ucsf.edu; Luigi.Notarangelo@childrens.harvard.edu; dbuchbinder@choc.org FU Intramural Research Program of the National Institute of Allergy and Infectious Disease (NIAID), National Institute of Health (NIH) FX This work was supported in part by funds from the Intramural Research Program of the National Institute of Allergy and Infectious Disease (NIAID), National Institute of Health (NIH). NR 26 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2016 VL 36 IS 7 BP 725 EP 732 DI 10.1007/s10875-016-0326-x PG 8 WC Immunology SC Immunology GA DV9FS UT WOS:000383246400015 PM 27539235 ER PT J AU Griggs, C Butler, K AF Griggs, Cornelia Butler, Kathryn TI Damage Control and the Open Abdomen: Challenges for the Nonsurgical Intensivist SO JOURNAL OF INTENSIVE CARE MEDICINE LA English DT Review DE damage control surgery; abdominal compartment syndrome; open abdomen; enteroatmospheric fistula ID ABDOMINAL COMPARTMENT SYNDROME; INTESTINAL ISCHEMIA-REPERFUSION; RAISED INTRAABDOMINAL PRESSURE; RESPIRATORY-DISTRESS-SYNDROME; EARLY FASCIAL CLOSURE; TUMOR-NECROSIS-FACTOR; ACTIVATED FACTOR-VII; ACUTE LUNG INJURY; TRAUMA PATIENTS; ENTEROCUTANEOUS FISTULA AB Background: As strategies in acute care surgery focus on damage control to restore physiology, intensivists spanning all disciplines care for an increasing number of patients requiring massive transfusion, temporary abdominal closures, and their sequelae. Objective: To equip the nonsurgical intensivist with evidence-based management principles for patients with an open abdomen after damage control surgery. Data Source: Search of PubMed database and manual review of bibliographies from selected articles. Data Synthesis and Conclusions: Temporary abdominal closure improves outcomes in patients with abdominal compartment syndrome, hemorrhagic shock, and intra-abdominal sepsis but creates new challenges with electrolyte derangement, hypovolemia, malnutrition, enteric fistulas, and loss of abdominal wall domain. Intensive care of such patients mandates attention to resuscitation, sepsis control, and expedient abdominal closure. C1 [Griggs, Cornelia] Massachusetts Gen Hosp, Fruit St, Boston, MA 02114 USA. [Butler, Kathryn] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Griggs, C (reprint author), Massachusetts Gen Hosp, Fruit St, Boston, MA 02114 USA. EM cgriggs@partners.org NR 82 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0885-0666 EI 1525-1489 J9 J INTENSIVE CARE MED JI J. Intensive Care Med. PD OCT PY 2016 VL 31 IS 9 BP 567 EP 576 DI 10.1177/0885066615594352 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA DV5NM UT WOS:000382974600001 PM 26180038 ER PT J AU Rosenthal, MB Alidina, S Friedberg, MW Singer, SJ Eastman, D Li, ZH Schneider, EC AF Rosenthal, Meredith B. Alidina, Shehnaz Friedberg, Mark W. Singer, Sara J. Eastman, Diana Li, Zhonghe Schneider, Eric C. TI Impact of the Cincinnati Aligning Forces for Quality Multi-Payer Patient Centered Medical Home Pilot on Health Care Quality, Utilization, and Costs SO MEDICAL CARE RESEARCH AND REVIEW LA English DT Article DE patient-centered medical home; evaluation; quality; utilization; costs ID ACCOUNTABLE CARE; INTERVENTION; REFORM AB To evaluate the potential for a patient-centered medical home initiative to reduce utilization and cost while improving quality, we examined a natural experiment involving 11 primary care practices in Cincinnati, Ohio, that participated in the Aligning Forces for Quality Multi-Payer Patient Centered Medical Home pilot. Our research design involved difference-in-difference analyses, comparing changes in utilization, costs, and quality between patients attributed to pilot practices compared with those attributed to a matched comparison cohort after 2 years of active engagement by the practices. The Cincinnati pilot was associated with a reduction of ambulatory care-sensitive emergency department visits of approximately 0.7 per 1,000 member months or approximately 22.6% (p = .01). While there was a reduction in total costs of care of $7,679 per 1,000 member months, the difference did not reach statistical significance. After 2 years of the pilot, lipid testing in diabetics had increased by 2.7 percentage points (a 3.3% improvement; p < .0001). Patient-centered medical homes have the potential to improve the quality of care and reduce emergency department use but expectations for cost control in a relatively short time horizon and absent other changes may be unrealistic. C1 [Rosenthal, Meredith B.; Alidina, Shehnaz; Singer, Sara J.; Eastman, Diana; Li, Zhonghe; Schneider, Eric C.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Alidina, Shehnaz; Friedberg, Mark W.; Schneider, Eric C.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Friedberg, Mark W.; Schneider, Eric C.] RAND Corp, Boston, MA USA. [Friedberg, Mark W.; Singer, Sara J.; Schneider, Eric C.] Harvard Med Sch, Boston, MA USA. [Singer, Sara J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rosenthal, MB (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM mrosenth@hsph.harvard.edu OI Schneider, Eric/0000-0002-1132-5084 FU Commonwealth Fund FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support for this research was provided by the Commonwealth Fund. NR 15 TC 2 Z9 2 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-5587 EI 1552-6801 J9 MED CARE RES REV JI Med. Care Res. Rev. PD OCT PY 2016 VL 73 IS 5 BP 532 EP 545 DI 10.1177/1077558715618566 PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DV5FM UT WOS:000382952100002 PM 26612180 ER PT J AU Benzer, JK Mohr, DC Evans, L Young, G Meterko, MM Moore, SC Seibert, MN Osatuke, K Stolzmann, KL White, B Charns, MP AF Benzer, Justin K. Mohr, David C. Evans, Leigh Young, Gary Meterko, Mark M. Moore, Scott C. Seibert, Marjorie Nealon Osatuke, Katerine Stolzmann, Kelly L. White, Bert Charns, Martin P. TI Team Process Variation Across Diabetes Quality of Care Trajectories SO MEDICAL CARE RESEARCH AND REVIEW LA English DT Article DE teams; workload; coordination; primary care; diabetes mellitus; veterans ID CENTERED MEDICAL HOME; RANDOMIZED-CONTROLLED-TRIAL; HEALTH-CARE; THE-LITERATURE; MENTAL MODELS; METAANALYSIS; PERFORMANCE; MANAGEMENT; CLIMATE; BURNOUT AB Conceptual frameworks in health care do not address mechanisms whereby teamwork processes affect quality of care. We seek to fill this gap by applying a framework of teamwork processes to compare different patterns of primary care performance over time. We thematically analyzed 114 primary care staff interviews across 17 primary care clinics. We purposefully selected clinics using diabetes quality of care over 3 years using four categories: consistently high, improving, worsening, and consistently low. Analyses compared participant responses within and between performance categories. Differences were observed among performance categories for action processes (monitoring progress and coordination), transition processes (goal specification and strategy formulation), and interpersonal processes (conflict management and affect management). Analyses also revealed emergent concepts related to psychological and organizational context that were reported to affect team processes. This study is a first step toward a comprehensive model of how teamwork processes might affect quality of care. C1 [Benzer, Justin K.; Mohr, David C.; Evans, Leigh; Meterko, Mark M.; Seibert, Marjorie Nealon; Stolzmann, Kelly L.; White, Bert; Charns, Martin P.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave 152-M, Boston, MA 02130 USA. [Benzer, Justin K.; Mohr, David C.; Evans, Leigh; Meterko, Mark M.; Charns, Martin P.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Benzer, Justin K.] VISN 17 Ctr Excellence Res Returning War Vet, Waco, TX USA. [Young, Gary] Northeastern Univ, Ctr Hlth Policy & Healthcare Res, Boston, MA 02115 USA. [Moore, Scott C.; Osatuke, Katerine] Vet Hlth Adm, Natl Ctr Org Dev, Cincinnati, OH USA. RP Benzer, JK (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave 152-M, Boston, MA 02130 USA. EM justin.benzer@va.gov FU Department of Veterans Affairs, VA Health Services Research Development [CDA 11-246, IIR 05-221] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This material is based on work supported by the Department of Veterans Affairs, VA Health Services Research & Development (CDA 11-246; IIR 05-221). NR 41 TC 0 Z9 0 U1 8 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-5587 EI 1552-6801 J9 MED CARE RES REV JI Med. Care Res. Rev. PD OCT PY 2016 VL 73 IS 5 BP 565 EP 589 DI 10.1177/1077558715617380 PG 25 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DV5FM UT WOS:000382952100004 PM 26670549 ER PT J AU Shin, JA Parkes, A El-Jawahri, A Traeger, L Knight, H Gallagher, ER Temel, JS AF Shin, Jennifer A. Parkes, Amanda El-Jawahri, Areej Traeger, Lara Knight, Helen Gallagher, Emily R. Temel, Jennifer S. TI Retrospective evaluation of palliative care and hospice utilization in hospitalized patients with metastatic breast cancer SO PALLIATIVE MEDICINE LA English DT Article DE Breast neoplasms; neoplasm metastasis; hospitalization; palliative care; hospices ID OF-LIFE CARE; MENTAL-HEALTH; DEATH; PLACE; END; PREDICTORS; CAREGIVERS; SURVIVAL AB Background: Hospitalizations in patients with metastatic cancer occur commonly at the end of life but have not been well-described in individuals with metastatic breast cancer. Aim: To describe the reasons for admission and frequency of palliative care and hospice utilization in hospitalized patients with metastatic breast cancer. Design: This was a retrospective chart review of patients who had their first hospitalization with a diagnosis of metastatic breast cancer between 1 January 2009 and 31 December 2010. To standardize follow-up time, we collected data for 3years post the index hospitalization. Setting/participants: We identified 123 consecutive patients who were hospitalized for the first time with a diagnosis of metastatic breast cancer at a single, tertiary care center. Results: Uncontrolled symptoms accounted for half (50%, 62/123) of index admissions. The majority of patients died during the follow-up period (76%, 94/123), and the median time from index admission to death was 6months (range: 0-34months). Approximately half (53%, 50/94) died in the hospital or within 14days of last hospital discharge, and less than one-third (29%, 27/94) were referred to hospice after their last hospitalization. The inpatient palliative care team evaluated 57% (54/94) of those who died at least once during an admission, but only 17% (16/94) of patients attended an outpatient palliative care appointment. Conclusions: Hospitalized patients with metastatic breast cancer are commonly admitted for uncontrolled symptoms and have a poor prognosis. However, only a minority receive outpatient palliative care or are referred to hospice during their last hospitalization prior to death. C1 [Shin, Jennifer A.; El-Jawahri, Areej; Gallagher, Emily R.; Temel, Jennifer S.] Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Ctr Canc, 55 Fruit St,Lawrence House 308, Boston, MA 02114 USA. [Shin, Jennifer A.; El-Jawahri, Areej; Traeger, Lara; Gallagher, Emily R.; Temel, Jennifer S.] Harvard Med Sch, 55 Fruit St,Lawrence House 308, Boston, MA 02114 USA. [Parkes, Amanda] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Traeger, Lara] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Knight, Helen] Johns Hopkins Sch Med, Baltimore, MD USA. RP Shin, JA (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Ctr Canc, 55 Fruit St,Lawrence House 308, Boston, MA 02114 USA.; Shin, JA (reprint author), Harvard Med Sch, 55 Fruit St,Lawrence House 308, Boston, MA 02114 USA. EM jashin@partners.org FU National Cancer Institute at the National Institutes of Health [R25CA092203]; National Cancer Institute [K24CA181253] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: J.A.S. was supported by the National Cancer Institute at the National Institutes of Health (R25CA092203). J.S.T. was supported by a National Cancer Institute Career Development Award (K24CA181253). NR 24 TC 0 Z9 0 U1 6 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-2163 EI 1477-030X J9 PALLIATIVE MED JI Palliat. Med. PD OCT PY 2016 VL 30 IS 9 BP 854 EP 861 DI 10.1177/0269216316637238 PG 8 WC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medicine, General & Internal SC Health Care Sciences & Services; Public, Environmental & Occupational Health; General & Internal Medicine GA DV6CP UT WOS:000383018800007 PM 26979670 ER PT J AU Ingelfinger, JR Kalantar-Zadeh, K Schaefer, F AF Ingelfinger, Julie R. Kalantar-Zadeh, Kamyar Schaefer, Franz CA World Kidney Day Steering Comm TI Reply to comment on World Kidney Day 2016: averting the legacy of kidney disease-focus on childhood SO PEDIATRIC NEPHROLOGY LA English DT Letter C1 [Ingelfinger, Julie R.] Harvard Med Sch, Massachusetts Gen Hosp Children, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Kalantar-Zadeh, Kamyar] Univ Calif Irvine, Sch Med, Div Nephrol & Hypertens, Irvine, CA 92717 USA. [Schaefer, Franz] Ctr Pediat & Adolescent Med, Div Pediat Nephrol, Neuenheimer Feld 430, D-69120 Heidelberg, Germany. RP Ingelfinger, JR (reprint author), Harvard Med Sch, Massachusetts Gen Hosp Children, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD OCT PY 2016 VL 31 IS 10 BP 1711 EP 1711 DI 10.1007/s00467-016-3388-3 PG 1 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA DU3AI UT WOS:000382082600024 PM 27363712 ER PT J AU Dowdell, S Grassberger, C Sharp, G Paganetti, H AF Dowdell, Stephen Grassberger, Clemens Sharp, Greg Paganetti, Harald TI Fractionated Lung IMPT Treatments: Sensitivity to Setup Uncertainties and Motion Effects Based on Single-Field Homogeneity SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE intensity-modulated proton therapy; interplay effect; setup uncertainties; lung cancer; proton therapy ID MODULATED PROTON THERAPY; SCANNED PARTICLE BEAMS; 4D MONTE-CARLO; RANGE UNCERTAINTIES; TUMOR MOTION; RADIOTHERAPY; INTERPLAY; CANCER; IRRADIATION; ALGORITHMS AB Treatment uncertainties in radiotherapy are either systematic or random. This study evaluates the sensitivity of fractionated intensity-modulated proton therapy (IMPT) lung treatments to systematic and random setup uncertainties. Treatments in which single-field homogeneity was restricted to within +/- 20% (IMPT20%) were compared to full IMPT (IMPTfull) for 10 patients with lung cancer. Four-dimensional Monte Carlo calculations were performed using patient computed tomography geometries with +/- 5 mm systematic or random setup uncertainties applied over a 35 x 2.5Gy(RBE) treatment course. Fifty fractionated courses were simulated for each patient using both IMPT delivery methods with random setup uncertainties applied each fraction and for 3 energy-dependent spot sizes (big spots, sigma approximate to 18-9 mm; intermediate spots, sigma approximate to 11-5 mm; and small spots, sigma approximate to 4-2 mm). These results were compared to Monte Carlo recalculations of the original treatment plan assuming zero setup uncertainty. Results are presented as the difference in equivalent uniform dose (EUD), V-95 (V-95), and target dose homogeneity (D-1-D-99). Over the whole patient cohort, the EUD was 2.0 +/- 0.5 (big spots), 1.9 +/- 0.7 (intermediate spots), and 1.3 +/- 0.4 (small spots) times more sensitive to +/- 5 mm systematic setup uncertainties in IMPTfull compared to IMPT20%. IMPTfull is 1.9 +/- 0.9 (big spots), 2.1 +/- 1.1 (intermediate spots), and 1.5 +/- 0.6 (small spots) times more sensitive to random setup uncertainties than IMPT20% over a fractionated treatment course. The V-95 is at least 1.4 times more sensitive to systematic and random setup uncertainties for IMPTfull for all spot sizes considered. The D-1-D-99 values coincided within uncertainty limits for both IMPT delivery methods for the 3 spot sizes considered, with higher mean values always observed for IMPTfull. The paired t-test indicated that variations observed between IMPTfull and IMPT20% were significantly different for the majority of scenarios. Significantly larger variations were observed in EUD and V-95 in IMPTfull lung treatments in addition to higher mean D-1-D-99. The steep intra-target dose gradients in IMPTfull make it more susceptible to systematic and random setup uncertainties. C1 [Dowdell, Stephen; Grassberger, Clemens; Sharp, Greg; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Dowdell, Stephen; Grassberger, Clemens; Sharp, Greg; Paganetti, Harald] Harvard Med Sch, Boston, MA USA. [Dowdell, Stephen] Shoalhaven Canc Care Ctr, Illawarra Shoalhaven Canc & Haematol Network, Dept Radiat Oncol Med Phys, Nowra, NSW, Australia. RP Dowdell, S (reprint author), Shoalhaven Canc Care Ctr, POB 246, Nowra, NSW 2541, Australia. EM stephen.dowdell@sesiahs.health.nsw.gov.au FU National Cancer Institute [R01CA111590] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by National Cancer Institute Grant R01CA111590. NR 32 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-0346 EI 1533-0338 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD OCT PY 2016 VL 15 IS 5 BP 689 EP 696 DI 10.1177/1533034615595761 PG 8 WC Oncology SC Oncology GA DV8UO UT WOS:000383212400016 PM 26208837 ER PT J AU Boltze, J Ayata, C AF Boltze, Johannes Ayata, Cenk TI Challenges and Controversies in Translational Stroke Research - an Introduction SO TRANSLATIONAL STROKE RESEARCH LA English DT Article ID REPERFUSION; GUIDELINES; FRAMEWORK; RECOVERY; THERAPY; TRIALS C1 [Boltze, Johannes] Fraunhofer Inst Cell Therapy & Immunol, Leipzig, Germany. [Boltze, Johannes] Univ Lubeck, Fraunhofer Res Inst Marine Biotechnol, Lubeck, Germany. [Boltze, Johannes] Univ Lubeck, Inst Med & Marine Biotechnol, Lubeck, Germany. [Ayata, Cenk] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Neurovasc Res Lab, Charlestown, MA USA. [Ayata, Cenk] Harvard Med Sch, Massachusetts Gen Hosp, Stroke Serv, Boston, MA USA. [Ayata, Cenk] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Neurosci Intens Care Unit, Boston, MA USA. [Ayata, Cenk] Neurovasc Res Lab, Neurosci Ctr, 149 13th St, Charlestown, MA 02129 USA. RP Ayata, C (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Neurovasc Res Lab, Charlestown, MA USA.; Ayata, C (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Stroke Serv, Boston, MA USA.; Ayata, C (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Neurosci Intens Care Unit, Boston, MA USA.; Ayata, C (reprint author), Neurovasc Res Lab, Neurosci Ctr, 149 13th St, Charlestown, MA 02129 USA. EM cayata@mgh.harvard.edu NR 27 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD OCT PY 2016 VL 7 IS 5 BP 355 EP 357 DI 10.1007/s12975-016-0492-4 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV4KK UT WOS:000382894300001 PM 27581304 ER PT J AU Hoffmann, U Sheng, HX Ayata, C Warner, DS AF Hoffmann, Ulrike Sheng, Huaxin Ayata, Cenk Warner, David S. TI Anesthesia in Experimental Stroke Research SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Anesthesia; Anesthetic; Brain; Ischemia; Stroke ID CEREBRAL-BLOOD-FLOW; CORTICAL SPREADING DEPRESSION; POSITRON-EMISSION-TOMOGRAPHY; MITOCHONDRIAL PERMEABILITY TRANSITION; EXTRACELLULAR GLUTAMATE CONCENTRATION; SPONTANEOUSLY HYPERTENSIVE-RAT; APOPTOSIS-REGULATING PROTEINS; ISCHEMIC NEURONAL INJURY; TEMPORARY FOCAL ISCHEMIA; NITROUS OXIDE ANESTHESIA AB Anesthetics have enabled major advances in development of experimental models of human stroke. Yet, their profound pharmacologic effects on neural function can confound the interpretation of experimental stroke research. Anesthetics have species-, drug-, and dose-specific effects on cerebral blood flow and metabolism, neurovascular coupling, autoregulation, ischemic depolarizations, excitotoxicity, inflammation, neural networks, and numerous molecular pathways relevant for stroke outcome. Both preconditioning and postconditioning properties have been described. Anesthetics also modulate systemic arterial blood pressure, lung ventilation, and thermoregulation, all of which may interact with the ischemic insult as well as the therapeutic interventions. These confounds present a dilemma. Here, we provide an overview of the anesthetic mechanisms of action and molecular and physiologic effects on factors relevant to stroke outcomes that can guide the choice and optimization of the anesthetic regimen in experimental stroke. C1 [Hoffmann, Ulrike; Sheng, Huaxin; Warner, David S.] Duke Univ, Med Ctr, Dept Anesthesiol, Multidisciplinary Neuroprotect Labs, Box 3094, Durham, NC 27710 USA. [Ayata, Cenk] Massachusetts Gen Hosp, Neurovasc Res Lab, Dept Radiol & Neurol, 149 13th St, Charlestown, MA 02129 USA. [Ayata, Cenk] Harvard Med Sch, 149 13th St, Charlestown, MA 02129 USA. RP Warner, DS (reprint author), Duke Univ, Med Ctr, Dept Anesthesiol, Multidisciplinary Neuroprotect Labs, Box 3094, Durham, NC 27710 USA. EM david.warner@duke.edu FU National Institutes of Health [1R21NS087157-02] FX Supported in part by the National Institutes of Health (1R21NS087157-02). NR 141 TC 2 Z9 2 U1 12 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD OCT PY 2016 VL 7 IS 5 BP 358 EP 367 DI 10.1007/s12975-016-0491-5 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DV4KK UT WOS:000382894300002 PM 27534542 ER PT J AU Kimmel, AD Martin, EG Galadima, H Bono, RS Tehrani, AB Cyrus, JW Henderson, M Freedberg, KA Krist, AH AF Kimmel, April D. Martin, Erika G. Galadima, Hadiza Bono, Rose S. Tehrani, Ali Bonakdar Cyrus, John W. Henderson, Margaret Freedberg, Kenneth A. Krist, Alexander H. TI Clinical outcomes of HIV care delivery models in the US: a systematic review SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE HIV; AIDS; healthcare delivery; specialty care; primary care; primary care redesign; nursing; telemedicine; systematic review ID HUMAN-IMMUNODEFICIENCY-VIRUS; QUALITY-OF-CARE; ANTIRETROVIRAL THERAPY; PHYSICIAN SPECIALIZATION; PERCEIVED BARRIERS; EXPERIENCE; INFECTION; AIDS; SURVIVAL; SUPPRESSION AB With over 1 million people living with HIV, the US faces national challenges in HIV care delivery due to an inadequate HIV specialist workforce and the increasing role of non-communicable chronic diseases in driving morbidity and mortality in HIV-infected patients. Alternative HIV care delivery models, which include substantial roles for advanced practitioners and/or coordination between specialty and primary care settings in managing HIV-infected patients, may address these needs. We aimed to systematically review the evidence on patient-level HIV-specific and primary care health outcomes for HIV-infected adults receiving outpatient care across HIV care delivery models. We identified randomized trials and observational studies from bibliographic and other databases through March 2016. Eligible studies met pre-specified eligibility criteria including on care delivery models and patient-level health outcomes. We considered all available evidence, including non-experimental studies, and evaluated studies for risk of bias. We identified 3605 studies, of which 13 met eligibility criteria. Of the 13 eligible studies, the majority evaluated specialty-based care (9 studies). Across all studies and care delivery models, eligible studies primarily reported mortality and antiretroviral use, with specialty-based care associated with mortality reductions at the clinician and practice levels and with increased antiretroviral initiation or use at the clinician level but not the practice level. Limited and heterogeneous outcomes were reported for other patient-level HIV-specific outcomes (e.g., viral suppression) as well as for primary care health outcomes across all care delivery models. No studies addressed chronic care outcomes related to aging. Limited evidence was available across geographic settings and key populations. As re-design of care delivery in the US continues to evolve, better understanding of patient-level HIV-related and primary care health outcomes, especially across different staffing models and among different patient populations and geographic locations, is urgently needed to improve HIV disease management. C1 [Kimmel, April D.; Galadima, Hadiza; Bono, Rose S.; Tehrani, Ali Bonakdar; Cyrus, John W.; Henderson, Margaret; Krist, Alexander H.] Virginia Commonwealth Univ, Sch Med, Dept Hlth Behav & Policy, 1 Capital Sq,830 E Main St,9th Floor, Richmond, VA 23298 USA. [Martin, Erika G.] Nelson A Rockefeller Inst Govt, Albany, NY USA. [Martin, Erika G.] SUNY Albany, Rockefeller Coll Publ Affairs & Policy, Albany, NY 12222 USA. [Galadima, Hadiza] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Freedberg, Kenneth A.] Harvard Med Sch, Boston, MA USA. [Freedberg, Kenneth A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kimmel, AD (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Hlth Behav & Policy, 1 Capital Sq,830 E Main St,9th Floor, Richmond, VA 23298 USA. EM adkimmel@vcu.edu RI Henderson, Margaret/B-1776-2010; OI Henderson, Margaret/0000-0001-6578-1766; Cyrus, John/0000-0001-5331-5151 FU National Institutes of Health [CTSA award from the National Center for Advancing Translational Sciences] [KL2TR000057]; National Institutes of Health [from the National Institute of Allergy and Infectious Diseases and Health Resources and Services Administration] [R01 AI42006, H97HA27534] FX This research was supported in part by the National Institutes of Health [CTSA award number KL2TR000057 from the National Center for Advancing Translational Sciences and R01 AI42006 from the National Institute of Allergy and Infectious Diseases and Health Resources and Services Administration [H97HA27534]. The funding sources played no role in the study, including study design; collection, analysis, and/or interpretation of data; the writing of the manuscript; and the decision to submit the manuscript for publication. NR 37 TC 1 Z9 1 U1 12 U2 12 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD OCT PY 2016 VL 28 IS 10 BP 1215 EP 1222 DI 10.1080/09540121.2016.1178702 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA DU9PO UT WOS:000382550100001 PM 27177151 ER PT J AU Batchelder, AW Lounsbury, DW Palma, A Carrico, A Pachankis, J Schoenbaum, E Gonzalez, JS AF Batchelder, Abigail W. Lounsbury, David W. Palma, Anton Carrico, Adam Pachankis, John Schoenbaum, Ellie Gonzalez, Jeffrey S. TI Importance of substance use and violence in psychosocial syndemics among women with and at-risk for HIV SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE Syndemic; women; HIV; AIDS; substance use; violence; risk behaviors ID PSYCHOLOGICAL DISTRESS; HEALTH-PROBLEMS; UNITED-STATES; SEX; ABUSE; VULNERABILITY; SYMPTOMS; POVERTY; IMPACT; MEN AB Women in the US continue to be affected by HIV through heterosexual contact. Sexual risk behaviors among women have been associated with a syndemic, or a mutually reinforcing set of conditions, including childhood sexual abuse (CSA), depression, substance use, violence, and financial hardship. Baseline data from a cohort of women with and at-risk for HIV (N=620; 52% HIV+) were analyzed with Poisson regression to assess evidence for additive, independent and interactive effects among syndemic conditions in relation to reported sexual risk behaviors (e.g., unprotected and transactional sex) over the past 6 months, controlling for age and HIV status. The number of syndemic conditions was incrementally associated with more types of sexual risk behaviors. For example, women with all five syndemic conditions reported 72% more types of risk behaviors over 6 months, as compared to women without any syndemic conditions. Compared to women with no syndemic conditions, women with three syndemic conditions reported 34% more and women with one syndemic condition reported 13% more types of risk behaviors. Endorsing substance use in the past 6 months, reporting CSA, and experiencing violence as an adult were independently associated with 49%, 12%, and 8% more types of risk behaviors, respectively compared to women without these conditions. Endorsing both substance use and violence was associated with 27% more types of risk behaviors. These associations were not moderated by HIV status. Understanding specific relationships and interactions are needed to more effectively prioritize limited resources in addressing the psychosocial syndemic associated with sexual risk behavior among women with and at-risk for HIV. Our results identify interrelated psychosocial factors that could be targeted by intervention studies aiming to reduce high-risk sex in this population. C1 [Batchelder, Abigail W.; Gonzalez, Jeffrey S.] Yeshiva Univ, Ferkauf Grad Sch Psychol, Bronx, NY USA. [Batchelder, Abigail W.] Univ Calif San Francisco, Osher Ctr Integrat Med, San Francisco, CA 94143 USA. [Lounsbury, David W.; Palma, Anton; Schoenbaum, Ellie; Gonzalez, Jeffrey S.] Yeshiva Univ, Dept Epidemiol & Populat Hlth, Albert Einstein Coll Med, Bronx, NY USA. [Palma, Anton] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Carrico, Adam] Univ Calif San Francisco, Sch Nursing, Dept Community Hlth Syst, San Francisco, CA 94143 USA. [Pachankis, John] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Gonzalez, Jeffrey S.] Yeshiva Univ, Dept Med Endocrinol, Albert Einstein Coll Med, Bronx, NY USA. RP Batchelder, AW (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Behav Med, 1 Bowdoin Sq,7th Floor, Boston, MA 02115 USA. EM abatchelder@mgh.harvard.edu FU [R01 DA13564]; [T32AT003997]; [T32AI114398] FX This work was in part supported by R01 DA13564 (PI: Ellie Schoenbaum, M.D.), T32AT003997, and T32AI114398. NR 23 TC 0 Z9 0 U1 12 U2 12 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD OCT PY 2016 VL 28 IS 10 BP 1316 EP 1320 DI 10.1080/09540121.2016.1173637 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA DU9PO UT WOS:000382550100016 ER PT J AU Miyazaki, M Arai, Y Myoui, A Gobara, H Sone, M Rosenthal, DI Tsushima, Y Kanazawa, S Ehara, S Endo, K AF Miyazaki, Masaya Arai, Yasuaki Myoui, Akira Gobara, Hideo Sone, Miyuki Rosenthal, Daniel I. Tsushima, Yoshito Kanazawa, Susumu Ehara, Shigeru Endo, Keigo TI Phase I/II Multi-Institutional Study of Percutaneous Radiofrequency Ablation for Painful Osteoid Osteoma (JIVROSG-0704) SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article DE Osteoid osteoma; Radiofrequency ablation; Clinical trial ID COOL-TIP ELECTRODES; FOLLOW-UP; CT; THERMOCOAGULATION; THERMOABLATION; COAGULATION; ENERGY AB This multicenter prospective study was conducted to evaluate the safety and efficacy of percutaneous radiofrequency ablation (RFA) for painful osteoid osteoma (OO). Patients with OO (femur: n = 17, tibia: n = 2, humerus: n = 1, rib: n = 1) were enrolled and treated with RFA. In phase I, nine patients were evaluated for safety. In phase II, 12 patients were accrued, and an intent-to-treat analysis was performed on all patients. The primary endpoint was to evaluate the treatment safety. The secondary endpoint was to evaluate the efficacy for pain relief by the visual analogue scale (VAS) at 4 weeks after RFA. Treatment efficacy was classified as significantly effective (SE) when VAS score decreased by aeyen5 or score was < 2, moderately effective when VAS score decreased by < 5-aeyen2 and score was aeyen2, and not effective (NE) when VAS score decreased by < 2 or score was increased. Cases where the need for analgesics increased after treatment were also NE. RFA procedures were completed in all patients. Minor adverse effects (AEs) were observed as 4.8-14.3 % in 12 patients, and no major AEs were observed. Mean VAS score was 7.1 before treatment, 1.6 at 1 week, 0.3 at 4 weeks, and 0.2 at 3 months. All procedures were classified as SE. Pain recurrence was not noted in any patient during follow-up (mean: 15.1 months). RFA is a safe, highly effective, and fast-acting treatment for painful extraspinal OO. Future studies with a greater number of patients are needed. C1 [Miyazaki, Masaya; Tsushima, Yoshito; Endo, Keigo] Gunma Univ Hosp, Dept Intervent Radiol, 3-39-15 Showa Machi, Maebashi, Gunma 3718511, Japan. [Miyazaki, Masaya; Tsushima, Yoshito; Endo, Keigo] Gunma Univ Hosp, Clin Ultrasound Ctr, 3-39-15 Showa Machi, Maebashi, Gunma 3718511, Japan. [Arai, Yasuaki; Sone, Miyuki] Natl Ctr Hosp, Div Diagnost Radiol, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan. [Myoui, Akira] Osaka Univ Hosp, Med Ctr Translat Res, 2-15 Yamadaoka, Suita, Osaka 5650871, Japan. [Gobara, Hideo; Kanazawa, Susumu] Okayama Univ, Dept Radiol, Sch Med, Kita Ku, 2-5-1 Shikatacho, Okayama 7008558, Japan. [Rosenthal, Daniel I.] Harvard Med Sch, Dept Radiol, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Ehara, Shigeru] Iwate Med Univ, Sch Med, Dept Radiol, 19-1 Uchimaru, Morioka, Iwate 0208505, Japan. RP Miyazaki, M (reprint author), Gunma Univ Hosp, Dept Intervent Radiol, 3-39-15 Showa Machi, Maebashi, Gunma 3718511, Japan.; Miyazaki, M (reprint author), Gunma Univ Hosp, Clin Ultrasound Ctr, 3-39-15 Showa Machi, Maebashi, Gunma 3718511, Japan. EM mmiyazak@gunma-u.ac.jp FU Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan [01901625] FX This study was funded by a Health and Labour Sciences Research Grant (Number 01901625) from the Ministry of Health, Labour and Welfare of Japan. NR 24 TC 1 Z9 2 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0174-1551 EI 1432-086X J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD OCT PY 2016 VL 39 IS 10 BP 1464 EP 1470 DI 10.1007/s00270-016-1438-7 PG 7 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DV1NT UT WOS:000382688600013 PM 27491406 ER PT J AU Rachakonda, G Vu, T Jin, L Samanta, D Datta, PK AF Rachakonda, Girish Vu, Trung Jin, Lin Samanta, Debangshu Datta, Pran K. TI Role of TGF-beta-induced Claudin-4 expression through c-Jun signaling in non-small cell lung cancer SO CELLULAR SIGNALLING LA English DT Article DE Claudin-4; TGF-beta; c-jun; Smad; Migration; Tumorigenicity ID OVARIAN-CANCER; GASTRIC-CARCINOMA; PANCREATIC-CANCER; BARRIER FUNCTION; PROTEINS; OCCLUDIN; IDENTIFICATION; TRANSCRIPTION; PERMEABILITY; METASTASIS AB Claudia-4 has been identified as an integral member of tight junctions and has been found to be upregulated in various types of cancers especially in metastatic cancers. However, the molecular mechanism of the upregulation of Claudin-4 and its role in lung tumorigenesis are unknown. The aim of the present study is to investigate the role of Claudin-4 on migration and tumorigenicity of lung cancer cells and to examine the regulatory effects of TGF-beta on Claudin-4 expression. We have observed that TGF-beta induces the expression of Claudin-4 dramatically in lung cell lines in a time dependent manner. TGF-beta-induced Smad signaling is important for enhancing Claudin-4mRNA level through inducing its promoter activity. Treatment with curcumin, a c-Jun inhibitor, or stable knockdown of c-Jun abrogates TGF-beta-induced Claudin-4 expression suggesting an involvement of the c-Jun pathway. Notably, TGF-beta-induced Claudin-4 expression through c-Jun pathway plays a role in TGF-beta-mediated motility and tumorigenicity of these cells. In support of these observations, we have uncovered that Claudin-4 is upregulated in 14 of 24 (58%) lung tumors when compared with normal lung tissue. This is the first study to show how TGF-beta regulates the expression of Claudin-4 through c-Jun signaling and how this pathway contributes to the migratory and tumorigenic phenotype of lung tumor cells. (C) 2016 Published by Elsevier Inc. C1 [Rachakonda, Girish; Jin, Lin; Samanta, Debangshu; Datta, Pran K.] Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN USA. [Vu, Trung; Jin, Lin; Datta, Pran K.] Univ Alabama Birmingham, Dept Med, Div Hematol & Oncol, UAB Comprehens Canc Ctr, Birmingham, AL 35294 USA. [Jin, Lin; Datta, Pran K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Rachakonda, Girish] Meharry Med Coll, Dept Microbiol & Immunol, Nashville, TN 37208 USA. [Samanta, Debangshu] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Datta, PK (reprint author), Univ Alabama Birmingham, Dept Med, Div Hematol & Oncol, 1824 6th Ave South,WTI 520C, Birmingham, AL 35294 USA. EM prandatta@uabmc.edu FU Department of Veterans Affairs Merit Review Award [R01 CA95195]; Faculty Development Award from UAB Comprehensive Cancer Center [P30 CA013148] FX This work was supported by R01 CA95195, Department of Veterans Affairs Merit Review Award, and a Faculty Development Award from UAB Comprehensive Cancer Center, P30 CA013148 (to P.K.D.). NR 32 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD OCT PY 2016 VL 28 IS 10 BP 1537 EP 1544 DI 10.1016/j.cellsig.2016.07.006 PG 8 WC Cell Biology SC Cell Biology GA DU6UW UT WOS:000382351100010 PM 27424491 ER PT J AU Melrose, RJ Brommelhoff, JA Narvaez, T Natta, L Jones, HHR Sakhai, S Wong, L Curtis, S Horning, SM AF Melrose, Rebecca J. Brommelhoff, Jessica A. Narvaez, Theresa Natta, Laura Jones, Hannah H. Riskin Sakhai, Sherwin Wong, Lawrence Curtis, Stacey Horning, Sheena M. TI The use of Information and Communication technology when completing instrumental activities of daily living SO COMPUTERS IN HUMAN BEHAVIOR LA English DT Article DE ICT; Technology; Activities of daily living; Aging; Memory ID MILD COGNITIVE IMPAIRMENT; ACQUIRED BRAIN-INJURY; EVERYDAY TECHNOLOGY; OLDER-ADULTS; ALZHEIMERS-DISEASE; COMPUTER USE; QUESTIONNAIRE; DIFFICULTIES; DISABILITIES; ASSOCIATION AB Purpose of the study: An important aspect of cognitive assessment is inquiry of the patient's ability to manage instrumental activities of daily living (IADLs), including finances, medication, and transportation. Information and Communication technology (ICT, e.g. smartphones, computers) has become increasingly prevalent in American culture. We aimed to characterize what IADLs were being completed with ICI, and what factors predict ICT use to manage IADLs. Design and methods: We administered a self-report survey to 505 Veterans seeking care at the VA Greater Los Angeles Healthcare System. Results: Seventy percent reported regular ICI use. Of ICT users, 76% reported use for finances, 86% for shopping, 72% for health management, 75% for transportation, and 97% for communication. Logistic regression was used to identify predictors of high ICT use. Longer duration of computer use was significant in all models. Younger age, higher education, and better self-reported memory were associated with greater use for a subset of IADLs. Veterans with more health problems were more likely to use ICT to manage their healthcare. Implications: These findings suggest that Veterans are using ICT to support IADLs. It appears appropriate for clinicians to incorporate questions about ICT use into IADLs assessment, which may assist in detecting subtle changes to day to day functioning and improve the accurate diagnosis of cognitive disorders. Published by Elsevier Ltd. C1 [Melrose, Rebecca J.; Brommelhoff, Jessica A.; Narvaez, Theresa; Natta, Laura; Jones, Hannah H. Riskin; Sakhai, Sherwin; Wong, Lawrence; Curtis, Stacey; Horning, Sheena M.] West LA VA, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd 116AE, Los Angeles, CA USA. [Melrose, Rebecca J.; Brommelhoff, Jessica A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Horning, Sheena M.] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA. RP Melrose, RJ (reprint author), West LA VA, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd 116AE, Los Angeles, CA USA. EM Rebecca.Melrose@va.gov; Jbrommelhoff@gmail.com; Theresa.Narvaez@va.gov; Lnatta@altamirarecovery.com; Hannah.Riskin-Jones@va.gov; Ssakhai@paloaltou.edu; Lawrence.Wong@va.gov; Stacey.Curtis@va.gov; SheenaHorning@gmail.com OI Horning, Sheena/0000-0002-9704-0070 FU VA Career Development Award FX R. Melrose was supported by a VA Career Development Award. NR 38 TC 0 Z9 0 U1 8 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0747-5632 EI 1873-7692 J9 COMPUT HUM BEHAV JI Comput. Hum. Behav. PD OCT PY 2016 VL 63 BP 471 EP 479 DI 10.1016/j.chb.2016.05.045 PG 9 WC Psychology, Multidisciplinary; Psychology, Experimental SC Psychology GA DU6QP UT WOS:000382340000051 ER PT J AU Jacobs, AS Schwartz, MD Valdimarsdottir, H Nusbaum, RH Hooker, GW DeMarco, TA Heinzmann, JE McKinnon, W McCormick, SR Davis, C Forman, AD Lebensohn, AP Dalton, E Tully, DM Graves, KD Similuk, M Kelly, S Peshkin, BN AF Jacobs, Aryana S. Schwartz, Marc D. Valdimarsdottir, Heiddis Nusbaum, Rachel H. Hooker, Gillian W. DeMarco, Tiffani A. Heinzmann, Jessica E. McKinnon, Wendy McCormick, Shelley R. Davis, Claire Forman, Andrea D. Lebensohn, Alexandra Perez Dalton, Emily Tully, Diana Moglia Graves, Kristi D. Similuk, Morgan Kelly, Scott Peshkin, Beth N. TI Patient and genetic counselor perceptions of in-person versus telephone genetic counseling for hereditary breast/ovarian cancer SO FAMILIAL CANCER LA English DT Article DE BRCA1/BRCA2; Genetic counseling; Patient satisfaction; Telephone counseling ID AFRICAN-AMERICAN WOMEN; RISK-ASSESSMENT; FAMILY PHYSICIANS; BREAST; COMMUNICATION; TRIAL; SUSCEPTIBILITY; VALIDATION; DELIVERY; STRESS AB Telephone genetic counseling (TC) for high-risk women interested in BRCA1/2 testing has been shown to yield positive outcomes comparable to usual care (UC; in-person) genetic counseling. However, little is known about how genetic counselors perceive the delivery of these alternate forms of genetic counseling. As part of a randomized trial of TC versus UC, genetic counselors completed a 5-item genetic counselor process questionnaire (GCQ) assessing key elements of pre-test sessions (information delivery, emotional support, addressing questions and concerns, tailoring of session, and facilitation of decision-making) with the 479 female participants (TC, N = 236; UC, N = 243). The GCQ scores did not differ for TC vs. UC sessions (t (477) = 0.11, p = 0.910). However, multivariate analysis showed that participant race/ethnicity significantly predicted genetic counselor perceptions (beta = 0.172, p < 0.001) in that the GCQ scores were lower for minorities in TC and UC. Exploratory analyses suggested that GCQ scores may be associated with patient preference for UC versus TC (t (79) = 2.21, p = 0.030). Additionally, we found that genetic counselor ratings of session effectiveness were generally concordant with patient perceptions of the session. These data indicate that genetic counselors perceive that key components of TC can be delivered as effectively as UC, and that these elements may contribute to specific aspects of patient satisfaction. However, undefined process differences may be present which account for lower counselor perceptions about the effectiveness of their sessions with minority women (i.e., those other than non-Hispanic Whites). We discuss other potential clinical and research implications of our findings. C1 [Jacobs, Aryana S.; Schwartz, Marc D.; Graves, Kristi D.; Peshkin, Beth N.] Georgetown Univ, Jess & Mildred Fisher Ctr Hereditary Canc & Clin, Lombardi Comprehens Canc Ctr, Dept Oncol,Med Ctr, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. [Valdimarsdottir, Heiddis] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Valdimarsdottir, Heiddis] Reykjavik Univ, Dept Psychol, Reykjavik, Iceland. [Nusbaum, Rachel H.; Tully, Diana Moglia] GeneDx, Gaithersburg, MD USA. [Hooker, Gillian W.] NextGxDx Inc, Franklin, TN USA. [DeMarco, Tiffani A.] Inova Hlth Syst, Inova Translat Med Inst, Canc Genet Counseling Program, Falls Church, VA USA. [Heinzmann, Jessica E.] Atlant Hlth Syst, Carol G Simon Canc Ctr, Summit, NJ USA. [McKinnon, Wendy] Univ Vermont, Familial Canc Program, Ctr Canc, Burlington, VT USA. [McCormick, Shelley R.] Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA 02114 USA. [Davis, Claire] Sarah Lawrence Coll, Joan H Marks Grad Program Human Genet, Yonkers, NY USA. [Forman, Andrea D.] Fox Chase Canc Ctr, Dept Clin Genet, Risk Assessment Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Lebensohn, Alexandra Perez] Stanford Womens Canc Ctr, Stanford Healthcare, Stanford, CA USA. [Dalton, Emily] Ambry Genet, Aliso Viejo, CA USA. [Similuk, Morgan] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kelly, Scott] George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. RP Peshkin, BN (reprint author), Georgetown Univ, Jess & Mildred Fisher Ctr Hereditary Canc & Clin, Lombardi Comprehens Canc Ctr, Dept Oncol,Med Ctr, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. EM peshkinb@georgetown.edu FU National Cancer Institute [R01 CA108933, P30 CA051008]; Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research FX The study was supported by Grants R01 CA108933 and P30 CA051008 from the National Cancer Institute and by the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 41 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 EI 1573-7292 J9 FAM CANCER JI Fam. Cancer PD OCT PY 2016 VL 15 IS 4 BP 529 EP 539 DI 10.1007/s10689-016-9900-x PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA DV1LB UT WOS:000382681500005 PM 26969308 ER PT J AU Ford, J Palzes, V Roach, BJ Fryer, SL Mathalon, DH AF Ford, Judith Palzes, Vanessa Roach, Brian J. Fryer, Susanna L. Mathalon, Daniel H. TI Action-based predictive coding is abnormal in psychotic patients SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 18th World Congress of Psychophysiology of the International Organization of Psychophysiology (IOP) CY AUG 31-SEP 04, 2016 CL Havana, CUBA SP Int Org Psychophysiol C1 [Ford, Judith; Roach, Brian J.; Fryer, Susanna L.; Mathalon, Daniel H.] UCSF, San Francisco, CA USA. [Ford, Judith; Palzes, Vanessa; Roach, Brian J.; Fryer, Susanna L.; Mathalon, Daniel H.] San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD OCT PY 2016 VL 108 SI SI MA 463 BP 13 EP 13 DI 10.1016/j.ijpsycho.2016.07.045 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DU7QC UT WOS:000382408700044 ER PT J AU Mathalon, DH Hamilton, H Bachman, P Belger, A Carrion, R Duncan, E Johannesen, J Niznikiewicz, M Cadenhead, K AF Mathalon, Daniel H. Hamilton, Holly Bachman, Peter Belger, Aysenil Carrion, Ricardo Duncan, Erica Johannesen, Jason Niznikiewicz, Margaret Cadenhead, Kristin CA Consortium NAPLS TI Mismatch Negativity and Repetition Positivity Predict Transition to Psychosis in Clinical High Risk Individuals SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 18th World Congress of Psychophysiology of the International Organization of Psychophysiology (IOP) CY AUG 31-SEP 04, 2016 CL Havana, CUBA SP Int Org Psychophysiol C1 [Mathalon, Daniel H.; Hamilton, Holly] Univ CA San Francisco, San Francisco, CA 94117 USA. [Mathalon, Daniel H.; Hamilton, Holly] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Bachman, Peter] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Belger, Aysenil] Univ N Carolina, Chapel Hill, NC 27599 USA. [Carrion, Ricardo] Hillside Hosp, Glen Oaks, NY 11004 USA. [Duncan, Erica] Emory Univ, Atlanta, GA 30322 USA. [Johannesen, Jason] Yale Univ, New Haven, CT 06520 USA. [Niznikiewicz, Margaret] Harvard Univ, Boston, MA 02115 USA. [Cadenhead, Kristin; Consortium NAPLS] Univ CA San Diego, San Diego, CA 92093 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD OCT PY 2016 VL 108 SI SI MA 471 BP 37 EP 37 DI 10.1016/j.ijpsycho.2016.07.122 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DU7QC UT WOS:000382408700122 ER PT J AU Quiroz, YT Tobon, C Munoz, C Deason, R McKeever, J Velilla, L Arboleda-Velasquez, J Lopera, F Budson, A AF Quiroz, Yakeel T. Tobon, Carlos Munoz, Claudia Deason, Rebecca McKeever, Joshua Velilla, Lina Arboleda-Velasquez, Joseph Lopera, Francisco Budson, Andrew TI Neural Correlates of Recognition Memory in Preclinical Young-Onset Dementia SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 18th World Congress of Psychophysiology of the International Organization of Psychophysiology (IOP) CY AUG 31-SEP 04, 2016 CL Havana, CUBA SP Int Org Psychophysiol C1 [Quiroz, Yakeel T.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Quiroz, Yakeel T.; Tobon, Carlos; Munoz, Claudia; Velilla, Lina; Lopera, Francisco] Grp Neurociencias Antioquia, Medellin, Colombia. [Deason, Rebecca] Texas State Univ, San Marcos, TX USA. [McKeever, Joshua] VA Palo Alto, Palo Alto, CA USA. [Arboleda-Velasquez, Joseph] Schepens Eye Res Inst, Boston, MA USA. [Budson, Andrew] Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD OCT PY 2016 VL 108 SI SI MA 485 BP 51 EP 51 DI 10.1016/j.ijpsycho.2016.07.170 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DU7QC UT WOS:000382408700170 ER PT J AU Ho, ECY Truccolo, W AF Ho, E. C. Y. Truccolo, Wilson TI Interaction between synaptic inhibition and glial-potassium dynamics leads to diverse seizure transition modes in biophysical models of human focal seizures SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE Focal epilepsy; Seizure dynamics; Spike-wave discharges; Gamma oscillations ID SINGLE-NEURON DYNAMICS; GAMMA-OSCILLATIONS; SPREADING DEPRESSION; EPILEPTIC CORTEX; NETWORK MODEL; FIRE NEURONS; SYNCHRONY; FLUCTUATIONS; PROPAGATION; INTERNEURON AB How focal seizures initiate and evolve in human neocortex remains a fundamental problem in neuroscience. Here, we use biophysical neuronal network models of neocortical patches to study how the interaction between inhibition and extracellular potassium ([K (+)] (o) ) dynamics may contribute to different types of focal seizures. Three main types of propagated focal seizures observed in recent intracortical microelectrode recordings in humans were modelled: seizures characterized by sustained (similar to 30-60 Hz) gamma local field potential (LFP) oscillations; seizures where the onset in the propagated site consisted of LFP spikes that later evolved into rhythmic (similar to 2-3 Hz) spike-wave complexes (SWCs); and seizures where a brief stage of low-amplitude fast-oscillation (similar to 10-20 Hz) LFPs preceded the SWC activity. Our findings are fourfold: (1) The interaction between elevated [K (+)] (o) (due to abnormal potassium buffering by glial cells) and the strength of synaptic inhibition plays a predominant role in shaping these three types of seizures. (2) Strengthening of inhibition leads to the onset of sustained narrowband gamma seizures. (3) Transition into SWC seizures is obtained either by the weakening of inhibitory synapses, or by a transient strengthening followed by an inhibitory breakdown (e.g. GABA depletion). This reduction or breakdown of inhibition among fast-spiking (FS) inhibitory interneurons increases their spiking activity and leads them eventually into depolarization block. Ictal spike-wave discharges in the model are then sustained solely by pyramidal neurons. (4) FS cell dynamics are also critical for seizures where the evolution into SWC activity is preceded by low-amplitude fast oscillations. Different levels of elevated [K (+)] (o) were important for transitions into and maintenance of sustained gamma oscillations and SWC discharges. Overall, our modelling study predicts that the interaction between inhibitory interneurons and [K (+)] (o) glial buffering under abnormal conditions may explain different types of ictal transitions and dynamics during propagated seizures in human focal epilepsy. C1 [Ho, E. C. Y.; Truccolo, Wilson] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Ho, E. C. Y.; Truccolo, Wilson] Brown Univ, Inst Brain Sci, Providence, RI 02912 USA. [Truccolo, Wilson] US Dept Vet Affairs, Ctr Neurorestorat & Neurotechnol, Providence, RI 02903 USA. RP Ho, ECY; Truccolo, W (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA.; Ho, ECY; Truccolo, W (reprint author), Brown Univ, Inst Brain Sci, Providence, RI 02912 USA.; Truccolo, W (reprint author), US Dept Vet Affairs, Ctr Neurorestorat & Neurotechnol, Providence, RI 02903 USA. EM ernest_ho@brown.edu; wilson_truccolo@brown.edu FU National Institute of Neurological Disorders and Stroke (NINDS) [R01NS079533]; U.S. Department of Veterans Affairs, Merit Review Award [I01RX000668]; Pablo J. Salame '88 Goldman Sachs endowed Assistant Professorship of Computational Neuroscience FX This research was supported by: the National Institute of Neurological Disorders and Stroke (NINDS), grant R01NS079533; the U.S. Department of Veterans Affairs, Merit Review Award I01RX000668; and the Pablo J. Salame '88 Goldman Sachs endowed Assistant Professorship of Computational Neuroscience. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 66 TC 1 Z9 1 U1 7 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 EI 1573-6873 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD OCT PY 2016 VL 41 IS 2 BP 225 EP 244 DI 10.1007/s10827-016-0615-7 PG 20 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA DU7ON UT WOS:000382404600007 ER PT J AU Cole, AP Leow, JJ Chang, SL Chung, BI Meyer, CP Kibel, AS Menon, M Nguyen, PL Choueiri, TK Reznor, G Lipsitz, SR Sammon, JD Sun, M Trinh, QD AF Cole, Alexander P. Leow, Jeffrey J. Chang, Steven L. Chung, Benjamin I. Meyer, Christian P. Kibel, Adam S. Menon, Mani Nguyen, Paul L. Choueiri, Toni K. Reznor, Gally Lipsitz, Stuart R. Sammon, Jesse D. Sun, Maxine Quoc-Dien Trinh TI Surgeon and Hospital Level Variation in the Costs of Robot-Assisted Radical Prostatectomy SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; prostatectomy; robotic surgical procedures; health care costs; health services ID UNITED-STATES; HEALTH-CARE; GEOGRAPHIC-VARIATION; CANCER; VOLUME; TECHNOLOGIES; ADOPTION; DISEASE; RISK AB Purpose: We assessed surgeon and hospital level variation in robot-assisted radical prostatectomy costs and predictors of high and low cost surgery. Materials and Methods: The study population consisted of a weighted sample of 291,015 men who underwent robot-assisted radical prostatectomy for prostate cancer by 667 surgeons at 197 U.S. hospitals from 2003 to 2013. We evaluated 90-day direct hospital costs (2014 USD) in the Premier Hospital Database. High costs per robot-assisted radical prostatectomy were those above the 90th percentile and low costs were those below the 10th percentile. Results: Mean hospital cost per robot-assisted radical prostatectomy was $11,878 (95% CI $11,804-$11,952). Mean cost was $2,837 (95% CI $2,805-$2,869) in the low cost group vs $25,906 (95% CI $24,702-$25,490) in the high cost group. Nearly a third of the variation in robot-assisted radical prostatectomy cost was attributable to hospital characteristics and more than a fifth was attributable to surgeon characteristics (R-squared 30.43% and 21.25%, respectively). High volume surgeons and hospitals (90th percentile or greater) had decreased odds of high cost surgery (surgeons: OR 0.24, 95% CI 0.11-0.54; hospitals: OR 0.105, 95% CI 0.02-0.46). The performance of robot-assisted radical prostatectomy at a high volume hospital was associated with increased odds of low cost robot-assisted radical prostatectomy (OR 839, 95% CI 122-greater than 999). Conclusions: This study provides insight into the role of surgeons and hospitals in robot-assisted radical prostatectomy costs. Given the substantial variability, identifying and remedying the root cause of outlier costs may yield substantial benefits. C1 [Cole, Alexander P.; Chang, Steven L.; Kibel, Adam S.; Quoc-Dien Trinh] Brigham & Womens Hosp, Div Urol, 75 Francis St, Boston, MA 02115 USA. [Leow, Jeffrey J.; Chang, Steven L.; Meyer, Christian P.; Reznor, Gally; Lipsitz, Stuart R.; Sun, Maxine; Quoc-Dien Trinh] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, 75 Francis St, Boston, MA 02115 USA. [Nguyen, Paul L.] Harvard Med Sch, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 45 Francis St,ASB 2-3, Boston, MA 02115 USA. [Choueiri, Toni K.] Harvard Med Sch, Dana Farber Brigham & Womens Canc Ctr, Lank Ctr Genitourinary Oncol, 45 Francis St,ASB 2-3, Boston, MA 02115 USA. [Chung, Benjamin I.] Stanford Univ, Med Ctr, Dept Urol, Stanford, CA 94305 USA. [Menon, Mani; Sammon, Jesse D.] Henry Ford Hlth Syst, Vattikuti Urol Inst, Detroit, MI USA. RP Trinh, QD (reprint author), Harvard Med Sch, Brigham & Womens Hosp, 45 Francis St,ASB 2-3, Boston, MA 02115 USA. EM trinh.qd@gmail.com FU Vattikuti Urology Institute FX Supported by an unrestricted educational grant from the Vattikuti Urology Institute. NR 28 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD OCT PY 2016 VL 196 IS 4 BP 1090 EP 1095 DI 10.1016/j.juro.2016.04.087 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DV1ZL UT WOS:000382720500038 PM 27157376 ER PT J AU Sternberg, KM Pais, VM Larson, T Han, J Hernandez, N Eisner, B AF Sternberg, Kevan M. Pais, Vernon M., Jr. Larson, Troy Han, Jullet Hernandez, Natalia Eisner, Brian TI Is Hydronephrosis on Ultrasound Predictive of Ureterolithiasis in Patients with Renal Colic? SO JOURNAL OF UROLOGY LA English DT Article DE ureteral calculi; hydronephrosis; ultrasonography; tomography; x-ray computed; diagnostic imaging ID UNENHANCED HELICAL CT; ACUTE FLANK PAIN; COMPUTED-TOMOGRAPHY; URETERAL CALCULI; ULTRASONOGRAPHY; NEPHROLITHIASIS; PASSAGE AB Purpose: Renal ultrasound accurately identifies hydronephrosis but it is less sensitive than computerized tomography for the detection of ureterolithiasis. We investigated whether the presence of hydronephrosis on ultrasound was associated with a ureteral stone in patients who underwent both ultrasound and computerized tomography during the evaluation of acute renal colic. Materials and Methods: We retrospectively reviewed the records of patients from 3 institutions who were evaluated for acute renal colic by both ultrasound and computerized tomography between 2012 and 2015. Patients were included in analysis if ultrasound and computerized tomography were performed on the same day. The presence of ureterolithiasis, stone location and hydronephrosis was reviewed and compared between imaging modalities. Results: Ureteral stones were present in 85 of 144 patients. Ultrasound identified hydronephrosis in 89.8% of patients and a ureteral stone in 25.9%. Computerized tomography identified hydronephrosis in 91.8% of patients and a ureteral stone in 98.8%. In 75.0% of cases the presence or absence of hydronephrosis on ultrasound correctly predicted the presence or absence of a ureteral stone on computerized tomography. Hydronephrosis on ultrasound had a positive predictive value of 0.77 for the presence of a ureteral stone and a negative predictive value of 0.71 for the absence of a ureteral stone. Conclusions: Hydronephrosis on ultrasound did not accurately predict the presence or absence of a ureteral stone on computerized tomography in 25.0% of the patients in this study. Ultrasound is an important tool for evaluating hydronephrosis associated with renal colic but patients may benefit from other studies to confirm the presence or absence of ureteral stones. C1 [Sternberg, Kevan M.; Larson, Troy] Univ Vermont, Med Ctr, Div Urol, 111 Colchester Ave, Burlington, VT 05401 USA. [Pais, Vernon M., Jr.; Han, Jullet] Dartmouth Hitchcock Med Ctr, Urol Sect, Lebanon, NH 03766 USA. [Hernandez, Natalia; Eisner, Brian] Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, Boston, MA USA. RP Sternberg, KM (reprint author), Univ Vermont, Med Ctr, Div Urol, 111 Colchester Ave, Burlington, VT 05401 USA. EM Kevan.sternberg@uvmhealth.org FU Ravine Group; Boston Scientific; Bard; Retrophin; Olympus FX Financial interest and/or other relationship with Ravine Group, Boston Scientific, Bard, Retrophin and Olympus. NR 18 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD OCT PY 2016 VL 196 IS 4 BP 1149 EP 1152 DI 10.1016/j.juro.2016.04.076 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA DV1ZL UT WOS:000382720500061 PM 27154825 ER PT J AU DeBoer, R Koval, G Mulkey, F Wetzler, M Devine, S Marcucci, G Stone, RM Larson, RA Bloomfield, CD Geyer, S Mullighan, CG Stock, W AF DeBoer, Rebecca Koval, Gregory Mulkey, Flora Wetzler, Meir Devine, Steven Marcucci, Guido Stone, Richard M. Larson, Richard A. Bloomfield, Clara D. Geyer, Susan Mullighan, Charles G. Stock, Wendy TI Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph plus ) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665 SO LEUKEMIA & LYMPHOMA LA English DT Article DE Drug resistance; lymphoid leukemia; prognostication; transcription factor changes ID CHRONIC MYELOID-LEUKEMIA; BCR-ABL; HYPER-CVAD; IMATINIB TREATMENT; THERAPY; IKAROS; GENE; TIME; DASATINIB; RESISTANT AB Recent studies have identified oncogenic lesions in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and ABL1 kinase mutations that confer resistance to tyrosine kinase inhibitors. We sought to determine the prevalence and clinical impact of these lesions in patients on CALGB 10001, a previously reported Phase II study of imatinib, chemotherapy, and hematopoietic cell transplant in adult Ph+ALL. Of the 58 enrolled, 22 relapsed. By direct sequencing, an ABL1 kinase mutation known to induce imatinib resistance was present at relapse in 13 of 20. Using quantitative PCR assays, the mutations were detectable at diagnosis or early during treatment in most (62%) relapsed patients. Aberrations in IKZF1, CDKN2A/B, and PAX5 were assessed in 28 samples using SNP arrays and genomic DNA sequencing. Of these, 22 (79%) had IKZF1 deletion. The combination of IKZF1 deletion and p210 BCR-ABL1 (p<0.0001), high white blood cell count (p=0.021), and minimal residual disease (p=0.013) were associated with worse disease-free survival. C1 [DeBoer, Rebecca; Koval, Gregory; Larson, Richard A.; Stock, Wendy] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Mulkey, Flora] Duke Univ, Med Ctr, Alliance Stat & Data Ctr, Durham, NC USA. [Wetzler, Meir] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Devine, Steven; Bloomfield, Clara D.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Marcucci, Guido] City Hope Natl Med Ctr, Ctr Comprehens Canc, Duarte, CA USA. [Stone, Richard M.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Geyer, Susan] Univ S Florida, Hlth Informat Inst, Tampa, FL USA. [Mullighan, Charles G.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Stock, W (reprint author), Univ Chicago, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM wstock@medicine.bsd.uchicago.edu FU Pew Scholar in the Biomedical Sciences; St. Baldrick's Foundation Scholar award; Alliance for Clinical Trials [U10CA180821, U10CA180882]; NCI [RC4 CA156329]; St Jude Cancer Support Grant [P30 CA021765]; American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital; [U10CA180861]; [CA140158 CA016058-40]; [U24CA196171-01]; [CA: 1-U10-CA180835-01] FX This work was supported by U10CA180821 and U10CA180882 (Alliance for Clinical Trials); CA: 1-U10-CA180835-01 (WS); U10CA180861, CA140158 CA016058-40, U24CA196171-01 (CDB); NCI RC4 CA156329, St Jude Cancer Support Grant P30 CA021765, the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital (CM); Dr Mullighan was supported by a Pew Scholar in the Biomedical Sciences and by a St. Baldrick's Foundation Scholar award. We would also like to acknowledge Jing Ma, Pathology, St. Jude Research Hospital and the Clinical Applications of Core Technology Laboratory of the Hartwell Center for Bioinformatics and Biotechnology at St. Jude Children's Research Hospital. NR 33 TC 3 Z9 3 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD OCT PY 2016 VL 57 IS 10 BP 2298 EP 2306 DI 10.3109/10428194.2016.1144881 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA DT4ZR UT WOS:000381490800009 PM 26892479 ER PT J AU Mandeville, JB Sander, CYM Wey, HY Hooker, JM Hansen, HD Svarer, C Knudsen, GM Rosen, BR AF Mandeville, Joseph B. Sander, Christin Y. M. Wey, Hsiao-Ying Hooker, Jacob M. Hansen, Hanne D. Svarer, Claus Knudsen, Gitte M. Rosen, Bruce R. TI A regularized full reference tissue model for PET neuroreceptor mapping SO NEUROIMAGE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; DOPAMINE TRANSMISSION; HEALTHY HUMANS; DYNAMIC PET; HUMAN BRAIN; BINDING; RECEPTOR; REWARD; PARAMETERS AB The full reference tissue model (FRTM) is a PET analysis framework that includes both free and specifically bound compartments within tissues, together with rate constants defining association and dissociation from the specifically bound compartment. The simplified reference tissue model (SRTM) assumes instantaneous exchange between tissue compartments, and this "1-tissue" approximation reduces the number of parameters and enables more robust mapping of non-displaceable binding potentials. Simulations based upon FRTM have shown that SRTM exhibits biases that are spatially dependent, because biases depend upon binding potentials. In this work, we describe a regularized model (rFRTM) that employs a global estimate of the dissociation rate constant from the specifically bound compartment (k(4)). The model provides an internal calibration for optimizing k(4) through the reference-region outflow rate k(2)', a model parameter that should be a global constant but varies regionally in SRTM. Estimates of k(4) by rFRTM are presented for four PET radioligands. We show that SRTM introduces bias in parameter estimates by assuming an infinite value for k(4), and that rFRTM ameliorates bias with an appropriate choice of k(4). Theoretical considerations and simulations demonstrate that rFRTM reduces bias in non-displaceable binding potentials. A two-parameter reduction of the model (rFRTM(2)) provides robust mapping at a voxel-wise level. With a structure similar to SRTM, the model is easily implemented and can be applied as a PET reference region analysis that reduces parameter bias without substantially altering parameter variance. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mandeville, Joseph B.; Sander, Christin Y. M.; Wey, Hsiao-Ying; Hooker, Jacob M.; Rosen, Bruce R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hansen, Hanne D.; Svarer, Claus; Knudsen, Gitte M.] Rigshosp, Neurobiol Res Unit, DK-2100 Copenhagen, Denmark. [Hansen, Hanne D.; Svarer, Claus; Knudsen, Gitte M.] Univ Copenhagen, DK-2100 Copenhagen, Denmark. RP Mandeville, JB (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM jbm@nmr.mgh.harvard.edu RI Knudsen, Gitte/C-1368-2013 OI Knudsen, Gitte/0000-0003-1508-6866 FU National Institutes of Health [R21NS090169, K99DA037928, R90DA023427, P41EB015896, S10RR026666, S10RR022976, S10RR019933, S10RR017208]; Danish Innovation Foundation through Center for Experimental Medicine Neuropharmacology at the University of Copenhagen [4108-00004B]; Danish Innovation Foundation through Center for Experimental Medicine Neuropharmacology at the University of Rigshospitalet [4108-00004B] FX This research was supported by grants from the National Institutes of Health (R21NS090169, K99DA037928, R90DA023427, P41EB015896, S10RR026666, S10RR022976, S10RR019933, S10RR017208) and the Danish Innovation Foundation (4108-00004B) through the Center for Experimental Medicine Neuropharmacology at the University of Copenhagen and Rigshospitalet. The authors declare no conflict of interest. NR 37 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2016 VL 139 BP 405 EP 414 DI 10.1016/j.neuroimage.2016.06.044 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DT6GX UT WOS:000381583500039 PM 27364474 ER PT J AU Wachinger, C Reuter, M AF Wachinger, Christian Reuter, Martin CA Alzheimers Dis Neuroimaging Initia Australian Imaging Biomarkers Life TI Domain adaptation for Alzheimer's disease diagnostics SO NEUROIMAGE LA English DT Article DE Computer-aided diagnosis; Alzheimer's disease; Classification; Domain adaptation ID MILD COGNITIVE IMPAIRMENT; SURFACE-BASED ANALYSIS; CORTICAL SURFACE; COORDINATE SYSTEM; SHAPE-FEATURES; BASE-LINE; SEGMENTATION; BIOMARKERS; BRAIN; RECONSTRUCTION AB With the increasing prevalence of Alzheimer's disease, research focuses on the early computer-aided diagnosis of dementia with the goal to understand the disease process, determine risk and preserving factors, and explore preventive therapies. By now, large amounts of data from multi-site studies have been made available for developing, training, and evaluating automated classifiers. Yet, their translation to the clinic remains challenging, in part due to their limited generalizability across different datasets. In this work, we describe a compact classification approach that mitigates overfitting by regularizing the multinomial regression with the mixed l(1)/l(2) norm. We combine volume, thickness, and anatomical shape features from MRI scans to characterize neuroanatomy for the three-class classification of Alzheimer's disease, mild cognitive impairment and healthy controls. We demonstrate high classification accuracy via independent evaluation within the scope of the CADDementia challenge. We, furthermore, demonstrate that variations between source and target datasets can substantially influence classification accuracy. The main contribution of this work addresses this problem by proposing an approach for supervised domain adaptation based on instance weighting. Integration of this method into our classifier allows us to assess different strategies for domain adaptation. Our results demonstrate (i) that training on only the target training set yields better results than the naive combination (union) of source and target training sets, and (ii) that domain adaptation with instance weighting yields the best classification results, especially if only a small training component of the target dataset is available. These insights imply that successful deployment of systems for computer-aided diagnostics to the clinic depends not only on accurate classifiers that avoid overfitting, but also on a dedicated domain adaptation strategy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wachinger, Christian] Univ Munich, Dept Child & Adolescent Psychiat, Psychosomat & Psychotherapy, Munich, Germany. [Wachinger, Christian; Reuter, Martin] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Wachinger, Christian; Reuter, Martin] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Wachinger, C (reprint author), Waltherstr 23, D-80337 Munich, Germany. EM christian.wachinger@med.uni-muenchen.de RI Wachinger, Christian/L-7358-2016 OI Wachinger, Christian/0000-0002-3652-1874 FU Humboldt foundation; National Cancer Institute [1K25CA181632-01]; Massachusetts Alzheimer's Disease Research Center [5P50AG005134]; MGH Neurology Clinical Trials Unit; Harvard NeuroDiscovery Center, Genentech [G-40819]; NVIDIA hardware award; A. A. Martinos Center for Biomedical Imaging [P41RR014075, P41EB015896, U24RR021382]; Commonwealth Scientific and Industrial Research Organisation (CSIRO); Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; 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; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; Takeda Pharmaceutical Company; Canadian Institutes of Health Research; [1S10RR023401]; [1S10RR019307]; [1S10RR023043] FX We thank Kayhan Batmanghelich, Polina Golland, Chun Hao Huang, and the CADDementia organizers for interesting discussions. Support for this research was provided in part by the Humboldt foundation, the National Cancer Institute (1K25CA181632-01), the Massachusetts Alzheimer's Disease Research Center (5P50AG005134), the MGH Neurology Clinical Trials Unit, the Harvard NeuroDiscovery Center, Genentech (G-40819), and an NVIDIA hardware award. Further support was provided by the A. A. Martinos Center for Biomedical Imaging (P41RR014075, P41EB015896, U24RR021382), and Shared Instrumentation Grants (1S10RR023401, 1S10RR019307, 1S10RR023043).; Data used in the preparation of this article were obtained from the CADDementia challenge (http://caddementia.grand-challenge.org). Data used in the preparation of this article were obtained from the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) funded by the Commonwealth Scientific and Industrial Research Organisation (CSIRO), which was made available at the ADNI database (www.loni.ucla.edu/ADNI).; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health 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; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare;; 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; Neurotrack Technologies; 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. NR 52 TC 1 Z9 1 U1 4 U2 4 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 OCT 1 PY 2016 VL 139 BP 470 EP 479 DI 10.1016/j.neuroimage.2016.05.053 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DT6GX UT WOS:000381583500045 PM 27262241 ER PT J AU Kim, C Barrett-Connor, E Aroda, VR Mather, KJ Christophi, CA Horton, ES Pi-Sunyer, X Bray, GA Labrie, F Golden, SH AF Kim, Catherine Barrett-Connor, Elizabeth Aroda, Vanita R. Mather, Kieren J. Christophi, Costas A. Horton, Edward S. Pi-Sunyer, Xavier Bray, George A. Labrie, Fernand Golden, Sherita Hill CA Diabet Prevention Program Res Grp TI Testosterone and depressive symptoms among men in the Diabetes Prevention Program SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Testosterone; Androgens; Mood; Glucose-intolerance ID ANDROGEN RECEPTOR POLYMORPHISM; LIFE-STYLE INTERVENTION; MIDDLE-AGED MEN; QUALITY-OF-LIFE; OLDER MEN; BIOAVAILABLE TESTOSTERONE; REPLACEMENT THERAPY; METABOLIC SYNDROME; ELDERLY-MEN; OBESE MEN AB Objective: We examined associations between intensive lifestyle intervention (ILS) and changes in testosterone and associations with mood among middle-aged men. Design: Secondary analysis of men (n = 886) participating in the Diabetes Prevention Program which randomized glucose-intolerant, overweight men to ILS, metformin, or placebo between 1996 and 1999. Main outcome measures: Changes in testosterone between baseline and 1-year follow-up asnd associations of these changes with mood measures (Beck Depression Inventory [BDI-II], Beck Anxiety Inventory [BAI]). Results: Median baseline testosterone was 10.98 nmol/l and 44% (n = 385) had testosterone < 10.41 nmol/l or 300 ng/dl. Testosterone increases were greater among men randomized to ILS vs. metformin vs. placebo (1.15 nmol/l vs. -0.12 nmol/l vs. -0.27 nmol/l, p < 0.001). The association between changes in testosterone and mood differed by study arm (p < 0.001 for interaction); there were no significant associations between changes in testosterone and mood changes among men in the ILS or placebo arms. Among men in the metformin arm, increases in testosterone were significantly associated with decreases in BDI-II (improved depressive symptoms) (beta-coefficient -0.2336, p = 0.0002) indicating a 0.23 decrease in BDI-II for every 1 nmol/l increase in testosterone and decreases in BAI (improved anxiety symptoms) (beta-coefficient -0.2147, p = 0.0014). Similar patterns were observed for bioavailable testosterone. Conclusions: Among overweight middle-aged men with glucose-intolerance, ILS increased endogenous testosterone slightly but without significant improvements in mood. Metformin did not increase testosterone, but among metformin users, testosterone increases were associated with improvements in mood. Thus, interventions that increase endogenous testosterone may not also improve mood. (C) 2016 Published by Elsevier Ltd. C1 [Kim, Catherine] Univ Michigan, Ann Arbor, MI 48109 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, La Jolla, CA 92093 USA. [Aroda, Vanita R.] MedStar Hlth Res Inst, Hyattsville, MD USA. [Mather, Kieren J.] Indiana Univ, Indianapolis, IN 46204 USA. [Christophi, Costas A.] George Washington Univ, Rockville, MD USA. [Horton, Edward S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Pi-Sunyer, Xavier] Columbia Univ, New York, NY USA. [Bray, George A.] Louisiana State Univ, Baton Rouge, LA USA. [Labrie, Fernand] Endoceutics, Quebec City, PQ, Canada. [Golden, Sherita Hill] Johns Hopkins Univ, Baltimore, MD USA. RP Kim, C (reprint author), 2800 Plymouth Rd,Bldg 16,Room 430W, Ann Arbor, MI 48109 USA. EM cathkim@umich.edu FU NIDDK; National institute of Child Health and Human Development; National Institute on Aging; National Eye Institute; National Heart Lung and Blood Institute; Office of Research on Women's Health; National Center for Minority Health and Human Disease; Centers for Disease Control and Prevention; American Diabetes Association; Bristol-Myers Squibb; Parke-Davis; Intramural Research Program; Indian Health Service; [R01 DK072041] FX The study was also supported by R01 DK072041. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding was also provided by the National institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the Office of Research on Women's Health, the National Center for Minority Health and Human Disease, the Centers for Disease Control and Prevention, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP, Lipha (Merck-Sante) provided medication and LifeScan Inc. donated materials during the DPP and DPPOS. NR 46 TC 1 Z9 1 U1 5 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD OCT PY 2016 VL 72 BP 63 EP 71 DI 10.1016/j.psyneuen.2016.06.009 PG 9 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA DV0FY UT WOS:000382594600008 PM 27371769 ER PT J AU Throckmorton, AD Rhodes, DJ Hughes, KS Degnim, AC Dickson-Witmer, D AF Throckmorton, Alyssa D. Rhodes, Deborah J. Hughes, Kevin S. Degnim, Amy C. Dickson-Witmer, Diana TI Dense Breasts: What Do Our Patients Need to Be Told and Why? SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID MAMMOGRAPHIC-DENSITY; CANCER RISK; DIGITAL MAMMOGRAPHY; NOTIFICATION LEGISLATION; PREVENTION TRIAL; UNITED-STATES; FOLLOW-UP; WOMEN; TOMOSYNTHESIS; TAMOXIFEN AB More than 50 % of states have state-mandated density notification for patients with heterogeneously or extremely dense breasts. Increased breast density carries a risk of masking a cancer and delaying diagnosis. Supplemental imaging is optional and often recommended for certain patients. There are no evidence-based consensus guidelines for screening patients with density as their only risk factor. Breast cancer risk assessment and breast cancer prevention strategies should be discussed with women with dense breasts. C1 [Throckmorton, Alyssa D.] Vanderbilt Univ, Dept Surg, Nashville, TN 37240 USA. [Throckmorton, Alyssa D.] Baptist Canc Ctr, Memphis, TN USA. [Rhodes, Deborah J.] Mayo Clin, Dept Med, Rochester, MN USA. [Hughes, Kevin S.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Degnim, Amy C.] Mayo Clin, Dept Surg, Rochester, MN USA. [Dickson-Witmer, Diana] Christiana Care Hlth Syst, Helen F Graham Canc Ctr & Res Inst, Newark, DE USA. RP Throckmorton, AD (reprint author), Vanderbilt Univ, Dept Surg, Nashville, TN 37240 USA.; Throckmorton, AD (reprint author), Baptist Canc Ctr, Memphis, TN USA. EM Alyssa.throckmorton@bmg.md NR 72 TC 1 Z9 1 U1 5 U2 5 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 OCT PY 2016 VL 23 IS 10 BP 3119 EP 3127 DI 10.1245/s10434-016-5400-3 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA DU5UA UT WOS:000382277400007 PM 27401446 ER PT J AU Clifford, E Hughes, KS Roberts, M Pirzadeh-Miller, S McLaughlin, SA AF Clifford, Edward Hughes, Kevin S. Roberts, Maegan Pirzadeh-Miller, Sara McLaughlin, Sarah A. TI Assessing, Counseling, and Treating Patients at High Risk for Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID MUTATION CARRIERS; CONTRALATERAL MASTECTOMY; UNCERTAIN SIGNIFICANCE; PMS2 MUTATIONS; BRCA2 MUTATION; LYNCH-SYNDROME; VARIANTS; SURVIVAL; CHEMOPREVENTION; METAANALYSIS AB Identifying patients at high risk of carrying pathogenic variants in genes is a crucial part of providing both accurate counseling and evidence-based treatment recommendations. Current risk assessment models have strengths and weaknesses that may limit their applicability to specific clinical circumstances. Clinicians must have knowledge regarding variations in available models, how they should be used, and what data they can expect from specific models. In addition, indications for genetic testing are expanding, and the adoption of next-generation sequencing has allowed the creation of multigene testing panels. Complex consequences of panel testing have included an increase in the incidence of identifying variants of uncertain significance and the identification of pathogenic variants in genes for which treatment guidelines are not available. Women diagnosed with breast cancer who carry pathogenic variants in genes with proven associations with breast cancer (BRCA1/2) or highly likely associations (PTEN, PALB2) require additional risk assessment to facilitate treatment decisions that will limit in-breast tumor recurrence and contralateral breast cancer. C1 [Clifford, Edward] BaylorScott & White, Dept Surg, Dallas, TX USA. [Hughes, Kevin S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Roberts, Maegan] GeneDx, Genet Counseling, Gaithersburg, MD USA. [Pirzadeh-Miller, Sara] UT Southwestern, Dept Canc Genet, Moncrief Canc Inst, Dallas, TX USA. [McLaughlin, Sarah A.] Mayo Clin, Dept Surg, Jacksonville, FL 32224 USA. RP McLaughlin, SA (reprint author), Mayo Clin, Dept Surg, Jacksonville, FL 32224 USA. EM Mclaughlin.sarah@mayo.edu NR 31 TC 0 Z9 0 U1 7 U2 10 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 OCT PY 2016 VL 23 IS 10 BP 3128 EP 3132 DI 10.1245/s10434-016-5399-5 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA DU5UA UT WOS:000382277400008 PM 27401444 ER PT J AU Plichta, JK Rai, U Tang, R Coopey, SB Buckley, JM Gadd, MA Specht, MC Hughes, KS Taghian, AG Smith, BL AF Plichta, Jennifer K. Rai, Upahvan Tang, Rong Coopey, Suzanne B. Buckley, Julliette M. Gadd, Michele A. Specht, Michelle C. Hughes, Kevin S. Taghian, Alphonse G. Smith, Barbara L. TI Factors Associated with Recurrence Rates and Long-Term Survival in Women Diagnosed with Breast Cancer Ages 40 and Younger SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID DOXORUBICIN PLUS CYCLOPHOSPHAMIDE; SURGICAL ADJUVANT BREAST; CONSERVING THERAPY; RANDOMIZED-TRIALS; PREMENOPAUSAL WOMEN; TUMOR RECURRENCE; LOCAL RECURRENCE; RISK-FACTORS; FOLLOW-UP; STAGE AB Young age at breast cancer diagnosis has been associated with increased risk of recurrence and mortality. We reevaluated this assumption in a large, modern cohort of women diagnosed with breast cancer at age aecurrency sign40 years. We identified women with breast cancer at age aecurrency sign40 years at a single institution from 1996-2008. We assessed locoregional recurrence (LRR), distant recurrence, disease-free survival (DFS), and overall survival (OS), and correlated patient and tumor characteristics with outcomes. We identified 584 women aged aecurrency sign40 years with breast cancer. Median age was 37 years, and median follow-up was 124 months; 61.5 % were stages 0-I and 38.5 % were stages II-III. Overall, 57.4 % had lumpectomies and 42.5 % mastectomies. DFS was 93 % at 5 years and 84.5 % at 10 years. OS was 93 % at 5 years and 86.5 % at 10 years. On multivariate analysis, worse DFS was associated with positive nodes (p = 0.002); worse OS was associated with larger tumor size (p = 0.042). When stratified by lumpectomy versus mastectomy, there were no significant differences in survival or recurrence. For lumpectomy patients, DFS was 96 % at 5 years and 88 % at 10 years; OS was 96 % at 5 years and 89 % at 10 years. For mastectomy patients, DFS was 89.5 % at 5 years and 79 % at 10 years; OS was 90 % at 5 years and 83 % at 10 years. Lumpectomy LRR rates were 1 % at 5 years and 4 % at 10 years. Mastectomy LRR rates were 3.5 % at 5 years and 8.7 % at 10 years. Outcomes for women with breast cancer at age aecurrency sign40 years have improved. Lumpectomy recurrence rates are low, suggesting that lumpectomy is oncologically safe for young breast cancer patients. C1 [Plichta, Jennifer K.; Rai, Upahvan; Tang, Rong; Coopey, Suzanne B.; Buckley, Julliette M.; Gadd, Michele A.; Specht, Michelle C.; Hughes, Kevin S.; Smith, Barbara L.] Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA. [Taghian, Alphonse G.; Smith, Barbara L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Smith, BL (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA.; Smith, BL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM blsmith1@mgh.harvard.edu NR 35 TC 0 Z9 0 U1 7 U2 8 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 OCT PY 2016 VL 23 IS 10 BP 3212 EP 3220 DI 10.1245/s10434-016-5404-z PG 9 WC Oncology; Surgery SC Oncology; Surgery GA DU5UA UT WOS:000382277400020 PM 27406095 ER PT J AU Mamtani, A Gonzalez, JJ Neo, D Slanetz, PJ Houlihan, MJ Herold, CI Recht, A Hacker, MR Sharma, R AF Mamtani, Anita Gonzalez, Julie J. Neo, Dayna Slanetz, Priscilla J. Houlihan, Mary Jane Herold, Christina I. Recht, Abram Hacker, Michele R. Sharma, Ranjna TI Early-Stage Breast Cancer in the Octogenarian: Tumor Characteristics, Treatment Choices, and Clinical Outcomes SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID ELDERLY-PATIENTS; ADJUVANT TRASTUZUMAB; TREATMENT PATTERNS; RANDOMIZED-TRIALS; 15-YEAR SURVIVAL; OLDER PATIENTS; SENTINEL NODE; WOMEN; AGE; CHEMOTHERAPY AB Nodal staging with sentinel node biopsy (SLNB), post-lumpectomy radiotherapy (RT), and endocrine therapy (ET) for estrogen receptor-positive (ER+) tumors is valuable in the treatment of early-stage (stages 1 or 2) breast cancer but used less often for elderly women. This retrospective study investigated women referred for surgical evaluation of biopsy-proven primary early-stage invasive breast cancer from January 2001 to December 2010. Clinicopathologic features, treatment course, and outcomes for women ages 80-89 years and 50-59 years were compared. The study identified 178 eligible women ages 80-89 years and 169 women ages 50-59 years. The elderly women more often had grade 1 or 2 disease (p = 0.003) and ER+ tumors (p = 0.007) and less frequently had undergone adjuvant therapies (all p aecurrency sign 0.001). Lumpectomy was performed more commonly for the elderly (92 vs. 83 %, p = 0.02), and axillary surgery was less commonly performed (46 vs. 96 %; p < 0.001). Fewer elderly women had undergone post-lumpectomy RT (42 vs. 89 %; p < 0.001) and ET for ER+ tumors (72 vs. 95 %; p < 0.001). During the median follow-up period of 56 months for the 80- to 89-year old group and 98 months for the 50- to 59-year-old group, death from breast cancer was similar (4 vs. 5 %; p = 0.5). The two groups respectively experienced 7 versus 6 locoregional recurrences and 11 versus 13 distant recurrences. The octogenarians had disease survivorship similar to that of the younger women despite less frequent use of adjuvant therapies, likely reflecting lower-risk disease features. Whether increased use of axillary surgery, post-lumpectomy RT, and/or ET for ER+ tumors would further improve outcomes is an important area for further study, but treatment should not be deferred solely on the basis of age. C1 [Mamtani, Anita; Gonzalez, Julie J.; Houlihan, Mary Jane; Sharma, Ranjna] Harvard Med Sch, Dept Surg, Beth Israel Deaconess Med Ctr, Breast Serv, Boston, MA 02215 USA. [Neo, Dayna; Hacker, Michele R.] Harvard Med Sch, Dept Obstet & Gynecol, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Slanetz, Priscilla J.] Harvard Med Sch, Dept Radiol, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Herold, Christina I.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Recht, Abram] Harvard Med Sch, Dept Radiat Oncol, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Sharma, R (reprint author), Harvard Med Sch, Dept Surg, Beth Israel Deaconess Med Ctr, Breast Serv, Boston, MA 02215 USA. EM rsharma1@bidmc.harvard.edu FU Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University and its affiliated academic health care centers FX This work was conducted with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and with financial contributions from Harvard University and its affiliated academic health care centers. NR 31 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 OCT PY 2016 VL 23 IS 10 BP 3371 EP 3378 DI 10.1245/s10434-016-5368-z PG 8 WC Oncology; Surgery SC Oncology; Surgery GA DU5UA UT WOS:000382277400041 PM 27364507 ER PT J AU Ligi, D Mosti, G Croce, L Raffetto, JD Mannello, F AF Ligi, Daniela Mosti, Giovanni Croce, Lidia Raffetto, Joseph D. Mannello, Ferdinando TI Chronic venous disease - Part II: Proteolytic biomarkers in wound healing SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Chronic Venous Insufficiency; Wound healing; Glycosaminoglycan; Venous leg ulcer; Matrix metalloproteinase; Tissue inhibitors of metalloproteinase ID MATRIX METALLOPROTEINASE INDUCER; LEG ULCERS; TISSUE INHIBITOR; DIFFERENTIAL EXPRESSION; INFLAMMATORY PATHWAYS; COLLAGENASE-3 MMP-13; ELEVATED EXPRESSION; CONSENSUS STATEMENT; CELL APOPTOSIS; SULODEXIDE AB Venous leg ulcers (VLU) are characterized by sustained proteolytic microenvironment impairing the healing process. Wound fluid (WF) reflect the biomolecular activities occurring within the wound area; however, it is unclear if WF from different healing phases have different proteolytic profiles and how VLU microenvironment affects the wound healing mechanisms. We investigated the proteolytic network of WF from distinct VLU phases, and in WF- and LPS-stimulated THP-1 monocytes treated with glycosaminoglycan sulodexide, a well known therapeutic approach for VLU healing. WF were collected from patients with VLU during inflammatory (Infl) and granulating (Gran) phases. WF and THP-1 supernatants were analyzed for nine matrix metalloproteinases (MMP) and four tissue inhibitors of metalloproteinases (TIMP) by multiplex immunoassays. Our results demonstrated that: 1) WF from Infl VLU contained significantly increased concentrations of MMP-2, MMP-9, MMP-12, TIMP-1, and TIMP-2 compared to Gran WF; 2) WF from Gran VLU showed significantly increased levels of MMP-1, MMP-7, MMP-13, and TIMP-4 compared to Infl WF; 3) LPS- and WF-stimulation of THP-1 cells significantly increased the expression of several MMP compared to untreated cells; 4) Sulodexide treatment of both LPS- and WF-stimulated THP-1 significantly down -regulated the release of several MMPs. Our study provides evidence -based medicine during treatment of patients with VLU. WF from Infl and Gran VLU have different MMP and TIMP signatures, consistent with their clinical state. The modulation of proteolytic pathways in wound microenvironment by glycosaminoglycan sulodexide, provide insights for translating research into clinical practice during VLU therapy. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ligi, Daniela; Croce, Lidia; Mannello, Ferdinando] Univ Carlo Bo, Sect Clin Biochem & Mol Genet, Dept Biomol Sci, Via O Ubaldini 7, I-61029 Urbino, PU, Italy. [Mosti, Giovanni] Barbantinis Clin, Dept Angiol, Via Calcio 2, I-55100 Lucca, Italy. [Raffetto, Joseph D.] VA Boston Healthcare Syst, Div Vasc Surg, West Roxbury, MA USA. [Raffetto, Joseph D.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. RP Mannello, F (reprint author), Univ Carlo Bo, Sect Clin Biochem & Mol Genet, Dept Biomol Sci, Via O Ubaldini 7, I-61029 Urbino, PU, Italy. EM ferdinando.mannello@uniurb.it OI Mannello, Ferdinando/0000-0001-8112-6139 NR 80 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD OCT PY 2016 VL 1862 IS 10 BP 1900 EP 1908 DI 10.1016/j.bbadis.2016.07.011 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DU7RW UT WOS:000382413300006 PM 27460704 ER PT J AU Ligi, D Mosti, G Croce, L Raffetto, JD Mannello, F AF Ligi, Daniela Mosti, Giovanni Croce, Lidia Raffetto, Joseph D. Mannello, Ferdinando TI Chronic venous disease - Part I: Inflammatory biomarkers in wound healing SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Chronic venous insufficiency; Inflammation; Glycosaminoglycan; Sulodexide; Venous leg ulcer; Wound healing ID CHRONIC LEG ULCERS; ADHESION MOLECULES ICAM-1; NECROSIS-FACTOR-ALPHA; GROWTH-FACTORS; DOUBLE-BLIND; EXTRACELLULAR-MATRIX; DERMAL FIBROBLASTS; CYTOKINE LEVELS; TISSUE-REPAIR; SULODEXIDE AB Venous leg ulcers (VLUs) produce wound fluid (WF), as a result of inflammatory processes within the wound. It is unclear if WF from different healing phases of VLU has a peculiar biochemical profile and how VLU microenvironment affects the wound healing mechanisms. This study was conducted to evaluate the cytokine/chemokine profiles in WF from distinct VLU phases, in WF- and LPS-stimulated monocytes and treated with glycosaminoglycan Sulodexide, a therapeutic option for VLU healing. WF and plasma were collected from patients with VLU during active inflammatory (Infl) and granulating (Gran) phases. Demographics, clinical characteristics and pain measurements were evaluated. WF, plasma, and THP-1 supernatants were analyzed for 27 inflammatory mediators by multiplex immunoassay. Our results demonstrated that: 1) pain was significantly increased in patients with Infl compared to Gran VLU; 2) cytokine profile of Infl WF was found to be statistically different from that Gran WF, as well significantly increased respect to plasma; 3) LPS- and WF-stimulation of THP-1 cells significantly increased the expression of several cytokines compared to untreated cells; 4) Sulodexide treatment of both LPS- and WF-stimulated THP-1 monocytes was able to significantly down-regulate the release of peculiar inflammatory mediators. Our study highlighted the importance to understand biomolecular processes underlying CVI when providing treatment for chronic VLU. Identification of inflammatory biomarkers in leg ulcer microenvironment, may provide useful tools for predicting healing outcome and developing targeted therapies. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ligi, Daniela; Croce, Lidia; Mannello, Ferdinando] Univ Carlo Bo, Sect Clin Biochem & Mol Genet, Dept Biomol Sci, Via O Ubaldini 7, I-61029 Urbino, PU, Italy. [Mosti, Giovanni] Barbantini Clin, Dept Angiol, Via Calcio 2, I-55100 Lucca, Italy. [Raffetto, Joseph D.] VA Boston Healthcare Syst, Div Vasc Surg, West Roxbury, MA USA. [Raffetto, Joseph D.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. RP Mannello, F (reprint author), Univ Carlo Bo, Sect Clin Biochem & Mol Genet, Dept Biomol Sci, Via O Ubaldini 7, I-61029 Urbino, PU, Italy. EM ferdinando.mannello@uniurb.it NR 87 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD OCT PY 2016 VL 1862 IS 10 BP 1964 EP 1974 DI 10.1016/j.bbadis.2016.07.018 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DU7RW UT WOS:000382413300012 PM 27478145 ER PT J AU Hill, J Shields, J Passero, V AF Hill, Jordan Shields, Jenna Passero, Vida TI Tyrosine kinase inhibitor-associated syndrome of inappropriate secretion of anti-diuretic hormone SO JOURNAL OF ONCOLOGY PHARMACY PRACTICE LA English DT Article DE Dasatinib; tyrosine kinase inhibitor; syndrome of inappropriate secretion of anti-diuretic hormone; hyponatremia ID MANAGEMENT; IMATINIB AB Hyponatremia is a common complication among cancer patients. Certain antineoplastic agents have been associated with syndrome of inappropriate secretion of anti-diuretic hormone-induced hyponatremia. The most common agents associated with secretion of anti-diuretic hormone are vinca alkaloids, platinum compounds, and alkylating agents. We report a case of secretion of anti-diuretic hormone associated with tyrosine kinase inhibitors. C1 [Hill, Jordan; Shields, Jenna; Passero, Vida] Vet Affairs Pittsburgh Healthcare Syst, Dept Clin Pharm, Pittsburgh, PA USA. RP Shields, J (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Dept Pharm, Univ Dr, Pittsburgh, PA 15240 USA. EM Jenna.Shields@va.gov NR 7 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1078-1552 EI 1477-092X J9 J ONCOL PHARM PRACT JI J. Oncol. Pharm. Pract. PD OCT PY 2016 VL 22 IS 5 BP 729 EP 732 DI 10.1177/1078155215592023 PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DU7SM UT WOS:000382414900010 PM 26089312 ER PT J AU Chatnuntawech, I Martin, A Bilgic, B Setsompop, K Adalsteinsson, E Schiavi, E AF Chatnuntawech, Itthi Martin, Adrian Bilgic, Berkin Setsompop, Kawin Adalsteinsson, Elfar Schiavi, Emanuele TI Vectorial total generalized variation for accelerated multi-channel multi-contrast MRI SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Multi-contrast magnetic resonance imaging; Compressed sensing; Parallel imaging; Total generalized variation; Alternating direction method of multipliers (ADMM) ID IMAGE-RECONSTRUCTION; MOTION CORRECTION; SENSE RECONSTRUCTION; MINIMIZATION; ROBUST AB Purpose: To develop and implement an efficient reconstruction technique to improve accelerated multi-channel multi-contrast MRI. Theory and Methods: The vectorial total generalized variation (TGV) operator is used as a regularizer for the sensitivity encoding (SENSE) technique to improve image quality of multi-channel multi-contrast MRI. The alternating direction method of multipliers (ADMM) is used to efficiently reconstruct the data. The performance of the proposed method (MC-TGV-SENSE) is assessed on two healthy volunteers at several acceleration factors. Results: As demonstrated on the in vivo results, MC-TGV-SENSE had the lowest root-mean-square error (RMSE), highest structural similarity index, and best visual quality at all acceleration factors, compared to other methods under consideration. MC-TGV-SENSE yielded up to 17.3% relative RMSE reduction compared to the widely used total variation regularized SENSE. Furthermore, we observed that the reconstruction time of MC-TGV-SENSE is reduced by approximately a factor of two with comparable RMSEs by using the proposed ADMM-based algorithm as opposed to the more commonly used Chambolle-Pock primal-dual algorithm for the TGV-based reconstruction. Conclusion: MC-TGV-SENSE is a better alternative than the existing reconstruction methods for accelerated multi-channel multi-contrast MRI. The proposed method exploits shared information among the images (MC), mitigates staircasing artifacts (TGV), and uses the encoding power of multiple receiver coils (SENSE). (C) 2016 Elsevier Inc. All rights reserved. C1 [Chatnuntawech, Itthi; Martin, Adrian; Adalsteinsson, Elfar] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Martin, Adrian; Schiavi, Emanuele] Univ Rey Juan Carlos, Appl Math, Madrid, Spain. [Bilgic, Berkin; Setsompop, Kawin] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Bilgic, Berkin; Setsompop, Kawin] Harvard Med Sch, Boston, MA USA. [Adalsteinsson, Elfar] MIT, Harvard MIT Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Adalsteinsson, Elfar] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Chatnuntawech, I (reprint author), MIT, Room 36-776A,77 Massachusetts Ave, Cambridge, MA 02139 USA.; Martin, A (reprint author), Univ Rey Juan Carlos, Dept 2 021, Calle Tulipan S-N, Madrid 28933, Spain. EM ichatnun@mit.edu; adrian.martin@urjc.es; berkin@nmr.mgh.harvard.edu; kawin@nmr.mgh.harvard.edu; elfar@mit.edu; emanuele.schiavi@urjc.es OI Martin, Adrian/0000-0001-7127-0073 FU Project of the Spanish Ministry of Economy and Competitiveness [TEC2012-39095-C03-02] FX Project TEC2012-39095-C03-02 of the Spanish Ministry of Economy and Competitiveness. R01 EB017219, EB006847, EB017337. NR 41 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD OCT PY 2016 VL 34 IS 8 BP 1161 EP 1170 DI 10.1016/j.mri.2016.05.014 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DU7TC UT WOS:000382416500017 PM 27262829 ER PT J AU Ladas, EJ Orjuela, M Stevenson, K Cole, PD Lin, MK Athale, UH Clavell, LA Leclerc, JM Michon, B Schorin, MA Welch, JG Asselin, BL Sallan, SE Silverman, LB Kelly, KM AF Ladas, Elena J. Orjuela, Manuela Stevenson, Kristen Cole, Peter D. Lin, Meiko Athale, Uma H. Clavell, Luis A. Leclerc, Jean-Marie Michon, Bruno Schorin, Marshall A. Welch, Jennifer Greene Asselin, Barbara L. Sallan, Stephen E. Silverman, Lewis B. Kelly, Kara M. TI Dietary intake and childhood leukemia: The Diet and Acute Lymphoblastic Leukemia Treatment (DALLT) cohort study SO NUTRITION LA English DT Article DE Dietary intake; Nutritional status; Micronutrient intake: macronutrient intake; Obesity; Pediatric oncology; Acute lymphoblastic leukemia ID BODY-MASS INDEX; FOOD FREQUENCY QUESTIONNAIRE; NUTRITIONAL-STATUS; L-ASPARAGINASE; ENERGY-INTAKE; CHILDREN; CHEMOTHERAPY; INCREASES; SURVIVAL; OBESITY AB Objective: Children with acute lymphoblastic leukemia (ALL) are at elevated risk for nutrition related morbidity both during and after therapy. We present the demographic characteristics and nutrient intake at study entry of a prospective cohort in which evaluating dietary intake in children diagnosed with ALL was investigated. Methods: Dietary intake data were collected for participants enrolled on the Dana-Farber Cancer Institute ALL Consortium Protocol. Dietary intake was assessed with a food frequency questionnaire and was compared with the dietary reference intake by ALL risk group (standard and high risk). Results: Dietary intake data were collected from 81% of participants (n = 640). We found that 27% of participants were overweight/obese. Intake of total calories and other nutrients exceeded the dietary reference intake in up to 79% of children. This was evident in both risk groups and was pronounced among younger children. For micronutrients, dietary intake of calcium, vitamin D (females only), and zinc differed significantly between patients with standard-risk and those with high-risk ALL. Conclusions: This study was successful in collecting dietary intake data at the time of cancer diagnosis in a multicenter setting in a pediatric population at high-risk for nutrition-related morbidity. We identified "at-risk" dietary intakes, which vary by sex and ALL risk group; such patients may benefit from future dietary interventions. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ladas, Elena J.; Orjuela, Manuela; Kelly, Kara M.] Columbia Univ, Med Ctr, Div Pediat Hematol Oncol Stem Cell Transplant, New York, NY USA. [Ladas, Elena J.] Columbia Univ, Inst Human Nutr, New York, NY 10032 USA. [Orjuela, Manuela] Columbia Univ, Med Ctr, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Stevenson, Kristen; Sallan, Stephen E.; Silverman, Lewis B.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. [Cole, Peter D.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Lin, Meiko] Columbia Univ, Teachers Coll, New York, NY 10027 USA. [Athale, Uma H.] McMaster Childrens Hosp, Hamilton Hlth Sci, Div Hematol Oncol, Hamilton, ON, Canada. [Clavell, Luis A.] San Jorge Childrens Hosp, San Juan, PR USA. [Leclerc, Jean-Marie] Univ Montreal, St Justine Univ Hosp, Charles Bruneau Canc Ctr, Hematol Oncol Div, Montreal, PQ, Canada. [Michon, Bruno] Ctr Hosp Univ Quebec, Ste Foy, PQ, Canada. [Schorin, Marshall A.] Inova Childrens Hosp, Falls Church, VA USA. [Welch, Jennifer Greene] Brown Univ, Hasbro Childrens Hosp, Div Pediat Hematol Oncol, Providence, RI 02912 USA. [Asselin, Barbara L.] Univ Rochester, Med Ctr, Dept Pediat, Golisano Childrens Hosp,Sch Med, Rochester, NY 14642 USA. RP Ladas, EJ (reprint author), Columbia Univ, Med Ctr, Div Pediat Hematol Oncol Stem Cell Transplant, New York, NY USA.; Ladas, EJ (reprint author), Columbia Univ, Inst Human Nutr, New York, NY 10032 USA. EM ejd14@cumc.columbia.edu FU Tamarind Foundation; Mentored Research Scholar Grant [127000-MRSG-14-157-01-CCE]; American Cancer Society; American Institute for Cancer Research [AICR CU09-1011] FX Financial support was provided by the Tamarind Foundation, Mentored Research Scholar Grant (127000-MRSG-14-157-01-CCE), American Cancer Society, and American Institute for Cancer Research (AICR CU09-1011). Conception and design of the study (E. J. L, M. O., K. M. K.). Generation, collection, and assembly of data (E. J. L., M. O., P. D. C., U. H. A., L. A. C., J.-M. L., B. M., M. A. S., J. G. W., B. L A., S. E. S., L B. S.). Analysis and/or interpretation of data (E. J. L., M. O., K. S., M. L., K. M. K.). Drafting or revision of the manuscript (E. J. L, M. O., K. S., M. L, P. D. C., U. H. A., L A. C., J.-M. L, B. M., M. A. S., J. G. W., B. L A., S. E. S., L B. S.). approval of the final version of the manuscript (E. J. L, M. O., K. S., M. L, P. D. C., U. H. A., L A. C., J.-M. L., B. M., M. A. S., J. G. W., B. L A., S. E. S., L B. S.). NR 35 TC 0 Z9 0 U1 11 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-9007 EI 1873-1244 J9 NUTRITION JI Nutrition PD OCT PY 2016 VL 32 IS 10 BP 1103 EP 1109 DI 10.1016/j.nut.2016.03.014 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7YE UT WOS:000382429700010 PM 27318855 ER PT J AU Lam, RW Iverson, GL Evans, VC Yatham, LN Stewart, K Tam, EM Axler, A Woo, C AF Lam, Raymond W. Iverson, Grant L. Evans, Vanessa C. Yatham, Lakshmi N. Stewart, Kurtis Tam, Edwin M. Axler, Auby Woo, Cindy TI The effects of desvenlafaxine on neurocognitive and work functioning in employed outpatients with major depressive disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Depressive disorders; Cognition; Functioning; Disability; Occupational functioning ID PERFORMANCE QUESTIONNAIRE HPQ; HEALTH-ORGANIZATION HEALTH; COGNITIVE IMPAIRMENT; MOOD DISORDERS; DOUBLE-BLIND; BIPOLAR DISORDER; PRIMARY-CARE; DEFICITS; EFFICACY; PLACEBO AB Background: Major depressive disorder (MDD) is associated with staggering personal and economic costs, a major proportion of which stem from impaired psychosocial and occupational functioning. Few studies have examined the impact of depression-related cognitive dysfunction on work functioning. We examined the association between neurocognitive and work functioning in employed patients with MDD. Methods: Employed adult outpatients (n=36) with MDD of at least moderate severity (>= 23 on the Montgomery Asberg Depression Rating Scale, MADRS) and subjective cognitive complaints completed neurocognitive tests (CNS Vital Signs computerized battery) and validated self-reports of their work functioning (LEAPS, HPQ) before and after 8 weeks of open-label treatment with flexibly-dosed desvenlafaxine 50-100 mg/day. Relationships between neurocognitive tests and functional measures were examined using bivariate correlational and multiple regression analyses, as appropriate. An ANCOVA model examined whether significant change in neurocognitive performance, defined as improvement of >= 1 SD in the Neurocognition Index (NCI) from baseline to post-treatment, was associated with improved outcomes. Results: Patients showed significant improvements in depressive symptom, neurocognitive, and work functioning measures following treatment with desvenlafaxine (e.g., MADRS response=77% and MADRS remission=49%). There were no significant correlations between changes in NCI or cognitive domain subscales and changes in MADRS, LEAPS, or HPQ scores. However, patients demonstrating significant improvement in NCI scores (n=11, 29%) had significantly greater improvement in clinical and work functioning outcomes compared to those without NCI improvement. Limitations: The limitations of this study include small sample size, lack of a placebo control group, and lack of a healthy comparison group. Our sample also had more years of education and higher premorbid intelligence than the general population. Conclusions: There were no significant correlations between changes in neurocognitive and work functioning measures in this study. However, meaningful improvement in neurocognitive functioning with desvenlafaxine was associated with greater improvement in both mood and occupational outcomes. This suggests that addressing cognitive dysfunction may improve clinical and occupational outcomes in employed patients with MDD. However, the relationship between neurocognitive and work functioning in MDD is complex and requires further study. (C) 2016 Elsevier B.V. All rights reserved. C1 [Lam, Raymond W.; Iverson, Grant L.; Evans, Vanessa C.; Yatham, Lakshmi N.; Stewart, Kurtis; Tam, Edwin M.; Axler, Auby; Woo, Cindy] Univ British Columbia, Dept Psychiat, Mood Disorders Ctr Excellence, Djavad Mowafaghian Ctr Brain Hlth, Vancouver, BC, Canada. [Iverson, Grant L.] Harvard Med Sch, Dept Phys Med & Rehabil, Red Sox Fdn, Massachusetts Gen Hosp,Home Base Program, Boston, MA USA. RP Lam, RW (reprint author), Univ British Columbia, Dept Psychiat, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. EM r.lam@ubc.ca FU Pfizer Canada FX This study was funded by an investigator-initiated Grant from Pfizer Canada. The sponsor had no role in the design, conduct, analysis or publication of the study. CTRN: NCT01468610. NR 57 TC 2 Z9 2 U1 6 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT PY 2016 VL 203 BP 55 EP 61 DI 10.1016/j.jad.2016.05.074 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DT9QA UT WOS:000381836200008 PM 27280963 ER PT J AU Deckersbach, T Peters, AT Sylvia, LG Gold, AK Magalhaes, PVD Henry, DB Frank, E Otto, MW Berk, M Dougherty, DD Nierenberg, AA Miklowitz, DJ AF Deckersbach, Thilo Peters, Amy T. Sylvia, Louisa G. Gold, Alexandra K. da Silva Magalhaes, Pedro Vieira Henry, David B. Frank, Ellen Otto, Michael W. Berk, Michael Dougherty, Darin D. Nierenberg, Andrew A. Miklowitz, David J. TI A cluster analytic approach to identifying predictors and moderators of psychosocial treatment for bipolar depression: Results from STEP-BD SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Cluster analyses; Psychotherapy ID TREATMENT ENHANCEMENT PROGRAM; SOCIAL RHYTHM THERAPY; RANDOMIZED CONTROLLED-TRIAL; I DISORDER; ANXIETY DISORDERS; CLINICAL-TRIALS; PSYCHOTHERAPY; ILLNESS; INTERVENTION; COMORBIDITY AB Background: We sought to address how predictors and moderators of psychotherapy for bipolar depression identified individually in prior analyses can inform the development of a metric for prospectively classifying treatment outcome in intensive psychotherapy (IP) versus collaborative care (CC) adjunctive to pharmacotherapy in the Systematic Treatment Enhancement Program (STEP-BD) study. Methods: We conducted post-hoc analyses on 135 STEP-BD participants using cluster analysis to identify subsets of participants with similar clinical profiles and investigated this combined metric as a moderator and predictor of response to IP. We used agglomerative hierarchical cluster analyses and k-means clustering to determine the content of the clinical profiles. Logistic regression and Cox proportional hazard models were used to evaluate whether the resulting clusters predicted or moderated likelihood of recovery or time until recovery. Results: The cluster analysis yielded a two-cluster solution: 1) "less-recurrent/severe" and 2) "chronic/recurrent." Rates of recovery in IP were similar for less-recurrent/severe and chronic/recurrent participants. Less-recurrent/severe patients were more likely than chronic/recurrent patients to achieve recovery in CC (p=.040, OR=4.56). IP yielded a faster recovery for chronic/recurrent participants, whereas CC led to recovery sooner in the less-recurrent/severe cluster (p=.034, OR=2.62). Limitations: Cluster analyses require list-wise deletion of cases with missing data so we were unable to conduct analyses on all STEP-BD participants. Conclusions: A well-powered, parametric approach can distinguish patients based on illness history and provide clinicians with symptom profiles of patients that confer differential prognosis in CC vs. IP. (C) 2016 Elsevier B.V. All rights reserved. C1 [Deckersbach, Thilo; Sylvia, Louisa G.; Gold, Alexandra K.; Dougherty, Darin D.; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Deckersbach, Thilo; Sylvia, Louisa G.; Dougherty, Darin D.; Nierenberg, Andrew A.] Harvard Med Sch, Boston, MA USA. [Peters, Amy T.; Henry, David B.] Univ Illinois, Chicago, IL USA. [da Silva Magalhaes, Pedro Vieira] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Frank, Ellen] Univ Pittsburgh, Pittsburgh, PA USA. [Otto, Michael W.] Boston Univ, Boston, MA 02215 USA. [Berk, Michael] Deakin Univ, Melbourne, Vic, Australia. [Berk, Michael] Univ Melbourne, Melbourne, Vic, Australia. [Miklowitz, David J.] UCLA Sch Med, Los Angeles, CA USA. RP Deckersbach, T (reprint author), Dept Psychiat, 149-2628,Massachusetts Gen Hosp Bldg 149,13th St, Charlestown, MA 02129 USA. EM tdeckersbach@partners.org FU NIMH NIH HHS [N01 MH080001, R37 MH029618] NR 41 TC 0 Z9 0 U1 10 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT PY 2016 VL 203 BP 152 EP 157 DI 10.1016/j.jad.2016.03.064 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DT9QA UT WOS:000381836200019 PM 27289316 ER PT J AU Yoo, HJ Hong, JP Cho, MJ Fava, M Mischoulon, D Heo, JY Kim, K Jeon, HJ AF Yoo, Hye Jin Hong, Jin Pyo Cho, Maeng Je Fava, Maurizio Mischoulon, David Heo, Jung-Yoon Kim, Kiwon Jeon, Hong Jin TI Lifetime suicidal ideation and attempt in adults with full major depressive disorder versus sustained depressed mood SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Sustained depressed mood; Major depressive disorder; Suicidal ideation; Suicide attempt ID RISK-FACTORS; ANXIETY DISORDERS; ASSOCIATION; PREVALENCE; PREDICTORS; ALCOHOL; WORTHLESSNESS; HOPELESSNESS; OUTPATIENTS; MORTALITY AB Background: Major depressive disorder (MDD) is a well-known risk factor for suicidality, but depressed mood has been used non-specifically to describe the emotional state. We sought to compare influence of MDD versus sustained depressed mood on suicidality. Methods: A total of 12,532 adults, randomly selected through the one-person-per-household method, completed a face-to-face interview using the Korean version of Composite International Diagnostic Interview (K-CIDI) and a questionnaire for lifetime suicidal ideation (LSI) and lifetime suicidal attempt (LSA). Results: Of 12,361 adults, 565 were assessed as 'sustained depressed mood group' having depressed mood for more than two weeks without MDD (4.6%), and 810 adults were assessed as having full MDD (6.55%) which consisted of 'MDD with depressed mood group' (6.0%) and `MDD without depressed mood group' (0.5%). The MDD with depressed mood group showed higher odds ratios for LSI and LSA than the sustained depressed mood group. Contrarily, no significant differences were found in LSI and LSA between the MDD group with and without depressed mood. MDD showed significant associations with LSI (AOR=2.83, 95%CI 2.12-3.78) and LSA (AOR=2.17, 95%CI 1.34-3.52), whereas sustained depressed mood showed significant associations with neither LSI nor LSA after adjusting for MDD and other psychiatric comorbidities. Interaction effect of sustained depressed mood with MDD was significant for LSI but not for LSA. Conclusions: Sustained depressed mood was not related to LSI and LSA after adjusting for psychiatric comorbidities, whereas MDD was significantly associated with both LSI and LSA regardless of the presence of sustained depressed mood. (C) 2016 Elsevier B.V. All rights reserved. C1 [Yoo, Hye Jin; Hong, Jin Pyo; Heo, Jung-Yoon; Kim, Kiwon; Jeon, Hong Jin] Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Dept Psychiat,Depress Ctr, 50 Irwon Dong, Seoul 135710, South Korea. [Cho, Maeng Je] Seoul Natl Univ, Coll Med, Dept Psychiat & Behav Sci, Seoul, South Korea. [Fava, Maurizio; Mischoulon, David] Harvard Med Sch, Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA USA. [Jeon, Hong Jin] Sungkyunkwan Univ, SAIHST, Dept Hlth Sci & Technol, Dept Med Device Management & Res, Seoul, South Korea. [Jeon, Hong Jin] Sungkyunkwan Univ, SAIHST, Dept Clin Res Design & Evaluat, Seoul, South Korea. RP Jeon, HJ (reprint author), Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Dept Psychiat,Depress Ctr, 50 Irwon Dong, Seoul 135710, South Korea. EM jeonhj@skku.edu FU Korean Ministry of Health Welfare; National Research Foundation of Korea FX The Korean Ministry of Health & Welfare and the National Research Foundation of Korea had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 46 TC 1 Z9 1 U1 6 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT PY 2016 VL 203 BP 275 EP 280 DI 10.1016/j.jad.2016.06.007 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DT9QA UT WOS:000381836200035 PM 27314814 ER PT J AU Wu, KF Gao, X Shi, BY Chen, SY Zhou, X Li, ZD Gan, YH Cui, L Kang, JX Li, WD Huang, R AF Wu, Kefeng Gao, Xiang Shi, Baoyan Chen, Shiyu Zhou, Xin Li, Zhidong Gan, Yuhong Cui, Liao Kang, Jing Xuan Li, Wende Huang, Ren TI ENRICHED ENDOGENOUS n-3 POLYUNSATURATED FATTY ACIDS ALLEVIATE COGNITIVE AND BEHAVIORAL DEFICITS IN A MICE MODEL OF ALZHEIMER'S DISEASE SO NEUROSCIENCE LA English DT Article DE Alzheimer's disease; polyunsaturated fatty acids; amyloid precursor protein ID TRANSGENIC MOUSE MODEL; DOCOSAHEXAENOIC ACID; AMYLOID-BETA; PSYCHIATRIC-DISORDERS; OMEGA-6/OMEGA-3 RATIO; FAT-1 MICE; DECLINE; OMEGA-3-FATTY-ACIDS; BRAIN; IMPAIRMENT AB Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accompanied by memory deficits and neuropsychiatric dysfunction. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have seemly therapeutic potential in AD, but the benefit of n-3 PUFAs is still in debates. Here, we employed a transgenic mice carry fat-1 gene to encode n-3 desaturase from Caenorhabditis elegans, which increase endogenous n-3 PUFAs by converting n-6 PUFAs to n-3 PUFAs crossed with amyloid precursor protein (APP) Tg mice to evaluate the protective effects of endogenous n-3 PUFAs on cognitive and behavioral deficits of APP Tg mice. We fed APP, APP/fat-1 and fat-1 mice with n-6 PUFAs rich diet. Brain tissues were collected at 3, 9 and 12 months for fatty acid and gene expression analysis, histology and protein assays. Morris Water Maze Test, open field test and elevated plus maze test were performed to measure the behavior capability. From the results, the expression of fat-1 transgene increased cortical n-3: n-6 PUFAs ratio and n-3 PUFAs concentrations, and sensorimotor dysfunction and cognitive deficits in AD were significantly less severe in APP/fat-1 mice with endogenous n-3 PUFAs than in APP mice controls. The protection against disturbance of spontaneous motor activity and cognitive deficits in AD was strongly correlated with increased n-3: n-6 PUFAs ratio and endogenous n-3 PUFAs, reduced APP generation, inhibited amyloid beta peptide aggregation, suppressed nuclear factor-kappa B and astroglia activation, and reduced death of neurons in the cortex of APP/fat-1 mice compared with APP mice controls. In conclusion, our study demonstrates that an available medication with the maintenance of enriched n-3 PUFAs in the brain could slow down cognitive decline and prevent neuropsychological disorder in AD. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Wu, Kefeng; Shi, Baoyan; Chen, Shiyu; Zhou, Xin; Cui, Liao; Li, Wende] Guangdong Med Coll, Guangdong Key Lab Res & Dev Nat Drug, Zhanjiang, Guangdong, Peoples R China. [Gao, Xiang] Affiliated Hosp Guangdong Med Coll, Stem Cell Res & Cellular Therapy Ctr, Zhanjiang, Peoples R China. [Shi, Baoyan; Chen, Shiyu; Li, Wende; Huang, Ren] Guangdong Lab Animals Monitoring Inst, Guangdong Key Lab Lab Anim, Guangzhou, Guangdong, Peoples R China. [Li, Zhidong; Gan, Yuhong; Cui, Liao] Guangdong Med Coll, Dept Pharmacol, Zhanjiang 524023, Guangdong, Peoples R China. [Kang, Jing Xuan] Massachusetts Gen Hosp, Lab Lipid Med & Technol, Boston, MA 02114 USA. RP Li, WD; Huang, R (reprint author), 2 Wenming Dong Rd, Zhanjiang 524023, Guangdong, Peoples R China. EM lwd@gdlami.com; labking@sohu.com FU National Natural Science Foundation, P. R. China [31272389]; Natural Science Foundation of Guangdong Province [S2011011000559]; Science and Technology Project of Guangdong Province [2013B060300037] FX The National Natural Science Foundation, P. R. China (31272389), Natural Science Foundation of Guangdong Province (S2011011000559), Science and Technology Project of Guangdong Province (2013B060300037). NR 67 TC 1 Z9 1 U1 20 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD OCT 1 PY 2016 VL 333 BP 345 EP 355 DI 10.1016/j.neuroscience.2016.07.038 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DU1BU UT WOS:000381942000030 PM 27474225 ER PT J AU Lee, JA Kim, YM Kim, TH Lee, SH Lee, CA Cho, CW Jeon, JW Park, JK Kim, SK Jung, BG Lee, BJ AF Lee, Jin-A Kim, Yun-Mi Kim, Tae-Hoon Lee, Sang-Ho Lee, Cho-A Cho, Cheong-Weon Jeon, Jong-woon Park, Jin-kyu Kim, Sang-Ki Jung, Bock-Gie Lee, Bong-Joo TI Nasal delivery of chitosan-coated poly(lactide-co-glycolide)-encapsulated honeybee (Apis mellifera) venom promotes Th 1-specific systemic and local intestinal immune responses in weaned pigs SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE Chitosan; Poly(lactide-co-dlycolide); Mucoadhesive nanoparticle; Honeybee venom; Immune boosting effect ID RESPIRATORY SYNDROME VIRUS; DENDRITIC-CELL ACTIVATION; MUCOSAL IMMUNITY; PLGA MICROSPHERES; VACCINE DELIVERY; VIRAL CLEARANCE; UP-REGULATION; NANOPARTICLES; MICROPARTICLES; IMMUNIZATION AB Nasal delivery is a convenient and acceptable route for drug administration, and has been shown to elicit a much more potent local and systemic response compared with other drug delivery routes. We previously demonstrated that rectal administration of poly(lactide-co-glycolide)-encapsulated honeybee venom (P-HBV) could enhance systemic Th 1-specific immune responses. We therefore synthesized chitosan-coated P-HBV (CP-HBV) and then evaluated the immune-boosting efficacy of nasally administered CP-HBV on systemic and local intestinal immunity compared with non-chitosan-coated P-HBV. The nasally delivered CP-HBV effectively enhanced Th 1-specific responses, eliciting a significant increase in the CD3(+)CD4(+)CD8(-) Th cell population, lymphocyte proliferation capacity, and expression of Th 1 cytokines (IFN-gamma, IL-12, and IL-2) in peripheral blood mononuclear cells. Furthermore, these immune-boosting effects persisted up to 21 days post CP-HBV administration. Nasal administration of CP-HBV also led to an increase of not only the CD4(+) Th 1 and IFN-gamma secreting CD4(+) Th 1 cell population but also Th 1-specific cytokines and transcription factors, including IL-12, IFN-gamma, STAT4, and T-bet, in isolated mononuclear cells from the spleen and ileum. (C) 2016 Elsevier B.V. All rights reserved. C1 [Lee, Jin-A; Kim, Yun-Mi; Kim, Tae-Hoon; Lee, Bong-Joo] Chonnam Natl Univ, Coll Vet Med, Dept Vet Infect Dis, Kwangju 500757, South Korea. [Lee, Sang-Ho] Chonnam Natl Univ, Coll Vet Med, Dept Vet Obstet, Kwangju 500757, South Korea. [Lee, Cho-A; Cho, Cheong-Weon] Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea. [Lee, Cho-A; Cho, Cheong-Weon] Chungnam Natl Univ, Inst Drug Res & Dev, Taejon 305764, South Korea. [Jeon, Jong-woon; Park, Jin-kyu] Wissen Co Ltd, 410 Bio Venture Town,461-8, Daejeon 305811, South Korea. [Kim, Sang-Ki] Kongju Natl Univ, Dept Compan & Lab Anim Sci, Yesan 304702, Chungnam, South Korea. [Jung, Bock-Gie] Univ Texas Hlth Ctr Tyler, Dept Pulm Immunol, Ctr Pulm & Infect Dis Control, Tyler, TX 75708 USA. [Lee, Jin-A] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, 55 Fruit St, Boston, MA 02114 USA. RP Lee, BJ (reprint author), Chonnam Natl Univ, Coll Vet Med, Dept Vet Infect Dis, Kwangju 500757, South Korea.; Jung, BG (reprint author), Univ Texas Hlth Ctr Tyler, Dept Pulm Immunol, Ctr Pulm & Infect Dis Control, Tyler, TX 75708 USA. EM skulljung@gmail.com; bjlee@chonnam.ac.kr FU Ministry of Trade, Industry and Energy (MOTIE) of Republic of Korea; Korea Institute for Advancement of Technology (KIAT) [A006500322] FX This study was supported by the Ministry of Trade, Industry and Energy (MOTIE) of Republic of Korea and the Korea Institute for Advancement of Technology (KIAT) through the Promoting Regional Specialized Industry Program (Grant No. A006500322). We would like to thank Da-Yae Jun, Ji-Min Kim, Jun-Own Mo, Hyeonje Kim, Hye-Seong Park, and Min-Ju Hwang for their assistance with the animal studies. The authors have no conflict(s) of interest(s) to declare. NR 34 TC 0 Z9 0 U1 14 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 EI 1873-2534 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD OCT PY 2016 VL 178 BP 99 EP 106 DI 10.1016/j.vetimm.2016.07.005 PG 8 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA DT9OY UT WOS:000381833400013 PM 27496748 ER PT J AU Zhao, W Ho, L Wang, J Bi, WN Yemul, S Ward, L Freire, D Mazzola, P Brathwaite, J Mezei, M Sanchez, R Elder, GA Pasinetti, GM AF Zhao, Wei Ho, Lap Wang, Jun Bi, Weina Yemul, Shrishailam Ward, Libby Freire, Daniel Mazzola, Paolo Brathwaite, Justin Mezei, Mihaly Sanchez, Roberto Elder, Gregory A. Pasinetti, Giulio Maria TI In Silico Modeling of Novel Drug Ligands for Treatment of Concussion Associated Tauopathy SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE CONCUSSION; OLFACTORY RECEPTOR; G PROTEIN-COUPLED RECEPTORS; IN SILICO SCREENING; TAU PHOSPHORYLATION ID TRAUMATIC BRAIN-INJURY; PROTEIN STRUCTURES; TRANSGENIC MICE; PREDICTION; RECEPTORS; EXPOSURE; DISEASE; SITES; TOOLS AB The objective of this study was to develop an in silico screening model for characterization of potential novel ligands from commercial drug libraries able to functionally activate certain olfactory receptors (ORs), which are members of the class A rhodopsin-like family of G protein couple receptors (GPCRs), in the brain of murine models of concussion. We previously found that concussions may significantly influence expression of certain ORs, for example, OR4M1 in subjects with a history of concussion/traumatic brain injury (TBI). In this study, we built a 3-D OR4M1 model and used it in in silico screening of potential novel ligands from commercial drug libraries. We report that in vitro activation of OR4M1 with the commercially available ZINC library compound 10915775 led to a significant attenuation of abnormal tau phosphorylation in embryonic cortico-hippocampal neuronal cultures derived from NSE-OR4M1 transgenic mice, possibly through modulation of the JNK signaling pathway. The attenuation of abnormal tau phosphorylation was rather selective since ZINC10915775 significantly decreased tau phosphorylation on tau Ser202/T205 (AT8 epitope) and tau Thr212/Ser214 (AT100 epitope), but not on tau Ser396/404 (PHF-1 epitope). Moreover, no response of ZINC10915775 was found in control hippocampal neuronal cultures derived from wild type littermates. Our in silico model provides novel means to pharmacologically modulate select ubiquitously expressed ORs in the brain through high affinity ligand activation to prevent and eventually to treat concussion induced down regulation of ORs and subsequent cascade of tau pathology. J. Cell. Biochem. 117: 2241-2248, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Zhao, Wei; Ho, Lap; Wang, Jun; Bi, Weina; Yemul, Shrishailam; Ward, Libby; Freire, Daniel; Mazzola, Paolo; Brathwaite, Justin; Elder, Gregory A.; Pasinetti, Giulio Maria] Icahn Sch Med Mt Sinai, Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. [Zhao, Wei; Wang, Jun; Pasinetti, Giulio Maria] James J Peters VA Med Ctr, Geriatr Res Educ Clin Ctr, Bronx, NY USA. [Mazzola, Paolo] Univ Milano Bicocca, Sch Med & Surg, Monza, Italy. [Mezei, Mihaly; Sanchez, Roberto] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA. [Mezei, Mihaly; Sanchez, Roberto] Icahn Sch Med Mt Sinai, Expt Therapeut Inst, New York, NY 10029 USA. [Elder, Gregory A.; Pasinetti, Giulio Maria] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. RP Pasinetti, GM (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu FU Department of Defense [W81XWH-12-1-0582]; Veterans Affairs [Merit 1I01RX000996-01] FX This study was supported by the Department of Defense (Grant W81XWH-12-1-0582) to GMP and by the Veterans Affairs (Merit 1I01RX000996-01) to GAE. This material is also the result of work supported in part with resources and the use of facilities at the James J. Peters Veterans Affairs Medical Center, Bronx, NY. In addition, Dr. Pasinetti holds a Career Scientist Award in the Research and Development unit and is the Director of the Basic and Biomedical Research and Training Program, GRECC, James J. Peters Veterans Affairs Medical Center. We also acknowledge that the contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 23 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT PY 2016 VL 117 IS 10 BP 2241 EP 2248 DI 10.1002/jcb.25521 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS6LE UT WOS:000380892500006 PM 26910498 ER PT J AU Bonilla, C Lewis, SJ Rowlands, MA Gaunt, TR Smith, GD Gunnell, D Palmer, T Donovan, JL Hamdy, FC Neal, DE Eeles, R Easton, D Kote-Jarai, Z Al Olama, AA Benlloch, S Muir, K Giles, GG Wiklund, F Gronberg, H Haiman, CA Schleutker, J Nordestgaard, BG Travis, RC Pashayan, N Khaw, KT Stanford, JL Blot, WJ Thibodeau, S Maier, C Kibel, AS Cybulski, C Cannon-Albright, L Brenner, H Park, J Kaneva, R Batra, J Teixeira, MR Pandha, H Lathrop, M Martin, RM Holly, JMP AF Bonilla, Carolina Lewis, Sarah J. Rowlands, Mari-Anne Gaunt, Tom R. Smith, George Davey Gunnell, David Palmer, Tom Donovan, Jenny L. Hamdy, Freddie C. Neal, David E. Eeles, Rosalind Easton, Doug Kote-Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Wiklund, Fredrik Groenberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Borge G. Travis, Ruth C. Pashayan, Nora Khaw, Kay-Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen Maier, Christiane Kibel, Adam S. Cybulski, Cezary Cannon-Albright, Lisa Brenner, Hermann Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Lathrop, Mark Martin, Richard M. Holly, Jeff M. P. CA PRACTICAL Consortium TI Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE insulin-like growth factors; insulin-like growth factor-binding proteins; prostate cancer; Mendelian randomization; single nucleotide polymorphisms; IGFBP3; ProtecT; PRACTICAL; ALSPAC; UKHLS ID GENOME-WIDE ASSOCIATION; IGF-I; RISK; IGFBP-3; POLYMORPHISM; VARIABLES; MEN; ESTIMATORS; MULTIPLE; CHILDREN AB Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In approximate to 700 men without prostate cancer and two replication cohorts (N approximate to 900 and approximate to 9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high ( 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (approximate to 265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. What's New? Circulating insulin-like growth factors (IGF) and their binding proteins have been associated with prostate cancer risk in observational epidemiological studies but it is not clear whether there is a causal relationship with disease. To address this question, the authors used Mendelian randomization, a method that uses genetic variants as proxies for measured exposures. Their results implicate the IGF pathway in general in prostate cancer development but specific biomarkers remain to be determined. C1 [Bonilla, Carolina; Lewis, Sarah J.; Rowlands, Mari-Anne; Gaunt, Tom R.; Smith, George Davey; Gunnell, David; Donovan, Jenny L.; Martin, Richard M.] Univ Bristol, Sch Social & Community Med, Canynge Hall,39 Whatley Rd, Bristol BS8 2PS, Avon, England. [Bonilla, Carolina; Lewis, Sarah J.; Gaunt, Tom R.; Smith, George Davey; Martin, Richard M.] Univ Bristol, Integrat Epidemiol Unit, MRC, Bristol BS8 2PS, Avon, England. [Palmer, Tom] Univ Lancaster, Dept Math & Stat, Lancaster, England. [Hamdy, Freddie C.; Neal, David E.] Univ Oxford, Nuffield Dept Surg, Oxford, England. [Neal, David E.] Univ Cambridge, Surg Oncol Urooncol S4, Addenbrookes Hosp, Box 279,Hills Rd, Cambridge, England. [Eeles, Rosalind; Kote-Jarai, Zsofia] Inst Canc Res, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. [Eeles, Rosalind] Royal Marsden NHS Fdn Trust, London, England. [Eeles, Rosalind] Royal Marsden NHS Fdn Trust, Surrey, England. [Easton, Doug; Al Olama, Ali Amin; Benlloch, Sara] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Muir, Kenneth] Univ Warwick, Coventry, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester M13 9PL, Lancs, England. [Giles, Graham G.] Canc Council Victoria, 615 St Kilda Rd, Melbourne, Vic 3004, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Wiklund, Fredrik; Groenberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Haiman, Christopher A.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. [Schleutker, Johanna] Univ Tampere, Inst Biomed Technol BioMediTech, Tampere, Finland. [Schleutker, Johanna] FimLab Labs, Tampere, Finland. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev Ringvej 75, DK-2730 Herlev, Denmark. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Pashayan, Nora] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Pashayan, Nora] UCL, Dept Appl Hlth Res, 1-19 Torrington Pl, London WC1E 7HB, England. [Khaw, Kay-Tee] Univ Cambridge, Cambridge Inst Publ Hlth, Forvie Site, Robinson Way, Cambridge CB2 0SR, England. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Blot, William J.] Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD USA. [Thibodeau, Stephen] Mayo Clin, Rochester, MN USA. [Maier, Christiane] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Maier, Christiane] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Dana Farber Canc Inst, 45 Francis St ASB 2-3, Boston, MA USA. [Kibel, Adam S.] Washington Univ, St Louis, MO USA. [Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Park, Jong] H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control, 12902 Magnolia Dr, Tampa, FL USA. [Kaneva, Radka] Med Univ Sofia, Mol Med Ctr, 2 Zdrave St, Sofia 1431, Bulgaria. [Kaneva, Radka] Med Univ Sofia, Dept Med Chem & Biochem, 2 Zdrave St, Sofia 1431, Bulgaria. [Batra, Jyotsna] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr Qld, Brisbane, Qld, Australia. [Batra, Jyotsna] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld, Australia. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Oporto, Portugal. [Pandha, Hardev] Univ Surrey, Guildford GU2 7XH, Surrey, England. [Lathrop, Mark] Commissariat Energie Atom, Ctr Natl Genotypage, Evry, France. [Lathrop, Mark] McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Martin, Richard M.; Holly, Jeff M. P.] NIHR Bristol Biomed Res Unit Nutr, Bristol, Avon, England. [Holly, Jeff M. P.] Univ Bristol, Sch Clin Sci North Bristol, IGFs & Metab Endocrinol Grp, Bristol, Avon, England. RP Martin, RM (reprint author), Univ Bristol, Sch Social & Community Med, Canynge Hall,39 Whatley Rd, Bristol BS8 2PS, Avon, England. EM richard.martin@bristol.ac.uk RI Gaunt, Tom/O-3918-2014; Davey Smith, George/A-7407-2013; Brenner, Hermann/B-4627-2017; OI Gaunt, Tom/0000-0003-0924-3247; Davey Smith, George/0000-0002-1407-8314; Brenner, Hermann/0000-0002-6129-1572; Bonilla, Carolina/0000-0002-9972-6383; Lewis, Sarah/0000-0003-4311-6890; albright, lisa/0000-0003-2602-3668 FU World Cancer Research Fund [2011/419]; Cancer Research UK [C18281/A19169, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; MRC; University of Bristol [G0600705, MC_UU_12013/19]; National Institute for Health Research (NIHR); National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme [HTA 96/20/99, ISRCTN20141297]; European Community [223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defense [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund FX Grant sponsor: World Cancer Research Fund; Grant number: 2011/419; Grant sponsor: Cancer Research UK; Grant number: C18281/A19169; Grant sponsor: MRC and the University of Bristol; Grant number: G0600705, MC_UU_12013/19 (to Integrative Epidemiology Unit (IEU)); Grant sponsor: Cancer Research UK; Grant number: C18281/A19169 (to Integrative Cancer Epidemiology Programme); Grant sponsor: National Institute for Health Research (NIHR) (to Bristol Biomedical Research Unit in Nutrition, which is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol); Grant sponsor: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (to ProtecT study); Grant number: HTA 96/20/99; ISRCTN20141297; Grant sponsor: European Community's Seventh Framework Programme (grant agreement no 223175); Grant number: HEALTH-F2-2009-223175) (COGS) (to PRACTICAL and the iCOGS infrastructure); Grant sponsor: Cancer Research UK; Grant numbers: C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565; Grant sponsor: National Institutes of Health; Grant number: CA128978; Grant sponsor: Post-Cancer GWAS initiative; Grant numbers: 1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative; Grant sponsor: Department of Defense; Grant number: W81XWH-10-1-0341; Grant sponsors: Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund NR 47 TC 0 Z9 0 U1 6 U2 21 PU WILEY 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 OCT 1 PY 2016 VL 139 IS 7 BP 1520 EP 1533 DI 10.1002/ijc.30206 PG 14 WC Oncology SC Oncology GA DR5YB UT WOS:000379977200009 PM 27225428 ER PT J AU Mashamba-Thompson, TP Sartorius, B Stevens, FCJ Drain, PK AF Mashamba-Thompson, Tivani P. Sartorius, Benn Stevens, Fred C. J. Drain, Paul K. TI Experiential Bloom's Taxonomy learning framework for point-of-care diagnostics training of primary healthcare workers SO AFRICAN JOURNAL OF LABORATORY MEDICINE LA English DT Article ID RAPID TESTS; NURSES C1 [Mashamba-Thompson, Tivani P.; Sartorius, Benn] Univ KwaZulu Natal, Sch Nursing & Publ Hlth, Dept Publ Hlth Med, Durban, South Africa. [Stevens, Fred C. J.] Maastricht Univ, Dept Educ Dev & Res, Fac Hlth Med & Life Sci, Maastricht, Netherlands. [Drain, Paul K.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Drain, Paul K.] Univ Washington, Dept Med, Seattle, WA USA. [Drain, Paul K.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Drain, Paul K.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. RP Mashamba-Thompson, TP (reprint author), Univ KwaZulu Natal, Sch Nursing & Publ Hlth, Dept Publ Hlth Med, Durban, South Africa. EM mashamba-thompson@ukzn.ac.za NR 20 TC 0 Z9 0 U1 7 U2 7 PU AOSIS PI CAPE TOWN PA POSTNET SUITE 55, PRIVATE BAG X22, TYGERVALLEY, CAPE TOWN, 00000, SOUTH AFRICA SN 2225-2002 EI 2225-2010 J9 AFR J LAB MED JI Afr. J. Lab. Med. PD SEP 30 PY 2016 VL 5 IS 1 AR a449 DI 10.4102/ajlm.v5i1.449 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ED1LF UT WOS:000388606200001 ER PT J AU Sok, D Briney, B Jardine, JG Kulp, DW Menis, S Pauthner, M Wood, A Lee, EC Le, KM Jones, M Ramos, A Kalyuzhniy, O Adachi, Y Kubitz, M MacPherson, S Bradley, A Friedrich, GA Schief, WR Burton, DR AF Sok, Devin Briney, Bryan Jardine, Joseph G. Kulp, Daniel W. Menis, Sergey Pauthner, Matthias Wood, Andrew Lee, E-Chiang Le, Khoa M. Jones, Meaghan Ramos, Alejandra Kalyuzhniy, Oleksandr Adachi, Yumiko Kubitz, Michael MacPherson, Skye Bradley, Allan Friedrich, Glenn A. Schief, William R. Burton, Dennis R. TI Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice SO SCIENCE LA English DT Article ID B-CELL RECEPTORS; VACCINE DESIGN; CRYSTAL-STRUCTURE; IMMUNOGEN DESIGN; STRUCTURAL BASIS; ENVELOPE TRIMER; RECOGNITION; ENV; LINEAGE; BINDING AB A major obstacle to a broadly neutralizing antibody (bnAb)-based HIV vaccine is the activation of appropriate B cell precursors. Germline-targeting immunogens must be capable of priming rare bnAb precursors in the physiological setting. We tested the ability of the VRCO1-class bnAb germline-targeting immunogen eOD-GT8 60mer (60-subunit self-assembling nanoparticle) to activate appropriate precursors in mice transgenic for human immunoglobulin (Ig) loci. Despite an average frequency of, at most, about one VRCO1-class precursor per mouse, we found that at least 29% of singly immunized mice produced a VRCO1-class memory response, suggesting that priming generally succeeded when at least one precursor was present. The results demonstrate the feasibility of using germline targeting to prime specific and exceedingly rare bnAb-precursor B cells within a humanlike repertoire. C1 [Sok, Devin; Briney, Bryan; Jardine, Joseph G.; Kulp, Daniel W.; Menis, Sergey; Pauthner, Matthias; Le, Khoa M.; Jones, Meaghan; Ramos, Alejandra; Kalyuzhniy, Oleksandr; Adachi, Yumiko; Kubitz, Michael; MacPherson, Skye; Schief, William R.; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Sok, Devin; Briney, Bryan; Jardine, Joseph G.; Kulp, Daniel W.; Menis, Sergey; Pauthner, Matthias; Le, Khoa M.; Jones, Meaghan; Ramos, Alejandra; Kalyuzhniy, Oleksandr; Adachi, Yumiko; Kubitz, Michael; MacPherson, Skye; Schief, William R.; Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat IAVI Neutralizing Antibo, La Jolla, CA 92037 USA. [Sok, Devin; Briney, Bryan; Jardine, Joseph G.; Kulp, Daniel W.; Menis, Sergey; Pauthner, Matthias; Le, Khoa M.; Jones, Meaghan; Ramos, Alejandra; Kalyuzhniy, Oleksandr; Adachi, Yumiko; Kubitz, Michael; MacPherson, Skye; Schief, William R.; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Wood, Andrew; Lee, E-Chiang; Bradley, Allan; Friedrich, Glenn A.] Kymab Ltd, Bennet Bldg B930,Babraham Res Campus, Cambridge CB22 3AT, England. [Bradley, Allan] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Schief, William R.; Burton, Dennis R.] MIT & Harvard, Massachusetts Gen Hosp, Ragan Inst, Cambridge, MA 02129 USA. RP Schief, WR; Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.; Schief, WR; Burton, DR (reprint author), Scripps Res Inst, Int AIDS Vaccine Initiat IAVI Neutralizing Antibo, La Jolla, CA 92037 USA.; Schief, WR; Burton, DR (reprint author), Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA.; Schief, WR; Burton, DR (reprint author), MIT & Harvard, Massachusetts Gen Hosp, Ragan Inst, Cambridge, MA 02129 USA. EM schief@scripps.edu; burton@scripps.edu FU IAVI; U.S. Agency for International Development; Ministry of Foreign Affairs of the Netherlands; Bill & Melinda Gates Foundation; Ragon Institute of MGH, MIT, and Harvard; Helen Hay Whitney Foundation; National Institute of Allergy and Infectious Diseases [P01 AI094419, CHAVI-ID 1UM1AI100663] FX We thank P. Kellam for comments on the manuscript. This work was partially funded by IAVI with the generous support of the U.S. Agency for International Development, Ministry of Foreign Affairs of the Netherlands, and the Bill & Melinda Gates Foundation; a full list of IAVI donors is available at www.iavi.org (W.R.S., D.R.B). This work was also supported by the Bill and Melinda Gates Foundation (G.A.F., A.B.); the Ragon Institute of MGH, MIT, and Harvard (D.R.B. and W.R.S.); the Helen Hay Whitney Foundation (J.G.J.); and National Institute of Allergy and Infectious Diseases grants P01 AI094419 (W.R.S.) and CHAVI-ID 1UM1AI100663 (W.R.S., D.R.B.). The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. All mice were maintained, and all procedures carried out, under United Kingdom Home Office License 70/8718 and with the approval of the Sanger Institute Animal Welfare and Ethical Review Body. The VRC01-class paired sequences described in this study were deposited in GenBank under accession numbers KX814864 to KX814919. Materials and information concerning the immunogens are available by material transfer agreement from the Scripps Research Institute. IAVI and the Scripps Research Institute have filed a patent (U.S. PCT Application no. PCT/US2016/038162) relating to the eOD-GT8 immunogens in this manuscript, which included inventors J.G.J., D.W.K., S.M., and W.R.S. W.R.S. is a cofounder and stockholder in Compuvax Inc., which has programs in non-HIV vaccine design that might benefit indirectly from this research. D.R.B. is a paid consultant of IAVI, which may benefit from this research. The Kymab mouse strains described are corporate assets protected by multiple patents; access to these mice is available through licensing. A.W., E-C. L., A.B., and G.F. hold equity in Kymab, Ltd., and Kymab, Ltd., holds patents and patent applications related to the Kymouse technology and the use of that technology in vaccine characterization. A.B. and G.F. are officers of Kymab, Ltd., which may benefit from this research. NR 43 TC 3 Z9 3 U1 5 U2 5 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 SEP 30 PY 2016 VL 353 IS 6307 BP 1557 EP 1560 DI 10.1126/science.aah3945 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB8YU UT WOS:000387678700050 PM 27608668 ER PT J AU Peterson, RL Galaleldeen, A Villarreal, J Taylor, AB Cabelli, DE Hart, PJ Culotta, VC AF Peterson, Ryan L. Galaleldeen, Ahmad Villarreal, Johanna Taylor, Alexander B. Cabelli, Diane E. Hart, P. John Culotta, Valeria C. TI The Phylogeny and Active Site Design of Eukaryotic Copper-only Superoxide Dismutases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; CANDIDA-ALBICANS; ZINC; BINDING; SOD1; GENE; PH; EVOLUTION; ERYTHROCUPREIN; MECHANISM AB In eukaryotes the bimetallic Cu/Zn superoxide dismutase (SOD) enzymes play important roles in the biology of reactive oxygen species by disproportionating superoxide anion. Recently, we reported that the fungal pathogen Candida albicans expresses a novel copper-only SOD, known as SOD5, that lacks the zinc cofactor and electrostatic loop (ESL) domain of Cu/Zn-SODs for substrate guidance. Despite these abnormalities, C. albicans SOD5 can disproportionate superoxide at rates limited only by diffusion. Here we demonstrate that this curious copper-only SOD occurs throughout the fungal kingdom as well as in phylogenetically distant oomycetes or "pseudofungi" species. It is the only form of extracellular SOD in fungi and oomycetes, in stark contrast to the extracellular Cu/Zn-SODs of plants and animals. Through structural biology and biochemical approaches we demonstrate that these copper-only SODs have evolved with a specialized active site consisting of two highly conserved residues equivalent to SOD5 Glu-110 and Asp-113. The equivalent positions are zinc binding ligands in Cu/ZnSODs and have evolved in copper-only SODs to control catalysis and copper binding in lieu of zinc and the ESL. Similar to the zinc ion in Cu/Zn-SODs, SOD5 Glu-110 helps orient a key copper-coordinating histidine and extends the pH range of enzyme catalysis. SOD5 Asp-113 connects to the active site in a manner similar to that of the ESL in Cu/Zn-SODs and assists in copper cofactor binding. Copper-only SODs are virulence factors for certain fungal pathogens; thus this unique active site may be a target for future anti-fungal strategies. C1 [Peterson, Ryan L.; Culotta, Valeria C.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. [Galaleldeen, Ahmad; Villarreal, Johanna] St Marys Univ, Dept Biol Sci, San Antonio, TX 78228 USA. [Galaleldeen, Ahmad; Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Cabelli, Diane E.] Brookhaven Natl Labs, Dept Chem, Upton, NY 11973 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. RP Culotta, VC (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. EM vculott1@jhu.edu FU National Institutes of Health [P41 GM103403, P30 CA054174]; United States Department of Energy [DE-AC02-06CH11357]; Office of the Vice President for Research; United States Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98-CH10886] FX We thank Drs. Julie Gleason and Brian Learn for helpful discussions and Professor Jiou Wang for assistance with protein purification. Support for Northeastern Collaborative Access Team beamline 24-ID-E was provided by National Institutes of Health Grant P41 GM103403 and United States Department of Energy Grant DE-AC02-06CH11357. The X-Ray Crystallography Core Laboratory at the University of Texas Health Science Center at San Antonio is supported in part by the Office of the Vice President for Research and by National Institutes of Health Grant P30 CA054174 (Cancer Therapy and Research Center). Pulse radiolysis studies were carried out using the Van de Graaff facilities of the BNL Accelerator Center for Energy Research, which is supported by United States Department of Energy, Office of Science, Office of Basic Energy Sciences through Grant DE-AC02-98-CH10886. NR 58 TC 0 Z9 0 U1 6 U2 6 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 SEP 30 PY 2016 VL 291 IS 40 BP 20911 EP 20923 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DY8UG UT WOS:000385406200010 PM 27535222 ER PT J AU Cheng, YF Tong, MJ Edge, ASB AF Cheng, Yen-Fu Tong, Mingjie Edge, Albert S. B. TI Destabilization of Atoh1 by E3 Ubiquitin Ligase Huwe1 and Casein Kinase 1 Is Essential for Normal Sensory Hair Cell Development SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAMMALIAN INNER-EAR; BETA-CATENIN; NEURAL DIFFERENTIATION; PROGENITOR CELLS; STEM-CELLS; NULL MICE; PROLIFERATION; DEGRADATION; EPITHELIA; PROTEIN AB Proneural basic helix-loop-helix transcription factor, Atoh1, plays a key role in the development of sensory hair cells. We show here that the level of Atoh1 must be accurately controlled by degradation of the protein in addition to the regulation of Atoh1 gene expression to achieve normal cellular patterning during development of the cochlear sensory epithelium. The stability of Atoh1 was regulated by the ubiquitin proteasome system through the action of Huwe1, a HECT-domain, E3 ubiquitin ligase. An interaction between Huwe1 and Atoh1 could be visualized by a proximity ligation assay and was confirmed by co-immunoprecipitation and mass spectrometry. Transfer of a lysine 48-linked polyubiquitin chain to Atoh1 by Huwe1 could be demonstrated both in intact cells and in a cell-free system, and proteasome inhibition or Huwe1 silencing increased Atoh1 levels. The interaction with Huwe1 and polyubiquitylation were blocked by disruption of casein kinase 1 (CK1) activity, and mass spectrometry and mutational analysis identified serine 334 as an important phosphorylation site for Atoh1 ubiquitylation and subsequent degradation. Phosphorylation by CK1 thus targeted the protein for degradation. Development of an extra row of inner hair cells in the cochlea and an approximate doubling in the number of afferent synapses was observed after embryonic or early postnatal deletion of Huwe1 in cochlear-supporting cells, and hair cells died in the early postnatal period when Huwe1 was knocked out in the developing cochlea. These data indicate that the regulation of Atoh1 by the ubiquitin proteasome pathway is necessary for hair cell fate determination and survival. C1 [Cheng, Yen-Fu; Edge, Albert S. B.] Harvard Univ, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02138 USA. [Cheng, Yen-Fu; Edge, Albert S. B.] MIT, Cambridge, MA 02138 USA. [Cheng, Yen-Fu; Tong, Mingjie; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Cheng, Yen-Fu; Tong, Mingjie; Edge, Albert S. B.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Edge, ASB (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM albert_edge@meei.harvard.edu FU National Institutes of Health [RO1 DC007174, P30 DC005209]; American Hearing Research Foundation; Yen Tjing Ling Medical Foundation (Taiwan); Amelia-Peabody Foundation; Shulsky Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants RO1 DC007174 and P30 DC005209 (NIDCD). This work was also supported by the American Hearing Research Foundation, the Yen Tjing Ling Medical Foundation (Taiwan), the Amelia-Peabody Foundation, the Shulsky Foundation, David H. Koch, and Robert Boucai. The authors declare that they have no conflicts of interest with the contents of this paper. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 51 TC 0 Z9 0 U1 3 U2 3 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 SEP 30 PY 2016 VL 291 IS 40 BP 21096 EP 21109 DI 10.1074/jbc.M116.722124 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DY8UG UT WOS:000385406200025 PM 27542412 ER PT J AU Choi, SG Wang, Q Jia, JJ Chikina, M Pincas, H Dolios, G Sasaki, K Wang, R Minamino, N Salton, SRJ Sealfon, SC AF Choi, Soon Gang Wang, Qian Jia, Jingjing Chikina, Maria Pincas, Hanna Dolios, Georgia Sasaki, Kazuki Wang, Rong Minamino, Naoto Salton, Stephen R. J. Sealfon, Stuart C. TI Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BONE MORPHOGENETIC PROTEIN-2; NEUROENDOCRINE REGULATORY PEPTIDE-1; GNRH PULSE FREQUENCY; BETA-SUBUNIT TRANSCRIPTION; PITUITARY-CELL-CULTURES; EARLY BREAST-CANCER; IN-VIVO; DIFFERENTIAL REGULATION; L-BETA-T2 CELLS; MALE RATS AB Reproductive function is controlled by the pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates the expression of the gonadotropins luteinizing hormone and FSH in pituitary gonadotropes. Paradoxically, Fshb gene expression is maximally induced at lower frequency GnRH pulses, which provide a very low average concentration of GnRH stimulation. We studied the role of secreted factors in modulating gonadotropin gene expression. Inhibition of secretion specifically disrupted gonadotropin subunit gene regulation but left early gene induction intact. We characterized the gonadotrope secretoproteome and global mRNA expression at baseline and after G alpha(s) knockdown, which has been found to increase Fshb gene expression (1). We identified 1077 secreted proteins or peptides, 19 of which showed mRNA regulation by GnRH or/and G alpha(s) knockdown. Among several novel secreted factors implicated in Fshb gene regulation, we focused on the neurosecretory protein VGF. Vgf mRNA, whose gene has been implicated in fertility (2), exhibited high induction by GnRH and depended on G alpha(s). In contrast with Fshb induction, Vgf induction occurred preferentially at high GnRH pulse frequency. We hypothesized that a VGF-derived peptide might regulate Fshb gene induction. siRNA knockdown or extracellular immunoneutralization of VGF augmented Fshb mRNA induction by GnRH. GnRH stimulated the secretion of the VGF-derived peptide NERP1. NERP1 caused a concentration-dependent decrease in Fshb gene induction. These findings implicate a VGF-derived peptide in selective regulation of the Fshb gene. Our results support the concept that signaling specificity from the cell membrane GnRH receptor to the nuclear Fshb gene involves integration of intracellular signaling and exosignaling regulatory motifs. C1 [Choi, Soon Gang; Wang, Qian; Jia, Jingjing; Chikina, Maria; Pincas, Hanna; Sealfon, Stuart C.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Dolios, Georgia; Wang, Rong] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Sealfon, Stuart C.] Icahn Sch Med Mt Sinai, Ctr Adv Res Diagnost Assays, New York, NY 10029 USA. [Salton, Stephen R. J.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Sasaki, Kazuki; Minamino, Naoto] Natl Cerebral & Cardiovasc Ctr, Res Inst, Dept Mol Pharmacol, Osaka 5658565, Japan. [Choi, Soon Gang] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. RP Sealfon, SC (reprint author), Icahn Sch Med Mt Sinai, Annenberg 14-44,Box 1137,One Gustave L Levy Pl, New York, NY 10029 USA. EM stuart.sealfon@mssm.edu OI Salton, Stephen/0000-0003-4087-8427 FU National Institutes of Health [DK46943, R21/R33 MH083496, RO1 DE021996, RO1 MH086499, P30 NS061777, S10 RR022415]; Diabetes Action and Education Foundation; Hope for Depression Research Foundation FX This work was supported by National Institutes of Health Grants DK46943, R21/R33 MH083496, RO1 DE021996, RO1 MH086499, P30 NS061777, and S10 RR022415; the Diabetes Action and Education Foundation; and the Hope for Depression Research Foundation. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 85 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 30 PY 2016 VL 291 IS 40 BP 21322 EP + DI 10.1074/jbc.M116.740365 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DY8UG UT WOS:000385406200042 PM 27466366 ER PT J AU Perkins, JM Lee, HY James, KS Oh, J Krishna, A Heo, J Lee, JK Subramanian, SV AF Perkins, Jessica M. Lee, Hwa-Young James, K. S. Oh, Juhwan Krishna, Aditi Heo, Jongho Lee, Jong-koo Subramanian, S. V. TI Marital status, widowhood duration, gender and health outcomes: a cross-sectional study among older adults in India SO BMC PUBLIC HEALTH LA English DT Article DE Widowhood; Aging; India; Gender; Self-rated health; Chronic disease; Cognition; Psychological distress ID CARDIOVASCULAR RISK-FACTORS; LATER LIFE; LONGITUDINAL ANALYSIS; SOCIOECONOMIC-STATUS; DEPRESSIVE SYMPTOMS; MORTALITY; MARRIAGE; SELECTION; CHINESE; WOMEN AB Background: Previous research has demonstrated health benefits of marriage and the potential for worse outcomes during widowhood in some populations. However, few studies have assessed the relevance of widowhood and widowhood duration to a variety of health-related outcomes and chronic diseases among older adults in India, and even fewer have examined these relationships stratified by gender. Methods: Using a cross-sectional representative sample of 9,615 adults aged 60 years or older from 7 states in diverse regions of India, we examine the relationship between widowhood and self-rated health, psychological distress, cognitive ability, and four chronic diseases before and after adjusting for demographic characteristics, socioeconomic status, living with children, and rural-urban location for men and women, separately. We then assess these associations when widowhood accounts for duration. Results: Being widowed as opposed to married was associated with worse health outcomes for women after adjusting for other explanatory factors. Widowhood in general was not associated with any outcomes for men except for cognitive ability, though men who were widowed within 0-4 years were at greater risk for diabetes compared to married men. Moreover, recently widowed women and women who were widowed long-term were more likely to experience psychological distress, worse self-rated health, and hypertension, even after adjusting for other explanatory variables, whereas women widowed 5-9 years were not, compared to married women. Conclusions: Gender, the duration of widowhood, and type of outcome are each relevant pieces of information when assessing the potential for widowhood to negatively impact health. Future research should explore how the mechanisms linking widowhood to health vary over the course of widowhood. Incorporating information about marital relationships into the design of intervention programs may help better target potential beneficiaries among older adults in India. C1 [Perkins, Jessica M.; Subramanian, S. V.] Harvard TH Chan Sch Publ Hlth, Harvard Ctr Populat & Dev Studies, Boston, MA USA. [Perkins, Jessica M.] Massachusetts Gen Hosp, Massachusetts Ctr Global Hlth, Boston, MA 02114 USA. [Lee, Hwa-Young; Oh, Juhwan; Heo, Jongho; Lee, Jong-koo] Seoul Natl Univ, Coll Med, JW LEE Ctr Global Med, 71 Ihwajang Gil, Seoul 110810, South Korea. [James, K. S.] Jawaharlal Nehru Univ, New Delhi, India. [Krishna, Aditi; Subramanian, S. V.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Heo, Jongho] San Diego State Univ, Publ Hlth Joint Doctoral Program, San Diego, CA 92182 USA. [Heo, Jongho] Univ Calif San Diego, San Diego, CA 92103 USA. [Lee, Jong-koo] Seoul Natl Univ, Coll Med, Dept Family Med, Seoul, South Korea. RP Lee, JK (reprint author), Seoul Natl Univ, Coll Med, JW LEE Ctr Global Med, 71 Ihwajang Gil, Seoul 110810, South Korea.; Lee, JK (reprint author), Seoul Natl Univ, Coll Med, Dept Family Med, Seoul, South Korea. EM docmohw@snu.ac.kr NR 87 TC 1 Z9 1 U1 8 U2 8 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 SEP 30 PY 2016 VL 16 AR 1032 DI 10.1186/s12889-016-3682-9 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX4UD UT WOS:000384375700001 PM 27716203 ER PT J AU Teng, MX Love, MI Davis, CA Djebali, S Dobin, A Graveley, BR Li, S Mason, CE Olson, S Pervouchine, D Sloan, CA Wei, XT Zhan, LJ Irizarry, RA AF Teng, Mingxiang Love, Michael I. Davis, Carrie A. Djebali, Sarah Dobin, Alexander Graveley, Brenton R. Li, Sheng Mason, Christopher E. Olson, Sara Pervouchine, Dmitri Sloan, Cricket A. Wei, Xintao Zhan, Lijun Irizarry, Rafael A. TI A benchmark for RNA-seq quantification pipelines (vol 17, 74, 2016) SO GENOME BIOLOGY LA English DT Correction C1 [Teng, Mingxiang; Love, Michael I.; Irizarry, Rafael A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Teng, Mingxiang; Love, Michael I.; Irizarry, Rafael A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. [Davis, Carrie A.; Dobin, Alexander] Cold Spring Harbor Lab, Funct Genom Grp, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. [Djebali, Sarah; Pervouchine, Dmitri] CRG, Bioinformat & Genom Programme, Doctor Aiguader 88, Barcelona 08003, Spain. [Djebali, Sarah; Pervouchine, Dmitri] UPF, Doctor Aiguader 88, Barcelona 08003, Spain. [Graveley, Brenton R.; Olson, Sara; Wei, Xintao; Zhan, Lijun] UConn Hlth Ctr, Inst Syst Genom, Dept Genet & Genome Sci, Farmington, CT 06030 USA. [Li, Sheng; Mason, Christopher E.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA. [Sloan, Cricket A.] Stanford Univ, Dept Genet, 300 Pasteur Dr,MC 5477, Stanford, CA 94305 USA. [Teng, Mingxiang] Harbin Inst Technol, Sch Comp Sci & Technol, Harbin, Peoples R China. RP Irizarry, RA (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA.; Irizarry, RA (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. EM rafa@jimmy.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD SEP 30 PY 2016 VL 17 AR 203 DI 10.1186/s13059-016-1060-7 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DX6AC UT WOS:000384463000002 PM 27716375 ER PT J AU Hung, HI Klein, OJ Peterson, SW Rokosh, SR Osseiran, S Nowell, NH Evans, CL AF Hung, Hsin-I Klein, Oliver J. Peterson, Sam W. Rokosh, Sarah R. Osseiran, Sam Nowell, Nicholas H. Evans, Conor L. TI PLGA nanoparticle encapsulation reduces toxicity while retaining the therapeutic efficacy of EtNBS-PDT in vitro SO SCIENTIFIC REPORTS LA English DT Article ID PHOTODYNAMIC THERAPY; EXTRACELLULAR ACIDITY; DRUG-RESISTANCE; OVARIAN-CANCER; LUNG-CANCER; CELLS; VIVO; HYPOXIA; HEAD; PHOTOSENSITIZERS AB Photodynamic therapy regimens, which use light-activated molecules known as photosensitizers, are highly selective against many malignancies and can bypass certain challenging therapeutic resistance mechanisms. Photosensitizers such as the small cationic molecule EtNBS (5-ethylamino-9-diethyl-aminobenzo[ a] phenothiazinium chloride) have proven potent against cancer cells that reside within acidic and hypoxic tumour microenvironments. At higher doses, however, these photosensitizers induce "dark toxicity" through light-independent mechanisms. In this study, we evaluated the use of nanoparticle encapsulation to overcome this limitation. Interestingly, encapsulation of the compound within poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-EtNBS) was found to significantly reduce EtNBS dark toxicity while completely retaining the molecule's cytotoxicity in both normoxic and hypoxic conditions. This dual effect can be attributed to the mechanism of release: EtNBS remains encapsulated until external light irradiation, which stimulates an oxygen-independent, radical-mediated process that degrades the PLGA nanoparticles and releases the molecule. As these PLGA-encapsulated EtNBS nanoparticles are capable of penetrating deeply into the hypoxic and acidic cores of 3D spheroid cultures, they may enable the safe and efficacious treatment of otherwise unresponsive tumour regions. C1 [Hung, Hsin-I; Klein, Oliver J.; Peterson, Sam W.; Rokosh, Sarah R.; Osseiran, Sam; Nowell, Nicholas H.; Evans, Conor L.] Massachusetts Gen Hosp, Harvard Med Sch, Wellman Ctr Photomed, 149 13th St, Charlestown, MA 02129 USA. [Osseiran, Sam] Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave E25-519, Cambridge, MA 02139 USA. RP Evans, CL (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Wellman Ctr Photomed, 149 13th St, Charlestown, MA 02129 USA. EM evans.conor@mgh.harvard.edu FU National Institutes of Health [1 DP2 OD007096-1]; Harvard Ludwig Center FX This work was supported by the National Institutes of Health through the NIH Director's New Innovator Award Program, Grant No. 1 DP2 OD007096-1 and the Harvard Ludwig Center. Information on the New Innovator Award Program can be found at http://nihroadmap.nih.gov/newinnovator/. NR 51 TC 0 Z9 0 U1 16 U2 16 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 SEP 30 PY 2016 VL 6 AR 33234 DI 10.1038/srep33234 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4GC UT WOS:000384338200001 PM 27686626 ER PT J AU Claycomb, M Roley, ME Contractor, AA Armour, C Dranger, P Wang, L Elhai, JD AF Claycomb, Meredith Roley, Michelle E. Contractor, Ateka A. Armour, Cherie Dranger, Paula Wang, Li Elhai, Jon D. TI The relationship between negative expressivity, anger, and PTSD symptom clusters SO PSYCHIATRY RESEARCH LA English DT Article DE PTSD; Negative expression; Anger ID POSTTRAUMATIC-STRESS-DISORDER; EXPOSURE AB More investigation is needed to understand how specific posttraumatic stress disorder (PTSD) symptom clusters relate to the internal experience of anger and overt negative behaviors in response to anger (negative expressivity). We investigated whether anger mediated relations between PTSD symptom clusters and negative expressivity. Multiple regression revealed lower PTSD intrusion symptoms associated with higher levels of negative expressivity. Anger mediated this relationship. Higher avoidance symptoms related to higher negative expressivity. Clinical implications, limitations, and strengths are discussed. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Claycomb, Meredith; Elhai, Jon D.] Univ Toledo, Dept Psychol, Mail Stop 948,2801 W Bancroft St, Toledo, OH 43606 USA. [Roley, Michelle E.] Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. [Roley, Michelle E.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. [Contractor, Ateka A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Armour, Cherie] Univ Ulster, Psychol Res Inst, Sch Psychol, Coleraine, Londonderry, North Ireland. [Dranger, Paula] Valparaiso Univ, Sexual Assault Awareness & Facilitat Educ Off SAA, Valparaiso, IN 46383 USA. [Dranger, Paula] Licensed Clin Addict Counseling Grad Certificate, Valparaiso, IN USA. [Wang, Li] Chinese Acad Sci, Inst Psychol, Key Lab Mental Hlth, Beijing, Peoples R China. [Elhai, Jon D.] Univ Toledo, Dept Psychiat, 2801 W Bancroft St, Toledo, OH 43606 USA. [Contractor, Ateka A.] Univ North Texas, Dept Psychol, Denton, TX 76203 USA. RP Elhai, JD (reprint author), Univ Toledo, Dept Psychol, Mail Stop 948,2801 W Bancroft St, Toledo, OH 43606 USA. EM contact@jon-elhai.com OI Armour, Cherie/0000-0001-7649-3874; Roley, Michelle/0000-0002-9269-418X FU Elsevier Foundation; DoD [W81XHW-07-1-0409]; NIH [1R21MH098198-01A1]; Ministry of Science and Technology of the People's Republic of China [2013BAI08B02]; Chinese Academy of Sciences [KJZD-EW-L04]; National Natural Science Foundation of China [31271099, 31471004] FX We wish to draw the Editor's attention to the following facts, which may be considered as potential conflicts of interest, and to financial contributions to this work. One coauthor, Jon Elhai, received financial support in the form of editorship fees from Elsevier Foundation, royalties from John Wiley and Sons, Other (occasional fees as an expert witness in court), and the Menninger Clinic. He also received financial support in the form of a Grant from DoD (W81XHW-07-1-0409) and NIH (1R21MH098198-01A1) accounting for 5% of his salary. Li Wang's work was supported by grants from the Ministry of Science and Technology of the People's Republic of China (No. 2013BAI08B02), the Chinese Academy of Sciences (No. KJZD-EW-L04), and the National Natural Science Foundation of China (Nos. 31271099, 31471004). No other co-authors have potential conflicts of interest to disclose and there has been no significant financial support for this work that could have influenced its outcome. NR 9 TC 0 Z9 0 U1 5 U2 5 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 SEP 30 PY 2016 VL 243 BP 1 EP 4 DI 10.1016/j.psychres.2016.06.012 PG 4 WC Psychiatry SC Psychiatry GA DW7EA UT WOS:000383812800001 PM 27343408 ER PT J AU Mitchell, KS Wolf, EJ AF Mitchell, Karen S. Wolf, Erika J. TI PTSD, food addiction, and disordered eating in a sample of primarily older veterans: The mediating role of emotion regulation SO PSYCHIATRY RESEARCH LA English DT Article DE Eating disorders; Men; Veterans ID POSTTRAUMATIC-STRESS-DISORDER; COMORBIDITY SURVEY-REPLICATION; WOMEN VETERANS; SUBSTANCE USE; SELF-REPORT; PREVALENCE; SCALE; VALIDATION; SYMPTOMS; CRITERIA AB Posttraumatic stress disorder (PTSD) has been associated with eating disorders (EDs) and addictive behaviors, including the relatively new construct food addiction. However, few studies have investigated mechanisms that account for these associations, and men are underrepresented in studies of EDs and food addiction. We examined whether lifetime PTSD symptoms were associated with current food addiction and ED symptoms, and whether emotion regulation (expressive suppression and cognitive re-appraisal), which has been associated with both PTSD and EDs, mediated these relations, in a sample of trauma-exposed, male (n=642) and female (n=55) veterans. Participants were recruited from the Knowledge Networks-GfK Research Panel and completed an online questionnaire. Structural equation modeling revealed that PTSD was directly associated with ED symptoms, food addiction, expressive suppression, and cognitive reappraisal in the full sample and with all constructs except cognitive re-appraisal in the male subsample. Expressive suppression was significantly associated with ED symptoms and mediated the PTSD- ED relation. These results highlight the importance of investigating PTSD as a risk factor for food addiction and ED symptoms and the potential mediating role of emotion regulation in the development of PTSD and EDs in order to identify targets for treatments. Published by Elsevier Ireland Ltd. C1 [Mitchell, Karen S.; Wolf, Erika J.] VA Boston Healthcare Syst, Natl Ctr PTSD, 150 S Huntington Ave 116B-3, Boston, MA 02130 USA. [Mitchell, Karen S.; Wolf, Erika J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Mitchell, KS (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 150 S Huntington Ave 116B-3, Boston, MA 02130 USA. EM karen.mitchell5@va.gov FU United States (U.S.) Department of Veterans Affairs, Clinical Sciences Research and Development Program; [K01 MH093750] FX Karen Mitchell's contribution was partly supported by K01 MH093750. This work was also supported by a Career Development Award to Erika J. Wolf from the United States (U.S.) Department of Veterans Affairs, Clinical Sciences Research and Development Program. The funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. 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. NR 52 TC 0 Z9 0 U1 7 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 SEP 30 PY 2016 VL 243 BP 23 EP 29 DI 10.1016/j.psychres.2016.06.013 PG 7 WC Psychiatry SC Psychiatry GA DW7EA UT WOS:000383812800004 PM 27344589 ER PT J AU Sippel, LM Mota, NP Kachadourian, LK Krystal, JH Southwick, SM Harpaz-Rotem, I Pietrzak, RH AF Sippel, Lauren M. Mota, Natalie P. Kachadourian, Lorig K. Krystal, John H. Southwick, Steven M. Harpaz-Rotem, Ilan Pietrzak, Robert H. TI The burden of hostility in US Veterans: Results from the National Health and Resilience in Veterans Study SO PSYCHIATRY RESEARCH LA English DT Article DE Risk factors; Protective factors; Anger; Aggression; Veterans ID POSTTRAUMATIC-STRESS-DISORDER; RISK-FACTORS; VIETNAM VETERANS; ALCOHOL-CONSUMPTION; MILITARY PERSONNEL; BEHAVIORAL RISK; SOCIAL SUPPORT; AUDIT-C; VIOLENCE; VALIDATION AB Hostility is associated with substantial mental and physical health consequences. Population-based data regarding the nature and longitudinal course of hostility in U.S. veterans are scarce. We analyzed data from 2157 U.S. veterans who participated in the National Health and Resilience in Veterans Study, a nationally representative, prospective cohort study of U.S. veterans. We identified the prevalence of longitudinal courses of hostility (chronic, increasing, decreasing, or no hostility). We then evaluated relationships between sociodemographic, risk, and protective correlates measured at baseline and longitudinal courses of two aspects of hostility-aggressive urges and difficulties controlling anger. The majority of veterans (61.2%) reported experiencing difficulties controlling anger and a sizable minority of veterans (23.9%) reported experiencing aggressive urges over a two-year period. Protective psychosocial characteristics (e.g., optimism) and aspects of social connectedness (e.g., secure attachment style) were negatively associated with hostility. Psychological distress predicted all symptomatic hostility courses, while alcohol misuse predicted chronic aggressive urges and all symptomatic courses of difficulties controlling anger. These findings provide the first known population-based evaluation of the prevalence, course, and risk and protective correlates of hostility in U.S. veterans, and suggest targets for prevention and treatment efforts that can help mitigate risk for hostility in this population. Published by Elsevier Ireland Ltd. C1 [Sippel, Lauren M.; Mota, Natalie P.; Kachadourian, Lorig K.; Krystal, John H.; Southwick, Steven M.; Harpaz-Rotem, Ilan; Pietrzak, Robert H.] US Dept Vet Affairs, Natl Ctr PTSD, VA Connecticut Healthcare Syst, 950 Campbell Ave 15W, West Haven, CT USA. [Sippel, Lauren M.; Mota, Natalie P.; Kachadourian, Lorig K.; Krystal, John H.; Southwick, Steven M.; Harpaz-Rotem, Ilan; Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, 333 Cedar St, New Haven, CT USA. [Mota, Natalie P.] Univ Manitoba, Dept Clin Hlth Psychol, Winnipeg, MB, Canada. RP Sippel, LM (reprint author), VA Connecticut Healthcare Syst, Natl Ctr PTSD, 950 Campbell Ave 151D, West Haven, CT 06516 USA. EM lauren.sippel@yale.edu FU Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs; U. S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder FX Preparation of this manuscript was supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs (regarding the authors Lauren M. Sippel and Lorig K. Kachadourian). The National Health and Resilience in Veterans Study was supported by the U. S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder and a private donation. The views and opinions expressed in this report are those of the authors and should not be construed to represent the U. S. government. The funding source had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 55 TC 1 Z9 1 U1 9 U2 9 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 SEP 30 PY 2016 VL 243 BP 421 EP 430 DI 10.1016/j.psychres.2016.06.040 PG 10 WC Psychiatry SC Psychiatry GA DW7EA UT WOS:000383812800066 PM 27450745 ER PT J AU Hough, CM Luks, TL Lai, KR Vigil, O Guillory, S Nongpiur, A Fekri, SM Kupferman, E Mathalon, DH Mathews, CA AF Hough, Christina M. Luks, Tracy L. Lai, Karen Vigil, Ofilio Guillory, Sylvia Nongpiur, Arvind Fekri, Shiva M. Kupferman, Eve Mathalon, Daniel H. Mathews, Carol A. TI Comparison of brain activation patterns during executive function tasks in hoarding disorder and non-hoarding OCD SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Neuroimaging; fMRI; Stroop; Go/No-go; Conflict monitoring; Response inhibition; Hoarding disorder ID OBSESSIVE-COMPULSIVE DISORDER; ANTERIOR CINGULATE CORTEX; VOXEL-BASED MORPHOMETRY; RESPONSE-INHIBITION; COGNITIVE CONTROL; SYMPTOM DIMENSIONS; ERROR-DETECTION; NEURAL MECHANISMS; DECISION-MAKING; GO/NOGO TASK AB We examined differences in regional brain activation during tests of executive function in individuals with Hoarding Disorder (HD), Obsessive Compulsive Disorder (OCD), and healthy controls (HC) using functional magnetic resonance imaging (fMRI). Participants completed computerized versions of the Stroop and Go/No-Go task. We found that during the conflict monitoring and response inhibition condition in the Go/No-Go task, individuals with HD had significantly greater activity than controls in the anterior cingulate cortex (ACC) and right dorsolateral prefrontal cortex (DLPFC). HD also exhibited significantly greater right DLPFC activity than OCD. We also observed significant differences in activity between HD and HC and between HD and OCD in regions (ACC, anterior insula, orbitofrontal cortex, and striatum) involved in evaluating stimulus-response-reward associations, or the personal and task-relevant value of stimuli and behavioral responses to stimuli. These results support the hypothesis that individuals with HD have difficulty deciding on the value or task relevance of stimuli, and may perceive an abnormally high risk of negative feedback for difficult or erroneous cognitive behavior. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Hough, Christina M.; Lai, Karen; Vigil, Ofilio; Guillory, Sylvia; Fekri, Shiva M.; Kupferman, Eve; Mathalon, Daniel H.; Mathews, Carol A.] Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA USA. [Luks, Tracy L.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Guillory, Sylvia; Mathalon, Daniel H.] San Francisco VA Med Ctr, Dept Psychiat, San Francisco, CA USA. [Nongpiur, Arvind; Mathews, Carol A.] Univ Florida, Dept Psychiat, Gainesville, FL 32611 USA. [Nongpiur, Arvind] North Eastern Indira Gandhi Reg Inst Hlth & Med S, Dept Psychiat, Shillong, Meghalaya, India. [Lai, Karen] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Vigil, Ofilio] Univ Calif Davis, Davis, CA 95616 USA. [Guillory, Sylvia] Univ Massachusetts, Dept Psychol, Boston, MA 02125 USA. [Fekri, Shiva M.] Univ Colorado, Dept Psychol, Denver, CO 80202 USA. RP Mathews, CA (reprint author), Univ Florida, Coll Med, 100 S Newell Dr L4-100, Gainesville, FL 32610 USA. EM carolmathews@ufl.edu FU NIMH [R21 MH087748, K08 MH081065, R01 0977669]; Fogarty International Training Program in Chronic Non-Communicable Diseases and Disorders at the University of Florida [1D43TW009120] FX This research was supported by NIMH Grants R21 MH087748, K08 MH081065 and R01 0977669, and a gift from the Althea Foundation. Post-Doctoral support to AN is by the Fogarty International Training Program in Chronic Non-Communicable Diseases and Disorders at the University of Florida, Grant # 1D43TW009120 (Cottler PI). NR 71 TC 0 Z9 0 U1 13 U2 13 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 SEP 30 PY 2016 VL 255 BP 50 EP 59 DI 10.1016/j.pscychresns.2016.07.007 PG 10 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DW8VY UT WOS:000383934800007 PM 27522332 ER PT J AU Nelms, BD Waldron, L Barrera, LA Weflen, AW Goettel, JA Guo, GJ Montgomery, RK Neutra, MR Breault, DT Snapper, SB Orkin, SH Bulyk, ML Huttenhower, C Lencer, WI AF Nelms, Bradlee D. Waldron, Levi Barrera, Luis A. Weflen, Andrew W. Goettel, Jeremy A. Guo, Guoji Montgomery, Robert K. Neutra, Marian R. Breault, David T. Snapper, Scott B. Orkin, Stuart H. Bulyk, Martha L. Huttenhower, Curtis Lencer, Wayne I. TI CellMapper: rapid and accurate inference of gene expression in difficult-to-isolate cell types SO GENOME BIOLOGY LA English DT Article DE Cell type; Expression; Microarray; Genome-wide association study; Inflammatory bowel disease ID INFLAMMATORY-BOWEL-DISEASE; BRAIN TRANSCRIPTOME; MICROARRAY DATA; MOUSE; DECONVOLUTION; DATABASE; COEXPRESSION; INFORMATION; PREDICTION; DIVERSITY AB We present a sensitive approach to predict genes expressed selectively in specific cell types, by searching publicly available expression data for genes with a similar expression profile to known cell-specific markers. Our method, CellMapper, strongly outperforms previous computational algorithms to predict cell type-specific expression, especially for rare and difficult-to-isolate cell types. Furthermore, CellMapper makes accurate predictions for human brain cell types that have never been isolated, and can be rapidly applied to diverse cell types from many tissues. We demonstrate a clinically relevant application to prioritize candidate genes in disease susceptibility loci identified by GWAS. C1 [Nelms, Bradlee D.; Weflen, Andrew W.; Goettel, Jeremy A.; Montgomery, Robert K.; Neutra, Marian R.; Snapper, Scott B.; Lencer, Wayne I.] Childrens Hosp, Div Gastroenterol, 300 Longwood Ave, Boston, MA 02115 USA. [Nelms, Bradlee D.; Barrera, Luis A.; Weflen, Andrew W.; Goettel, Jeremy A.; Montgomery, Robert K.; Neutra, Marian R.; Breault, David T.; Snapper, Scott B.; Orkin, Stuart H.; Bulyk, Martha L.; Lencer, Wayne I.] Harvard Med Sch, Boston, MA 02115 USA. [Nelms, Bradlee D.; Barrera, Luis A.; Lencer, Wayne I.] Harvard Univ, Grad Program Biophys, Cambridge, MA 02138 USA. [Waldron, Levi] CUNY, Sch Publ Hlth, New York, NY 10027 USA. [Barrera, Luis A.; Bulyk, Martha L.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Barrera, Luis A.; Bulyk, Martha L.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Guo, Guoji] Zhejiang Univ, Sch Med, Ctr Stem Cell & Regenerat Med, Hangzhou 310058, Zhejiang, Peoples R China. [Neutra, Marian R.; Breault, David T.; Snapper, Scott B.; Lencer, Wayne I.] Harvard Med Sch, Harvard Digest Dis Ctr, Boston, MA 02115 USA. [Breault, David T.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Snapper, Scott B.] Brigham & Womens Hosp, Dept Gastroenterol, 75 Francis St, Boston, MA 02115 USA. [Orkin, Stuart H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Childrens Hosp, Harvard Stem Cell Inst, 300 Longwood Ave, Boston, MA 02115 USA. [Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Huttenhower, Curtis] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Nelms, BD (reprint author), Childrens Hosp, Div Gastroenterol, 300 Longwood Ave, Boston, MA 02115 USA.; Nelms, BD (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM bnelms.research@gmail.com; wayne.lencer@childrens.harvard.edu OI Nelms, Bradlee/0000-0002-2381-2170; Waldron, Levi/0000-0003-2725-0694 FU US National Science Foundation Graduate Research Fellowship; NIDDK Harvard Digestive Disease Center from the National Institutes of Health [P30 DK034854]; National Institutes of Health [R01 HG003985]; NIH/NCC Comprehensive Cancer Center [P30 CA06516]; [R01 DK084424]; [R01 DK048106] FX This project was supported by a US National Science Foundation Graduate Research Fellowship to B.D.N. and L.A.B., by grants R01 DK084424, R01 DK048106, and the NIDDK Harvard Digestive Disease Center P30 DK034854 from the National Institutes of Health to W.I.L, grant R01 HG003985 from the National Institutes of Health to M.L.B., and by the NIH/NCC Comprehensive Cancer Center through grant P30 CA06516. NR 55 TC 1 Z9 1 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD SEP 29 PY 2016 VL 17 AR 201 DI 10.1186/s13059-016-1062-5 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DX6AA UT WOS:000384462800003 PM 27687735 ER PT J AU Ha, K Shen, YP Graves, T Kim, CH Kim, HG AF Ha, Kyungsoo Shen, Yiping Graves, Tyler Kim, Cheol-Hee Kim, Hyung-Goo TI The presence of two rare genomic syndromes, 1q21 deletion and Xq28 duplication, segregating independently in a family with intellectual disability SO MOLECULAR CYTOGENETICS LA English DT Article DE Intellectual disability; 1q21 microdeletion; MECP2; Xq28 duplication; X chromosome inactivation; Segregation of two rare syndromes ID ZONULAR PULVERULENT CATARACT; SEVERE MENTAL-RETARDATION; RETT-SYNDROME; COPY-NUMBER; MILD OVEREXPRESSION; ATRIAL-FIBRILLATION; MECP2 DUPLICATIONS; CHROMOSOME 1Q21.1; MUTATION ANALYSIS; BINDING PROTEIN AB Background: 1q21 microdeletion syndrome is a rare contiguous gene deletion disorder with de novo or autosomal dominant inheritance patterns and its phenotypic features include intellectual disability, distinctive facial dysmorphism, microcephaly, cardiac abnormalities, and cataracts. MECP2 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by intellectual disability, global developmental delay, and other neurological complications including late-onset seizures. Previously, these two different genetic syndromes have not been reported segregating independently in a same family. Case presentation: Here we describe two siblings carrying either a chromosome 1q21 microdeletion or a chromosome Xq28 duplication. Using a comparative genomic hybridization (CGH) array, we identified a 1.24 Mb heterozygous deletion at 1q21 resulting in the loss of 9 genes in a girl with learning disability, hypothyroidism, short stature, sensory integration disorder, and soft dysmorphic features including cupped ears and a unilateral ear pit. We also characterized a 508 kb Xq28 duplication encompassing MECP2 in her younger brother with hypotonia, poor speech, cognitive and motor impairment. The parental CGH and quantitative PCR (qPCR) analyses revealed that the 1q21 deletion in the elder sister is de novo, but the Xq28 duplication in the younger brother was originally inherited from the maternal grandmother through the mother, both of whom are asymptomatic carriers. RT-qPCR assays revealed that the affected brother has almost double the amount of MECP2 mRNA expression compared to other family members of both genders including maternal grandmother and mother who have the same Xq28 duplication with no phenotype. This suggests the X chromosome with an Xq28 duplication in the carrier females is preferentially silenced. Conclusion: From our understanding, this would be the first report showing the independent segregation of two genetically unrelated syndromes, 1q21 microdeletion and Xq28 duplication, in a same family, especially in siblings. Although these two chromosomal abnormalities share some similar phenotypes such as intellectual disability, mild dysmorphic features, and cardiac abnormalities, the presence of two unrelated and rare syndromes in siblings is very unusual. Therefore, further comprehensive investigations in similar cases are required for future studies. C1 [Ha, Kyungsoo] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA. [Ha, Kyungsoo; Graves, Tyler; Kim, Hyung-Goo] Augusta Univ, Dept Obstet & Gynecol, Sect Reprod Endocrinol Infertil & Genet, Augusta, GA 30912 USA. [Shen, Yiping] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kim, Cheol-Hee] Chungnam Natl Univ, Dept Biol, Daejeon 34134, South Korea. [Kim, Hyung-Goo] Augusta Univ, Dept Neurosci & Regenerat Med, 1120 15th St, Augusta, GA 30912 USA. RP Kim, HG (reprint author), Augusta Univ, Dept Obstet & Gynecol, Sect Reprod Endocrinol Infertil & Genet, Augusta, GA 30912 USA. EM hkim@augusta.edu FU NIH [T32HL07676]; Bio & Medical Technology Development Program of the National Research Foundation (NRF) - Ministry of Science, ICT Future [NRF-2015M3A9A8029261]; National Research Foundation of Korea (NRF) grant - Korean government Ministry of Science, ICT and Future Planning (MSIP) [2014R1A2A1A11053562] FX KH is supported by a postdoctoral training grant from NIH (T32HL07676). CK was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future (NRF-2015M3A9A8029261) and the National Research Foundation of Korea (NRF) grant funded by the Korean government Ministry of Science, ICT and Future Planning (MSIP) (2014R1A2A1A11053562). We are also grateful for the funding support provided by Caroline Jones-Carrick and Collin Carrick. NR 61 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8166 J9 MOL CYTOGENET JI Mol. Cytogenet. PD SEP 29 PY 2016 VL 9 AR 74 DI 10.1186/s13039-016-0286-0 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DX6BG UT WOS:000384466600001 PM 27708714 ER PT J AU Lindblad, O Cordero, E Puissant, A Macaulay, L Ramos, A Kabir, NN Sun, J Vallon-Christersson, J Haraldsson, K Hemann, MT Borg, A Levander, F Stegmaier, K Pietras, K Ronnstrand, L Kazi, JU AF Lindblad, O. Cordero, E. Puissant, A. Macaulay, L. Ramos, A. Kabir, N. N. Sun, J. Vallon-Christersson, J. Haraldsson, K. Hemann, M. T. Borg, A. Levander, F. Stegmaier, K. Pietras, K. Ronnstrand, L. Kazi, J. U. TI Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML SO ONCOGENE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; FLT3-ITD+ AML; IN-VITRO; FLT3; MUTATIONS; INHIBITORS; KINASE; PKC412; SENSITIVITY; RAPAMYCIN AB Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3. C1 [Lindblad, O.; Cordero, E.; Macaulay, L.; Sun, J.; Pietras, K.; Ronnstrand, L.; Kazi, J. U.] Lund Univ, Dept Lab Med, Div Translat Canc Res, Medicon Village 404 C3, S-22363 Lund, Skane, Sweden. [Lindblad, O.; Macaulay, L.; Sun, J.; Ronnstrand, L.; Kazi, J. U.] Lund Univ, Dept Lab Med, Lund Stem Cell Ctr, Lund, Sweden. [Lindblad, O.] Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden. [Puissant, A.; Stegmaier, K.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Puissant, A.; Stegmaier, K.] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA. [Ramos, A.; Hemann, M. T.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kabir, N. N.; Kazi, J. U.] KN Biomed Res Inst, Lab Computat Biochem, Barisal, Bangladesh. [Vallon-Christersson, J.; Haraldsson, K.; Borg, A.] Lund Univ, Dept Oncol & Pathol, Lund, Sweden. [Levander, F.] Lund Univ, Dept Immunotechnol, BILS, Lund, Sweden. RP Kazi, JU (reprint author), Lund Univ, Dept Lab Med, Div Translat Canc Res, Medicon Village 404 C3, S-22363 Lund, Skane, Sweden. EM kazi.uddin@med.lu.se OI Vallon-Christersson, Johan/0000-0002-2195-0385; Kazi, Julhash/0000-0002-0719-5336 FU Kungliga Fysiografiska Sallskapet i Lund; Ollie and Elof Ericssons Stiftelse; Ake-Wiberg Stiftelse; Lars Hiertas Minne Stiftelse; Stiftelsen Olle Engkvist Byggmastare; Harald Jeanssons Stiftelse and Harald och Greta Jeanssons Stiftelse; Swedish Childhood Cancer Foundation; Crafoord foundation; Stiftelsen Clas Groschinskys Minnesfond; Swedish Cancer Foundation; Swedish Research Council; Region Skane; Research Funds at Skane University Hospital; Gunnar Nilssons Cancer Foundation; NIH [R01CA140292] FX We thank Dr Peter J Valk at Erasmus University Medical Center for help with AML patient data and Dr David Weinstock for leading the development of a bank of patient-derived xenograft models of leukemia at the DFCI. This research was funded by Kungliga Fysiografiska Sallskapet i Lund (JUK), Ollie and Elof Ericssons Stiftelse (JUK), Ake-Wiberg Stiftelse (JUK), Lars Hiertas Minne Stiftelse (JUK), Stiftelsen Olle Engkvist Byggmastare (JUK), Harald Jeanssons Stiftelse and Harald och Greta Jeanssons Stiftelse (JUK), the Swedish Childhood Cancer Foundation (JUK), the Crafoord foundation (JUK), Stiftelsen Clas Groschinskys Minnesfond (JUK), Swedish Cancer Foundation (LR), Swedish Research Council (LR), Region Skane (LR), the Research Funds at Skane University Hospital (LR), Gunnar Nilssons Cancer Foundation (LR) and the NIH R01CA140292 (KS). JUK is a recipient of Assistant Professorship (forskarassistenttjanst) grant from the Swedish Childhood Cancer Foundation. KP is the Goran & Birgitta Grosskopf Professor of Molecular Medicine at Lund University. NR 45 TC 4 Z9 4 U1 5 U2 5 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 SEP 29 PY 2016 VL 35 IS 39 BP 5119 EP 5131 DI 10.1038/onc.2016.41 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DX5PI UT WOS:000384433000004 PM 26999641 ER PT J AU Irwin, KE Freudenreich, O Peppercorn, J Taghian, AG Freer, PE Gudewicz, TM AF Irwin, Kelly E. Freudenreich, Oliver Peppercorn, Jeffrey Taghian, Alphonse G. Freer, Phoebe E. Gudewicz, Thomas M. TI Case 30-2016: A 63-Year-Old Woman with Bipolar Disorder, Cancer, and Worsening Depression SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POSITIVE BREAST-CANCER; MENTAL-ILLNESS; SCHIZOPHRENIA; MORTALITY; RADIOTHERAPY; COHORT; WOMEN; CARE; STATES; TRIAL C1 [Irwin, Kelly E.; Freudenreich, Oliver] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Freer, Phoebe E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Gudewicz, Thomas M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Peppercorn, Jeffrey] Massachusetts Gen Hosp, Div Med Oncol, Boston, MA 02114 USA. [Irwin, Kelly E.; Freudenreich, Oliver] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. [Peppercorn, Jeffrey] Harvard Med Sch, Dept Med, Boston, MA USA. [Taghian, Alphonse G.] Harvard Med Sch, Dept Radiat Oncol, Boston, MA USA. [Freer, Phoebe E.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Gudewicz, Thomas M.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Irwin, KE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Irwin, KE (reprint author), Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. OI Freer, Phoebe/0000-0001-6886-7100 NR 22 TC 0 Z9 0 U1 4 U2 4 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 SEP 29 PY 2016 VL 375 IS 13 BP 1270 EP 1281 DI 10.1056/NEJMcpc1609309 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DX3HU UT WOS:000384265000011 PM 27682037 ER PT J AU Salik, J AF Salik, Jonathan TI Crystallopathies SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Salik, Jonathan] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Salik, J (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jsalik@partners.org NR 3 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 SEP 29 PY 2016 VL 375 IS 13 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DX3HU UT WOS:000384265000031 ER PT J AU Rosenbluh, J Mercer, J Shrestha, Y Oliver, R Tamayo, P Doench, JG Tirosh, I Piccioni, F Hartenian, E Horn, H Fagbami, L Root, DE Jaffe, J Lage, K Boehm, JS Hahn, WC AF Rosenbluh, Joseph Mercer, Johnathan Shrestha, Yashaswi Oliver, Rachel Tamayo, Pablo Doench, John G. Tirosh, Itay Piccioni, Federica Hartenian, Ella Horn, Heiko Fagbami, Lola Root, David E. Jaffe, Jacob Lage, Kasper Boehm, Jesse S. Hahn, William C. TI Genetic and Proteomic Interrogation of Lower Confidence Candidate Genes Reveals Signaling Networks in beta-Catenin-Active Cancers SO CELL SYSTEMS LA English DT Article ID HUMAN-CELLS; INTERACTION MAP; SCREENS; GENOME; COMPLEX; VULNERABILITIES; PATHWAY; QUANTIFICATION; IDENTIFICATION; REGULATORS AB Genome-scale expression studies and comprehensive loss-of-function genetic screens have focused almost exclusively on the highest confidence candidate genes. Here, we describe a strategy for characterizing the lower confidence candidates identified by such approaches. We interrogated 177 genes that we classified as essential for the proliferation of cancer cells exhibiting constitutive beta-catenin activity and integrated data for each of the candidates, derived from orthogonal short hairpin RNA (shRNA) knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-mediated gene editing knockout screens, to yield 69 validated genes. We then characterized the relationships between sets of these genes using complementary assays: medium-throughput stable isotope labeling by amino acids in cell culture (SILAC)-based mass spectrometry, yielding 3,639 protein-protein interactions, and a CRISPR-mediated pairwise double knockout screen, yielding 375 combinations exhibiting greateror lesser-than-additive phenotypic effects indicating genetic interactions. These studies identify previously unreported regulators of beta-catenin, define functional networks required for the survival of beta-catenin- active cancers, and provide an experimental strategy that may be applied to define other signaling networks. C1 [Rosenbluh, Joseph; Mercer, Johnathan; Shrestha, Yashaswi; Oliver, Rachel; Doench, John G.; Tirosh, Itay; Piccioni, Federica; Hartenian, Ella; Horn, Heiko; Fagbami, Lola; Root, David E.; Jaffe, Jacob; Lage, Kasper; Boehm, Jesse S.; Hahn, William C.] Broad Inst Harvard & MIT, 415 Main St, Cambridge, MA 02142 USA. [Rosenbluh, Joseph; Oliver, Rachel; Hahn, William C.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Mercer, Johnathan; Horn, Heiko; Lage, Kasper] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Tamayo, Pablo] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Tamayo, Pablo] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. RP Hahn, WC (reprint author), Broad Inst Harvard & MIT, 415 Main St, Cambridge, MA 02142 USA.; Hahn, WC (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM william_hahn@dfci.harvard.edu FU Carlos Slim Foundation in Mexico; NIH [U01 CA176058, R01-CA154480-01A1] FX We would like to thank Chet Birger for help with analysis of the double CRISPR-Cas9 screen. This work was conducted as part of the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico and was funded in part by NIH grants U01 CA176058 (W.C.H.) and R01-CA154480-01A1 (P.T.). NR 53 TC 1 Z9 1 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD SEP 28 PY 2016 VL 3 IS 3 BP 302 EP + DI 10.1016/j.cels.2016.09.001 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN1MW UT WOS:000395775300012 PM 27684187 ER PT J AU Wiens, MO Kumbakumba, E Larson, CP Moschovis, PP Barigye, C Kabakyenga, J Ndamira, A English, L Kissoon, N Zhou, GH Ansermino, JM AF Wiens, Matthew O. Kumbakumba, Elias Larson, Charles P. Moschovis, Peter P. Barigye, Celestine Kabakyenga, Jerome Ndamira, Andrew English, Lacey Kissoon, Niranjan Zhou, Guohai Ansermino, J. Mark TI Scheduled Follow-Up Referrals and Simple Prevention Kits Including Counseling to Improve Post-Discharge Outcomes Among Children in Uganda: A Proof-of-Concept Study SO GLOBAL HEALTH-SCIENCE AND PRACTICE LA English DT Article ID BURDEN AB Post-hospital discharge is a vulnerable time for recurrent illness and death among children. An intervention package consisting of (1) referrals for scheduled follow-up visits, (2) discharge counseling, and (3) simple prevention items such as soap and oral rehydration salts resulted in much higher health seeking and hospital readmissions compared with historical controls. Background: Recurrent illness following hospital discharge is a major contributor to childhood mortality in resource-poor countries. Yet post-discharge care is largely ignored by health care workers and policy makers due to a lack of resources to identify children with recurrent illness and a lack of cohesive systems to provide care. The purpose of this proof-of-concept study was to evaluate the effectiveness of a bundle of interventions at discharge to improve health outcomes during the vulnerable post-discharge period. Methods: The study was conducted between December 2014 and April 2015. Eligible children were between ages 6 months and 5 years who were admitted with a suspected or proven infectious disease to one of two hospitals in Mbarara, Uganda. A bundle of interventions was provided at the time of discharge. This bundle included post-discharge referrals for follow-up visits and a discharge kit. The post-discharge referral was to ensure follow-up with a nearby health care provider on days 2, 7, and 14 following discharge. The discharge kit included brief educational counseling along with simple preventive items as incentives (soap, a mosquito net, and oral rehydration salts) to reinforce the education. The primary study outcome was the number of post-discharge referral visits completed. Secondary study outcomes included satisfaction with the intervention, rates of readmission after 60 days, and post-discharge mortality rates. In addition, outcomes were compared with a historical control group, enrolled using the same inclusion criteria and outcome-ascertainment methods. Results: During the study, 216 children were admitted, of whom 14 died during hospitalization. Of the 202 children discharged, 85% completed at least 1 of the 3 follow-up referral visits, with 48% completing all 3 visits. Within 60 days after discharge, 22 children were readmitted at least once and 5 children (2.5%) died. Twelve (43%) readmissions occurred during a scheduled follow-up visit. Compared with prospectively enrolled historical controls, the post-discharge referral for follow-up increased the odds of readmission (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.14 to 3.23) and care sought after discharge (OR, 14.61; 95% CI, 9.41 to 22.67). Overall satisfaction with the bundle of interventions was high, with most caregivers strongly agreeing that the discharge kit and post-discharge referrals improved their ability to care for their child. Conclusions: Interventions initiated at the time of discharge have the potential to profoundly affect the landscape of care during illness recovery and lead to significantly improved outcomes among children under 5 years of age. C1 [Wiens, Matthew O.; Kumbakumba, Elias; Larson, Charles P.; Kissoon, Niranjan; Zhou, Guohai; Ansermino, J. Mark] Univ British Columbia, Vancouver, BC, Canada. [Moschovis, Peter P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barigye, Celestine; Kabakyenga, Jerome; Ndamira, Andrew] Mbarara Univ Sci & Technol, Mbarara, Uganda. [English, Lacey] Univ N Carolina, Chapel Hill, NC USA. RP Wiens, MO (reprint author), Univ British Columbia, Vancouver, BC, Canada. EM mowiens@outlook.com OI Ansermino, J Mark/0000-0001-8427-2035 FU Grand Challenges Canada; Mitacs Canada; National Institutes of Health [5-F32-HL124951]; Thrasher Research Fund FX This study was funded by Grand Challenges Canada. Dr. Wiens is supported by a fellowship from Mitacs Canada. Dr. Moschovis is supported by the National Institutes of Health (5-F32-HL124951) and the Thrasher Research Fund. We gratefully acknowledge the contributions of Annet Twinomuguni, Justine Kamazima, Clare Komugisha, Solome Kobugyenyi, Brenda Kembabazi, Alexander Mutungi, and Hassan Bariahikwa. Without their dedication, this study could not have been completed. NR 9 TC 0 Z9 0 U1 1 U2 1 PU US AGENCY INT DEVELOPMENT-USAID PI BALTIMORE PA US AGENCY INT DEVELOPMENT-USAID, BALTIMORE, MD 00000 USA SN 2169-575X J9 GLOB HEALTH-SCI PRAC JI Glob. Health PD SEP 28 PY 2016 VL 4 IS 3 BP 422 EP 434 DI 10.9745/GHSP-D-16-00069 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EG6UF UT WOS:000391181100008 PM 27628107 ER PT J AU Darcq, E Morisot, N Phamluong, K Warnault, V Jeanblanc, J Longo, FM Massa, SM Ron, D AF Darcq, Emmanuel Morisot, Nadege Phamluong, Khanhky Warnault, Vincent Jeanblanc, Jerome Longo, Frank M. Massa, Stephen M. Ron, Dorit TI The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking SO JOURNAL OF NEUROSCIENCE LA English DT Article DE addiction; alcohol; BDNF; dorsal striatum; neurotrophic factor; p75NTR ID NERVE GROWTH-FACTOR; ETHANOL-CONSUMPTION; CORTICOSTRIATAL BDNF; HOMEOSTATIC PATHWAY; GENE POLYMORPHISM; PROTEIN-SYNTHESIS; RNA INTERFERENCE; SERUM-LEVELS; P75(NTR); ACTIVATION AB Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) keeps alcohol intake in moderation. For example, activation of the BDNF receptor tropomyosin receptor kinase B (TrkB) in the DLS reduces intake in rats that consume moderate amounts of alcohol. Here, we tested whether long-term excessive consumption of alcohol produces neuroadaptations in BDNF signaling in the rat DLS. We found that BDNF was no longer able to gate alcohol self-administration after a history of repeated cycles of binge alcohol drinking and withdrawal. We then elucidated the possible neuroadaptations that could block the ability of BDNF to keep consumption of alcohol in moderation. We report that intermittent access to 20% alcohol in a two-bottle choice paradigm that models excessive alcohol drinking produces a mobilization of DLS p75 neurotrophin receptor (p75NTR), whose activities oppose those of the Trk receptors, including TrkB. These neuroadaptations were not observed in the DLS of rats exposed to continuous access to 10% alcohol or in rats consuming sucrose. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of the p75NTR gene in the DLS, as well as intra-DLS infusion or systemic administration of the p75NTR modulator, LM11A-31, significantly reduced binge drinking of alcohol. Together, our results suggest that excessive alcohol consumption produces a change in BDNF signaling in the DLS, which is mediated by the recruitment of p75NTR. Our data also imply that modulators of p75NTR signaling could be developed as medications for alcohol abuse disorders. C1 [Darcq, Emmanuel; Morisot, Nadege; Phamluong, Khanhky; Warnault, Vincent; Jeanblanc, Jerome; Ron, Dorit] Univ Calif San Francisco, Dept Neurol, 675 Nelson Rising Lane,Box 0663, San Francisco, CA 94143 USA. [Longo, Frank M.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Massa, Stephen M.] San Francisco VA Med Ctr, Lab Computat Neurochem & Drug Discovery, San Francisco, CA 94121 USA. [Darcq, Emmanuel] McGill Univ, Douglas Res Ctr, Montreal, PQ H4H 1R3, Canada. [Jeanblanc, Jerome] Univ Picardie Jules Verne, Res Grp Alcohol & Pharmacodependences, INSERM ERI 24, F-80000 Amiens, France. [Warnault, Vincent] Univ Popeu Fabra, Neurobiol Behav Res Grp, Barcelona 08002, Spain. RP Ron, D (reprint author), Univ Calif San Francisco, Dept Neurol, 675 Nelson Rising Lane,Box 0663, San Francisco, CA 94143 USA. EM dorit.ron@ucsf.edu RI warnault, vincent/M-8195-2015 OI warnault, vincent/0000-0002-9812-3791 FU NIAAA [R01 AA016848, R37 AA01684, P50 AA017072]; Jean Perkins Foundation; VA Merit Grant [I01BX000267] FX This work was supported by NIAAA Grants R01 AA016848, R37 AA01684, and P50 AA017072 (D.R.), the Jean Perkins Foundation (F.L.), and VA Merit Grant I01BX000267 (S.M.M.). We thank Samuel Sakhai for reading this manuscript. NR 70 TC 0 Z9 0 U1 3 U2 3 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 SEP 28 PY 2016 VL 36 IS 39 BP 10116 EP 10127 DI 10.1523/JNEUROSCI.4597-14.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EC8BB UT WOS:000388363800012 PM 27683907 ER PT J AU Jacobs, EG Weiss, BK Makris, N Whitfield-Gabrieli, S Buka, SL Klibanski, A Goldstein, JM AF Jacobs, Emily G. Weiss, Blair K. Makris, Nikos Whitfield-Gabrieli, Sue Buka, Stephen L. Klibanski, Anne Goldstein, Jill M. TI Impact of Sex and Menopausal Status on Episodic Memory Circuitry in Early Midlife SO JOURNAL OF NEUROSCIENCE LA English DT Article DE episodic memory; estradiol; fMRI; hippocampus; menopause; PFC ID DENDRITIC SPINE DENSITY; HORMONE REPLACEMENT THERAPY; ESTROGEN-RECEPTOR-ALPHA; FEMALE RHESUS-MONKEYS; ADULT LIFE-SPAN; WORKING-MEMORY; POSTMENOPAUSAL WOMEN; PREFRONTAL CORTEX; ALZHEIMERS-DISEASE; COGNITIVE FUNCTION AB Cognitive neuroscience of aging studies traditionally target participants age 65 and older. However, epidemiological surveys show that many women report increased forgetfulness earlier in the aging process, as they transition to menopause. In this population-based fMRI study, we stepped back by over a decade to characterize the changes in memory circuitry that occur in early midlife, as a function of sex and women's reproductive stage. Participants (N = 200; age range, 45-55) performed a verbal encoding task during fMRI scanning. Reproductive histories and serologic evaluations were used to determine menopausal status. Results revealed a pronounced impact of reproductive stage on task-evoked hippocampal responses, despite minimal difference in chronological age. Next, we examined the impact of sex and reproductive stage on functional connectivity across task-related brain regions. Postmenopausal women showed enhanced bilateral hippocampal connectivity relative to premenopausal and perimenopausal women. Across women, lower 17 beta-estradiol concentrations were related to more pronounced alterations in hippocampal connectivity and poorer performance on a subsequent memory retrieval task, strongly implicating sex steroids in the regulation of this circuitry. Finally, subgroup analyses revealed that high-performing postmenopausal women (relative to low and middle performers) exhibited a pattern of brain activity akin to premenopausal women. Together, these findings underscore the importance of considering reproductive stage, not simply chronological age, to identify neuronal and cognitive changes that unfold in the middle decades of life. In keeping with preclinical studies, these human findings suggest that the decline in ovarian estradiol production during menopause plays a significant role in shaping memory circuitry. C1 [Jacobs, Emily G.; Goldstein, Jill M.] Brigham & Womens Hosp, Dept Med, Div Womens Hlth, Boston, MA 02120 USA. [Jacobs, Emily G.; Weiss, Blair K.; Goldstein, Jill M.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02120 USA. [Jacobs, Emily G.; Makris, Nikos; Goldstein, Jill M.] Harvard Med Sch, Boston, MA 02120 USA. [Jacobs, Emily G.; Makris, Nikos; Goldstein, Jill M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr, Charlestown, MA 02129 USA. [Whitfield-Gabrieli, Sue] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Buka, Stephen L.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02903 USA. [Klibanski, Anne] Massachusetts Gen Hosp, Dept Med, Neuroendocrine Unit, Boston, MA 02114 USA. RP Jacobs, EG; Goldstein, JM (reprint author), Harvard Med Sch, Brigham & Womens Hosp, 1 Brigham Circle, Boston, MA 02120 USA. EM emily.jacobs@psych.ucsb.edu; jill_goldstein@hms.harvard.edu FU NIMH [MH090291]; Office of Research on Women's Health; NICHD Building Interdisciplinary Research Careers in Women's Health program [K12 HD051959]; Harvard Clinical and Translational Science Center (NIH Grant) [UL1 RR025758] FX This work was supported by NIMH Grant MH090291 (J.M.G.); the Office of Research on Women's Health and NICHD Building Interdisciplinary Research Careers in Women's Health program, Grant K12 HD051959 (E.G.J.); and the Harvard Clinical and Translational Science Center (NIH Grant UL1 RR025758). We thank Harlyn Aizley for administering structured clinical interviews, Anne Remington for project administration, Katie Lancaster and Julia Longenecker for help with data collection, and Dr. Shalendar Bhasin for overseeing mass spectrometry. NR 83 TC 0 Z9 0 U1 3 U2 3 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 SEP 28 PY 2016 VL 36 IS 39 BP 10163 EP 10173 DI 10.1523/JNEUROSCI.0951-16.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EC8BB UT WOS:000388363800016 PM 27683911 ER PT J AU Detappe, A Kunjachan, S Sancey, L Motto-Ros, V Biancur, D Drane, P Guieze, R Makrigiorgos, GM Tillement, O Langer, R Berbeco, R AF Detappe, Alexandre Kunjachan, Sijumon Sancey, Lucie Motto-Ros, Vincent Biancur, Douglas Drane, Pascal Guieze, Romain Makrigiorgos, G. Mike Tillement, Olivier Langer, Robert Berbeco, Ross TI Advanced multimodal nanoparticles delay tumor progression with clinical radiation therapy SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Image-guided radiation therapy; Radiosensitizer; Theranostics; Nanoparticles ID GOLD NANOPARTICLES; SILICA NANOPARTICLES; AGUIX NANOPARTICLES; PANCREATIC-CANCER; DOSE ENHANCEMENT; DRUG-DELIVERY; GADOLINIUM; CELLS; RADIOSENSITIZATION; NANOMEDICINES AB Radiation therapy is a major treatment regimen for more than 50% of cancer patients. The collateral damage induced on healthy tissues during radiation and the minimal therapeutic effect on the organ-of-interest (target) is a major clinical concern. Ultra-small, renal clearable, silica based gadolinium chelated nanoparticles (SiGdNP) provide simultaneous MR contrast and radiation dose enhancement. The high atomic number of gadolinium provides a large photoelectric cross-section for increased photon interaction, even for high-energy clinical radiation beams. Imaging and therapy functionality of SiGdNP were tested in cynomolgus monkeys and pancreatic tumor-bearing mice models, respectively. A significant improvement in tumor cell damage (double strand DNA breaks), growth suppression, and overall survival under clinical radiation therapy conditions were observed in a human pancreatic xenograft model. For the first time, safe systemic administration and systematic renal clearance was demonstrated in both tested species. These findings strongly support the translational potential of SiGdNP for MR-guided radiation therapy in cancer treatment. (C) 2016 Elsevier B.V. All rights reserved. C1 [Detappe, Alexandre; Kunjachan, Sijumon; Biancur, Douglas; Drane, Pascal; Makrigiorgos, G. Mike; Berbeco, Ross] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Detappe, Alexandre; Sancey, Lucie; Motto-Ros, Vincent; Tillement, Olivier] Univ Lyon 1, Inst Lumiere Mat, CNRS UMR5306, Lyon, France. [Guieze, Romain] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02215 USA. [Langer, Robert] MIT, David H Koch Inst Integrat Canc Res, Dept Chem Engn, Cambridge, MA 02139 USA. RP Kunjachan, S; Berbeco, R (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. OI Kunjachan, Sijumon /0000-0002-5359-9219; Detappe, Alexandre/0000-0001-9364-1621 FU JCRT Foundation; Nano-H, France FX We acknowledge the efforts by F. Rossetti and F. Lux for the synthesis of gadolinium-based nanoparticles and S. Peled and E. Canet-Soulas for their help with MR acquisitions. This project was supported, in part, by the JCRT Foundation and the Nano-H, France. NR 43 TC 5 Z9 5 U1 9 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD SEP 28 PY 2016 VL 238 BP 103 EP 113 DI 10.1016/j.jconrel.2016.07.021 PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DX9FV UT WOS:000384699900010 PM 27423325 ER PT J AU Maura, D Hazan, R Kitao, T Ballok, AE Rahme, LG AF Maura, Damien Hazan, Ronen Kitao, Tomoe Ballok, Alicia E. Rahme, Laurence G. TI Evidence for Direct Control of Virulence and Defense Gene Circuits by the Pseudomonas aeruginosa Quorum Sensing Regulator, MvfR SO SCIENTIFIC REPORTS LA English DT Article ID TO-CELL COMMUNICATION; ESCHERICHIA-COLI; QUINOLONE SIGNAL; HYDROGEN-PEROXIDE; SECRETION SYSTEM; PERSISTER CELLS; DNA-BINDING; OPPORTUNISTIC PATHOGEN; ANTIBIOTIC TOLERANCE; II SECRETION AB Pseudomonas aeruginosa defies eradication by antibiotics and is responsible for acute and chronic human infections due to a wide variety of virulence factors. Currently, it is believed that MvfR (PqsR) controls the expression of many of these factors indirectly via the pqs and phnAB operons. Here we provide strong evidence that MvfR may also bind and directly regulate the expression of additional 35 loci across the P. aeruginosa genome, including major regulators and virulence factors, such as the quorum sensing (QS) regulators lasR and rhlR, and genes involved in protein secretion, translation, and response to oxidative stress. We show that these anti-oxidant systems, AhpC-F, AhpB-TrxB2 and Dps, are critical for P. aeruginosa survival to reactive oxygen species and antibiotic tolerance. Considering that MvfR regulated compounds generate reactive oxygen species, this indicates a tightly regulated QS self-defense anti-poisoning system. These findings also challenge the current hierarchical regulation model of P. aeruginosa QS systems by revealing new interconnections between them that suggest a circular model. Moreover, they uncover a novel role for MvfR in self-defense that favors antibiotic tolerance and cell survival, further demonstrating MvfR as a highly desirable anti-virulence target. C1 [Maura, Damien; Hazan, Ronen; Kitao, Tomoe; Ballok, Alicia E.; Rahme, Laurence G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Maura, Damien; Hazan, Ronen; Kitao, Tomoe; Ballok, Alicia E.; Rahme, Laurence G.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Maura, Damien; Hazan, Ronen; Kitao, Tomoe; Ballok, Alicia E.; Rahme, Laurence G.] Shriners Hosp Children Boston, Boston, MA 02114 USA. [Hazan, Ronen] Hebrew Univ Jerusalem, Inst Dent Sci, POB 12272, IL-91120 Jerusalem, Israel. [Hazan, Ronen] Hebrew Univ Jerusalem, Sch Dent Med, POB 12272, IL-91120 Jerusalem, Israel. RP Rahme, LG (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.; Rahme, LG (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.; Rahme, LG (reprint author), Shriners Hosp Children Boston, Boston, MA 02114 USA. EM rahme@molbio.mgh.harvard.edu FU Shriners Hospital Postdoctoral Fellowship [84206]; Cystic Fibrosis Foundation fellowship [BALLOK15F0]; Shriners [8770]; Cystic Fibrosis Foundation [11P0]; NIAID [R33AI105902, R56AI063433] FX We thank Anthony Anselmo and Ruslan Sadreyev from the MGH Department of Molecular Biology for their help on ChIPseq and RNAseq analysis. This work was supported by Shriners Hospital Postdoctoral Fellowship #84206 to D.M., Cystic Fibrosis Foundation fellowship #BALLOK15F0 to A.B. and by the research grants, Shriners #8770, Cystic Fibrosis Foundation #11P0, NIAID R33AI105902 and R56AI063433 to L.G.R. NR 99 TC 0 Z9 0 U1 8 U2 8 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 SEP 28 PY 2016 VL 6 AR 34083 DI 10.1038/srep34083 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX1ZE UT WOS:000384165600001 PM 27678057 ER PT J AU Bouyssou, JMC Ghobrial, IM Roccaro, AM AF Bouyssou, Juliette M. C. Ghobrial, Irene M. Roccaro, Aldo M. TI Targeting SDF-1 in multiple myeloma tumor microenvironment SO CANCER LETTERS LA English DT Review DE SDF-1; CXCR4; Multiple myeloma; Microenvironment; Bone marrow ID STROMAL-DERIVED FACTOR-1-ALPHA; BONE-MARROW MICROENVIRONMENT; CELL-ADHESION; RECEPTOR CXCR4; MURINE MODEL; PLASMA-CELLS; IN-VITRO; MIGRATION; EXPRESSION; AXIS AB Multiple myeloma (MM) is a type of B-cell malignancy that remains incurable to date. The bone marrow (BM) microenvironment plays a crucial role in MM progression. The chemokine SDF-1 (CXCL12) is an important actor of the BM microenvironment that has the ability to regulate numerous processes related to its malignant transformation during MM development. The activity of SDF-1 is mainly mediated by its specific receptor CXCR4, which is expressed at the surface of MM cells and various other BM cell types. Current treatments available for MM patients mainly target tumor cells but have limited effects on the BM microenvironment. In this context, SDF-1 and CXCR4 represent ideal targets for the normalization of the MM-supportive BM microenvironment. The present review focuses on the activity of SDF-1 in the MM BM microenvironment and the current efforts carried out to target the SDF-1/CXCR4 axis for treatment of MM. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Bouyssou, Juliette M. C.; Ghobrial, Irene M.; Roccaro, Aldo M.] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, 450 Brookline Ave,HIM 246, Boston, MA 02215 USA. [Bouyssou, Juliette M. C.] INSERM, UMR 1163, Lab Cellular & Mol Mech Hematol Disorders & Thera, Paris, France. RP Roccaro, AM (reprint author), Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, 450 Brookline Ave,HIM 246, Boston, MA 02215 USA. EM aldo_roccaro@dfci.harvard.edu FU NCI [R01CA154648]; Leukemia and Lymphoma Society [6236-13]; Multiple Myeloma Research Foundation [061213] FX Supported in part by NCI (R01CA154648), the Leukemia and Lymphoma Society (6236-13) and the Multiple Myeloma Research Foundation (061213). NR 56 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD SEP 28 PY 2016 VL 380 IS 1 BP 315 EP 318 DI 10.1016/j.canlet.2015.11.028 PG 4 WC Oncology SC Oncology GA DT5ON UT WOS:000381532600037 PM 26655999 ER PT J AU Loupe, JM Miller, PJ Bonner, BP Maggi, EC Vijayaraghavan, J Zabaleta, J Taylor, CM Tsien, F Crabtree, JS Hollenbach, AD AF Loupe, Jacob M. Miller, Patrick J. Bonner, Benjamin P. Maggi, Elaine C. Vijayaraghavan, Jyothi Zabaleta, Jovanny Taylor, Christopher M. Tsien, Fern Crabtree, Judy S. Hollenbach, Andrew D. TI Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects SO ONCOTARGET LA English DT Article DE aneuploidy; Pax3-FOXO1; myogenesis; phosphorylation; alveolar rhabdomyosarcoma ID CHILDRENS ONCOLOGY GROUP; REFRACTORY SOLID TUMORS; ALVEOLAR RHABDOMYOSARCOMA; GENE-EXPRESSION; PHASE-2 TRIAL; YOUNG-ADULTS; PAX3; PAX3-FKHR; CANCER; CELLS AB While many solid tumors are defined by the presence of a particular oncogene, the role that this oncogene plays in driving transformation through the acquisition of aneuploidy and overcoming growth arrest are often not known. Further, although aneuploidy is present in many solid tumors, it is not clear whether it is the cause or effect of malignant transformation. The childhood sarcoma, Alveolar Rhabdomyosarcoma (ARMS), is primarily defined by the t(2;13)(q35;q14) translocation, creating the PAX3-FOXO1 fusion protein. It is unclear what role PAX3-FOXO1 plays in the initial stages of tumor development through the acquisition and persistence of aneuploidy. In this study we demonstrate that PAX3-FOXO1 serves as a driver mutation to initiate a cascade of mRNA and miRNA changes that ultimately reprogram proliferating myoblasts to induce the formation of ARMS. We present evidence that cells containing PAX3-FOXO1 have changes in the expression of mRNA and miRNA essential for maintaining proper chromosome number and structure thereby promoting aneuploidy. Further, we demonstrate that the presence of PAX3-FOXO1 alters the expression of growth factor related mRNA and miRNA, thereby overriding aneuploid-dependent growth arrest. Finally, we present evidence that phosphorylation of PAX3-FOXO1 contributes to these changes. This is one of the first studies describing how an oncogene and post-translational modifications drive the development of a tumor through the acquisition and persistence of aneuploidy. This mechanism has implications for other solid tumors where large-scale genomics studies may elucidate how global alterations contribute to tumor phenotypes allowing the development of much needed multi-faceted tumor-specific therapeutic regimens. C1 [Loupe, Jacob M.; Miller, Patrick J.; Bonner, Benjamin P.; Maggi, Elaine C.; Vijayaraghavan, Jyothi; Tsien, Fern; Crabtree, Judy S.; Hollenbach, Andrew D.] Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA 70112 USA. [Zabaleta, Jovanny] Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA USA. [Zabaleta, Jovanny] Louisiana State Univ, Hlth Sci Ctr, Stanley S Scott Canc Ctr, New Orleans, LA USA. [Taylor, Christopher M.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA USA. [Loupe, Jacob M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Richard B Simches Res Ctr, Boston, MA 02114 USA. [Miller, Patrick J.] Tulane Univ, New Orleans, LA 70118 USA. RP Hollenbach, AD (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA 70112 USA. EM aholle@lsuhsc.edu FU National Cancer Institute [R01CA138656]; Louisiana State University School of Medicine Research Enhancement Bridge Grant; Louisiana Cancer Research Consortium (LCRC); National Institute of General Medicine Sciences (NIGMS) [P20GM103501, P30GM114732, U54GM104940-01]; National Institute on Minority Health and Health Disparities (NIMHD) [P20MD004817, U54MD006176-01] FX Funding for this project is from the National Cancer Institute grant R01CA138656, the Louisiana State University School of Medicine Research Enhancement Bridge Grant, and the Louisiana Cancer Research Consortium (LCRC) (ADH). JZ has been partially supported by grants from the National Institute of General Medicine Sciences (NIGMS) grants P20GM103501, subproject #2, P30GM114732, and U54GM104940-01, and the National Institute on Minority Health and Health Disparities (NIMHD) grants P20MD004817, and U54MD006176-01. NR 55 TC 0 Z9 0 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 SEP 27 PY 2016 VL 7 IS 39 BP 62814 EP 62835 DI 10.18632/oncotarget.11716 PG 22 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2DN UT WOS:000387167800003 PM 27588498 ER PT J AU Ruff, CT AF Ruff, Christian T. TI The Reality of "Real-World" Data More Questions Than Answers SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE anticoagulation; atrial fibrillation; hemorrhage; stroke ID EAST-ASIAN PATIENTS; ATRIAL-FIBRILLATION; STROKE PREVENTION; ORAL ANTICOAGULANTS; WARFARIN; TRIAL; SUBANALYSIS; EFFICACY; CHINESE; SAFETY C1 [Ruff, Christian T.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Ruff, Christian T.] Harvard Med Sch, Boston, MA USA. RP Ruff, CT (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM cruff@partners.org NR 13 TC 0 Z9 0 U1 1 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 SEP 27 PY 2016 VL 68 IS 13 BP 1402 EP 1403 DI 10.1016/j.jacc.2016.06.063 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ5WX UT WOS:000385933800004 PM 27659461 ER PT J AU van der Harst, P van Setten, J Verweij, N Vogler, G Franke, L Maurano, MT Wang, XC Leach, IM Eijgelsheim, M Sotoodehnia, N Hayward, C Sorice, R Meirelles, O Lyytikainen, LP Polasek, O Tanaka, T Arking, DE Ulivi, S Trompet, S Muller-Nurasyid, M Smith, AV Dorr, M Kerr, KF Magnani, JW Del Greco, F Zhang, WH Nolte, IM Silva, CT Padmanabhan, S Tragante, V Esko, T Abecasis, GR Adriaens, ME Andersen, K Barnett, P Bis, JC Bodmer, R Buckley, BM Campbell, H Cannon, MV Chakravarti, A Chen, LY Delitala, A Devereux, RB Doevendans, PA Dominiczak, AF Ferrucci, L Ford, I Gieger, C Harris, TB Haugen, E Heinig, M Hernandez, DG Hillege, HL Hirschhorn, JN Hofman, A Hubner, N Hwang, SJ Iorio, A Kahonen, M Kellis, M Kolcic, I Kooner, IK Kooner, JS Kors, JA Lakatta, EG Lage, K Launer, LJ Levy, D Lundby, A Macfarlane, PW May, D Meitinger, T Metspalu, A Nappo, S Naitza, S Neph, S Nord, AS Nutile, T Okin, PM Olsen, JV Oostra, B Penninger, JM Pennacchio, LA Pers, TH Perz, S Peters, A Pinto, YM Pfeufer, A Pilia, MG Pramstaller, PP Prins, BP Raitakari, OT Raychaudhuri, S Rice, KM Rossin, EJ Rotter, JI Schafer, S Schlessinger, D Schmidt, CO Sehmi, J Sillje, HHW Sinagra, G Sinner, MF Slowikowski, K Soliman, EZ Spector, TD Spiering, W Stamatoyannopoulos, JA Stolk, RP Strauch, K Tan, ST Tarasov, KV Trinh, B Uitterlinden, AG van den Boogaard, M van Duijn, CM van Gilst, WH Viikari, JS Visscher, PM Vitart, V Volker, U Waldenberger, M Weichenberger, CX Westra, HJ Wijmenga, C Wolffenbuttel, BH Yang, J Bezzina, CR Munroe, PB Snieder, H Wright, AF Rudan, I Boyer, LA Asselbergs, FW van Veldhuisen, DJ Stricker, BH Psaty, BM Ciullo, M Sanna, S Lehtimaki, T Wilson, JF Bandinelli, S Alonso, A Gasparini, P Jukema, JW Kaab, S Gudnason, V Felix, SB Heckbert, SR de Boer, RA Newton-Cheh, C Hicks, AA Chambers, JC Jamshidi, Y Visel, A Christoffels, VM Isaacs, A Samani, NJ de Bakker, PIW AF van der Harst, Pim van Setten, Jessica Verweij, Niek Vogler, Georg Franke, Lude Maurano, Matthew T. Wang, Xinchen Leach, Irene Mateo Eijgelsheim, Mark Sotoodehnia, Nona Hayward, Caroline Sorice, Rossella Meirelles, Osorio Lyytikainen, Leo-Pekka Polasek, Ozren Tanaka, Toshiko Arking, Dan E. Ulivi, Sheila Trompet, Stella Mueller-Nurasyid, Martina Smith, Albert V. Doerr, Marcus Kerr, Kathleen F. Magnani, Jared W. Del Greco, Fabiola Zhang, Weihua Nolte, Ilja M. Silva, Claudia T. Padmanabhan, Sandosh Tragante, Vinicius Esko, Tonu Abecasis, Gonclo R. Adriaens, Michiel E. Andersen, Karl Barnett, Phil Bis, Joshua C. Bodmer, Rolf Buckley, Brendan M. Campbell, Harry Cannon, Megan V. Chakravarti, Aravinda Chen, Lin Y. Delitala, Alessandro Devereux, Richard B. Doevendans, Pieter A. Dominiczak, Anna F. Ferrucci, Luigi Ford, Ian Gieger, Christian Harris, Tamara B. Haugen, Eric Heinig, Matthias Hernandez, Dena G. Hillege, Hans L. Hirschhorn, Joel N. Hofman, Albert Hubner, Norbert Hwang, Shih-Jen Iorio, Annamaria Kahonen, Mika Kellis, Manolis Kolcic, Ivana Kooner, Ishminder K. Kooner, Jaspal S. Kors, Jan A. Lakatta, Edward G. Lage, Kasper Launer, Lenore J. Levy, Daniel Lundby, Alicia Macfarlane, Peter W. May, Dalit Meitinger, Thomas Metspalu, Andres Nappo, Stefania Naitza, Silvia Neph, Shane Nord, Alex S. Nutile, Teresa Okin, Peter M. Olsen, Jesper V. Oostra, Ben A. Penninger, Josef M. Pennacchio, Len A. Pers, Tune H. Perz, Siegfried Peters, Annette Pinto, Yigal M. Pfeufer, Arne Pilia, Maria Grazia Pramstaller, Peter P. Prins, Bram P. Raitakari, Olli T. Raychaudhuri, Soumya Rice, Ken M. Rossin, Elizabeth J. Rotter, Jerome I. Schafer, Sebastian Schlessinger, David Schmidt, Carsten O. Sehmi, Jobanpreet Sillje, Herman H. W. Sinagra, Gianfranco Sinner, Moritz F. Slowikowski, Kamil Soliman, Elsayed Z. Spector, Timothy D. Spiering, Wilko Stamatoyannopoulos, John A. Stolk, Ronald P. Strauch, Konstantin Tan, Sian-Tsung Tarasov, Kirill V. Trinh, Bosco Uitterlinden, Andre G. van den Boogaard, Malou van Duijn, Cornelia M. van Gilst, Wiek H. Viikari, Jorma S. Visscher, Peter M. Vitart, Veronique Voelker, Uwe Waldenberger, Melanie Weichenberger, Christian X. Westra, Harm-Jan Wijmenga, Cisca Wolffenbuttel, Bruce H. Yang, Jian Bezzina, Connie R. Munroe, Patricia B. Snieder, Harold Wright, Alan F. Rudan, Igor Boyer, Laurie A. Asselbergs, Folkert W. van Veldhuisen, Dirk J. Stricker, Bruno H. Psaty, Bruce M. Ciullo, Marina Sanna, Serena Lehtimaki, Terho Wilson, James F. Bandinelli, Stefania Alonso, Alvaro Gasparini, Paolo Jukema, J. Wouter Kaeaeb, Stefan Gudnason, Vilmundur Felix, Stephan B. Heckbert, Susan R. de Boer, Rudolf A. Newton-Cheh, Christopher Hicks, Andrew A. Chambers, John C. Jamshidi, Yalda Visel, Axel Christoffels, Vincent M. Isaacs, Aaron Samani, Nilesh J. de Bakker, Paul I. W. TI 52 Genetic Loci Influencing Myocardial Mass SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE electrocardiogram; genetic association study; heart failure; left ventricular hypertrophy; QRS ID LEFT-VENTRICULAR HYPERTROPHY; CARDIAC-HYPERTROPHY; REGULATORY DNA; ELECTROCARDIOGRAM; MORTALITY; DISEASE; VOLTAGE; DYSFUNCTION; GENOME; HEART AB BACKGROUND Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 x 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets. (C) 2016 by the American College of Cardiology Foundation. C1 [van der Harst, Pim; Verweij, Niek; Leach, Irene Mateo; Cannon, Megan V.; Hillege, Hans L.; Sillje, Herman H. W.; van Gilst, Wiek H.; van Veldhuisen, Dirk J.; de Boer, Rudolf A.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9700 RB Groningen, Netherlands. [van der Harst, Pim; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Hanzepl 1, NL-9700 RB Groningen, Netherlands. [van der Harst, Pim; Asselbergs, Folkert W.] Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands. [van Setten, Jessica; Tragante, Vinicius; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [van Setten, Jessica; Tragante, Vinicius; Doevendans, Pieter A.; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [Vogler, Georg; Bodmer, Rolf; Trinh, Bosco] Sanford Burnham Prebys Med Discovery Inst, Dev Aging & Regenerat, La Jolla, CA USA. [Maurano, Matthew T.; Haugen, Eric; Neph, Shane; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Maurano, Matthew T.; Wijmenga, Cisca] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA. [Maurano, Matthew T.] NYU, Dept Pathol, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. [Maurano, Matthew T.] NYU, Inst Syst Genet, Langone Med Ctr, New York, NY USA. [Wang, Xinchen; Boyer, Laurie A.] MIT, Dept Biol, Cambridge, MA USA. [Eijgelsheim, Mark; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Eijgelsheim, Mark; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Hayward, Caroline; Vitart, Veronique; Wright, Alan F.; Wilson, James F.] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Sorice, Rossella; Nappo, Stefania; Nutile, Teresa; Ciullo, Marina] Inst Genet & Biophys A Buzzati Traverso, Naples, Italy. [Meirelles, Osorio; Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland. [Polasek, Ozren; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland. [Polasek, Ozren; Kolcic, Ivana] Univ Split, Dept Publ Hlth, Fac Med, Split, Croatia. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Arking, Dan E.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ulivi, Sheila; Gasparini, Paolo] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Mueller-Nurasyid, Martina; Sinner, Moritz F.; Kaeaeb, Stefan] Univ Munich, Dept Med 1, Univ Hosp Munich, Campus Grosshadern, Munich, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] Univ Munich, Inst Med Informat Biometry & Epidemiol, Genet Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina; Meitinger, Thomas; Peters, Annette; Kaeaeb, Stefan] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Andersen, Karl; Peters, Annette; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Doerr, Marcus; Felix, Stephan B.] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Doerr, Marcus; Voelker, Uwe; Felix, Stephan B.] DZHK Partner Site, Greifswald, Germany. [Kerr, Kathleen F.; Padmanabhan, Sandosh; Rice, Ken M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Magnani, Jared W.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Del Greco, Fabiola; Pfeufer, Arne; Pramstaller, Peter P.; Weichenberger, Christian X.; Hicks, Andrew A.] Bolzano EURAC, European Acad Bozen, Ctr Biomed, Bolzano, Italy. [Del Greco, Fabiola; Pfeufer, Arne; Pramstaller, Peter P.; Weichenberger, Christian X.; Hicks, Andrew A.] Univ Lubeck, Lubeck, Germany. [Zhang, Weihua; Chambers, John C.] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Zhang, Weihua; Kooner, Ishminder K.; Kooner, Jaspal S.; Sehmi, Jobanpreet; Tan, Sian-Tsung; Chambers, John C.] Ealing Hosp NHS Trust, Southall, Middx, England. [Nolte, Ilja M.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Silva, Claudia T.; Oostra, Ben A.; van Duijn, Cornelia M.; Isaacs, Aaron] Univ Med Ctr Rotterdam, Dept Epidemiol, Genet Epidemiol Unit, Erasmus MC, Rotterdam, Netherlands. [Silva, Claudia T.] Univ Rosario, Doctoral Program Biomed Sci, Bogota, Colombia. [Silva, Claudia T.] Univ Rosario, Dept Genet GENIUROS, Escuela Med & Ciencias Salud, Bogota, Colombia. [Dominiczak, Anna F.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Esko, Tonu; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Esko, Tonu; Hirschhorn, Joel N.; Pers, Tune H.] Childrens Hosp Boston, Div Endocrinol, Boston, MA USA. [Esko, Tonu; Hirschhorn, Joel N.; Pers, Tune H.] Childrens Hosp Boston, Ctr Basic & Translat Obes Res, Boston, MA USA. [Abecasis, Gonclo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Adriaens, Michiel E.; Pinto, Yigal M.; Bezzina, Connie R.] Univ Amsterdam, Acad Med Ctr, Dept Expt Cardiol, Amsterdam, Netherlands. [Adriaens, Michiel E.] Maastricht Univ, Maastricht Ctr Syst Biol, Maastricht, Netherlands. [Andersen, Karl] Landspitali Univ Hosp, Reykjavik, Iceland. [Barnett, Phil; van den Boogaard, Malou; Christoffels, Vincent M.] Univ Amsterdam, Acad Med Ctr, Dept Anat Embryol & Physiol, Amsterdam, Netherlands. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Buckley, Brendan M.] Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Chen, Lin Y.] Univ Minnesota, Dept Med, Div Cardiovasc, Box 736 UMHC, Minneapolis, MN 55455 USA. [Delitala, Alessandro; Gieger, Christian; Naitza, Silvia; Pilia, Maria Grazia; Sanna, Serena] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Devereux, Richard B.; Okin, Peter M.] Weill Cornell Med, Div Cardiol, Dept Med, New York, NY USA. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Gieger, Christian; Perz, Siegfried; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Gieger, Christian; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Heinig, Matthias; Hubner, Norbert; Schafer, Sebastian] Max Delbruck Ctr Mol Med MDC, Cardiovasc & Metab Dis, Berlin, Germany. [Heinig, Matthias] Max Planck Inst Mol Genet, Dept Computat Biol, Berlin, Germany. [Heinig, Matthias] Helmholtz Zentrum Munchen, Inst Computat Biol, Neuherberg, Germany. [Hernandez, Dena G.] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Hirschhorn, Joel N.; Pers, Tune H.; Westra, Harm-Jan; Newton-Cheh, Christopher] Broad Inst, Med & Populat Genet Program, Cambridge, MA USA. [Hirschhorn, Joel N.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Hubner, Norbert; Schafer, Sebastian] DZHK Partner Site, Berlin, Germany. [Hwang, Shih-Jen] NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Iorio, Annamaria; Sinagra, Gianfranco] Univ Trieste, Cardiovasc Dept, Trieste, Italy. [Iorio, Annamaria; Sinagra, Gianfranco] Univ Trieste, Postgrad Sch Cardiovasc Dis, Trieste, Italy. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere, Finland. [Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kellis, Manolis; Lage, Kasper] Broad Inst, Cambridge, MA USA. [Kooner, Jaspal S.; Sehmi, Jobanpreet; Tan, Sian-Tsung] Imperial Coll London, Natl Heart & Lung Inst, London, England. [Kors, Jan A.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Lakatta, Edward G.; Tarasov, Kirill V.] NIA, Lab Cardiovasc Sci, Baltimore, MD 21224 USA. [Lage, Kasper] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lage, Kasper; Rossin, Elizabeth J.] Harvard Univ, Harvard Med Sch, Boston, MA 02115 USA. [Levy, Daniel; Slowikowski, Kamil] NHLBI, Ctr Populat Studies, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lundby, Alicia; Olsen, Jesper V.; Soliman, Elsayed Z.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark. [Lundby, Alicia] Univ Copenhagen, Fac Hlth & Med Sci, Dept Biomed Sci, Copenhagen, Denmark. [Macfarlane, Peter W.] Univ Glasgow, Inst Cardiovasc & Med Sci, Electrocardiol Sect, Glasgow, Lanark, Scotland. [May, Dalit] Clalit Hlth Serv, Dept Family Med, Jerusalem, Israel. [May, Dalit] Hebrew Univ Jerusalem, Hadassah Med Sch, Jerusalem, Israel. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Nord, Alex S.; Pennacchio, Len A.; Visel, Axel] Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA USA. [Nord, Alex S.] Univ Calif Davis, Ctr Neurosci, Dept Neurobiol Physiol & Behav, Davis, CA 95616 USA. [Nord, Alex S.] Univ Calif Davis, Ctr Neurosci, Dept Psychiat & Behav Sci, Davis, CA 95616 USA. [Penninger, Josef M.] Austrian Acad Sci, Inst Mol Biotechnol, Vienna, Austria. [Pennacchio, Len A.; Visel, Axel] DOE Joint Genome Inst, Walnut Creek, CA USA. [Pers, Tune H.] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Pers, Tune H.] Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark. [Perz, Siegfried] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Neuherberg, Germany. [Pfeufer, Arne] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Dept Bioinformat & Syst Biol IBIS, Neuherberg, Germany. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Prins, Bram P.; Jamshidi, Yalda] St Georges Univ London, Cardiogenet Lab, Human Genet Res Ctr, London, England. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raychaudhuri, Soumya] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA USA. [Raychaudhuri, Soumya] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Rossin, Elizabeth J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat & Med, Torrance, CA 90509 USA. [Schafer, Sebastian] Natl Heart Ctr Singapore, Natl Heart Res Inst Singapore, Singapore, Singapore. [Schmidt, Carsten O.] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Slowikowski, Kamil] Harvard Univ, Bioinformat & Integrat Genom, Cambridge, MA 02138 USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Epidemiol Cardiol Res Ctr, Winston Salem, NC USA. [Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Spiering, Wilko] Univ Med Ctr Utrecht, Dept Vasc Med, Utrecht, Netherlands. [Viikari, Jorma S.] Turku Univ Hosp, Div Med, Turku, Finland. [Viikari, Jorma S.] Univ Turku, Dept Med, Turku, Finland. [Viikari, Jorma S.] Univ Queensland, Queensland Brain Inst, St Lucia, Qld, Australia. [Visscher, Peter M.; Yang, Jian] Univ Queensland, Diamantina Inst, Translat Res Inst, Woolloongabba, Qld, Australia. [Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany. [Westra, Harm-Jan] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Westra, Harm-Jan] Brigham & Womens Hosp, Dept Med, Div Rheumatol, 75 Francis St, Boston, MA 02115 USA. [Westra, Harm-Jan] Harvard Med Sch, Boston, MA USA. [Westra, Harm-Jan] Partners Ctr Personalized Genet Med, Boston, MA USA. [Wolffenbuttel, Bruce H.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Munroe, Patricia B.] Queen Mary Univ London, Clin Pharmacol, London, England. [Munroe, Patricia B.] Queen Mary Univ London, Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Munroe, Patricia B.] Queen Mary Univ London, Natl Inst Hlth, Barts & London Sch Med, Res Biomed Res Unit, London, England. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Ciullo, Marina] IRCCS Neuromed, Isernia, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Alonso, Alvaro] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Gasparini, Paolo] Univ Trieste, Trieste, Italy. [Gasparini, Paolo] Sidra Med & Res Ctr, Doha, Qatar. [Jukema, J. Wouter] Netherlands Heart Inst, Utrecht, Netherlands. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Visel, Axel] Univ Calif, Sch Nat Sci, Merced, CA USA. [Isaacs, Aaron] Maastricht Univ, Dept Biochem, Maastricht Ctr Syst Biol, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, BHF Cardiovasc Res Ctr, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester, Leics, England. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands. RP van der Harst, P (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9700 RB Groningen, Netherlands.; van der Harst, P (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Hanzepl 1, NL-9700 RB Groningen, Netherlands. EM p.van.der.harst@umcg.nl RI Lundby, Alicia/H-3322-2013; Naitza, Silvia/D-5620-2017; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Hicks, Andrew/E-9518-2017; Franke, Lude/P-7036-2016; Wijmenga, Cisca/D-2173-2009; Visel, Axel/A-9398-2009; Penninger, Josef/I-6860-2013; Yang, Jian/A-5852-2010; Padmanabhan, Sandosh/S-3963-2016; Alonso, Alvaro/A-4917-2010; Verweij, Niek/A-4499-2017; OI Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Hicks, Andrew/0000-0001-6320-0411; Franke, Lude/0000-0002-5159-8802; Visel, Axel/0000-0002-4130-7784; Penninger, Josef/0000-0002-8194-3777; Yang, Jian/0000-0003-2001-2474; Alonso, Alvaro/0000-0002-2225-8323; Haugen, Eric/0000-0001-7444-8981; Adriaens, Michiel/0000-0002-4472-7119; Schafer, Sebastian/0000-0002-6909-8275; SINAGRA, GIANFRANCO/0000-0003-2700-8478; Peters, Annette/0000-0001-6645-0985 FU GlaxoSmithKline; Zoll LifeCor; Johnson Johnson; Metabiota FX Dr. Abecasis has served on the scientific advisory board for Regeneron Genetics Center. Dr. Haugen's current employer (Altius Institute) receives research funding from GlaxoSmithKline. Dr. Pennacchio is a salaried employee and ownsstock in Metabiota. Dr. Stamatoyannopoulos is the director of a nonprofit research institute. Dr. Psaty has served on the data and safety monitoring board for a clinical trial funded by Zoll LifeCor; and has served on the steering committee of the Yale Open Data Access project funded by Johnson & Johnson. Dr. de Bakker is currently an employee of and owns equity in Vertex Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. van der Harst, van Setten, Verweij, Vogler, Franke, Maurano, Wang, Mateo Leach, Chambers, Jamshidi, Visel, Christoffels, Isaacs, Samani, and de Bakker contributed equally to this work. NR 26 TC 4 Z9 4 U1 12 U2 12 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 SEP 27 PY 2016 VL 68 IS 13 BP 1435 EP 1448 DI 10.1016/j.jacc.2016.07.729 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ5WX UT WOS:000385933800009 PM 27659466 ER PT J AU Latif, R Realubit, RB Karan, C Mezei, M Davies, TF AF Latif, Rauf Realubit, Ronald B. Karan, Charles Mezei, Mihaly Davies, Terry F. TI TSH Receptor Signaling Abrogation by a Novel Small Molecule SO FRONTIERS IN ENDOCRINOLOGY LA English DT Article DE TSH receptor; small molecule; antagonist ID STIMULATING HORMONE-RECEPTOR; PROTEIN-COUPLED RECEPTOR; HUMAN THYROTROPIN RECEPTOR; CRYSTAL-STRUCTURE; GRAVES-DISEASE; TRANSMEMBRANE DOMAIN; THYROID-FUNCTION; AGONISTS; LOOP; ANTAGONIST AB Pathological activation of the thyroid-stimulating hormone receptor (TSHR) is caused by thyroid-stimulating antibodies in patients with Graves' disease (GD) or by somatic and rare genomic mutations that enhance constitutive activation of the receptor influencing both G protein and non-G protein signaling. Potential selective small molecule antagonists represent novel therapeutic compounds for abrogation of such abnormal TSHR signaling. In this study, we describe the identification and in vitro characterization of a novel small molecule antagonist by high-throughput screening (HTS). The identification of the TSHR antagonist was performed using a transcription-based TSH-inhibition bioassay. TSHR-expressing CHO cells, which also expressed a luciferase-tagged CRE response element, were optimized using bovine TSH as the activator, in a 384 well plate format, which had a Z score of 0.3-0.6. Using this HTS assay, we screened a diverse library of similar to 80,000 compounds at a final concentration of 16.7 mu M. The selection criteria for a positive hit were based on a mean signal threshold of >= 50% inhibition of control TSH stimulation. The screening resulted in 450 positive hits giving a hit ratio of 0.56%. A secondary confirmation screen against TSH and forskolin - a post receptor activator of adenylyl cyclase - confirmed one TSHR-specific candidate antagonist molecule (named VA-K-14). This lead molecule had an IC50 of 12.3 mu M and a unique chemical structure. A parallel analysis for cell viability indicated that the lead inhibitor was non-cytotoxic at its effective concentrations. In silico docking studies performed using a TSHR transmembrane model showed the hydrophobic contact locations and the possible mode of inhibition of TSHR signaling. Furthermore, this molecule was capable of inhibiting TSHR stimulation by GD patient sera and monoclonal-stimulating TSHR antibodies. In conclusion, we report the identification of a novel small molecule TSHR inhibitor, which has the potential to be developed as a therapeutic antagonist for abrogation of TSHR signaling by TSHR autoantibodies in GD. C1 [Latif, Rauf; Davies, Terry F.] Icahn Sch Med Mt Sinai, Thyroid Res Unit, James J Peters VA Med Ctr, New York, NY 10029 USA. [Realubit, Ronald B.; Karan, Charles] Columbia Univ, Sulzberger Columbia Genome Ctr, New York, NY USA. [Mezei, Mihaly] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA. RP Latif, R (reprint author), Icahn Sch Med Mt Sinai, Thyroid Res Unit, James J Peters VA Med Ctr, New York, NY 10029 USA. EM rauf.latif@mssm.edu FU NIH [DK069713]; VA Merit Award [BX000800] FX The authors thank Drs. R. Baliram, Risheng Ma, and Syed A Morshed for critical reading of the manuscript and their comments. The authors also wish to thank Miss Xhensila Hyka from Sulzberger Columbia Genome Center, Columbia University for her technical assistance. This work was supported in part by NIH grant DK069713 & the VA Merit Award BX000800 (to TD). NR 50 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD SEP 27 PY 2016 VL 7 AR 130 DI 10.3389/fendo.2016.00130 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DY8EP UT WOS:000385361900001 PM 27729899 ER PT J AU Spera, K Rubin, D Gupta, T Fantaneanu, T Henderson, GV AF Spera, Kristyn Rubin, Daniel Gupta, Tina Fantaneanu, Tadeu Henderson, Galen V. TI Clinical Reasoning: An 87-year-old man with chronic obstructive pulmonary disease and acute encephalopathy SO NEUROLOGY LA English DT Editorial Material ID ADRENAL INSUFFICIENCY; CRISIS AB An 87-year-old man with diastolic heart failure, coronary artery disease, TIAs, chronic obstructive pulmonary disease (COPD), hypothyroidism, chronic kidney disease, aplastic anemia, and benign prostatic hypertrophy with chronic indwelling catheter was transferred to the neurocritical care unit for acute encephalopathy. The patient initially presented to an outside facility with progressive lethargy evolving over 12 hours from a fully functional baseline. At the outside hospital, he was febrile (103.7 degrees F) and hypotensive (62/40 mm Hg), without leukocytosis (white count 5.6 K/L) but with urinalysis demonstrating evidence of infection. Empiric IV vancomycin and cefepime were started. CT scan of the chest, abdomen, and pelvis was unrevealing of an infectious source. MRI of the brain was also unremarkable. His mental status declined further over the following 4 days, prompting an EEG that revealed generalized periodic discharges (GPDs). The patient was treated with levetiracetam and transferred to our hospital out of concern for nonconvulsive status epilepticus (NCSE). Upon arrival to the neurocritical care unit, physical examination revealed persistent hypotension (79/44 mm Hg) that responded well to IV fluids without vasopressors and a Glasgow Coma Scale score of 8 with eyes opening to noxious stimulus only. He was mumbling unintelligible words and withdrew all 4 limbs antigravity to pain. C1 [Spera, Kristyn; Rubin, Daniel] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. [Gupta, Tina] Brigham & Womens Hosp, Dept Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fantaneanu, Tadeu; Henderson, Galen V.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. RP Spera, K (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM kspera@partners.org FU NHLBI NIH HHS [T32 HL007609] NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 27 PY 2016 VL 87 IS 13 BP e135 EP e139 DI 10.1212/WNL.0000000000003149 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA DX8XG UT WOS:000384674300002 PM 27672171 ER PT J AU Kim, M Lu, FL Zhang, Y AF Kim, Minchul Lu, Falong Zhang, Yi TI Loss of HDAC-Mediated Repression and Gain of NF-kappa B Activation Underlie Cytokine Induction in ARID1A-and PIK3CA-Mutation-Driven Ovarian Cancer SO CELL REPORTS LA English DT Article ID CLEAR-CELL CARCINOMA; CHROMATIN-REMODELING COMPLEX; HISTONE DEACETYLASE; RNA-SEQ; MUTATIONS; IDENTIFICATION; TUMORIGENESIS; TRANSCRIPTION; BIOLOGY; PATHWAY AB ARID1A is frequently mutated in ovarian clear cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here, we established an in vitro model of OCCC by introducing ARID1A knockdown and mutant PIK3CA into a normal human ovarian epithelial cell line, resulting in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while the PIK3CA mutation releases RelA from I kappa B, leading to cytokine gene activation. We show that an NF-kappa B inhibitor partly attenuates the proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and in a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC and suggests that NF-kappa B inhibition could be a potential therapeutic option. C1 [Kim, Minchul; Lu, Falong; Zhang, Yi] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Kim, Minchul; Lu, Falong; Zhang, Yi] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Kim, Minchul; Lu, Falong; Zhang, Yi] Boston Childrens Hosp, Dept Pediat, Div Hematol Oncol, Boston, MA 02115 USA. [Zhang, Yi] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Zhang, Yi] Harvard Stem Cell Inst, WAB 149G,200 Longwood Ave, Boston, MA 02115 USA. RP Zhang, Y (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA.; Zhang, Y (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Zhang, Y (reprint author), Boston Childrens Hosp, Dept Pediat, Div Hematol Oncol, Boston, MA 02115 USA.; Zhang, Y (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Zhang, Y (reprint author), Harvard Stem Cell Inst, WAB 149G,200 Longwood Ave, Boston, MA 02115 USA. EM yzhang@genetics.med.harvard.edu RI Lu, Falong/Q-3013-2016 FU NIH FX We thank Drs. Jin-Sung Liu for the T80 and T29 cell lines and Luis Tuesta for critical reading of the manuscript. M.K. is supported by an NIH F32 Postdoctoral Training Fellowship. Y.Z. is an investigator of the Howard Hughes Medical Institute. NR 50 TC 0 Z9 0 U1 7 U2 7 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 SEP 27 PY 2016 VL 17 IS 1 BP 275 EP 288 DI 10.1016/j.celrep.2016.09.003 PG 14 WC Cell Biology SC Cell Biology GA DX0CH UT WOS:000384028600023 PM 27681437 ER PT J AU Krishnasamy, Y Ramshesh, VK Gooz, M Schnellmann, RG Lemasters, JJ Zhong, Z AF Krishnasamy, Yasodha Ramshesh, Venkat K. Gooz, Monika Schnellmann, Rick G. Lemasters, John J. Zhong, Zhi TI Ethanol and High Cholesterol Diet Causes Severe Steatohepatitisand Early Liver Fibrosis in Mice SO PLOS ONE LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; HEPATIC STELLATE CELLS; MITOCHONDRIAL PERMEABILITY TRANSITION; PROTEIN-CALORIE MALNUTRITION; CYTOCHROME-C-OXIDASE; ALCOHOLIC LIVER; NONALCOHOLIC STEATOHEPATITIS; OXIDATIVE STRESS; UNITED-STATES; UP-REGULATION AB Background and Aim Because ethanol consumption is commonly associated with a high cholesterol diet, we examined whether combined consumption of ethanol and high cholesterol increases liver injury and fibrosis. Methods Male C57BL/6J mice were fed diets containing: 1) 35% of calories from corn oil (CTR), 2) CTR plus 0.5% (w/v) cholesterol (Chol), 3) CTR plus ethanol (27% of calories) (EtOH), or 4) EtOH+Chol for 3 months. Results In mice fed Chol or EtOH alone, ALT increased to similar to 160 U/L, moderate hepatic steatosis occurred, and leukocyte infiltration, necrosis, and apoptosis increased modestly, but no observable fibrosis developed. By contrast in mice fed EtOH+Chol, ALT increased to similar to 270 U/L, steatosis was more extensive and mostly macrovesicular, and expression of proinflammatory molecules (HMGB-1, TLR4, TNF alpha, ICAM-1) and leukocyte infiltration increased substantially. Necrosis and apoptosis also increased. Trichrome staining and second harmonic generation microscopy revealed hepatic fibrosis. Fibrosis was mostly sinusoidal and/or perivenular, but in some mice bridging fibrosis occurred. Expression of smooth muscle alpha-actin and TGF-beta 1 increased slightly by Chol, moderately by EtOH, and markedly by EtOH+Chol. TGF-beta pseudoreceptor BAMBI increased slightly by Chol, remained unchanged by EtOH and decreased by EtOH+Chol. MicroRNA-33a, which enhances TGF-beta fibrotic effects, and phospho-Smad2/3, the down-stream signal of TGF-beta, also increased more greatly by EtOH+Chol than Chol or EtOH. Metalloproteinase-2 and -9 were decreased only by EtOH+Chol. Conclusion High dietary cholesterol and chronic ethanol consumption synergistically increase liver injury, inflammation, and profibrotic responses and suppress antifibrotic responses, leading to severe steatohepatitis and early fibrosis in mice. C1 [Krishnasamy, Yasodha; Ramshesh, Venkat K.; Gooz, Monika; Schnellmann, Rick G.; Lemasters, John J.; Zhong, Zhi] Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. [Schnellmann, Rick G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Lemasters, John J.] Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Lemasters, John J.] Russian Acad Sci, Inst Theoret & Expt Biophys, Pushchino, Moscow Region, Russia. RP Zhong, Z (reprint author), Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. EM Zhong@musc.edu FU National Institutes of Health [AA017756, DK073336, DK037034]; NIH [1P30 CA138313, S10 OD018113, C06 RR015455] FX This work was supported, in part, by Grants AA017756, DK073336 and DK037034 from the National Institutes of Health. The Cell & Molecular Imaging Core of the Hollings Cancer Center at the Medical University of South Carolina supported by NIH Grant 1P30 CA138313 and the Shared Instrumentation Grant S10 OD018113 provided instrumentation and assistance for SHG microscopy. Animals were housed in the Animal Resources at Medical University of South Carolina supported by NIH Grant C06 RR015455. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 0 Z9 0 U1 6 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 SEP 27 PY 2016 VL 11 IS 9 AR e0163342 DI 10.1371/journal.pone.0163342 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX2AT UT WOS:000384169900017 PM 27676640 ER PT J AU Spira, A Disis, ML Schiller, JT Vilar, E Rebbeck, TR Bejar, R Ideker, T Arts, J Yurgelun, MB Mesirov, JP Rao, A Garber, J Jaffee, EM Lippman, SM AF Spira, Avrum Disis, Mary L. Schiller, John T. Vilar, Eduardo Rebbeck, Timothy R. Bejar, Rafael Ideker, Trey Arts, Janine Yurgelun, Matthew B. Mesirov, Jill P. Rao, Anjana Garber, Judy Jaffee, Elizabeth M. Lippman, Scott M. TI Leveraging premalignant biology for immune-based cancer prevention SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE premalignancy; biology; vaccines; cancer prevention; immune oncology ID MISMATCH REPAIR DEFICIENCY; CARCINOMA IN-SITU; ACUTE MYELOID-LEUKEMIA; COLORECTAL-CANCER; BREAST-CANCER; SOMATIC MUTATIONS; TUMOR-DEVELOPMENT; MYELOPROLIFERATIVE NEOPLASMS; CLONAL HEMATOPOIESIS; GENETIC ALTERATIONS AB Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system's ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative. C1 [Spira, Avrum] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Disis, Mary L.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Schiller, John T.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Vilar, Eduardo] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Rebbeck, Timothy R.] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02215 USA. [Bejar, Rafael; Ideker, Trey; Mesirov, Jill P.; Lippman, Scott M.] Univ Calif San Diego, Dept Med, Moores Canc Ctr, La Jolla, CA 92093 USA. [Arts, Janine] Pharmaceut Co Johnson & Johnson, Janssen Oncol Res & Dev, B-2300 Beerse, Belgium. [Yurgelun, Matthew B.; Garber, Judy] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02215 USA. [Rao, Anjana] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA. [Jaffee, Elizabeth M.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21287 USA. RP Lippman, SM (reprint author), Univ Calif San Diego, Dept Med, Moores Canc Ctr, La Jolla, CA 92093 USA. EM slippman@ucsd.edu FU National Cancer Institute [P30-CA023100-29] FX The authors thank Nikki Lytle and Leona Flores for editorial assistance with this article. S.M.L. was supported for this work by National Cancer Institute Grant P30-CA023100-29. NR 147 TC 2 Z9 2 U1 13 U2 13 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 SEP 27 PY 2016 VL 113 IS 39 BP 10750 EP 10758 DI 10.1073/pnas.1608077113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW9DD UT WOS:000383954700020 PM 27638202 ER PT J AU Sabuncu, MR Ge, T Holmes, AJ Smoller, JW Buckner, RL Fischl, B AF Sabuncu, Mert R. Ge, Tian Holmes, Avram J. Smoller, Jordan W. Buckner, Randy L. Fischl, Bruce CA Alzheimers Dis Neuroimaging Initia TI Morphometricity as a measure of the neuroanatomical signature of a trait SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neuroimaging; brain morphology; statistical association ID LONGITUDINAL NEUROIMAGE DATA; HUMAN BRAIN; MAXIMUM-LIKELIHOOD; CEREBRAL-CORTEX; COMMON SNPS; MRI SCANS; HERITABILITY; SCHIZOPHRENIA; CONNECTOME; PREVALENCE AB Complex physiological and behavioral traits, including neurological and psychiatric disorders, often associate with distributed anatomical variation. This paper introduces a global metric, called morphometricity, as a measure of the anatomical signature of different traits. Morphometricity is defined as the proportion of phenotypic variation that can be explained by macroscopic brain morphology. We estimate morphometricity via a linear mixed-effects model that uses an anatomical similarity matrix computed based on measurements derived from structural brain MRI scans. We examined over 3,800 unique MRI scans from nine large-scale studies to estimate the morphometricity of a range of phenotypes, including clinical diagnoses such as Alzheimer's disease, and non-clinical traits such as measures of cognition. Our results demonstrate that morphometricity can provide novel insights about the neuroanatomical correlates of a diverse set of traits, revealing associations that might not be detectable through traditional statistical techniques. C1 [Sabuncu, Mert R.; Ge, Tian; Holmes, Avram J.; Buckner, Randy L.; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sabuncu, Mert R.; Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02138 USA. [Ge, Tian; Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Ge, Tian; Smoller, Jordan W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02138 USA. [Holmes, Avram J.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Holmes, Avram J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buckner, Randy L.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02128 USA. RP Sabuncu, MR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Sabuncu, MR (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02138 USA. EM msabuncu@nmr.mgh.harvard.edu OI Preda, Adrian /0000-0003-3373-2438 FU National Institute for Biomedical Imaging and Bioengineering [P41EB015896, R01EB006758, R21EB018907, R01EB019956]; National Institute on Aging [5R01AG008122, R01AG016495]; National Institute for Neurological Disorders and Stroke [R01NS0525851, R21NS072652, R01NS070963, R01NS083534, 5U01NS086625]; Shared Instrumentation [1S10RR023401, 1S10RR019307, 1S10RR023043]; NIH Blueprint for Neuroscience Research Grant [5U01-MH093765]; multiinstitutional Human Connectome Project; Center for Brain Science Neuroinformatics Research Group; NIH [R01NS070963, R01NS083534, R41AG052246, 1K25EB013649-01, 1R21AG050122-01A1, K01MH099232, K24MH094614, R01MH101486]; MGH ECOR Tosteson Postdoctoral Fellowship Award FX We thank the 20 individual investigators at Harvard and Massachusetts General Hospital (MGH) who generously contributed data to the overall project. Support for this research was provided in part by National Institute for Biomedical Imaging and Bioengineering Grants P41EB015896, R01EB006758, R21EB018907, and R01EB019956; National Institute on Aging Grants 5R01AG008122 and R01AG016495; and National Institute for Neurological Disorders and Stroke Grants R01NS0525851, R21NS072652, R01NS070963, R01NS083534, and 5U01NS086625 and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Additional support was provided by the NIH Blueprint for Neuroscience Research Grant 5U01-MH093765, part of the multiinstitutional Human Connectome Project. Data were provided in part by the Brain Genomics Superstruct Project of Harvard University and MGH, with support from the Center for Brain Science Neuroinformatics Research Group, Athinoula A. Martinos Center for Biomedical Imaging, Center for Human Genetic Research, and Stanley Center for Psychiatric Research. Data used in preparation of this article were also obtained from the ADNI database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_L ist.pdf. This research was also funded in part by NIH Grants R01NS083534, R01NS070963, R41AG052246, 1K25EB013649-01, and 1R21AG050122-01A1 (to M.R.S.); K01MH099232 (to A.J.H.); K24MH094614 and R01MH101486 (to J.W.S.); and an MGH ECOR Tosteson Postdoctoral Fellowship Award (to T.G.). J.W.S. is a Tepper Family MGH Research Scholar. NR 55 TC 0 Z9 0 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2016 VL 113 IS 39 BP E5749 EP E5756 DI 10.1073/pnas.1604378113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW9DD UT WOS:000383954700008 PM 27613854 ER PT J AU Bazou, D Ng, MR Song, JW Chin, SM Maimon, N Munn, LL AF Bazou, Despina Ng, Mei Rosa Song, Jonathan W. Chin, Shan Min Maimon, Nir Munn, Lance L. TI Flow-induced HDAC1 phosphorylation and nuclear export in angiogenic sprouting SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN-KINASE CK2; HISTONE DEACETYLASE; ENDOTHELIAL-CELLS; SHEAR-STRESS; EPIGENETIC REGULATION; EXTRACELLULAR-MATRIX; PROGENITOR CELLS; TISSUE ANALOG; TIP CELLS; EXPRESSION AB Angiogenesis requires the coordinated growth and migration of endothelial cells (ECs), with each EC residing in the vessel wall integrating local signals to determine whether to remain quiescent or undergo morphogenesis. These signals include vascular endothelial growth factor (VEGF) and flow-induced mechanical stimuli such as interstitial flow, which are both elevated in the tumor microenvironment. However, it is not clear how VEGF signaling and mechanobiological activation due to interstitial flow cooperate during angiogenesis. Here, we show that endothelial morphogenesis is histone deacetylase-1-(HDAC1) dependent and that interstitial flow increases the phosphorylation of HDAC1, its activity, and its export from the nucleus. Furthermore, we show that HDAC1 inhibition decreases endothelial morphogenesis and matrix metalloproteinase-14 (MMP14) expression. Our results suggest that HDAC1 modulates angiogenesis in response to flow, providing a new target for modulating vascularization in the clinic. C1 [Bazou, Despina; Ng, Mei Rosa; Chin, Shan Min; Maimon, Nir; Munn, Lance L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, 100 Blossom St, Boston, MA 02114 USA. [Bazou, Despina; Ng, Mei Rosa; Chin, Shan Min; Maimon, Nir; Munn, Lance L.] Harvard Med Sch, 100 Blossom St, Boston, MA 02114 USA. [Song, Jonathan W.] Ohio State Univ, Dept Mech & Aerosp Engn, E406 201 W 19th Ave, Columbus, OH 43210 USA. RP Munn, LL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, 100 Blossom St, Boston, MA 02114 USA.; Munn, LL (reprint author), Harvard Med Sch, 100 Blossom St, Boston, MA 02114 USA. EM munn@steele.mgh.harvard.edu OI Song, Jonathan/0000-0002-6991-5298 FU National Institutes of Health [R01HL106584] FX The authors would like to acknowledge funding from the National Institutes of Health (R01HL106584). NR 51 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 27 PY 2016 VL 6 AR 34046 DI 10.1038/srep34046 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX2SO UT WOS:000384221300001 PM 27669993 ER PT J AU Kaelin, WG Ratcliffe, PJ Semenza, GL AF Kaelin, William G., Jr. Ratcliffe, Peter J. Semenza, Gregg L. TI Pathways for Oxygen Regulation and Homeostasis The 2016 Albert Lasker Basic Medical Research Award SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID HYPOXIA; HYDROXYLATION; ENHANCER; PROTEIN; HIF AB The 2016 Albert Lasker Basic Medical Research Award has been presented to William G. Kaelin, Peter J. Ratcliffe, and Gregg L. Semenza for the discovery and elucidation of pathways by which humans and other multicellular organisms sense and respond to changes in oxygen availability. C1 [Kaelin, William G., Jr.] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. [Kaelin, William G., Jr.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kaelin, William G., Jr.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Ratcliffe, Peter J.] Univ Oxford, Oxford, England. [Ratcliffe, Peter J.] Francis Crick Inst, London, England. [Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. [Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21218 USA. RP Kaelin, WG (reprint author), Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA.; Kaelin, WG (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA.; Kaelin, WG (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA.; Ratcliffe, PJ (reprint author), Univ Oxford, Oxford, England.; Ratcliffe, PJ (reprint author), Francis Crick Inst, London, England.; Semenza, GL (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA.; Semenza, GL (reprint author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21218 USA. EM william_kaelin@dfci.harvard.edu; peter.ratcliffe@ndm.ox.ac.uk; gsemenza@jhmi.edu NR 6 TC 0 Z9 0 U1 4 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 27 PY 2016 VL 316 IS 12 BP 1252 EP 1253 DI 10.1001/jama.2016.12386 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DW9EW UT WOS:000383959800011 PM 27622845 ER PT J AU Ibrahim, SA Kim, H McConnell, KJ AF Ibrahim, Said A. Kim, Hyunjee McConnell, K. John TI The CMS Comprehensive Care Model and Racial Disparity in Joint Replacement SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID KNEE; ARTHROPLASTY; RACE; HIP C1 [Ibrahim, Said A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ibrahim, Said A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Kim, Hyunjee; McConnell, K. John] Oregon Hlth & Sci Univ, Ctr Hlth Syst Effectiveness, Portland, OR 97201 USA. RP Ibrahim, SA (reprint author), Univ Penn, Perelman Sch Med, Ctr Hlth Equ Res & Promot, Philadelphia VA Med Ctr Annex, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM said.ibrahim2@va.gov FU NIAMS NIH HHS [K24 AR055259] NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 27 PY 2016 VL 316 IS 12 BP 1258 EP 1259 DI 10.1001/jama.2016.12330 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DW9EW UT WOS:000383959800014 PM 27653166 ER PT J AU Silverman, MG Ference, BA Im, K Wiviott, SD Giugliano, RP Grundy, SM Braunwald, E Sabatine, MS AF Silverman, Michael G. Ference, Brian A. Im, Kyungah Wiviott, Stephen D. Giugliano, Robert P. Grundy, Scott M. Braunwald, Eugene Sabatine, Marc S. TI Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID CORONARY-HEART-DISEASE; RANDOMIZED CONTROLLED-TRIAL; DENSITY-LIPOPROTEIN CHOLESTEROL; TYPE-2 DIABETES-MELLITUS; PLACEBO-CONTROLLED TRIAL; EXTENDED-RELEASE NIACIN; HIGH-DOSE ATORVASTATIN; MYOCARDIAL-INFARCTION; PRIMARY PREVENTION; HYPERTENSIVE PATIENTS AB IMPORTANCE The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. OBJECTIVE To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. DATA SOURCES AND STUDY SELECTION The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included. DATA EXTRACTION AND SYNTHESIS Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression. MAIN OUTCOMES AND MEASURES The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level. RESULTS A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P <.001) for statins and 0.75 (95% CI, 0.66-0.86; P =.002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P =.72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P <.001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P =.002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P <.001). CONCLUSIONS AND RELEVANCE In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events. C1 [Silverman, Michael G.; Im, Kyungah; Wiviott, Stephen D.; Giugliano, Robert P.; Braunwald, Eugene; Sabatine, Marc S.] Harvard Med Sch, Brigham andWomens Hosp, Div Cardiovasc Med, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Ference, Brian A.] Wayne State Univ, Sch Med, Div Cardiovasc Med, Detroit, MI USA. [Grundy, Scott M.] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Ctr Human Nutr, Dallas, TX USA. RP Sabatine, MS (reprint author), Harvard Med Sch, Brigham andWomens Hosp, Div Cardiovasc Med, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM msabatine@partners.org FU NHLBI NIH HHS [T32 HL007604] NR 68 TC 12 Z9 12 U1 21 U2 21 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 SEP 27 PY 2016 VL 316 IS 12 BP 1289 EP 1297 DI 10.1001/jama.2016.13985 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DW9EW UT WOS:000383959800020 PM 27673306 ER PT J AU Keenan, WT Rupp, AC Ross, RA Somasundaram, P Hiriyanna, S Wu, Z Badea, TC Robinson, PR Lowell, BB Hattar, SS AF Keenan, William Thomas Rupp, Alan C. Ross, Rachel A. Somasundaram, Preethi Hiriyanna, Suja Wu, Zhijian Badea, Tudor C. Robinson, Phyllis R. Lowell, Bradford B. Hattar, Samer S. TI A visual circuit uses complementary mechanisms to support transient and sustained pupil constriction SO ELIFE LA English DT Article ID RETINAL GANGLION-CELLS; CYCLASE-ACTIVATING POLYPEPTIDE; MELANOPSIN-KNOCKOUT MICE; CONE PHOTORECEPTORS; LIGHT RESPONSE; CIRCADIAN RESPONSES; ROD PHOTORECEPTORS; LACKING PACAP; REFLEX; VISION AB Rapid and stable control of pupil size in response to light is critical for vision, but the neural coding mechanisms remain unclear. Here, we investigated the neural basis of pupil control by monitoring pupil size across time while manipulating each photoreceptor input or neurotransmitter output of intrinsically photosensitive retinal ganglion cells (ipRGCs), a critical relay in the control of pupil size. We show that transient and sustained pupil responses are mediated by distinct photoreceptors and neurotransmitters. Transient responses utilize input from rod photoreceptors and output by the classical neurotransmitter glutamate, but adapt within minutes. In contrast, sustained responses are dominated by non-conventional signaling mechanisms: melanopsin phototransduction in ipRGCs and output by the neuropeptide PACAP, which provide stable pupil maintenance across the day. These results highlight a temporal switch in the coding mechanisms of a neural circuit to support proper behavioral dynamics. C1 [Keenan, William Thomas; Rupp, Alan C.; Hattar, Samer S.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Ross, Rachel A.] Harvard Med Sch, Dept Psychiat, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Ross, Rachel A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Somasundaram, Preethi; Robinson, Phyllis R.] Univ Marlyand, Dept Biol Sci, Baltimore, MD USA. [Hiriyanna, Suja; Wu, Zhijian; Badea, Tudor C.] NEI, NIH, Bethesda, MD 20892 USA. [Lowell, Bradford B.] Harvard Med Sch, Div Endocrinol Diabet & Metab, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Lowell, Bradford B.] Harvard Med Sch, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Lowell, Bradford B.] Harvard Med Sch, Program Neurosci, Boston, MA USA. [Hattar, Samer S.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21218 USA. RP Hattar, SS (reprint author), Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA.; Hattar, SS (reprint author), Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21218 USA. EM shattar@jhu.edu OI Rupp, Alan/0000-0001-5363-4494; Keenan, William/0000-0003-3381-744X FU National Eye Institute [R21 EY024452]; National Institute of General Medical Sciences [RO1 GM076430]; National Eye Institute Intramural research program [EY000504-06]; National Heart Lung and Blood Institute [5T32HL007374-36]; Harvard Medical School Department of Psychiatry FX National Eye Institute R21 EY024452 William Thomas Keenan Alan C Rupp Samer S Hattar; National Institute of General Medical Sciences RO1 GM076430 William Thomas Keenan Alan C Rupp Samer S Hattar; National Eye Institute Intramural research program EY000504-06 Tudor C Badea; National Heart Lung and Blood Institute 5T32HL007374-36 Rachel A Ross; Harvard Medical School Department of Psychiatry Dupont Warren Fellowship Rachel A Ross; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 75 TC 0 Z9 0 U1 3 U2 3 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 26 PY 2016 VL 5 AR e15392 DI 10.7554/eLife.15392 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EB0LB UT WOS:000387034200001 ER PT J AU Keshavarz-Motamed, Z Nezami, FR Partida, RA Nakamura, K Staziaki, PV Ben-Assa, E Ghoshhajra, B Bhatt, AB Edelman, ER AF Keshavarz-Motamed, Zahra Nezami, Farhad Rikhtegar Partida, Ramon A. Nakamura, Kenta Staziaki, Pedro Vinicius Ben-Assa, Eyal Ghoshhajra, Brian Bhatt, Ami B. Edelman, Elazer R. TI Elimination of Transcoarctation Pressure Gradients Has No Impact on Left Ventricular Function or Aortic Shear Stress After Intervention in Patients With Mild Coarctation SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE aortic hemodynamics; left ventricle function; mild coarctation; peak-to-peak pressure gradient; transcatheter intervention ID CONGENITAL HEART-DISEASE; TERM-FOLLOW-UP; BLOOD-PRESSURE; BALLOON ANGIOPLASTY; STENT IMPLANTATION; ELASTIC PROPERTIES; SUCCESSFUL REPAIR; SURGICAL REPAIR; IN-VITRO; ADULTS AB OBJECTIVES This study sought to investigate the impact of transcatheter intervention on left ventricular function and aortic hemodynamics in patients with mild coarctation of the aorta (COA). BACKGROUND The optimal method and timing of transcatheter intervention for COA remains unclear, especially when the severity of COA is mild (peak-to-peak transcoarctation pressure gradient <20 mm Hg). Debate rages regarding the risk/benefit ratio of intervention versus long-term effects of persistent minimal gradient in this heterogeneous population with differing blood pressures, ventricular function, and peripheral perfusion. METHODS We developed a unique computational fluid dynamics and lumped parameter modeling framework based on patient-specific hemodynamic input parameters and validated it against patient-specific clinical outcomes (before and after intervention). We used clinically measured hemodynamic metrics and imaging of the aorta and the left ventricle in 34 patients with mild COA to make these correlations. RESULTS Despite dramatic reduction in the transcoarctation pressure gradient (catheter and Doppler echocardiography pressure gradients reduced by 75% and 47.3%, respectively), there was only modest effect on aortic flow and no significant impact on aortic shear stress (the maximum time-averaged wall shear stress in descending aorta was reduced 5.1%). In no patient did transcatheter intervention improve left ventricular function (e. g., stroke work and normalized stroke work were reduced by only 4.48% and 3.9%, respectively). CONCLUSIONS Transcatheter intervention that successfully relieves mild COA pressure gradients does not translate to decreased myocardial strain. The effects of the intervention were determined to the greatest degree by ventricular-vascular coupling hemodynamics and provide a novel valuable mechanism to evaluate patients with COA that may influence clinical practice. (C) 2016 by the American College of Cardiology Foundation. C1 [Keshavarz-Motamed, Zahra; Nezami, Farhad Rikhtegar; Partida, Ramon A.; Nakamura, Kenta; Ben-Assa, Eyal; Edelman, Elazer R.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave,Bldg E25-438, Cambridge, MA 02139 USA. [Partida, Ramon A.; Nakamura, Kenta; Staziaki, Pedro Vinicius; Ghoshhajra, Brian; Bhatt, Ami B.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Div, Boston, MA USA. [Edelman, Elazer R.] Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Boston, MA USA. RP Keshavarz-Motamed, Z (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave,Bldg E25-438, Cambridge, MA 02139 USA. EM zahra_km@MIT.EDU FU National Institutes of Health [R01 GM 49039]; American Heart Association postdoctoral fellowship [16POST26420039]; SNSF EPM fellowship [P2EZP3_155599] FX Dr. Edelman is supported in part by grants from the National Institutes of Health (R01 GM 49039). Dr. Keshavarz-Motamed is supported in part by American Heart Association postdoctoral fellowship (16POST26420039). Dr. Rikhtegar Nezami is supported by SNSF EPM fellowship (P2EZP3_155599). NR 43 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD SEP 26 PY 2016 VL 9 IS 18 BP 1953 EP 1965 DI 10.1016/j.jcin.2016.06.054 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ2ZZ UT WOS:000385713800018 PM 27659574 ER PT J AU West, JA Mito, M Kurosaka, S Takumi, T Tanegashima, C Chujo, T Yanaka, K Kingston, RE Hirose, T Bond, C Fox, A Nakagawa, S AF West, Jason A. Mito, Mari Kurosaka, Satoshi Takumi, Toru Tanegashima, Chiharu Chujo, Takeshi Yanaka, Kaori Kingston, Robert E. Hirose, Tetsuro Bond, Charles Fox, Archa Nakagawa, Shinichi TI Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization SO JOURNAL OF CELL BIOLOGY LA English DT Article ID LONG NONCODING RNA; CELL-FREE FORMATION; XIST RNA; SUBNUCLEAR BODIES; BINDING PROTEINS; MESSENGER-RNAS; LNCRNA NEAT1; PURIFICATION; TARGETS; TDP-43 AB Paraspeckles are nuclear bodies built on the long noncoding RNA Neat1, which regulates a variety of physiological processes including cancer progression and corpus luteum formation. To obtain further insight into the molecular basis of the function of paraspeckles, we performed fine structural analyses of these nuclear bodies using structural illumination microscopy. Notably, paraspeckle proteins are found within different layers along the radially arranged bundles of Neat1 transcripts, forming a characteristic core-shell spheroidal structure. In cells lacking the RNA binding protein Fus, paraspeckle spheroids are disassembled into smaller particles containing Neat1, which are diffusely distributed in the nucleoplasm. Sequencing analysis of RNAs purified from paraspeckles revealed that AG-rich transcripts associate with Neat1, which are distributed along the shell of the paraspeckle spheroids. We propose that paraspeckles sequester core components inside the spheroids, whereas the outer surface associates with other components in the nucleoplasm to fulfill their function. C1 [West, Jason A.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [West, Jason A.; Kingston, Robert E.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Mito, Mari; Yanaka, Kaori; Nakagawa, Shinichi] RIKEN, RNA Biol Lab, Wako, Saitama 3510198, Japan. [Kurosaka, Satoshi; Takumi, Toru] RIKEN Brain Sci Inst, Wako, Saitama 3510198, Japan. [Tanegashima, Chiharu] RIKEN Ctr Life Sci Technol, Phyloinformat Unit, Chuo Ku, Kobe, Hyogo 6500047, Japan. [Chujo, Takeshi; Hirose, Tetsuro] Hokkaido Univ, Inst Med Genet, Sapporo, Hokkaido 0600815, Japan. [Bond, Charles] Univ Western Australia, Sch Chem & Biochem, Crawley, WA 6009, Australia. [Fox, Archa] Univ Western Australia, Sch Anat Physiol & Human Biol, Crawley, WA 6009, Australia. [Fox, Archa] Queen Elizabeth II Med Ctr, Harry Perkins Inst Med Res, Nedlands, WA 6009, Australia. [Nakagawa, Shinichi] Hokkaido Univ, Fac Pharmaceut Sci, RNA Biol Lab, Sapporo, Hokkaido 0600812, Japan. [West, Jason A.] Biogen, Cambridge, MA 02142 USA. RP Nakagawa, S (reprint author), RIKEN, RNA Biol Lab, Wako, Saitama 3510198, Japan.; Nakagawa, S (reprint author), Hokkaido Univ, Fac Pharmaceut Sci, RNA Biol Lab, Sapporo, Hokkaido 0600812, Japan. EM nakagawas@pharm.hokudai.ac.jp RI Nakagawa, Shinichi/I-4192-2014; West, Jason/I-4445-2014 OI Nakagawa, Shinichi/0000-0002-6806-7493; West, Jason/0000-0002-7252-8651 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [26113005, 23111005] FX This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (26113005 and 23111005). NR 47 TC 4 Z9 4 U1 6 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD SEP 26 PY 2016 VL 214 IS 7 BP 817 EP 830 DI 10.1083/jcb.201601071 PG 14 WC Cell Biology SC Cell Biology GA DX9IU UT WOS:000384707600007 PM 27646274 ER PT J AU Wizeman, JW Nicholas, AP Ishigami, A Mohan, R AF Wizeman, John W. Nicholas, Anthony P. Ishigami, Akihito Mohan, Royce TI Citrullination of glial intermediate filaments is an early response in retinal injury SO MOLECULAR VISION LA English DT Article ID FIBRILLARY ACIDIC PROTEIN; PEPTIDYLARGININE DEIMINASE; ALZHEIMERS-DISEASE; MULLER CELLS; MACULAR DEGENERATION; MULTIPLE-SCLEROSIS; VIMENTIN; PROLIFERATION; EXPRESSION; ACTIVATION AB Purpose: A hallmark of retinal gliosis is the increased detection and modification of the type III intermediate filament (IF) proteins vimentin and glial fibrillary acidic protein (GFAP). Here, we investigated vimentin and GFAP in Muller glia in a mouse model of alkali injury, focusing on the posttranslational modification of citrullination. Methods: Mice were injured by corneal exposure to 1.0 N NaOH, and eyes were enucleated at different time points following injury. The levels of soluble and cytoskeletal forms of IF proteins and citrullination were measured using western blot analysis. Citrullinated GFAP was identified by immunoprecipitation followed by two-dimensional (2D) isoelectric focusing-polyacrylamide gel electrophoresis (IEF-PAGE) western blotting using a specific antibody that recognizes citrullinated GFAP. Vimentin, GFAP, and citrullinated proteins were localized in the retina by immunohistochemistry (IHC). Drug treatments were investigated in retinal explant cultures of posterior eyecups obtained from mouse eyes that were injured in vivo. Results: Detection of GFAP in injured retinas increased over a period of 1 to 7 days, showing increased levels in both soluble and cytoskeletal forms of this IF protein. The global level of citrullinated proteins was also induced over this period, with low-salt buffer extraction showing the most abundant early changes in citrullination. Using IHC, we found that GFAP filaments assembled at Muller glial end feet, growing in size with time through the inner layers of the retina at 1-3 h postinjury. Interestingly, over this early time period, levels of soluble citrullinated proteins also increased within the retina, as detected by western blotting, coincident with the localization of the citrullinated epitopes on growing GFAP filaments and existing vimentin filaments by 3 h after injury. Taking advantage of the in vivo injury model to promote a robust gliotic response, posterior eyecups from 7-day postinjured eyes were treated in explant cultures with the peptidyl arginine deiminase inhibitor Cl-amidine, which was found to reduce global citrullination. Surprisingly, the detection of injury-induced high-molecular-weight GFAP species containing citrullinated epitopes was also reduced by Cl-amidine treatment. Using a low dose of the potent type III IF drug withaferin A (WFA), we showed that Cl-amidine treatment in combination with WFA reduced global protein citrullination further, suggesting that GFAP may be a key component of pathological citrullinated targets. Conclusions: Our findings illuminate citrullination as a potential novel target for trauma-induced retinal gliosis. We also propose that strategies for combining drugs targeting type III IFs and citrullination may potentiate tissue repair, which is an idea that needs to be validated in vivo. C1 [Wizeman, John W.; Mohan, Royce] Univ Connecticut, Ctr Hlth, Dept Neurosci, 263 Farmington Ave, Farmington, CT 06030 USA. [Nicholas, Anthony P.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Nicholas, Anthony P.] Birmingham VA Med Ctr, Birmingham, AL USA. [Ishigami, Akihito] Tokyo Metropolitan Inst Gerontol, Mol Regulat Aging, Tokyo, Japan. RP Mohan, R (reprint author), Univ Connecticut, Ctr Hlth, Dept Neurosci, 263 Farmington Ave, Farmington, CT 06030 USA. EM mohan@uchc.edu FU National Eye Institute/NIH grant [R01EY016782]; John A. and Florence Mattern Solomon Endowed Chair in Vision Biology and Eye Diseases FX This work was supported in part by funding from the National Eye Institute/NIH grant R01EY016782 and from the John A. and Florence Mattern Solomon Endowed Chair in Vision Biology and Eye Diseases. Conflicts of Interest: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Royce Mohan is one of the inventors on US Patent 8,283,323. NR 57 TC 0 Z9 0 U1 1 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD SEP 26 PY 2016 VL 22 BP 1137 EP 1155 PG 19 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA DX7OB UT WOS:000384576500001 PM 27703308 ER PT J AU Posfai, M Gao, JX Cornelius, SP Barabasi, AL D'Souza, RM AF Posfai, Marton Gao, Jianxi Cornelius, Sean P. Barabasi, Albert-Laszlo D'Souza, Raissa M. TI Controllability of multiplex, multi-time-scale networks SO PHYSICAL REVIEW E LA English DT Article ID COMPLEX NETWORKS; INTERDEPENDENT NETWORKS; CORE PERCOLATION; RANDOM GRAPHS; LOAD AB The paradigm of layered networks is used to describe many real-world systems, from biological networks to social organizations and transportation systems. While recently there has been much progress in understanding the general properties of multilayer networks, our understanding of how to control such systems remains limited. One fundamental aspect that makes this endeavor challenging is that each layer can operate at a different time scale; thus, we cannot directly apply standard ideas from structural control theory of individual networks. Here we address the problem of controlling multilayer and multi-time-scale networks focusing on two-layer multiplex networks with one-to-one interlayer coupling. We investigate the practically relevant case when the control signal is applied to the nodes of one layer. We develop a theory based on disjoint path covers to determine the minimum number of inputs (N-i) necessary for full control. We show that if both layers operate on the same time scale, then the network structure of both layers equally affect controllability. In the presence of time-scale separation, controllability is enhanced if the controller interacts with the faster layer: Ni decreases as the time-scale difference increases up to a critical time-scale difference, above which Ni remains constant and is completely determined by the faster layer. We show that the critical time-scale difference is large if layer I is easy and layer II is hard to control in isolation. In contrast, control becomes increasingly difficult if the controller interacts with the layer operating on the slower time scale and increasing time-scale separation leads to increased Ni, again up to a critical value, above which Ni still depends on the structure of both layers. This critical value is largely determined by the longest path in the faster layer that does not involve cycles. By identifying the underlying mechanisms that connect time-scale difference and controllability for a simplified model, we provide crucial insight into disentangling how our ability to control real interacting complex systems is affected by a variety of sources of complexity. C1 [Posfai, Marton; D'Souza, Raissa M.] Univ Calif Davis, Complex Sci Ctr, Davis, CA 95616 USA. [Posfai, Marton; D'Souza, Raissa M.] Univ Calif Davis, Dept Comp Sci, Davis, CA 95616 USA. [Posfai, Marton] Eotvos Lorand Univ, Dept Phys Complex Syst, H-1117 Budapest, Hungary. [Gao, Jianxi; Cornelius, Sean P.; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Barabasi, Albert-Laszlo] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary. [D'Souza, Raissa M.] Univ Calif Davis, Dept Mech & Aerosp Engn, Davis, CA 95616 USA. [D'Souza, Raissa M.] Santa Fe Inst, 1399 Hyde Pk Rd, Santa Fe, NM 87501 USA. RP Posfai, M (reprint author), Univ Calif Davis, Complex Sci Ctr, Davis, CA 95616 USA.; Posfai, M (reprint author), Univ Calif Davis, Dept Comp Sci, Davis, CA 95616 USA.; Posfai, M (reprint author), Eotvos Lorand Univ, Dept Phys Complex Syst, H-1117 Budapest, Hungary. EM posfai@ucdavis.edu FU U.S. Army Research Office [W911NF-09-2-0053]; U.S. Army Research Office MURI [W911NF-13-1-0340]; Defense Threat Reduction Agency Basic Research [HDTRA1-10-1-0088, HDTRA1-10-1-00100] FX We thank Yang-Yu Liu, Philipp Hovel, and Zsofia Penzvalto for useful discussions. We gratefully acknowledge support from U.S. Army Research Office Cooperative Agreement No. W911NF-09-2-0053, U.S. Army Research Office MURI Award No. W911NF-13-1-0340, and the Defense Threat Reduction Agency Basic Research Awards No. HDTRA1-10-1-0088 and No. HDTRA1-10-1-00100. NR 46 TC 0 Z9 0 U1 16 U2 16 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD SEP 26 PY 2016 VL 94 IS 3 AR 032316 DI 10.1103/PhysRevE.94.032316 PG 14 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA DX0TM UT WOS:000384078100006 PM 27739809 ER PT J AU Han, YM Park, JM Kang, JX Cha, JY Lee, HJ Jeong, M Go, EJ Hahm, KB AF Han, Young-Min Park, Jong-Min Kang, Jing X. Cha, Ji-Young Lee, Ho-Jae Jeong, Migeyong Go, Eun-Jin Hahm, Ki Baik TI Mitigation of indomethacin-induced gastrointestinal damages in fat-1 transgenic mice via gate-keeper action of omega-3-polyunsaturated fatty acids SO SCIENTIFIC REPORTS LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; GASTRIC-MUCOSAL INJURY; FISH-OIL; LIPID RAFTS; NSAIDS; RATS; PHOSPHOLIPIDS; MEMBRANES; INSIGHT; PHOSPHATIDYLCHOLINE AB Non-steroidal anti-inflammatory drugs (NSAIDs) damage the gastrointestinal (GI) epithelial cell membranes by inducing several signals through lipid raft organization after membrane incorporation, whereas omega-3 polyunsaturated fatty acids (PUFAs) relieve inflammation, reduce oxidative stress, and provide cytoprotection, consequent to lipid raft disorganization. Therefore, we hypothesized that omega-3 PUFAs can protect the GI from NSAID-induced damages by initiating the gatekeeper action of cell membranes, subsequent to anti-inflammatory and anti-oxidative actions. Administration of indomethacin (IND) leads to the formation of lipid rafts and activation of caveolin-1; however, no such observations were made upon co-administration of eicosapentaenoic acid (EPA) and IND. In addition, the EPA-induced lipid raft disorganization, caveolin-1 inactivation, and cellular cytotoxicity were inhibited when target cells were knocked-out using G-protein coupled receptor 120 (GPR 120). EPA significantly attenuated IND-induced oxidative damage and apoptosis. IND administration induced significant ulceration, bleeding, and oedema in the stomach or small intestine of wild-type (WT) mice; however, such severe damages to the GI significantly decreased in fat-1 transgenic (TG) mice (P < 0.001), which exhibited decreased cyclooxygenase-2 expression and apoptosis, decreased interleukin-1 beta and FAS concentrations, and increased heme oxygenase-1 concentration. Our study indicates that the gatekeeper function of omega-3 PUFAs improves GI safety when administered with NSAID. C1 [Han, Young-Min; Park, Jong-Min; Jeong, Migeyong; Go, Eun-Jin; Hahm, Ki Baik] CHA Canc Prevent Res Ctr, CHA Bio Complex, Songnam, South Korea. [Kang, Jing X.] Harvard Med Sch, Massachusetts Gen Hosp, Lab Lipid Med & Technol, Boston, MA 02129 USA. [Cha, Ji-Young; Lee, Ho-Jae] Gachon Univ, Lee Gil Ya Diabet & Canc Inst, Inchon, South Korea. [Hahm, Ki Baik] CHA Univ, CHA Bundang Med Ctr, Digest Dis Ctr, Songnam, South Korea. RP Hahm, KB (reprint author), CHA Canc Prevent Res Ctr, CHA Bio Complex, Songnam, South Korea.; Hahm, KB (reprint author), CHA Univ, CHA Bundang Med Ctr, Digest Dis Ctr, Songnam, South Korea. EM hahmkb@cha.ac.kr FU Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [2014R1A1A2058732] FX We thank Prof. Eun Hee Kim for experimental assistance. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2058732). NR 45 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 23 PY 2016 VL 6 AR 33992 DI 10.1038/srep33992 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX0PZ UT WOS:000384067500001 ER PT J AU Detappe, A Kunjachan, S Drane, P Kotb, S Myronakis, M Biancur, DE Ireland, T Wagar, M Lux, F Tillement, O Berbeco, R AF Detappe, Alexandre Kunjachan, Sijumon Drane, Pascal Kotb, Shady Myronakis, Marios Biancur, Douglas E. Ireland, Thomas Wagar, Matthew Lux, Francois Tillement, Olivier Berbeco, Ross TI Key clinical beam parameters for nanoparticle-mediated radiation dose amplification SO SCIENTIFIC REPORTS LA English DT Article ID GADOLINIUM-BASED NANOPARTICLES; GOLD NANOPARTICLES; IN-VIVO; AGUIX NANOPARTICLES; OXIDE NANOPARTICLES; PHOTON BEAMS; THERAPY; CANCER; ENHANCEMENT; RADIOSENSITIZATION AB As nanoparticle solutions move towards human clinical trials in radiation therapy, the influence of key clinical beam parameters on therapeutic efficacy must be considered. In this study, we have investigated the clinical radiation therapy delivery variables that may significantly affect nanoparticle-mediated radiation dose amplification. We found a benefit for situations which increased the proportion of low energy photons in the incident beam. Most notably, "unflattened" photon beams from a clinical linear accelerator results in improved outcomes relative to conventional "flat" beams. This is measured by significant DNA damage, tumor growth suppression, and overall improvement in survival in a pancreatic tumor model. These results, obtained in a clinical setting, clearly demonstrate the influence and importance of radiation therapy parameters that will impact clinical radiation dose amplification with nanoparticles. C1 [Detappe, Alexandre; Kunjachan, Sijumon; Drane, Pascal; Kotb, Shady; Myronakis, Marios; Biancur, Douglas E.; Wagar, Matthew; Berbeco, Ross] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Detappe, Alexandre; Kotb, Shady; Lux, Francois; Tillement, Olivier] Univ Lyon 1, Inst Lumiere Matiere, CNRS, UMR5306, Lyon, France. [Ireland, Thomas] Boston Univ, LA ICP MS & ICP ES Labs, Boston, MA 02215 USA. RP Berbeco, R (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. EM RBerbeco@LROC.Harvard.edu OI Kunjachan, Sijumon /0000-0002-5359-9219; Detappe, Alexandre/0000-0001-9364-1621 FU National Cancer Institute (NCI) [R21 CA188833]; program "Investissement d'Avenir" from the LABEX PRIMES of Lyon 1 University [ANR-11-IDEX-0063] FX This project was supported, in part, by award number R21 CA188833 from the National Cancer Institute (NCI). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or NIH. S.K. received financial support through the program "Investissement d'Avenir" (ANR-11-IDEX-0063) from the LABEX PRIMES of Lyon 1 University. NR 40 TC 0 Z9 0 U1 7 U2 7 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 SEP 23 PY 2016 VL 6 AR 34040 DI 10.1038/srep34040 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX0RS UT WOS:000384072700001 PM 27658637 ER PT J AU Wuerthner, BA Avila-Wallace, M AF Wuerthner, Barbara A. Avila-Wallace, Maria TI Cervical cancer Screening, management, and prevention SO NURSE PRACTITIONER LA English DT Article DE cervical cancer prevention; cervical cancer screening; cervical precancer treatment; Pap test ID HPV; VACCINATION; GUIDELINES AB Cervical cancer incidence in the United States is estimated to affect 12,900 women in 2016, with 4,100 deaths. Screening for this cancer with Pap test and adjunct human papillomavirus testing has made cervical cancer a treatable disease. This article reviews screening, treatment recommendations, and prevention for cervical cancer. C1 [Wuerthner, Barbara A.; Avila-Wallace, Maria] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wuerthner, BA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 22 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0361-1817 EI 1538-8662 J9 NURSE PRACT JI Nurse Pract. PD SEP 22 PY 2016 VL 41 IS 9 BP 18 EP 23 DI 10.1097/01.NPR.0000490390.43604.5f PG 6 WC Nursing SC Nursing GA EB0KI UT WOS:000387032300005 PM 27513347 ER PT J AU Johnson, SD Young, MRI AF Johnson, Sara D. Young, M. Rita I. TI Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokins Production and Slows Progression to Cancer SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE head and neck cancer; HNSCC; immune; premalignant oral lesions; cytokines; T cell ID SQUAMOUS-CELL CARCINOMA; NECK-CANCER; DENDRITIC CELLS; T-CELLS; CYCLOOXYGENASE-2 EXPRESSION; PROGNOSTIC-SIGNIFICANCE; SUPPRESSOR-CELLS; HEAD; INHIBITION; CELECOXIB AB Current treatment options for head and neck squamous cell carcinoma (HNSCC) patients are often ineffective due to tumor-localized and systemic immunosuppression. Using the 4-NQO mouse model of oral carcinogenesis, this study showed that premalignant oral lesion cells produce higher levels of the immune modulator, PGE2, compared to HNSCC cells. Inhibiting prostaglandin production of premalignant lesion cells with the pan-cyclooxygenase inhibitor indomethacin stimulated their induction of spleen cell cytokine production. In contrast, inhibiting HNSCC prostaglandin production did not stimulate their induction of spleen cell cytokine production. Treatment of mice bearing premalignant oral lesions with indomethacin slowed progression of premalignant oral lesions to HNSCC. Flow cytometric analysis of T cells in the regional lymph nodes of lesion-bearing mice receiving indomethacin treatment showed an increase in lymph node cellularity and in the absolute number of CD8(+) T cells expressing IFN-gamma compared to levels in lesion-bearing mice receiving diluent control treatment. The cytokine-stimulatory effect of indomethacin treatment was not localized to regional lymph nodes but was also seen in the spleen of mice with premalignant oral lesions. Together, these data suggest that inhibiting prostaglandin production at the premalignant lesion stage boosts immune capability and improves clinical outcomes. C1 [Johnson, Sara D.; Young, M. Rita I.] Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC 29401 USA. [Johnson, Sara D.] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Young, M. Rita I.] Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. RP Young, MRI (reprint author), Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC 29401 USA.; Young, MRI (reprint author), Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. EM youngmr@musc.edu FU Clinical Sciences Research and Development Program of the Department of Veterans Affairs [I01-CX000851]; National Institutes of Health [RO1-CA128837] FX This work was supported by the Clinical Sciences Research and Development Program (I01-CX000851) of the Department of Veterans Affairs and by grants from the National Institutes of Health (RO1-CA128837) (MY). NR 43 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD SEP 22 PY 2016 VL 7 AR UNSP 379 DI 10.3389/fimmu.2016.00379 PG 12 WC Immunology SC Immunology GA DW5KM UT WOS:000383683600002 PM 27713748 ER PT J AU Monteiro, J Kaelin, W Ratcliffe, P AF Monteiro, Joao Kaelin, William Ratcliffe, Peter TI Making Sense of the Unexpected SO CELL LA English DT Editorial Material C1 [Kaelin, William] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Ratcliffe, Peter] Univ Oxford, Nuffield Dept Med, Oxford OX1 2JD, England. NR 0 TC 0 Z9 0 U1 2 U2 2 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 SEP 22 PY 2016 VL 167 IS 1 BP 35 EP 38 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1GW UT WOS:000386341500009 ER PT J AU Sykes, DB Kfoury, YS Mercier, FE Wawer, MJ Law, JM Haynes, MK Lewis, TA Schajnovitz, A Jain, ES Lee, D Meyer, H Pierce, KA Tolliday, NJ Waller, A Ferrara, SJ Eheim, AL Stoeckigt, D Maxcy, KL Cobert, JM Bachand, J Szekely, BA Mukherjee, S Sklar, LA Kotz, JD Clish, CB Sadreyev, RI Clemons, PA Janzer, A Schreiber, SL Scadden, DT AF Sykes, David B. Kfoury, Youmna S. Mercier, Francois E. Wawer, Mathias J. Law, Jason M. Haynes, Mark K. Lewis, Timothy A. Schajnovitz, Amir Jain, Esha Lee, Dongjun Meyer, Hanna Pierce, Kerry A. Tolliday, Nicola J. Waller, Anna Ferrara, Steven J. Eheim, Ashley L. Stoeckigt, Detlef Maxcy, Katrina L. Cobert, Julien M. Bachand, Jacqueline Szekely, Brian A. Mukherjee, Siddhartha Sklar, Larry A. Kotz, Joanne D. Clish, Clary B. Sadreyev, Ruslan I. Clemons, Paul A. Janzer, Andreas Schreiber, Stuart L. Scadden, David T. TI Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia SO CELL LA English DT Article ID BREQUINAR SODIUM NSC-368390; BONE-MARROW-CELLS; PHASE-I; O-GLCNACYLATION; NSC 368390; A77 1726; DUP 785; EXPRESSION; HOXA9; MICROARRAY AB While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML. C1 [Sykes, David B.; Kfoury, Youmna S.; Mercier, Francois E.; Schajnovitz, Amir; Jain, Esha; Lee, Dongjun; Maxcy, Katrina L.; Cobert, Julien M.; Bachand, Jacqueline; Szekely, Brian A.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Sykes, David B.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Wawer, Mathias J.; Tolliday, Nicola J.; Ferrara, Steven J.] Broad Inst MIT & Harvard, Ctr Dev Therapeut, Cambridge, MA 02142 USA. [Law, Jason M.; Lewis, Timothy A.; Kotz, Joanne D.; Clemons, Paul A.; Schreiber, Stuart L.] Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA. [Haynes, Mark K.; Waller, Anna; Sklar, Larry A.] Univ New Mexico, Ctr Mol Discovery, Albuquerque, NM 87131 USA. [Meyer, Hanna; Eheim, Ashley L.; Janzer, Andreas] Bayer Pharma AG, D-13353 Berlin, Germany. [Pierce, Kerry A.; Clish, Clary B.] Broad Inst, Metabolite Profiling Platform, Cambridge, MA 02142 USA. [Mukherjee, Siddhartha] Columbia Univ, Sch Med, Irving Canc Res Ctr, New York, NY 10032 USA. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Med Sch, Boston, MA 02114 USA. [Sykes, David B.; Kfoury, Youmna S.; Mercier, Francois E.; Schajnovitz, Amir; Lee, Dongjun; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Sykes, David B.; Kfoury, Youmna S.; Mercier, Francois E.; Schajnovitz, Amir; Lee, Dongjun; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Schreiber, Stuart L.] Howard Hughes Med Inst, Cambridge, MA 02138 USA. RP Sykes, DB; Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Sykes, DB; Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.; Sykes, DB; Scadden, DT (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Sykes, DB; Scadden, DT (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM dbsykes@mgh.harvard.edu; dscadden@mgh.harvard.edu OI lee, dongjun/0000-0001-6828-401X FU HSCI-CRM Flow Cytometry Facility; Scott Mordecai in the Department of Pathology Flow and Image Cytometry Core [NIH 1S10OD012027-01A1]; Partners HealthCare Personalized Medicine Translational Genomics Core; Genomics Platform at the Broad Institute; NIH [1R03DA032471-01]; NIH Molecular Library Program [U54 HG005032-1, U54 MH084690-1]; American Society of Hematology; Alex's Lemonade Stand Foundation; Leukemia and Lymphoma Society; Harvard Catalyst; American Cancer Society Institutional Research Grant; Harvard Stem Cell Institute; Ludwig Center at Harvard; Amelia Peabody Charitable Fund; Gerald and Darlene Jordan Chair of Medicine at Harvard University; Bayer Pharma AG FX The authors would like to thank Alexa Carver at Massachusetts General Hospital (MGH); Michael Churchill at Columbia University; and Anthony Arvanites, Lance Davidow, and Lee Rubin at the Harvard Stem Cell Institute for their help in optimizing the primary small-molecule screen. We thank Thomas Graf for the lysozyme GFP knockin mouse; Timothy Ley for providing the murine myeloid differentiation microarray data; David Tan, who created the mouse graphic; and Mark Kamps, who provided insight and support throughout the project. We thank Kathleen Higgins and Scott Vafai of the Broad Institute for their help with the Seahorse oxygen consumption experiment. We thank Amir Schajnovitz for sharing his model of MLL/AF9 leukemia for the in vivo comparison of brequinar with standard chemotherapy. We thank Sven Christian for his work profiling the human AML cell lines and their response to DHODH inhibition. We were supported by the HSCI-CRM Flow Cytometry Facility, by Scott Mordecai in the Department of Pathology Flow and Image Cytometry Core (NIH 1S10OD012027-01A1), by the Partners HealthCare Personalized Medicine Translational Genomics Core, and by the Genomics Platform at the Broad Institute. The small-molecule screen was supported by NIH grant 1R03DA032471-01 (to D.B.S.) and the NIH Molecular Library Program (U54 HG005032-1 awarded to S.L.S. and U54 MH084690-1 awarded to L.A.S.). D.B.S. was supported by grants from the American Society of Hematology, Alex's Lemonade Stand Foundation, the Leukemia and Lymphoma Society, Harvard Catalyst, and an American Cancer Society Institutional Research Grant. D.T.S. was supported by the Harvard Stem Cell Institute and the Ludwig Center at Harvard, as well as the Amelia Peabody Charitable Fund, and the Gerald and Darlene Jordan Chair of Medicine at Harvard University. H.M., A.L.E., D.S., and A.J. are employees of Bayer Pharma AG. The work was supported in part by a collaboration with Bayer Pharma AG. NR 48 TC 6 Z9 6 U1 9 U2 9 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 SEP 22 PY 2016 VL 167 IS 1 BP 171 EP + DI 10.1016/j.cell.2016.08.057 PG 31 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1GW UT WOS:000386341500023 PM 27641501 ER PT J AU An, G Acharya, C Feng, XY Wen, K Zhong, MK Zhang, L Munshi, NC Qiu, LG Tai, YT Anderson, KC AF An, Gang Acharya, Chirag Feng, Xiaoyan Wen, Kenneth Zhong, Mike Zhang, Li Munshi, Nikhil C. Qiu, Lugui Tai, Yu-Tzu Anderson, Kenneth C. TI Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication SO BLOOD LA English DT Article ID BONE-MARROW MICROENVIRONMENT; CELL MATURATION ANTIGEN; IFN-GAMMA; T-CELLS; CHECKPOINT BLOCKADE; DENDRITIC CELLS; PLASMA-CELLS; CROSS-TALK; IN-VITRO; TUMOR AB The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesions in patients with multiple myeloma (MM). Mechanisms remain elusive as to whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment. Here, we first show that OCs significantly protect MM cells against T-cell-mediated cytotoxicity via direct inhibition of proliferating CD4(+) and CD8(+) T cells. The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis. Importantly, the levels of these molecules, except CD38, are higher in OCs than in MM cells. Anti-PD-L1 monoclonal antibody (mAb) and IDO inhibitor partly overcome OC-inhibited T-cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), secreted by OCs, are significantly upregulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PD-L1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly upregulated during osteoclastogenesis. When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO. Taken together, these results define the expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support the combination of targeting these molecules to improve anti-MM immunity. C1 [An, Gang; Acharya, Chirag; Feng, Xiaoyan; Wen, Kenneth; Zhong, Mike; Zhang, Li; Munshi, Nikhil C.; Tai, Yu-Tzu; Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA USA. [An, Gang; Acharya, Chirag; Feng, Xiaoyan; Wen, Kenneth; Zhong, Mike; Zhang, Li; Munshi, Nikhil C.; Tai, Yu-Tzu; Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Ctr, Boston, MA USA. [An, Gang; Feng, Xiaoyan; Qiu, Lugui] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China. [An, Gang; Feng, Xiaoyan; Qiu, Lugui] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China. [An, Gang; Feng, Xiaoyan; Qiu, Lugui] Peking Union Med Coll, Tianjin, Peoples R China. RP Qiu, LG (reprint author), Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China.; Qiu, LG (reprint author), Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China.; Qiu, LG (reprint author), Peking Union Med Coll, Tianjin, Peoples R China.; Anderson, KC (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02215 USA. EM qiulg@ihcams.ac.cn; kenneth_anderson@dfci.harvard.edu FU National Institutes of Health (NIH) [RO1050947]; NIH National Cancer Institute [PO1-CA078378]; Dana-Farber/Harvard Cancer Center/Specialized Programs of Research Excellence in Multiple Myeloma [P50CA100707]; National Natural Science Fund [81400175, 81670202] FX This study was supported by grants from the National Institutes of Health (NIH), Research Project Grant Program (RO1050947), NIH National Cancer Institute (PO1-CA078378), Dana-Farber/Harvard Cancer Center/Specialized Programs of Research Excellence in Multiple Myeloma (P50CA100707 [K.C.A.]); and the National Natural Science Fund (81400175, 81670202). K.C.A. is an American Cancer Society Clinical Research Professor. NR 51 TC 3 Z9 3 U1 5 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 22 PY 2016 VL 128 IS 12 BP 1590 EP 1603 DI 10.1182/blood-2016-03-707547 PG 14 WC Hematology SC Hematology GA DZ3HA UT WOS:000385734800014 PM 27418644 ER PT J AU Pavlasova, G Borsky, M Seda, V Cerna, K Osickova, J Doubek, M Mayer, J Calogero, R Trbusek, M Pospisilova, S Davids, MS Kipps, TJ Brown, JR Mraz, M AF Pavlasova, Gabriela Borsky, Marek Seda, Vaclav Cerna, Katerina Osickova, Jitka Doubek, Michael Mayer, Jiri Calogero, Raffaele Trbusek, Martin Pospisilova, Sarka Davids, Matthew S. Kipps, Thomas J. Brown, Jennifer R. Mraz, Marek TI Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MARROW STROMAL CELLS; DOWN-REGULATION; PLUS RITUXIMAB; IN-VIVO; RECEPTOR; EXPRESSION; APOPTOSIS; ACTIVATION; BTK AB Agents targeting B-cell receptor (BCR) signaling-associated kinases such as Bruton tyrosine kinase (BTK) or phosphatidylinositol 3-kinase can induce mobilization of neoplastic B cells from the lymphoid tissues into the blood, which makes them potentially ideal to combine with anti-CD20 monoclonal antibodies (such as rituximab, obinutuzumab, or ofatumumab) for treatment of B-cell lymphomas and chronic lymphocytic leukemia (CLL). Here we show that interactions between leukemia cells and stromal cells (HS-5) upregulate CD20 on CLL cells and that administering ibrutinib downmodulates CD20(MS4A1) expression in vivo. We observed that CLL cells that have recently exited the lymph node microenvironment and moved into the peripheral blood (CXCR4(dim)CD5(bright) subpopulation) have higher cell surface levels of CD20 than the cells circulating in the bloodstream for a longer time (CXCR4(bright)CD5(dim) cells). We found that CD20 is directly upregulated by CXCR4 ligand stromal cell-derived factor 1 (SDF-1 alpha, CXCL12) produced by stromal cells, and BTK-inhibitor ibrutinib and CXCR4-inhibitor plerixafor block SDF-1 alpha-mediated CD20 upregulation. Ibrutinib also downmodulated Mcl1 levels in CLL cells in vivo and in coculture with stromal cells. Overall, our study provides a first detailed mechanistic explanation of CD20 expression regulation in the context of chemokine signaling and microenvironmental interactions, which may have important implications for microenvironment-targeting therapies. C1 [Pavlasova, Gabriela; Seda, Vaclav; Cerna, Katerina; Mraz, Marek] Masaryk Univ, Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic. [Pavlasova, Gabriela; Borsky, Marek; Seda, Vaclav; Cerna, Katerina; Osickova, Jitka; Doubek, Michael; Mayer, Jiri; Trbusek, Martin; Pospisilova, Sarka; Mraz, Marek] Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic. [Pavlasova, Gabriela; Borsky, Marek; Seda, Vaclav; Cerna, Katerina; Osickova, Jitka; Doubek, Michael; Mayer, Jiri; Trbusek, Martin; Pospisilova, Sarka; Mraz, Marek] Masaryk Univ, Fac Med, Brno, Czech Republic. [Calogero, Raffaele] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy. [Davids, Matthew S.; Brown, Jennifer R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kipps, Thomas J.] Univ Calif San Diego, Dept Med, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Mraz, M (reprint author), Masaryk Univ, Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic. EM marek.mraz@email.cz FU Ministry of Education, Youth, and Sports of the Czech Republic from the National Programme for Sustainability II funds [LQ1601]; Czech Science Foundation [16-13334Y]; Ministry of Health of the Czech Republic [16-29622A, 65269705, Sup 3/16]; SoMoPro II Programme - European Union [4SGA8684]; South-Moravian Region; Ministry of Education, Youth, and Sports of the Czech Republic, within program COST CZ [LD15144]; European Hematology Association FX This work was supported by the Ministry of Education, Youth, and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601), within special support paid from the National Programme for Sustainability II funds; the Czech Science Foundation (project 16-13334Y); the Ministry of Health of the Czech Republic (grant 16-29622A), all rights reserved; the SoMoPro II Programme (project 4SGA8684), cofinanced by European Union and the South-Moravian Region; the Ministry of Health of the Czech Republic, conceptual development of research organization (FNBr, 65269705, Sup 3/16); the Ministry of Education, Youth, and Sports of the Czech Republic, within program COST CZ (project LD15144); and a research fellowship award granted by the European Hematology Association. NR 24 TC 0 Z9 0 U1 20 U2 20 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 SEP 22 PY 2016 VL 128 IS 12 BP 1609 EP 1613 DI 10.1182/blood-2016-04-709519 PG 5 WC Hematology SC Hematology GA DZ3HA UT WOS:000385734800016 PM 27480113 ER PT J AU Huhn, AJ Guerra, RM Harvey, EP Bird, GH Walensky, LD AF Huhn, Annissa J. Guerra, Rachel M. Harvey, Edward P. Bird, Gregory H. Walensky, Loren D. TI Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors SO CELL CHEMICAL BIOLOGY LA English DT Article ID CELL LUNG-CANCER; CHRONIC LYMPHOCYTIC-LEUKEMIA; STABILIZED ALPHA-HELICES; BH3 HELIX; PROAPOPTOTIC ACTIVITY; BCL-2 DOMAINS; OPEN-LABEL; ACTIVATION; MCL-1; RESISTANCE AB Anti-apoptotic BCL-2 family proteins block cell death by trapping the critical alpha-helical BH3 domains of pro-apoptotic members in a surface groove. Cancer cells hijack this survival mechanism by over-expressing a spectrum of anti-apoptotic members, mounting formidable apoptotic blockades that resist chemotherapeutic treatment. Drugging the BH3-binding pockets of anti-apoptotic proteins has become a highest-priority goal, fueled by the clinical success of ABT-199, a selective BCL-2 inhibitor, in reactivating apoptosis in BCL-2-dependent cancers. BFL-1 is a BCL-2 homolog implicated in melanoma, lymphoma, and other cancers, and remains undrugged. A natural juxtaposition of two unique cysteines at the binding interface of the NOXA BH3 helix and BFL-1 pocket informed the development of stapled BH3 peptides bearing acrylamide warheads to irreversibly inhibit BFL-1 by covalent targeting. Given the frequent proximity of native cysteines to regulatory binding surfaces, covalent stapled peptide inhibitors provide a new therapeutic strategy for targeting pathologic protein interactions. C1 [Huhn, Annissa J.; Guerra, Rachel M.; Harvey, Edward P.; Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Huhn, Annissa J.; Guerra, Rachel M.; Harvey, Edward P.; Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Linde Program Canc Chem Biol, 450 Brookline Ave, Boston, MA 02215 USA. RP Bird, GH; Walensky, LD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA.; Bird, GH; Walensky, LD (reprint author), Dana Farber Canc Inst, Linde Program Canc Chem Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM greg_bird@dfci.harvard.edu; loren_walensky@dfci.harvard.edu FU NIH [1R35CA197583]; Melanoma Research Alliance Team Science Award [306333]; Leukemia and Lymphoma Society (LLS) Marshall A. Lichtman Specialized Center of Research project grant [7009-12]; LLS Scholar Award [1299-15] FX We thank E. Smith for graphics support and T. Oo for technical assistance with stapled peptide synthesis. This research was supported by NIH grant 1R35CA197583, a Melanoma Research Alliance Team Science Award (306333), a Leukemia and Lymphoma Society (LLS) Marshall A. Lichtman Specialized Center of Research project grant (7009-12), and an LLS Scholar Award (1299-15) to L.D.W. L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics. NR 46 TC 3 Z9 3 U1 12 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2451-9448 J9 CELL CHEM BIOL JI Cell Chem. Biol. PD SEP 22 PY 2016 VL 23 IS 9 BP 1123 EP 1134 DI 10.1016/j.chembiol.2016.07.022 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX9RA UT WOS:000384731600014 PM 27617850 ER PT J AU Singh, JA Yu, SH AF Singh, Jasvinder A. Yu, Shaohua TI Allopurinol reduces the risk of myocardial infarction (MI) in the elderly: a study of Medicare claims SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE Allopurinol; Myocardial infarction; MI; Risk factor; Pharmacoepidemiology; Elderly; Predictor; Coronary artery disease; CAD ID IMPROVES ENDOTHELIAL FUNCTION; CHRONIC KIDNEY-DISEASE; CHRONIC HEART-FAILURE; LEFT-VENTRICULAR MASS; XANTHINE-OXIDASE INHIBITION; FREE-RADICAL GENERATION; TERM-FOLLOW-UP; BLOOD-PRESSURE; URIC-ACID; SYSTEMATIC ANALYSIS AB Background: Previous observational studies that have examined the association of allopurinol with myocardial infarction (MI) have provided contradictory results. One study showed that allopurinol reduced the risk, while another study showed an increased risk with allopurinol. Therefore, our objective was to assess whether allopurinol use is associated with a reduction in the risk of MI in the elderly. Method: We used the 2006-2012 5 % random sample of Medicare beneficiaries to study the association of new allopurinol initiation and the risk of incident MI in a cohort study. Multivariable-adjusted Cox regression models adjusted for age, gender, race, and Charlson index, in addition to various cardio-protective medications (beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, diuretics, statins). We calculated hazard ratios (HRs) with 95 % confidence intervals (CIs). Sensitivity analyses adjusted for coronary artery disease (CAD) risk factors, including hypertension, hyperlipidemia, diabetes, and smoking. Results: Of the 29,298 episodes of incident allopurinol use, 1544 were associated with incident MI (5.3 % episodes). Allopurinol use was associated with reduced hazards of MI, with a HR of 0.85 (95 % CI, 0.77 to 0.95). Compared to no allopurinol use, longer durations of allopurinol use were associated with a lower HR of MI: 1-180 days, 0.98 (95 % CI, 0.84 to 1.14); 181 days to 2 years, 0.83 (95 % CI, 0.72 to 0.95); and >2 years, 0.70 (95 % CI, 0.56 to 0.88). Other factors associated with a higher hazard of MI were: age 75 to <85 years and >= 85 years, male gender, higher Charlson index score, and the use of an ACE inhibitor. Adjustment for CAD risk factors confirmed these findings. Conclusion: Incident allopurinol use was associated with a reduction in the risk of incident MI in the elderly. Longer durations of allopurinol use reduced the risk of incident MI incrementally. Future studies should assess the underlying mechanisms for MI prevention and assess the risk-benefit ratio for allopurinol use. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA. [Singh, Jasvinder A.; Yu, Shaohua] Univ Alabama Birmingham, Sch Med, Dept Med, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. [Singh, Jasvinder A.; Yu, Shaohua] Univ Alabama Birmingham, Div Epidemiol, Sch Publ Hlth, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Sch Med, Dept Med, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Div Epidemiol, Sch Publ Hlth, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com FU UAB Division of Rheumatology FX This material is the result of work supported by research funds from UAB Division of Rheumatology and the resources and use of facilities at the Birmingham VA Medical Center. NR 56 TC 1 Z9 1 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PD SEP 22 PY 2016 VL 18 AR 209 DI 10.1186/s13075-016-1111-1 PG 11 WC Rheumatology SC Rheumatology GA DX3SC UT WOS:000384292200001 ER PT J AU Linnman, C Catana, C Svardsudd, K Appel, L Engler, H Langstrom, B Sorensen, J Furmark, T Fredrikson, M Borsook, D Peterson, M AF Linnman, Clas Catana, Ciprian Svardsudd, Kurt Appel, Lieuwe Engler, Henry Langstrom, Bengt Sorensen, Jens Furmark, Tomas Fredrikson, Mats Borsook, David Peterson, Magnus TI Decreased Brain Neurokinin-1 Receptor Availability in Chronic Tennis Elbow SO PLOS ONE LA English DT Article ID REGIONAL PAIN SYNDROME; POSITRON-EMISSION-TOMOGRAPHY; GENE-RELATED PEPTIDE; SUBSTANCE-P; NK1 RECEPTORS; DORSAL-HORN; IN-VIVO; EXPRESSION; EPICONDYLALGIA; INFLAMMATION AB Substance P is released in painful and inflammatory conditions, affecting both peripheral processes and the central nervous system neurokinin 1 (NK1) receptor. There is a paucity of data on human brain alterations in NK1 expression, how this system may be affected by treatment, and interactions between central and peripheral tissue alterations. Ten subjects with chronic tennis elbow (lateral epicondylosis) were selected out of a larger (n = 120) randomized controlled trial evaluating graded exercise as a treatment for chronic tennis elbow (lateral epicondylosis). These ten subjects were examined by positron emission tomography (PET) with the NK1-specific radioligand 11C-GR205171 before, and eight patients were followed up after treatment with graded exercise. Brain binding in the ten patients before treatment, reflecting NK1-receptor availability (NK1-RA), was compared to that of 18 healthy subjects and, longitudinally, to the eight of the original ten patients that agreed to a second PET examination after treatment. Before treatment, patients had significantly lower NK1-RA in the insula, vmPFC, postcentral gyrus, anterior cingulate, caudate, putamen, amygdala and the midbrain but not the thalamus and cerebellum, with the largest difference in the insula contralateral to the injured elbow. No significant correlations between brain NK1-RA and pain, functional severity, or peripheral NK1-RA in the affected limb were observed. In the eight patients examined after treatment, pain ratings decreased in everyone, but there were no significant changes in NK1-RA. These findings indicate a role for the substance P (SP) / NK1 receptor system in musculoskeletal pain and tissue healing. As neither clinical parameters nor successful treatment response was reflected in brain NK1-RA after treatment, this may reflect the diverse function of the SP/NK1 system in CNS and peripheral tissue, or a change too small or slow to capture over the three-month treatment. C1 [Linnman, Clas; Borsook, David] Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Ctr Pain & Brain, Boston, MA USA. [Catana, Ciprian] Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA USA. [Svardsudd, Kurt; Peterson, Magnus] Uppsala Univ, Dept Publ Hlth & Caring Sci, Family Med & Clin Epidemiol, Uppsala, Sweden. [Appel, Lieuwe; Engler, Henry; Langstrom, Bengt; Sorensen, Jens] Uppsala Univ, Dept Radiol Oncol & Radiat Sci, Uppsala PET Ctr, Uppsala, Sweden. [Engler, Henry] Univ Republica, Uruguayan Ctr Mol Imaging CUDIM, Fac Med, Montevideo, Uruguay. [Engler, Henry] Univ Republica, Fac Sci, Montevideo, Uruguay. [Langstrom, Bengt] Uppsala Univ, Dept Biochem & Organ Chem, Uppsala, Sweden. [Langstrom, Bengt] Imperial Coll, Fac Med, Neuropsychopharmacol Sect, London, England. [Furmark, Tomas; Fredrikson, Mats] Uppsala Univ, Dept Psychol, Uppsala, Sweden. [Fredrikson, Mats] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. RP Peterson, M (reprint author), Uppsala Univ, Dept Publ Hlth & Caring Sci, Family Med & Clin Epidemiol, Uppsala, Sweden. EM Clas.Linnman@childrens.harvard.edu; magnus.peterson@pubcare.uu.se FU Swedish Research Council [K2005-27X-15293-01A]; Amersham Fund at Uppsala University; Research Fund at Uppsala County Council; Family Medicine Foundation; Uppsala University; Scant Design Foundation BY INGER JENS BRUUN FX The study was supported by grants from the Swedish Research Council (grant no. K2005-27X-15293-01A), The Amersham Fund at Uppsala University, The Research Fund at Uppsala County Council, The Family Medicine Foundation, Uppsala University and the International Association for the study of Pain (IASP) collaborative grant by Scant Design Foundation BY INGER & JENS BRUUN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2016 VL 11 IS 9 AR e0161563 DI 10.1371/journal.pone.0161563 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW8GO UT WOS:000383893200009 PM 27658244 ER PT J AU Pallin, DJ Bry, L Dwyer, RC Lipworth, AD Leung, DY Camargo, CA Kupper, TS Filbin, MR Murphy, GF AF Pallin, Daniel J. Bry, Lynn Dwyer, Richard C. Lipworth, Adam D. Leung, Donald Y. Camargo, Carlos A., Jr. Kupper, Thomas S. Filbin, Michael R. Murphy, George F. TI Toward an Objective Diagnostic Test for Bacterial Cellulitis SO PLOS ONE LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; SOFT-TISSUE INFECTIONS; DERMATOLOGY CONSULTATION; SKIN INFECTIONS; PROCALCITONIN; EMERGENCE; OFFICES AB Background Prior studies repeatedly showed that cultures of skin lesions diagnosed as "cellulitis" are usually negative. However, lack of a gold standard for diagnosis (against which culture might be judged) and failure to assess the human immune response are important limitations of prior work. In this pilot study, we aimed to develop a criterion standard for research on bacterial cellulitis, to evaluate the sensitivity of procalcitonin for bacterial cellulitis, and to use gene expression analysis to find other candidate diagnostic markers. Methods We classified lesions via biopsies, 16s rRNA gene detection, culture, and histopathology. We quantified procalcitonin expression in blood. We also used Nanostring technology to quantify transcription of immunomodulators that may distinguish cases from inflamed controls. Results Of 28 participants, 15 had a clinical diagnosis of cellulitis, six had a diagnosis of non-infectious dermatitis, and seven were normal volunteers. Of the "cellulitis'' patients, three (20%) had pathogens isolated, and were designated confirmed cases. Procalcitonin was undetectable in all three. HLA-DQA1 was expressed 34-fold more in confirmed cases vs. controls (fold change of geometric mean). Heat maps depicting multiplex gene expression analysis revealed a distinct profile of gene expression in confirmed cases relative to comparators. Conclusions Most ''cellulitis'' patients had microbiologically-negative biopsies. Procalcitonin was undetectable, and HLA-DQA1 elevated, in confirmed bacterial cases. Multivariable transcriptomic profiling results supported our algorithm's ability to identify patients with true bacterial cellulitis. A larger sample may allow discovery of an immunological signature capable of distinguishing bacterial cellulitis from its mimics in clinical practice. C1 [Pallin, Daniel J.; Dwyer, Richard C.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Bry, Lynn; Murphy, George F.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Lipworth, Adam D.; Kupper, Thomas S.] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Leung, Donald Y.] Natl Jewish Med Hlth, Dept Pediat, Denver, CO USA. [Camargo, Carlos A., Jr.; Filbin, Michael R.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Pallin, DJ (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. EM dpallin@partners.org FU BioMerieux Inc.; [P30-DK034854] FX This work was funded by BioMerieux Inc. and P30-DK034854 (Bry). P30-DK034854 (Bry) provided support to the BWH Center for Clinical and Translational Metagenomics for microbiologic studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2016 VL 11 IS 9 AR e0162947 DI 10.1371/journal.pone.0162947 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW8GO UT WOS:000383893200043 PM 27656884 ER PT J AU Gupta-Wright, A Fielding, KL van Oosterhout, JJ Wilson, DK Corbett, EL Flach, C Reddy, KP Walensky, RP Peters, JA Alufandika-Moyo, M Lawn, SD AF Gupta-Wright, Ankur Fielding, Katherine L. van Oosterhout, Joep J. Wilson, Douglas K. Corbett, Elizabeth L. Flach, Clare Reddy, Krishna P. Walensky, Rochelle P. Peters, Jurgens A. Alufandika-Moyo, Melanie Lawn, Stephen D. TI Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial SO BMC INFECTIOUS DISEASES LA English DT Article DE TB; HIV; HIV-associated TB; Screening; LAM; Xpert ID XPERT MTB/RIF ASSAY; HIV-ASSOCIATED TUBERCULOSIS; RESOURCE-LIMITED SETTINGS; PULMONARY TUBERCULOSIS; DIAGNOSTIC-ACCURACY; LIPOARABINOMANNAN TEST; INFECTED ADULTS; SOUTH-AFRICA; METAANALYSIS; EXTRAPULMONARY AB Background: HIV-associated tuberculosis (TB) co-infection remains an enormous burden to international public health. Post-mortem studies have highlighted the high proportion of HIV-positive adults admitted to hospital with TB. Determine TB-LAM and Xpert MTB/RIF assays can substantially increase diagnostic yield of TB within one day of hospital admission. However, it remains unclear if this approach can impact clinical outcomes. The STAMP trial aims to test the hypothesis that the implementation a urine-based screening strategy for TB can reduce all cause-mortality among HIV-positive patients admitted to hospital when compared to current, sputum-based screening. Methods: The trial is a pragmatic, individually randomised, multi-country (Malawi and South Africa) clinical trial with two study arms (1: 1 recruitment). Unselected HIV-positive patients admitted to medical wards, irrespective of presentation, meeting the inclusion criteria and giving consent will be randomized to screening for TB using either: (i) 'standard of care'-testing of sputum using the Xpert MTB/RIF assay (Xpert) or (ii) 'intervention'-testing of sputum using Xpert and testing of urine using (a) Determine TB-LAM lateral-flow assay and (b) Xpert following concentration of urine by centrifugation. Patients will be excluded if they have received TB treatment in the previous 12 months, if they have received isoniazid preventive therapy in the last 6 months, if they are aged <18 years or they live outside the pre-specified geographical area. Results will be provided to the responsible medical team as soon as available to inform decisions regarding TB treatment. Both the study and routine medical team will be masked to study arm allocation. 1300 patients will be enrolled per arm (equal numbers at the two trial sites). The primary endpoint is all-cause mortality at 56 days. An economic analysis will be conducted to project long-term outcomes for shorter-term trial data, including cost-effectiveness. Discussion: This pragmatic trial assesses an intervention to reduce the high mortality caused by HIV-associated TB, which could feasibly be scaled up in high-burden settings if shown to be efficacious and cost-effective. We discuss the challenges of designing a trial to assess the impact on mortality of laboratory-based TB screening interventions given frequent initiation of empirical treatment and a failure of several previous clinical trials to demonstrate an impact on clinical outcomes. We also elaborate on the practical and ethical issues of 'testing a test' in general. C1 [Gupta-Wright, Ankur; Corbett, Elizabeth L.; Peters, Jurgens A.; Lawn, Stephen D.] London Sch Hyg & Trop Med, Dept Clin Res, London, England. [Gupta-Wright, Ankur; Corbett, Elizabeth L.] Univ Malawi, Coll Med, Malawi Liverpool Wellcome Trust Clin Res Program, Blantyre, Malawi. [Fielding, Katherine L.; Flach, Clare] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London, England. [Fielding, Katherine L.] Univ Witwatersrand, Johannesburg, South Africa. [van Oosterhout, Joep J.; Alufandika-Moyo, Melanie] Dignitas Int, Zomba, Malawi. [van Oosterhout, Joep J.] Univ Malawi, Coll Med, Dept Med, Blantyre, Malawi. [Wilson, Douglas K.] Univ KwaZulu Natal, Edendale Hosp, Dept Internal Med, Pietermaritzburg, South Africa. [Reddy, Krishna P.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Walensky, Rochelle P.] Harvard Univ, Harvard Med Sch, Ctr AIDS Res, Boston, MA USA. [Lawn, Stephen D.] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, Cape Town, South Africa. RP Gupta-Wright, A (reprint author), London Sch Hyg & Trop Med, Dept Clin Res, London, England.; Gupta-Wright, A (reprint author), Univ Malawi, Coll Med, Malawi Liverpool Wellcome Trust Clin Res Program, Blantyre, Malawi. EM ankurgw@outlook.com FU Joint Global Health Trials scheme grant from the MRC/DFID/Wellcome Trust (STAMP Trial) [MR/M007375/1]; Royal College of Physicians, London, UK (JMGP fellowship) FX This trial is funded by a Joint Global Health Trials scheme grant from the MRC/DFID/Wellcome Trust (STAMP Trial; grant no. MR/M007375/1). AGW is also funded by the Royal College of Physicians, London, UK (JMGP fellowship). The funders do not have any direct roles in the design or conduct of this trial, but request regular reporting of progress for routine grant/trial administration. NR 38 TC 3 Z9 3 U1 6 U2 6 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 SEP 22 PY 2016 VL 16 AR 501 DI 10.1186/s12879-016-1837-z PG 11 WC Infectious Diseases SC Infectious Diseases GA DW5AW UT WOS:000383655400001 PM 27659507 ER PT J AU Dingens, AS Fairfortune, TS Reed, S Mitchell, C AF Dingens, Adam S. Fairfortune, Tessa S. Reed, Susan Mitchell, Caroline TI Bacterial vaginosis and adverse outcomes among full-term infants: a cohort study SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Bacterial vaginosis; Term; Adverse neonatal outcomes; Neonatal sepsis ID LOW-BIRTH-WEIGHT; FOR-GESTATIONAL-AGE; PRETERM BIRTH; WASHINGTON-STATE; INTRAAMNIOTIC INFECTION; EARLY-PREGNANCY; LINKED BIRTH; WOMEN; DELIVERY; ASSOCIATION AB Background: Bacterial vaginosis (BV) during pregnancy is a well-established risk factor for preterm birth and other preterm pregnancy complications. Little is known about adverse neonatal outcomes associated with BV exposure in full-term births, nor its influence on adverse outcomes independent of its effect on gestational age. The purpose of this study was to examine the relationship between BV during pregnancy and adverse neonatal outcomes among full-term and preterm infants. Methods: We conducted a retrospective cohort study of Washington State mother/infant pairs from 2003-2013, stratified by full-term (primary outcomes) and preterm births (secondary outcomes). BV-exposed and unexposed women were frequency-matched based on year of delivery. BV exposure and adverse outcomes [assisted ventilation/respiratory distress, neonatal intensive care unit (NICU) admission, neonatal sepsis, fetal mortality, and infant mortality] were identified using birth certificates, ICD-9 codes from linked hospital records, and death certificates. Associations between BV exposure and outcomes were assessed using multivariable Poisson regression, adjusted for maternal demographics, gestational age, and other pregnancy complications, including infections. Results: A total of 12,340 mother/infant pairs were included: 2,468 BV-exposed (2198 term, 267 preterm) and 9,872 BV unexposed (9156 term, 708 preterm). Among full-term infants, BV-exposed mothers were younger, more likely to be Black or Hispanic, more likely to have had a sexually transmitted infection, and less likely to have a college degree than unexposed mothers. Term BV exposed infants were more likely to have meconium at delivery. Following adjustment, BV was associated with an increased risk of assisted ventilation/respiratory distress at birth (aRR = 1.28, 95 % CI 1.02-1.61), NICU admission (aRR = 1.42, 95 % CI 1.11-1.82), and neonatal sepsis (aRR = 1.60, 95 % CI 1.13-2.27) among full-term infants. These associations were independent of the presence of chorioamnionitis or meconium. Among preterm infants, BV-exposure was associated with an increased risk for NICU admissions only (aRR = 1.24, 95 % CI 1.04-1.46). Conclusions: BV exposure during pregnancy is associated with adverse neonatal outcomes even among infants born full-term. These findings amongst full-term infants are novel, and highlight neonatal implications of BV in pregnancy independent of BV's effect on preterm birth. C1 [Dingens, Adam S.; Fairfortune, Tessa S.; Reed, Susan] Univ Washington, Sch Publ Hlth, Dept Epidemiol, 1959 NE Pacific St Hlth Sci Bldg, Seattle, WA 98195 USA. [Dingens, Adam S.] Univ Washington, Mol & Cellular Biol Program, 1959 NE Pacific St, Seattle, WA 98195 USA. [Dingens, Adam S.; Reed, Susan] Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N, Seattle, WA 98109 USA. [Reed, Susan] Harborview Med Ctr, 325 Ninth Ave, Seattle, WA 98104 USA. [Mitchell, Caroline] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, 55 Fruit St, Boston, MA 02114 USA. [Mitchell, Caroline] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. RP Dingens, AS (reprint author), Univ Washington, Sch Publ Hlth, Dept Epidemiol, 1959 NE Pacific St Hlth Sci Bldg, Seattle, WA 98195 USA.; Dingens, AS (reprint author), Univ Washington, Mol & Cellular Biol Program, 1959 NE Pacific St, Seattle, WA 98195 USA.; Dingens, AS (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N, Seattle, WA 98109 USA. EM adingens@uw.edu OI Dingens, Adam/0000-0001-9603-9409 FU NSF Graduate Research Fellowship [DGE-1256082]; NIH Interdisciplinary Training Grant [T32 CA080416] FX AD was supported by an NSF Graduate Research Fellowship (DGE-1256082) and an NIH Interdisciplinary Training Grant (T32 CA080416). These funders played no role in the study design, data collection, analysis, writing, or decision to publish. NR 28 TC 2 Z9 2 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD SEP 22 PY 2016 VL 16 AR 278 DI 10.1186/s12884-016-1073-y PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DW7ON UT WOS:000383840700001 PM 27658456 ER PT J AU Ding, YH Gao, H Zhang, Y Li, Y Vasdev, N Gao, YD Chen, Y Zhang, Q AF Ding, Yahui Gao, Huier Zhang, Yu Li, Ye Vasdev, Neil Gao, Yingdai Chen, Yue Zhang, Quan TI Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article DE Alantolactone; Acute myeloid leukemia stem cells; KG1a; Apoptosis ID ACUTE MYELOGENOUS LEUKEMIA; NF-KAPPA-B; MINIMAL RESIDUAL DISEASE; APOPTOSIS; EXPRESSION; AML; PATHWAY; GENERATION; RESISTANCE; INHIBITOR AB Background: The poor outcomes for patients diagnosed with acute myeloid leukemia (AML) are largely attributed to leukemia stem cells (LSCs) which are difficult to eliminate with conventional therapy and responsible for relapse. Thus, new therapeutic strategies which could selectively target LSCs in clinical leukemia treatment and avoid drug resistance are urgently needed. However, only a few small molecules have been reported to show anti-LSCs activity. Methods: The aim of the present study was to identify alantolactone as novel agent that can ablate acute myeloid leukemia stem and progenitor cells from AML patient specimens and evaluate the anticancer activity of alantolactone in vitro and in vivo. Results: The present study is the first to demonstrate that alantolactone, a prominent eudesmane-type sesquiterpene lactone, could specifically ablate LSCs from AML patient specimens. Furthermore, in comparison to the conventional chemotherapy drug, cytosine arabinoside (Ara-C), alantolactone showed superior effects of leukemia cytotoxicity while sparing normal hematopoietic cells. Alantolactone induced apoptosis with a dose-dependent manner by suppression of NF-kB and its downstream target proteins. DMA-alantolactone, a water-soluble prodrug of alantolactone, could suppress tumor growth in vivo. Conclusions: Based on these results,we propose that alantolactone may represent a novel LSCs-targeted therapy and eudesmane-type sesquiterpene lactones offer a new scaffold for drug discovery towards anti-LSCs agents. C1 [Ding, Yahui; Li, Ye; Chen, Yue; Zhang, Quan] Nankai Univ, Coll Pharm, State Key Lab Med Chem Biol, Haihe Educ Pk,38 Tongyan Rd, Tianjin 300353, Peoples R China. [Ding, Yahui; Li, Ye; Chen, Yue; Zhang, Quan] Nankai Univ, Tianjin Key Lab Mol Drug Res, Haihe Educ Pk,38 Tongyan Rd, Tianjin 300353, Peoples R China. [Gao, Huier; Zhang, Yu; Gao, Yingdai] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin 300020, Peoples R China. [Gao, Huier; Zhang, Yu; Gao, Yingdai] Chinese Acad Med Sci, Hosp Blood Dis, Tianjin 300020, Peoples R China. [Gao, Huier; Zhang, Yu; Gao, Yingdai] Peking Union Med Coll, Tianjin 300020, Peoples R China. [Vasdev, Neil] Massachusetts Gen Hosp, Gordon Ctr Med Imaging, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Vasdev, Neil] Harvard Med Sch, Dept Radiol, Boston, MA USA. RP Zhang, Q (reprint author), Nankai Univ, Coll Pharm, State Key Lab Med Chem Biol, Haihe Educ Pk,38 Tongyan Rd, Tianjin 300353, Peoples R China.; Zhang, Q (reprint author), Nankai Univ, Tianjin Key Lab Mol Drug Res, Haihe Educ Pk,38 Tongyan Rd, Tianjin 300353, Peoples R China. EM zhangquan612@163.com FU National Natural Science Foundation of China (NSFC) [81370086, 81573308, 81421002, 81430004, 81570100, 81500086]; National Basic Research Program of China [2016YFA0100602, 2012CB966600]; Key Technologies R&D Program of Tianjin [13RCGFSY19500] FX This work was supported by the National Natural Science Foundation of China (NSFC) (NOs. 81370086 and 81573308 to Q.Z.; NOs. 81421002, 81430004, 81570100, and 81500086 to Y.G.), the National Basic Research Program of China (NO. 2016YFA0100602 and 2012CB966600) and the Key Technologies R&D Program of Tianjin (13RCGFSY19500). NR 39 TC 2 Z9 2 U1 9 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD SEP 22 PY 2016 VL 9 AR 93 DI 10.1186/s13045-016-0327-5 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA DW9BZ UT WOS:000383951000001 ER PT J AU Dickinson, ME Flenniken, AM Ji, X Teboul, L Wong, MD White, JK Meehan, TF Weninger, WJ Westerberg, H Adissu, H Baker, CN Bower, L Brown, JM Caddle, LB Chiani, F Clary, D Cleak, J Daly, MJ Denegre, JM Doe, B Dolan, ME Edie, SM Fuchs, H Gailus-Durner, V Galli, A Gambadoro, A Gallegos, J Guo, SY Horner, NR Hsu, CW Johnson, SJ Kalaga, S Keith, LC Lanoue, L Lawson, TN Lek, M Mark, M Arschall, SM Mason, J McElwee, ML Newbigging, S Nutter, LMJ Peterson, KA Ramirez-Solis, R Rowland, DJ Ryder, E Samocha, KE Seavitt, JR Selloum, M Szoke-Kovacs, Z Tamura, M Trainor, AG Tudose, I Wakana, S Warren, J Wendling, O West, DB Wong, L Yoshiki, A MacArthur, DG Tocchini-Valentini, GP Gao, X Flicek, P Bradley, A Skarnes, WC Justice, MJ Parkinson, HE Moore, M Wells, S Braun, RE Svenson, KL de Angelis, MH Herault, Y Mohun, T Mallon, AM Henkelman, RM Brown, SDM Adams, DJ Lloyd, KCK McKerlie, C Beaudet, AL Bucan, M Murray, SA AF Dickinson, Mary E. Flenniken, Ann M. Ji, Xiao Teboul, Lydia Wong, Michael D. White, Jacqueline K. Meehan, Terrence F. Weninger, Wolfgang J. Westerberg, Henrik Adissu, Hibret Baker, Candice N. Bower, Lynette Brown, James M. Caddle, L. Brianna Chiani, Francesco Clary, Dave Cleak, James Daly, Mark J. Denegre, James M. Doe, Brendan Dolan, Mary E. Edie, Sarah M. Fuchs, Helmut Gailus-Durner, Valerie Galli, Antonella Gambadoro, Alessia Gallegos, Juan Guo, Shiying Horner, Neil R. Hsu, Chih-Wei Johnson, Sara J. Kalaga, Sowmya Keith, Lance C. Lanoue, Louise Lawson, Thomas N. Lek, Monkol Mark, Manuel Arschall, Susan M. Mason, Jeremy McElwee, Melissa L. Newbigging, Susan Nutter, Lauryl M. J. Peterson, Kevin A. Ramirez-Solis, Ramiro Rowland, Douglas J. Ryder, Edward Samocha, Kaitlin E. Seavitt, John R. Selloum, Mohammed Szoke-Kovacs, Zsombor Tamura, Masaru Trainor, Amanda G. Tudose, Ilinca Wakana, Shigeharu Warren, Jonathan Wendling, Olivia West, David B. Wong, Leeyean Yoshiki, Atsushi MacArthur, Daniel G. Tocchini-Valentini, Glauco P. Gao, Xiang Flicek, Paul Bradley, Allan Skarnes, William C. Justice, Monica J. Parkinson, Helen E. Moore, Mark Wells, Sara Braun, Robert E. Svenson, Karen L. de Angelis, Martin Hrabe Herault, Yann Mohun, Tim Mallon, Ann-Marie Henkelman, R. Mark Brown, Steve D. M. Adams, David J. Lloyd, K. C. Kent McKerlie, Colin Beaudet, Arthur L. Bucan, Maja Murray, Stephen A. CA Int Mouse Phenotyping Consortium TI High-throughput discovery of novel developmental phenotypes SO NATURE LA English DT Article ID MAMMALIAN GENE-FUNCTION; MOUSE EMBRYO; GLYCOGENIN-1 DEFICIENCY; GENOME-WIDE; MICRO-CT; SCREENS; DISEASE; EXPRESSION; RESOURCE; IDENTIFICATION AB Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts. C1 [Dickinson, Mary E.; Hsu, Chih-Wei; Kalaga, Sowmya; Keith, Lance C.; McElwee, Melissa L.; Wong, Leeyean] Dept Mol Physiol & Biophys, Houston, TX 77030 USA. [Flenniken, Ann M.; Wong, Michael D.; Adissu, Hibret; Newbigging, Susan; Nutter, Lauryl M. J.; Henkelman, R. Mark; McKerlie, Colin] Toronto Ctr Phenogen, Toronto, ON M5T 3H7, Canada. [Flenniken, Ann M.] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Ji, Xiao] Univ Penn, Perelman Sch Med, Genom & Computat Biol Program, Philadelphia, PA 19104 USA. [Teboul, Lydia; Westerberg, Henrik; Brown, James M.; Cleak, James; Horner, Neil R.; Johnson, Sara J.; Lawson, Thomas N.; Szoke-Kovacs, Zsombor; Wells, Sara; Mallon, Ann-Marie; Brown, Steve D. M.] Med Res Council Harwell, Mammalian Genet Unit, Harwell OX11 0RD, Oxon, England. [Teboul, Lydia; Westerberg, Henrik; Brown, James M.; Cleak, James; Horner, Neil R.; Johnson, Sara J.; Lawson, Thomas N.; Szoke-Kovacs, Zsombor; Wells, Sara; Mallon, Ann-Marie; Brown, Steve D. M.] Mary Lyon Ctr, Harwell OX11 0RD, Oxon, England. [Wong, Michael D.; Henkelman, R. Mark] Hosp Sick Children, Mouse Imaging Ctr, Toronto, ON M5T 3H7, Canada. [White, Jacqueline K.; Doe, Brendan; Galli, Antonella; Ramirez-Solis, Ramiro; Ryder, Edward; Bradley, Allan; Skarnes, William C.; Adams, David J.] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England. [Meehan, Terrence F.; Clary, Dave; Mason, Jeremy; Tudose, Ilinca; Warren, Jonathan; Flicek, Paul; Parkinson, Helen E.] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. [Weninger, Wolfgang J.] Med Univ Vienna, Ctr Anat & Cell Biol, A-1090 Vienna, Austria. [Adissu, Hibret; Newbigging, Susan; Nutter, Lauryl M. J.; Justice, Monica J.; McKerlie, Colin] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Baker, Candice N.; Caddle, L. Brianna; Denegre, James M.; Dolan, Mary E.; Edie, Sarah M.; Peterson, Kevin A.; Braun, Robert E.; Svenson, Karen L.; Murray, Stephen A.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Bower, Lynette; Clary, Dave; Lanoue, Louise; Rowland, Douglas J.; Trainor, Amanda G.; Lloyd, K. C. Kent] Univ Calif Davis, Mouse Biol Program, Davis, CA 95618 USA. [Chiani, Francesco; Gambadoro, Alessia; Tocchini-Valentini, Glauco P.] Italian Natl Res Council CNR, Inst Cell Biol & Neurobiol, Monterotondo Mouse Clin, I-00015 Monterotondo, Italy. [Daly, Mark J.; Lek, Monkol; Samocha, Kaitlin E.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Daly, Mark J.; Lek, Monkol; Samocha, Kaitlin E.; MacArthur, Daniel G.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Fuchs, Helmut; Gailus-Durner, Valerie; Arschall, Susan M.; de Angelis, Martin Hrabe] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, D-85764 Neuherberg, Germany. [Fuchs, Helmut; Gailus-Durner, Valerie; Arschall, Susan M.; de Angelis, Martin Hrabe] German Mouse Clin, D-85764 Neuherberg, Germany. [Gallegos, Juan; Seavitt, John R.; Justice, Monica J.; Beaudet, Arthur L.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Guo, Shiying; Gao, Xiang] Nanjing Univ, Nanjing Biomed Res Inst, Collaborat Innovat Ctr Genet & Dev, SKL Pharmaceut Biotechnol & Model Anim Res Ctr, Nanjing 210061, Jiangsu, Peoples R China. [Mark, Manuel; Selloum, Mohammed; Wendling, Olivia; Herault, Yann] Univ Strasbourg, ICS, Infrastruct Natl PHENOMIN, F-67404 Illkirch Graffenstaden, France. [Mark, Manuel; Selloum, Mohammed; Wendling, Olivia; Herault, Yann] Univ Strasbourg, INSERM, CNRS, IGBMC, F-67404 Illkirch Graffenstaden, France. [Tamura, Masaru; Wakana, Shigeharu; Yoshiki, Atsushi] RIKEN, BioResource Ctr, Tsukuba, Ibaraki 3050074, Japan. [West, David B.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Moore, Mark] IMPC, San Anselmo, CA 94960 USA. [de Angelis, Martin Hrabe] Tech Univ Munich, Sch Life Sci Weihenstephan, Chair Expt Genet, D-81675 Freising Weihenstephan, Germany. [de Angelis, Martin Hrabe] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany. [Mohun, Tim] Francis Crick Inst, Mill Hill Lab, Mill Hill, London NW1 1AT, England. [Bucan, Maja] Univ Penn, Perlman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Bucan, Maja] Univ Penn, Dept Psychiat, Perlman Sch Med, Philadelphia, PA 19104 USA. RP Murray, SA (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM steve.murray@jax.org RI Gailus-Durner, Valerie/M-7337-2014; Yoshiki, Atsushi/A-6036-2016; Herault, Yann/B-5500-2012; Tamura, Masaru/D-1416-2017; Hrabe de Angelis, Martin/F-5531-2012; OI Yoshiki, Atsushi/0000-0002-9450-5151; Horner, Neil/0000-0002-0550-4537; /0000-0002-2796-5123; Herault, Yann/0000-0001-7049-6900; Tamura, Masaru/0000-0002-0311-8827; Hrabe de Angelis, Martin/0000-0002-7898-2353; Gambadoro, Alessia/0000-0002-3563-2759; Weninger, Wolfgang J/0000-0003-0575-0073; Flicek, Paul/0000-0002-3897-7955; Meehan, Terrence/0000-0003-1980-3228; Birling, Marie-Christine/0000-0002-3372-8108 FU NIH [U42 OD011185, U54 HG006332, U54 HG006348-S1, OD011174, HG006364-03S1, U42 OD011175, U54 HG006370]; Wellcome Trust; Medical Research Council Strategic Award; Government of Canada through Genome Canada; Ontario Genomics [OGI-051]; Wellcome Trust Strategic Award " Deciphering the Mechanisms of Developmental Disorders (DMDD)" [WT100160]; National Centre for Scientific Research (CNRS); French National Institute of Health and Medical Research (INSERM); University of Strasbourg (UDS); Centre Europeen de Recherche en Biologie et en Medecine; Agence Nationale de la Recherche [ANR-10-IDEX-0002-02, ANR-10-INBS- 07 PHENOMIN]; German Federal Ministry of Education and Research [01KX1012] FX The authors thank all IMPC members and partners for their contribution to the consortium effort, including this study, and acknowledge the contributions of J. Rossant, S. L. Adamson, and T. Bubela. This work was supported by NIH grants U42 OD011185 (S.A.M.), U54 HG006332 (R.E.B., K.S.), U54 HG006348-S1 and OD011174 (A.L.B.), HG006364-03S1 and U42 OD011175 (K.C.K.L.), U54 HG006370 (P.F., A.-M.M., H.E.P., S.D.M.B.) and additional support provided by the The Wellcome Trust, Medical Research Council Strategic Award (L.T., S.W., S.D.M.B.), Government of Canada through Genome Canada and Ontario Genomics (OGI-051)(C.M., S.D.M.B.), Wellcome Trust Strategic Award " Deciphering the Mechanisms of Developmental Disorders (DMDD)" (WT100160) (D.A., T.M.), National Centre for Scientific Research (CNRS), the French National Institute of Health and Medical Research (INSERM), the University of Strasbourg (UDS), the "Centre Europeen de Recherche en Biologie et en Medecine", the "Agence Nationale de la Recherche" under the frame programme " Investissements d'Avenir" labelled ANR-10-IDEX-0002-02, ANR-10-INBS- 07 PHENOMIN to (Y.H.), The German Federal Ministry of Education and Research by Infrafrontier grant 01KX1012 (S.M., V.G.D., H.F., M.H.d.A.) NR 59 TC 7 Z9 7 U1 21 U2 21 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 SEP 22 PY 2016 VL 537 IS 7621 BP 508 EP + DI 10.1038/nature19356 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW3MO UT WOS:000383545900047 PM 27626380 ER PT J AU Patil, MD Bhaumik, J Babykutty, S Banerjee, UC Fukumura, D AF Patil, M. D. Bhaumik, J. Babykutty, S. Banerjee, U. C. Fukumura, D. TI Arginine dependence of tumor cells: targeting a chink in cancer's armor SO ONCOGENE LA English DT Review ID RECOMBINANT HUMAN ARGINASE; ADI-PEG 20; HUMAN HEPATOCELLULAR-CARCINOMA; APOPTOSIS-INDUCING FACTOR; ENDOTHELIAL GROWTH-FACTOR; POTENTIAL ANTITUMOR DRUG; NITRIC-OXIDE SYNTHASE; ARGININOSUCCINATE-SYNTHETASE; IN-VITRO; DEIMINASE ADI AB Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities. C1 [Patil, M. D.; Bhaumik, J.; Banerjee, U. C.] Natl Inst Pharmaceut Educ & Res, Dept Pharmaceut Technol Biotechnol, Mohali, Punjab, India. [Babykutty, S.; Fukumura, D.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, 100 Blossom St, Boston, MA 02114 USA. [Babykutty, S.; Fukumura, D.] Harvard Med Sch, 100 Blossom St, Boston, MA 02114 USA. RP Fukumura, D (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, 100 Blossom St, Boston, MA 02114 USA.; Fukumura, D (reprint author), Harvard Med Sch, 100 Blossom St, Boston, MA 02114 USA. EM dai@steele.mgh.harvard.edu FU National Institutes of Health [CA080124, CA096915, CA126642, CA197743] FX This work was supported in part by National Institutes of Health (CA080124, CA096915, CA126642, CA197743). NR 215 TC 4 Z9 4 U1 11 U2 11 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 SEP 22 PY 2016 VL 35 IS 38 BP 4957 EP 4972 DI 10.1038/onc.2016.37 PG 16 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DW9GT UT WOS:000383965300001 PM 27109103 ER PT J AU Johnston, KT Dang, PA Specht, MC Letourneau, AR Gudewicz, TM AF Johnston, Katherine T. Dang, Pragya A. Specht, Michelle C. Letourneau, Alyssa R. Gudewicz, Thomas M. TI Case 29-2016: A 53-Year-Old Woman with Pain and a Mass in the Breast SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PATIENT; CANCER C1 [Johnston, Katherine T.; Letourneau, Alyssa R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Dang, Pragya A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Specht, Michelle C.] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. [Gudewicz, Thomas M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Johnston, Katherine T.; Letourneau, Alyssa R.] Harvard Med Sch, Dept Med, Boston, MA USA. [Dang, Pragya A.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Specht, Michelle C.] Harvard Med Sch, Dept Surg, Boston, MA USA. [Gudewicz, Thomas M.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Johnston, KT (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Johnston, KT (reprint author), Harvard Med Sch, Dept Med, Boston, MA USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 22 PY 2016 VL 375 IS 12 BP 1172 EP 1180 DI 10.1056/NEJMcpc1609109 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DW3JE UT WOS:000383537100011 PM 27653568 ER PT J AU McAvoy, KM Scobie, KN Berger, S Russo, C Guo, NN Decharatanachart, P Vega-Ramirez, H Miake-Lye, S Whalen, M Nelson, M Bergami, M Bartsch, D Hen, R Berninger, B Sahay, A AF McAvoy, Kathleen M. Scobie, Kimberly N. Berger, Stefan Russo, Craig Guo, Nannan Decharatanachart, Pakanat Vega-Ramirez, Hugo Miake-Lye, Sam Whalen, Michael Nelson, Mark Bergami, Matteo Bartsch, Dusan Hen, Rene Berninger, Benedikt Sahay, Amar TI Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits SO NEURON LA English DT Article ID ADULT HIPPOCAMPAL NEUROGENESIS; ENHANCED SYNAPTIC PLASTICITY; PATTERN SEPARATION; GRANULE CELLS; CRITICAL PERIOD; OLFACTORY-BULB; BORN; MICE; AGE; REVEALS AB The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased NSC activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and NSC activation, leaving the DG modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in mature DGCs increased survival of adult-born DGCs without affecting proliferation or DGC activity. Enhanced integration of adult-born DGCs transiently reorganized adult-born DGC local afferent connectivity and promoted global remapping in the DG. Rejuvenation of the DG by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision. C1 [McAvoy, Kathleen M.; Russo, Craig; Guo, Nannan; Decharatanachart, Pakanat; Vega-Ramirez, Hugo; Miake-Lye, Sam; Sahay, Amar] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [McAvoy, Kathleen M.; Russo, Craig; Guo, Nannan; Vega-Ramirez, Hugo; Sahay, Amar] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [McAvoy, Kathleen M.; Guo, Nannan; Vega-Ramirez, Hugo; Sahay, Amar] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Scobie, Kimberly N.; Hen, Rene] Columbia Univ, Dept Neurosci, New York, NY 10032 USA. [Scobie, Kimberly N.; Hen, Rene] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Berger, Stefan; Bartsch, Dusan] Heidelberg Univ, Cent Inst Mental Hlth, Dept Mol Biol, D-68159 Mannheim, Germany. [Berger, Stefan; Bartsch, Dusan] Heidelberg Univ, Med Fac Mannheim, D-68159 Mannheim, Germany. [Whalen, Michael] Massachusetts Gen Hosp, Neurosci Ctr, Boston, MA 02129 USA. [Nelson, Mark] Echelon Biosci, Salt Lake City, UT 84108 USA. [Bergami, Matteo] Cologne Excellence Cluster Cellular Stress Respon, Joseph Stelzmann Str 26, D-50931 Cologne, Germany. [Bergami, Matteo] Univ Hosp Cologne, Joseph Stelzmann Str 26, D-50931 Cologne, Germany. [Berninger, Benedikt] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55128 Mainz, Germany. [Sahay, Amar] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Sahay, A (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Sahay, A (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Sahay, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Sahay, A (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM asahay@mgh.harvard.edu FU German Research Foundation [CRC 1193/1 A02]; U.S. National Institutes of Health Biobehavioral Research Awards for Innovative New Scientists (BRAINS) [1-R01MH104175]; NIH-NIA [1R01AG048908-01A1]; Ellison Medical Foundation New Scholar in Aging; Whitehall Foundation; Inscopix Decode award; Ellison Family Philanthropic; Harvard Neurodiscovery Center/MADRC Center Pilot Grant Award; HSCI Development grant; HSCI Harvard Internship Program Award FX We wish to thank members of the A.S. lab and co-authors for their comments on the manuscript, Dr. Dayu Lin for the c-fos plasmid, Dr. Karl-Klaus Conzelmann for the rabies virus and Sreyan Chowdhury, Duong Chu and Tomer Langberg for technical assistance. Reagent generation in B.B. lab was supported by German Research Foundation (CRC 1193/1 A02). A.S. is supported by U.S. National Institutes of Health Biobehavioral Research Awards for Innovative New Scientists (BRAINS) 1-R01MH104175, NIH-NIA 1R01AG048908-01A1, Ellison Medical Foundation New Scholar in Aging, Whitehall Foundation, Inscopix Decode award, Ellison Family Philanthropic support, Harvard Neurodiscovery Center/MADRC Center Pilot Grant Award, and HSCI Development grant. C.R. and P.D. were supported by HSCI Harvard Internship Program Award. We dedicate this manuscript to the late Dr. Joseph Altman who pioneered the field of adult hippocampal neurogenesis (Altman and Das, 1965). NR 68 TC 7 Z9 7 U1 5 U2 5 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 SEP 21 PY 2016 VL 91 IS 6 BP 1356 EP 1373 DI 10.1016/j.neuron.2016.08.009 PG 18 WC Neurosciences SC Neurosciences & Neurology GA EA6SW UT WOS:000386760300019 PM 27593178 ER PT J AU Pun, SC Neilan, TG AF Pun, Shawn C. Neilan, Tomas G. TI Cardiovascular side effects of small molecule therapies for cancer SO EUROPEAN HEART JOURNAL LA English DT Editorial Material C1 [Pun, Shawn C.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Cardiooncol Program, Boston, MA 02114 USA. [Neilan, Tomas G.] Massachusetts Gen Hosp, Dept Med, Cardiooncol Program, Div Cardiol,Cardiac MR PET CT Program,Dept Radiol, Boston, MA 02114 USA. RP Neilan, TG (reprint author), Massachusetts Gen Hosp, Dept Med, Cardiooncol Program, Div Cardiol,Cardiac MR PET CT Program,Dept Radiol, Boston, MA 02114 USA. EM tneilan@mgh.harvard.edu NR 0 TC 0 Z9 0 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 SEP 21 PY 2016 VL 37 IS 36 BP 2742 EP 2745 DI 10.1093/eurheartj/ehw361 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ7DU UT WOS:000386025600004 PM 27694541 ER PT J AU Rice, MS Bertrand, KA VanderWeele, TJ Rosner, BA Liao, XM Adami, HO Tamimi, RM AF Rice, Megan S. Bertrand, Kimberly A. VanderWeele, Tyler J. Rosner, Bernard A. Liao, Xiaomei Adami, Hans-Olov Tamimi, Rulla M. TI Mammographic density and breast cancer risk: a mediation analysis SO BREAST CANCER RESEARCH LA English DT Article ID INITIATIVE RANDOMIZED-TRIAL; ESTROGEN-PLUS-PROGESTIN; BODY-SIZE; PREMENOPAUSAL WOMEN; POSTMENOPAUSAL WOMEN; LIFE-COURSE; PARENCHYMAL PATTERNS; PHYSICAL-ACTIVITY; DIFFERENT PERIODS; SURROGATE MARKER AB Background: High mammographic density ( MD) is a strong risk factor for breast cancer. However, it is unclear whether high MD is an intermediate phenotype or whether breast cancer risk factors influence breast cancer risk and MD independently. Methods: Our study population included 1290 invasive breast cancer cases and 3422 controls from the Nurses' Health Studies. We estimated the percent of the total association between the risk factor and breast cancer that was mediated by MD. Results: In both pre- and postmenopausal women, the association between history of biopsy-confirmed benign breast disease and risk was partially mediated by percent MD (percent mediated (PM) = 17 %, p < 0.01 and PM = 33 %, p = 0.04, respectively). In premenopausal women, the associations between early life body size (adolescent somatotype and BMI at age 18) and breast cancer risk were substantially mediated by percent MD (PM = 73 %, p = 0.05 and PM = 82 %, p = 0.04, respectively). In postmenopausal women, the proportion of the associations of childhood somatotype and adolescent somatotype that were mediated by percent MD were lower (PM = 26 %, p = 0.01 for both measures). Hormone therapy use at mammogram was significantly mediated by percent MD in postmenopausal women (PM = 22 %, p < 0.01). Associations with other risk factors, such as age at menarche or family history of breast cancer, were not mediated by percent MD. Conclusions: Percent MD partially mediated some of the associations between risk factors and breast cancer, though the magnitude varied by risk factor and menopausal status. These findings suggest that high MD may be an intermediate in some biological pathways for breast cancer development. C1 [Rice, Megan S.] Massachusetts Gen Hosp, Dept Med, Clin & Translat Epidemiol Unit, 55 Fruit St,Bartlett 9, Boston, MA 02116 USA. [Bertrand, Kimberly A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [VanderWeele, Tyler J.; Liao, Xiaomei; Adami, Hans-Olov; Tamimi, Rulla M.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Rosner, Bernard A.; Tamimi, Rulla M.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. [Liao, Xiaomei] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Adami, Hans-Olov] Univ Oslo, Inst Hlth & Soc, Dept Epidemiol, Oslo, Norway. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. RP Rice, MS (reprint author), Massachusetts Gen Hosp, Dept Med, Clin & Translat Epidemiol Unit, 55 Fruit St,Bartlett 9, Boston, MA 02116 USA. EM mrice1@mgh.harvard.edu FU National Cancer Institute, National Institutes of Health [UM1 CA186107, P01 CA87969, UM1 CA176726, R01 CA175080, R01 CA124865, R01 CA131332, T32 CA09001]; Avon Foundation for Women; Susan G. Komen for the Cure(R); Simeon J. Fortin Charitable Foundation, Bank of America, N.A., Co-Trustee FX This study was supported by research grants from the National Cancer Institute, National Institutes of Health, UM1 CA186107, P01 CA87969, UM1 CA176726, R01 CA175080, R01 CA124865, R01 CA131332, and T32 CA09001, Avon Foundation for Women, and Susan G. Komen for the Cure (R). KAB was supported by the Simeon J. Fortin Charitable Foundation, Bank of America, N.A., Co-Trustee. NR 40 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD SEP 21 PY 2016 VL 18 AR 94 DI 10.1186/s13058-016-0750-0 PG 13 WC Oncology SC Oncology GA DX5YQ UT WOS:000384459000001 PM 27654859 ER PT J AU Wang, YG Huang, YY Wang, Y Lyu, PJ Hamblin, MR AF Wang, Yuguang Huang, Ying-Ying Wang, Yong Lyu, Peijun Hamblin, Michael R. TI Photobiomodulation (blue and green light) encourages osteoblastic-differentiation of human adipose-derived stem cells: role of intracellular calcium and light-gated ion channels SO SCIENTIFIC REPORTS LA English DT Article ID LEVEL LASER THERAPY; BONE-MARROW; BRIGHT LIGHT; PROLIFERATION; IRRADIATION; RECEPTOR; OPTOGENETICS; EXPRESSION; INDUCTION; GRAFT AB Human adipose-derived stem cells (hASCs) have the potential to differentiate into several different cell types including osteoblasts. Photobiomodulation (PBM) or low level laser therapy (LLLT) using red or near-infrared wavelengths has been reported to have effects on both proliferation and osteogenic differentiation of stem cells. We examined the effects of delivering four different wavelengths (420 nm, 540 nm, 660 nm, 810 nm) at the same dose (3 J/cm(2)) five times (every two days) on hASCs cultured in osteogenic medium over three weeks. We measured expression of the following transcription factors by RT-PCR: RUNX2, osterix, and the osteoblast protein, osteocalcin. The 420 nm and 540 nm wavelengths were more effective in stimulating osteoblast differentiation compared to 660 nm and 810 nm. Intracellular calcium was higher after 420 nm and 540 nm, and could be inhibited by capsazepine and SKF96365, which also inhibited osteogenic differentiation. We hypothesize that activation of light-gated calcium ion channels by blue and green light could explain our results. C1 [Wang, Yuguang; Wang, Yong; Lyu, Peijun] Peking Univ, Ctr Digital Dent, Sch & Hosp Stomatol, Beijing, Peoples R China. [Wang, Yuguang; Wang, Yong; Lyu, Peijun] Natl Engn Lab Digital & Mat Technol Stomatol, Beijing, Peoples R China. [Wang, Yuguang; Huang, Ying-Ying; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Wang, Yuguang; Huang, Ying-Ying; Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Lyu, PJ (reprint author), Peking Univ, Ctr Digital Dent, Sch & Hosp Stomatol, Beijing, Peoples R China.; Lyu, PJ (reprint author), Natl Engn Lab Digital & Mat Technol Stomatol, Beijing, Peoples R China.; Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hamblin, MR (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA.; Hamblin, MR (reprint author), Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM kqlpj@bjmu.edu.cn; hamblin@helix.mgh.harvard.edu FU PKUSS grant [PKUSS20140208]; Ministry of Education grant [113002A]; US NIH [AI050875] FX Yuguang Wang was funded by PKUSS grant PKUSS20140208 and Ministry of Education grant 113002A. Michael R Hamblin was funded by US NIH grant AI050875. NR 54 TC 0 Z9 0 U1 9 U2 9 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 SEP 21 PY 2016 VL 6 AR 33719 DI 10.1038/srep33719 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW3UC UT WOS:000383567600001 PM 27650508 ER PT J AU Steichen, JM Kulp, DW Tokatlian, T Escolano, A Dosenovic, P Stanfield, RL McCoy, LE Ozorowski, G Hu, XZ Kalyuzhniy, O Briney, B Schiffner, T Garces, F Freund, NT Gitlin, AD Menis, S Georgeson, E Kubitz, M Adachi, Y Jones, M Mutafyan, AA Yun, DS Mayer, CT Ward, AB Burton, DR Wilson, IA Irvine, DJ Nussenzweig, MC Schief, WR AF Steichen, Jon M. Kulp, Daniel W. Tokatlian, Talar Escolano, Amelia Dosenovic, Pia Stanfield, Robyn L. McCoy, Laura E. Ozorowski, Gabriel Hu, Xiaozhen Kalyuzhniy, Oleksandr Briney, Bryan Schiffner, Torben Garces, Fernando Freund, Natalia T. Gitlin, Alexander D. Menis, Sergey Georgeson, Erik Kubitz, Michael Adachi, Yumiko Jones, Meaghan Mutafyan, Andrew A. Yun, Dong Soo Mayer, Christian T. Ward, Andrew B. Burton, Dennis R. Wilson, Ian A. Irvine, Darrell J. Nussenzweig, Michel C. Schief, William R. TI HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies SO IMMUNITY LA English DT Article ID B-CELL RECEPTORS; ENVELOPE TRIMER; MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; IMMUNOGEN DESIGN; IN-VITRO; POTENT; ENV; RECOGNITION; EVOLUTION AB Broadly neutralizing antibodies (bnAbs) against the N332 supersite of the HIV envelope (Env) trimer are the most common bnAbs induced during infection, making them promising leads for vaccine design. Wild-type Env glycoproteins lack detectable affinity for supersite-bnAb germline precursors and are therefore unsuitable immunogens to prime supersite-bnAb responses. We employed mammalian cell surface display to design stabilized Env trimers with affinity for germline-reverted precursors of PGT121-class supersite bnAbs. The trimers maintained native-like antigenicity and structure, activated PGT121 inferred-germline B cells ex vivo when multimerized on liposomes, and primed PGT121-like responses in PGT121 inferred-germline knockin mice. Design intermediates have levels of epitope modification between wild-type and germline-targeting trimers; their mutation gradient suggests sequential immunization to induce bnAbs, in which the germline- targeting prime is followed by progressively less-mutated design intermediates and, lastly, with native trimers. The vaccine design strategies described could be utilized to target other epitopes on HIV or other pathogens. C1 [Steichen, Jon M.; Kulp, Daniel W.; McCoy, Laura E.; Hu, Xiaozhen; Kalyuzhniy, Oleksandr; Briney, Bryan; Schiffner, Torben; Menis, Sergey; Georgeson, Erik; Kubitz, Michael; Adachi, Yumiko; Jones, Meaghan; Burton, Dennis R.; Schief, William R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Steichen, Jon M.; Kulp, Daniel W.; Stanfield, Robyn L.; McCoy, Laura E.; Ozorowski, Gabriel; Hu, Xiaozhen; Kalyuzhniy, Oleksandr; Briney, Bryan; Schiffner, Torben; Garces, Fernando; Menis, Sergey; Georgeson, Erik; Kubitz, Michael; Adachi, Yumiko; Jones, Meaghan; Ward, Andrew B.; Burton, Dennis R.; Wilson, Ian A.; Schief, William R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Steichen, Jon M.; Kulp, Daniel W.; Stanfield, Robyn L.; McCoy, Laura E.; Ozorowski, Gabriel; Hu, Xiaozhen; Kalyuzhniy, Oleksandr; Briney, Bryan; Schiffner, Torben; Garces, Fernando; Menis, Sergey; Georgeson, Erik; Kubitz, Michael; Adachi, Yumiko; Jones, Meaghan; Ward, Andrew B.; Burton, Dennis R.; Wilson, Ian A.; Schief, William R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Tokatlian, Talar; Mutafyan, Andrew A.; Yun, Dong Soo; Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Escolano, Amelia; Dosenovic, Pia; Freund, Natalia T.; Gitlin, Alexander D.; Mayer, Christian T.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Stanfield, Robyn L.; Ozorowski, Gabriel; Garces, Fernando; Ward, Andrew B.; Wilson, Ian A.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Burton, Dennis R.; Irvine, Darrell J.; Schief, William R.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Irvine, Darrell J.; Nussenzweig, Michel C.; Schief, William R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. RP Schief, WR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.; Schief, WR (reprint author), Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA.; Schief, WR (reprint author), Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA.; Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA.; Schief, WR (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA.; Nussenzweig, MC (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM nussen@mail.rockefeller.edu; schief@scripps.edu RI Ward, Andrew/F-9203-2014 OI Ward, Andrew/0000-0001-7153-3769 FU National Institute of Allergy and Infectious Diseases [CHAVI-ID 1UM1AI100663, P01 AI110657, R01 AI084817]; Ragon Institute of MGH; Harvard; Internation AIDS Vaccine Initiative (IAVI); United States Agency for International Development; Ministry of Foreign Affairs of the Netherlands; Bill & Melinda Gates Foundation; DOE Office of Biological and Environmental Research; NIH; National Institute of General Medical Sciences [P41GM103393]; MIT FX We thank Takayuki Ota and David Nemazee for providing lentivirus protocols and reagents and Leo Stamatatos and Jean-Philippe Julien for comments on the manuscript. This work was supported by National Institute of Allergy and Infectious Diseases grants CHAVI-ID 1UM1AI100663 (to W.R.S., D.J.I., M.C.N., I.A.W., D.R.B., and A.B.W.), P01 AI110657 (to I.A.W.), and R01 AI084817 (to I.A.W.) and by the Ragon Institute of MGH, MIT, and Harvard (to D.R.B., D.J.I., and W.R.S.). This work was also partially funded by the Internation AIDS Vaccine Initiative (IAVI) with the generous support of the United States Agency for International Development, the Ministry of Foreign Affairs of the Netherlands, and the Bill & Melinda Gates Foundation; a full list of IAVI donors is available at www.iavi.org (W.R.S., D.R.B, A.B.W., and I.A.W.). Portions of this research were carried out at the Stanford Synchrotron Radiation Lightsource (SSRL), a directorate of the SLAC National Accelerator Laboratory, and an Office of Science user facility operated for the U.S. Department of Energy (DOE) Office of Science by Stanford University. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, the NIH, and the National Institute of General Medical Sciences (including P41GM103393). The Scripps Research Institute and IAVI have filed for a patent related to immunogens in this manuscript, with inventors J.M.S., D.W.K., X.H., S.M., and W.R.S. Materials and information will be provided under a material transfer agreement. W.R.S. is a co-founder and stockholder in Compuvax, which has programs in non-HIV vaccine design that might benefit indirectly from this research. NR 59 TC 11 Z9 11 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD SEP 20 PY 2016 VL 45 IS 3 BP 483 EP 496 DI 10.1016/j.immuni.2016.08.016 PG 14 WC Immunology SC Immunology GA EC9HD UT WOS:000388454300008 PM 27617678 ER PT J AU Conteduca, G Fenoglio, D Parodi, A Battaglia, F Kalli, F Negrini, S Tardito, S Ferrera, F Salis, A Millo, E Pasquale, G Barra, G Damonte, G Indiveri, F Ferrone, S Filaci, G AF Conteduca, Giuseppina Fenoglio, Daniela Parodi, Alessia Battaglia, Florinda Kalli, Francesca Negrini, Simone Tardito, Samuele Ferrera, Francesca Salis, Annalisa Millo, Enrico Pasquale, Giuseppe Barra, Giusi Damonte, Gianluca Indiveri, Francesco Ferrone, Soldano Filaci, Gilberto TI AIRE polymorphism, melanoma antigen-specific T cell immunity, and susceptibility to melanoma SO ONCOTARGET LA English DT Article DE AIRE; MAGE; medullary thymic epithelial cells; single nucleotide polymorphism; tolerance; Immunology and Microbiology Section; Immune response; Immunity ID REGULATOR GENE AIRE; EPITHELIAL-CELLS; CANCER VACCINES; DENDRITIC CELLS; TUMOR-CELLS; EXPRESSION; LYMPHOCYTES; SELF; MUTATIONS; RESPONSES AB AIRE is involved in susceptibility to melanoma perhaps regulating T cell immunity against melanoma antigens (MA). To address this issue, AIRE and MAGEB2 expressions were measured by real time PCR in medullary thymic epithelial cells (mTECs) from two strains of C57BL/6 mice bearing either T or C allelic variant of the rs1800522 AIRE SNP. Moreover, the extent of apoptosis induced by mTECs in MAGEB2-specific T cells and the susceptibility to in vivo melanoma B16F10 cell challenge were compared in the two mouse strains. The C allelic variant, protective in humans against melanoma, induced lower AIRE and MAGEB2 expression in C57BL/6 mouse mTECs than the T allele. Moreover, mTECs expressing the C allelic variant induced lower extent of apoptosis in MAGEB2-specific syngeneic T cells than mTECs bearing the T allelic variant (p < 0.05). Vaccination against MAGEB2 induced higher frequency of MAGEB2-specific CTL and exerted higher protective effect against melanoma development in mice bearing the CC AIRE genotype than in those bearing the TT one (p < 0.05). These findings show that allelic variants of one AIRE SNP may differentially shape the MA-specific T cell repertoire potentially influencing susceptibility to melanoma. C1 [Conteduca, Giuseppina; Fenoglio, Daniela; Parodi, Alessia; Battaglia, Florinda; Kalli, Francesca; Negrini, Simone; Tardito, Samuele; Ferrera, Francesca; Salis, Annalisa; Millo, Enrico; Damonte, Gianluca; Indiveri, Francesco; Filaci, Gilberto] Univ Genoa, Ctr Excellence Biomed Res, Genoa, Italy. [Fenoglio, Daniela; Indiveri, Francesco; Filaci, Gilberto] Univ Genoa, Dept Internal Med, Genoa, Italy. [Fenoglio, Daniela; Filaci, Gilberto] IRCCS AOU San Martino IST, Genoa, Italy. [Pasquale, Giuseppe; Barra, Giusi] Univ Naples 2, Dept Clin & Expt Med, Naples, Italy. [Ferrone, Soldano] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. RP Filaci, G (reprint author), Univ Genoa, Ctr Excellence Biomed Res, Genoa, Italy.; Filaci, G (reprint author), Univ Genoa, Dept Internal Med, Genoa, Italy.; Filaci, G (reprint author), IRCCS AOU San Martino IST, Genoa, Italy. EM gfilaci@unige.it FU FIRC (Italian Foundation for Cancer Research); Compagnia di San Paolo, Torino, entitled "Immunoterapia anti-tumorale: analisi d'efficacia dei principali protocolli tradizionali d'immunizzazione e validazione dell'efficacia dell'inibizione dell'interleuchina 10 nel trattamento del melanoma"; MIUR, PRIN project entitled "Immunoterapia anti-tumorale operata attraverso l'inibizione dei circuiti regolatori citochino-dipendenti"; PHS - National Cancer Institute [RO1CA138188, RO1CA110249] FX This work was supported by a grant from FIRC (Italian Foundation for Cancer Research) for fellowship support, a grant from Compagnia di San Paolo, Torino, entitled "Immunoterapia anti-tumorale: analisi d'efficacia dei principali protocolli tradizionali d'immunizzazione e validazione dell'efficacia dell'inibizione dell'interleuchina 10 nel trattamento del melanoma", a grant from MIUR, PRIN project entitled "Immunoterapia anti-tumorale operata attraverso l'inibizione dei circuiti regolatori citochino-dipendenti", and PHS grants RO1CA138188 and RO1CA110249 awarded by the National Cancer Institute. NR 44 TC 0 Z9 0 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 SEP 20 PY 2016 VL 7 IS 38 BP 60872 EP 60884 DI 10.18632/oncotarget.11506 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2CN UT WOS:000387164700007 PM 27563821 ER PT J AU Lu, MY Huang, CI Hsieh, MY Hsieh, TJ Hsi, E Tsai, PC Tsai, YS Lin, CC Hsieh, MH Liang, PC Lin, YH Hou, NJ Yeh, ML Huang, CF Lin, ZY Chen, SC Huang, JF Chuang, WL Dai, CY Yu, ML AF Lu, Ming-Ying Huang, Ching-I Hsieh, Ming-Yen Hsieh, Tusty-Juan Hsi, Edward Tsai, Pei-Chien Tsai, Yi-Shan Lin, Ching-Chih Hsieh, Meng-Hsuan Liang, Po-Cheng Lin, Yi-Hung Hou, Nai-Jen Yeh, Ming-Lun Huang, Chung-Feng Lin, Zu-Yau Chen, Shinn-Cherng Huang, Jee-Fu Chuang, Wan-Long Dai, Chia-Yen Yu, Ming-Lung TI Dynamics of PBMC gene expression in hepatitis C virus genotype 1-infected patients during combined peginterferon/ribavirin therapy SO ONCOTARGET LA English DT Article DE hepatitis C; interferon; sustained virologic response ID RAPID VIROLOGICAL RESPONSE; PEGYLATED INTERFERON; PLUS RIBAVIRIN; HISTONE MODIFICATIONS; RANDOMIZED-TRIAL; INFECTION; HCV; ALPHA-2A; METHYLATION; IDENTIFICATION AB Hepatitis C virus (HCV) can replicate in peripheral blood mononuclear cells (PBMCs), which can produce interferon to defend against virus infection. We hypothesized that dynamic gene expression in PBMCs might impact the treatment efficacy of peginterferon/ribavirin in HCV patients. PBMCs were collected at baseline, 1st week and 4th week of treatment from 27 chronic HCV-1 patients with 48-week peginterferon/ribavirin therapy (screening dataset n = 7; validation dataset n = 20). A sustained virologic response (SVR) was defined as undetectable HCV RNA throughout the 24 weeks after end-of-treatment. A complete early virologic response (cEVR) was defined as negative HCV RNA at treatment week 12. Forty-three differentially expressed genes identified by Affymetrix microarray were validated by quantitative polymerase chain reaction. Thirteen genes at week 1 and 24 genes at week 4 were upregulated in the SVR group compared with the non-SVR group. We selected 8 target genes (RSAD2, LOC26010, HERC5, HERC6, IF144, SERPING1, IFITM3, and DDX60) at week 1 as the major components of the predictive model. This predictive model reliably stratified the responders and non-responders at week 1 (AUC = 0.89, p = 0.007 for SVR; AUC = 0.95, p = 0.003 for cEVR), especially among patients carrying the IL28B rs8099917 TT genotype (AUC = 0.89, p = 0.02 for SVR; AUC = 1.0, p = 0.008 for cEVR). The performance of this predictive model was superior to traditional predictors, including the rapid virologic response, viral load and IL28B genotype. C1 [Hsieh, Ming-Yen; Tsai, Pei-Chien; Tsai, Yi-Shan; Lin, Ching-Chih; Liang, Po-Cheng; Lin, Yi-Hung; Yeh, Ming-Lun; Huang, Chung-Feng; Lin, Zu-Yau; Chen, Shinn-Cherng; Huang, Jee-Fu; Chuang, Wan-Long; Dai, Chia-Yen; Yu, Ming-Lung] Kaohsiung Med Univ Hosp, Dept Internal Med & Hepatitis Ctr, Hepatobiliary Div, Kaohsiung, Taiwan. [Hsieh, Meng-Hsuan; Yeh, Ming-Lun; Huang, Chung-Feng; Lin, Zu-Yau; Chen, Shinn-Cherng; Huang, Jee-Fu; Chuang, Wan-Long; Dai, Chia-Yen; Yu, Ming-Lung] Kaohsiung Med Univ, Coll Med, Fac Internal Med, Kaohsiung, Taiwan. [Hsieh, Meng-Hsuan; Yeh, Ming-Lun; Huang, Chung-Feng; Lin, Zu-Yau; Chen, Shinn-Cherng; Huang, Jee-Fu; Chuang, Wan-Long; Dai, Chia-Yen; Yu, Ming-Lung] Kaohsiung Med Univ, Grad Inst Clin Med, Kaohsiung, Taiwan. [Hsieh, Meng-Hsuan; Yeh, Ming-Lun; Huang, Chung-Feng; Lin, Zu-Yau; Chen, Shinn-Cherng; Huang, Jee-Fu; Chuang, Wan-Long; Dai, Chia-Yen; Yu, Ming-Lung] Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan. [Yu, Ming-Lung] Natl Sun Yat Sen Univ, Inst Biomed Sci, Kaohsiung, Taiwan. [Huang, Ching-I; Hou, Nai-Jen] Kaohsiung Med Univ, Kaohsiung Municipal Hsiao Kang Hosp, Dept Internal Med, Kaohsiung, Taiwan. [Huang, Chung-Feng] Kaohsiung Med Univ, Kaohsiung Municipal Ta Tung Hosp, Dept Occupat Med, Kaohsiung, Taiwan. [Hsieh, Meng-Hsuan] Kaohsiung Med Univ Hosp, Dept Prevent Med, Kaohsiung, Taiwan. [Lu, Ming-Ying; Yeh, Ming-Lun; Dai, Chia-Yen] Kaohsiung Med Univ, Grad Inst Med, Coll Med, Kaohsiung, Taiwan. [Hsieh, Tusty-Juan] Kaohsiung Med Univ, Dept Genome Med, Coll Med, Kaohsiung, Taiwan. [Hsi, Edward] Kaohsiung Med Univ Hosp, Dept Med Res, Kaohsiung, Taiwan. [Yu, Ming-Lung] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Ctr Liver, Boston, MA 02115 USA. RP Dai, CY; Yu, ML (reprint author), Kaohsiung Med Univ Hosp, Dept Internal Med & Hepatitis Ctr, Hepatobiliary Div, Kaohsiung, Taiwan.; Dai, CY; Yu, ML (reprint author), Kaohsiung Med Univ, Coll Med, Fac Internal Med, Kaohsiung, Taiwan.; Dai, CY; Yu, ML (reprint author), Kaohsiung Med Univ, Grad Inst Clin Med, Kaohsiung, Taiwan.; Dai, CY; Yu, ML (reprint author), Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan.; Yu, ML (reprint author), Natl Sun Yat Sen Univ, Inst Biomed Sci, Kaohsiung, Taiwan.; Dai, CY (reprint author), Kaohsiung Med Univ, Grad Inst Med, Coll Med, Kaohsiung, Taiwan.; Yu, ML (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Ctr Liver, Boston, MA 02115 USA. EM daichiayen@gmail.com; fish6069@gmail.com FU Kaohsiung Medical University [KMU-TP104E07, KMU-TP104E08, KMU-TP104E09, KMU-TP104D12]; Kaohsiung Medical University Hospital [KMUH102-2R03, KMUH102-2R04]; National Science Council, Taiwan [NSC 96-2314-B-037-044-MY3]; "Center for Infectious Disease and Cancer Research" of Kaohsiung Medical University; "Lipid Science and Aging Research Center" of Kaohsiung Medical University FX This study was supported by grants from the Kaohsiung Medical University (KMU-TP104E07, KMU-TP104E08, KMU-TP104E09, and KMU-TP104D12), Kaohsiung Medical University Hospital (KMUH102-2R03 and KMUH102-2R04) and the National Science Council, Taiwan (NSC 96-2314-B-037-044-MY3). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. We are grateful for the support from the "Center for Infectious Disease and Cancer Research" and "Lipid Science and Aging Research Center" of Kaohsiung Medical University. NR 45 TC 0 Z9 0 U1 2 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 SEP 20 PY 2016 VL 7 IS 38 BP 61325 EP 61335 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2CN UT WOS:000387164700039 PM 27542257 ER PT J AU Mirkheshti, N Park, S Jiang, S Cropper, J Werner, SL Song, CS Chatterjee, B AF Mirkheshti, Nooshin Park, Sulgi Jiang, Shoulei Cropper, Jodie Werner, Sherry L. Song, Chung S. Chatterjee, Bandana TI Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer SO ONCOTARGET LA English DT Article DE androgen receptor; CYP17A1; HSD3 beta 1; mTORC1; AMPK ID SERINE 81 PHOSPHORYLATION; CELL-DEATH; INCREASED SURVIVAL; IN-VIVO; AUTOPHAGY; ACTIVATION; GROWTH; AMPK; CASTRATION; PATHWAY AB Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors. AR expression, its transcriptional activity, and androgen biosynthesis regulating enzymes CYP17A1, HSD3 beta 1 were reduced by sub-micro molar salinomycin. Estrogen receptor-a expression was unchanged. Loss of phosphorylated AR at serine-81, which is an index for nuclear AR activity, preceded total AR reduction. Rapamycin enhanced the AR protein level without altering phosphoAR-Ser81 and CYP17A1. Inactivation of mTORC1, evident from reduced phosphorylation of mTOR and downstream effectors, as well as AMPK activation led to robust autophagy induction. Apoptosis increased modestly, albeit significantly, by sub-micro molar salinomycin. Enhanced stimulatory TSC2 phosphorylation at Ser-1387 by AMPK, and reduced inhibitory TSC2 phosphorylation at Ser-939/Thr-1462 catalyzed by AKT augmented TSC2/TSC1 activity, which led to mTORC1 inhibition. AMPK-mediated raptor phosphorylation further reduced mTOR's kinase function and mTORC1 activity. Our novel finding on dual inhibition of AR and mTORC1 suggests that salinomycin is potentially active as monotherapy against advanced prostate cancer. C1 [Mirkheshti, Nooshin; Park, Sulgi; Jiang, Shoulei; Cropper, Jodie; Song, Chung S.; Chatterjee, Bandana] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78245 USA. [Werner, Sherry L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78245 USA. [Chatterjee, Bandana] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Chatterjee, B (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78245 USA.; Chatterjee, B (reprint author), South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM chatterjee@uthscsa.edu FU VA Merit-review grant [1I01BX000280]; Research Career Scientist Award from VA; DOD IDEA grant [W81XWH-14-1-0606]; Morrison Trust Foundation [P30-CA054174] FX The study was supported by VA Merit-review grant (1I01BX000280), Research Career Scientist Award from VA (to BC), DOD IDEA grant (W81XWH-14-1-0606) and Morrison Trust Foundation. P30-CA054174 (NIH), awarded to Cancer Therapy & Research Center at UTHSCSA, provided Pathology & FACS Core Services. NR 54 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 20 PY 2016 VL 7 IS 38 BP 62240 EP 62254 DI 10.18632/oncotarget.11404 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2CN UT WOS:000387164700107 PM 27557496 ER PT J AU Rozic, G Paukov, L Jakubikova, J Ben-Shushan, D Duek, A Leiba, A Avigdor, A Nagler, A Leiba, M AF Rozic, Gabriela Paukov, Lena Jakubikova, Jana Ben-Shushan, Dikla Duek, Adrian Leiba, Adi Avigdor, Abraham Nagler, Arnon Leiba, Merav TI The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo SO ONCOTARGET LA English DT Article DE multiple myeloma; cell cycle; apoptosis; tubulin; AKT ID P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; INDUCED APOPTOSIS; CELLS; DEXAMETHASONE; THALIDOMIDE; SURVIVAL; AKT; MCL-1; OVEREXPRESSION AB Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy. STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump. STK405759 was not cytotoxic to peripheral blood mononuclear cells, including activated B and T lymphocytes. This compound caused mitotic arrest and apoptosis of myeloma cells characterized by cleavage of poly (ADP-ribose) polymerase-1 and caspase-8, as well as decreased protein expression of mcl-1. The combination of STK405759 with bortezomib, lenalidomide or dexamethasone had synergistic cytotoxic activity. In in vivo studies, STK405759-treated mice had significantly decreased MM tumor burden and prolonged survival compared to vehicle treated-mice. These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM. C1 [Rozic, Gabriela; Paukov, Lena; Ben-Shushan, Dikla; Duek,