FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Ilkovski, B Pagnamenta, AT O'Grady, GL Kinoshita, T Howard, MF Lek, M Thomas, B Turner, A Christodoulou, J Sillence, D Knight, SJL Popitsch, N Keays, DA Anzilotti, C Goriely, A Waddell, LB Brilot, F North, KN Kanzawa, N Macarthur, DG Taylor, JC Kini, U Murakami, Y Clarke, NF AF Ilkovski, Biljana Pagnamenta, Alistair T. O'Grady, Gina L. Kinoshita, Taroh Howard, Malcolm F. Lek, Monkol Thomas, Brett Turner, Anne Christodoulou, John Sillence, David Knight, Samantha J. L. Popitsch, Niko Keays, David A. Anzilotti, Consuelo Goriely, Anne Waddell, Leigh B. Brilot, Fabienne North, Kathryn N. Kanzawa, Noriyuki Macarthur, Daniel G. Taylor, Jenny C. Kini, Usha Murakami, Yoshiko Clarke, Nigel F. TI Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies SO HUMAN MOLECULAR GENETICS LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; MENTAL-RETARDATION SYNDROME; GPI ANCHOR DEFICIENCY; HYPERPHOSPHATASIA; BIOSYNTHESIS; GENE; PROMOTER; EPILEPSY; GENOME AB Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (similar to 20-50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5'-UTR regions despite their typically low coverage in exome data. C1 [Ilkovski, Biljana; O'Grady, Gina L.; Brilot, Fabienne; North, Kathryn N.; Clarke, Nigel F.] Childrens Hosp, Inst Neurosci & Muscle Res, Westmead, NSW 2145, Australia. [Sillence, David] Childrens Hosp, Western Sydney Genet Program, Westmead, NSW 2145, Australia. [Pagnamenta, Alistair T.; Howard, Malcolm F.; Knight, Samantha J. L.; Popitsch, Niko; Taylor, Jenny C.] Univ Oxford, Wellcome Trust Ctr Human Genet, Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX1 2JD, England. [Anzilotti, Consuelo] Univ Oxford, Henry Wellcome Bldg Mol Physiol, Oxford OX3 7BN, England. [O'Grady, Gina L.; Waddell, Leigh B.; Brilot, Fabienne; North, Kathryn N.; Clarke, Nigel F.] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Kinoshita, Taroh; Kanzawa, Noriyuki; Murakami, Yoshiko] Osaka Univ, Dept Immunoregulat, Microbial Dis Res Inst, Suita, Osaka 5650871, Japan. [Kinoshita, Taroh; Kanzawa, Noriyuki; Murakami, Yoshiko] Osaka Univ, WPI Immunol Frontier Res Ctr, Suita, Osaka 5650871, Japan. [Lek, Monkol; Thomas, Brett; Macarthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; Thomas, Brett; Macarthur, Daniel G.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Turner, Anne] Sydney Childrens Hosp, Dept Clin Genet, Sydney, NSW, Australia. [Christodoulou, John; Sillence, David] Childrens Hosp, Sch Clin, Discipline Genet Med, Sydney, NSW, Australia. [Keays, David A.] Inst Mol Pathol, A-1030 Vienna, Austria. [Goriely, Anne] Univ Oxford, Weatherall Inst Mol Med, Oxford OX3 9DS, England. [North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Kini, Usha] Oxford Univ Hosp NHS Trust, Dept Clin Genet, Oxford OX3 9DU, England. RP Kini, U (reprint author), Childrens Hosp, Inst Neurosci & Muscle Res, Locked Bag 4001, Westmead, NSW 2145, Australia. EM Usha.Kini@ouh.nhs.uk; nigel.clarke@health.nsw.gov.au RI Kinoshita, Taroh/C-7353-2009; North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Christodoulou, John/0000-0002-8431-0641 FU National Health & Medical Research Council of Australia [APP571287, APP1035828, APP1022707]; National Institute for Health Research (NIHR) Biomedical Research Centre Oxford; Department of Health's NIHR Biomedical Research Centres funding scheme; Wellcome Trust [090532/Z/09/Z]; Medical Research Council [G0900747 91070] FX This work was supported by the National Health & Medical Research Council of Australia (APP571287-KN, NC, APP1035828-NC and APP1022707-KN, NC) and National Institute for Health Research (NIHR) Biomedical Research Centre Oxford with funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z and Medical Research Council Hub grant G0900747 91070) for generating the sequencing data. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 26 TC 10 Z9 10 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2015 VL 24 IS 21 BP 6146 EP 6159 DI 10.1093/hmg/ddv331 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CT7WA UT WOS:000363024000016 PM 26293662 ER PT J AU Schaefer, B Haschka, D Finkenstedt, A Petersen, BS Theurl, I Henninger, B Janecke, AR Wang, CY Lin, HY Veits, L Vogel, W Weiss, G Franke, A Zoller, H AF Schaefer, Benedikt Haschka, David Finkenstedt, Armin Petersen, Britt-Sabina Theurl, Igor Henninger, Benjamin Janecke, Andreas R. Wang, Chia-Yu Lin, Herbert Y. Veits, Lothar Vogel, Wolfgang Weiss, Guenter Franke, Andre Zoller, Heinz TI Impaired hepcidin expression in alpha-1-antitrypsin deficiency associated with iron overload and progressive liver disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID ALPHA(1)-ANTITRYPSIN DEFICIENCY; JUVENILE HEMOCHROMATOSIS; GENETIC HEMOCHROMATOSIS; PROTEASE MATRIPTASE-2; DOWN-REGULATION; RECEPTOR ALK3; METABOLISM; MUTATIONS; HEMOJUVELIN; MECHANISMS AB Liver disease due to alpha-1-antitrypsin deficiency (A1ATD) is associated with hepatic iron overload in a subgroup of patients. The underlying cause for this association is unknown. The aim of the present study was to define the genetics of this correlation and the effect of alpha-1-antitrypsin (A1AT) on the expression of the iron hormone hepcidin. Full exome and candidate gene sequencing were carried out in a family with A1ATD and hepatic iron overload. Regulation of hepcidin expression by A1AT was studied in primary murine hepatocytes. Cells co-transfected with hemojuvelin (HJV) and matriptase-2 (MT-2) were used as a model to investigate the molecular mechanism of this regulation. Observed familial clustering of hepatic iron overload with A1ATD suggests a genetic cause, but genotypes known to be associated with hemochromatosis were absent. Individuals homozygous for the A1AT Z-allele with environmental or genetic risk factors such as steatosis or heterozygosity for the HAMP non-sense mutation p.Arg59* presented with severe hepatic siderosis. In hepatocytes, A1AT induced hepcidin mRNA expression in a dose-dependent manner. Experiments in overexpressing cells show that A1AT reduces cleavage of the hepcidin inducing bone morphogenetic protein co-receptor HJV via inhibition of the membrane-bound serine protease MT-2. The acute-phase protein A1AT is an inducer of hepcidin expression. Through this mechanism, A1ATD could be a trigger of hepatic iron overload in genetically predisposed individuals or patients with environmental risk factors for hepatic siderosis. C1 [Schaefer, Benedikt; Finkenstedt, Armin; Vogel, Wolfgang; Zoller, Heinz] Med Univ Innsbruck, Dept Med Gastroenterol & Hepatol 2, A-6020 Innsbruck, Austria. [Haschka, David; Theurl, Igor; Weiss, Guenter] Med Univ Innsbruck, Dept Med 6, Infect Dis, Immunol,Rheumatol,Pneumol, A-6020 Innsbruck, Austria. [Henninger, Benjamin] Med Univ Innsbruck, Dept Radiol, A-6020 Innsbruck, Austria. [Janecke, Andreas R.] Med Univ Innsbruck, Dept Pediat 1, A-6020 Innsbruck, Austria. [Janecke, Andreas R.] Med Univ Innsbruck, Dept Human Genet, A-6020 Innsbruck, Austria. [Petersen, Britt-Sabina; Franke, Andre] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany. [Wang, Chia-Yu; Lin, Herbert Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol, Boston, MA USA. [Wang, Chia-Yu; Lin, Herbert Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA USA. [Veits, Lothar] Klinikum Bayreuth, Inst Pathol, D-95445 Bayreuth, Germany. RP Zoller, H (reprint author), Med Univ Innsbruck, Dept Med Gastroenterol & Hepatol 2, Anichstr 35, A-6020 Innsbruck, Austria. EM heinz.zoller@i-med.ac.at RI Petersen, Britt-Sabina/I-1671-2012; Franke, Andre/B-2151-2010 OI Petersen, Britt-Sabina/0000-0001-9022-9017; Franke, Andre/0000-0003-1530-5811 FU National Institutes of Health NIDDK [DK071837]; Austrian Academy of Science (OEAW) FX H.Y.L. was supported in part by National Institutes of Health NIDDK RO1 grant DK071837, and D.H. by a DOC Fellowship of the Austrian Academy of Science (OEAW). NR 58 TC 3 Z9 3 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2015 VL 24 IS 21 BP 6254 EP 6263 DI 10.1093/hmg/ddv348 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CT7WA UT WOS:000363024000024 PM 26310624 ER PT J AU Keamy, DG Chhabra, KR Hartnick, CJ AF Keamy, Donald G. Chhabra, Karan R. Hartnick, Christopher J. TI Predictors of complications following adenotonsillectomy in children with severe obstructive sleep apnea SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Sleep medicine; Obstructive sleep apnea; Polysomnography; Postoperative complications; Apnea-hypopnea index; Adenotonsillectomy ID RESPIRATORY COMPLICATIONS; RISK-FACTORS; TONSILLECTOMY; ADENOIDECTOMY; COMPROMISE AB Objective: To identify pre-operative risk factors predicting complications following adenotonsillectomy in children with severe OSA. Methods: Retrospective chart review in an academic tertiary care center. Children with symptoms of OSA with overnight polysomnography (PSG) revealing apnea-hypopnea index (AHI) >10, who underwent adenotonsillectomy with overnight postoperative observation between 2008 and 2012. Univariate logistic regression was used to assess odds ratio (OR) of individual risk factors versus postoperative complications such as overnight desaturations <90%, length of stay (LOS) > 24 h, supplemental oxygen requirement, and transfer to a higher level of care. Results: All patients (n = 157) with severe OSA were observed overnight. Mean age was 5.3 +/- 3.7 years. Twenty-five (15.9%) patients had LOS > 24 h. Forty-two (26.8%) had overnight desaturations <90%. AHI >= 15 and O-2 saturation nadir <80% on preop polysomnography (PSG) were independent predictors of post-op O-2 saturation <90% and LOS >24 h. (p < 0.05). PSG minimum saturation <80% was the strongest predictor of all variables examined with an OR of 6.98 (3.15-15.48, 95% CI) for desaturation <90% and 5.19 (2.11-12.75, 95% CI) for LOS >24 h. Preop PSG O-2 saturation < 90% predicted overnight post op oxygen requirement with an OR of 338 (1.39-8.25, 95%CI). Conclusions: Preoperative polysomnography yields significant independent predictors of post-op complications in children with OSA. While AHI is a significant independent predictor, minimum O-2 saturation on preop PSG appeared the strongest predictor when <80%. Patients with these risk factors, especially low O-2 on PSG, warrant overnight observation with continuous pulse oximetry. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Keamy, Donald G.; Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, Pediat Otolaryngol, Boston, MA 02114 USA. [Chhabra, Karan R.] Rutgers Robert Wood Johnson Med Sch, New Brunswick, NJ 08901 USA. RP Chhabra, KR (reprint author), Rutgers Robert Wood Johnson Med Sch, New Brunswick, NJ 08901 USA. EM krchhabra@gmail.com FU American Pediatric Society/Society for Pediatric Research FX Karan Chhabra received a research grant from the American Pediatric Society/Society for Pediatric Research to support his participation in this study. We thank Rie Maurer, MA for performing the statistical analysis for this study. NR 22 TC 2 Z9 2 U1 1 U2 2 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 NOV PY 2015 VL 79 IS 11 BP 1838 EP 1841 DI 10.1016/j.ijporl.2015.08.021 PG 4 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA CT8MC UT WOS:000363069700011 PM 26315929 ER PT J AU Dumit, NY Abboud, S Massouh, A Magilvy, JK AF Dumit, Nuhad Y. Abboud, Sarah Massouh, Angela Magilvy, Joan K. TI Role of the Lebanese family caregivers in cardiac self-care: acollective approach SO JOURNAL OF CLINICAL NURSING LA English DT Article DE collective care; emotional role; family caregiver's role; family obligation; informational role; instrumental role; interdependent self-care; self-care perception; supportive role ID HEART-FAILURE; SOCIAL SUPPORT; MYOCARDIAL-INFARCTION; DISEASE; PATIENT; HEALTH; GUIDELINE; ADHERENCE; LIFE AB Aims and objectivesThe purpose of this study was to explore perceptions of cardiac self-care among Lebanese family caregivers of cardiac patients. The specific aims were to describe the cultural context of cardiac care-giving in Lebanon and to explore the roles of family caregivers in enhancing self-care practices in patients with cardiac diseases. BackgroundThe role of family caregivers in Lebanon, a country in the Middle East, is assumed to extend beyond care-giving to making decisions on behalf of the patient and assuming responsibility for patient care. To date, there has been no study done to empirically validate this impression. DesignThe design of the study is qualitative descriptive that used semi-structured individual interviews with family caregivers of Lebanese cardiac patients. MethodThirteen family caregivers of cardiac patients were recruited from a referral medical centre in Lebanon. The participants were designated by their patients and interviewed in a place of their choice. ResultsOne overarching and three themes emerged from data analysis describing roles of family care givers in cardiac self-care. The overarching theme was: Family caregivers of Lebanese cardiac patients were unfamiliar with the term, concept and meaning of Self-Care. The moral and emotional duty to care for the family member stemmed from obligation and responsibility towards patients (theme I). Interdependent care (theme II) between cardiac patients and their families emerged as a significant cultural role. Family members play multiple supportive roles in care-giving namely emotional, informational and instrumental role (theme III). ConclusionIn this study, family caregiver role is shown to be based in the sense of obligation and duty towards the sick family member who collectively provide different types of supportive care. Relevance to clinical practiceNurses have to give significant importance to the family caregiver role as an integral part of any culturally sensitive patient/family intervention. C1 [Dumit, Nuhad Y.; Massouh, Angela] Amer Univ Beirut, Sch Nursing, Continuing Educ, Beirut, Lebanon. [Abboud, Sarah] Univ Penn, Sch Nursing, Ctr Global Womens Hlth, Philadelphia, PA 19104 USA. [Abboud, Sarah] Univ Penn, Sch Nursing, Ctr Hlth Equ Res, Philadelphia, PA 19104 USA. [Magilvy, Joan K.] Univ Colorado Denver, Coll Nursing, Aurora, CO USA. RP Dumit, NY (reprint author), Amer Univ Beirut, Sch Nursing, Continuing Educ, Riad El Solh 1107 2020, Beirut, Lebanon. EM ny00@aub.edu.lb FU NINR NIH HHS [T32 NR007100] NR 36 TC 1 Z9 1 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1067 EI 1365-2702 J9 J CLIN NURS JI J. Clin. Nurs. PD NOV PY 2015 VL 24 IS 21-22 BP 3318 EP 3326 DI 10.1111/jocn.12949 PG 9 WC Nursing SC Nursing GA CT6FF UT WOS:000362907300029 PM 26249817 ER PT J AU Staller, K Khalili, H Kuo, B AF Staller, Kyle Khalili, Hamed Kuo, Braden TI Constipation prophylaxis reduces length of stay in elderly hospitalized heart failure patients with home laxative use SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE bowel protocols; congestive heart failure; constipation; hospitalization; laxatives ID CRITICALLY-ILL PATIENTS; BURDEN; COMPLICATIONS; PREDICTORS; ADMISSION; HEALTH; TRENDS; RISK AB Background and AimElderly, hospitalized patients suffer disproportionately from constipation; however, little data suggest that constipation prophylaxis reduces length of stay (LOS). We performed a retrospective analysis of elderly patients admitted to our hospital with congestive heart failure (CHF) to determine the effects of constipation prophylaxis on LOS. MethodsPatients 65 years old admitted with the diagnosis of CHF in 2012 were evaluated for home and hospital laxative use on admission. Our primary outcome was LOS. We used linear regression modeling to independently evaluate the impact of constipation prophylaxis on LOS. ResultsAmong 618 patients who were eligible for our study, 201 (32.5%) were using laxatives at home, whereas 254 (41.1%) were started on a prophylactic laxative on admission. There was no significant difference in LOS between patients receiving prophylaxis versus those who did not (P=0.32). Patients with home laxative use had a 1 day longer LOS compared to those without laxative use (6 vs 5, P=0.03). Among patients with home laxative use, there were 2 days longer LOS in those who were not given constipation prophylaxis on admission (8 vs 6, P=0.002). After multivariate adjustment, failure to use constipation prophylaxis in patients with home laxative use was the only independent predictor of increased LOS (P=0.03). ConclusionsAmong elderly patients admitted for CHF exacerbations, failure to use constipation prophylaxis in patients with home laxative use is associated with a significantly longer LOS. Our data suggest that routine use of bowel prophylaxis for elderly CHF patients with preexisting constipation may reduce LOS. C1 [Staller, Kyle; Khalili, Hamed; Kuo, Braden] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Staller, Kyle; Khalili, Hamed; Kuo, Braden] Harvard Univ, Sch Med, Boston, MA USA. RP Staller, K (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. EM kstaller@mgh.harvard.edu OI Staller, Kyle/0000-0003-4925-4290 NR 31 TC 4 Z9 4 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0815-9319 EI 1440-1746 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD NOV PY 2015 VL 30 IS 11 BP 1596 EP 1602 DI 10.1111/jgh.13011 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CT6DG UT WOS:000362901300011 PM 25969162 ER PT J AU Edwards, RA Colchamiro, R Tolan, E Browne, S Foley, M Jenkins, L Mainello, K Vallu, R Hanley, LE Boisvert, ME Forgit, J Ghiringhelli, K Nordstrom, C AF Edwards, Roger A. Colchamiro, Rachel Tolan, Ellen Browne, Susan Foley, Mary Jenkins, Lucia Mainello, Kristen Vallu, Rohith Hanley, Lauren E. Boisvert, Mary Ellen Forgit, Julie Ghiringhelli, Kara Nordstrom, Christina TI Online Continuing Education for Expanding Clinicians' Roles in Breastfeeding Support SO JOURNAL OF HUMAN LACTATION LA English DT Article DE breastfeeding; continuing education; online tutorial AB Lack of health professional support is an important variable affecting mothers' achievement of breastfeeding goals. Online continuing education is a recognized pathway for disseminating content for improving clinicians' knowledge and supporting efforts to change practices. At the time we developed our project, free, accredited continuing education for physicians related to breastfeeding management that could be easily accessed using portable devices (via tablets/smartphones) was not available. Such resources were in demand, especially for facilities pursuing designation through the Baby-Friendly Hospital Initiative. We assembled a government, academic, health care provider, and professional society partnership to create such a tutorial that would address the diverse content needed for supporting breastfeeding mothers postdischarge in the United States. Our 1.5-hour-long continuing medical and nursing education was completed by 1606 clinicians (1172 nurses [73%] and 434 physicians [27%]) within 1 year. More than 90% of nurses and over 98% of physicians said the tutorial achieved its 7 learning objectives related to breastfeeding physiology, broader factors in infant feeding decisions and practices, the American Academy of Pediatrics' policy statement, and breastfeeding management/troubleshooting. Feedback received from the tutorial led to the creation of a second tutorial consisting of another 1.5 hours of continuing medical and nursing education related to breast examination and assessment prior to delivery, provision of anticipatory guidance to pregnant women interested in breastfeeding, maternity care practices that influence breastfeeding outcomes, breastfeeding preterm infants, breastfeeding's role in helping address disparities, and dispelling common myths. The tutorials contribute to achievement of 8 Healthy People 2020 Maternal, Infant and Child Health objectives. C1 [Edwards, Roger A.; Colchamiro, Rachel; Tolan, Ellen; Forgit, Julie; Ghiringhelli, Kara; Nordstrom, Christina] Massachusetts Dept Publ Hlth, Boston, MA 02108 USA. [Edwards, Roger A.; Mainello, Kristen] Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Browne, Susan] Amer Acad Pediat, Waltham, MA USA. [Foley, Mary; Jenkins, Lucia] Hallmark Hlth Syst, Melrose Wakefield Hosp, Melrose, MA USA. [Vallu, Rohith] Northeastern Univ, Coll Comp & Informat Sci, Boston, MA 02115 USA. [Hanley, Lauren E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Boisvert, Mary Ellen] Beth Israel Deaconess Plymouth, Plymouth, MA USA. RP Nordstrom, C (reprint author), Massachusetts Dept Publ Hlth, Div Prevent & Wellness, 250 Washington St, Boston, MA 02108 USA. EM christina.nordstrom@state.ma.us RI 杜, 美晨/S-4063-2016 OI 杜, 美晨/0000-0002-1562-1155 FU Centers for Disease Control and Prevention (CDC) [3U58DP001400-05W1]; Centers for Disease Control and Prevention [CDC-RFA-DP13-1305] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for the first online tutorial has been received from the Centers for Disease Control and Prevention (CDC) on the grant that funded the work (CDC DNPAO Supplemental Funding to Support Breastfeeding Promotion and Support Activities, Award 3U58DP001400-05W1). Funding for the second online tutorial has been received from Cooperative Agreement CDC-RFA-DP13-1305, "State Public Health Actions to Prevent and Control Diabetes, Heart Disease, Obesity and Associated Risk Factors and Promote School Health," from the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily reflect the official views of the CDC, the Department of Health and Human Services, or the federal government. NR 11 TC 0 Z9 0 U1 1 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0890-3344 EI 1552-5732 J9 J HUM LACT JI J. Hum. Lact. PD NOV PY 2015 VL 31 IS 4 SI SI BP 582 EP 586 DI 10.1177/0890334415585977 PG 5 WC Nursing; Obstetrics & Gynecology; Pediatrics SC Nursing; Obstetrics & Gynecology; Pediatrics GA CT3DD UT WOS:000362686100003 PM 26013061 ER PT J AU Zhang, R Borges, CM Fan, MY Harris, JE Turka, LA AF Zhang, Ruan Borges, Christopher M. Fan, Martin Y. Harris, John E. Turka, Laurence A. TI Requirement for CD28 in Effector Regulatory T Cell Differentiation, CCR6 Induction, and Skin Homing SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HOMEOSTASIS; SUBSET; CD4(+)CD25(+); EXPRESSION; STABILITY; PHENOTYPE; VIVO AB The skin, similar to most nonlymphoid tissues, contains substantial numbers of T cells. Among these, memory T cells serve a sentinel role to protect against pathogens, and regulatory T cells (Tregs) terminate immune responses as a check against unrestrained inflammation. Previously, we created conditional knockout mice with Treg-specific deletion of CD28. Although these mice have normal numbers of Tregs, these cells have lower levels of CTLA-4, PD-1, and CCR6, and the animals develop systemic autoimmunity characterized by prominent skin inflammation. In this study, we have performed a detailed analysis of the skin disease in these mice. Our data show that Treg-expressed CD28 is required for optimal maturation of CD44(lo)CD62L(hi) central Tregs into CD44(hi)CD62L(lo) effector Tregs (eTregs), as well as induction of CCR6 among the cells that do become eTregs. Although CD28-deficient Tregs are able to regulate inflammation normally when injected directly into the skin, they fail to home properly to inflamed skin. Collectively, these results suggest a key role for CD28 costimulation in promoting a central Treg to eTreg transition with appropriate upregulation of chemokine receptors such as CCR6 that are required for tissue homing. C1 [Zhang, Ruan; Borges, Christopher M.; Fan, Martin Y.; Turka, Laurence A.] Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA 02129 USA. [Borges, Christopher M.; Fan, Martin Y.; Turka, Laurence A.] Harvard Univ, Sch Med, Div Med Sci, Boston, MA 02115 USA. [Harris, John E.] Univ Massachusetts, Sch Med, Dept Med, Div Dermatol, Worcester, MA 01605 USA. RP Turka, LA (reprint author), Massachusetts Gen Hosp East, Ctr Transplantat Sci, Bldg 149-5101,13th St, Boston, MA 02129 USA. EM lturka@partners.org FU National Institutes of Health [AI-037691, T32 AI007529]; Harvard University FX This work was supported by National Institutes of Health Grants AI-037691 (to L.A.T.) and T32 AI007529 (to C.M.B. and M.Y.F.) and by the Herchel Smith Graduate Fellowship from Harvard University (to M.Y.F.). NR 24 TC 4 Z9 4 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2015 VL 195 IS 9 BP 4154 EP 4161 DI 10.4049/jimmunol.1500945 PG 8 WC Immunology SC Immunology GA CT7BQ UT WOS:000362968500013 PM 26408668 ER PT J AU Kuhlthau, K Luff, D Delahaye, J Wong, A Yock, T Huang, M Park, ER AF Kuhlthau, Karen Luff, Donna Delahaye, Jennifer Wong, Alicia Yock, Torunn Huang, Mary Park, Elyse R. TI Health-Related Quality of Life of Adolescent and Young Adult Survivors of Central Nervous System Tumors: Identifying Domains From a Survivor Perspective SO JOURNAL OF PEDIATRIC ONCOLOGY NURSING LA English DT Article DE adolescent and young adult; survivor; central nervous system tumor; health-related quality of life ID CHILDHOOD-CANCER SURVIVOR; BRAIN-TUMORS; FOLLOW-UP; RADIOTHERAPY; MEDULLOBLASTOMA; MALIGNANCIES; OUTCOMES AB This article uses qualitative methods to describe the domains of health-related quality of life (HRQoL) that adolescent and young adult (AYA) survivors of central nervous system (CNS) tumors identify as important. Survivors clearly attributed aspects of their current HRQoL to their disease or its treatment. We identified 7 key domains of AYA CNS tumor survivorship: physical health, social well-being, mental health, cognitive functioning, health behaviors, sexual and reproductive health, and support systems. Although most aspects of HRQoL that survivors discussed represented new challenges, there were several areas where survivors pointed out positive outcomes. There is a need for a HRQoL tool designed for this population of survivors, given their unique treatment and survivorship experience. Aspects of HRQoL related to cognition, sexual and reproductive health, health behaviors, and support systems are not typically included in generic HRQoL tools but should be assessed for this population. Developing HRQoL measurement instruments that capture the most significant aspects of HRQoL will improve the ability to track HRQoL in AYA CNS tumor survivors and in the long-term management of common sequelae from CNS tumors and their treatments. C1 [Kuhlthau, Karen; Delahaye, Jennifer; Wong, Alicia; Yock, Torunn; Huang, Mary; Park, Elyse R.] Massachusetts Gen Hosp, Boston, MA 01950 USA. [Kuhlthau, Karen; Yock, Torunn; Huang, Mary; Park, Elyse R.] Harvard Univ, Sch Med, Boston, MA USA. [Luff, Donna] Boston Childrens Hosp, Boston, MA USA. [Wong, Alicia] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Kuhlthau, K (reprint author), Massachusetts Gen Hosp, MassGen Hosp Children, Ctr Child & Adolescent Hlth Res & Policy, 100 Cambridge St,15th Floor, Boston, MA 01950 USA. EM kkuhlthau@mgh.harvard.edu FU Lance Armstrong Foundation FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by a grant from the Lance Armstrong Foundation. NR 18 TC 3 Z9 3 U1 3 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1043-4542 EI 1532-8457 J9 J PEDIATR ONCOL NURS JI J. Pediatr. Oncol. Nurs. PD NOV-DEC PY 2015 VL 32 IS 6 BP 385 EP 393 DI 10.1177/1043454214563752 PG 9 WC Oncology; Nursing SC Oncology; Nursing GA CT7JV UT WOS:000362991900004 PM 25616371 ER PT J AU Williams, PD Piamjariyakul, U Shanberg, R Williams, AR AF Williams, Phoebe D. Piamjariyakul, Ubolrat Shanberg, Rachel Williams, Arthur R. TI Monitoring and Alleviation of Symptom Occurrence and Severity Among Thai Children and Adolescents During Cancer Treatments SO JOURNAL OF PEDIATRIC ONCOLOGY NURSING LA English DT Article DE pediatric cancer treatments; symptom monitoring and alleviation; Therapy-Related Symptom Checklist for Children; TRSC-C; parental care; complementary care; culture ID THERAPY-RELATED SYMPTOMS; QUALITY-OF-LIFE; PEDIATRIC ONCOLOGY PATIENTS; SELF-CARE; CHRONIC ILLNESS; SIBLINGS; SCALE; INTERVENTION; PERFORMANCE; DISABILITY AB Background: Symptom monitoring and alleviation are important during pediatric cancer treatments. Aims: To examine the use of the Therapy-Related Symptom Checklist for Children (TRSC-C; Thai version) for reported occurrence, severity, and management of treatment-related symptoms within a cohort of Thai pediatric oncology patients/parents Method: Cross-sectional study; convenience sample: 100 parents of 71 male children/29 females, 63% with leukemia, 37%, other diagnoses; age-groups: <5 years, n = 33; 5 to 11 years, n = 44; 12 to 17 years, n = 25. Parents reported children's symptom occurrence/severity on the TRSC-C; and complementary care methods on the Symptom Alleviation: Self-Care Methods and their symptom alleviation methods. All tools had good psychometric properties. Results: 18 symptoms on the 30-item TRSC-C occurred in 42% to 95% of children. Mean severity of symptoms was between 1.0 (a bit) and 2.0 (quite a bit); 5-month to 11-year-old children had higher (worse) TRSC-C total scores. Complementary care was used and reported. Conclusions: Monitoring of multiple symptoms with the TRSC-C and parental symptom alleviation helped children. Clinical Implications: Thai parents/patients need and accept assistance in monitoring/managing side effects of pediatric cancer therapy. C1 [Williams, Phoebe D.; Piamjariyakul, Ubolrat] Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. [Shanberg, Rachel] Univ Chicago, Comer Childrens Hosp, Chicago, IL 60637 USA. [Williams, Arthur R.] James A Haley Vet Affairs Med Ctr, US Dept Vet Affairs, CINDRR, Tampa, FL USA. [Williams, Arthur R.] George Mason Univ, Hlth Care Res & Policy, Hlth Adm & Policy, Washington, DC USA. RP Williams, PD (reprint author), Univ Kansas, Med Ctr, Sch Nursing, 3905 Rainbow Blvd,Mail Stop 4043, Kansas City, KS 66160 USA. EM pwilliam@kumc.edu NR 53 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1043-4542 EI 1532-8457 J9 J PEDIATR ONCOL NURS JI J. Pediatr. Oncol. Nurs. PD NOV-DEC PY 2015 VL 32 IS 6 BP 417 EP 428 DI 10.1177/1043454214563754 PG 12 WC Oncology; Nursing SC Oncology; Nursing GA CT7JV UT WOS:000362991900008 PM 25616370 ER PT J AU Bosma, NH Teunis, T Eberlin, KR Jupiter, JB AF Bosma, Niels H. Teunis, Teun Eberlin, Kyle R. Jupiter, Jesse B. TI Lower Limb Replantation after Guillotine Amputation: A 29-Year Follow-Up SO JOURNAL OF RECONSTRUCTIVE MICROSURGERY LA English DT Letter ID LOWER-EXTREMITY REPLANTATION; LEG C1 [Bosma, Niels H.; Teunis, Teun; Jupiter, Jesse B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Eberlin, Kyle R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg, Boston, MA 02114 USA. RP Jupiter, JB (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. EM jjupiter1@mgh.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0743-684X EI 1098-8947 J9 J RECONSTR MICROSURG JI J. Reconstr. Microsurg. PD NOV PY 2015 VL 31 IS 9 BP 681 EP 683 DI 10.1055/s-0035-1558429 PG 3 WC Surgery SC Surgery GA CT6ML UT WOS:000362927000010 PM 26382871 ER PT J AU Smith, MR Rathkopf, DE Mulders, PFA Carles, J Van Poppel, H Li, JH Kheoh, T Griffin, TW Molina, A Ryan, CJ AF Smith, Matthew R. Rathkopf, Dana E. Mulders, Peter F. A. Carles, Joan Van Poppel, Hendrik Li, Jinhui Kheoh, Thian Griffin, Thomas W. Molina, Arturo Ryan, Charles J. TI Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naive Patients with Metastatic Castration Resistant Prostate Cancer SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; aged; 17-(3-pyridyl)-5; 16-androstadien-3beta-acetate; drug tolerance; treatment outcome ID DOCETAXEL-BASED CHEMOTHERAPY; WORKING GROUP; RECOMMENDATIONS; SURVIVAL; MEN; AGE AB Purpose: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of abiraterone acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysis (55% of total overall survival events) for the COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer) trial. Materials and Methods: Patients were stratified and randomized 1: 1 to abiraterone acetate 1,000 mg plus prednisone/prednisolone 5 mg twice daily (abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg twice daily (prednisone alone). Co-primary end points were radiographic progression-free and overall survival. Median time to event and HR were estimated using the Kaplan-Meier method and a Cox model, respectively. Results: A total of 350 elderly patients treated with abiraterone-prednisone had significant improvements in overall and radiographic progression-free survival vs those with prednisone alone (HR 0.71, 95% CI 0.53-0.96 vs HR 0.63, 95% CI 0.48-0.83), similar to 738 younger patients (HR 0.81, 95% CI 0.63-1.03 vs HR 0.49, 95% CI 0.40-0.59). All secondary end points favored the abiraterone-prednisone arm for both age subgroups. Specific adverse events with abiraterone-prednisone were similar between the age subgroups. Elderly patients in both treatment arms had higher rates of fluid retention and cardiac disorders than younger patients, although rates of dose reduction or treatment interruptions due to adverse events were low in both age subgroups. Conclusions: Abiraterone acetate demonstrated clinical benefit and was well tolerated in elderly and younger men with chemotherapy naive, metastatic castration resistant prostate cancer. Thus, findings support it as a treatment option for elderly patients who may not tolerate other therapies with greater toxicity. C1 [Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Dept Genitourinary Oncol, Boston, MA USA. [Rathkopf, Dana E.] Mem Sloan Kettering Canc Ctr, Dept Oncol & Internal Med, New York, NY 10021 USA. [Mulders, Peter F. A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Carles, Joan] Vall dHebron Univ Hosp, Dept Oncol, Barcelona, Spain. [Van Poppel, Hendrik] Katholieke Univ Leuven, Dept Urol, Univ Hosp, Leuven, Belgium. [Li, Jinhui] Janssen Res & Dev, Dept Biostat Oncol, Raritan, NJ USA. [Kheoh, Thian] Janssen Res & Dev, Dept Biostat & Programming, San Diego, CA USA. [Griffin, Thomas W.] Janssen Res & Dev, Dept WC Clin Oncol, Los Angeles, CA USA. [Molina, Arturo] Janssen Res & Dev, Dept Oncol, Los Angeles, CA USA. [Ryan, Charles J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. RP Smith, MR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Canc Yawkey 7030,55 Fruit St, Boston, MA 02114 USA. EM smith.matthew@mgh.harvard.edu OI Rathkopf, Dana/0000-0002-4503-7582 FU Janssen Research & Development unit of Cougar Biotechnology FX Supported by Janssen Research & Development (formerly Ortho Biotech Oncology Research & Development) unit of Cougar Biotechnology. NR 17 TC 11 Z9 11 U1 0 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 NOV PY 2015 VL 194 IS 5 BP 1277 EP 1284 DI 10.1016/j.juro.2015.07.004 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CT5UF UT WOS:000362875800030 PM 26151676 ER PT J AU Zhang, R Sutcliffe, S Giovannucci, E Willett, WC Platz, EA Rosner, BA Dimitrakoff, JD Wu, K AF Zhang, Ran Sutcliffe, Siobhan Giovannucci, Edward Willett, Walter C. Platz, Elizabeth A. Rosner, Bernard A. Dimitrakoff, Jordan D. Wu, Kana TI Lifestyle and Risk of Chronic Prostatitis/Chronic Pelvic Pain Syndrome in a Cohort of United States Male Health Professionals SO JOURNAL OF UROLOGY LA English DT Editorial Material DE prostatitis; pain; obesity; smoking; hypertension ID BODY-MASS INDEX; SYMPTOM INDEX; CLINICAL CHARACTERISTICS; MEN; PREVALENCE; ASSOCIATION; COMMUNITY; PROSTATE AB Purpose: Although chronic prostatitis/chronic pelvic pain syndrome is a prevalent urological disorder among men of all ages, its etiology remains unknown. Only a few previous studies have examined associations between lifestyle factors and chronic prostatitis/chronic pelvic pain syndrome, of which most were limited by the cross-sectional study design and lack of control for possible confounders. To address these limitations we performed a cohort study of major lifestyle factors (obesity, smoking and hypertension) and chronic prostatitis/chronic pelvic pain syndrome risk in the HPFS (Health Professionals Follow-up Study), a large ongoing cohort of United States based male health professionals. Materials and Methods: The HPFS includes 51,529 men who were 40 to 75 years old at baseline in 1986. At enrollment and every 2 years thereafter participants have completed questionnaires on lifestyle and health conditions. In 2008 participants completed an additional set of questions on recent chronic prostatitis/chronic pelvic pain syndrome pain symptoms modified from the NIH (National Institutes of Health)-CPSI (Chronic Prostatitis Symptom Index) as well as questions on approximate date of symptom onset. The 653 participants with NIH-CPSI pain scores 8 or greater who first experienced symptoms after 1986 were considered incident chronic prostatitis/chronic pelvic pain syndrome cases and the 19,138 who completed chronic prostatitis/chronic pelvic pain syndrome questions but did not report chronic prostatitis/chronic pelvic pain syndrome related pain were considered noncases. Results: No associations were observed for baseline body mass index, waist circumference, waist-to-hip ratio, cigarette smoking and hypertension with chronic prostatitis/chronic pelvic pain syndrome risk (each OR <= 1.34). Conclusions: In this large cohort study none of the lifestyle factors examined was associated with chronic prostatitis/chronic pelvic pain syndrome risk. As the etiology of chronic prostatitis/chronic pelvic pain syndrome remains unknown, additional prospective studies are needed to elucidate modifiable risk factors for this common condition. C1 [Zhang, Ran; Giovannucci, Edward; Willett, Walter C.; Wu, Kana] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Zhang, Ran; Giovannucci, Edward; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rosner, Bernard A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Giovannucci, Edward; Willett, Walter C.; Rosner, Bernard A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Giovannucci, Edward; Willett, Walter C.; Rosner, Bernard A.; Dimitrakoff, Jordan D.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Dimitrakoff, Jordan D.] Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, Boston, MA 02114 USA. [Sutcliffe, Siobhan] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA. [Sutcliffe, Siobhan] Washington Univ, Sch Med, Dept Surg, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Platz, Elizabeth A.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol,Sch Med, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD USA. RP Wu, K (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave,Bldg 2,Room 333, Boston, MA 02115 USA. EM kwu@hsph.harvard.edu OI Sutcliffe, Siobhan/0000-0002-4613-8107 FU NCI NIH HHS [P01 CA055075, R01 CA133891, U19 CA055075, UM1 CA167552] NR 29 TC 2 Z9 4 U1 1 U2 4 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 NOV PY 2015 VL 194 IS 5 BP 1295 EP 1300 DI 10.1016/j.juro.2015.05.100 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA CT5UF UT WOS:000362875800037 PM 26070893 ER PT J AU Mavros, Y O'neill, E Connerty, M Bean, JF Broe, K Kiel, DP Maclean, D Taylor, A Fielding, RA Singh, MAF AF Mavros, Yorgi O'neill, Evelyn Connerty, Maureen Bean, Jonathan F. Broe, Kerry Kiel, Douglas P. Maclean, David Taylor, Ann Fielding, Roger A. Singh, Maria A. Fiatarone TI \Oxandrolone Augmentation of Resistance Training in Older Women: A Randomized Trial SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE SARCOPENIA; FRAILTY; OXANDROLONE; RESISTANCE TRAINING ID PHYSICAL-ACTIVITY SCALE; BODY-FAT DISTRIBUTION; SKELETAL-MUSCLE; ANDROGEN THERAPY; UNITED-STATES; FRAIL ELDERS; WEIGHT-LOSS; SARCOPENIA; EXERCISE; TISSUE AB Introduction: Sarcopenia is disproportionately present in older women with disability, and optimum treatment is not clear. We conducted a double-blind, randomized, placebo-controlled trial to determine whether oxandrolone administration in elderly women improves body composition or physical function beyond that which occurs in response to progressive resistance training ( PRT). Methods: Twenty-nine sedentary women ( age 74.9 +/- 6.8 yr; 5.9 +/- 2.8 medications per day) were randomized to receive high-intensity PRT ( three times a week for 12 wk) combined with either oxandrolone ( 10 mg.d(-1)) or an identical placebo. Peak strength was assessed for leg press, chest press, triceps, knee extension, and knee flexion. Power was assessed for leg press and chest press. Physical function measures included static and dynamic balance, chair rise, stair climb, gait speed, and 6-min walk test. Body composition was assessed using dual energy x-ray absorptiometry. Results: Oxandrolone treatment augmented increases in lean tissue for the whole body ( 2.6 kg; 95% confidence interval ( CI), 1.0- 4.2 kg; P = 0.003), arms ( 0.3 kg; 95% CI, 0.1-0.5 kg; P = 0.001), legs ( 0.8 kg; 95% CI, 0.1- 1.4 kg; P = 0.018), and trunk ( 1.4 kg; 95% CI, 0.4- 2.3 kg; P = 0.004). Oxandrolone also augmented loss of fat tissue of the whole body ( -1 kg; 95% CI, -1.6 to -0.4; P = 0.002), arms ( -0.2 kg; 95% CI, -0.5 to -0.02 kg; P = 0.032), legs ( -0.4 kg; 95% CI, -0.6 to -0.1; P = 0.009), and tended to reduce trunk fat ( -0.4 kg; 95% CI, -0.9 to 0.04; P = 0.07). Improvements in muscle strength and power, chair stand, and dynamic balance were all significant over time ( P < 0.05) but not different between groups ( P 9 0.05). Conclusions: Oxandrolone improves body composition adaptations to PRT in older women over 12 wk without augmenting muscle function or functional performance beyond that of PRT alone. C1 [Mavros, Yorgi; Singh, Maria A. Fiatarone] Univ Sydney, Exercise Hlth & Performance Fac Res Grp, Lidcombe, NSW 2141, Australia. [O'neill, Evelyn; Connerty, Maureen; Broe, Kerry; Kiel, Douglas P.; Singh, Maria A. Fiatarone] Hebrew SeniorLife, Inst Aging Res, Boston, MA USA. [Bean, Jonathan F.] Spaulding Rehabil Hosp, Boston, MA USA. [Bean, Jonathan F.] Harvard Univ, Dept Phys Med & Rehabil, Sch Med, Boston, MA USA. [Bean, Jonathan F.] Boston VA Healthcare Syst, New England GRECC, Boston, MA USA. [Kiel, Douglas P.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA USA. [Maclean, David] Oncol Clin Res, Boston, MA USA. [Taylor, Ann] Novartis Inst BioMed Res, Cambridge, MA USA. [Fielding, Roger A.; Singh, Maria A. Fiatarone] Tufts Univ, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Nutr Exercise Physiol & Sarcopenia Lab, Boston, MA 02111 USA. [Singh, Maria A. Fiatarone] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. RP Mavros, Y (reprint author), Univ Sydney, Fac Hlth Sci, Exercise Hlth & Performance Fac Res Grp, Bldg K,75 East St, Lidcombe, NSW 2141, Australia. EM yorgi.mavros@sydney.edu.au RI Bean, Jonathan/F-5798-2017; OI Bean, Jonathan/0000-0001-8385-8210; Kiel, Douglas/0000-0001-8474-0310; Mavros, Yorgi/0000-0002-2588-0425 FU Pfizer, Inc. [A9001008]; Pfizer Pharmaceuticals [A9001008]; Eli Lilly; Amgen; Merck Sharp; Dohme; Policy Analysis, Inc.; U.S. Department of Agriculture [58-1950-0-014] FX This study was funded by a grant from Pfizer, Inc. (Protocol A9001008).; The study was sponsored by Pfizer Pharmaceuticals, registered as protocol number A9001008. The study was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12615000191594).; Ann Taylor was an employee of Pfizer, Inc., and is currently employed at Novartis Institutes for BioMedical Research. David MacLean was an employee of Pfizer, Inc. at the time of the trial. Douglas Kiel is a recipient of a grant from Eli Lilly, Amgen, Merck Sharp, and Dohme and Policy Analysis, Inc., and is also on the scientific advisory board for Novartis Pharmaceuticals, Merck Sharpe and Dohme, and Amgen. There were no other conflicts of interest to declare. This material is based upon work supported by the U.S. Department of Agriculture under agreement No. 58-1950-0-014. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the U.S. Department of Agriculture. NR 42 TC 3 Z9 3 U1 6 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD NOV PY 2015 VL 47 IS 11 BP 2257 EP 2267 DI 10.1249/MSS.0000000000000690 PG 11 WC Sport Sciences SC Sport Sciences GA CT6RU UT WOS:000362940900002 PM 25899102 ER PT J AU Chen, H Hey, J Chen, K AF Chen, Hua Hey, Jody Chen, Kun TI Inferring Very Recent Population Growth Rate from Population-Scale Sequencing Data: Using a Large-Sample Coalescent Estimator SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE genetics diversity; population growth rate; large-sample sequencing; coalescent ID ALLELE-FREQUENCY-SPECTRUM; SINGLE-NUCLEOTIDE POLYMORPHISMS; DEMOGRAPHIC HISTORY; SEGREGATING SITES; GENE GENEALOGIES; INFERENCE; VARIANTS; REVEALS; MODEL; SIZE AB Large-sample or population-level sequencing data provide unprecedented opportunities for inferring detailed population histories, especially recent demographic histories. On the other hand, it challenges most existing population genetic methods: Simulation-based approaches require intensive computation, and analytical approaches are often numerically intractable when the sample size is large. We propose a computationally efficient method for simultaneous estimation of population size, the rate, and onset time of population growth in the very recent history, using the pattern of the total number of segregating sites as a function of sample size. Coalescent simulation shows that it can accurately and efficiently estimate the parameters of recent population growth from large-scale data. This approach has the flexibility to model population history with multiple growth stages or other epochs, and it is robust when the sample size is very large or at the population scale, for which the Kingman's coalescent assumption is not valid. This approach is applied to recently published data and estimates the recent population growth rate in the European population to be 1.49% with the onset time 7.26 ka, and the rate in the African population to be 0.735% with the onset time 10.01 ka. C1 [Chen, Hua] Chinese Acad Sci, Beijing Inst Genom, Ctr Computat Genom, Beijing, Peoples R China. [Hey, Jody] Temple Univ, Ctr Computat Genet & Genom, Philadelphia, PA 19122 USA. [Chen, Kun] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Chen, H (reprint author), Chinese Acad Sci, Beijing Inst Genom, Ctr Computat Genom, Beijing, Peoples R China. EM chenh@big.ac.cn OI Chen, Hua/0000-0002-9829-6561 FU Chinese Academy of Sciences; National Science Foundation [CNS-09-58854]; NIH [R01-GM078204] FX The authors are grateful to Dr Joshua Akey, Dr Anand Bhaskar, Dr Heng Li, and Dr John Novembre for guidance in data analysis and simulations, to Dr Bing Su for insightful comments and hosting the visit to KIZ, to the editor and the anonymous reviewers for their valuable comments. This research was supported in part by the Hundred Talents Program of the Chinese Academy of Sciences (H.C.), the National Science Foundation through major research instrumentation grant number CNS-09-58854, and an NIH grant R01-GM078204 (J.H.). NR 51 TC 2 Z9 2 U1 2 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD NOV PY 2015 VL 32 IS 11 BP 2996 EP 3011 DI 10.1093/molbev/msv158 PG 16 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA CT7YZ UT WOS:000363033100016 PM 26187437 ER PT J AU Chokshi, RH Larsen, AT Bhayana, B Cotten, JF AF Chokshi, Rikki H. Larsen, Aaron T. Bhayana, Brijesh Cotten, Joseph F. TI Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore SO MOLECULAR PHARMACOLOGY LA English DT Article ID OBSTRUCTIVE SLEEP-APNEA; CRYSTAL-STRUCTURE; K+-CHANNEL; GENERAL-ANESTHETICS; ATRIAL-FIBRILLATION; IN-VITRO; TANDEM; KCNK9; MICE; CONTRIBUTE AB Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899 (2 ''-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide), and doxapram inhibit TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore (K2P) potassium channel function and stimulate breathing. To better understand the molecular mechanism(s) of action of these drugs, we undertook studies to identify amino acid residues in the TASK-3 protein that mediate this inhibition. Guided by homology modeling and molecular docking, we hypothesized that PKTHPP and A1899 bind in the TASK-3 intracellular pore. To test our hypothesis, we mutated each residue in or near the predicted PKTHPP and A1899 binding site (residues 118-128 and 228-248), individually, to a negatively charged aspartate. We quantified each mutation's effect on TASK-3 potassium channel concentration response to PKTHPP. Studies were conducted on TASK-3 transiently expressed in Fischer rat thyroid epithelial monolayers; channel function was measured in an Ussing chamber. TASK-3 pore mutations at residues 122 (L122D, E, or K) and 236 (G236D) caused the IC50 of PKTHPP to increase more than 1000-fold. TASK-3 mutants L122D, G236D, L239D, and V242D were resistant to block by PKTHPP, A1899, and doxapram. Our data are consistent with a model in which breathing stimulant compounds PKTHPP, A1899, and doxapram inhibit TASK-3 function by binding at a common site within the channel intracellular pore region, although binding outside the channel pore cannot yet be excluded. C1 [Chokshi, Rikki H.; Cotten, Joseph F.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Larsen, Aaron T.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Larsen, Aaron T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Bhayana, Brijesh] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Cotten, JF (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM jcotten@mgh.harvard.edu FU Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine; National Institutes of Health [HL117871]; Simons Collaboration on the Origins of Life; Fonds de recherche du Quebec, Nature et technologies; Autonomous Province of Trento FX This research was supported by the Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine; the National Institutes of Health [Grant HL117871]; the Simons Collaboration on the Origins of Life; the Fonds de recherche du Quebec, Nature et technologies; and the Autonomous Province of Trento. NR 56 TC 2 Z9 2 U1 2 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD NOV PY 2015 VL 88 IS 5 BP 926 EP 934 DI 10.1124/mol.115.100107 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CT8AO UT WOS:000363037400009 PM 26268529 ER PT J AU Fryer, SL Roach, BJ Ford, JM Turner, JA van Erp, TGM Voyvodic, J Preda, A Belger, A Bustillo, J O'Leary, D Mueller, BA Lim, KO McEwen, SC Calhoun, VD Diaz, M Glover, G Greve, D Wible, CG Vaidya, J Potkin, SG Mathalon, DH AF Fryer, Susanna L. Roach, Brian J. Ford, Judith M. Turner, Jessica A. van Erp, Theo G. M. Voyvodic, James Preda, Adrian Belger, Aysenil Bustillo, Juan O'Leary, Daniel Mueller, Bryon A. Lim, Kelvin O. McEwen, Sarah C. Calhoun, Vince D. Diaz, Michelle Glover, Gary Greve, Douglas Wible, Cynthia G. Vaidya, Jatin Potkin, Steven G. Mathalon, Daniel H. TI Relating Intrinsic Low-Frequency BOLD Cortical Oscillations to Cognition in Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID RESTING-STATE FMRI; 1ST-EPISODE SCHIZOPHRENIA; FUNCTIONAL CONNECTIVITY; DEFAULT NETWORK; TREATMENT-NAIVE; WORKING-MEMORY; BRAIN NETWORKS; FLUCTUATIONS; AMPLITUDE; CORTEX AB The amplitude of low-frequency fluctuations (ALFF) in the blood oxygenation level-dependent (BOLD) signal during resting-state fMRI reflects the magnitude of local low-frequency BOLD oscillations, rather than interregional connectivity. ALFF is of interest to studies of cognition because fluctuations in spontaneous intrinsic brain activity relate to, and possibly even constrain, task-evoked brain responses in healthy people. Lower ALFF has been reported in schizophrenia, but the cognitive correlates of these reductions remain unknown. Here, we assess relationships between ALFF and attention and working memory in order to establish the functional relevance of intrinsic BOLD oscillatory power alterations with respect to specific cognitive impairments in schizophrenia. As part of the multisite FBIRN study, resting-state fMRI data were collected from schizophrenia subjects (SZ; n=168) and healthy controls (HC; n=166). Voxelwise fractional ALFF (fALFF), a normalized ALFF measure, was regressed on neuropsychological measures of sustained attention and working memory in SZ and HC to identify regions showing either common slopes across groups or slope differences between groups (all findings P<0.01 height, P<0.05 family-wise error cluster corrected). Poorer sustained attention was associated with smaller fALFF in the left superior frontal cortex and bilateral temporoparietal junction in both groups, with additional relationships in bilateral posterior parietal, posterior cingulate, dorsal anterior cingulate (ACC), and right dorsolateral prefrontal cortex (DLPFC) evident only in SZ. Poorer working memory was associated with smaller fALFF in bilateral ACC/mPFC, DLPFC, and posterior parietal cortex in both groups. Our findings indicate that smaller amplitudes of low-frequency BOLD oscillations during rest, measured by fALFF, were significantly associated with poorer cognitive performance, sometimes similarly in both groups and sometimes only in SZ, in regions known to subserve sustained attention and working memory. Taken together, these data suggest that the magnitude of resting-state BOLD oscillations shows promise as a biomarker of cognitive function in health and disease. C1 [Fryer, Susanna L.; Ford, Judith M.; Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Fryer, Susanna L.; Roach, Brian J.; Ford, Judith M.; Mathalon, Daniel H.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Turner, Jessica A.; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [van Erp, Theo G. M.; Preda, Adrian; Potkin, Steven G.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Voyvodic, James; Diaz, Michelle] Duke Univ, Dept Psychiat, Raleigh, NC USA. [Belger, Aysenil] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Bustillo, Juan; Calhoun, Vince D.] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. [O'Leary, Daniel; Vaidya, Jatin] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Mueller, Bryon A.; Lim, Kelvin O.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [McEwen, Sarah C.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Glover, Gary] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Greve, Douglas] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wible, Cynthia G.] Harvard Univ, Dept Psychiat, Boston, MA 02115 USA. [Wible, Cynthia G.] VA Boston Healthcare Syst, Brockton, MA USA. RP Mathalon, DH (reprint author), Univ Calif San Francisco, Dept Psychiat, 4150 Clement St, San Francisco, CA 94121 USA. EM daniel.mathalon@ucsf.edu RI Preda, Adrian /K-8889-2013 OI Preda, Adrian /0000-0003-3373-2438 FU CSRD VA [IK2 CX001028]; NCATS NIH HHS [UL1 TR001449]; NCRR NIH HHS [U24 RR021992]; NIMH NIH HHS [K01 MH099431] NR 45 TC 7 Z9 7 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2015 VL 40 IS 12 BP 2705 EP 2714 DI 10.1038/npp.2015.119 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5GK UT WOS:000362836700006 PM 25944410 ER PT J AU Economopoulos, KP Theocharidis, V McKenzie, TJ Sergentanis, TN Psaltopoulou, T AF Economopoulos, Konstantinos P. Theocharidis, Vasileios McKenzie, Travis J. Sergentanis, Theodoros N. Psaltopoulou, Theodora TI Robotic vs. Laparoscopic Roux-En-Y Gastric Bypass: a Systematic Review and Meta-Analysis SO OBESITY SURGERY LA English DT Review DE Roux-en-Y gastric bypass; Laparoscopic; Robotic; Robotic-assisted ID LEARNING-CURVE; MORBID-OBESITY; BARIATRIC SURGERY; OUTCOMES; EXPERIENCE AB We aim to summarize the available literature on patients treated with robotic RYGB and compare the clinical outcomes of patients treated with robotic RYGB with those treated with the standard laparoscopic RYGB. A systematic literature search of PubMed and Scopus databases was conducted in accordance with the PRISMA guidelines. Fourteen comparative and 11 non-comparative studies were included in this study, reporting data on 5145 patients. This study points to comparable clinical outcomes between robotic and laparoscopic RYGB. Robotic-assisted RYGB was associated with significantly less frequent anastomotic stricture events, reoperations, and a decreased length of hospital stay compared with the standard laparoscopic procedures; however, these findings should be interpreted with caution given the low number and poor quality of the studies currently available in the literature. C1 [Economopoulos, Konstantinos P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Economopoulos, Konstantinos P.; Theocharidis, Vasileios; Sergentanis, Theodoros N.] Soc Jr Doctors, Athens, Greece. [Theocharidis, Vasileios] Univ Athens, Sch Med, GR-11527 Athens, Greece. [McKenzie, Travis J.] Mayo Clin, Dept Surg, Rochester, MN USA. [Sergentanis, Theodoros N.; Psaltopoulou, Theodora] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. RP Economopoulos, KP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 101 Merrimack St, Boston, MA 02114 USA. EM keconomopoulos@mgh.harvard.edu; vasileios.theo@gmail.com; Mckenzie.Travis@mayo.edu; tsergent@med.uoa.gr; tpsaltop@med.uoa.gr OI Economopoulos, Konstantinos/0000-0003-4856-0405 NR 37 TC 2 Z9 2 U1 1 U2 4 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 NOV PY 2015 VL 25 IS 11 BP 2180 EP 2189 DI 10.1007/s11695-015-1870-9 PG 10 WC Surgery SC Surgery GA CT1RP UT WOS:000362578700069 PM 26344797 ER PT J AU Hittle, LE Powell, DA Jones, JW Tofigh, M Goodlett, DR Moskowitz, SM Ernst, RK AF Hittle, Lauren E. Powell, Daniel A. Jones, Jace W. Tofigh, Majid Goodlett, David R. Moskowitz, Samuel M. Ernst, Robert K. TI Site-specific activity of the acyltransferases HtrB1 and HtrB2 in Pseudomonas aeruginosa lipid A biosynthesis SO PATHOGENS AND DISEASE LA English DT Article DE Pseudomonas aeruginosa; LPS; acyltransferase; membrane remodeling; HtrB; lipid A ID TEMPERATURE REQUIREMENT GENE; COLI MSBB GENE; ESCHERICHIA-COLI; OUTER-MEMBRANE; HAEMOPHILUS-INFLUENZAE; MULTICOPY SUPPRESSOR; DRUG-RESISTANCE; TYPHIMURIUM; ACYLATION; LAURATE AB Pseudomonas aeruginosa (PA) is an opportunistic Gram-negative pathogen associated with nosocomial infections, acute infections and chronic lung infections in patients with cystic fibrosis. The ability of PA to cause infection can be attributed to its ability to adapt to a multitude of environments. Modification of the lipid A portion of lipopolysaccharide (LPS) is a vital mechanism Gram-negative pathogens use to remodel the outer membrane in response to environmental stimuli. Lipid A, the endotoxic moiety of LPS, is the major component of the outer leaflet of the outer membrane of Gram-negative bacteria making it a critical factor for bacterial adaptation. One way PA modifies its lipid A is through the addition of laurate and 2-hydroxylaurate. This secondary or late acylation is carried out by the acyltransferase, HtrB (LpxL). Analysis of the PA genome revealed the presence of two htrB homologs, PA0011 (htrB1) and PA3242 (htrB2). In this study, we were able to show that each gene identified is responsible for site-specific modification of lipid A. Additionally, deletions of either gene altered resistance to specific classes of antibiotics, cationic antimicrobial peptides and increased membrane permeability suggesting a role for these enzymes in maintaining optimal membrane organization and integrity. C1 [Hittle, Lauren E.; Powell, Daniel A.; Tofigh, Majid; Ernst, Robert K.] Univ Maryland, Sch Dent, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA. [Jones, Jace W.; Goodlett, David R.] Univ Washington, Sch Pharm, Dept Med Chem, Seattle, WA 98195 USA. [Moskowitz, Samuel M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Moskowitz, Samuel M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02114 USA. RP Ernst, RK (reprint author), Univ Maryland, Sch Dent, Dept Microbial Pathogenesis, Rm9205,650 W Baltimore St 8 South, Baltimore, MD 21201 USA. EM rkernst@umaryland.edu FU National Institutes of Health [R01AI047938]; University of Maryland School of Pharmacy Mass Spectrometry Center [SOP1841-IQB2014] FX We thank Francesca Gardner and Kelsey Gregg for their editorial assistance. These studies were supported by the National Institutes of Health grant R01AI047938 (RKE). The MS experiments conducted by JWJ were performed at the University of Washington's Proteomics Resource, Seattle, Washington (UWPR95794). Additional support was provided by the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014). NR 31 TC 3 Z9 3 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD NOV PY 2015 VL 73 IS 8 AR UNSP ftv053 DI 10.1093/femspd/ftv053 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT7FA UT WOS:000362978200001 PM 26223882 ER PT J AU Liao, SY Liu, YQ Chen, XJ Tan, YD Mei, J Song, WZ Gan, L Wang, HL Yin, S Dong, XJ Chi, S Deng, SP AF Liao, Shunyao Liu, Yunqiang Chen, Xiaojuan Tan, Yuande Mei, Jie Song, Wenzhong Gan, Lu Wang, Hailian Yin, Shi Dong, Xianjue Chi, Shu Deng, Shaoping TI The Impact of Genetic Variants for Different Physiological Characterization of Type 2 Diabetes Loci on Gestational Insulin Signaling in Nondiabetic Pregnant Chinese Women SO REPRODUCTIVE SCIENCES LA English DT Article DE gestational insulin signaling; genetic variants; gestational diabetes ID GENOME-WIDE ASSOCIATION; FASTING PLASMA-GLUCOSE; MELATONIN RECEPTOR 1B; BETA-CELL FUNCTION; COMMON VARIANTS; HAN CHINESE; PROINSULIN CONVERSION; GLYCEMIC TRAITS; INCREASED RISK; CDKAL1 AB We investigate the impact of genetic variants on transiently upregulated gestational insulin signaling. We recruited 1152 unrelated nondiabetic pregnant Han Chinese women (age 28.5 +/- 4.1 years; body mass index [BMI] 21.4 +/- 2.6 kg/m(2)) and gave them oral glucose tolerance tests. Matsuda index of insulin sensitivity, homeostatic model assessment of insulin resistance, indices of insulin disposition, early-phase insulin release, fasting state, and 0 to 120 minute's proinsulin to insulin conversion were used to dissect insulin physiological characterization. Several variants related to -cell function were genotyped. The genetic impacts were analyzed using logistic regression under an additive model. By adjusting for maternal age, BMI, and the related interactions, the genetic variants in ABCC8, CDKAL1, CDKN2A, HNF1B, KCNJ11, and MTNR1B were detected to impact gestational insulin signaling through heterogeneous mechanisms; however, compared with that in nonpregnant metabolism, the genetic effects seem to be eminently and heavily influenced by maternal age and BMI, indicating possible particular mechanisms underlying gestational metabolism and diabetic pathogenesis. C1 [Liao, Shunyao; Gan, Lu; Wang, Hailian; Yin, Shi; Dong, Xianjue; Deng, Shaoping] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sch Med, Ctr Diabet, Chengdu 610072, Peoples R China. [Liao, Shunyao; Gan, Lu; Wang, Hailian; Yin, Shi; Dong, Xianjue; Deng, Shaoping] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sch Med, Inst Transplantat, Chengdu 610072, Peoples R China. [Liu, Yunqiang] Sichuan Univ, West China Hosp, Dept Med Genet, Div Morbid Genom,State Key Lab Biotherapy, Chengdu 610064, Peoples R China. [Chen, Xiaojuan] Columbia Univ, Coll Phys & Surg, Columbia Ctr Translat Immunol, New York, NY USA. [Tan, Yuande] Hunan Normal Univ, Coll Life Sci, Changsha, Hunan, Peoples R China. [Mei, Jie] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sch Med, Dept Obstet & Gynecol, Chengdu 610072, Peoples R China. [Song, Wenzhong; Chi, Shu] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sch Med, Dept Nucl Med, Chengdu 610072, Peoples R China. [Deng, Shaoping] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Human Islet Lab, Boston, MA USA. RP Liao, SY (reprint author), Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sch Med, Ctr Diabet, Yihuanlu Xierduan32, Chengdu 610072, Peoples R China. EM shunyaol@yahoo.com; sdeng10@yahoo.com FU National Natural Science Foundation of China [81471430]; Key project of Sichuan Provincial Department of Science and Technology FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the research grants to Shunyao Liao from National Natural Science Foundation of China (81471430) and from the Key project of Sichuan Provincial Department of Science and Technology. NR 41 TC 0 Z9 0 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD NOV PY 2015 VL 22 IS 11 BP 1421 EP 1428 DI 10.1177/1933719115580995 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CT8IM UT WOS:000363058900012 PM 25878199 ER PT J AU Morales-Oyarvide, V Mino-Kenudson, M Ferrone, CR Gonzalez-Gonzalez, LA Warshaw, AL Lillemoe, KD Fernandez-del Castillo, C AF Morales-Oyarvide, Vicente Mino-Kenudson, Mari Ferrone, Cristina R. Gonzalez-Gonzalez, Luis A. Warshaw, Andrew L. Lillemoe, Keith D. Fernandez-del Castillo, Carlos TI Acute pancreatitis in intraductal papillary mucinous neoplasms: A common predictor of malignant intestinal subtype SO SURGERY LA English DT Article ID CLINICAL-CHARACTERISTICS; MUC2; SEQUENCE; BEHAVIOR; TUMORS AB Background. Acute pancreatitis (AP) is a common presenting symptom of intraductal papillary mucinous neoplasms (IPMN). Our objective was to evaluate the clinical and pathologic features of IPMN that present with AP. We hypothesized that the intestinal epithelial subtype, which produces a highly viscous mucin containing MUC2 glycoprotein, is associated with the development of AP Methods. We performed a case-control study, evaluating 325 patients with IPMN resected at our institution. Clinicopathologic features were assessed for patients with and without a history of AP and compared between the 2 groups. Results. A history of AP was found in 69 patients (21%). Of those, 33 (48%) experienced a single episode, and some patients had as many as 10 distinct attacks. Three patients presented with necrotizing pancreatitis requiring operative debridement. After resection, recurrent AP occurred in only 14%. A history of AP was associated with younger age (61 vs 70, P < .001), main duct involvement (odds ratio [OR] 1.73, 95% confidence interval [95% CI] 1.00-3.01; P = .049), intestinal subtype (OR 4.84, 95% CI 2.71-8.67; P < .001), and high-grade dysplasia (OR 1.82, 95% CI 1.07-3.11; P = .028). On multivariate analysis, AP was an independent predictor of intestinal subtype (OR 4.69, 95% CI 2.48-8.84, P < .001), malignancy (OR 1.97, 95% CI 1.07-3.63, P = .029), and main duct involvement (OR 1.87, 95% CI 1.02-3.43, P = .044). Conclusion. AP is a frequent presenting symptom of IPMN. These patients are younger and have greater odds of harboring malignant intestinal-type IPMN involving the main pancreatic duct. C1 [Morales-Oyarvide, Vicente; Ferrone, Cristina R.; Warshaw, Andrew L.; Lillemoe, Keith D.; Fernandez-del Castillo, Carlos] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Mino-Kenudson, Mari] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Gonzalez-Gonzalez, Luis A.] Metro West Med Ctr, Dept Med, Framingham, MA USA. RP Fernandez-del Castillo, C (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St,WAC 460, Boston, MA 02114 USA. EM cfernandez@mgh.harvard.edu NR 25 TC 2 Z9 2 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD NOV PY 2015 VL 158 IS 5 BP 1219 EP 1225 DI 10.1016/j.surg.2015.04.029 PG 7 WC Surgery SC Surgery GA CT7PA UT WOS:000363005800007 PM 26077509 ER PT J AU Ramly, EP Larentzakis, A Bohnen, JD Mavros, M Chang, Y Lee, J Yeh, DD Demoya, M King, DR Fagenholz, PJ Velmahos, GC Kaafarani, HMA AF Ramly, Elie P. Larentzakis, Andreas Bohnen, Jordan D. Mavros, Michael Chang, Yuchiao Lee, Jarone Yeh, D. Dante Demoya, Marc King, David R. Fagenholz, Peter J. Velmahos, George C. Kaafarani, Haytham M. A. TI The financial impact of intraoperative adverse events in abdominal surgery SO SURGERY LA English DT Article; Proceedings Paper CT 10th Annual Academic Surgical Congress CY FEB, 2015 CL Las Vegas, NV ID QUALITY IMPROVEMENT PROGRAM; PATIENT SAFETY INDICATORS; SURGICAL QUALITY; POSTOPERATIVE COMPLICATIONS; HEALTH-CARE; COSTS; CLASSIFICATION AB Background. Little evidence currently exists regarding the clinical or financial impact of intraoperative adverse events (iAEs). We sought to study the additional health care charges attributable to the occurrence of an iAE. Methods. The administrative and ACS-NSQIP databases at our tertiary academic medical center were linked for all patients undergoing abdominal surgery (January 2007 October 2012). The ICD-9-CM-based Patient Safety Indicator "accidental puncture/laceration" was used to screen the linked database for potential iAEs. All iAEs were confirmed subsequently through standardized review of all flagged medical records. Multivariate analyses controlling for demographics, comorbidities/laboratory values, procedure type, and approach and complexity of surgery were performed to assess the increase in health care charges independently predicted by the occurrence of iAEs. Results. Of 9,111 patients, 183 were confirmed to have iAEs. Patients in the iAE group had higher median total charges ($27,169 [IQR, 17,302-44,952] vs $13,312 [IQR, 8,586-22,012]; P <.001), direct charges ($17,808 [IQR, 11,520-28,9301 vs $8,738 [IQR, 5,686-14,227]; P <.001) and indirect charges ($9,396 [IQR, 5,932-16,144] vs $4,568 [IQR, 2,887-7,824]; P <.001) when compared with patients without iAEs. Multivariate analyses demonstrated that iAEs independently predict an increase in total hospitalization charges by 41% (95% CI, 30-52%; P <.001). Specifically, the direct, indirect, operating room, laboratory/radiology, and alimentation/medical therapy charges increased by 42, 39, 27, 54, and 48%, respectively (all P <.001). Conclusion. In addition to the morbidity incurred by patients, the occurrence of an iAE is associated with major additional health care charges. In an era of value-based health care, understanding and preventing iAEs can lead to major cost savings alongside improvements in patient safety and surgical quality. C1 [Ramly, Elie P.; Larentzakis, Andreas; Bohnen, Jordan D.; Mavros, Michael; Chang, Yuchiao; Lee, Jarone; Yeh, D. Dante; Demoya, Marc; King, David R.; Fagenholz, Peter J.; Velmahos, George C.; Kaafarani, Haytham M. A.] Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Massachusetts Gen Hosp, Dept Surg,Med Sch, Boston, MA 02114 USA. RP Kaafarani, HMA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Surg,Dept Surg, 165 Cambridge St Suite 810, Boston, MA 02114 USA. EM hkaafarani@mgh.harvard.edu OI King, David/0000-0003-1028-1478 NR 29 TC 3 Z9 3 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD NOV PY 2015 VL 158 IS 5 BP 1382 EP 1388 DI 10.1016/j.surg.2015.04.023 PG 7 WC Surgery SC Surgery GA CT7PA UT WOS:000363005800025 PM 26026793 ER PT J AU Phitayakorn, R Minehart, RD Pian-Smith, MCM Hemingway, MW Petrusa, ER AF Phitayakorn, Roy Minehart, R. D. Pian-Smith, M. C. M. Hemingway, M. W. Petrusa, E. R. TI Practicality of using galvanic skin response to measure intraoperative physiologic autonomic activation in operating room team members SO SURGERY LA English DT Article; Proceedings Paper CT 7th Annual Meeting of the Consortium-of-ACS-Accredited-Education-Institutes CY MAR 21-22, 2014 CL Chicago, IL SP Consortium ACS, Accredited Educ Inst ID STRESS AB Background. Physiologic and psychological stress are commonly experienced by operating room (OR) personnel, yet there is little research about the stress levels in OR teams and their impact on performance. Previously published procedures to measure physiologic activation are invasive and impractical for the OR. The purpose of this study was to determine the practicality of a new watch-sized device to measure galvanic skin response (GSR) in OR team members during high-fidelity surgical simulations. Methods. Interprofessional OR teams wore sensors on the wrist (all) and ankle (surgeons and scrub nurses/technicians) during the orientation, case, and debriefing phases for 17 simulations of a surgical airway case. Data were compared across all simulation phases, collectively and for each professional group. Results. Forty anesthesiology residents, 35 surgery residents, 27 OR nurses, 12 surgical technicians, and 7 CRNAs participated. Collectively, mean wrist GSR levels significantly increased from orientation phase to the case (0.40-0.62 mu S; P < .001) and remained elevated even after the simulation was over (0.40-0.67 mu S; P < .001). Surgery residents were the only group that demonstrated continued increases in wrist GSR levels throughout the entire simulation (change in GSR <= 0.21 to 0.32 to 0.11 mu S; P < .01). Large intraindividual differences 200 times) were found in both wrist and ankle GSR. There was no correlation between wrist and ankle data. Conclusion. Continuous GSR monitoring of all professionals during OR simulations is feasible, but would be difficult to implement in an actual OR environment. Large variation in individual levels of physiologic activation suggests complementary qualitative research is needed to better understand how people respond to stressful OR situations. C1 [Phitayakorn, Roy; Petrusa, E. R.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Phitayakorn, Roy; Minehart, R. D.; Pian-Smith, M. C. M.; Hemingway, M. W.; Petrusa, E. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Learning Lab, Boston, MA USA. [Hemingway, M. W.] Harvard Univ, Sch Med, Dept Perioperat Serv, Boston, MA USA. [Minehart, R. D.; Pian-Smith, M. C. M.] Harvard Univ, Sch Med, Dept Anesthesiol Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA USA. RP Phitayakorn, R (reprint author), Massachusetts Gen Hosp, Dept Surg, Wang ACC, Suite 460,15 Parkman St, Boston, MA 02114 USA. EM rphitayakorn@mgh.harvard.edu OI Phitayakorn, Roy/0000-0002-8327-1484 NR 13 TC 2 Z9 2 U1 4 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD NOV PY 2015 VL 158 IS 5 BP 1415 EP 1420 DI 10.1016/j.surg.2015.04.009 PG 6 WC Surgery SC Surgery GA CT7PA UT WOS:000363005800030 PM 26032820 ER PT J AU Phitayakorn, R Minehart, RD Hemingway, MW Pian-Smith, MCM Petrusa, E AF Phitayakorn, Roy Minehart, Rebecca D. Hemingway, Maureen W. Pian-Smith, May C. M. Petrusa, Emil TI The relationship between intraoperative teamwork and management skills in patient care SO SURGERY LA English DT Article; Proceedings Paper CT 7th Annual Meeting of the Consortium-of-ACS-Accredited-Education-Institutes CY MAR 21-22, 2014 CL Chicago, IL SP Consortium ACS, Accredited Educ Inst ID CLOSED MALPRACTICE CLAIMS; OF-THE-LITERATURE; OPERATING-ROOM; NONTECHNICAL SKILLS; SIMULATION; SAFETY; COMMUNICATION; ANESTHESIA; CHECKLIST; INSURERS AB Background. Optimal team performance in the operating room (OR) requires a combination of interactions among OR professionals and adherence to clinical guidelines. Theoretically, it is possible that OR teams could communicate very well but fail to follow acceptable standards of patient care and vice versa. OR simulations offer an ideal research environment to study this relationship. The goal of this study was to determine the relationship between ratings of OR teamwork and communication with adherence to patient care guidelines in a simulated scenarios of malignant hyperthermia (MH). Methods. An interprofessional research team (2 anesthesiologists, I surgeon, an OR nurse, and a social scientist) reviewed videos of 5 intraoperative teams managing a simulated patient who manifested MH while undergoing general anesthesia for an epigastric herniorraphy in a high-fidelity, in situ OR. Participant teams consisted of 2 residents from anesthesiology, 1 from surgery, 1 OR nurse, and I certified surgical technician. Teamwork and communication were assessed with 4 published tools: Anesthesiologists' Non-Technical Skills (ANTS), Scrub Practitioners List of Intra-operative Non-Technical Skills. (SPLINTS), Non-Technical Skills for Surgeons (NOTSS), and Objective Teamwork Assessment System (OTAS). We developed an evidence-based MH checklist to assess overall patient care. Results. Interrater agreement for teamwork tools was moderate. Average rater agreement was 0.51 For ANTS, 0.67 for SPLINTS, 0.51 for NOTSS, and 0.70 for OTAS. Observer agreement for the MH checklist was high (0.88). Correlations between teamwork and MH checklist were not significant. Teams were different in percent of the MH actions taken (range, 50-91%; P = .006). Conclusion. In this pilot study, intraoperative teamwork and communication were not related to overall patient care management. Separating nontechnical and technical skills when teaching OR teamwork is artificial and may even be damaging, because such an approach could produce teams with excellent communication skills as they unsuccessfully manage the patient. OR simulations offer a unique opportunity to research how to best integrate both of these domains to improve patient care. C1 [Phitayakorn, Roy; Petrusa, Emil] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Phitayakorn, Roy; Minehart, Rebecca D.; Hemingway, Maureen W.; Pian-Smith, May C. M.; Petrusa, Emil] Harvard Univ, Sch Med, MGH Learning Lab, Massachusetts Gen Hosp, Boston, MA USA. [Minehart, Rebecca D.; Pian-Smith, May C. M.] Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA USA. [Hemingway, Maureen W.] Harvard Univ, Sch Med, Dept Perioperat Serv, Massachusetts Gen Hosp, Boston, MA USA. RP Phitayakorn, R (reprint author), Massachusetts Gen Hosp, Dept Surg, Wang ACC, Suite 460,15 Parkman St, Boston, MA 02114 USA. EM rphitayakorn@mgh.harvard.edu OI Phitayakorn, Roy/0000-0002-8327-1484 NR 27 TC 0 Z9 0 U1 5 U2 23 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD NOV PY 2015 VL 158 IS 5 BP 1434 EP 1440 DI 10.1016/j.surg.2015.03.031 PG 7 WC Surgery SC Surgery GA CT7PA UT WOS:000363005800033 PM 25999257 ER PT J AU Munshi, NC AF Munshi, Nikhil C. TI Association of Agent Orange With Plasma Cell Disorder Further Evidence SO JAMA ONCOLOGY LA English DT Editorial Material ID MULTIPLE-MYELOMA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; HETEROGENEITY C1 [Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA USA. [Munshi, Nikhil C.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Munshi, NC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,M230, Boston, MA 02215 USA. EM Nikhil_Munshi@DFCI.Harvard.edu FU PHS HHS [P50-100007, P01-155258, P01-78378, R01-124929] NR 15 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1035 EP 1036 DI 10.1001/jamaoncol.2015.3015 PG 2 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700006 PM 26335544 ER PT J AU Chen, WY AF Chen, Wendy Y. TI Measuring the Effectiveness of Mammography SO JAMA ONCOLOGY LA English DT Editorial Material ID NEGATIVE BREAST-CANCER; TRASTUZUMAB; COHORT C1 [Chen, Wendy Y.] Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. [Chen, Wendy Y.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Chen, WY (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM wendy.chen@channing.harvard.edu NR 17 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1037 EP 1038 DI 10.1001/jamaoncol.2015.3286 PG 2 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700007 PM 26501739 ER PT J AU Dueck, AC Mendoza, TR Mitchell, SA Reeve, BB Castro, KM Rogak, LJ Atkinson, TM Bennett, AV Denicoff, AM O'Mara, AM Li, YL Clauser, SB Bryant, DM Bearden, JD Gillis, TA Harness, JK Siegel, RD Paul, DB Cleeland, CS Schrag, D Sloan, JA Abernethy, AP Bruner, DW Minasian, LM Basch, E AF Dueck, Amylou C. Mendoza, Tito R. Mitchell, Sandra A. Reeve, Bryce B. Castro, Kathleen M. Rogak, Lauren J. Atkinson, Thomas M. Bennett, Antonia V. Denicoff, Andrea M. O'Mara, Ann M. Li, Yuelin Clauser, Steven B. Bryant, Donna M. Bearden, James D., III Gillis, Theresa A. Harness, Jay K. Siegel, Robert D. Paul, Diane B. Cleeland, Charles S. Schrag, Deborah Sloan, Jeff A. Abernethy, Amy P. Bruner, Deborah W. Minasian, Lori M. Basch, Ethan CA Natl Canc Inst PRO-CTCAE Study Grp TI Validity and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO JAMA ONCOLOGY LA English DT Article ID CLINICIAN; SYMPTOMS; CHEMOTHERAPY; INSTRUMENT; TOXICITIES; AGREEMENT; ONCOLOGY; QLQ-C30; TRIALS AB IMPORTANCE To integrate the patient perspective into adverse event reporting, the National Cancer Institute developed a patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). OBJECTIVE To assess the construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items. DESIGN, SETTING, AND PARTICIPANTS A total of 975 adults with cancer undergoing outpatient chemotherapy and/or radiation therapy enrolled in this questionnaire-based study between January 2011 and February 2012. Eligible participants could read English and had no clinically significant cognitive impairment. They completed PRO-CTCAE items on tablet computers in clinic waiting rooms at 9 US cancer centers and community oncology practices at 2 visits 1 to 6 weeks apart. A subset completed PRO-CTCAE items during an additional visit 1 business day after the first visit. MAIN OUTCOMES AND MEASURES Primary comparators were clinician-reported Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30). RESULTS A total of 940 of 975 (96.4%) and 852 of 940 (90.6%) participants completed PRO-CTCAE items at visits 1 and 2, respectively. At least 1 symptom was reported by 938 of 940 (99.8%) participants. Participants' median age was 59 years; 57.3% were female, 32.4% had a high school education or less, and 17.1% had an ECOG PS of 2 to 4. All PRO-CTCAE items had at least 1 correlation in the expected direction with a QLQ-C30 scale (111 of 124, P <.05 for all). Stronger correlations were seen between PRO-CTCAE items and conceptually related QLQ-C30 domains. Scores for 94 of 124 PRO-CTCAE items were higher in the ECOG PS 2 to 4 vs 0 to 1 group (58 of 124, P <.05 for all). Overall, 119 of 124 items met at least 1 construct validity criterion. Test-retest reliability was 0.7 or greater for 36 of 49 prespecified items (median [range] intraclass correlation coefficient, 0.76 [0.53-.96]). Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were statistically significant for 27 prespecified items (median [range] r = 0.43 [0.10-. 56]; all P <=.006). CONCLUSIONS AND RELEVANCE Evidence demonstrates favorable validity, reliability, and responsiveness of PRO-CTCAE in a large, heterogeneous US sample of patients undergoing cancer treatment. Studies evaluating other measurement properties of PRO-CTCAE are under way to inform further development of PRO-CTCAE and its inclusion in cancer trials. C1 [Dueck, Amylou C.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA. [Mendoza, Tito R.; Cleeland, Charles S.] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Houston, TX 77030 USA. [Mitchell, Sandra A.; Castro, Kathleen M.; Clauser, Steven B.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Reeve, Bryce B.; Bennett, Antonia V.; Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Rogak, Lauren J.; Basch, Ethan] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Atkinson, Thomas M.; Li, Yuelin] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 1275 York Ave, New York, NY 10021 USA. [Denicoff, Andrea M.; Minasian, Lori M.] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [O'Mara, Ann M.] NCI, Canc Prevent Div, Rockville, MD USA. [Bryant, Donna M.] Canc Program Our Lady Lake & Mary Bird Perkins, Dept Clin Res, Baton Rouge, LA USA. [Bearden, James D., III] Gibbs Canc Ctr & Res Inst, Spartanburg, SC USA. [Gillis, Theresa A.] Christiana Care Hlth Syst, Helen Graham Canc Ctr, Newark, DE USA. [Gillis, Theresa A.] Christiana Care Hlth Syst, Res Inst, Newark, DE USA. [Harness, Jay K.] St Joseph Hosp Orange, Ctr Canc Prevent & Treatment, Orange, CA USA. [Siegel, Robert D.] Hartford Hosp, Helen & Harry Gray Canc Ctr, Hartford, CT 06115 USA. [Schrag, Deborah] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Sloan, Jeff A.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Abernethy, Amy P.] Duke Univ, Dept Med, Med Ctr, Durham, NC USA. [Bruner, Deborah W.] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Atlanta, GA 30322 USA. RP Dueck, AC (reprint author), Mayo Clin, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM dueck@mayo.edu FU National Cancer Institute [HHSN261200800043C, HHSN261201000063C, HHSN261200800001E] FX This study was supported by contracts from the National Cancer Institute: HHSN261200800043C, HHSN261201000063C, and HHSN261200800001E. NR 31 TC 41 Z9 41 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1051 EP 1059 DI 10.1001/jamaoncol.2015.2639 PG 10 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700008 PM 26270597 ER PT J AU McDaniel, AS Stall, JN Hovelson, DH Cani, AK Liu, CJ Tomlins, SA Cho, KR AF McDaniel, Andrew S. Stall, Jennifer N. Hovelson, Daniel H. Cani, Andi K. Liu, Chia-Jen Tomlins, Scott A. Cho, Kathleen R. TI Next-Generation Sequencing of Tubal Intraepithelial Carcinomas SO JAMA ONCOLOGY LA English DT Article ID EPITHELIAL OVARIAN-CANCER; SEROUS CARCINOMA; PATHOGENESIS; MUTATIONS; ORIGIN; TUMORS; WOMEN AB IMPORTANCE High-grade serous carcinoma (HGSC) is the most prevalent and lethal form of ovarian cancer. HGSCs frequently arise in the distal fallopian tubes rather than the ovary, developing from small precursor lesions called serous tubal intraepithelial carcinomas (TICs, or more specifically, STICs). While STICs have been reported to harbor TP53 mutations, detailed molecular characterizations of these lesions are lacking. OBSERVATIONS We performed targeted next-generation sequencing (NGS) on formalin-fixed, paraffin-embedded tissue from 4 women, 2 with HGSC and 2 with uterine endometrioid carcinoma (UEC) who were diagnosed as having synchronous STICs. We detected concordant mutations in both HGSCs with synchronous STICs, including TP53 mutations as well as assumed germline BRCA1/2 alterations, confirming a clonal association between these lesions. Next-generation sequencing confirmed the presence of a STIC clonally unrelated to 1 case of UEC, and NGS of the other tubal lesion diagnosed as a STIC unexpectedly supported the lesion as a micrometastasis from the associated UEC. CONCLUSIONS AND RELEVANCE We demonstrate that targeted NGS can identify genetic alterations in minute lesions, such as TICs, and confirm TP53 mutations as early driving events for HGSC. Next-generation sequencing also demonstrated unexpected associations between presumed STICs and synchronous carcinomas, providing evidence that some TICs are actually metastases rather than HGSC precursors. C1 [McDaniel, Andrew S.; Cani, Andi K.; Liu, Chia-Jen; Tomlins, Scott A.; Cho, Kathleen R.] Univ Michigan, Dept Pathol, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA. [Stall, Jennifer N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hovelson, Daniel H.] Univ Michigan, Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Tomlins, Scott A.; Cho, Kathleen R.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Cho, Kathleen R.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. RP Tomlins, SA (reprint author), Univ Michigan, Sch Med, 1524 BSRB,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM tomlinss@umich.edu FU A. Alfred Taubman Medical Research Institute FX This work was supported in part by the A. Alfred Taubman Medical Research Institute (SAT). NR 14 TC 11 Z9 11 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1128 EP 1132 DI 10.1001/jamaoncol.2015.1618 PG 5 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700020 PM 26181193 ER PT J AU Moasser, MM Krop, IE AF Moasser, Mark M. Krop, Ian E. TI The Evolving Landscape of HER2 Targeting in Breast Cancer SO JAMA ONCOLOGY LA English DT Review ID EPIDERMAL-GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; ADJUVANT CHEMOTHERAPY; TRASTUZUMAB EMTANSINE; PIK3CA MUTATIONS; LUNG-CANCER; PHOSPHATIDYLINOSITOL 3-KINASE; MONOCLONAL-ANTIBODY; 1ST-LINE TREATMENT; ANTITUMOR-ACTIVITY AB The development of human epidermal growth factor receptor 2 (HER2)-targeting agents for the treatment of HER2-amplified breast cancer has dramatically improved outcomes for patients with this disease. The value of HER2 as a therapeutic target encompasses 2 entirely different mechanistic dimensions. The first approach exploits the fact that HER2 is clearly a disease-driving oncogene to deliver HER2 kinase inhibitors, apparently a highly rational approach to the treatment of HER2-amplified cancers. However, the functionally relevant HER2-HER3 complex has proven much more difficult to inhibit than had been anticipated, and because of its modest efficacy, the HER2 inhibitor lapatinib is currently used predominantly in combinations and in very advanced stages of disease. The second approach exploits the massive cell surface expression of HER2 and delivers of a variety of cytotoxic or immunologic effectors with great selectivity to these cancer cells. This approach has proven transformative, with 3 such drugs introduced into practice to date. The HER2-specific antibody trastuzumab, in combination with chemotherapy, has shown substantial effect in the management of HER2-amplifed breast cancer at all stages of disease and lines of therapy-and the addition of the second HER2 antibody pertuzumab substantially increases the magnitude of this effect in all of the contexts tested thus far. While the immunologic effectors stimulated by these naked HER2 antibodies provide only modest activity as monotherapy, the toxin-carrying antibody trastuzumab-emtansine provides substantial single-agent activity and is being developed for both early-and late-stage disease. The diverse mechanistic landscape afforded by the target HER2 has proven to be fertile ground for drug development, but it has also created complexity and misconception in understanding these agents' modes of action, undermining the development of clinically useful predictive biomarkers. This accounts for the failure of signaling-based biomarkers to predict clinical trastuzumab resistance and shifted the focus to markers of immunologic activity with greater success. The evolving world of HER2 targeting is reviewed herein. C1 [Moasser, Mark M.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Krop, Ian E.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Moasser, MM (reprint author), Univ Calif San Francisco, Box 1387, San Francisco, CA 94143 USA. EM mark.moasser@ucsf.edu; ikrop@partners.org FU National Institutes of Health [CA122216, CA112970]; Susan J. Komen for the Cure FX Dr Moasser was supported by National Institutes of Health grants CA122216 and CA112970. Dr Krop was supported by Susan J. Komen for the Cure. NR 83 TC 12 Z9 12 U1 1 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1154 EP 1161 DI 10.1001/jamaoncol.2015.2286 PG 8 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700023 PM 26204261 ER PT J AU Wu, JX Arcega, R Donahue, TR Tomlinson, JS Reber, HA Hines, J AF Wu, James X. Arcega, Ramir Donahue, Timothy R. Tomlinson, James S. Reber, Howard A. Hines, Joe TI Pancreatic Oncocytic Intraductal Papillary Mucinous Neoplasms: Three Case Reports and Review of Cases in Literature SO JOURNAL OF THE PANCREAS LA English DT Review DE Oncocytic Intraductal Papillary Mucinous Neoplasm; Intraductal Oncocytic Papillary Neoplasm ID JUICE CYTOLOGY; INVASIVE-CARCINOMA; IPMN; MANAGEMENT; SUBTYPE; MUTATIONS; GNAS AB Objectives Oncocytic intraductal papillary mucinous neoplasias represent a rare morphological subtype of intraductal papillary mucinous neoplasias, accounting for 1-8% of cases. Our aim was to characterize clinical factors associated with oncocytic intraductal papillary mucinous neoplasias, and factors that may predict invasive carcinoma. Methods Patient data for three consecutive cases of oncocytic intraductal papillary mucinous neoplasia were abstracted from electronic medical records. Literature search was performed using Pubmed and Google Scholar search engines using the keywords, "oncocytic intraductal papillary mucinous neoplasm," "oncocytic intraductal papillary mucinous neoplasia," "intraductal oncocytic papillary neoplasm," and "intraductal oncocytic papillary neoplasms." Studies that reported age, gender, invasiveness, and main versus branch duct involvement were included. Results We detailed three case reports and identified 77 previously published cases of oncocytic intraductal papillary mucinous neoplasia. The mean age at diagnosis was 61.6 years. There was a significant association of oncocytic intraductal papillary mucinous neoplasias with male gender (P= 0.03), but not with main/mixed versus branch duct involvement (P= 0.053). Invasive carcinoma was observed in 55.8% of oncocytic intraductal papillary mucinous neoplasias. In a subgroup of patients that underwent KRAS mutation testing (N= 25), 7(28%) harbored a KRAS mutation; KRAS mutation did not predict presence of invasive carcinoma (P= 1.00). Conclusions Clinical factors or KRAS mutation testing cannot currently predict the malignant potential of oncocytic intraductal papillary mucinous neoplasias. Management of oncocytic intraductal papillary mucinous neoplasias should still be based upon macroscopic criteria. C1 [Wu, James X.; Donahue, Timothy R.; Tomlinson, James S.; Reber, Howard A.; Hines, Joe] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Arcega, Ramir] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Donahue, Timothy R.; Tomlinson, James S.; Reber, Howard A.; Hines, Joe] Univ Calif Los Angeles, Ctr Pancreat Dis, Los Angeles, CA USA. [Tomlinson, James S.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. RP Wu, JX (reprint author), Dept Surg, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM JamesWu@mednet.ucla.ed NR 37 TC 0 Z9 0 U1 0 U2 0 PU E S BURIONI RICERCHE BIBLIOGRAFICHE PI GENOVA PA CORSO FIRENZE 41-2, GENOVA, 16136, ITALY SN 1590-8577 J9 J PANCREAS JI J. Pancreas PD NOV PY 2015 VL 16 IS 6 BP 626 EP 632 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DY6KS UT WOS:000385225400020 ER PT J AU Ataer-Cansizoglu, E Bolon-Canedo, V Campbell, JP Bozkurt, A Erdogmus, D Kalpathy-Cramer, J Patel, S Jonas, K Chan, RVP Ostmo, S Chiang, MF AF Ataer-Cansizoglu, Esra Bolon-Canedo, Veronica Campbell, J. Peter Bozkurt, Alican Erdogmus, Deniz Kalpathy-Cramer, Jayashree Patel, Samir Jonas, Karyn Chan, R. V. Paul Ostmo, Susan Chiang, Michael F. CA i-Rop Res Consortium TI Computer-Based Image Analysis for Plus Disease Diagnosis in Retinopathy of Prematurity: Performance of the "i-ROP'' System and Image Features Associated With Expert Diagnosis SO TRANSLATIONAL VISION SCIENCE & TECHNOLOGY LA English DT Article DE computer-based image analysis; retinopathy of prematurity; machine learning ID VASCULAR TORTUOSITY; OPTIC DISK; AGREEMENT; FELLOWS; ACCURACY; DISTANCE; INFANTS; WIDTH; CARE AB Purpose: We developed and evaluated the performance of a novel computer-based image analysis system for grading plus disease in retinopathy of prematurity (ROP), and identified the image features, shapes, and sizes that best correlate with expert diagnosis. Methods: A dataset of 77 wide-angle retinal images from infants screened for ROP was collected. A reference standard diagnosis was determined for each image by combining image grading from 3 experts with the clinical diagnosis from ophthalmoscopic examination. Manually segmented images were cropped into a range of shapes and sizes, and a computer algorithm was developed to extract tortuosity and dilation features from arteries and veins. Each feature was fed into our system to identify the set of characteristics that yielded the highest-performing system compared to the reference standard, which we refer to as the "i-ROP'' system. Results: Among the tested crop shapes, sizes, and measured features, point-based measurements of arterial and venous tortuosity (combined), and a large circular cropped image (with radius 6 times the disc diameter), provided the highest diagnostic accuracy. The i-ROP system achieved 95% accuracy for classifying preplus and plus disease compared to the reference standard. This was comparable to the performance of the 3 individual experts (96%, 94%, 92%), and significantly higher than the mean performance of 31 nonexperts (81%). Conclusions: This comprehensive analysis of computer-based plus disease suggests that it may be feasible to develop a fully-automated system based on wide-angle retinal images that performs comparably to expert graders at three-level plus disease discrimination. C1 [Ataer-Cansizoglu, Esra; Bozkurt, Alican; Erdogmus, Deniz] Northeastern Univ, Cognit Syst Lab, Boston, MA 02115 USA. [Bolon-Canedo, Veronica] Univ A Coruna, Dept Comp Sci, La Coruna, Spain. [Campbell, J. Peter; Ostmo, Susan; Chiang, Michael F.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Casey Eye Inst, Portland, OR 97201 USA. [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Patel, Samir; Jonas, Karyn; Chan, R. V. Paul] Weill Cornell Med Coll, Dept Ophthalmol, New York, NY USA. [Chiang, Michael F.] Oregon Hlth & Sci Univ, Dept Med Informat, Portland, OR 97201 USA. [Chiang, Michael F.] Oregon Hlth & Sci Univ, Dept Clin Epidemiol, Portland, OR 97201 USA. RP Chiang, MF (reprint author), Oregon Hlth & Sci Univ, Dept Ophthalmol, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM chiangm@ohsu.edu OI Jonas, Karyn /0000-0001-9038-6979 FU National Institutes of Health, Bethesda, MD [EY19474, P30 EY010572, EY22387]; Research to Prevent Blindness (New York, NY); St. Giles Foundation; Bernadotte Foundation for Children's Eyecare; Novartis Excellence in Ophthalmic Vision Award - XOVA; iNsight Foundation FX M.F. Chiang is supported by NIH grant EY19474 from the National Institutes of Health, Bethesda, MD. M.F. Chiang and J.P. Campbell are supported by grant P30 EY010572 from the National Institutes of Health (Bethesda, MD), and by unrestricted departmental funding from Research to Prevent Blindness (New York, NY). J. Kalpathy-Cramer and M.F. Chiang are supported by NIH grant EY22387. R.V.P. Chan is supported by the St. Giles Foundation, the Bernadotte Foundation for Children's Eyecare, Novartis Excellence in Ophthalmic Vision Award - XOVA, unrestricted departmental funding from Research to Prevent Blindness, and the iNsight Foundation. NR 34 TC 8 Z9 8 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 2164-2591 J9 TRANSL VIS SCI TECHN JI Transl. Vis. Sci. Technol. PD NOV PY 2015 VL 4 IS 6 AR 5 DI 10.1167/tvst.4.6.5 PG 12 WC Ophthalmology SC Ophthalmology GA ED2IP UT WOS:000388667500005 PM 26644965 ER PT J AU Epstein-Peterson, ZD Sullivan, AJ Enzinger, AC Trevino, KM Zollfrank, AA Balboni, MJ VanderWeele, TJ Balboni, TA AF Epstein-Peterson, Zachary D. Sullivan, Adam J. Enzinger, Andrea C. Trevino, Kelly M. Zollfrank, Angelika A. Balboni, Michael J. VanderWeele, Tyler J. Balboni, Tracy A. TI Examining Forms of Spiritual Care Provided in the Advanced Cancer Setting SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE spiritual care; end-of-life care; religion; spirituality ID QUALITY-OF-LIFE; NEAR-DEATH; END; ASSOCIATIONS; PERCEPTIONS; PHYSICIANS; DECISIONS; SUPPORT AB Spiritual care (SC) is important to the care of seriously ill patients. Few studies have examined types of SC provided and their perceived impact. This study surveyed patients with advanced cancer (N = 75, response rate [RR] = 73%) and oncology nurses and physicians (N = 339, RR = 63%). Frequency and perceived impact of 8 SC types were assessed. Spiritual care is infrequently provided, with encouraging or affirming beliefs the most common type (20%). Spiritual history taking and chaplaincy referrals comprised 10% and 16%, respectively. Most patients viewed each SC type positively, and SC training predicted provision of many SC types. In conclusion, SC is infrequent, and core elements of SCspiritual history taking and chaplaincy referralsrepresent a minority of SC. Spiritual care training predicts provision of SC, indicting its importance to advancing SC in the clinical setting. C1 [Epstein-Peterson, Zachary D.; Enzinger, Andrea C.; Balboni, Michael J.; Balboni, Tracy A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sullivan, Adam J.; VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Biostat & Epidemiol, Boston, MA 02115 USA. [Enzinger, Andrea C.; Balboni, Michael J.; Balboni, Tracy A.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Trevino, Kelly M.] Rowan Univ, Dept Psychol, Glassboro, NJ USA. [Zollfrank, Angelika A.] Massachusetts Gen Hosp Chaplaincy, Boston, MA USA. RP Balboni, TA (reprint author), Harvard Univ, Sch Med, 450 Brookline Ave,Dana 1101, Boston, MA 02115 USA. EM tbalboni@lroc.harvard.edu FU American Society of Clinical Oncology Young Investigator Award and Career Development Award; John Templeton Foundation Award; Healthcare Chaplaincy Award; University of Chicago Program in Religion and Medicine Faculty Scholars Award FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: American Society of Clinical Oncology Young Investigator Award and Career Development Award (TAB), John Templeton Foundation Award (TJV), Healthcare Chaplaincy Award (TAB, AAZ, TJV, and MJB), and University of Chicago Program in Religion and Medicine Faculty Scholars Award (MJB). NR 19 TC 2 Z9 2 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD NOV PY 2015 VL 32 IS 7 BP 750 EP 757 DI 10.1177/1049909114540318 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CT0LH UT WOS:000362486500010 PM 25005589 ER PT J AU Coopey, SB Smith, BL AF Coopey, Suzanne B. Smith, Barbara L. TI The Nipple is Just Another Margin SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID SPARING MASTECTOMY C1 [Coopey, Suzanne B.; Smith, Barbara L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA 02115 USA. RP Coopey, SB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA 02115 USA. EM scoopey@partners.org NR 11 TC 4 Z9 4 U1 0 U2 4 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 NOV PY 2015 VL 22 IS 12 BP 3764 EP 3766 DI 10.1245/s10434-015-4648-3 PG 3 WC Oncology; Surgery SC Oncology; Surgery GA CT0UP UT WOS:000362513100002 PM 26036186 ER PT J AU Rosenberg, SM Sepucha, K Ruddy, KJ Tamimi, RM Gelber, S Meyer, ME Schapira, L Come, SE Borges, VF Golshan, M Winer, EP Partridge, AH AF Rosenberg, Shoshana M. Sepucha, Karen Ruddy, Kathryn J. Tamimi, Rulla M. Gelber, Shari Meyer, Meghan E. Schapira, Lidia Come, Steven E. Borges, Virginia F. Golshan, Mehra Winer, Eric P. Partridge, Ann H. TI Local Therapy Decision-Making and Contralateral Prophylactic Mastectomy in Young Women with Early-Stage Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID CARCINOMA IN-SITU; RISK-REDUCING MASTECTOMY; UNILATERAL MASTECTOMY; DATA-BASE; PERCEPTIONS; COMPLICATIONS; INVOLVEMENT; KNOWLEDGE; OUTCOMES; SURGERY AB Rates of contralateral prophylactic mastectomy (CPM) have increased in the United States, with younger women with breast cancer the most likely to have CPM. As part of an ongoing cohort study of young women diagnosed with breast cancer at age a parts per thousand currency sign40 years, we conducted multinomial logistic regression of data from 560 women with unilateral Stage I-III disease to identify factors associated with: (1) CPM versus unilateral mastectomy (UM); (2) CPM versus breast-conserving surgery (BCS). Median age at diagnosis was 37 years; 66 % of women indicated that their doctor said that BCS was an option or was recommended. Of all women, 42.9 % had CPM, 26.8 % UM, and 30.4 % BCS. Among women who said the surgical decision was patient-driven, 59.9 % had CPM, 22.8 % BCS, and 17.3 % UM. Clinical characteristics associated with CPM versus BCS included HER2 positivity, nodal involvement, larger tumor size, lower BMI, parity, and testing positive for a BRCA mutation. Emotional and decisional factors associated with CPM versus UM and BCS included anxiety, less fear of recurrence, and reporting a patient-driven decision. Women who reported a physician-driven decision were less likely to have had CPM than both of the other surgeries, whereas higher confidence with the decision was associated with having CPM versus BCS. Many young women with early-stage breast cancer are choosing CPM. The association between CPM and emotional and decisional factors suggest that improved communication together with better psychosocial support may improve the decision-making process. C1 [Rosenberg, Shoshana M.; Meyer, Meghan E.; Winer, Eric P.; Partridge, Ann H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sepucha, Karen; Schapira, Lidia] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ruddy, Kathryn J.] Mayo Clin, Dept Med Oncol, Rochester, MN USA. [Tamimi, Rulla M.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Gelber, Shari] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Come, Steven E.] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. [Borges, Virginia F.] Univ Colorado, Div Med Oncol, Aurora, CO USA. [Golshan, Mehra] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Rosenberg, SM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM ahpartridge@partners.org FU NCI NIH HHS [R01 CA169175, R25 CA057711] NR 35 TC 10 Z9 10 U1 0 U2 9 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 NOV PY 2015 VL 22 IS 12 BP 3809 EP 3815 DI 10.1245/s10434-015-4572-6 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA CT0UP UT WOS:000362513100011 PM 25930247 ER PT J AU Dinh, C Strohmeier, D Luessi, M Gullmar, D Baumgarten, D Haueisen, J Hamalainen, MS AF Dinh, Christoph Strohmeier, Daniel Luessi, Martin Guellmar, Daniel Baumgarten, Daniel Haueisen, Jens Haemaelaeinen, Matti S. TI Real-Time MEG Source Localization Using Regional Clustering SO BRAIN TOPOGRAPHY LA English DT Article DE Magnetoencephalography; Real-time; Source localization; Minimum-norm estimates; K-means clustering; Brain atlas ID PRIMARY SOMATOSENSORY CORTEX; INVERSE PROBLEM; QUANTIFICATION; RESOLUTION; ACCURACY; BRAIN; MODEL; EEG AB With its millisecond temporal resolution, Magnetoencephalography (MEG) is well suited for real-time monitoring of brain activity. Real-time feedback allows the adaption of the experiment to the subject's reaction and increases time efficiency by shortening acquisition and off-line analysis. Two formidable challenges exist in real-time analysis: the low signal-to-noise ratio (SNR) and the limited time available for computations. Since the low SNR reduces the number of distinguishable sources, we propose an approach which downsizes the source space based on a cortical atlas and allows to discern the sources in the presence of noise. Each cortical region is represented by a small set of dipoles, which is obtained by a clustering algorithm. Using this approach, we adapted dynamic statistical parametric mapping for real-time source localization. In terms of point spread and crosstalk between regions the proposed clustering technique performs better than selecting spatially evenly distributed dipoles. We conducted real-time source localization on MEG data from an auditory experiment. The results demonstrate that the proposed real-time method localizes sources reliably in the superior temporal gyrus. We conclude that real-time source estimation based on MEG is a feasible, useful addition to the standard on-line processing methods, and enables feedback based on neural activity during the measurements. C1 [Dinh, Christoph; Luessi, Martin; Haemaelaeinen, Matti S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MIT, Charlestown, MA 02129 USA. [Dinh, Christoph; Strohmeier, Daniel; Baumgarten, Daniel; Haueisen, Jens] Tech Univ Ilmenau, Inst Biomed Engn & Informat, D-98693 Ilmenau, Germany. [Guellmar, Daniel] Univ Jena, Inst Diagnost & Intervent Radiol, Med Phys Grp, D-07743 Jena, Germany. [Haueisen, Jens] Univ Jena, Biomagnet Ctr, Dept Neurol, D-07743 Jena, Germany. RP Dinh, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MIT, 149 13th St, Charlestown, MA 02129 USA. EM chdinh@nmr.mgh.harvard.edu OI Baumgarten, Daniel/0000-0001-6109-3368 FU German Research Foundation (DFG) [Ba 4858/1-1]; National Institutes of Health (NIH) [5R01EB009048, 2P41EB015896]; IZKF Jena [J21]; German Academic Exchange Service (DAAD) FX This work was funded by the German Research Foundation (DFG, grant Ba 4858/1-1), National Institutes of Health (NIH, grants 5R01EB009048 and 2P41EB015896), IZKF Jena (J21) and the German Academic Exchange Service (DAAD). NR 28 TC 1 Z9 1 U1 3 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0896-0267 EI 1573-6792 J9 BRAIN TOPOGR JI Brain Topogr. PD NOV PY 2015 VL 28 IS 6 BP 771 EP 784 DI 10.1007/s10548-015-0431-9 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT2YT UT WOS:000362673600001 PM 25782980 ER PT J AU Clynes, MA Edwards, MH Buehring, B Dennison, EM Binkley, N Cooper, C AF Clynes, M. A. Edwards, M. H. Buehring, B. Dennison, E. M. Binkley, N. Cooper, C. TI Definitions of Sarcopenia: Associations with Previous Falls and Fracture in a Population Sample SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE Epidemiology; Sarcopenia; Dysmobility; Falls; Fractures ID EUROPEAN WORKING GROUP; HERTFORDSHIRE COHORT; OLDER-ADULTS; GAIT SPEED; PREVALENCE; STRENGTH; WOMEN; OSTEOPOROSIS; PEOPLE; EWGSOP AB Sarcopenia is common in later life and may be associated with adverse health outcomes such as disability, falls and fracture. There is no consensus definition for its diagnosis although diagnostic algorithms have been proposed by the European Working Group for Sarcopenia in Older People (EWGSOP), the International Working Group on Sarcopenia (IWGS) and the Foundation for the National Institutes of Health Sarcopenia Project (FNIH). More recently, Binkley and colleagues devised a score-based system for the diagnosis of "dysmobility syndrome" in an attempt to combine adverse musculoskeletal phenotypes, including sarcopenia and osteoporosis, in order to identify older individuals at particular risk. We applied these criteria to participants from the Hertfordshire Cohort Study to define their prevalence in an unselected cohort of UK community-dwelling older adults and assess their relationships with previous falls and fracture. Body composition and areal bone mineral density were measured using dual-energy X-ray absorptiometry, gait speed was determined by a 3-m walk test and grip strength was assessed with a Jamar hand-held dynamometer. Researcher-administered questionnaires were completed detailing falls and fracture history. The prevalence of sarcopenia in this cohort was 3.3, 8.3 and 2.0 % using the EWGSOP, IWGS and related definition of FNIH, respectively; 24.8 % of individuals had dysmobility syndrome. Individuals with dysmobility reported significantly higher number of falls (last year and since the age of 45 years) (p < 0.01) than those without it, but no increased fracture rate was observed in this group (p = 0.96). Those with sarcopenia as defined by the IWGS reported significantly higher falls in the last year and prevalent fractures (falls in the last year: OR 2.51; CI 1.09-5.81; p = 0.03; fractures OR 2.50; CI 1.05-5.92; p = 0.04) but these significant associations were not seen when the EWGSOP definition was applied. The IWGS definition of sarcopenia appears to be an effective means of identifying individuals at risk of prevalent adverse musculoskeletal events. C1 [Clynes, M. A.; Edwards, M. H.; Dennison, E. M.; Cooper, C.] Univ Southampton, MRC, Lifecourse Epidemiol Unit, Southampton, Hants, England. [Buehring, B.; Binkley, N.] Univ Wisconsin, Osteoporosis Res Program, Div Geriatr & Gerontol, Dept Med,Sch Med & Publ Hlth, Madison, WI 53705 USA. [Buehring, B.; Binkley, N.] William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI 53705 USA. [Dennison, E. M.] Victoria Univ, Wellington, New Zealand. [Cooper, C.] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, NIHR Musculoskeletal Biomed Res Unit, Oxford OX3 5UG, England. [Cooper, C.] Univ Southampton, NIHR Nutr Biomed Res Ctr, Southampton SO16 6YD, Hants, England. [Cooper, C.] Univ Hosp Southampton NHS Trust, Southampton Gen Hosp, Southampton SO16 6YD, Hants, England. RP Cooper, C (reprint author), Univ Southampton, MRC, Lifecourse Epidemiol Unit, Southampton, Hants, England. EM cc@mrc.soton.ac.uk RI Buehring, Bjoern/L-5581-2013 OI Buehring, Bjoern/0000-0003-3841-624X FU Medical Research Council of Great Britain; Arthritis Research UK; International Osteoporosis Foundation; NIHR Nutrition BRC, University of Southampton; NIHR Musculoskeletal BRU, University of Oxford; University of Southampton National Institute of Health FX The Hertfordshire Cohort Study was supported by the Medical Research Council of Great Britain; Arthritis Research UK and the International Osteoporosis Foundation. The work herein was also supported by the NIHR Nutrition BRC, University of Southampton and the NIHR Musculoskeletal BRU, University of Oxford. We thank all of the men and women who took part in the Hertfordshire Cohort Study; the HCS Research Staff and Vanessa Cox who managed the data. Michael Clynes was supported by the University of Southampton National Institute of Health. NR 29 TC 9 Z9 9 U1 3 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-967X EI 1432-0827 J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD NOV PY 2015 VL 97 IS 5 BP 445 EP 452 DI 10.1007/s00223-015-0044-z PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CT1SB UT WOS:000362580000003 PM 26223791 ER PT J AU Fu, Y Rope, R Fargue, S Cohen, HT Holmes, RP Cohen, DM AF Fu, Y. Rope, R. Fargue, S. Cohen, H. T. Holmes, R. P. Cohen, D. M. TI A mutation creating an out-of-frame alternative translation initiation site in the GRHPR 5UTR causing primary hyperoxaluria type II SO CLINICAL GENETICS LA English DT Article DE hyperoxaluria; mutation; translation; human ID IMPERFECTA TYPE-V; REDUCTASE GRHPR; GENE; 5'-UTR; CELLS; CODON AB Primary hyperoxaluria type II is a recessive genetic disorder caused by mutations in the GRHPR gene. Although several dozen mutations have been described, all affect coding or transcript splicing. A man suspected of having primary hyperoxaluria type II was heterozygous for a novel single-nucleotide deletion (c.694delC) in GRHPR affecting Gln(232), which introduced a pre-mature termination (p.Gln232Argfs*3). Two 5untranslated region (UTR) variants of unknown significance were also noted. We show that these two variants occur in cis, on the opposite allele, and introduce-immediately upstream of the canonical translation initiation site-a novel out-of-frame translational start site. In vitro studies using the GRHPR 5UTR fused to a luciferase reporter show that the variant start site pre-empted initiation at the canonical translational start site, and this was corroborated within the broader context of 1.3kb of the GRHPR proximal promoter. This latter mechanism may be underappreciated in general; reports of clinically significant functional variation of this type are extremely rare. C1 [Fu, Y.; Rope, R.; Cohen, D. M.] Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, Portland, OR 97239 USA. [Fu, Y.; Rope, R.; Cohen, D. M.] Portland VA Med Ctr, Portland, OR 97239 USA. [Fargue, S.; Holmes, R. P.] Univ Alabama Birmingham, Sch Med, Dept Urol, Birmingham, AL 35294 USA. [Cohen, H. T.] Boston Univ, Sch Med, Renal Sect, Boston, MA 02118 USA. RP Cohen, DM (reprint author), Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, Mailcode CH12R,3303 SW Bond Ave, Portland, OR 97239 USA. EM cohend@ohsu.edu OI Fargue, sonia/0000-0001-7451-7481 FU National Institutes of Health; Department of Veterans Affairs FX This project was supported by the National Institutes of Health and by the Department of Veterans Affairs. NR 15 TC 0 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD NOV PY 2015 VL 88 IS 5 BP 494 EP 498 DI 10.1111/cge.12541 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CT3BW UT WOS:000362682200014 PM 25410531 ER PT J AU Freedman, RA AF Freedman, Rachel A. TI Treatment of Breast Cancer in the Elderly SO CURRENT ONCOLOGY REPORTS LA English DT Review DE Breast cancer; Elderly; Older; Adjuvant treatment ID LUMPECTOMY PLUS TAMOXIFEN; ADJUVANT CHEMOTHERAPY; OLDER WOMEN; RANDOMIZED-TRIAL; RACIAL/ETHNIC DIFFERENCES; POSTMENOPAUSAL WOMEN; RACIAL-DIFFERENCES; HORMONAL-THERAPY; TRASTUZUMAB; SURVIVAL AB Despite the fact that the US population is aging and the numbers of older patients with breast cancer are increasing, many questions remain on how to optimally treat this patient population. Accrual of older cancer patients to clinical trials has been stagnant, and consequently, evidence-based recommendations are often limited by a lack of prospective data to inform decisions. Increasingly, one's functional status has been recognized as a critical factor in predicting for treatment toxicity, and tools such as the geriatric assessment will likely become a routine part of clinical practice over time. Here, adjuvant treatment considerations for older patients will be reviewed, including what is known about treatment efficacy, utilization patterns, and toxicity for older breast cancer patients. Improving enrollment of older patients onto clinical trials should be a national priority; it is only through prospective assessment that we can improve our approaches to treating our older patients with cancer. C1 Dana Farber Canc Inst, Boston, MA 02215 USA. RP Freedman, RA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM rafreedman@partners.org FU Puma Biotechnology; Genentech FX Rachel A. Freedman is the PI for two studies that receive institutional funding from Puma Biotechnology and Genentech but she does not receive any personal funding from these companies. NR 55 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3790 EI 1534-6269 J9 CURR ONCOL REP JI Curr. Oncol. Rep. PD NOV PY 2015 VL 17 IS 11 AR 51 DI 10.1007/s11912-015-0475-8 PG 8 WC Oncology SC Oncology GA CT1RT UT WOS:000362579100004 PM 26412227 ER PT J AU Declercq, E Stern, JE Luke, B Cabral, H Gopal, D Belanoff, C Diop, H Kotelchuck, M AF Declercq, Eugene Stern, Judy E. Luke, Barbara Cabral, Howard Gopal, Daksha Belanoff, Candice Diop, Hafsatou Kotelchuck, Milton TI Maternal Postpartum Hospitalization Following Assisted Reproductive Technology Births SO EPIDEMIOLOGY LA English DT Letter ID DATABASE; HEALTH C1 [Declercq, Eugene; Cabral, Howard; Gopal, Daksha; Belanoff, Candice] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Stern, Judy E.] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Luke, Barbara] Michigan State Univ, E Lansing, MI 48824 USA. [Diop, Hafsatou] Massachusetts Dept Publ Hlth, Boston, MA USA. [Kotelchuck, Milton] Harvard Univ, Sch Med, MassGen Hosp Children, Boston, MA USA. RP Declercq, E (reprint author), Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. EM declercq@bu.edu FU National Institute of Child Health and Human Development [R01HD064595, R01HD067270] FX The project described was supported by Award Numbers R01HD064595 and R01HD067270 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development or the National Institutes of Health. NR 5 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2015 VL 26 IS 6 BP E64 EP E65 DI 10.1097/EDE.0000000000000371 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT1JE UT WOS:000362553800001 PM 26317669 ER PT J AU Ek, WE Reznichenko, A Ripke, S Niesler, B Zucchelli, M Rivera, NV Schmidt, PT Pedersen, NL Magnusson, P Talley, NJ Holliday, EG Houghton, L Gazouli, M Karamanolis, G Rappold, G Burwinkel, B Surowy, H Rafter, J Assadi, G Li, L Papadaki, E Gambaccini, D Marchi, S Colucci, R Blandizzi, C Barbaro, R Karling, P Walter, S Ohlsson, B Tornblom, H Bresso, F Andreasson, A Dlugosz, A Simren, M Agreus, L Lindberg, G Boeckxstaens, G Bellini, M Stanghellini, V Barbara, G Daly, MJ Camilleri, M Wouters, MM D'Amato, M AF Ek, Weronica E. Reznichenko, Anna Ripke, Stephan Niesler, Beate Zucchelli, Marco Rivera, Natalia V. Schmidt, Peter T. Pedersen, Nancy L. Magnusson, Patrik Talley, Nicholas J. Holliday, Elizabeth G. Houghton, Lesley Gazouli, Maria Karamanolis, George Rappold, Gudrun Burwinkel, Barbara Surowy, Harald Rafter, Joseph Assadi, Ghazaleh Li, Ling Papadaki, Evangelia Gambaccini, Dario Marchi, Santino Colucci, Rocchina Blandizzi, Corrado Barbaro, Raffaella Karling, Pontus Walter, Susanna Ohlsson, Bodil Tornblom, Hans Bresso, Francesca Andreasson, Anna Dlugosz, Aldona Simren, Magnus Agreus, Lars Lindberg, Greger Boeckxstaens, Guy Bellini, Massimo Stanghellini, Vincenzo Barbara, Giovanni Daly, Mark J. Camilleri, Michael Wouters, Mira M. D'Amato, Mauro TI Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts SO GUT LA English DT Article ID HUMAN KDEL RECEPTOR; CHOLERA-TOXIN; ENDOPLASMIC-RETICULUM; PROTEIN DELPHILIN; ASSOCIATION; VISUALIZATION; DISORDERS; TRANSPORT; INTERACTS; VARIANTS AB Objective IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. Design We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. Results One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31 x 10(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations. C1 [Ek, Weronica E.; Reznichenko, Anna; Zucchelli, Marco; Rivera, Natalia V.; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Papadaki, Evangelia; Bresso, Francesca; D'Amato, Mauro] Karolinska Inst, Dept Biosci & Nutr, SE-14183 Stockholm, Sweden. [Ripke, Stephan; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan; Daly, Mark J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Niesler, Beate; Rappold, Gudrun] Heidelberg Univ, Inst Human Genet, Dept Human Mol Genet, Heidelberg, Germany. [Schmidt, Peter T.; Bresso, Francesca; Dlugosz, Aldona] Karolinska Univ Hosp, Karolinska Inst, Dept Gastroenterol & Hepatol, Stockholm, Sweden. [Pedersen, Nancy L.; Magnusson, Patrik] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-14183 Stockholm, Sweden. [Talley, Nicholas J.; Holliday, Elizabeth G.] Univ Newcastle, Fac Hlth & Med, Newcastle, NSW 2300, Australia. [Houghton, Lesley] Univ Manchester, Inst Inflammat & Repair, Fac Med & Human Sci, Manchester, Lancs, England. [Houghton, Lesley] Mayo Clin, Div Gastroenterol & Hepatol, Jacksonville, FL 32224 USA. [Gazouli, Maria] Univ Athens, Sch Med, Biol Lab, GR-11527 Athens, Greece. [Karamanolis, George] Univ Athens, Sch Med, Acad Dept Gastroenterol, GR-11527 Athens, Greece. [Burwinkel, Barbara; Surowy, Harald] German Canc Res Ctr DKFZ Heidelberg, Mol Epidemiol Grp, Heidelberg, Germany. [Burwinkel, Barbara; Surowy, Harald] Heidelberg Univ, Univ Womens Clin, Dept Obstet & Gynaecol, Div Mol Biol Breast Canc, Heidelberg, Germany. [Gambaccini, Dario; Marchi, Santino] Univ Pisa, Dept Gastroenterol, Gastroenterol Unit, Pisa, Italy. [Colucci, Rocchina; Blandizzi, Corrado] Univ Pisa, Dept Clin & Expt Med, Div Pharmacol & Chemotherapy, Pisa, Italy. [Barbaro, Raffaella; Stanghellini, Vincenzo; Barbara, Giovanni] Univ Bologna, S Orsola M Malpighi Hosp, Dept Med & Surg Sci, Bologna, Italy. [Karling, Pontus] Umea Univ, Dept Med, Umea, Sweden. [Walter, Susanna] Linkoping Univ, Div Gastroenterol, Inst Clin & Expt Med, Linkoping, Sweden. [Ohlsson, Bodil] Skanes Univ Hosp, Dept Clin Sci, Malmo, Sweden. [Tornblom, Hans; Simren, Magnus] Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Inst Med, Gothenburg, Sweden. [Andreasson, Anna; Agreus, Lars] Karolinska Inst, Dept Neurobiol Care Sci & Soc, SE-14183 Stockholm, Sweden. [Andreasson, Anna] Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden. [Boeckxstaens, Guy; Wouters, Mira M.] Leuven Univ, Translat Res Ctr Gastrointestinal Disorders, Leuven, Belgium. [Camilleri, Michael] Mayo Clin, Clin Enter Neurosci Translat & Epidemiol Res, Rochester, MN USA. RP D'Amato, M (reprint author), Karolinska Inst, Dept Biosci & Nutr, Halsovag 7-9, SE-14183 Stockholm, Sweden. EM mauro.damato@ki.se RI Wouters, Mira/K-1371-2013; Rivera, Natalia V/S-4231-2016; Magnusson, Patrik/C-4458-2017; OI Wouters, Mira/0000-0002-3438-1919; Rivera, Natalia V/0000-0002-1298-1243; Andreasson, Anna/0000-0003-0203-7977; Assadi, Ghazaleh/0000-0002-3723-9141; D'Amato, Mauro/0000-0003-2743-5197; Dlugosz, Aldona/0000-0003-3540-2571 FU Swedish Research Council [VR 2010-2976]; Medical Faculty of the University of Heidelberg; Research Foundation-Flanders (FWO) [G.0905.07]; FWO FX This work was supported by funds from the Swedish Research Council to MD (VR 2010-2976) and the Medical Faculty of the University of Heidelberg to BN. GB was funded by a governmental grant (Odysseus programme, G.0905.07) of the Research Foundation-Flanders (FWO). MMW is supported by a FWO postdoctoral fellowship. NR 37 TC 10 Z9 10 U1 3 U2 15 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD NOV PY 2015 VL 64 IS 11 BP 1774 EP 1782 DI 10.1136/gutjnl-2014-307997 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CT1WQ UT WOS:000362593700016 PM 25248455 ER PT J AU Mirkovic, J Elias, K Drapkin, R Barletta, JA Quade, B Hirsch, MS AF Mirkovic, Jelena Elias, Kevin Drapkin, Ronny Barletta, Justine A. Quade, Bradley Hirsch, Michelle S. TI GATA3 expression in gestational trophoblastic tissues and tumours SO HISTOPATHOLOGY LA English DT Article DE choriocarcinoma; endometrial adenocarcinoma; GATA3; hydatidiform mole; immunohistochemistry; Mullerian; placenta; trophoblast ID COMPREHENSIVE ANALYSIS; BREAST; IMMUNOHISTOCHEMISTRY; DIFFERENTIATION; CARCINOMAS; UTILITY AB AimsGATA3 is a zinc-finger transcription factor that is important for trophoblast differentiation. GATA3 is sensitive for urothelial and breast carcinomas, but the specificity is low. The aim of this study was to investigate the expression of GATA3 in trophoblast-related tissues and neoplasia. Methods and resultsGATA3 immunohistochemistry was performed on 33 placentas, one atypical placental site nodule, 25 hydatidiform moles (HMs), and 13 gestational trophoblastic tumours (GTTs). One hundred and sixty endometrial adenocarcinomas were also stained. Western blotting was performed on trophoblastic cell lines and compared to other cancer cell lines. Immature placentas were characterized by strong, diffuse nuclear GATA3 staining. Mature placentas showed less expression with scattered positive cells in the villous cytotrophoblast. HMs showed diffuse expression in cytotrophoblast and implantation site trophoblast, and heterogeneous expression in extravillous trophoblast. All GTTs were positive for GATA3. All endometrial adenocarcinomas were GATA3-negative. Western blotting demonstrated GATA3 in choriocarcinoma, whereas the placenta, and cervical and endometrial cancer cell lines, were negative. ConclusionsAll trophoblast lineages were positive for GATA3. The extent of GATA3 expression varied between immature and mature placentas, suggesting a role in trophoblast maturation. GATA3 does not distinguish normal placenta, HMs, or GTTs. Nevertheless, GATA3 may help in distinguishing trophoblastic tumors from Mullerian epithelial malignancies and a subset of tumours of unknown origin. C1 [Mirkovic, Jelena; Barletta, Justine A.; Quade, Bradley; Hirsch, Michelle S.] Brigham & Womens Hosp, Dept Pathol, Womens & Perinatal Pathol Div, Boston, MA 02115 USA. [Mirkovic, Jelena; Elias, Kevin; Barletta, Justine A.; Quade, Bradley; Hirsch, Michelle S.] Harvard Univ, Sch Med, Boston, MA USA. [Elias, Kevin] Brigham & Womens Hosp, Div Gynecol Oncol, Boston, MA 02115 USA. [Drapkin, Ronny] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Hirsch, MS (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St,Amory 3, Boston, MA 02115 USA. EM mhirsch1@partners.org RI Drapkin, Ronny/E-9944-2016; OI Drapkin, Ronny/0000-0002-6912-6977; Elias, Kevin/0000-0003-1502-5553 FU Debra and Robert First Fund; Honorable Tina Brozman Foundation; White Foundation FX The authors wish to acknowledge administrative and laboratory assistance from the Brigham and Women's Hospital histology and immunohistochemistry laboratories, and the Dana Farber/Harvard Cancer Center tissue microarray core facility. Research support was provided by the Debra and Robert First Fund (R. Drapkin and K. Elias), the Honorable Tina Brozman Foundation (R. Drapkin), and the White Foundation (K. Elias). This work was presented in part at the 103rd Annual Meeting of the United States and Canadian Academy of Pathology, San Diego, CA, 2014. NR 23 TC 5 Z9 7 U1 0 U2 6 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 NOV PY 2015 VL 67 IS 5 BP 636 EP 644 DI 10.1111/his.12681 PG 9 WC Cell Biology; Pathology SC Cell Biology; Pathology GA CT3TJ UT WOS:000362729500005 PM 25753145 ER PT J AU Truong-Bolduc, QC Bolduc, GR Medeiros, H Vyas, JM Wang, Y Hooper, DC AF Truong-Bolduc, Q. C. Bolduc, G. R. Medeiros, H. Vyas, J. M. Wang, Y. Hooper, D. C. TI Role of the Tet38 Efflux Pump in Staphylococcus aureus Internalization and Survival in Epithelial Cells SO INFECTION AND IMMUNITY LA English DT Article ID FIBRONECTIN-BINDING PROTEIN; ESCHERICHIA-COLI; IN-VIVO; CAMPYLOBACTER-JEJUNI; EXPRESSION; RESISTANCE; MGRA; NORB; REGULATOR; BACTERIA AB We previously identified the protein Tet38 as a chromosomally encoded efflux pump of Staphylococcus aureus that confers resistance to tetracycline and certain unsaturated fatty acids. Tet38 also contributes to mouse skin colonization. In this study, we discovered a novel regulator of tet38, named tetracycline regulator 21 (TetR21), that bound specifically to the tet38 promoter and repressed pump expression. A Delta tetR21 mutant showed a 5-fold increase in tet38 transcripts and an 8-fold increase in resistance to tetracycline and fatty acids. The global regulator MgrA bound to the tetR21 promoter and indirectly repressed the expression of tet38. To further assess the full role of Tet38 in S. aureus adaptability, we tested its effect on host cell invasion using A549 (lung) and HMEC-1 (heart) cell lines. We used S. aureus RN6390, its Delta tet38, Delta tetR21, and Delta mgrA mutants, and a Delta tet38 Delta tetR21 double mutant. After 2 h of contact, the Delta tet38 mutant was internalized in 6-fold-lower numbers than RN6390 in A549 and HMEC-1 cells, and the Delta tetR21 mutant was internalized in 2-fold-higher numbers than RN6390. A slight increase of 1.5-fold in internalization was found for the Delta mgrA mutant. The growth patterns of RN6390 and the Delta mgrA and Delta tetR21 mutants within A549 cells were similar, while no growth was observed for the Delta tet38 mutant. These data indicate that the Tet38 efflux pump is regulated by TetR21 and contributes to the ability of S. aureus to internalize and replicate within epithelial cells. C1 [Truong-Bolduc, Q. C.; Medeiros, H.; Vyas, J. M.; Wang, Y.; Hooper, D. C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02134 USA. [Bolduc, G. R.] Massasoit Community Coll, Brockton, MA USA. RP Hooper, DC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02134 USA. EM dhooper@mgh.harvard.edu FU U.S. Public Health Service from the National Institutes of Health [R37-AI23988, P01-AI083214]; NSF-ATE grant from the National Science Foundation [DUE 1205020] FX This work was supported by U.S. Public Health Service grants no. R37-AI23988 and P01-AI083214 (M. Gilmore, principal investigator) from the National Institutes of Health to D.C.H. and, in part, by an NSF-ATE grant (no. DUE 1205020) from the National Science Foundation to G.R.B. NR 44 TC 3 Z9 3 U1 0 U2 13 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 NOV PY 2015 VL 83 IS 11 BP 4362 EP 4372 DI 10.1128/IAI.00723-15 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NU UT WOS:000362494000018 PM 26324534 ER PT J AU Semenyuk, EG Poroyko, VA Johnston, PF Jones, SE Knight, KL Gerding, DN Driks, A AF Semenyuk, Ekaterina G. Poroyko, Valeriy A. Johnston, Pehga F. Jones, Sara E. Knight, Katherine L. Gerding, Dale N. Driks, Adam TI Analysis of Bacterial Communities during Clostridium difficile Infection in the Mouse SO INFECTION AND IMMUNITY LA English DT Article ID IN-SITU HYBRIDIZATION; OLIGONUCLEOTIDE PROBES; GASTROINTESTINAL-TRACT; INTESTINAL MICROBIOTA; GUT MICROBIOTA; DIARRHEA; DISEASE; HOST; ESTABLISHMENT; COLONIZATION AB Clostridium difficile infection (CDI) is a major cause of health care-associated disease. CDI initiates with ingestion of C. difficile spores, germination in the gastrointestinal (GI) tract, and then colonization of the large intestine. The interactions between C. difficile cells and other bacteria and with host mucosa during CDI remain poorly understood. Here, we addressed the hypothesis that, in a mouse model of CDI, C. difficile resides in multicellular communities (biofilms) in association with host mucosa. To do this, we paraffin embedded and then sectioned the GI tracts of infected mice at various days postinfection (p.i.). We then used fluorescent in situ hybridization (FISH) with 16S rRNA probes targeting most bacteria as well as C. difficile specifically. The results revealed that C. difficile is present as a minority member of communities in the outer (loose) mucus layer, in the cecum and colon, starting at day 1 p.i. To generate FISH probes that identify bacteria within mucus-associated communities harboring C. difficile, we characterized bacterial populations in the infected mouse GI tract using 16S rRNA gene sequence analysis of bacterial DNA prepared from intestinal content. This analysis revealed the presence of genera of several families belonging to Bacteroidetes and Firmicutes. These data suggest that formation of multispecies communities associated with the mucus of the cecum and colon is an important early step in GI tract colonization. They raise the possibility that other bacterial species in these communities modulate the ability of C. difficile to successfully colonize and, thereby, cause disease. C1 [Semenyuk, Ekaterina G.; Johnston, Pehga F.; Jones, Sara E.; Knight, Katherine L.; Driks, Adam] Loyola Univ Chicago, Stritch Sch Med, Dept Microbiol & Immunol, Maywood, IL 60153 USA. [Poroyko, Valeriy A.] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Johnston, Pehga F.; Gerding, Dale N.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. RP Driks, A (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Microbiol & Immunol, Maywood, IL 60153 USA. EM adriks@lumc.edu FU Falk Foundation; National Institutes of Health [R21AI097934, NIH 1R21AI099713-01] FX This work was funded by grants from the Falk Foundation and the National Institutes of Health (R21AI097934) to A.D. and was partly funded by a National Institutes of Health grant (NIH 1R21AI099713-01) to V.A.P. NR 46 TC 8 Z9 8 U1 5 U2 15 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 NOV PY 2015 VL 83 IS 11 BP 4383 EP 4391 DI 10.1128/IAI.00145-15 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NU UT WOS:000362494000020 PM 26324536 ER PT J AU Makris, N Liang, L Biederman, J Valera, EM Brown, AB Petty, C Spencer, TJ Faraone, SV Seidman, LJ AF Makris, Nikos Liang, Lichen Biederman, Joseph Valera, Eve M. Brown, Ariel B. Petty, Carter Spencer, Thomas J. Faraone, Stephen V. Seidman, Larry J. TI Toward Defining the Neural Substrates of ADHD: A Controlled Structural MRI Study in Medication-Naive Adults SO JOURNAL OF ATTENTION DISORDERS LA English DT Article DE ADHD; cerebellum; VBM; brain structure; treatment-naive ADHD ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; ANATOMICALLY SPECIFIED METHOD; LEARNING-DISABILITIES; BRAIN IMAGES; CEREBELLUM; CHILDREN; ROBUST; OPTIMIZATION; REGISTRATION AB Objective: We assessed the neural correlates of adult ADHD in treatment-naive participants, an approach necessary for identifying neural substrates unconfounded by medication effects. Method: The sample consisted of 24 medication-naive adults with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnosed ADHD and 24 healthy controls, comparable on age, sex, handedness, reading achievement, IQ, and psychiatric comorbidity. All participants were assessed with structured diagnostic interviews. Magnetic resonance imaging (MRI)-based regional voxel-based morphometry (r-VBM) was used to assess volumetric differences in a priori defined brain regions of interest. Results: VBM analysis revealed group differences in the hypothesized cortical and subcortical areas; however, only cerebellar volume reductions in ADHD retained significance (p < .05) after corrections for multiple comparisons. Conclusion: These results support the notion that medication-naive ADHD as expressed in adulthood, manifests subtle brain volume reductions from normal in the cerebellum, and possibly in other syndrome-congruent gray-matter structures. Larger samples are required to confirm these findings. C1 [Makris, Nikos; Liang, Lichen; Biederman, Joseph; Valera, Eve M.; Brown, Ariel B.; Petty, Carter; Spencer, Thomas J.; Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02129 USA. [Makris, Nikos; Biederman, Joseph; Valera, Eve M.; Brown, Ariel B.; Petty, Carter; Spencer, Thomas J.; Seidman, Larry J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Makris, N (reprint author), Massachusetts Gen Hosp, Ctr Morphometr Anal, 149,13th St,Room 10-006, Charlestown, MA 02129 USA. EM nikos@cma.mgh.harvard.edu OI Faraone, Stephen/0000-0002-9217-3982 FU NIDA [1R01DA027804-01]; NIMH [1R21MH084041-01A1]; NIMH MH/HD [62152]; Mental Illness and Neuroscience Discovery (MIND) Institute; National Research Service Award [NIMH F32 MH065040-01A1]; Peter Livingston Fellowship through the Harvard Medical School Department of Psychiatry; Clinical Research Training Program Fellowship in Biological and Social Psychiatry [MH-16259, MH 071535, R01 HD 067744]; NIMH MH [57934]; National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award; Pediatric Psychopharmacology Council Fund; Johnson and Johnson Center for the Study of Psychopathology; National Center for Research Resources [P41RR14075] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported, in part, by grants from NIDA 1R01DA027804-01, NIMH 1R21MH084041-01A1 (to N.M.); NIMH MH/HD 62152 and the Mental Illness and Neuroscience Discovery (MIND) Institute (to L.J.S.); National Research Service Award (NIMH F32 MH065040-01A1), Peter Livingston Fellowship through the Harvard Medical School Department of Psychiatry, the Clinical Research Training Program Fellowship in Biological and Social Psychiatry MH-16259, MH 071535 and R01 HD 067744 (to E.M.V.), NIMH MH 57934 (to S.V.F.); the National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award, the Pediatric Psychopharmacology Council Fund, and the Johnson and Johnson Center for the Study of Psychopathology (to J.B.); and The National Center for Research Resources (P41RR14075). NR 42 TC 4 Z9 4 U1 6 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 EI 1557-1246 J9 J ATTEN DISORD JI J. Atten. Disord. PD NOV PY 2015 VL 19 IS 11 SI SI BP 944 EP 953 DI 10.1177/1087054713506041 PG 10 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA CT1XR UT WOS:000362596600004 PM 24189200 ER PT J AU Harris, AHS Rubinsky, AD Hoggatt, KJ AF Harris, Alex H. S. Rubinsky, Anna D. Hoggatt, Katherine J. TI Possible Alternatives to Diagnosis-Based Denominators for Addiction Treatment Quality Measures SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Quality measurement; Quality comparisons; Validity; Methodology ID PERFORMANCE; FEASIBILITY; INDICATORS; ALCOHOL AB Consumers of healthcare quality measures are often unaware of how measured performance may be driven by diagnosing practices rather than the provision of high quality care. Reliance on quality metrics that depend on documented diagnoses can therefore subvert comparisons between clinicians, facilities or systems. In this study, three versions of an alcohol use disorder (AUD) treatment quality measure were calculated: method 1 the usual denominator including all diagnosed patients; method 2-a "population-based" denominator including the entire facility census; and method 3 an epidemiologically-derived denominator comprising the expected prevalence of AUD based on case-mix characteristics and geographic region. Performance rankings under the three specifications were calculated. Changes in percentile rank of up to 30-45% were observed between methods. Therefore, much of the observed between-facility differences on diagnosis-based quality measures may reflect variation in the propensity to diagnose rather than real differences in performance. Stakeholders must decide which of the validity threats produced by these different methods is least worrisome. Published by Elsevier Inc. C1 [Harris, Alex H. S.; Rubinsky, Anna D.] VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat & Subst Use Disorder, Qual Enhancement Res Initiat, Palo Alto, CA USA. [Hoggatt, Katherine J.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Hoggatt, Katherine J.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Harris, AHS (reprint author), VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat & Subst Use Disorder, Qual Enhancement Res Initiat, 795 Willow Rd, Menlo Pk, CA 94025 USA. EM Alexander.Harris2@va.gov FU VA Health Services Research and Development (HSRD) Service [IIR 10-370-2, RCS-14-232]; VA Substance Use Disorder Quality Enhancement Research Initiative [SUDQ-LIP-1208]; VA HSR&D QUERI Career Development Award [CDA 11-261] FX This study was funded by the VA Health Services Research and Development (HSR&D) Service (IIR 10-370-2; RCS-14-232), VA Substance Use Disorder Quality Enhancement Research Initiative (SUDQ-LIP-1208), and a VA HSR&D QUERI Career Development Award (CDA 11-261) to Dr. Hoggatt. None of the authors have any conflict of interest related to this work. The views expressed herein are not necessarily those of the Department of Veterans Affairs. NR 17 TC 2 Z9 2 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD NOV PY 2015 VL 58 BP 62 EP 66 DI 10.1016/j.jsat2015.06.004 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CS8BZ UT WOS:000362312000008 PM 26251046 ER PT J AU Burch, AE Morasco, BJ Petry, NM AF Burch, Ashley E. Morasco, Benjamin J. Petry, Nancy M. TI Patients Undergoing Substance Abuse Treatment and Receiving Financial Assistance for a Physical Disability Respond Well to Contingency Management Treatment SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Substance abuse treatment; Contingency management; Disability ID RESISTANT METHADONE PATIENTS; VOUCHER-BASED REINFORCEMENT; ADDICTION SEVERITY INDEX; RANDOMIZED-TRIAL; COCAINE ABSTINENCE; DISORDERS; PENSION; COHORT; RISK; COMORBIDITY AB Physical illness and disability are common in individuals with substance use disorders, but little is known about the impact of physical disability status on substance use treatment outcomes. This study examined the main and interactive effects of physical disability payment status on substance use treatment. Participants (N = 1,013) were enrolled in one of six prior randomized clinical trials comparing contingency management (CM) to standard care; 79 (7.8%) participants reported receiving disability payments, CM improved all three primary substance use outcomes: treatment retention, percent negative samples and longest duration of abstinence. There was no significant main effect of physical disability payment status on treatment outcomes; however, a significant treatment condition by physical disability status interaction effect emerged in terms of retention in treatment and duration of abstinence achieved. Patients who were receiving physical disability payments responded particularly well to CM, and their time in treatment and durations of drug and alcohol abstinence increased even more markedly with CM than did that of their counterparts who were not receiving physical disability assistance. These findings suggest an objectively defined cohort of patients receiving substance use treatment who respond particularly well to CM. (C) 2015 Elsevier Inc. All rights reserved. C1 [Burch, Ashley E.; Petry, Nancy M.] Univ Connecticut, Sch Med MC 3944, Calhoun Cardiol Ctr, Farmington, CT 06030 USA. [Burch, Ashley E.; Petry, Nancy M.] Univ Connecticut, Sch Med MC 3944, Dept Med, Farmington, CT 06030 USA. [Morasco, Benjamin J.] VA Portland Hlth Care Syst, Portland VA Med Ctr, Ctr Improve Vet Involvement Care, Portland, OR 97239 USA. [Morasco, Benjamin J.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. RP Petry, NM (reprint author), Univ Connecticut, Sch Med MC 3944, 263 Farmington Ave, Farmington, CT 06030 USA. EM aburch@uchc.edu; benjamin.morasco@va.gov; npetry@uchc.edu FU NCRR NIH HHS [M01 RR006192]; NIAAA NIH HHS [P60 AA003510, R01 AA021446]; NICHD NIH HHS [R01 HD075630]; NIDA NIH HHS [P30 DA023918, P50 DA009241, R01 DA013444, R01 DA018883, R01 DA027615] NR 43 TC 1 Z9 1 U1 2 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD NOV PY 2015 VL 58 BP 67 EP 71 DI 10.1016/j.jsat.2015.06.006 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CS8BZ UT WOS:000362312000009 PM 26184649 ER PT J AU Krupski, A Graves, MC Bumgardner, K Roy-Byrne, P AF Krupski, Antoinette Graves, Meredith C. Bumgardner, Kristin Roy-Byrne, Peter TI Comparison of Homeless and Non-Homeless Problem Drug Users Recruited from Primary Care Safety-Net Clinics SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Homeless; Medical service utilization and costs; Arrests; Mental health problems; Primary care ID RISK-FACTORS; RELIABILITY; PREDICTORS; VETERANS; VALIDITY; ADULTS AB Introduction: The present study of homeless non-treatment-seeking problem drug users was designed to complement and extend previous studies which focused exclusively on treatment-seeking homeless problem drug users. Method: Data were available for 866 primary care patients with drug problems, 30% homeless and 70% housed. Results: In the 2 years prior to baseline, homeless participants had less chronic medical co-morbidity than problem drug users who were housed yet were significantly more likely to have used emergency department services, to have used them more frequently, and at higher cost. Compared to their housed counterparts, homeless participants were also more likely to have been admitted to specialized chemical dependency treatment and/or detoxification services, to have been arrested for a felony or gross misdemeanor, and to report having psychiatric problems in the prior 30 days. Conclusions: Additional support may be necessary for homeless patients presenting in primary care to benefit from substance abuse treatment given their more severe drug use problems coupled with their co-morbid health, psychiatric, and psychosocial problems. (C) 2015 Elsevier Inc. All rights reserved. C1 [Krupski, Antoinette; Graves, Meredith C.; Bumgardner, Kristin; Roy-Byrne, Peter] Univ Washington, Dept Psychiat & Behav Sci, Harborview Med Ctr, Seattle, WA 98104 USA. [Graves, Meredith C.] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. RP Krupski, A (reprint author), Univ Washington, Dept Psychiat & Behav Sci, Harborview Med Ctr, Box 359911,325 9th Ave, Seattle, WA 98104 USA. EM krupski@uw.edu FU National Institute on Drug Abuse of the National Institutes of Health [R01DA026014] FX Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Number R01DA026014. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 18 TC 0 Z9 0 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD NOV PY 2015 VL 58 BP 84 EP 89 DI 10.1016/j.jsat.2015.06.007 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CS8BZ UT WOS:000362312000012 PM 26153073 ER PT J AU Fontana, CR Song, XQ Polymeri, A Goodson, JM Wang, XS Soukos, NS AF Fontana, Carla R. Song, Xiaoqing Polymeri, Angeliki Goodson, J. Max Wang, Xiaoshan Soukos, Nikolaos S. TI The effect of blue light on periodontal biofilm growth in vitro SO LASERS IN MEDICAL SCIENCE LA English DT Article DE Phototherapy; Blue light; Dental plaque; Periodontal bacteria; Biofilm ID PORPHYROMONAS-GINGIVALIS; FUSOBACTERIUM-NUCLEATUM; PROBIOTIC MOUTHWASH; VISIBLE-LIGHT; ORAL BACTERIA; ARGON-LASER; INFLAMMATION; IRRADIATION; DISEASE; PROBIORA(3) AB We have previously shown that blue light eliminates the black-pigmented oral bacteria Porphyromonas gingivalis, Prevotella intermedia, Prevotella nigrescens, and Prevotella melaninogenica. In the present study, the in vitro photosensitivity of the above black-pigmented microorganisms and four Fusobacteria species (Fusobacterium nucleatum ss. nucleatum, F. nucleatum ss. vincentii, F. nucleatum ss. polymorphum, Fusobacterium periodonticum) was investigated in pure cultures and human dental plaque suspensions. We also tested the hypothesis that phototargeting the above eight key periodontopathogens in plaque-derived biofilms in vitro would control growth within the dental biofilm environment. Cultures of the eight bacteria were exposed to blue light at 455 nm with power density of 80 mW/cm(2) and energy fluence of 4.8 J/cm(2). High-performance liquid chromatography (HPLC) analysis of bacteria was performed to demonstrate the presence and amounts of porphyrin molecules within microorganisms. Suspensions of human dental plaque bacteria were also exposed once to blue light at 455 nm with power density of 50 mW/cm(2) and energy fluence of 12 J/cm(2). Microbial biofilms developed from the same plaque were exposed to 455 nm blue light at 50 mW/cm(2) once daily for 4 min (12 J/cm(2)) over a period of 3 days (4 exposures) in order to investigate the cumulative action of phototherapy on the eight photosensitive pathogens as well as on biofilm growth. Bacterial growth was evaluated using the colony-forming unit (CFU) assay. The selective phototargeting of pathogens was studied using whole genomic probes in the checkerboard DNA-DNA format. In cultures, all eight species showed significant growth reduction (p < 0.05). HPLC demonstrated various porphyrin patterns and amounts of porphyrins in bacteria. Following phototherapy, the mean survival fractions were reduced by 28.5 and 48.2 % in plaque suspensions and biofilms, respectively, (p < 0.05). DNA probe analysis showed significant reduction in relative abundances of the eight bacteria as a group in plaque suspensions and biofilms. The cumulative blue light treatment suppressed biofilm growth in vitro. This may introduce a new avenue of prophylactic treatment for periodontal diseases. C1 [Fontana, Carla R.; Song, Xiaoqing; Polymeri, Angeliki; Soukos, Nikolaos S.] Forsyth Inst, Appl Mol Photomed Lab, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Fontana, Carla R.] Univ Sao Paulo State UNESP, Sch Pharmaceut Sci, Dept Clin Anal, BR-14801960 Araraquara, SP, Brazil. [Goodson, J. Max] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Wang, Xiaoshan] Forsyth Inst, Dept Appl Oral Sci, Epidemiol & Biostat Core, Cambridge, MA 02142 USA. RP Soukos, NS (reprint author), Forsyth Inst, Appl Mol Photomed Lab, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. EM fontanacr@fcfar.unesp.br; lsong@forsyth.org; apolymeri@forsyth.org; mgoodson@forsyth.org; xwang@forsyth.org; nsoukos@forsyth.org FU Colgate-Palmolive Company FX Carla R. Fontana was a fellow of CAPES Foundation, Brazilian government (process BEX 0547/05-0). We thank Dr. Chul Lee, Department of Preventive Medicine and Community Health, School of Medicine, The University of Texas Medical Branch, Galveston, Texas, for helping with the HPLC analysis. This work was supported in part by Colgate-Palmolive Company. Phototherapy studies with plaque suspensions and biofilms were carried out with the light source provided by PhotOral Inc. NR 39 TC 3 Z9 3 U1 3 U2 8 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0268-8921 EI 1435-604X J9 LASER MED SCI JI Lasers Med. Sci. PD NOV PY 2015 VL 30 IS 8 BP 2077 EP 2086 DI 10.1007/s10103-015-1724-7 PG 10 WC Engineering, Biomedical; Surgery SC Engineering; Surgery GA CT1TG UT WOS:000362583600005 PM 25759232 ER PT J AU Criss, S Baidal, JAW Goldman, RE Perkins, M Cunningham, C Taveras, EM AF Criss, Shaniece Baidal, Jennifer A. Woo Goldman, Roberta E. Perkins, Meghan Cunningham, Courtney Taveras, Elsie M. TI The Role of Health Information Sources in Decision-Making Among Hispanic Mothers During Their Children's First 1000 Days of Life SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Health information; Decision-making; Hispanic; Mothers; Pregnancy; Infants; Early childhood ID PREGNANT-WOMEN; UNITED-STATES; LOW-INCOME; INTERNET; SEEKING; CHILDHOOD; OBESITY; ADVICE AB This qualitative research aimed to explore how health information sources inform decision-making among Hispanic mothers during their children's first 1000 days of life (conception-age 24 months), and to generate appropriate health information sources and communication strategies for future interventions. We conducted seven focus groups with 49 Hispanic women who were pregnant or had children < 2 years old. Domains included interpersonal and media sources, source trustworthiness, dealing with contradictory information, and how information affects decision-making. We used immersion/crystallization process for analysis. Trusted health information sources included health care providers, female and male family members, BabyCenter.com and other Internet sources, selected social media, and television. Some immigrant women reported preferring the Internet citing less established local support networks. Women highlighted the importance of validating health information through checking multiple sources for consistency and resolving contradictory information. Mothers expressed interest in receiving reliable website links from healthcare professionals and outreach to extended family. Cultural factors, including immigration status, are important in understanding the use of health information sources and their role in decision-making about pregnancy and child health among Hispanic mothers. Healthcare providers and public health professionals should consider Hispanic mothers health information environment and provide culturally-relevant communication strategies and interventions during this high information-seeking time period. C1 [Criss, Shaniece; Goldman, Roberta E.] Harvard Univ, Dept Social & Behav Sci, Sch Publ Hlth, Boston, MA 02115 USA. [Baidal, Jennifer A. Woo] Boston Childrens Hosp, Div Gastroenterol & Nutr, Boston, MA 02115 USA. [Baidal, Jennifer A. Woo; Perkins, Meghan; Cunningham, Courtney; Taveras, Elsie M.] Massachusetts Gen Hosp, Div Gen Acad Pediat, Dept Pediat, Boston, MA 02114 USA. [Goldman, Roberta E.] Brown Univ, Warren Alpert Med Sch, Pawtucket, RI 02860 USA. RP Criss, S (reprint author), Harvard Univ, Dept Social & Behav Sci, Sch Publ Hlth, 677 Huntington Ave,Kresge Bldg, Boston, MA 02115 USA. EM scriss@mail.harvard.edu FU NIH [R01MD003963, 3T32DK7477-30 S1, 3R25CA057711]; Initiative to Maximize Student Diversity Award [GM055353-13]; Maternal and Child Health Bureau Award [T03MC07648] FX This study was supported by NIH grants from R01MD003963 (E.M.T.) and 3T32DK7477-30 S1 (J.W.B.); predoctoral training grants from NIH Award No. 3R25CA057711 (S.C.), the Initiative to Maximize Student Diversity Award No. GM055353-13 (S.C.); and Maternal and Child Health Bureau Award No. T03MC07648 (S.C.). NR 33 TC 2 Z9 2 U1 2 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD NOV PY 2015 VL 19 IS 11 BP 2536 EP 2543 DI 10.1007/s10995-015-1774-2 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT1QY UT WOS:000362576800023 PM 26122256 ER PT J AU Kleckner, IR Wormwood, JB Simmons, WK Barrett, LF Quigley, KS AF Kleckner, Ian R. Wormwood, Jolie Baumann Simmons, W. Kyle Barrett, Lisa Feldman Quigley, Karen S. TI Methodological recommendations for a heartbeat detection-based measure of interoceptive sensitivity SO PSYCHOPHYSIOLOGY LA English DT Article DE Heartbeat detection; Interoceptive sensitivity; Reliability; Power calculation; Simulation ID STATISTICAL POWER ANALYSIS; EMOTIONAL EXPERIENCE; DECISION-MAKING; VISCERAL PERCEPTION; ET-AL.; AWARENESS; BRAIN; SENSATIONS; ACCURACY; FEELINGS AB Heartbeat detection tasks are often used to measure cardiac interoceptive sensitivitythe ability to detect sensations from one's heart. However, there is little work to guide decisions on the optimum number of trials to use, which should balance reliability and power against task duration and participant burden. Here, 174 participants completed 100 trials of a widely used heartbeat detection task where participants attempt to detect whether presented tones occurred synchronously or asynchronously with their heartbeats. First, we quantified measurement reliability of the participant's accuracy derived from differing numbers of trials of the task using a correlation metric; we found that at least 40-60 trials were required to yield sufficient reliability. Next, we quantified power by simulating how the number of trials influenced the ability to detect a correlation between cardiac interoceptive sensitivity and other variables that differ across participants, including a variable measured from our sample (body mass index) as well as simulated variables of varying effect sizes. Using these simulations, we quantified the trade-offs between sample size, effect size, and number of trials in the heartbeat detection task such that a researcher can easily determine any one of these variables at given values of the other two variables. We conclude that using fewer than 40 trials is typically insufficient due to poor reliability and low power in estimating an effect size, although the optimal number of trials can differ by study. C1 [Kleckner, Ian R.; Wormwood, Jolie Baumann; Barrett, Lisa Feldman; Quigley, Karen S.] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Simmons, W. Kyle] Laureate Inst Brain Res, Tulsa, OK USA. [Simmons, W. Kyle] Univ Tulsa, Fac Community Med, Tulsa, OK 74104 USA. [Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA 02115 USA. [Quigley, Karen S.] Edith Nourse Rogers Mem VA Hosp, Bedford, MA USA. RP Kleckner, IR (reprint author), Northeastern Univ, Dept Psychol, 125 Nightingale Hall,360 Huntington Ave, Boston, MA 02115 USA. EM ian.kleckner@gmail.com OI Simmons, William/0000-0002-0399-9003 FU NIH HHS [DP1 OD003312, DP1OD003312]; NIMH NIH HHS [F32 MH096533, F32MH096533, K01 MH096175, K01MH096175-01] NR 50 TC 7 Z9 7 U1 3 U2 13 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 NOV PY 2015 VL 52 IS 11 BP 1432 EP 1440 DI 10.1111/psyp.12503 PG 9 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA CT0OW UT WOS:000362497000002 PM 26265009 ER PT J AU Gerrard, P Kazis, LE Ryan, CM Shie, VL Holavanahalli, R Lee, A Jette, A Fauerbach, JA Esselman, P Herndon, D Schneider, JC AF Gerrard, Paul Kazis, Lewis E. Ryan, Colleen M. Shie, Vivian L. Holavanahalli, Radha Lee, Austin Jette, Alan Fauerbach, James A. Esselman, Peter Herndon, David Schneider, Jeffrey C. TI Validation of the Community Integration Questionnaire in the adult burn injury population SO QUALITY OF LIFE RESEARCH LA English DT Article DE Community Integration Questionnaire; Burn outcomes; Rehabilitation; Burn injury; Community integration; Participation ID TRAUMATIC BRAIN-INJURY; ITEM RESPONSE THEORY; PSYCHOMETRIC PROPERTIES; INTERNATIONAL CLASSIFICATION; REHABILITATION; DISABILITY; OUTCOMES; VALIDITY; HEALTH AB Purpose With improved survival, long-term effects of burn injuries on quality of life, particularly community integration, are important outcomes. This study aims to assess the Community Integration Questionnaire's psychometric properties in the adult burn population. Methods Data were obtained from a multicenter longitudinal data set of burn survivors. The psychometric properties of the Community Integration Questionnaire (n = 492) were examined. The questionnaire items were evaluated for clinical and substantive relevance; validation procedures were conducted on different samples of the population; construct validity was assessed using exploratory factor analysis; internal consistency reliability was examined using Cronbach's alpha statistics; and item response theory was applied to the final models. Results The CIQ-15 was reduced by two questions to form the CIQ-13, with a two-factor structure, interpreted as self/family care and social integration. Item response theory testing suggests that Factor 2 captures a wider range of community integration levels. Cronbach's alpha was 0.80 for Factor 1, 0.77 for Factor 2, and 0.79 for the test as a whole. Conclusions The CIQ-13 demonstrates validity and reliability in the adult burn survivor population addressing issues of self/family care and social integration. This instrument is useful in future research of community reintegration outcomes in the burn population. C1 [Gerrard, Paul; Shie, Vivian L.; Schneider, Jeffrey C.] Harvard Univ, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Sch Med, Boston, MA 02114 USA. [Kazis, Lewis E.; Jette, Alan] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, CAPP, Boston, MA USA. [Ryan, Colleen M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Sumner Redstone Burn Ctr,Surg Serv, Boston, MA USA. [Holavanahalli, Radha] Univ Texas SW Med Ctr Dallas, Dept Phys Med & Rehabil, Dallas, TX 75390 USA. [Lee, Austin] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Fauerbach, James A.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Esselman, Peter] Univ Washington, Harborview Med Ctr, Dept Rehabil Med, Seattle, WA 98104 USA. [Herndon, David] Univ Texas Med Branch, Dept Surg & Pediat, Galveston, TX 77555 USA. [Ryan, Colleen M.] Shriners Hosp Children Boston, Boston, MA USA. RP Schneider, JC (reprint author), Harvard Univ, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Sch Med, 300 1st Ave, Boston, MA 02114 USA. EM jcschneider@partners.org NR 23 TC 4 Z9 4 U1 2 U2 2 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 NOV PY 2015 VL 24 IS 11 BP 2651 EP 2655 DI 10.1007/s11136-015-0997-4 PG 5 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS7TO UT WOS:000362289300009 PM 25986908 ER PT J AU Caqueo-Urizar, A Boyer, L Baumstarck, K Gilman, SE AF Caqueo-Urizar, Alejandra Boyer, Laurent Baumstarck, Karine Gilman, Stephen E. TI Subjective perceptions of cognitive deficits and their influences on quality of life among patients with schizophrenia SO QUALITY OF LIFE RESEARCH LA English DT Article DE Schizophrenia; Quality of life; Social deficits; Neurocognitive deficits ID SOCIAL COGNITION; MENTAL-ILLNESS; NEUROCOGNITION; PREDICTORS; PSYCHOSIS; BEHAVIOR; SCALE; AREA; MIND AB Purpose Functional outcomes in schizophrenia may be more closely related to social cognition than to neurocognition; however, the extent to which social cognition influences quality of life (QoL) remains unclear. We conducted a cross-sectional survey study of the impact of patients' and clinicians' subjective perceptions of neurocognitive and social cognitive deficits on quality of life. Methods The study included 253 patients with schizophrenia and their clinicians from public mental health clinics in Bolivia, Chile, and Peru. We utilized the GEOPTE Scale of Social Cognition for Psychosis, the Schizophrenia Quality of Life Questionnaire, and the Positive and Negative Syndrome Scale for schizophrenia. Results Patients' subjective perceptions of their neurocognitive deficits (B = -1.13; CI -1.56 to -0.70) were significantly associated with QoL, whereas there was no independent association between the clinicians' ratings of the patients' neurocognitive deficits and QoL (B = -0.33; CI -0.98 to 0.31). However, patients' subjective perceptions of their neurocognitive deficits were no longer associated with QoL (B = -0.23; CI -0.71 to 0.24) once their perceptions of social cognitive impairments were accounted for (B = -1.03; CI -1.39 to -0.68). Conclusion Patients' perceptions of their social cognitive function (but not neurocognitive functioning) have a significant impact on their QoL. Clinicians' ratings of patients' cognitive deficits were only weakly correlated with patients' subjective perceptions of their own neurocognitive, suggesting a mismatch between clinician and patient assessments of such deficits. Closer attention should therefore be paid toward patients' perception of their own deficits by clinicians in order to improve QoL. C1 [Caqueo-Urizar, Alejandra] Univ Tarapaca, Dept Filosofia & Psicol, Arica, Chile. [Caqueo-Urizar, Alejandra; Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Boyer, Laurent; Baumstarck, Karine] Aix Marseille Univ, Publ Hlth Chron Dis & Qual Life Res Unit EA 3279, F-13005 Marseille, France. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Caqueo-Urizar, A (reprint author), Univ Tarapaca, Dept Filosofia & Psicol, Ave 18 Septiembre 2222, Arica, Chile. EM acaqueo@uta.cl RI Boyer, Laurent/E-5728-2016; OI Boyer, Laurent/0000-0003-1229-6622; Gilman, Stephen/0000-0002-8331-6419 FU CONICYT; BECAS-CHILE Postdoctorado en el Extranjero [74140004]; Convenio de Desempeno UTA-MINEDUC FX This research was funded by CONICYT and BECAS-CHILE Postdoctorado en el Extranjero (Number 74140004) and also by the Convenio de Desempeno UTA-MINEDUC. We thank Felipe Ponce and Jorge Escudero for their assistance in the study and also the following people and facilities: Dr. Hugo Sanchez, Dr. Ricardo Alvites, Dr. Andres Collado, Gladys Coaquira, and Vilma Liendo; and we extend our special thanks to Dr. Jose Revilla from Hipolito Unanue Hospital in Tacna, Peru, Dr. Marcio Soto from Arequipa, Peru, Dr. Fernando Garitano, Dr. Mauricio Peredo, and Dra. Mabel Romero from Centro de Rehabilitacion y Salud Mental San Juan de Dios, and the Director of Hospital Psiquiatrico de la Caja Nacional de Salud from La Paz, Bolivia. We also thank Dra. Magdalena Gardilcic, Ester Lopez, and Alejandra Lagos from Servicio de Salud de Arica, Chile, and extend our special thanks to all the patients and caregivers who participated in this study. NR 56 TC 3 Z9 3 U1 5 U2 8 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 NOV PY 2015 VL 24 IS 11 BP 2753 EP 2760 DI 10.1007/s11136-015-1019-2 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS7TO UT WOS:000362289300020 PM 26038220 ER PT J AU Birmingham, P Buffum, MD Blegen, MA Lyndon, A AF Birmingham, Patricia Buffum, Martha D. Blegen, Mary A. Lyndon, Audrey TI Handoffs and Patient Safety: Grasping the Story and Painting a Full Picture SO WESTERN JOURNAL OF NURSING RESEARCH LA English DT Article DE handoff; handover; shift report; continuity of care ID OF-THE-LITERATURE; NURSING HANDOVER; SHIFT HANDOVERS; SURGICAL UNITS; NURSES; CARE; INFORMATION; SETTINGS; WORK; COMMUNICATION AB Effective handoff communication is critical for patient safety. Research is needed to understand how information processes occurring intra-shift impact handoff effectiveness. The purpose of this qualitative study was to examine medical-surgical nurses' (n = 21) perspectives about processes that promote and hinder patient safety intra-shift and during handoff. Results indicated that offgoing nurses' ability to grasp the story intra-shift was essential to convey the full picture during handoff. When oncoming nurses understood the picture being conveyed at the handoff, nurses jointly painted a full picture. Arriving and leaving the handoff with this level of information promoted patient safety. However, intra-shift disruptions often impeded nurses in their processes to grasp the story thus posing risks to patient safety. Improvement efforts need to target the different processes involved in grasping the story and painting a full picture. Future research needs to examine handoff practices and outcomes on units with good and poor practice environments. C1 [Birmingham, Patricia; Buffum, Martha D.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Buffum, Martha D.; Blegen, Mary A.; Lyndon, Audrey] Univ Calif San Francisco, San Francisco, CA USA. RP Birmingham, P (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA. EM Patricia.Birmingham@va.gov FU Alpha Eta Chapter, Sigma Theta Tau International; Department of Veterans Affairs (VA) Medical Center San Francisco; National Centre for Advancing Translational Sciences; National Institutes of Health (NIH) through UCSF-CTSI [KL2TR000143] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The primary investigator received funding for a research award from the Alpha Eta Chapter, Sigma Theta Tau International. This material is a result of work supported by resources from the Department of Veterans Affairs (VA) Medical Center San Francisco. No funding from VA was received for this project. The fourth author received support from the National Centre for Advancing Translational Sciences, National Institutes of Health (NIH), through UCSF-CTSI Grant KL2TR000143. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the VA or NIH. NR 50 TC 1 Z9 1 U1 2 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0193-9459 EI 1552-8456 J9 WESTERN J NURS RES JI West. J. Nurs. Res. PD NOV PY 2015 VL 37 IS 11 BP 1458 EP 1478 DI 10.1177/0193945914539052 PG 21 WC Nursing SC Nursing GA CT3SR UT WOS:000362727700006 PM 24951369 ER PT J AU Mavros, MN Kaafarani, HMA Mejaddam, AY Ramly, EP Avery, L Fagenholz, PJ Yeh, DD de Moya, MA Velmahos, GC AF Mavros, Michael N. Kaafarani, Haytham M. A. Mejaddam, Ali Y. Ramly, Elie P. Avery, Laura Fagenholz, Peter J. Yeh, D. Dante de Moya, Marc A. Velmahos, George C. TI Additional Imaging in Alert Trauma Patients with Cervical Spine Tenderness and a Negative Computed Tomographic Scan: Is it Needed? SO WORLD JOURNAL OF SURGERY LA English DT Article ID LOW-RISK CRITERIA; BLUNT TRAUMA; RADIOGRAPHY; RULE; IDENTIFICATION; INJURIES; NEXUS AB The value of additional imaging in clearing the cervical spine (C-spine) of alert trauma patients with tenderness on clinical exam and a negative computed tomographic (CT) scan is still unclear. All adult trauma patients with a Glasgow Coma Scale of 15, C-spine tenderness in the absence of neurologic signs, and a negative C-spine CT were included. The study period extended from September 2011 to June 2012. C-spine CT scans were interpreted in detail and considered negative in the absence of any findings indicating bony, ligamentous, or soft tissue injury around the C-spine. The incidence of C-spine injury was evaluated using early (< 24 h) repeat physical examination, MRI, and/or flexion-extension films. Of 2015 patients with a C-spine CT, 383 (19 %) fulfilled the inclusion criteria. The median age was 43 (IQR: 30-53) and 44.7 % were female. Thirty-six patients (9.4 %) underwent MRI (3.7 %), flexion-extension imaging (5.2 %), or both (0.5 %), with no significant injuries identified and subsequent removal of the collar allowed. The remaining patients were clinically cleared within 24 h of presentation. None of the patients developed neurological signs following removal of the collar. On bivariate analysis, no variable except for evaluation by trauma surgery was associated with performance of additional imaging. C-spine precautions can be withdrawn without additional imaging in most blunt trauma patients with C-spine tenderness but negative neurologic evaluation and C-spine CT. Focus should be placed on the detailed and comprehensive interpretation of the C-spine CT. C1 [Mavros, Michael N.; Kaafarani, Haytham M. A.; Mejaddam, Ali Y.; Ramly, Elie P.; Fagenholz, Peter J.; Yeh, D. Dante; de Moya, Marc A.; Velmahos, George C.] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Avery, Laura] Massachusetts Gen Hosp, Dept Radiol, Div Emergency Radiol, Boston, MA 02114 USA. [Velmahos, George C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Velmahos, George C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Velmahos, GC (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. EM gvelmahos@partners.org NR 15 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD NOV PY 2015 VL 39 IS 11 BP 2685 EP 2690 DI 10.1007/s00268-015-3182-6 PG 6 WC Surgery SC Surgery GA CS8GQ UT WOS:000362324900011 PM 26239776 ER PT J AU Hanson, JL Hariri, AR Williamson, DE AF Hanson, Jamie L. Hariri, Ahmad R. Williamson, Douglas E. TI Blunted Ventral Striatum Development in Adolescence Reflects Emotional Neglect and Predicts Depressive Symptoms SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Depression; Early life stress; Emotional neglect; fMRI; Longitudinal; Neurodevelopment ID STRESSFUL LIFE EVENTS; CHILDHOOD MALTREATMENT; MAJOR DEPRESSION; PSYCHIATRIC OUTPATIENTS; AMYGDALA REACTIVITY; SENSITIVE PERIODS; ADULT DEPRESSION; BRAIN ACTIVATION; POSITIVE AFFECT; 1ST ONSET AB BACKGROUND: Emotional neglect is associated with multiple negative outcomes, particularly increased risk for depression. Motivated by increasing evidence of reward-related ventral striatum (VS) dysfunction in depression, we investigated the role of developmental changes in VS activity on the emergence of depressive symptomatology as a function of emotional neglect. METHODS: We examined relationships between longitudinal neuroimaging of reward-related VS activity, assessments of mood, and measures of emotional neglect in 106 participants first scanned between ages 11 to 15 and then 2 years later. RESULTS: We found that greater levels of emotional neglect were associated with blunted development of reward-related VS activity between the first and second assessments (as indexed by lower residualized change scores). Additionally, we found that decreases in this reward-related VS activity were related to greater depressive symptomatology and partially mediated the association between emotional neglect and subsequent depressive symptomatology. CONCLUSIONS: Our results provide an important demonstration that blunted development of reward-related VS activity as a function of emotional neglect predicts the emergence of depressive symptoms in adolescents. Further, our results are consistent with emerging evidence for the importance of reward-related VS dysfunction in the etiology and pathophysiology of depression. These results are a first step toward developing the ability to predict, prevent, and treat stress-related psychopathology through the targeting of specific neural phenotypes. C1 [Hanson, Jamie L.; Hariri, Ahmad R.] Duke Univ, Dept Psychol & Neurosci, Neurogenet Lab, Durham, NC 27710 USA. [Williamson, Douglas E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Williamson, Douglas E.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Hanson, JL (reprint author), Duke Univ, Dept Psychol & Neurosci, 417 Chapel Dr,Duke West Campus, Durham, NC 27710 USA. EM jlh125@duke.edu FU National Institute on Alcohol Abuse and Alcoholism [R01AA016274]; Genetic and Environmental Risk endowment from the Dielmann Family (DEW); National Institute on Drug Abuse [R01DA033369, R01DA031579]; National Institute of Mental Health [MH087493]; National Institute on Drug Abuse through the Center for the Study of Adolescent Risk and Resilience [P30DA023026]; National Institute of Child Health and Human Development through the Center for Developmental Science, University of North Carolina at Chapel Hill [T32HD0737625] FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism (Grant R01AA016274 to DEW), the Genetic and Environmental Risk endowment from the Dielmann Family (DEW), the National Institute on Drug Abuse (Grants R01DA033369 and R01DA031579 to ARH), the National Institute of Mental Health (Grant MH087493 to Consuelo Walss-Bass), a Postdoctoral Fellowship provided by the National Institute on Drug Abuse through the Center for the Study of Adolescent Risk and Resilience (Grant P30DA023026 to JLH), and a postdoctoral fellowship provided by the National Institute of Child Health and Human Development (Grant T32HD0737625) through the Center for Developmental Science, University of North Carolina at Chapel Hill, to JLH. NR 83 TC 19 Z9 19 U1 5 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD NOV 1 PY 2015 VL 78 IS 9 BP 598 EP 605 DI 10.1016/j.biopsych.2015.05.010 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CS7OB UT WOS:000362271800004 PM 26092778 ER PT J AU Malchau, H Porter, ML AF Malchau, Henrik Porter, Martyn L. TI Editorial Comment: 2014 Meeting of The International Society of Arthroplasty Registers SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material C1 [Malchau, Henrik] Harvard Univ, Sch Med, Boston, MA USA. [Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Porter, Martyn L.] Wrightington Hosp, Ctr Hip Surg, Wigan WN6 9EP, Lancs, England. RP Porter, ML (reprint author), Wrightington Hosp, Ctr Hip Surg, Hall Ln, Wigan WN6 9EP, Lancs, England. EM martynporter@hipkneeclinic.com NR 3 TC 1 Z9 1 U1 2 U2 3 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 NOV PY 2015 VL 473 IS 11 BP 3368 EP 3369 DI 10.1007/s11999-015-4435-2 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900008 PM 26189004 ER PT J AU Greene, ME Rolfson, O Gordon, M Garellick, G Nemes, S AF Greene, Meridith E. Rolfson, Ola Gordon, Max Garellick, Goran Nemes, Szilard TI Standard Comorbidity Measures Do Not Predict Patient-reported Outcomes 1 Year After Total Hip Arthroplasty SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article; Proceedings Paper CT 3rd Meeting of the International-Society-of-Arthroplasty-Registers CY 2014 CL Boston, MA SP Int Soc Arthroplasty Registers ID ADMINISTRATIVE DATA; CO-MORBIDITY; REPLACEMENT; QUESTIONNAIRE; VALIDATION; REGISTER; SCORES AB Comorbidities influence surgical outcomes and therefore need to be included in risk adjustment when predicting patient-reported outcomes. However, there is no consensus on how best to use the available data about comorbidities in registry-based predictive models. The purposes of this study were (1) to determine whether the International Classification of Diseases, 10(th) Revision (ICD-10)-based comorbidity measures (Elixhauser, Charlson, and Royal College of Surgeons Charlson) offer added value in explaining patients' health-related quality of life (HRQoL), pain, and satisfaction after total hip arthroplasty (THA) when preoperative HRQoL, pain, and Charnley classification were known; and (2) to determine the ideal timeframe for recording the different diagnoses that serves as the basis for comorbidity measure calculations. There were 22,263 patients who had undergone THA with complete pre- and postoperative patient-reported outcome measures (PROMs) included in the Swedish Hip Arthroplasty Register between 2002 and 2007. The three comorbidity indices were calculated with ICD-10 codes identified in the Swedish National Patient Register from 1, 2, and 5 years before the patient underwent THA. The impact of the comorbidity indices on the PROM scores (EQ-5D index, EQ visual analog scale [VAS], pain VAS, and satisfaction VAS) was modeled with linear regression where the 1-year patient postoperative outcome score was the dependent variable and independent variables included patient preoperative Charnley classification, preoperative HRQoL and pain, and comorbidity indices. The partial R-2 value indicated how much each variable uniquely contributed to the predictive capacity of the model. The ICD-10-based comorbidity measures added little predictive value to the models for each of the outcomes of interest (EQ-5D index, EQ VAS, pain VAS, and satisfaction VAS). Charnley classification and the preoperative scores were the strongest predictors of both measures of postoperative HRQoL, of postoperative pain, and postoperative satisfaction with outcomes from surgery. Of all the predictors considered, only the Charnley classification was associated with all outcomes, irrespective of the timeframe considered. For each of the outcomes considered, there was a gradual increase in the models' predictive power with the length of the timeframe considered for calculating the comorbidity measures. For predicting outcomes 1 year after THA, we found that there was no added value in ICD-10-based comorbidity measures if patient Charnley classification and preoperative HRQoL and pain measures were known. Level III, therapeutic study. C1 [Greene, Meridith E.; Rolfson, Ola] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Greene, Meridith E.; Rolfson, Ola; Gordon, Max; Garellick, Goran; Nemes, Szilard] Swedish Hip Arthroplasty Register, Gothenburg, Sweden. [Greene, Meridith E.; Rolfson, Ola; Garellick, Goran; Nemes, Szilard] Univ Gothenburg, Dept Orthopaed, Inst Clin Sci, Sahlgrenska Acad, Gothenburg, Sweden. [Gordon, Max] Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden. RP Greene, ME (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, 55 Fruit St,GRJ 1125, Boston, MA 02114 USA. EM megreene@partners.org RI Gordon, Max/M-4330-2014; OI Gordon, Max/0000-0002-8080-5815; Rolfson, Ola/0000-0001-6534-1242 NR 23 TC 9 Z9 9 U1 0 U2 2 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 NOV PY 2015 VL 473 IS 11 BP 3370 EP 3379 DI 10.1007/s11999-015-4195-z PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900009 PM 25700999 ER PT J AU Greene, ME Rader, KA Garellick, G Malchau, H Freiberg, AA Rolfson, O AF Greene, Meridith E. Rader, Kevin A. Garellick, Goran Malchau, Henrik Freiberg, Andrew A. Rolfson, Ola TI The EQ-5D-5L Improves on the EQ-5D-3L for Health-related Quality-of-life Assessment in Patients Undergoing Total Hip Arthroplasty SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article; Proceedings Paper CT 3rd Meeting of the International-Society-of-Arthroplasty-Registers CY 2014 CL Boston, MA SP Int Soc Arthroplasty Registers ID STANDARD EQ-5D; 5-LEVEL VERSION; POPULATION AB The EQ-5D is a generic health survey that can be used to compare improvement across different interventions, measure changes in health-related quality of life over time, or to explore cost-effectiveness among treatments, hospitals, or providers. The original EQ-5D survey has three response options for each of five health dimensions; however, with so few response options, ceiling and floor effects are problematic in some populations. A new version, called the EQ-5D-5L, was developed, which gives respondents five answer options (the "5L" refers to five response levels, which is in contrast to the original survey's three levels). However, the validity of this version has not, to our knowledge, been evaluated in patients undergoing total hip arthroplasty (THA). The purposes of this study were (1) to characterize the redistribution of responses using the new version; (2) to describe the ceiling and floor effects in the current three-level version and identify whether the new EQ-5D-5L survey diminished these effects; and (3) to understand the convergent validity of the new version with the old and the EQ visual analog scale. Both versions of the survey were administered either preoperatively or 1 to 6 years after THA, allowing at least 2 weeks between administrations. Responses to the two versions were compared to determine response redistribution properties, ceiling and floor effects, and convergent validity. Sample sizes were determined so that the study would have 90% power to detect a Spearman correlation over 0.7 when comparing the responses of the three-level survey with the five-level survey and allowing for a rate of 25% loss to followup. Most patients before surgery used the new responses in the majority of dimensions, whereas the patients taking the test after surgery used the new responses predominantly for the pain dimension. The five-level diminished ceiling effects in both groups by up to 30% and diminished floor effects in the pain dimension for patients taking the assessment before surgery by 14%, which was the only dimension in either patient group that had high rates of floor effects. The correlation between the surveys' visual analog scale and response patterns was not different for the two versions of the survey in these populations. The EQ-5D five-level survey appears able to discriminate new health states indistinguishable in the original, which may allow more sensitive measurements of change in patients undergoing THA. The five-level survey should be considered for implementation in local and national registry monitoring of health-related quality of life in patients undergoing THA. C1 [Greene, Meridith E.; Malchau, Henrik; Freiberg, Andrew A.; Rolfson, Ola] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Greene, Meridith E.; Garellick, Goran; Malchau, Henrik; Rolfson, Ola] Swedish Hip Arthroplasty Register, Gothenburg, Sweden. [Greene, Meridith E.; Garellick, Goran; Malchau, Henrik; Rolfson, Ola] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Orthopaed, Gothenburg, Sweden. [Rader, Kevin A.] Harvard Univ, Dept Biostat, Cambridge, MA 02138 USA. RP Greene, ME (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, 55 Fruit St,GRJ 1125, Boston, MA 02114 USA. EM megreene@partners.org OI Rolfson, Ola/0000-0001-6534-1242 NR 19 TC 3 Z9 3 U1 1 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 NOV PY 2015 VL 473 IS 11 BP 3383 EP 3390 DI 10.1007/s11999-014-4091-y PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900011 PM 25488404 ER PT J AU Gromov, K Pedersen, AB Overgaard, S Gebuhr, P Malchau, H Troelsen, A AF Gromov, Kirill Pedersen, Alma B. Overgaard, Soren Gebuhr, Peter Malchau, Henrik Troelsen, Anders TI Do Rerevision Rates Differ After First-time Revision of Primary THA With a Cemented and Cementless Femoral Component? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article; Proceedings Paper CT 3rd Meeting of the International-Society-of-Arthroplasty-Registers CY 2014 CL Boston, MA SP Int Soc Arthroplasty Registers ID TOTAL HIP-ARTHROPLASTY; FOLLOW-UP; BONE LOSS; REGISTER; EPIDEMIOLOGY; FIXATION; IMPLANT; SURGERY; COHORT; RISK AB Worldwide use of cementless fixation for total hip arthroplasty (THA) is on the rise despite some evidence from the world's registries suggesting inferior survivorship compared with cemented techniques. The patterns of bone loss associated with failed cementless and cemented THAs may prejudice the results of future revision procedures; however, this has not been documented. The purpose of this study was to compare (1) the risk for rerevision of first revision THA; (2) the patterns of femoral bone loss at the time of first revision of primary THA; (3) the reasons for first revision of primary THA; and (4) the time to first revision of primary THA between primary cementless and cemented femoral components. Primary THAs with cemented (n = 1791) and uncemented (n = 805) femoral components that subsequently sustained first revision of the femoral component were identified from the Danish Hip Arthroplasty Registry (DHR). As of 2012, 120,988 primary THAs and 19,282 revisions were registered in the DHR with completeness of 97% and 90% for primary and revision THA, respectively. Median followup for revisions of primary THA with cemented and cementless femoral component was 4 years (range, 0-17 years) and 2 years (range, 0-16 years), respectively. Survival of first revision THA, with second revision of the femur as outcome, was evaluated using hazard ratios (HRs) with 95% confidence interval (CI) adjusting for potential confounding. All patient- and surgery-related data are collected from Danish medical databases. Recording of bone defects in the DHR is based on surgeons' intraoperative findings. With the numbers studied, we found no differences in the risk of second revision between the overall cohort between cementless and cemented techniques (HR, 1.32; 95% CI, 0.97-1.80; p = 0.076); however, a second revision for any reason was more likely in patients < 70 years old in whom the index arthroplasty was performed using a cementless technique (HR, 1.48; 95% CI, 1.01-2.17; p = 0.046). Increasingly severe femoral bone defects of type II (30% [532 of 1791] versus 13% [104 of 805]; p < 0.001) type III (11% [200 of 1791] versus 2% [12 of 805]; p < 0.001) and type IV (1% [26 of 1791] versus 0.4% [three of 805]; p = 0.016) were more frequent at revisions of cemented femoral components compared with cementless femoral components. Indications for first revision differed between primary cemented and uncemented femoral components, because a larger proportion of cemented femoral components was revised as a result of aseptic loosening compared with cementless femoral components (74% [1329 of 1791] versus 25% [197 of 805]; p < 0.001), whereas a larger proportion of cementless femoral components was revised as a result of a fracture compared with cemented femoral components (46% [371 of 805] versus 10% [168 of 1791]; p < 0.001). Failure before 5 years was more likely in cementless femoral components than cemented femoral components (91% [733 of 805] versus 44% [749 of 1791], p < 0.001). We found no differences in the risk of second revision in the overall cohort between cementless and cemented techniques; however, we observed an increased risk for rerevision THA performed on patients < 70 years whose index THAs were performed using cementless components when looking at all causes for revision, even after adjusting for the most likely confounding factors. Our data suggest that increased use of cementless fixation in primary THA may lead to inferior survivorship of first revision THA. Level III, therapeutic study. C1 [Gromov, Kirill; Gebuhr, Peter; Troelsen, Anders] Copenhagen Univ Hosp Hvidovre, Dept Orthoped Surg, DK-2650 Copenhagen, Denmark. [Pedersen, Alma B.] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. [Overgaard, Soren] Odense Univ Hosp, Dept Orthopaed Surg, Traumatol & Clin Inst, DK-5000 Odense, Denmark. [Malchau, Henrik] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed, Boston, MA USA. [Gromov, Kirill] Copenhagen Univ Hosp Hvidovre, Dept Orthoped, DK-2650 Copenhagen, Denmark. RP Gromov, K (reprint author), Copenhagen Univ Hosp Hvidovre, Dept Orthoped, Kattegaard Alle 30, DK-2650 Copenhagen, Denmark. EM kirgromov@gmail.com NR 29 TC 3 Z9 3 U1 0 U2 2 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 NOV PY 2015 VL 473 IS 11 BP 3391 EP 3398 DI 10.1007/s11999-015-4245-6 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900012 PM 25762017 ER PT J AU Ring, D Ayers, DC AF Ring, David Ayers, David C. TI Editorial Comment: Symposium: Psychosocial Aspects of Musculoskeletal Illness SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material C1 [Ring, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ayers, David C.] Univ Massachusetts, Sch Med, Dept Orthopaed Surg, Worcester, MA USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 3 TC 1 Z9 1 U1 0 U2 0 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 NOV PY 2015 VL 473 IS 11 BP 3468 EP 3469 DI 10.1007/s11999-015-4544-y PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900024 PM 26338520 ER PT J AU Cho, CH Song, KS Hwang, I Warner, JJP AF Cho, Chul-Hyun Song, Kwang-Soon Hwang, Ilseon Warner, Jon J. P. TI Does Rotator Cuff Repair Improve Psychologic Status and Quality of Life in Patients With Rotator Cuff Tear? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID KNEE REPLACEMENT; WHOQOL-BREF; HEALTH; ANXIETY; DEPRESSION; PAIN; VALIDITY; SATISFACTION; INSTRUMENT; DISABILITY AB Recently, psychological status, patient-centered outcomes, and health-related quality of life (HRQoL) in patients with scheduled or who underwent orthopaedic surgeries have been emphasized. The relationship between preoperative psychological status and postoperative clinical outcome in patients with rotator cuff repair has not yet been investigated. The primary objective of this study was to investigate changes in psychological status (depression, anxiety, insomnia) and HRQoL after rotator cuff repair. The secondary objective was to assess whether preoperative depression, anxiety, and insomnia predict clinical outcome after rotator cuff repair. Forty-seven patients who underwent rotator cuff repair prospectively completed the visual analog scale (VAS) pain score, the UCLA Scale, the American Shoulder and Elbow Surgeons' Scale (ASES), the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), and the World Health Organization Quality-of-life Scale Abbreviated Version (WHOQOL-BREF) before surgery and at 3, 6, and 12 months after surgery. Repeated-measures analysis of variance was used to evaluate the serial changes in psychological parameters and outcome measurements. The chi-square test was also used to compare preoperative and postoperative prevalence of depression, anxiety, and insomnia. Finally, multiple regression analysis was applied to determine the relationship between preoperative psychological status and postoperative clinical outcome. With surgery, depression, anxiety, and insomnia decreased, whereas quality of life increased. The mean HADS-D and HADS-A scores and the mean PSQI score decreased from 3.7 +/- A 3.3, 4.3 +/- A 4.3, and 6.6 +/- A 3.6, respectively, before surgery to 2.1 +/- A 2.3, 1.4 +/- A 2.4, and 4.2 +/- A 3.3, respectively, at 12 months after surgery (HADS-D mean difference 1.6 [95% confidence interval {CI}, 0.6-2.6], p = 0.003; HADS-A mean difference 2.9 [1.5-4.4], p < 0.001; PSQI mean difference 2.4 [1.3-3.4], p < 0.001). The mean WHOQOL-BREF score increased from 60.4 +/- A 11.0 before surgery to 67.4 +/- A 11.8 at 12 months after surgery (mean difference -7.0 [95% CI, -10.7 to -3.4], p < 0.001). At 12 months after surgery, there were decreases in the prevalence of depression (six of 47 [22.8%] versus three of 47 [6.4%], p = 0.002), anxiety (11 of 47 [23.4%] versus two of 47 [4.3%], p = 0.016), and insomnia (33 of 47 [70.2%] versus 20 of 47 [42.6%], p = 0.022). Preoperative HADS-depression, HADS-anxiety, and PSQI scores did not correlate with the VAS pain score, UCLA, or ASES scores at 12 months after surgery. Psychological status and HRQoL improved with decreasing pain and increasing functional ability from 3 months after surgery. Preoperative depression, anxiety, and insomnia did not predict poor outcome after rotator cuff repair. Our findings suggest that successful rotator cuff repair may improve psychological status and HRQoL. Level II, prospective study. C1 [Cho, Chul-Hyun] Keimyung Univ, Pain Res Ctr, Dept Orthoped Surg, Dongsan Med Ctr,Sch Med, Taegu 700712, South Korea. [Song, Kwang-Soon] Keimyung Univ, Sch Med, Dept Orthoped Surg, Dongsan Med Ctr, Taegu, South Korea. [Hwang, Ilseon] Keimyung Univ, Sch Med, Dept Pathol, Dongsan Med Ctr, Taegu, South Korea. [Warner, Jon J. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Shoulder Serv, Boston, MA USA. RP Cho, CH (reprint author), Keimyung Univ, Pain Res Ctr, Dept Orthoped Surg, Dongsan Med Ctr,Sch Med, 56 Dalsung Ro, Taegu 700712, South Korea. EM oscho5362@dsmc.or.kr OI Song, Kwang Soon/0000-0001-6029-1901; Hwang, Ilseon/0000-0002-6122-4417; Cho, Chul-Hyun/0000-0003-0252-8741 NR 24 TC 2 Z9 2 U1 0 U2 7 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 NOV PY 2015 VL 473 IS 11 BP 3494 EP 3500 DI 10.1007/s11999-015-4258-1 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900029 PM 25791445 ER PT J AU Kortlever, JTP Janssen, SJ van Berckel, MMG Ring, D Vranceanu, AM AF Kortlever, Joost T. P. Janssen, Stein J. van Berckel, Marijn M. G. Ring, David Vranceanu, Ana Maria TI What Is the Most Useful Questionnaire for Measurement of Coping Strategies in Response to Nociception? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID PAIN CATASTROPHIZING SCALE; SELF-EFFICACY QUESTIONNAIRE; IDIOPATHIC ARM PAIN; PSYCHOLOGICAL INFLEXIBILITY; ITEM BANK; VALIDATION; VALIDITY; OUTCOMES; VERSION; FIBROMYALGIA AB There are several measures of coping strategies in response to nociception. These measures all correlate highly both with each other and with symptom intensity and magnitude of disability in patients with upper limb illness. This study aims to determine if distinct measures of coping strategies in response to nociception address the same underlying aspect of human illness behavior. Our primary study question was: is there one common aspect of human illness behavior measured by (1) the Pain Catastrophizing Scale (PCS); (2) the Psychological Inflexibility in Pain Scale (PIPS); (3) the Patient-Reported Outcomes Measurement Information System-Pain Interference (PROMIS-PI) Computer Adaptive Test (CAT); and (4) the Pain Self-Efficacy Questionnaire (PSEQ)? Secondarily, we aimed to determine which of the four questionnaires is most psychometrically sound. We measured correlations among questionnaires, coverage, reliability, completion time, and collinearity of these questionnaires when entered together in a multivariable model with the shortened version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) upper extremity disability questionnaire. In this prospective study, 138 consecutive new or followup English-speaking patients aged 18 years or older presenting to a tertiary care referral center with traumatic and nontraumatic upper extremity conditions were invited to participate between March and May 2014. One hundred thirty-four (97%) patients agreed to participate and completed the four questionnaires in random order before their visit with the physician. We used exploratory factor analysis to assess whether there was a single common trait-an underlying aspect of human illness behavior-measured by these questionnaires. Interquestionnaire correlation was assessed using Spearman rank correlation coefficients; coverage by assessing floor and ceiling effect (proportion of scores at lower and upper limit); reliability by Cronbach's alpha measure of internal consistency; completion time in seconds using Kruskal-Wallis analysis; and collinearity statistics through a regression model with QuickDASH. Exploratory factor analysis identified a common trait measured by these four measures-coping strategies in response to nociception-indicated by a substantial correlation of every individual questionnaire with the underlying trait (PCS: 0.74, PIPS: 0.84, PROMIS-PI: 0.83, PSEQ: -0.86). All interquestionnaire correlations were also large to substantial and were highest for PROMIS-PI with PSEQ (rho = -0.84, p < 0.001) and lowest for PROMIS-PI with PCS (rho = 0.67, p < 0.001). Internal consistencies were high (PCS: 0.93, PIPS: 0.88, PSEQ: 0.92, and not determined for the PROMIS-PI as a result of its CAT administration). PROMIS-PI was the quickest to complete (30 seconds [interquartile range, 24-44]) compared with the others (PCS: 91 seconds [66-122], p < 0.001; PIPS: 105 seconds [82-141], p < 0.001; PSEQ: 78 seconds [60-101], p < 0.001). The four coping questionnaires had a low partial r(2) and a relatively high variation inflation factor, indicating multicollinearity. PROMIS-PI was found to have the strongest correlation with QuickDASH (beta coefficient: 0.63; standard error: 0.10; p < 0.001). There is evidence that the four widely used measures of coping strategies in response to nociception address a single common aspect of human illness behavior, which negatively impacts upper extremity disability. Future studies assessing functional outcome should incorporate a measure of human illness behavior as it strongly relates to disability. Given that all of these measures address the same important aspect of human illness behavior, we recommend the PROMIS-PI CAT as the most efficient measure. C1 [Kortlever, Joost T. P.; Janssen, Stein J.; van Berckel, Marijn M. G.; Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Orthopaed Hand & Upper Extrem, Boston, MA 02114 USA. [Vranceanu, Ana Maria] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Behav Med Serv, Boston, MA 02114 USA. RP Vranceanu, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Behav Med Serv, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM avranceanu@mgh.harvard.edu NR 30 TC 2 Z9 2 U1 1 U2 8 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 NOV PY 2015 VL 473 IS 11 BP 3511 EP 3518 DI 10.1007/s11999-015-4419-2 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900031 PM 26105152 ER PT J AU Hageman, MGJS Reddy, R Makarawung, DJS Briet, JP van Dijk, CN Ring, D AF Hageman, Michiel G. J. S. Reddy, Rajesh Makarawung, Dennis J. S. Briet, Jan Paul van Dijk, C. Niek Ring, David TI Do Upper Extremity Trauma Patients Have Different Preferences for Shared Decision-making Than Patients With Nontraumatic Conditions? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; BREAST-CANCER; HEALTH-CARE; INFORMATION; VALIDITY; QUESTIONNAIRE; INVOLVEMENT; QUICKDASH; WOMEN; PAIN AB Shared decision-making is a combination of expertise, available scientific evidence, and the preferences of the patient and surgeon. Some surgeons contend that patients are less capable of participating in decisions about traumatic conditions than nontraumatic conditions. (1) Do patients with nontraumatic conditions have different preferences for shared decision-making when compared with those who sustained acute trauma? (2) Do disability, symptoms of depression, and self-efficacy correlate with preference for shared decision-making? In this prospective, comparative trial, we evaluated a total of 133 patients presenting to the outpatient practices of two university-based hand surgeons with traumatic or nontraumatic hand and upper extremity illnesses or conditions. Each patient completed questionnaires measuring their preferred role in healthcare decision-making (Control Preferences Scale [CPS]), symptoms of depression (Patients' Health Questionnaire), and pain self-efficacy (confidence that one can achieve one's goals despite pain; measured using the Pain Self-efficacy Questionnaire). Patients also completed a short version of the Disabilities of the Arm, Shoulder, and Hand questionnaire and an ordinal rating of pain intensity. There was no difference in decision-making preferences between patients with traumatic (CPS: 3 +/- 2) and nontraumatic conditions (CPS: 3 +/- 1 mean difference = 0.2 [95% confidence interval, -0.4 to 0.7], p = 0.78) with most patients (95 versus 38) preferring shared decision-making. More educated patients preferred a more active role in decision-making (beta = -0.1, r = 0.08, p = 0.001); however, differences in levels of disability, pain and function, depression, and pain-related self-efficacy were not associated with differences in patients' preferences in terms of shared decision-making. Patients who sustained trauma have on average the same preference for shared decision-making compared with patients who sustained no trauma. Now that we know the findings of this study, clinicians might be motivated to share their expertise about the treatment options, potential outcomes, benefits, and harms with the patient and to discuss their preference as well in a semiacute setting, resulting in a shared decision. C1 [Hageman, Michiel G. J. S.; Reddy, Rajesh; Makarawung, Dennis J. S.; Briet, Jan Paul; Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. [van Dijk, C. Niek] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu NR 25 TC 4 Z9 4 U1 0 U2 2 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 NOV PY 2015 VL 473 IS 11 BP 3542 EP 3548 DI 10.1007/s11999-015-4375-x PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900035 PM 26040968 ER PT J AU Janssen, SJ Teunis, T Guitton, TG Ring, D AF Janssen, Stein J. Teunis, Teun Guitton, Thierry G. Ring, David CA Sci Variation Grp TI Do Surgeons Treat Their Patients Like They Would Treat Themselves? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID SHARED DECISION-MAKING; GEOGRAPHICAL VARIATION; COGNITIVE BIAS; PREFERENCES; PHYSICIANS; HIP; RECOMMENDATIONS; OSTEOARTHRITIS; ALTERNATIVES; ARTHROPLASTY AB There is substantial unexplained geographical and surgeon-to-surgeon variation in rates of surgery. One would expect surgeons to treat patients and themselves similarly based on best evidence and accounting for patient preferences. (1) Are surgeons more likely to recommend surgery when choosing for a patient than for themselves? (2) Are surgeons less confident in deciding for patients than for themselves? Two hundred fifty-four (32%) of 790 Science of Variation Group (SOVG) members reviewed 21 fictional upper extremity cases (eg, distal radius fracture, De Quervain tendinopathy) for which surgery is optional answering two questions: (1) What treatment would you choose/recommend: operative or nonoperative? (2) On a scale from 0 to 10, how confident are you about this decision? Confidence is the degree that one believes that his or her decision is the right one (ie, most appropriate). Participants were orthopaedic, trauma, and plastic surgeons, all with an interest in treating upper extremity conditions. Half of the participants were randomized to choose for themselves if they had this injury or illness. The other half was randomized to make treatment recommendations for a patient of their age and gender. For the choice of operative or nonoperative, the overall recommendation for treatment was expressed as a surgery score per surgeon by dividing the number of cases they would operate on by the total number of cases (n = 21), where 100% is when every surgeon recommended surgery for every case. For confidence, we calculated the mean confidence for all 21 cases per surgeon; overall score ranges from 0 to 10 with a higher score indicating more confidence in the decision for treatment. Surgeons were more likely to recommend surgery for a patient (44.2% +/- A 14.0%) than they were to choose surgery for themselves (38.5% +/- A 15.4%) with a mean difference of 6% (95% confidence interval [CI], 2.1%-9.4%; p = 0.002). Surgeons were more confident in deciding for themselves than they were for a patient of similar age and gender (self: 7.9 +/- A 1.0, patient: 7.5 +/- A 1.2, mean difference: 0.35 [CI, 0.075-0.62], p = 0.012). Surgeons are slightly more likely to recommend surgery for a patient than they are to choose surgery for themselves and they choose for themselves with a little more confidence. Different perspectives, preferences, circumstantial information, and cognitive biases might explain the observed differences. This emphasizes the importance of (1) understanding patients' preferences and their considerations for treatment; (2) being aware that surgeons and patients might weigh various factors differently; (3) giving patients more autonomy by letting them balance risks and benefits themselves (ie, shared decision-making); and (4) assessing how dispassionate evidence-based decision aids help inform the patient and influences their decisional conflict. Level III, diagnostic study. C1 [Janssen, Stein J.; Teunis, Teun; Ring, David] Massachusetts Gen Hosp, Dept Hand Surg, Yawkey Ctr, Boston, MA 02114 USA. [Janssen, Stein J.; Teunis, Teun; Ring, David] Harvard Univ, Sch Med, Dept Orthopaed Surg, Boston, MA USA. [Guitton, Thierry G.] Acad Med Ctr Amsterdam, Dept Orthopaed Surg, Amsterdam, Netherlands. RP Ring, D (reprint author), Massachusetts Gen Hosp, Dept Hand Surg, Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Soong, Maximillian/0000-0003-0333-8181 NR 30 TC 2 Z9 2 U1 3 U2 10 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 NOV PY 2015 VL 473 IS 11 BP 3564 EP 3572 DI 10.1007/s11999-015-4304-z PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS2LI UT WOS:000361901900037 PM 25957212 ER PT J AU Scott, JA Palmer, EL AF Scott, J. A. Palmer, E. L. TI Radiology reports: a quantifiable and objective textual approach SO CLINICAL RADIOLOGY LA English DT Article ID AUTHORSHIP ATTRIBUTION; QUALITY; SKILLS AB AIM: To examine the feasibility of using automated lexical analysis in conjunction with machine learning to create a means of objectively characterising radiology reports for quality improvement. MATERIALS AND METHODS: Twelve lexical parameters were quantified from the collected reports of four radiologists. These included the number of different words used, number of sentences, reading grade, readability, usage of the passive voice, and lexical metrics of concreteness, ambivalence, complexity, passivity, embellishment, communication and cognition. Each radiologist was statistically compared to the mean of the group for each parameter to determine outlying report characteristics. The reproducibility of these parameters in a given radiologist's reporting style was tested by using only these 12 parameters as input to a neural network designed to establish the authorship of 60 unknown reports. RESULTS: Significant differences in report characteristics were observed between radiologists, quantifying and characterising deviations of individuals from the group reporting style. The 12 metrics employed in a neural network correctly identified the author in each of 60 unknown reports tested, indicating a robust parametric signature. CONCLUSION: Automated and quantifiable methods can be used to analyse reporting style and provide impartial and objective feedback as well as to detect and characterise significant differences from the group. The parameters examined are sufficiently specific to identify the authors of reports and can potentially be useful in quality improvement and residency training. (C) 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. C1 [Scott, J. A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Scott, JA (reprint author), Massachusetts Gen Hosp, Dept Radiol, White 427,55 Fruit St, Boston, MA 02114 USA. EM scott@helix.mgh.harvard.edu NR 20 TC 0 Z9 0 U1 0 U2 2 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 NOV PY 2015 VL 70 IS 11 BP 1185 EP 1191 DI 10.1016/j.crad.2015.06.080 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS2MF UT WOS:000361904300005 PM 26169580 ER PT J AU Goedecke, JH Keswell, D Weinreich, C Fan, J Hauksson, J Victor, H Utzschneider, K Levitt, NS Lambert, EV Kahn, SE Olsson, T AF Goedecke, Julia H. Keswell, Dheshnie Weinreich, Carsten Fan, Jia Hauksson, Jon Victor, Hendriena Utzschneider, Kristina Levitt, Naomi S. Lambert, Estelle V. Kahn, Steven E. Olsson, Tommy TI Ethnic differences in hepatic and systemic insulin sensitivity and their associated determinants in obese black and white South African women SO DIABETOLOGIA LA English DT Article DE Black African; Ectopic fat; Ethnicity; Euglycaemic-hyperinsulinaemic clamp; Hepatic insulin sensitivity; Liver fat; Peripheral insulin sensitivity; Skeletal muscle lipid ID SKELETAL-MUSCLE; ADIPOSE-TISSUE; RESISTANCE; EXPRESSION AB Aims/hypothesis There is evidence to suggest that ectopic fat deposition in liver and skeletal muscle may differ between black and white women resulting in organ-specific differences in insulin sensitivity. Accordingly, the aim of the study was to examine ethnic differences in hepatic and peripheral insulin sensitivity, and the association with hepatic and skeletal muscle lipid content, and skeletal muscle gene expression. Methods In a cross-sectional study including 30 obese premenopausal black and white women, body composition (dual energy x-ray absorptiometry), liver fat and skeletal muscle (soleus and tibialis anterior) fat accumulation (proton-magnetic resonance spectroscopy), skeletal muscle gene expression, insulin sensitivity (two-step isotope labelled, hyperinsulinaemic-euglycaemic clamp with 10 mU m(-2) min(-1) and 40 mU m(-2) min(-1) insulin infusions), and serum adipokines were measured. Results We found that, although whole-body insulin sensitivity was not different, obese white women presented with lower hepatic insulin sensitivity than black women (% suppression of endogenous glucose production [% supp EGP], median [interquartile range (IQR)]: 17 [5-51] vs 56 [29-100] %, p = 0.002). While liver fat tended to be lower (p = 0.065) and skeletal muscle fat deposition tended to be higher (p = 0.074) in black compared with white women, associations with insulin sensitivity were only observed in black women (% supp EGP vs liver fat: r = -0.57, p < 0.05 and % supp EGP vs soleus fat: r = -0.56, p < 0.05). Conclusions/interpretation These findings may suggest that black women are more sensitive to the effects of ectopic lipid deposition than white women. C1 [Goedecke, Julia H.] South African Med Res Council, Noncommunicable Dis Res Unit, ZA-7505 Tygerberg, South Africa. [Goedecke, Julia H.; Keswell, Dheshnie; Victor, Hendriena; Levitt, Naomi S.; Lambert, Estelle V.] Univ Cape Town, Dept Human Biol, Div Exercise Sci & Sports Med, ZA-7925 Cape Town, South Africa. [Weinreich, Carsten; Levitt, Naomi S.] Univ Cape Town, Dept Med, Div Diabet & Endocrinol, ZA-7925 Cape Town, South Africa. [Fan, Jia] Univ Cape Town, Dept Human Biol, MRC UCT Med Imaging Res Unit, ZA-7925 Cape Town, South Africa. [Hauksson, Jon] Umea Univ Hosp, Ctr Med Technol & Radiat Phys, S-90185 Umea, Sweden. [Utzschneider, Kristina; Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Utzschneider, Kristina; Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Olsson, Tommy] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Olsson, Tommy] Univ Stellenbosch, Wallenberg Res Ctr, Stellenbosch Inst Adv Study STIAS, ZA-7600 Stellenbosch, South Africa. RP Goedecke, JH (reprint author), South African Med Res Council, Noncommunicable Dis Res Unit, POB 19070, ZA-7505 Tygerberg, South Africa. EM julia.goedecke@mrc.ac.za RI Goedecke, Julia/E-1820-2016; OI Goedecke, Julia/0000-0001-6795-4771; Fan, Jia/0000-0002-0443-5904; Kahn, Steven/0000-0001-7307-9002 FU National Research Foundation of South Africa [73707]; United States Department of Veterans Affairs; Swedish Research Council [K2011-12237-15-6]; Swedish Heart and Lung Foundation; Umea University, Sweden FX This study was funded by the National Research Foundation of South Africa (Grant no. 73707), the United States Department of Veterans Affairs, the Swedish Research Council (K2011-12237-15-6), the Swedish Heart and Lung Foundation and Umea University, Sweden. NR 11 TC 2 Z9 2 U1 0 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 NOV PY 2015 VL 58 IS 11 BP 2647 EP 2652 DI 10.1007/s00125-015-3720-7 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS3RR UT WOS:000361993000022 PM 26232099 ER PT J AU Lu, ZY Zhang, XM Li, YC Lopes-Virella, MF Huang, Y AF Lu, Zhongyang Zhang, Xiaoming Li, Yanchun Lopes-Virella, Maria F. Huang, Yan TI TLR4 antagonist attenuates atherogenesis in LDL receptor-deficient mice with diet-induced type 2 diabetes SO IMMUNOBIOLOGY LA English DT Article DE Toll-like receptor 4; Atherosclerosis; Inflammation; Diabetes ID LOW-DENSITY-LIPOPROTEIN; TOLL-LIKE RECEPTORS; APOLIPOPROTEIN-E; INNATE IMMUNITY; RHODOPSEUDOMONAS-SPHAEROIDES; RHODOBACTER-SPHAEROIDES; INSULIN-RESISTANCE; KNOCKOUT MICE; ATHEROSCLEROSIS; INFLAMMATION AB Although a large number of studies have well documented a key role of toll-like receptor (TLR)4 in atherosclerosis, it remains undetermined if TLR4 antagonist attenuates atherogenesis in mouse model for type 2 diabetes. In this study, we induced type 2 diabetes in low-density lipoprotein receptor-deficient (LDLR-/-) mice by high-fat diet (HFD). At 8 weeks old, 20 mice were fed HFD and 20 mice fed regular chow (RC) for 24 weeks. In the last 10 weeks, half HFD-fed mice and half RC-fed mice were treated with Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist. After the treatment, atherosclerotic lesions in aortas were analyzed. Results showed that the HFD significantly increased body-weight, glucose, lipids including total cholesterol, triglycerides and free fatty acids, and insulin resistance, indicating that the HFD induced type 2 diabetes in LDLR-/- mice. Results also showed that Rs-LPS had no effect on HFD-increased metabolic parameters in both nondiabetic and diabetic mice. Lipid staining of aortas and histological analysis of cross-sections of aortic roots showed that diabetes increased atherosclerotic lesions, but Rs-LPS attenuated atherogenesis in diabetic mice. Furthermore, immunohistochemical studies showed that Rs-LPS reduced infiltration of monocytes/macrophages and expression of interleukin (IL)-6 and matrix metalloproteinase-9 in atherosclerotic lesions of diabetic mice. Finally, the antagonistic effect of Rs-LPS on TLR4 was demonstrated by our in vitro studies showing that Rs-LPS inhibited IL-6 secretion from macrophages and endothelial cells stimulated by LPS or LPS plus saturated fatty acid palmitate. Taken together, our study demonstrated that TLR4 antagonist was capable of attenuating vascular inflammation and atherogenesis in mice with HFD-induced type 2 diabetes. Published by Elsevier GmbH. C1 [Lopes-Virella, Maria F.; Huang, Yan] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Lu, Zhongyang; Zhang, Xiaoming; Li, Yanchun; Lopes-Virella, Maria F.; Huang, Yan] Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. RP Huang, Y (reprint author), Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, 114 Doughty St, Charleston, SC 29403 USA. EM huangyan@musc.edu FU Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs; NIH [R01 DE016353] FX This work was supported by a Merit Review grant from the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs and NIH grant R01 DE016353 (to Y.H.). NR 51 TC 11 Z9 11 U1 1 U2 21 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 NOV PY 2015 VL 220 IS 11 BP 1246 EP 1254 DI 10.1016/j.imbio.2015.06.016 PG 9 WC Immunology SC Immunology GA CS5TT UT WOS:000362141900007 PM 26162692 ER PT J AU Zemer-Wassercug, N Haim, M Leshem-Lev, D Orvin, KL Vaduganathan, M Gutstein, A Kadmon, E Mager, A Kornowski, R Lev, EI AF Zemer-Wassercug, Noa Haim, Moti Leshem-Lev, Dorit Orvin, Katia L. Vaduganathan, Muthiah Gutstein, Ariel Kadmon, Ehud Mager, Aviv Kornowski, Ran Lev, Eli I. TI The effect of dabigatran and rivaroxaban on platelet reactivity and inflammatory markers (vol 40, pg 340, 2015) SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Correction C1 [Zemer-Wassercug, Noa; Orvin, Katia L.; Gutstein, Ariel; Kadmon, Ehud; Mager, Aviv; Kornowski, Ran; Lev, Eli I.] Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. [Zemer-Wassercug, Noa; Haim, Moti; Leshem-Lev, Dorit; Orvin, Katia L.; Gutstein, Ariel; Kadmon, Ehud; Mager, Aviv; Kornowski, Ran; Lev, Eli I.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Haim, Moti] Meir Med Ctr, Dept Cardiol, Kefar Sava, Israel. [Leshem-Lev, Dorit] Rabin Med Ctr, Felsenstein Med Res Ctr, Petah Tiqwa, Israel. [Vaduganathan, Muthiah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Lev, EI (reprint author), Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. EM elil@clalit.org.il RI Haim, Moti/K-7381-2014 NR 1 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD NOV PY 2015 VL 40 IS 4 BP 523 EP 523 DI 10.1007/s11239-015-1271-x PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CS2LH UT WOS:000361901700020 PM 26323751 ER PT J AU Dolendo, MC Diez, CL Caranto, K Alcasabas, AP Lam, C Wilson, M Rodriguez-Galindo, C Sundar, G Quah, TC AF Dolendo, M. C. Diez, C. L. Caranto, K. Alcasabas, A. P. Lam, C. Wilson, M. Rodriguez-Galindo, C. Sundar, G. Quah, T. C. TI A RETINOBLASTOMA PROGRAM IMPROVES OUTCOMES AND ACCESS TO CARE FOR PATIENTS IN RESOURCE LIMITED SETTINGS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Dolendo, M. C.; Diez, C. L.; Caranto, K.] Southern Philippines Med Ctr, Sect Oncol, Dept Pediat, Davao, Philippines. [Alcasabas, A. P.] Philippine Gen Hosp, Sect Hematol Oncol, Dept Pediat, Manila, Philippines. [Lam, C.] St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. [Lam, C.] Int Outreach Program, Memphis, TN USA. [Wilson, M.] St Jude Childrens Res Hosp, Dept Surg, Div Ophthalmol & Pathol, Memphis, TN 38105 USA. [Rodriguez-Galindo, C.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sundar, G.] Natl Univ Singapore Hosp, Dept Ophthalmol, Singapore 117548, Singapore. [Quah, T. C.] Natl Univ Singapore Hosp, Sect Pediat Hematol Oncol, Khoo Teck Puat Childrens Med Inst, Singapore 117548, Singapore. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA P-530 BP S366 EP S366 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247201362 ER PT J AU Gupta, S Aitken, J Bartels, U Brierley, J Dolendo, M Friedrich, P Fuentes, S Garcia, C Gatta, G Gospodarowicz, M Gross, T Howard, S Molyneaux, E Moreno, F Pritchard-Jones, K Pole, J Ramirez, O Ries, L Rodriguez-Galindo, C Shin, HY Steliarova-Foucher, E Sung, L Supriyadi, E Swaminathan, R Torode, J Vora, T Kutluk, T Frazier, AL AF Gupta, S. Aitken, J. Bartels, U. Brierley, J. Dolendo, M. Friedrich, P. Fuentes, S. Garcia, C. Gatta, G. Gospodarowicz, M. Gross, T. Howard, S. Molyneaux, E. Moreno, F. Pritchard-Jones, K. Pole, J. Ramirez, O. Ries, L. Rodriguez-Galindo, C. Shin, H. Y. Steliarova-Foucher, E. Sung, L. Supriyadi, E. Swaminathan, R. Torode, J. Vora, T. Kutluk, T. Frazier, A. L. TI CONSENSUS-BASED PRINCIPLES AND CLASSIFICATION SYSTEMS FOR COLLECTING PAEDIATRIC CANCER STAGE IN POPULATION-BASED CANCER REGISTRIES SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Gupta, S.; Bartels, U.; Sung, L.] Hosp Sick Children, Div Haematol Oncol, Toronto, ON M5G 1X8, Canada. [Aitken, J.] Canc Care Queensland, Dept Res, Brisbane, Qld, Australia. [Brierley, J.; Gospodarowicz, M.] Princess Margaret Hosp, Div Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Dolendo, M.] Davao Med Ctr, Pediat Oncol, Davao, Philippines. [Friedrich, P.; Rodriguez-Galindo, C.; Frazier, A. L.] Dana Farber Canc Inst, Pediat Hematol Oncol, Boston, MA 02115 USA. [Fuentes, S.] Hostpital Nacl Ninos Benjamin Bloom, Oncol Serv, San Salvador, El Salvador. [Garcia, C.] Unidad Nacl Oncol Pediat, Pediat Oncol, Guatemala City, Guatemala. [Gatta, G.] Ist Nazl Studio & Cura Tumori, Epidemiol Unit, I-20133 Milan, Italy. [Gross, T.] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Howard, S.] Univ Tennessee, Coll Med, Memphis, TN USA. [Molyneaux, E.] Queen Elizabeth Cent Hosp, Dept Pediat, Blantyre, Malawi. [Moreno, F.] Natl Canc Inst, Paediat Canc Registry, Buenos Aires, DF, Argentina. [Pritchard-Jones, K.] Kings Coll London, Inst Child Hlth, London WC2R 2LS, England. [Pole, J.] Pediat Oncol Grp Ontario, POGO Res Unit, Toronto, ON, Canada. [Ramirez, O.] Univ Valle, Registro Poblac Canc Cali, Cali, Colombia. [Ries, L.] NCI, SEER Program, Bethesda, MD 20892 USA. [Shin, H. Y.] Seoul Natl Univ, Childrens Hosp, Pediat Oncol, Seoul, South Korea. [Steliarova-Foucher, E.] IARC, Canc Informat Sect, Lyon, France. [Supriyadi, E.] Univ Gadjah Mada, Div Pediat Hematol Oncol, Yogyakarta, Indonesia. [Swaminathan, R.] Canc Inst WIA, Canc Registry, Madras, Tamil Nadu, India. [Torode, J.] UICC, Geneva, Switzerland. [Vora, T.] Tata Mem Hosp, Pediat Med Oncol, Bombay, Maharashtra, India. [Kutluk, T.] Hacettepe Univ, Sch Med, Pediat Oncol, Ankara, Turkey. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA O-094 BP S169 EP S170 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200095 ER PT J AU Karlson, C Barrera, M Patenaude, A Kupst, MJ Gerhardt, C Vannatta, K AF Karlson, C. Barrera, M. Patenaude, A. Kupst, M. J. Gerhardt, C. Vannatta, K. TI IMPACT OF TUMOR TYPE, LOCATION, AND TREATMENT ON PHYSICAL AND EMOTIONAL OUTCOMES IN PEDIATRIC BRAIN TUMOR SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Karlson, C.] Univ Mississippi, Med Ctr, Pediat, Jackson, MS USA. [Barrera, M.] Hosp Sick Children, Psychol, Toronto, ON M5G 1X8, Canada. [Patenaude, A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Psychiat, Boston, MA 02115 USA. [Kupst, M. J.] Med Coll Wisconsin, Psychol, Milwaukee, WI 53226 USA. [Gerhardt, C.; Vannatta, K.] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Gerhardt, C.; Vannatta, K.] Ohio State Univ, Coll Med, Psychol Neuropsychol, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 NOV PY 2015 VL 62 SU 4 MA P-145 BP S276 EP S276 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200524 ER PT J AU Kulkarni, K Patenaude, A Lam, C Salavveria, C Mostert, S Njuguna, F AF Kulkarni, K. Patenaude, A. Lam, C. Salavveria, C. Mostert, S. Njuguna, F. TI PHYSICIAN PERSPECTIVES ON HOSPITAL DETENTION: THE UNEXPLORED PATH SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Kulkarni, K.] IWK Hlth Ctr, Halifax, NS, Canada. [Kulkarni, K.] Dalhousie Univ, Halifax, NS, Canada. [Patenaude, A.] Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Psychol Res & Clin Serv, Boston, MA 02115 USA. [Lam, C.] St Jude Childrens Res Hosp, Int Outreach Program, Memphis, TN 38105 USA. [Lam, C.] St Jude Childrens Res Hosp, Oncol, Memphis, TN 38105 USA. [Salavveria, C.] Hosp Nacl Ninos Benjamin, Oncol, San Salvador, El Salvador. [Mostert, S.] Vrije Univ Amsterdam, Med Ctr, Pediat Oncol Hematol, Amsterdam, Netherlands. [Njuguna, F.] Moi Univ, Dept Child Hlth & Paediat, Nairobi, Kenya. NR 0 TC 0 Z9 0 U1 1 U2 1 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 NOV PY 2015 VL 62 SU 4 MA P-598 BP S382 EP S383 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247201430 ER PT J AU Luna-Fineman, S Alejos, A Amador, G Alabi, S Barnoya, M Benavides, R Castellanos, M Dominguez, R Gamboa, J Fu, L Maldonado, C Morales, RA Ortiz, R Mendez, G Chantada, G Rodriguez-Galindo, C AF Luna-Fineman, S. Alejos, A. Amador, G. Alabi, S. Barnoya, M. Benavides, R. Castellanos, M. Dominguez, R. Gamboa, J. Fu, L. Maldonado, C. Morales, R. A. Ortiz, R. Mendez, G. Chantada, G. Rodriguez-Galindo, C. TI PRE-ENUCLEATION CHEMOTHERAPY IN ADVANCED INTRAOCULAR RETINOBLASTOMA IN CENTRAL AMERICA. LONG TERM FOLLOW-UP: AHOPCA II SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Luna-Fineman, S.] Stanford Univ, Pediat Hematol Oncol, Palo Alto, CA 94304 USA. [Alejos, A.] Unidad Nacl Oncol Pediat, Ophthalom, Guatemala City, Guatemala. [Amador, G.; Maldonado, C.] Hosp Escuela Tegucigalpa, Ophthalmol, Tegucigalpa, Honduras. [Alabi, S.] Hosp Bloom, Hematol Oncol, San Salvador, El Salvador. [Barnoya, M.] Unidad Nacl Oncol Pediat, Ophthalmol, Guatemalag, Guatemala. [Benavides, R.] Hosp Seguro Social, Ophthalmol, San Jose, Costa Rica. [Castellanos, M.] Unidad Nacioal Oncol Pediat, Hematol Oncol, Guatemala City, Guatemala. [Dominguez, R.] Hosp Bloom, Ophthalmol, San Salvador, El Salvador. [Gamboa, J.] Hosp Seguro Social, Pediat Hematol Oncol, San Jose, Costa Rica. [Fu, L.] Hosp Escuela Tegucigalpa, Pediat Hematol Oncol, Tegucigalpa, Honduras. [Morales, R. A.] Hosp La Mascota, Ophthalmol, Managua, Nicaragua. [Ortiz, R.; Mendez, G.] Hosp La Mascota, Hematol Oncol, Managua, Nicaragua. [Chantada, G.] Hoslpital Garrahan, Pediat Hematol Oncol, Buenos Aires, DF, Argentina. [Rodriguez-Galindo, C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Pediat Hematol Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA O-001 BP S144 EP S144 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200002 ER PT J AU Manley, P Trippett, T Smith, A Macy, M Leary, S Boklan, J Cohen, K Shen, L Herzog, C Veyrat-Follet, C Zhang, J Chi, S AF Manley, P. Trippett, T. Smith, A. Macy, M. Leary, S. Boklan, J. Cohen, K. Shen, L. Herzog, C. Veyrat-Follet, C. Zhang, J. Chi, S. TI PHASE I STUDY OF CABAZITAXEL IN PEDIATRIC PATIENTS WITH RELAPSED OR REFRACTORY SOLID TUMORS: A POETIC GROUP STUDY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Manley, P.; Chi, S.] Dana Farber Canc Inst, Pediat Oncol, Boston, MA 02115 USA. [Trippett, T.] Mem Sloan Kettering Canc Ctr, Pediat Hematol Oncol, New York, NY 10021 USA. [Smith, A.] Arnold Palmer Med Ctr, Pediat Hematol Oncol, Orlando, FL USA. [Macy, M.] Univ Colorado, Childrens Hosp Colorado, Pediat Hematol Oncol, Aurora, CO USA. [Leary, S.] Seattle Childrens Univ Washington, Seattle, WA USA. [Leary, S.] Fred Hutchinson Canc Res Ctr, Pediat Hematol Oncol, Seattle, WA 98104 USA. [Boklan, J.] Phoenix Childrens Hosp, Pediat Hematol Oncol, Phoenix, AZ USA. [Cohen, K.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Pediat Hematol Oncol, Baltimore, MD USA. [Shen, L.] Sanofi US, Sanofi Oncol, Bridgewater, MA USA. [Herzog, C.] Univ Texas MD Anderson Canc Ctr, Pediat Hematol Oncol, Houston, TX 77030 USA. [Veyrat-Follet, C.] Sanofi, Drug Disposit Disposit Safety & Anim Res Dept, Vitry Sur Seine, France. [Zhang, J.] Sanofi, Sanofi Oncol, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 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 NOV PY 2015 VL 62 SU 4 MA O-049 BP S157 EP S158 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200050 ER PT J AU Patenaude, A Lam, CG Salaverria, C Mostert, S Njuguna, F Kulkarni, K AF Patenaude, A. Lam, C. G. Salaverria, C. Mostert, S. Njuguna, F. Kulkarni, K. TI SIOP PODC GLOBAL TASK FORCE ON HOSPITAL DETENTION PRACTICES: COLLABORATING INTERNATIONALLY TO RAISE AWARENESS AND ENCOURAGE ADVOCACY AND ACTION TO END HOSPITAL DETENTION SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Patenaude, A.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Lam, C. G.] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Salaverria, C.] Hosp Nacl Ninos Benjamin Bloom, Dept Pediat Oncol, San Salvador, El Salvador. [Mostert, S.] Vrije Univ Amsterdam, Med Ctr, Dept Pediat Hematol Oncol, Amsterdam, Netherlands. [Njuguna, F.] Moi Univ, Dept Child Hlth & Pediat, Eldoret, Kenya. [Kulkarni, K.] Dalhousie Univ, Dept Pediat, IWK Hlth Ctr, Halifax, NS, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 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 NOV PY 2015 VL 62 SU 4 MA O-243 BP S207 EP S207 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200242 ER PT J AU Recklitis, C Blackmon, J Chang, G AF Recklitis, C. Blackmon, J. Chang, G. TI VALIDATING PROMIS ANXIETY AND DEPRESSION SHORT-FORMS IN YOUNG ADULT CANCER SURVIVORS: COMPARISON WITH A STRUCTURED DIAGNOSTIC INTERVIEW SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Recklitis, C.; Blackmon, J.] Dana Farber Canc Inst, Pediat Oncol, Boston, MA 02115 USA. [Chang, G.] VA Boston Healthcare Syst, Psychiat, Brockton, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 NOV PY 2015 VL 62 SU 4 MA O-113 BP S175 EP S175 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200114 ER PT J AU Richardson, P Smith, A Triplett, B Kernan, N Grupp, S Antin, J Lehmann, L Miloslavsky, M Hume, R Hannah, A Nejadnik, B Soiffer, R AF Richardson, P. Smith, A. Triplett, B. Kernan, N. Grupp, S. Antin, J. Lehmann, L. Miloslavsky, M. Hume, R. Hannah, A. Nejadnik, B. Soiffer, R. TI PEDIATRIC AND ADULT SUBGROUP RESULTS FROM AN ONGOING DEFIBROTIDE EXPANDED ACCESS PROGRAM IN THE US FOR PATIENTS WITH HEPATIC VENO-OCCLUSIVE DISEASE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Richardson, P.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr,Div Hematol Ma, Boston, MA 02115 USA. [Smith, A.] Univ Minnesota, Div Pediat Blood & Marrow Transplantat, Minneapolis, MN USA. [Triplett, B.] St Jude Childrens Res Hosp, Bone Marrow Transplantat & Cellular Therapy, Memphis, TN 38105 USA. [Kernan, N.] Mem Sloan Kettering Canc Ctr, Pediat BMT Serv, New York, NY 10021 USA. [Grupp, S.] Childrens Hosp Philadelphia, Pediat Oncol, Philadelphia, PA 19104 USA. [Antin, J.; Soiffer, R.] Dana Farber Canc Inst, Dept Med Oncol, Stem Cell Bone Marrow Transplantat Program, Div Hematol Malignancy, Boston, MA 02115 USA. [Lehmann, L.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Med Oncol, Ctr Stem Cell Transplantat,Div Hematol Malignancy, Boston, MA 02115 USA. [Miloslavsky, M.; Hume, R.; Hannah, A.; Nejadnik, B.] Jazz Pharmaceut Inc, Clin, Palo Alto, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA P-398 BP S336 EP S336 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247201229 ER PT J AU Richardson, P Smith, A Triplett, B Kernan, N Grupp, S Antin, J Lehmann, L Miloslavsky, M Hume, R Hannah, A Nejadnik, B Soiffer, R AF Richardson, P. Smith, A. Triplett, B. Kernan, N. Grupp, S. Antin, J. Lehmann, L. Miloslavsky, M. Hume, R. Hannah, A. Nejadnik, B. Soiffer, R. TI DAY+100 SURVIVAL ANALYSIS BY PRIOR HEMATOPOIETIC STEM CELL TRANSPLANT TYPE FROM AN ONGOING US STUDY OF DEFIBROTIDE FOR HEPATIC VENO-OCCLUSIVE DISEASE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Richardson, P.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr,Div Hematol Ma, Boston, MA 02115 USA. [Smith, A.] Univ Minnesota, Div Pediat Blood & Marrow Transplantat, Minneapolis, MN USA. [Triplett, B.] St Jude Childrens Res Hosp, Bone Marrow Transplantat & Cellular Therapy, Memphis, TN 38105 USA. [Kernan, N.] Mem Sloan Kettering Canc Ctr, Pediat BMT Serv, New York, NY 10021 USA. [Grupp, S.] Childrens Hosp Philadelphia, Pediat Oncol, Philadelphia, PA 19104 USA. [Antin, J.; Soiffer, R.] Dana Farber Canc Inst, Stem Cell Bone Marrow Transplantat Program, Div Hematol Malignancy, Dept Med Oncol, Boston, MA 02115 USA. [Lehmann, L.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Med Oncol, Ctr Stem Cell Transplantat,Div Hematol Malignancy, Boston, MA 02115 USA. [Miloslavsky, M.; Hume, R.; Hannah, A.; Nejadnik, B.] Jazz Pharmaceut Inc, Clin, Palo Alto, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA O-009 BP S146 EP S147 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200010 ER PT J AU Sullivan, C Abramovitz, L Gattuso, J O'Neill, JB Challinor, J AF Sullivan, C. Abramovitz, L. Gattuso, J. O'Neill, J. Brace Challinor, J. TI CHEMOTHERAPY/BIOTHERAPY NURSING EDUCATION IN LATIN AMERICA: AN INITIATIVE OF THE ASSOCIATION OF PEDIATRIC HEMATOLOGY/ONCOLOGY NURSES SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Sullivan, C.] St Jude Childrens Res Hosp, Int Outreach Program, Memphis, TN 38105 USA. [Abramovitz, L.] UCSF Med Ctr, Oncol, San Francisco, CA USA. [Gattuso, J.] St Jude Childrens Res Hosp, Nursing Res, Memphis, TN 38105 USA. [O'Neill, J. Brace] Dana Farber Canc Inst, Pediat Oncol, Boston, MA 02115 USA. [Challinor, J.] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA O-175 BP S191 EP S191 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200176 ER PT J AU Zhou, E Manley, P Marcus, K Recklitis, C AF Zhou, E. Manley, P. Marcus, K. Recklitis, C. TI MEDICAL AND PSYCHOSOCIAL CORRELATES OF INSOMNIA IN PEDIATRIC BRAIN TUMOR SURVIVORS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Zhou, E.; Recklitis, C.] Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. [Manley, P.] Dana Farber Canc Inst, Pediat Neurooncol, Boston, MA 02115 USA. [Marcus, K.] Dana Farber Canc Inst, Radiat Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA O-245 BP S207 EP S207 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200244 ER PT J AU Brama, H Guberman, S Abeles, M Stern, E Kanter, I AF Brama, Haya Guberman, Shoshana Abeles, Moshe Stern, Edward Kanter, Ido TI Synchronization among neuronal pools without common inputs: in vivo study SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE In vivo; Cell assemblies; Population dynamics; Neural networks; Synchronization ID MEMBRANE-POTENTIAL FLUCTUATIONS; FEEDFORWARD NETWORKS; NEOCORTICAL NEURONS; NONLOCAL MECHANISM; CORTICAL ACTIVITY; SYNFIRE CHAINS; SPINY NEURONS; INFORMATION; PROPAGATION; DELAY AB Periodic synchronization of activity among neuronal pools has been related to substantial neural processes and information throughput in the neocortical network. However, the mechanisms of generating such periodic synchronization among distributed pools of neurons remain unclear. We hypothesize that to a large extent there is interplay between the topology of the neocortical networks and their reverberating modes of activity. The firing synchronization is governed by a nonlocal mechanism, the network delay loops, such that distant neuronal pools without common drives can be synchronized. This theoretical interplay between network topology and the synchronized mode is verified using an iterative procedure of a single intracellularly recorded neuron in vivo, imitating the dynamics of the entire network. The input is injected to the neuron via the recording electrode as current and computed from the filtered, evoked spikes of its pre-synaptic sources, previously emulated by the same neuron. In this manner we approximate subthreshold synaptic inputs from afferent neuronal pools to the neuron. Embedding the activity of these recurrent motifs in the intact brain allows us to measure the effects of connection probability, synaptic strength, and ongoing activity on the neuronal synchrony. Our in vivo experiments indicate that an initial stimulus given to a single pool is dynamically evolving into the formations of zero-lag and cluster synchronization. By applying results from theoretical models and in vitro experiments to in vivo activity in the intact brain, we support the notion that this mechanism may account for the binding activity across distributed brain areas. C1 [Brama, Haya; Guberman, Shoshana; Abeles, Moshe; Stern, Edward; Kanter, Ido] Bar Ilan Univ, Gonda Interdisciplinary Brain Res Ctr, IL-52900 Ramat Gan, Israel. [Brama, Haya; Guberman, Shoshana; Abeles, Moshe; Stern, Edward; Kanter, Ido] Bar Ilan Univ, Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Guberman, Shoshana; Kanter, Ido] Bar Ilan Univ, Dept Phys, IL-52900 Ramat Gan, Israel. [Stern, Edward] Massachusetts Gen Hosp, Dept Neurol, MassGeneral Inst Neurodegenerat Dis, Boston, MA 02114 USA. RP Stern, E (reprint author), Massachusetts Gen Hosp, Dept Neurol, MassGeneral Inst Neurodegenerat Dis, Boston, MA 02114 USA. EM sterned@mail.biu.ac.il; ido.kanter@biu.ac.il FU Legacy Heritage Bio-Medical Program of the Israel Science Foundation [688/10] FX The authors thank Noa Menkes-Caspi, Vered Kellner, Shlomit Beker, Igor Reidler and Hana Arnon for technical assistance. Funding for this study was provided by the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (688/10). NR 45 TC 2 Z9 2 U1 1 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD NOV PY 2015 VL 220 IS 6 BP 3721 EP 3731 DI 10.1007/s00429-014-0886-6 PG 11 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA CR7XS UT WOS:000361566000040 PM 25230822 ER PT J AU Peek, HS Richards, M Muir, O Chan, SR Caton, M MacMillan, C AF Peek, Holly S. Richards, Misty Muir, Owen Chan, Steven Richard Caton, Michael MacMillan, Carlene TI Blogging and Social Media for Mental Health Education and Advocacy: a Review for Psychiatrists SO CURRENT PSYCHIATRY REPORTS LA English DT Review DE Internet; Social media; Blogging; Advocacy; Ethics; Professionalism ID CHALLENGES AB We live in a digital age where information can be found instantaneously via the Internet. Studies have shown that consumers search for much of their medical information on the Internet, particularly utilizing blogs and social media platforms. As the mental health field is riddled with misinformation and stigma, this offers a unique opportunity for psychiatrists and mental health professionals to reach a broad audience for mental health education and advocacy. In this review, we discuss the various methods and techniques for blogging and social media. We then review the current recommendations for ethics and professionalism as well as make recommendations to strengthen our guidance in this new and evolving field. C1 [Peek, Holly S.] Massachusetts Gen Hosp, Dept Child & Adolescent Psychiat, Boston, MA 02114 USA. [Richards, Misty] Univ Calif Los Angeles, Dept Child & Adolescent Psychiat, Los Angeles, CA 90095 USA. [Muir, Owen] NYU, Sch Med, Brooklyn, NY 11249 USA. [Muir, Owen] NYU, Hofstra North Shore LIJ Sch Med, Brooklyn, NY 11249 USA. [Chan, Steven Richard; Caton, Michael] Univ Calif Davis, Sch Med, Dept Psychiat, Sacramento, CA 95817 USA. [MacMillan, Carlene] NYU, Langone Med Ctr, Dept Child & Adolescent Psychiat, Ctr Child Study, New York, NY 10016 USA. RP Peek, HS (reprint author), Massachusetts Gen Hosp, Dept Child & Adolescent Psychiat, 55 Fruit St,Yawkey 6A, Boston, MA 02114 USA. EM hpeek@partners.org; mcrichards@mednet.ucla.edu; Owen.muir@nyumc.org; steven@berkeley.edu; mcaton@ucdavis.ed; Carlene.MacMillan@nyumc.org FU iMedicalApps FX Steven Richard Chan reports personal fees from iMedicalApps. NR 18 TC 3 Z9 3 U1 5 U2 26 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD NOV PY 2015 VL 17 IS 11 AR 88 DI 10.1007/s11920-015-0629-2 PG 8 WC Psychiatry SC Psychiatry GA CS0IC UT WOS:000361741100003 PM 26377948 ER PT J AU Lorente, JA Cardinal-Fernandez, P Munoz, D Frutos-Vivar, F Thille, AW Jaramillo, C Ballen-Barragan, A Rodriguez, JM Peuelas, O Ortiz, G Blanco, J Pinheiro, BV Nin, N Marin, MD Esteban, A Thompson, TB AF Lorente, Jose A. Cardinal-Fernandez, Pablo Munoz, Diego Frutos-Vivar, Fernando Thille, Arnaud W. Jaramillo, Carlos Ballen-Barragan, Aida Rodriguez, Jose M. Peuelas, Oscar Ortiz, Guillermo Blanco, Jose Pinheiro, Bruno Valle Nin, Nicolas del Carmen Marin, Maria Esteban, Andres Thompson, Taylor B. TI Acute respiratory distress syndrome in patients with and without diffuse alveolar damage: an autopsy study SO INTENSIVE CARE MEDICINE LA English DT Article DE Adult respiratory distress syndrome; Diffuse alveolar damage; Subphenotype; Histology; Autopsy; Hyaline membranes ID OPEN-LUNG-BIOPSY; BERLIN DEFINITION; CLINICAL-CRITERIA; ARDS; PNEUMONIA; MORTALITY; SECONDARY; TRIALS AB To demonstrate that among patients with acute respiratory distress syndrome (ARDS), the presence of diffuse alveolar damage (DAD) at histological examination, as compared to its absence, defines a specific subphenotype. We studied 149 patients who died in our ICU with the clinical diagnosis of ARDS according to the Berlin Definition (BD) and who had autopsy examination. We compared the change over time of different clinical variables in patients with (n = 49) and without (n = 100) DAD. A predictive model for the presence of DAD was developed and validated in an independent cohort of 57 patients with ARDS and postmortem examination (21 of them with DAD). Patients with DAD, as compared to patients without DAD, had a lower PaO2/FiO(2) ratio and dynamic respiratory system compliance, and a higher SOFA score and INR, and were more likely to die of hypoxemia and less likely to die of shock. In multivariate analysis, variables associated with DAD [odds ratio, 95 % confidence interval (CI)] were PaO2/FiO(2) ratio [0.988 (0.981-0.995)], dynamic respiratory system compliance [0.937 (0.892-0.984)] and age [0.972 (0.946-0.999)]. Areas under the ROC curve (95 % CI) for the classification of DAD using the regression model or the BD were, respectively, 0.74 (0.65-0.82) and 0.64 (0.55-0.72) (p = 0.03). In the validation cohort, the areas under the ROC curve for the diagnosis of DAD were 0.73 (0.56-0.90) and 0.67 (0.54-0.81) for the regression model and the BD, respectively. The presence of DAD appears to define a specific subphenotype in patients with ARDS. Targeting patients with DAD within the population of patients with the clinical diagnosis of ARDS might be appropriate to find effective therapies for this condition. C1 [Lorente, Jose A.; Frutos-Vivar, Fernando; Jaramillo, Carlos; Ballen-Barragan, Aida; Rodriguez, Jose M.; Peuelas, Oscar; Esteban, Andres] Hosp Univ Getafe, Serv Med Intens, Madrid 28905, Spain. [Lorente, Jose A.; Frutos-Vivar, Fernando; Ballen-Barragan, Aida; Rodriguez, Jose M.; Peuelas, Oscar; Esteban, Andres] CIBER Enfermedades Resp CIBERES, Madrid, Spain. [Lorente, Jose A.] Univ Europea, Madrid, Spain. [Cardinal-Fernandez, Pablo] Hosp Univ Sanchinarro, Madrid, Spain. [Munoz, Diego] Univ CES, Hosp Pablo Tobon Uribe, Medellin, Colombia. [Thille, Arnaud W.] CHU Poitiers, Med ICU, Poitiers, France. [Ortiz, Guillermo; Blanco, Jose] Univ Bosque, Bogota, Colombia. [Pinheiro, Bruno Valle] Univ Fed Juiz de Fora, Div Resp & Crit Care Med, Juiz De Fora, Brazil. [Nin, Nicolas] Hosp Espaol Juan Jose Crottoggini, Montevideo, Uruguay. [del Carmen Marin, Maria] Hosp Reg 1 Octubre, ISSSTE, Intens Care Serv, Mexico City, DF, Mexico. [Thompson, Taylor B.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Lorente, JA (reprint author), Hosp Univ Getafe, Serv Med Intens, Madrid 28905, Spain. EM joseangel.lorente@salud.madrid.org; pablocardinal@hotmail.com RI Pinheiro, Bruno/J-1699-2014; OI Frutos-Vivar, Fernando/0000-0002-4648-9636 NR 31 TC 18 Z9 18 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD NOV PY 2015 VL 41 IS 11 BP 1921 EP 1930 DI 10.1007/s00134-015-4046-0 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA CS1MM UT WOS:000361829900006 PM 26385863 ER PT J AU Bos, LD Cremer, OL Ong, DSY Caser, EB Barbas, CSV Villar, J Kacmarek, RM Schultz, MJ AF Bos, Lieuwe D. Cremer, Olaf L. Ong, David S. Y. Caser, Eliana B. Barbas, Carmen S. V. Villar, Jesus Kacmarek, Robert M. Schultz, Marcus J. TI External validation confirms the legitimacy of a new clinical classification of ARDS for predicting outcome SO INTENSIVE CARE MEDICINE LA English DT Letter ID RESPIRATORY-DISTRESS-SYNDROME; BERLIN DEFINITION C1 [Bos, Lieuwe D.; Schultz, Marcus J.] Univ Amsterdam, Acad Med Ctr, Dept Intens Care, NL-1105 AZ Amsterdam, Netherlands. [Cremer, Olaf L.; Ong, David S. Y.] Univ Med Ctr Utrecht, Dept Intens Care Med, Utrecht, Netherlands. [Ong, David S. Y.] Univ Med Ctr Utrecht, Dept Med Microbiol, Utrecht, Netherlands. [Villar, Jesus] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus] Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Las Palmas Gran Canaria, Palmas, Spain. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Dept Anesthesiol, Boston, MA 02115 USA. [Caser, Eliana B.] Univ Fed Espirito Santo, Dept Internal Med, Vitoria, ES, Brazil. [Barbas, Carmen S. V.] Univ Sao Paulo, Sch Med, Dept Pulm & Crit Care, Sao Paulo, Brazil. [Barbas, Carmen S. V.] Albert Einstein Hosp, Adult Intens Care Unit, Sao Paulo, Brazil. RP Bos, LD (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Intens Care, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM l.d.bos@amc.uva.nl RI Cremer, Olaf/G-3855-2016; OI Cremer, Olaf/0000-0003-4264-1108; Bos, Lieuwe/0000-0003-2911-4549 NR 5 TC 2 Z9 2 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD NOV PY 2015 VL 41 IS 11 BP 2004 EP 2005 DI 10.1007/s00134-015-3992-x PG 2 WC Critical Care Medicine SC General & Internal Medicine GA CS1MM UT WOS:000361829900027 PM 26202043 ER PT J AU Chetty, IJ Martel, MK Jaffray, DA Benedict, SH Hahn, SM Berbeco, R Deye, J Jeraj, R Kavanagh, B Krishnan, S Lee, N Low, DA Mankoff, D Marks, LB Ollendorf, D Paganetti, H Ross, B Siochi, RAC Timmerman, RD Wong, JW AF Chetty, Indrin J. Martel, Mary K. Jaffray, David A. Benedict, Stanley H. Hahn, Stephen M. Berbeco, Ross Deye, James Jeraj, Robert Kavanagh, Brian Krishnan, Sunil Lee, Nancy Low, Daniel A. Mankoff, David Marks, Lawrence B. Ollendorf, Daniel Paganetti, Harald Ross, Brian Siochi, Ramon Alfredo C. Timmerman, Robert D. Wong, John W. TI Technology for Innovation in Radiation Oncology SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CELL LUNG-CANCER; FUTURE PERSPECTIVES; GOLD NANOPARTICLES; ION RADIOTHERAPY; CLINICAL-TRIALS; PROTON-BEAM; THERAPY; RISK; MRI; IRRADIATION AB Radiation therapy is an effective, personalized cancer treatment that has benefited from technological advances associated with the growing ability to identify and target tumors with accuracy and precision. Given that these advances have played a central role in the success of radiation therapy as a major component of comprehensive cancer care, the American Society for Radiation Oncology (ASTRO), the American Association of Physicists in Medicine (AAPM), and the National Cancer Institute (NCI) sponsored a workshop entitled "Technology for Innovation in Radiation Oncology," which took place at the National Institutes of Health (NIH) in Bethesda, Maryland, on June 13 and 14, 2013. The purpose of this workshop was to discuss emerging technology for the field and to recognize areas for greater research investment. Expert clinicians and scientists discussed innovative technology in radiation oncology, in particular as to how these technologies are being developed and translated to clinical practice in the face of current and future challenges and opportunities. Technologies encompassed topics in functional imaging, treatment devices, nanotechnology, and information technology. The technical, quality, and safety performance of these technologies were also considered. A major theme of the workshop was the growing importance of innovation in the domain of process automation and oncology informatics. The technologically advanced nature of radiation therapy treatments predisposes radiation oncology research teams to take on informatics research initiatives. In addition, the discussion on technology development was balanced with a parallel conversation regarding the need for evidence of efficacy and effectiveness. The linkage between the need for evidence and the efforts in informatics research was clearly identified as synergistic. (C) 2015 Elsevier Inc. All rights reserved. C1 [Chetty, Indrin J.] Henry Ford Hosp, Dept Radiat Oncol, Detroit, MI 48202 USA. [Martel, Mary K.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Jaffray, David A.] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Jaffray, David A.] Princess Margaret Hosp, Dept Med Biophys, Toronto, ON M4X 1K9, Canada. [Benedict, Stanley H.] Univ Calif Davis, Ctr Canc, Dept Radiat Oncol, Sacramento, CA 95817 USA. [Hahn, Stephen M.; Krishnan, Sunil] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Berbeco, Ross] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Deye, James] Natl Canc Inst, Radiat Res Programs, Bethesda, MD USA. [Jeraj, Robert] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [Kavanagh, Brian] Univ Colorado, Dept Radiat Oncol, Aurora, CO USA. [Lee, Nancy] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. [Low, Daniel A.] Univ Calif Los Angeles, Dept Radiat Oncol, Los Angeles, CA 90024 USA. [Mankoff, David] Univ Washington, Sch Med, Dept Radiol, Seattle, WA USA. [Marks, Lawrence B.] Univ North Carolina Hosp, Dept Radiat Oncol, Chapel Hill, NC USA. [Ollendorf, Daniel] Inst Clin & Econ Review, Boston, MA USA. [Paganetti, Harald] Proton Therapy Ctr, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA USA. [Ross, Brian] Univ Michigan Hlth Syst, Dept Radiol, Ann Arbor, MI USA. [Siochi, Ramon Alfredo C.] W Virginia Univ, Dept Radiat Oncol, Morgantown, WV 26506 USA. [Timmerman, Robert D.] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. [Wong, John W.] Johns Hopkins Univ, Dept Radiat Oncol, Baltimore, MD USA. RP Martel, MK (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. EM mmartel@mdanderson.org FU American Society for Radiation Oncology; American Association of Physicists in Medicine FX The authors thank the National Cancer Institute for their support of the meeting in providing resources and hosting the meeting at the National Institutes of Health. They also thank the American Society for Radiation Oncology and the American Association of Physicists in Medicine for their financial assistance, without which this meeting would not have been possible. NR 54 TC 7 Z9 7 U1 3 U2 40 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2015 VL 93 IS 3 BP 485 EP 492 DI 10.1016/j.ijrobp.2015.07.007 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CS2ED UT WOS:000361879700003 PM 26460989 ER PT J AU Olson, AC Coleman, CN Hahn, SM DeWeese, TL Shulman, LN Chabner, BA Chao, N Martei, YM Mundt, AJ Grover, S AF Olson, Adam C. Coleman, C. Norman Hahn, Stephen M. DeWeese, Theodore L. Shulman, Lawrence N. Chabner, Bruce A. Chao, Nelson Martei, Yehoda M. Mundt, Arno J. Grover, Surbhi TI A Roadmap for a New Academic Pathway for Global Radiation Oncology SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID HEALTH C1 [Olson, Adam C.] Duke Canc Inst, Dept Radiat Oncol, Durham, NC USA. [Coleman, C. Norman] Int Canc Expert Corps, Chevy Chase, MD USA. [Hahn, Stephen M.] MD Anderson Canc Ctr, Div Radiat Oncol, Houston, TX USA. [DeWeese, Theodore L.] Johns Hopkins Med Inst, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21205 USA. [Shulman, Lawrence N.] Hosp Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Chabner, Bruce A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chao, Nelson] Duke Canc Inst, Div Hematol Malignancies & Cellular Therapy, Bone Marrow Transplant & Global Canc, Durham, NC USA. [Martei, Yehoda M.] Hosp Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Mundt, Arno J.] Univ Calif San Diego, Dept Radiat Med & Appl Sci, San Diego, CA 92103 USA. [Grover, Surbhi] Hosp Univ Penn, Dept Radiat Oncol, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Olson, AC (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, DUMC Box 3085, Durham, NC 27710 USA. EM adam.olson@duke.edu NR 10 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2015 VL 93 IS 3 BP 493 EP 496 DI 10.1016/j.ijrobp.2015.06.023 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CS2ED UT WOS:000361879700004 PM 26460990 ER PT J AU Tseng, YD Uno, H Hughes, ME Niland, JC Wong, YN Theriault, R Blitzblau, RC Moy, B Breslin, T Edge, SB Hassett, MJ Punglia, RS AF Tseng, Yolanda D. Uno, Hajime Hughes, Melissa E. Niland, Joyce C. Wong, Yu-Ning Theriault, Richard Blitzblau, Rachel C. Moy, Beverly Breslin, Tara Edge, Stephen B. Hassett, Michael J. Punglia, Rinaa S. TI Biological Subtype Predicts Risk of Locoregional Recurrence After Mastectomy and Impact of Postmastectomy Radiation in a Large National Database SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID HER2-POSITIVE BREAST-CANCER; ADJUVANT CHEMOTHERAPY; MOLECULAR SUBTYPES; RECEPTOR STATUS; TRASTUZUMAB; THERAPY; EXPRESSION; RADIOTHERAPY; PROGNOSIS; WOMEN AB Purpose: To evaluate locoregional recurrence (LRR) after mastectomy and impact of postmastectomy radiation (PMRT) by breast cancer subtype. Methods and Materials: Between 2000 and 2009, 5673 patients with stage I to III breast carcinoma underwent mastectomy and nodal evaluation; 30% received PMRT. Isolated LRR (iLRR) and LRR were compared across groups defined by biological subtype and receipt of trastuzumab: luminal A (estrogen [ER]/progesterone [PR] +, HER2-, low/intermediate grade), luminal B (ER/PR+, HER2+, high grade), HER2 with trastuzumab, HER2 without trastuzumab, and triple negative (TN; ER+, PR+, HER2+). LRR hazard ratios (HR) were estimated with multivariable Fine and Gray models. The effect of PMRT on LRR was evaluated with Fine and Gray models stratified by propensity for PMRT. Results: With a median follow-up time of 50.1 months, there were 19 iLRR and 109 LRR events. HER2 patients with trastuzumab had no iLRR and only a single LRR. Compared with luminal A patients, TN patients had significantly greater adjusted risk of iLRR (HR 14.10; 95% CI 2.97%-66.90%), with a similar trend among luminal B (HR 4.94; 95% CI 0.94%-25.82%) and HER2 patients without trastuzumab (HR 4.41; 95% CI 0.61%-32.11%). Although PMRT reduced LRR, the effect of PMRT varied by subgroup, with the greatest and smallest effects seen among luminal A (HR 0.17; 95% CI 0.05%-0.62%) and TN patients (HR 0.59; 95% CI 0.25%-1.35%), respectively. Conclusions: TN patients had the highest risk of LRR and the least benefit from PMRT; these patients may benefit from alternative treatment strategies. In contrast, in the era of HER2-directed therapy, the role of local therapy may need to be reassessed among HER2 patients. (C) 2015 Elsevier Inc. All rights reserved. C1 [Tseng, Yolanda D.] Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. [Uno, Hajime] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Hughes, Melissa E.; Hassett, Michael J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Niland, Joyce C.] City Hope Comprehens Canc Ctr, Dept Biostat, Duarte, CA USA. [Wong, Yu-Ning] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Theriault, Richard] Univ Texas MD Anderson Canc Ctr, Dept Gen Oncol, Houston, TX 77030 USA. [Blitzblau, Rachel C.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27710 USA. [Moy, Beverly] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Breslin, Tara] Northwestern Lake Forest Hosp, Dept Surg, Div Surg Oncol, Lake Forest, IL USA. [Edge, Stephen B.] Baptist Canc Ctr, Memphis, TN USA. [Edge, Stephen B.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Punglia, Rinaa S.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Punglia, Rinaa S.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Tseng, YD (reprint author), Univ Washington, Dept Radiat Oncol, 1959 NE Pacific St,Box 356043, Seattle, WA 98195 USA. EM ydt2@uw.edu FU JCRT Research Foundation FX Supported by a 2013 grant from the JCRT Research Foundation. NR 25 TC 5 Z9 5 U1 4 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2015 VL 93 IS 3 BP 622 EP 630 DI 10.1016/j.ijrobp.2015.07.006 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CS2ED UT WOS:000361879700019 PM 26461004 ER PT J AU Simeone, FJ Bredella, MA Chang, CY Torriani, M Huang, AJ AF Simeone, F. Joseph Bredella, Miriam A. Chang, Connie Y. Torriani, Martin Huang, Ambrose J. TI MRI appearance of the superior transverse scapular ligament SO SKELETAL RADIOLOGY LA English DT Article DE Superior transverse scapular ligament; STSL; Shoulder; MRI ID SUPRASCAPULAR NERVE ENTRAPMENT; PARSONAGE-TURNER-SYNDROME; ROTATOR CUFF TEAR; NOTCH; NEUROPATHY; DECOMPRESSION; GANGLION; RELEASE; ANATOMY; MUSCLE AB The superior transverse scapular ligament (STSL) forms the roof of the suprascapular notch, which is the most common location of entrapment of the suprascapular nerve, a cause of shoulder pain and weakness. The purpose of this study is to determine the frequency of visualization of the STSL on routine shoulder MRIs, to identify the sequences and imaging planes on which it is visualized most frequently, and to describe its typical MRI appearance, none of which have been previously addressed in the radiologic literature. One hundred twenty-one consecutive shoulder MRIs were reviewed for the presence or absence of the STSL, including the imaging plane and sequence that best depicted the ligament. Dimensions of the ligament were recorded. Fifty four of 121 shoulder MRIs were technically adequate for visualization of the STSL, and it was identified on 51 of these studies (94 %). There was no statistically significant difference between 1.5-T and 3-T systems. The best individual sequence for visualizing the STSL was the sagittal T1-weighted sequence, in which the STSL was visible on 75/80 technically adequate sequences (94 %). The sagittal plane was the best plane for visualizing the STSL, in which it was visible on 65/69 technically adequate studies (94 %). The STSL on average measured 12.8 +/- 1.5 mm in transverse dimension. The STSL can be visualized on the majority of shoulder MRIs and is best seen on sagittal T1-weighted images on our imaging protocol. Evaluation of the STSL can potentially help in identifying pathologic conditions affecting the suprascapular nerve. C1 [Simeone, F. Joseph; Bredella, Miriam A.; Chang, Connie Y.; Torriani, Martin; Huang, Ambrose J.] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Dept Radiol, Boston, MA 02114 USA. RP Simeone, FJ (reprint author), Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Dept Radiol, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. EM fsimeone@mgh.harvard.edu; mbredella@mgh.harvard.edu; cychang@mgh.harvard.edu; mtorriani@mgh.harvard.edu; ajhuang@mgh.harvard.edu NR 28 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD NOV PY 2015 VL 44 IS 11 BP 1663 EP 1669 DI 10.1007/s00256-015-2209-2 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA CR8YI UT WOS:000361640000014 PM 26210230 ER PT J AU Axon, RN Turner, M Buckley, R AF Axon, R. Neal Turner, Mason Buckley, Ryan TI An Update on Inpatient Hypertension Management SO CURRENT CARDIOLOGY REPORTS LA English DT Review DE Hypertension; Hospitalization; Hypertensive emergency; Cardiovascular disease ID PRESERVED EJECTION FRACTION; DECOMPENSATED HEART-FAILURE; JOINT NATIONAL COMMITTEE; HIGH BLOOD-PRESSURE; ISCHEMIC-STROKE; UNITED-STATES; 7TH REPORT; 1ST YEAR; HOSPITALIZATION; EMERGENCIES AB Hypertension is highly prevalent affecting nearly one third of the US adult population. Though generally approached as an outpatient disorder, elevated blood pressure is observed in a majority of hospitalized patients. The spectrum of hypertensive disease ranges from patients with hypertensive emergency including markedly elevated blood pressure and associated end-organ damage to asymptomatic patients with minimally elevated pressures of unclear significance. It is important to note that current evidence-based hypertension guidelines do not specifically address inpatient hypertension. This narrative review focuses primarily on best practices for diagnosing and managing nonemergent hypertension in the inpatient setting. We describe examples of common hypertensive syndromes, provide suggestions for optimal post-acute management, and point to evidence-based or consensus guidelines where available. In addition, we describe a practical approach to managing asymptomatic elevated blood pressure observed in the inpatient setting. Finally, arranging effective care transitions to ensure optimal ongoing hypertension management is appropriate in all cases. C1 [Axon, R. Neal] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Dept Med, Ralph H Johnson VAMC, Charleston, SC 29401 USA. [Axon, R. Neal; Buckley, Ryan] Ralph H Johnson Vet Affairs Med Ctr, Ralph H Johnson VAMC, Charleston, SC 29401 USA. [Turner, Mason] Med Univ S Carolina, Coll Med, Ralph H Johnson VAMC, Charleston, SC 29401 USA. RP Axon, RN (reprint author), Med Univ S Carolina, Div Gen Internal Med & Geriatr, Dept Med, Ralph H Johnson VAMC, MSC 111,109 Bee St, Charleston, SC 29401 USA. EM axon@musc.edu; turnerm@musc.edu; buckleyr@musc.edu RI Vila, Vanessa/B-4982-2014 NR 65 TC 2 Z9 2 U1 2 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD NOV PY 2015 VL 17 IS 11 AR 94 DI 10.1007/s11886-015-0648-y PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR6HX UT WOS:000361447600003 PM 26362300 ER PT J AU Zhao, KW Murray, EJB Murray, SS AF Zhao, Ke-Wei Murray, Elsa J. Brochmann Murray, Samuel S. TI Fibroblastic Synoviocytes Secrete Plasma Proteins Via (2)-Macroglobulins Serving as Intracellular and Extracellular Chaperones SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE (2)-MACROGLOBULIN; (1)-ANTITRYPSIN (A1AT); BLOOD: SYNOVIUM BARRIER; BONE MORPHOGENETIC PROTEIN-2; C-REACTIVE PROTEIN; CHAPERONE; INSULIN-LIKE GROWTH FACTOR-1; INTER--TRYPSIN INHIBITOR HEAVY CHAIN H4; MATRIX METALLOPROTEINASE; TRANSFORMING GROWTH FACTOR-1; HIG-82 CELLS; Spp24 ID RHEUMATOID-ARTHRITIS; SYNOVIAL-FLUID; PROTEOMIC ANALYSIS; ZONE PROTEIN; KNEE-JOINT; OSTEOARTHRITIS; ALPHA-2-MACROGLOBULIN; BINDING; CELLS; ALPHA(2)-MACROGLOBULIN AB Changes in plasma protein levels in synovial fluid (SF) have been implicated in osteoarthritis and rheumatoid arthritis. It was previously thought that the presence of plasma proteins in SF reflected ultrafiltration or extravasation from the vasculature, possibly due to retraction of inflamed endothelial cells. Recent proteomic analyses have confirmed the abundant presence of plasma proteins in SF from control and arthritic patients. Systematic depletion of high-abundance plasma proteins from SF and conditioned media from synoviocytes cultured in serum, and protein analysis under denaturing/reducing conditions have limited our understanding of sources and the native structures of plasma protein complexes in SF. Using Western blotting, qPCR, and mass spectrometry, we found that Hig-82 lapine fibroblastic synovicytes cultured under serum-free conditions expressed and secreted plasma proteins, including the cytokine-binding protein secreted phosphoprotein 24kDa (Spp24) and many of the proteases and protease inhibitors found in SF. Treating synoviocytes with TGF-1 or BMP-2 for 24h upregulated the expression of plasma proteins, including Spp24, (2)-HS-glycoprotein, (1)-antitrypsin, IGF-1, and C-reactive protein. Furthermore, many of the plasma proteins of mass <151kDa were secreted as disulfide-bound complexes with members of the (2)-macroglobulin (A2M) family, which serve as intracellular and extracellular chaperones, not protease inhibitors. Using brefeldin A to block vesicular traffic and protease inhibitors to inhibit endogenous activation of naive A2M, we demonstrated that the complexes were formed in the endoplasmic reticulum lumen and that Ca(2+)cysteine protease-dependent processes are involved. J. Cell. Biochem. 116: 2563-2576, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA C1 [Zhao, Ke-Wei] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv 151, Sepulveda, CA 91343 USA. [Murray, Elsa J. Brochmann; Murray, Samuel S.] Vet Affairs Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr 11E, Sepulveda, CA 91343 USA. [Murray, Elsa J. Brochmann; Murray, Samuel S.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Murray, Samuel S.] Univ Calif Los Angeles, Interdept Program Biomed Engn, Los Angeles, CA 90095 USA. RP Murray, SS (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr 11E, Sepulveda, CA 91343 USA. EM Samuel.Murray@va.gov FU Department of Veterans Affairs [1IPBX000511, 1IORX000383] FX Grant sponsor: Department of Veterans Affairs; Grant numbers: 1IPBX000511, 1IORX000383. NR 47 TC 2 Z9 2 U1 0 U2 14 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 NOV PY 2015 VL 116 IS 11 BP 2563 EP 2576 DI 10.1002/jcb.25201 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CR3MJ UT WOS:000361236800015 PM 25900303 ER PT J AU Sumner, JA Kronish, IM Pietrzak, RH Shimbo, D Shaffer, JA Parsons, FE Edmondson, D AF Sumner, Jennifer A. Kronish, Ian M. Pietrzak, Robert H. shimbo, Daichi Shaffer, Jonathan A. Parsons, Faith E. Edmondson, Donald TI Dimensional structure and correlates of posttraumatic stress symptoms following suspected acute coronary syndrome SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Posttraumatic stress disorder; Acute coronary syndrome; Latent structure; Confirmatory factor analysis ID CONFIRMATORY FACTOR-ANALYSIS; HEART-DISEASE; EMERGENCY-DEPARTMENT; DISORDER SYMPTOMS; MYOCARDIAL-INFARCTION; FACTORIAL INVARIANCE; MEDICATION ADHERENCE; PRIMARY-CARE; DEPRESSION; PTSD AB Background: Posttraumatic stress disorder (PTSD) is a heterogeneous construct, and some have suggested that PTSD triggered by acute coronary syndrome (ACS) may differ from PTSD due to prototypical traumas. Methods: We conducted the first examination of the latent structure of PTSD symptoms after suspected ACS in 399 adults in the REactions to Acute Care and Hospitalization (REACH) study, an observational cohort study of patients recruited from the emergency department during evaluation for ACS. Using confirmatory factor analysis, we compared the 4-factor dysphoria, 4-factor numbing, and 5-factor dysphoric arousal models of PTSD. Results: Although all models fit well, the dysphoria model was selected as the best-fitting model. Further, there was measurement invariance of the dysphoria model by sex. PTSD dimensions evidenced differential associations with indicators of threat perception during ACS evaluation and adherence to cardiprotective medication. Limitations: One limitation of this investigation is the use of self-report measures. In addition, only one-third of the sample was diagnosed with ACS at discharge; the remaining participants received diagnoses such as chest pain without a cardiac diagnosis, another symptom/disease process (e.g, hypertensive chronic kidney disease), or another cardiac disease. Conclusions: Findings suggest that suspected ACS-related PTSD symptoms are best-represented by a 4-factor structure distinguishing between specific (e.g., re-experiencing) and non-specific (dysphoria) symptoms of PTSD that has received support in the broader PTSD literature. (C) 2015 Elsevier B.V. All rights reserved. C1 [Sumner, Jennifer A.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Sumner, Jennifer A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kronish, Ian M.; shimbo, Daichi; Shaffer, Jonathan A.; Parsons, Faith E.; Edmondson, Donald] Columbia Univ, Med Ctr, Ctr Behav Cardiovasc Hlth, New York, NY 10032 USA. [Pietrzak, Robert H.] Vet Affairs Connecticut Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, US Dept Vet Affairs, Clin Neurosci Div, West Haven, CT 06516 USA. [Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06511 USA. RP Sumner, JA (reprint author), Columbia Univ, Med Ctr, Ctr Behav Cardiovasc Hlth, 622 W 168th St, PH 9-319, New York, NY 10032 USA. EM js4456@cumc.columbia.edu RI Edmondson, Donald/G-7486-2016 FU NHLBI NIH HHS [K23 HL098359, R01 HL123368, R01 HL117832] NR 47 TC 3 Z9 3 U1 4 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 NOV 1 PY 2015 VL 186 BP 178 EP 185 DI 10.1016/j.jad.2015.06.013 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CQ9WR UT WOS:000360966400027 PM 26241667 ER PT J AU Gonzalez, R Gonzalez, S Villa, E Ramirez, M Zavala, J Armas, R Contreras, J Dassori, A Leach, RJ Flores, D Jerez, A Raventos, H Ontiveros, A Nicolini, H Escamilla, M AF Gonzalez, Robert Gonzalez, Suzanne Villa, Erika Ramirez, Mercedes Zavala, Juan Armas, Regina Contreras, Javier Dassori, Albana Leach, Robin J. Flores, Deborah Jerez, Alvaro Raventos, Henriette Ontiveros, Alfonso Nicolini, Humberto Escamilla, Michael TI Identification of circadian gene variants in bipolar disorder in Latino populations SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Circadian; Bipolar disorder; Casein Kinase 1 Epsilon; Aryl Hydrocarbon Receptor Nuclear Translocator-Like; Latino; Family-based association test ID GLYCOGEN-SYNTHASE KINASE-3-BETA; FAMILY-BASED ASSOCIATION; SINGLE NUCLEOTIDE POLYMORPHISM; SLEEP PHASE SYNDROME; KINASE-I-EPSILON; ERB-ALPHA-GENE; CLOCK GENES; MOOD DISORDERS; SCHIZOAFFECTIVE DISORDER; 1ST-DEGREE RELATIVES AB Background: Variations in circaclian genes can impact biological rhythms. Given the rhythm disturbances that characterize bipolar disorder (BD), genes encoding components of molecular clocks are good candidate genes for the illness. Methods: A family based association analysis of circadian gene single nucleotide polymorphisms (SNPs) and BD was conducted in Latino pedigrees. 884 individuals from 207 pedigrees (473 BP phenotype and 411 unaffected family members) were genotyped. Family based single marker association testing was performed. Ancestral haplotypes (SNPs found to be in strong LD defined using confidence intervals) were also tested for association with BD. Results: Multiple suggestive associations between circadian gene SNPs and BD were noted. These included CSNK1E (rs1534891, p_000680) ARNTL (rs3789327, =0.021172), CSNK1D (rs4510078, p=0.022801), CLOCK (rs17777927, p =0.031664). Individually, none of the SNPs were significantly associated with BD after correction for multiple testing. However, a 4-locus CSNICIE haplotype encompassing the rs1534891 SNP (Z-score=2.685, permuted p=0.0076) and a 3-locus haplotype in ARNTL (Zscore=3269, permuted p=00011) showed a significant association with BD. Limitations: Larger samples are required to confirm these findings and assess the relationship between circadian gene SNPs and BD in Latinos. Conclusions: The results suggest that ARNTL and CSIds-hM4D-tdTomato mice. All data are contained in the manuscript and the supplementary materials. A.G. and E.K. were supported by the Gatsby Charitable Foundation and the NIH (grant R01 NS 067216). NR 26 TC 16 Z9 16 U1 9 U2 18 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 OCT 30 PY 2015 VL 350 IS 6260 BP 550 EP 554 DI 10.1126/science.aac8653 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU6RG UT WOS:000363660000046 PM 26516282 ER PT J AU Sewald, X Ladinsky, MS Uchil, PD Beloor, J Pi, RX Herrmann, C Motamedi, N Murooka, TT Brehm, MA Greiner, DL Shultz, LD Mempel, TR Bjorkman, PJ Kumar, P Mothes, W AF Sewald, Xaver Ladinsky, Mark S. Uchil, Pradeep D. Beloor, Jagadish Pi, Ruoxi Herrmann, Christin Motamedi, Nasim Murooka, Thomas T. Brehm, Michael A. Greiner, Dale L. Shultz, Leonard D. Mempel, Thorsten R. Bjorkman, Pamela J. Kumar, Priti Mothes, Walther TI Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection SO SCIENCE LA English DT Article ID DENDRITIC CELLS; T-CELLS; B-CELLS; VIROLOGICAL SYNAPSES; SUBCAPSULAR SINUS; HIV TRANSFER; LYMPH-NODE; MACROPHAGES; SIALOADHESIN; ANTIGEN AB Dendritic cells can capture and transfer retroviruses in vitro across synaptic cell-cell contacts to uninfected cells, a process called trans-infection. Whether trans-infection contributes to retroviral spread in vivo remains unknown. Here, we visualize how retroviruses disseminate in secondary lymphoid tissues of living mice. We demonstrate that murine leukemia virus (MLV) and human immunodeficiency virus (HIV) are first captured by sinus-lining macrophages. CD169/Siglec-1, an I-type lectin that recognizes gangliosides, captures the virus. MLV-laden macrophages then form long-lived synaptic contacts to trans-infect B-1 cells. Infected B-1 cells subsequently migrate into the lymph node to spread the infection through virological synapses. Robust infection in lymph nodes and spleen requires CD169, suggesting that a combination of fluid-based movement followed by CD169-dependent trans-infection can contribute to viral spread. C1 [Sewald, Xaver; Uchil, Pradeep D.; Pi, Ruoxi; Herrmann, Christin; Mothes, Walther] Yale Univ, Sch Med, Dept Microbial Pathogenesis, New Haven, CT 06510 USA. [Ladinsky, Mark S.; Bjorkman, Pamela J.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Beloor, Jagadish; Kumar, Priti] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Motamedi, Nasim] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Murooka, Thomas T.; Mempel, Thorsten R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Brehm, Michael A.; Greiner, Dale L.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01655 USA. [Shultz, Leonard D.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Sewald, X (reprint author), Univ Munich, Max Von Pettenkofer Inst, Munich, Germany. EM sewald@mvp.uni-muenchen.de; priti.kumar@yale.edu; walther.mothes@yale.edu FU NIH [R01 CA098727, S10 RR026697, P50GM082545, R01 AI097052, R01 DA036298, P01 AI078897, R01 AI112443]; Flow Cytometry Shared Resource of the Yale Cancer Center [P30 CA016359]; Leopoldina Fellowship [LPDS2009-21]; China Scholarship Council; Jackson Laboratory FX We thank J. Grover, J. Ventura, and K. Haugh for critical reading of the manuscript; P. Van Ness for advice with statistical analyses; and P. Crocker, D. Gonzalez, and A. Haberman for Siglec-/- mice and DsRed mice, respectively. Siglec-/- mice are available under a materials transfer agreement with P. Crocker (University of Dundee, UK). This work was supported by the NIH grants R01 CA098727 and S10 RR026697 to W.M.; P50GM082545 to P.J.B and W.M.; R01 AI097052, R01 DA036298, and P01 AI078897 to T.R.M.; R01 AI112443 to P. K; Flow Cytometry Shared Resource of the Yale Cancer Center P30 CA016359 and the Leopoldina Fellowship LPDS2009-21 to X.S.; and a fellowship from the China Scholarship Council-Yale World Scholars to R.P. D.L.G. and M.A.B. are consultants for and receive grants from The Jackson Laboratory. NR 27 TC 26 Z9 26 U1 4 U2 10 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 OCT 30 PY 2015 VL 350 IS 6260 BP 563 EP 567 DI 10.1126/science.aab2749 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU6RG UT WOS:000363660000049 PM 26429886 ER PT J AU Sher, L Siever, LJ Goodman, M McNamara, M Hazlett, EA Koenigsberg, HW New, AS AF Sher, Leo Siever, Larry J. Goodman, Marianne McNamara, Margaret Hazlett, Erin A. Koenigsberg, Harold W. New, Antonia S. TI Gender differences in the clinical characteristics and psychiatric comorbidity in patients with antisocial personality disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Gender; Antisocial personality disorder; Substance abuse; Mood disorder; Childhood abuse ID NATIONAL EPIDEMIOLOGIC SURVEY; DSM-IV DISORDERS; SEX BIAS; MENTAL-DISORDERS; ADOLESCENT MALTREATMENT; SURVEY REPLICATION; UNITED-STATES; FOLLOW-UP; BEHAVIOR; PREVALENCE AB Gender is an important variable in the study of mental health because of the actual and perceived differences between men and women. Relatively little is known how males and females differ in their manifestations of antisocial personality disorder (ASPD). Demographic and clinical features of 323 participants with ASPD were assessed and recorded. Women had fewer episodes of antisocial behavior involving or not involving police, higher scores on the Childhood Trauma Questionnaire (CTQ) and on Emotional Abuse and Sexual Abuse subscales of the CTQ compared to men. CTQ scores positively correlated with the number of episodes of antisocial behavior involving police in men but not in women. The percentage of patients with comorbid borderline and histrionic personality disorders was higher and the percentage of participants with cocaine use disorder was lower among women compared to men. Comorbid alcohol use disorder was frequent in both groups, while a higher percentage of women had comorbid mood disorders compared to men. Logistic regression analysis demonstrates that CTQ scores, histrionic personality disorder, and antisocial behavior involving the police drive the difference between the groups. Our findings indicate that treatment of individuals with ASPD should focus on the management of comorbid psychiatric disorders. Published by Elsevier Ireland Ltd. C1 [Sher, Leo; Siever, Larry J.; Goodman, Marianne; Hazlett, Erin A.; Koenigsberg, Harold W.; New, Antonia S.] James J Peters Vet Adm Med Ctr, Bronx, NY 10468 USA. [Sher, Leo; Siever, Larry J.; Goodman, Marianne; McNamara, Margaret; Hazlett, Erin A.; Koenigsberg, Harold W.; New, Antonia S.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Sher, L (reprint author), James J Peters Vet Adm Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM Leo.Sher@mssm.edu NR 58 TC 4 Z9 4 U1 7 U2 26 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 OCT 30 PY 2015 VL 229 IS 3 BP 685 EP 689 DI 10.1016/j.psychres.2015.08.022 PG 5 WC Psychiatry SC Psychiatry GA CS5TN UT WOS:000362141300003 PM 26296756 ER PT J AU Mohamed, S Johnson, GR Vertrees, JE Guarino, PD Weingart, K Young, IT Yoon, J Gleason, TC Kirkwood, KA Kilbourne, AM Gerrity, M Marder, S Biswas, K Hicks, P Davis, LL Chen, PJ Kelada, A Huang, GD Lawrence, DD LeGwin, M Zisook, S AF Mohamed, Somaia Johnson, Gary R. Vertrees, Julia E. Guarino, Peter D. Weingart, Kimberly Young, Ilanit Tal Yoon, Jean Gleason, Theresa C. Kirkwood, Katherine A. Kilbourne, Amy M. Gerrity, Martha Marder, Stephen Biswas, Kousick Hicks, Paul Davis, Lori L. Chen, Peijun Kelada, AlexandraMary Huang, Grant D. Lawrence, David D. LeGwin, Mary Zisook, Sidney TI The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations SO PSYCHIATRY RESEARCH LA English DT Article DE Study design; Methodology; Major depression; Antidepressants; Antipsychotics; Treatment resistance ID STAR-ASTERISK-D; SEROTONIN REUPTAKE INHIBITORS; ILLNESS RATING-SCALE; INDUCED WEIGHT-GAIN; DOUBLE-BLIND; CLINICAL-TRIALS; BUPROPION-SR; ATYPICAL ANTIPSYCHOTICS; PRACTICE GUIDELINES; ADJUNCTIVE THERAPY AB Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial. (C) 2015 Published by Elsevier Ireland Ltd. C1 [Mohamed, Somaia] Vet Hlth Adm, VA VISN New England Mental Illness Res Educ & Cli, West Haven, CT 06510 USA. [Mohamed, Somaia] Yale Univ, Sch Med, West Haven, CT 06516 USA. [Johnson, Gary R.; Guarino, Peter D.; Kirkwood, Katherine A.; Lawrence, David D.; LeGwin, Mary] VA Connecticut Healthcare Syst, VA Cooperat Studies Program Coordinating Ctr, West Haven, CT USA. [Vertrees, Julia E.] New Mexico VA Healthcare Syst, VA Cooperat Studies Program Clin Res Pharm Coordi, Albuquerque, NM USA. [Guarino, Peter D.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Weingart, Kimberly; Young, Ilanit Tal; Kelada, AlexandraMary; Zisook, Sidney] VA San Diego Healthcare Syst, San Diego, CA USA. [Weingart, Kimberly; Young, Ilanit Tal; Kelada, AlexandraMary; Zisook, Sidney] Univ Calif San Diego, San Diego, CA 92103 USA. [Yoon, Jean] VA Palo Alto, HERC, Menlo Pk, CA USA. [Gleason, Theresa C.; Kilbourne, Amy M.] US Dept Vet Affairs, Off Res & Dev, Washington, DC USA. [Kilbourne, Amy M.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Gerrity, Martha] Portland VA Healthcare Syst, Portland, OR USA. [Marder, Stephen] Univ Calif Los Angeles, VA Desert Pacific Mental Illness Res Educ & Clin, Los Angeles, CA USA. [Marder, Stephen] Univ Calif Los Angeles, Semel Inst Neurosci, Los Angeles, CA USA. [Biswas, Kousick] VA Maryland Healthcare Syst, VA Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [Hicks, Paul] Cent Texas Vet Healthcare Syst, Temple, TX USA. [Hicks, Paul] Texas A&M Hlth Sci Ctr Coll Med, Dept Psychiat & Behav Sci, Temple, TX USA. [Davis, Lori L.] Tuscaloosa VA Med Ctr, Tuscaloosa, AL USA. [Davis, Lori L.] Univ Alabama, Sch Med, Tuscaloosa, AL 35487 USA. [Chen, Peijun] Louis Stokes VA Med Ctr, Cleveland, OH USA. [Chen, Peijun] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Huang, Grant D.] US Dept Vet Affairs, Cooperat Studies Program Cent Off, Off Res & Dev, Washington, DC USA. RP Mohamed, S (reprint author), Vet Hlth Adm, VA VISN New England Mental Illness Res Educ & Cli, West Haven, CT 06510 USA. EM Somaia.Mohamed@va.gov FU Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, Washington, DC, USA as CSP [576] FX This study is supported and conducted by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, Washington, DC, USA as CSP #576, VA augmentation and switching treatments for improving depression outcomes (VAST-D) NR 68 TC 3 Z9 3 U1 3 U2 4 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 OCT 30 PY 2015 VL 229 IS 3 BP 760 EP 770 DI 10.1016/j.psychres.2015.08.005 PG 11 WC Psychiatry SC Psychiatry GA CS5TN UT WOS:000362141300015 PM 26279130 ER PT J AU Russo, M Mahon, K Shanahan, M Solon, C Ramjas, E Turpin, J Burdick, KE AF Russo, Manuela Mahon, Katie Shanahan, Megan Solon, Carly Ramjas, Elizabeth Turpin, Justin Burdick, Katherine E. TI The association between childhood trauma and facial emotion recognition in adults with bipolar disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Emotion recognition; Childhood trauma; Emotional neglect; Anger; Social cognition; Bipolar disorder ID BORDERLINE PERSONALITY; IMPAIRED RECOGNITION; RATING-SCALE; II DISORDER; ABUSE; SCHIZOPHRENIA; MALTREATMENT; VALIDITY; DEFICITS; ILLNESS AB Many patients with bipolar disorder (BD) have difficulties in facial emotion recognition, which may also be impaired in maltreated children and in subjects who have a positive history of childhood traumatic experiences. Childhood trauma is reported with a high prevalence in BD and it is considered a risk factor for the disorder. As the relationship between facial emotion recognition and childhood trauma in BD has not yet been directly investigated, in this study we examined whether the presence of a childhood trauma in affectively stable BD patients was associated with poorer performance in emotion recognition. Seventy-five BD I and II participants completed the Childhood Trauma Questionnaire retrospectively assessing five types of childhood trauma (emotional, physical and sexual abuse, and emotional and physical neglect) and the Emotion Recognition Task evaluating the ability to correctly identify six basic facial emotions (happiness, sadness, anger, disgust, fear and surprise). Our results suggest that the presence of childhood trauma in participants with BD is associated with a more severe clinical presentation (earlier onset, longer duration of illness, and higher depressive symptom ratings) and that BD patients with a positive childhood history of emotional neglect perform worse than those without such a history in recognizing anger. Published by Elsevier Ireland Ltd. C1 [Russo, Manuela; Mahon, Katie; Shanahan, Megan; Solon, Carly; Ramjas, Elizabeth; Turpin, Justin; Burdick, Katherine E.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Burdick, Katherine E.] James J Peters VA Med Ctr, Bronx, NY USA. RP Burdick, KE (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, 1 Gustave L Levy Pl Box 1230, New York, NY 10029 USA. EM Katherine.burdick@mssm.edu FU National Institute of Mental Health (NIMH) [R01 MH100125] FX This study was funded by Grants from the National Institute of Mental Health (NIMH) to KEB (R01 MH100125). NR 59 TC 3 Z9 3 U1 6 U2 24 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 OCT 30 PY 2015 VL 229 IS 3 BP 771 EP 776 DI 10.1016/j.psychres.2015.08.004 PG 6 WC Psychiatry SC Psychiatry GA CS5TN UT WOS:000362141300016 PM 26272021 ER PT J AU Smith, BN Tyzik, AL Neylan, TC Cohen, BE AF Smith, Brian N. Tyzik, Anna L. Neylan, Thomas C. Cohen, Beth E. TI PTSD and obesity in younger and older veterans: Results from the mind your heart study SO PSYCHIATRY RESEARCH LA English DT Article DE Posttraumatic stress disorder; Aging; Stress; Overweight; BMI; Physical health; Military ID POSTTRAUMATIC-STRESS-DISORDER; PHYSICAL-ACTIVITY; CONSTRUCT-VALIDITY; HEALTH BEHAVIORS; ADRENAL AXIS; ADULTS; ASSOCIATION; COMORBIDITY; SYMPTOMS; DISEASE AB Posttraumatic stress disorder (PTSD) is increasingly recognized as a relatively common condition that is associated with poor health, including obesity. With a sizable proportion of the population approaching older adulthood, it is important to understand PTSD-health associations in the context of age. Participants were recruited from two Veterans Administration medical centers and included 380 patients age 60 and over and 365 under age 60. PTSD diagnosis was determined by the Clinician Administered PTSD Scale. BMI was trichotomized into normal/under (<= 24.9), overweight (25.0-29.9), and obese (>= 30.0). Models were run in the total sample, as well as stratified by age group, and adjusted for demographics, depression, antipsychotic medication use, and physical activity. Current PTSD was associated with greater likelihood of overweight and obesity in the total sample, and lifetime PTSD was associated with significantly increased odds of obesity. In the stratified models, current and lifetime PTSD were associated with increased likelihood of overweight and obesity in the older group only. Results suggest that PTSD is associated with risk for overweight and obesity, an effect that may be particularly strong in older adults. These findings support the importance of examining PTSD and potential health correlates across the life course. Published by Elsevier Ireland Ltd. C1 [Smith, Brian N.; Tyzik, Anna L.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Smith, Brian N.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Neylan, Thomas C.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Neylan, Thomas C.; Cohen, Beth E.] San Francisco VA Med Ctr, San Francisco, CA USA. [Cohen, Beth E.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Smith, BN (reprint author), VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, 150 S Huntington Ave,116B-3, Boston, MA 02130 USA. EM Brian.Smith12@va.gov FU National Heart, Lung, and Blood Institute [K23 HL 094765-0]; Irene Perstein Foundation; University of California, San Francisco; National Center for PTSD; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System FX The Mind Your Heart Study was supported by the National Heart, Lung, and Blood Institute (K23 HL 094765-0, Beth Cohen, Principal Investigator), the Irene Perstein Foundation, and Departmental funds from the University of California, San Francisco. The article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The authors thank the National Center for PTSD for ongoing support. The authors also express their appreciation to colleagues of the Stress, Health, and Aging Research Program (SHARP), VA Boston Healthcare System; SHARP is supported by the National Center for PTSD and the Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System. We also wish to thank the Mind Your Heart Study participants and Dr. Mary Whooley. NR 43 TC 5 Z9 5 U1 6 U2 14 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 OCT 30 PY 2015 VL 229 IS 3 BP 895 EP 900 DI 10.1016/j.psychres.2015.07.044 PG 6 WC Psychiatry SC Psychiatry GA CS5TN UT WOS:000362141300033 PM 26210650 ER PT J AU Pace-Schott, EF Rubin, ZS Tracy, LE Spencer, RMC Orr, SP Verga, PW AF Pace-Schott, Edward F. Rubin, Zoe S. Tracy, Lauren E. Spencer, Rebecca M. C. Orr, Scott P. Verga, Patrick W. TI Emotional trait and memory associates of sleep timing and quality SO PSYCHIATRY RESEARCH LA English DT Article DE Sleep; Extinction; Fear conditioning; Trait anxiety; Neuroticism; Circadian rhythms ID POSTTRAUMATIC-STRESS-DISORDER; OBSESSIVE-COMPULSIVE DISORDER; SOCIAL ANXIETY DISORDER; FEAR EXTINCTION; CONDITIONED FEAR; EXPOSURE THERAPY; YOUNG-ADULTS; CHRONOTYPE; DEPRESSION; RECALL AB Poor ability to remember the extinction of conditioned fear, elevated trait anxiety, and delayed or disrupted nocturnal sleep are reported in anxiety disorders. The current study examines the interrelationship of these factors in healthy young-adult males. Skin-conductance response was conditioned to two differently colored lamps. One color but not the other was then extinguished. After varying delays, both colors were presented to determine extinction recall and generalization. Questionnaires measured sleep quality, morningness-eveningness, neuroticism and trait anxiety. A subset produced a mean 7.0 nights of actigraphy and sleep diaries. Median split of mean sleep midpoint defined early- and late-"sleep timers". Extinction was more rapidly learned in the morning than evening only in early timers who also better generalized extinction recall. Extinction recall was greater with higher sleep efficiency. Sleep efficiency and morningness were negatively associated with neuroticism and anxiety. However, neuroticism and anxiety did not predict extinction learning, recall or generalization. Therefore, neuroticism/anxiety and deficient fear extinction, although both associated with poor quality and late timing of sleep, are not directly associated with each other. Elevated trait anxiety, in addition to predisposing directly to anxiety disorders, may thus also indirectly promote such disorders by impairing sleep and, consequently, extinction memory. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Pace-Schott, Edward F.; Rubin, Zoe S.; Tracy, Lauren E.; Orr, Scott P.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Spencer, Rebecca M. C.; Verga, Patrick W.] Univ Massachusetts, Dept Psychol & Brain Sci, Amherst, MA 01003 USA. RP Pace-Schott, EF (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp East, CNY 149 13th St,Room 2624, Charlestown, MA 02129 USA. EM epace-schott@mgh.harvard.edu FU NIH/NIMH [R21MH090357, R21MH1 01567]; NIH/NIA [R00AG029710] FX Research supported by NIH/NIMH R21MH090357 and R21MH1 01567 (E.P.-S.) and NIH/NIA R00AG029710 (R.M.C.S). The authors thank Mohammed R. Milad, Ph.D. for the experimental protocol and valuable advice, Shilpa Vijayakumar, Nafis Ahmed, Megan Murphy and Jessica Kent for research assistance and Philip Cusimano for technical advice. NR 64 TC 2 Z9 2 U1 8 U2 36 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 OCT 30 PY 2015 VL 229 IS 3 BP 999 EP 1010 DI 10.1016/j.psychres.2015.05.069 PG 12 WC Psychiatry SC Psychiatry GA CS5TN UT WOS:000362141300048 PM 26257092 ER PT J AU Bako, P Bassiouni, M Eckhard, A Gerlinger, I Frick, C Lowenheim, H Muller, M AF Bako, Peter Bassiouni, Mohamed Eckhard, Andreas Gerlinger, Imre Frick, Claudia Loewenheim, Hubert Mueller, Marcus TI Methyl methacrylate embedding to study the morphology and immunohistochemistry of adult guinea pig and mouse cochleae SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Cochlea; Immunohistochemistry; Morphology; Organ of Corti; Resin embedding; Spiral ganglion neuron ID SPIRAL GANGLION NEURONS; ELECTRICAL-STIMULATION; INNER-EAR; PERIPHERIN; NERVE; IMMUNOREACTIVITY; REGENERATION; EXPRESSION; SURVIVAL; PROTEIN AB Background: Histological analysis of the cochlea is required to understand the physiological and pathological processes in the inner ear. In the past, many embedding techniques have been tested in the cochlea to find an optimal protocol that gives both good morphological and immunohistochemical results. Resins provide high quality cochlear morphology with reduced immunogenicity due to the higher polymerization temperature. New method: We used Technovit 9100 New (R), a low temperature embedding system based on methyl methacrylate, on adult guinea pig and mouse cochleae to evaluate preservation of the morphology and maintenance of the antigenicity. Results: Conventional toluidine blue staining, as well as immunohistochemical staining with a set of commonly used antibodies, showed highly preserved morphology and immunogenicity of decalcified adult guinea pig and mouse cochleae. Comparison with existing method(s): We demonstrate both, well-preserved morphology and preservation of antigenicity, superior to other embedding techniques. Conclusions: Our results showed that the Technovit 9100 New (R) embedding system provided highly preserved morphology and immunogenicity with our protocol in adult guinea pig and mouse cochleae. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Bako, Peter; Bassiouni, Mohamed; Eckhard, Andreas; Frick, Claudia; Mueller, Marcus] Univ Tubingen, Dept Otolaryngol Head & Neck Surg, Tubingen Hearing Res Ctr, Tubingen, Germany. [Bako, Peter; Gerlinger, Imre] Univ Pecs, Dept Otorhinolaryngol & Head & Neck Surg, Pecs, Hungary. [Eckhard, Andreas] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Eaton Peabody Lab, Boston, MA USA. [Loewenheim, Hubert; Mueller, Marcus] Carl von Ossietzky Univ Oldenburg, European Med Sch, Sch Med & Hlth Sci, Univ Hosp Otorhinolaryngol, D-26122 Oldenburg, Germany. [Loewenheim, Hubert; Mueller, Marcus] Carl von Ossietzky Univ Oldenburg, Res Ctr Neurosensory Sci, D-26111 Oldenburg, Germany. [Loewenheim, Hubert; Mueller, Marcus] Carl von Ossietzky Univ Oldenburg, Cluster Excellence Hearing4all, D-26111 Oldenburg, Germany. RP Muller, M (reprint author), Carl von Ossietzky Univ Oldenburg, European Med Sch, Sch Med & Hlth Sci, Univ Hosp Otorhinolaryngol, Med Campus,Steinweg 13-17, D-26122 Oldenburg, Germany. EM marcus.mueller@uni-tuebingen.de RI Muller, Marcus/B-3877-2016 OI Muller, Marcus/0000-0001-5881-7708 FU European Union [281056]; DAAD (German academic exchange service) FX The study was supported by the NanoCI project (project number: 281056) under the 7th Framework Program of the European Union. The first author received a grant from DAAD (German academic exchange service). Special thanks to Prof. Marlies Knipper for the Prestin and to Dr. Annie Wolff for the Peripherin antibodies. NR 26 TC 0 Z9 0 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 30 PY 2015 VL 254 BP 86 EP 93 DI 10.1016/j.jneumeth.2015.07.017 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CS1XI UT WOS:000361861800010 PM 26226655 ER PT J AU Raaum, SE Arbelaez, C Vallejo, CE Patino, AM Colbert-Getz, JM Milne, CK AF Raaum, Sonja E. Arbelaez, Christian Eduardo Vallejo, Carlos Patino, Andres M. Colbert-Getz, Jorie M. Milne, Caroline K. TI Emergency medicine and internal medicine trainees' smartphone use in clinical settings in the United States SO JOURNAL OF EDUCATIONAL EVALUATION FOR HEALTH PROFESSIONS LA English DT Article DE Cell phones; Emergency medicine; Internal medicine; Physicians; United States ID HEALTH-CARE; STUDENTS; INFORMATION; RESIDENTS; DOCTORS; PDA AB Purpose: Smartphone technology offers a multitude of applications (apps) that provide a wide range of functions for healthcare professionals. Medical trainees are early adopters of this technology, but how they use smartphones in clinical care remains unclear. Our objective was to further characterize smartphone use by medical trainees at two United States academic institutions, as well as their prior training in the clinical use of smartphones. Methods: In 2014, we surveyed 347 internal medicine and emergency medicine resident physicians at the University of Utah and Brigham and Women's Hospital about their smartphone use and prior training experiences. Scores (0%-100%) were calculated to assess the frequency of their use of general features (email, text) and patient-specific apps, and the results were compared according to resident level and program using the Mann-Whitney U-test. Results: A total of 184 residents responded (response rate, 53.0%). The average score for using general features, 14.4/20 (72.2%) was significantly higher than the average score for using patient-specific features and apps, 14.1/44 (33.0%, P<0.001). The average scores for the use of general features, were significantly higher for year 3-4 residents, 15.0/20 (75.1%) than year 1-2 residents, 14.1/20 (70.5%, P=0.035), and for internal medicine residents, 14.9/20 (74.6%) in comparison to emergency medicine residents, 12.9/20 (64.3%, P=0.001). The average score reflecting the use of patient-specific apps was significantly higher for year 3-4 residents, 16.1/44 (36.5%) than for year 1-2 residents, 13.7/44 (31.1%; P=0.044). Only 21.7% of respondents had received prior training in clinical smartphone use. Conclusion: Residents used smartphones for general features more frequently than for patient-specific features, but patient-specific use increased with training. Few residents have received prior training in the clinical use of smartphones. C1 [Raaum, Sonja E.; Milne, Caroline K.] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84112 USA. [Raaum, Sonja E.; Milne, Caroline K.] George E Whalen VA Hosp, Salt Lake City, UT USA. [Arbelaez, Christian; Patino, Andres M.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Eduardo Vallejo, Carlos] Univ Antioquia, Dept Emergency Med, Medellin, Colombia. [Colbert-Getz, Jorie M.] Univ Utah, Sch Med, Dept Internal Med Adm, Salt Lake City, UT USA. RP Raaum, SE (reprint author), Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84112 USA. EM sonja.raaum@hsc.utah.edu OI Milne, Caroline/0000-0002-4782-1901 NR 17 TC 0 Z9 0 U1 2 U2 3 PU NATL HEALTH PERSONNEL LICENSING EXAMINATION BOARD PI SEOUL PA 679-30 JAYANG-DONG, KWANGJIN-GU, SEOUL, 143-873, SOUTH KOREA SN 1975-5937 J9 J EDUC EVAL HEALTH P JI J. Educ. Eval. Health Prof. PD OCT 29 PY 2015 VL 12 AR UNSP 48 DI 10.3352/jeehp.2015.12.48 PG 6 WC Education & Educational Research SC Education & Educational Research GA DA9VO UT WOS:000368157900001 PM 26582632 ER PT J AU Zhu, JH Zhu, JQ Bougie, DW Aster, RH Springer, TA AF Zhu, Jianghai Zhu, Jieqing Bougie, Daniel W. Aster, Richard H. Springer, Timothy A. TI Structural basis for quinine-dependent antibody binding to platelet integrin alpha(IIb)beta(3) SO BLOOD LA English DT Article ID INDUCED IMMUNE THROMBOCYTOPENIA; B-CELLS; STATE AB Drug-induced immune thrombocytopenia (DITP) is caused by antibodies that react with specific platelet-membrane glycoproteins when the provoking drug is present. More than 100 drugs have been implicated as triggers for this condition, quinine being one of the most common. The cause of DITP in most cases appears to be a drug-induced antibody that binds to a platelet membrane glycoprotein only when the drug is present. How a soluble drug promotes binding of an otherwise nonreactive immunoglobulin to its target, leading to platelet destruction, is uncertain, in part because of the difficulties of working with polyclonal human antibodies usually available only in small quantities. Recently, quinine-dependent murine monoclonal antibodies were developed that recognize a defined epitope on the beta-propeller domain of the platelet integrin alpha(IIb) subunit (GPIIb) only when the drug is present and closely mimic the behavior of antibodies found in human patients with quinine-induced thrombocytopenia in vitro and in vivo. Here, we demonstrate specific, high-affinity binding of quinine to the complementarity-determining regions (CDRs) of these antibodies and define in crystal structures the changes induced in the CDR by this interaction. Because no detectable binding of quinine to the target integrin could be demonstrated in previous studies, the findings indicate that a hybrid paratope consisting of quinine and reconfigured antibody CDR plays a critical role in recognition of its target epitope by an antibody and suggest that, in this type of drug-induced immunologic injury, the primary reaction involves binding of the drug to antibody CDRs, causing it to acquire specificity for a site on a platelet integrin. C1 [Zhu, Jianghai; Zhu, Jieqing; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zhu, Jianghai; Zhu, Jieqing; Springer, Timothy A.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Bougie, Daniel W.; Aster, Richard H.] BloodCtr Wisconsin, Blood Res Inst, Milwaukee, WI USA. [Aster, Richard H.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. RP Springer, TA (reprint author), Boston Childrens Hosp, 3 Blackfan Circle,Room 3103, Boston, MA 02115 USA. EM timothy.springer@childrens.harvard.edu FU National Institutes of Health, National Heart, Lung, and Blood Institute [HL-103526, HL-13629] FX This work was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL-103526 and HL-13629). NR 29 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 29 PY 2015 VL 126 IS 18 BP 2138 EP 2145 DI 10.1182/blood-2015-04-639351 PG 8 WC Hematology SC Hematology GA CY4PI UT WOS:000366390100013 PM 26282540 ER PT J AU Chen, XY Spaeth, RB Freeman, SG Scarborough, DM Hashmi, JA Wey, HY Egorova, N Vangel, M Mao, JR Wasan, AD Edwards, RR Gollub, RL Kong, J AF Chen, Xiaoyan Spaeth, Rosa B. Freeman, Sonya G. Scarborough, Donna Moxley Hashmi, Javeria A. Wey, Hsiao-Ying Egorova, Natalia Vangel, Mark Mao, Jianren Wasan, Ajay D. Edwards, Robert R. Gollub, Randy L. Kong, Jian TI The modulation effect of longitudinal acupuncture on resting state functional connectivity in knee osteoarthritis patients SO MOLECULAR PAIN LA English DT Article DE Acupuncture; Knee osteoarthritis; Chronic pain; Resting state fMRI; Independent component analysis (ICA); Knee injury and Osteoarthritis Outcome Score (KOOS); Right frontoparietal network; Executive control network ID INDEPENDENT COMPONENT ANALYSIS; RANDOMIZED CLINICAL-TRIAL; CHRONIC PAIN; CENTRAL SENSITIZATION; PERIAQUEDUCTAL GRAY; PLACEBO ANALGESIA; COGNITIVE CONTROL; BRAIN NETWORKS; ELECTROACUPUNCTURE STIMULATION; ADJUNCTIVE THERAPY AB Recent advances in brain imaging have contributed to our understanding of the neural activity associated with acupuncture treatment. In this study, we investigated functional connectivity across longitudinal acupuncture treatments in older patients with knee osteoarthritis (OA). Over a period of 4 weeks (six treatments), we collected resting state functional magnetic resonance imaging (fMRI) scans from 30 patients before and after their first, third and sixth treatments. Clinical outcome showed a significantly greater pain subscore on the Knee Injury and Osteoarthritis Outcome Score (KOOS) (indicative of improvement) with verum acupuncture than with sham acupuncture. Independent component analysis (ICA) of the resting state fMRI data showed that the right frontoparietal network (rFPN) and the executive control network (ECN) showed enhanced functional connectivity (FC) with the rostral anterior cingulate cortex/medial prefrontal cortex, a key region in the descending pain modulatory system, in the verum groups as compared to the sham group after treatments. We also found that the rFPN connectivity with the left insula is (1) significantly associated with changes in KOOS pain score after treatments, and (2) significantly enhanced after verum acupuncture treatments as compared to sham treatment. Analysis of the acupuncture needle stimulation scan showed that compared with sham treatment, verum acupuncture activated the left operculum/insula, which also overlaps with findings observed in resting state analysis. Our results suggest that acupuncture may achieve its therapeutic effect on knee OA pain by modulating functional connectivity between the rFPN, ECN and the descending pain modulatory pathway. C1 [Chen, Xiaoyan; Spaeth, Rosa B.; Freeman, Sonya G.; Hashmi, Javeria A.; Wey, Hsiao-Ying; Egorova, Natalia; Gollub, Randy L.; Kong, Jian] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Scarborough, Donna Moxley] Massachusetts Gen Hosp, Mass Gen Orthopaed Sports Performance Ctr, Foxboro, MA USA. [Vangel, Mark; Gollub, Randy L.; Kong, Jian] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. [Vangel, Mark] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Mao, Jianren] Massachusetts Gen Hosp, Dept Anesthesiol, Charlestown, MA USA. [Edwards, Robert R.] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Edwards, Robert R.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Edwards, Robert R.] Harvard Univ, Sch Med, Boston, MA USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. RP Kong, J (reprint author), MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, 120,2nd Ave Suite 101, Charlestown, MA 02129 USA. EM kongj@nmr.mgh.harvard.edu OI Egorova, Natalia/0000-0002-9244-2900 FU NIH/NCCIH [R21AT004497, R01AT006364, R01AT008563]; NIH/NIDA [R03AT218317]; NCCIH [R01AT005280]; P01 AT006663 FX This work was supported by R21AT004497 (NIH/NCCIH), R03AT218317 (NIH/NIDA), R01AT006364 (NIH/NCCIH), R01AT008563 (NIH/NCCIH) to Jian Kong, R01AT005280 (NCCIH) to Randy Gollub, and P01 AT006663 to Bruce Rosen. NR 101 TC 7 Z9 8 U1 4 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD OCT 29 PY 2015 VL 11 AR 67 DI 10.1186/s12990-015-0071-9 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CU7SX UT WOS:000363742900001 PM 26511911 ER PT J AU Castro, V Shen, YY Yu, S Finan, S Pau, CT Gainer, V Keefe, CC Savova, G Murphy, SN Cai, TX Welt, CK AF Castro, Victor Shen, Yuanyuan Yu, Sheng Finan, Sean Pau, Cindy Ta Gainer, Vivian Keefe, Candace C. Savova, Guergana Murphy, Shawn N. Cai, Tianxi Welt, Corrine K. TI Identification of subjects with polycystic ovary syndrome using electronic health records SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Article DE Natural language processing; ICD9 code; Hyperandrogenism; Polycystic ovary morphology ID IMPAIRED GLUCOSE-TOLERANCE; MEDICAL-RECORDS; WOMEN; ADOLESCENTS; PREVALENCE; MANAGEMENT; DIAGNOSIS; FEATURES; CRITERIA AB Background: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder because of the variable criteria used for diagnosis. Therefore, International Classification of Diseases 9 (ICD-9) codes may not accurately capture the diagnostic criteria necessary for large scale PCOS identification. We hypothesized that use of electronic medical records text and data would more specifically capture PCOS subjects. Methods: Subjects with PCOS were identified in the Partners Healthcare Research Patients Data Registry by searching for the term "polycystic ovary syndrome" using natural language processing (n = 24,930). A training subset of 199 identified charts was reviewed and categorized based on likelihood of a true Rotterdam PCOS diagnosis, i.e. two out of three of the following: irregular menstrual cycles, hyperandrogenism and/or polycystic ovary morphology. Data from the history, physical exam, laboratory and radiology results were codified and extracted from notes of definite PCOS subjects. Thirty-two terms were used to build an algorithm for identifying definite PCOS cases and applied to the rest of the dataset. The positive predictive value cutoff was set at 76.8 % to maximize the number of subjects available for study. A true positive predictive value for the algorithm was calculated after review of 100 charts from subjects identified as definite PCOS cases with at least two documented Rotterdam criteria. The positive predictive value was compared to that calculated using 200 charts identified using the ICD-9 code for PCOS (256.4; n = 13,670). In addition, a cohort of previously recruited PCOS subjects was submitted for algorithm validation. Results: Chart review demonstrated that 64 % were confirmed as definitely PCOS using the algorithm, with a 9 % false positive rate. 66 % of subjects identified by ICD-9 code for PCOS could be confirmed as definitely PCOS, with an 8.5 % false positive rate. There was no significant difference in the positive predictive values using the two methods (p = 0.2). However, the number of charts that had insufficient confirmatory data was lower using the algorithm (5 % vs 11 %; p < 0.04). Of 477 subjects with PCOS recruited and examined individually and present in the database as patients, 451 were found within the algorithm dataset. Conclusions: Extraction of text parameters along with codified data improves the confidence in PCOS patient cohorts identified using the electronic medical record. However, the positive predictive value was not significantly different when using ICD-9 codes or the specific algorithm. Further studies are needed to determine the positive predictive value of the two methods in additional electronic medical record datasets. C1 [Castro, Victor; Gainer, Vivian; Murphy, Shawn N.] Massachusetts Gen Hosp, Informat Syst, Boston, MA 02114 USA. [Shen, Yuanyuan; Cai, Tianxi] Harvard Univ, Sch Publ Hlth, Biostat, Boston, MA 02115 USA. [Yu, Sheng] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Finan, Sean; Savova, Guergana] Childrens Hosp, Informat, Boston, MA 02115 USA. [Pau, Cindy Ta; Keefe, Candace C.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Murphy, Shawn N.] Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA. [Welt, Corrine K.] Univ Utah, Div Endocrinol Metab & Diabet, Salt Lake City, UT 84112 USA. RP Welt, CK (reprint author), Univ Utah, Div Endocrinol Metab & Diabet, EIHG 15 N 2030 E, Salt Lake City, UT 84112 USA. EM cwelt@genetics.utah.edu OI Welt, Corrine/0000-0002-8219-5504; Yu, Sheng/0000-0002-6347-0507 FU Partners Center for Personalized Genetic Medicine: Advancing Translational Genomics through Personalized Medicine Project; Eunice Kennedy Shriver National Institute Of Child Health & Human Development [R01HD065029]; Harvard Clinical and Translational Science Center [1 UL1 RR025758]; American Diabetes Association [1-10-CT-57]; National Center for Research Resources FX Grant funding: Partners Center for Personalized Genetic Medicine: Advancing Translational Genomics through Personalized Medicine Project, R01HD065029 from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development, Award Number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources and award 1-10-CT-57 from the American Diabetes Association. NR 22 TC 2 Z9 2 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD OCT 29 PY 2015 VL 13 AR 116 DI 10.1186/s12958-015-0115-z PG 8 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA CU6KF UT WOS:000363640200001 PM 26510685 ER PT J AU Tiacci, E Park, JH De Carolis, L Chung, SS Broccoli, A Scott, S Zaja, F Devlin, S Pulsoni, A Chung, YR Cimminiello, M Kim, E Rossi, D Stone, RM Motta, G Saven, A Varettoni, M Altman, JK Anastasia, A Grever, MR Ambrosetti, A Rai, KR Fraticelli, V Lacouture, ME Carella, AM Levine, RL Leoni, P Rambaldi, A Falzetti, F Ascani, S Capponi, M Martelli, MP Park, CY Pileri, SA Rosen, N Foa, R Berger, MF Zinzani, PL Abdel-Wahab, O Falini, B Tallman, MS AF Tiacci, E. Park, J. H. De Carolis, L. Chung, S. S. Broccoli, A. Scott, S. Zaja, F. Devlin, S. Pulsoni, A. Chung, Y. R. Cimminiello, M. Kim, E. Rossi, D. Stone, R. M. Motta, G. Saven, A. Varettoni, M. Altman, J. K. Anastasia, A. Grever, M. R. Ambrosetti, A. Rai, K. R. Fraticelli, V. Lacouture, M. E. Carella, A. M. Levine, R. L. Leoni, P. Rambaldi, A. Falzetti, F. Ascani, S. Capponi, M. Martelli, M. P. Park, C. Y. Pileri, S. A. Rosen, N. Foa, R. Berger, M. F. Zinzani, P. L. Abdel-Wahab, O. Falini, B. Tallman, M. S. TI Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INHIBITOR DABRAFENIB; MEK INHIBITION; MELANOMA; MUTATIONS; ACTIVATION; CANCER; RAF; VEMURAFENIB; SURVIVAL; CLADRIBINE AB BACKGROUND BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues. METHODS We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily) - one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial. RESULTS The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism. CONCLUSIONS A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.) C1 [Tiacci, E.; De Carolis, L.; Falzetti, F.; Ascani, S.; Capponi, M.; Martelli, M. P.; Falini, B.] Univ Perugia, Inst Hematol, Dept Med, I-06100 Perugia, Italy. [Tiacci, E.; De Carolis, L.; Falzetti, F.; Ascani, S.; Capponi, M.; Martelli, M. P.; Falini, B.] Univ Perugia, CREO, I-06100 Perugia, Italy. [Tiacci, E.; De Carolis, L.; Falzetti, F.; Ascani, S.; Capponi, M.; Martelli, M. P.; Falini, B.] Osped Santa Maria Misericordia, Perugia, Italy. [Broccoli, A.; Pileri, S. A.; Zinzani, P. L.] Univ Bologna, Sch Med, Units Hematol & Hematopathol, Dept Expt Diagnost & Specialty Med, Bologna, Italy. [Zaja, F.] Azienda Ospedaliero Univ, Dipartimento Sci Med Sperimentali & Clin, Ctr Trapianti & Terapie Cellulari Carlo Melzi, Hematol Unit, Udine, Italy. [Pulsoni, A.; Foa, R.] Univ Roma La Sapienza, Div Hematol, Dept Cellular Biotechnol & Hematol, Rome, Italy. [Capponi, M.] Azienda Osped Regionale San Carlo, Hematol & Bone Marrow Transplant Unit, Potenza, Italy. [Rossi, D.] Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy. [Motta, G.] Osped Ferrarotto, Hematol Unit, Catania, Italy. [Varettoni, M.] Policlin San Matteo, Fdn IRCCS, Dept Onco Hematol, Pavia, Italy. [Anastasia, A.] Spedali Civil Brescia, Hematol Unit, I-25125 Brescia, Italy. [Ambrosetti, A.] Univ Verona, Sect Hematol, Dept Med, I-37100 Verona, Italy. [Fraticelli, V.] Fdn Ric & Cura SS Giovanni Paolo II, Onco Hematol Unit, Campobasso, Italy. [Carella, A. M.] Univ San Martino, Azienda Osped, IRCCS, Ist Nazl Ric Cancro,Inst Hematol 1, Genoa, Italy. [Leoni, P.] Univ Osped Riuniti, Azienda Osped, Dept Hematol, Ancona, Italy. [Rambaldi, A.] Azienda Osped Papa Giovanni XXIII, Hematol & Bone Marrow Transplant Unit, Bergamo, Italy. [Park, J. H.; Chung, S. S.; Levine, R. L.; Abdel-Wahab, O.; Tallman, M. S.] Leukemia Serv, New York, NY USA. [Lacouture, M. E.] Mem Sloan Kettering Canc Ctr, Dept Med, Dermatol Serv, New York, NY 10021 USA. [Scott, S.; Chung, Y. R.; Kim, E.; Levine, R. L.; Park, C. Y.; Berger, M. F.; Abdel-Wahab, O.] Human Oncol & Pathogenesis Program, Dept Med, New York, NY USA. [Devlin, S.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Park, C. Y.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Rosen, N.] Mem Sloan Kettering Canc Ctr, Dept Pharmacol, New York, NY 10021 USA. [Berger, M. F.] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10021 USA. [Rai, K. R.] Hofstra North Shore Long Isl Jewish Sch Med, Div Hematol Oncol, New York, NY USA. [Stone, R. M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Saven, A.] Scripps Clin, Div Hematol & Oncol, La Jolla, CA 92037 USA. [Altman, J. K.] Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Grever, M. R.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH USA. RP Falini, B (reprint author), Univ Perugia, Osped Santa Maria Misericordia, Inst Hematol, CREO, I-06132 Perugia, Italy. EM brunangelo.falini@unipg.it RI Zinzani, Pier Luigi/J-9182-2016; Broccoli, Alessandro/K-1558-2016; Kim, Eunhee/Q-9162-2016 OI ZAJA, Francesco/0000-0003-3995-8817; Zinzani, Pier Luigi/0000-0002-2112-2651; Broccoli, Alessandro/0000-0001-5633-7313; Kim, Eunhee/0000-0001-7143-7769 FU Associazione Italiana per la Ricerca sul Cancro; EudraCT [2011-005487-13] FX Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13 NR 40 TC 23 Z9 23 U1 1 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 29 PY 2015 VL 373 IS 18 BP 1733 EP 1747 DI 10.1056/NEJMoa1506583 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA CU4QH UT WOS:000363514100009 PM 26352686 ER PT J AU Khosroshahi, A Digumarthy, SR Gibbons, FK Deshpande, V AF Khosroshahi, Arezou Digumarthy, Subba R. Gibbons, Fiona K. Deshpande, Vikram TI Case 34-2015: A 36-Year-Old Woman with a Lung Mass, Pleural Effusion, and Hip Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ERDHEIM-CHESTER DISEASE; INFLAMMATORY MYOFIBROBLASTIC TUMOR; IGG4-RELATED DISEASE; RETROPERITONEAL FIBROSIS; MANIFESTATIONS; PERIAORTITIS C1 [Khosroshahi, Arezou] Emory Univ, Dept Med, Sch Med, Atlanta, GA 30322 USA. [Digumarthy, Subba R.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Gibbons, Fiona K.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Deshpande, Vikram] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Digumarthy, Subba R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Gibbons, Fiona K.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Deshpande, Vikram] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Khosroshahi, A (reprint author), Emory Univ, Dept Med, Sch Med, Atlanta, GA 30322 USA. FU Affymetrix FX Dr. Deshpande reports receiving grant support to his institution from Affymetrix and holding a pending patent related to the detection of IgG4 and IgG with the use of in situ hybridization. No other potential conflict of interest relevant to this article was reported. NR 23 TC 0 Z9 0 U1 1 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 OCT 29 PY 2015 VL 373 IS 18 BP 1762 EP 1772 DI 10.1056/NEJMcpc1502151 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CU4QH UT WOS:000363514100013 PM 26510025 ER PT J AU Rosenfield, K Metzger, DC Scheinert, D AF Rosenfield, Kenneth Metzger, D. Christopher Scheinert, Dierk TI A Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Rosenfield, Kenneth] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Metzger, D. Christopher] Wellmont Cardiovasc Associates Heart Inst, Kingsport, TN USA. [Scheinert, Dierk] Univ Klinikum Leipzig, Leipzig, Germany. RP Rosenfield, K (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 29 PY 2015 VL 373 IS 18 BP 1785 EP 1786 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CU4QH UT WOS:000363514100027 PM 26510036 ER PT J AU Vuong, HE Muller, LPD Hardi, CN McMahon, DG Brecha, NC AF Vuong, H. E. Mueller, L. Perez de Sevilla Hardi, C. N. McMahon, D. G. Brecha, N. C. TI HETEROGENEOUS TRANSGENE EXPRESSION IN THE RETINAS OF THE TH-RFP, TH-Cre, TH-BAC-Cre AND DAT-Cre MOUSE LINES SO NEUROSCIENCE LA English DT Review DE transgenic; Cre-lox-system; GABA; glycine; dopamine; amacrine cells ID GREEN FLUORESCENT PROTEIN; POLYAXONAL AMACRINE CELLS; TYROSINE-HYDROXYLASE IMMUNOCYTOCHEMISTRY; RABBIT RETINA; GANGLION-CELLS; DOPAMINERGIC-NEURONS; MAMMALIAN RETINA; BIPOLAR CELLS; CAT RETINA; IMMUNOREACTIVE NEURONS AB Transgenic mouse lines are essential tools for understanding the connectivity, physiology and function of neuronal circuits, including those in the retina. This report compares transgene expression in the retina of a tyrosine hydroxylase (TH)-red fluorescent protein (RFP) mouse line with three catecholamine-related Cre recombinase mouse lines [TH-bacterial artificial chromosome (BAC)-, TH-, and dopamine transporter (DAT)-Cre] that were crossed with a ROSA26-tdTomato reporter line. Retinas were evaluated and immunostained with commonly used antibodies including those directed to TH, GABA and glycine to characterize the RFP or tdTomato fluorescent-labeled amacrine cells, and an antibody directed to RNA-binding protein with multiple splicing to identify ganglion cells. In TH-RFP retinas, types 1 and 2 dopamine (DA) amacrine cells were identified by their characteristic cellular morphology and type 1 DA cells by their expression of TH immunoreactivity. In the TH-BAC-, TH-, and DAT-tdTomato retinas, less than 1%, similar to 6%, and 0%, respectively, of the fluorescent cells were the expected type 1 DA amacrine cells. Instead, in the TH-BAC-tdTomato retinas, fluorescently labeled AII amacrine cells were predominant, with some medium diameter ganglion cells. In TH-tdTomato retinas, fluorescence was in multiple neurochemical amacrine cell types, including four types of polyaxonal amacrine cells. In DAT-tdTomato retinas, fluorescence was in GABA immunoreactive amacrine cells, including two types of bistratified and two types of monostratified amacrine cells. Although each of the Cre lines was generated with the intent to specifically label DA cells, our findings show a cellular diversity in Cre expression in the adult retina and indicate the importance of careful characterization of transgene labeling patterns. These mouse lines with their distinctive cellular labeling patterns will be useful tools for future studies of retinal function and visual processing. Published by Elsevier Ltd. on behalf of IBRO. C1 [Vuong, H. E.; Brecha, N. C.] Univ Calif Los Angeles, David Geffen Sch Med, Mol Cellular & Integrat Physiol Program, Los Angeles, CA 90095 USA. [Vuong, H. E.; Mueller, L. Perez de Sevilla; Brecha, N. C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Vuong, H. E.; Brecha, N. C.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Hardi, C. N.] Univ Calif Los Angeles, Coll Letters & Sci, Dept Psychol, Los Angeles, CA 90095 USA. [Brecha, N. C.] Univ Calif Los Angeles, David Geffen Sch Med, CURE Digest Dis Res Ctr, Los Angeles, CA 90095 USA. [McMahon, D. G.] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. [Brecha, N. C.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. RP Brecha, NC (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM nbrecha@ucla.edu FU NIH (Imaging and Stem Cell Biology Core; CURE: DDRC) [R01 EY04067, P30 DK41301]; VA; Whitcome Summer Undergraduate Research Fellowship; NIH [T32 EY007026, R01 EY09256] FX Support for these studies was from NIH R01 EY04067 (N.C.B.), P30 DK41301 (Imaging and Stem Cell Biology Core; CURE: DDRC), a VA Merit Review (N.C.B.), NIH T32 EY007026 (H.E.V.), Whitcome Summer Undergraduate Research Fellowship (C.N.H.) and NIH R01 EY09256 (D.G.M.). N.C.B. is a VA Career Research Scientist. NR 117 TC 2 Z9 2 U1 3 U2 11 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 29 PY 2015 VL 307 BP 319 EP 337 DI 10.1016/j.neuroscience.2015.08.060 PG 19 WC Neurosciences SC Neurosciences & Neurology GA CS2GJ UT WOS:000361886700028 PM 26335381 ER PT J AU Hinkley, LB Mizuiri, D Hong, OS Nagarajan, SS Cheung, SW AF Hinkley, Leighton B. Mizuiri, Danielle Hong, OiSaeng Nagarajan, Srikantan S. Cheung, Steven W. TI Increased striatal functional connectivity with auditory cortex in tinnitus SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE resting-state fMRI; tinnitus; striatum; auditory cortex; functional connectivity ID DEEP BRAIN-STIMULATION; RESTING-STATE FMRI; BASAL-GANGLIA; AREA LC; PHANTOM PERCEPTION; PREFRONTAL CORTEX; DEFAULT MODE; NETWORK; NEUROSCIENCE; DYSRHYTHMIA AB Tinnitus is a common auditory perceptual disorder whose neural substrates are under intense debate. One physiologically based model posits the dorsal striatum to play a key role in gating auditory phantoms to perceptual awareness. Here, we directly test this model along with the roles of auditory and auditory-limbic networks in tinnitus non-invasively by comparing resting state fMRI functional connectivity patterns in chronic tinnitus patients against matched control subjects without hearing loss. We assess resting-state functional connectivity of the caudate dorsal striatum (area LC), caudate head (CH), nucleus accumbens (NA), and primary auditory cortex (Al) to determine patterns of abnormal connectivity. In chronic tinnitus, increases in ipsilateral striatal auditory cortical connectivity are found consistently only in area LC. Other patterns of increased connectivity are as follows: (1) right striatal area LC, A1, CH, and NA with parietal cortex, (2) left and right CHs with dorsal pre frontal cortex, (3) NA and A1 with cerebellum, hippocampus, visual and ventral pre-frontal cortex. Those findings provide further support for a striatal gating model of tinnitus, where dysfunctionally permissive area LC enables auditory phantoms to reach perceptual awareness. C1 [Hinkley, Leighton B.; Mizuiri, Danielle; Nagarajan, Srikantan S.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Hong, OiSaeng] Univ Calif San Francisco, Sch Nursing, Dept Community Hlth Syst, San Francisco, CA 94143 USA. [Nagarajan, Srikantan S.; Cheung, Steven W.] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, San Francisco, CA 94143 USA. [Cheung, Steven W.] San Francisco VA Med Ctr, Surg Serv, San Francisco, CA USA. RP Cheung, SW (reprint author), Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, San Francisco, CA 94143 USA. EM sri@ucsf.edu; steven.cheung@ucsf.edu FU Department of Defense [W81XWH-13-1-0494]; UCSE Academic Senate Committee; Coleman Memorial and Hearing Research, Inc FX This work was supported by the Department of Defense (Award W81XWH-13-1-0494 to SC), UCSE Academic Senate Committee (Individual Investigator Grant to SC), and Coleman Memorial and Hearing Research, Inc, endowment funds. NR 56 TC 2 Z9 2 U1 0 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD OCT 28 PY 2015 VL 9 AR 568 DI 10.3389/fnhum2015.00568 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA CY5ZN UT WOS:000366486800001 PM 26578924 ER PT J AU Zou, CB Li, J Xiong, S Chen, Y Wu, Q Li, XY Weathington, NM Han, SH Snavely, C Chen, BB Mallampalli, RK AF Zou, Chunbin Li, Jin Xiong, Sheng Chen, Yan Wu, Qin Li, Xiuying Weathington, Nathaniel M. Han, SeungHye Snavely, Courtney Chen, Bill B. Mallampalli, Rama K. TI Mortality factor 4 like 1 protein mediates epithelial cell death in a mouse model of pneumonia SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ACUTE LUNG INJURY; HUMAN MRG15; CHROMO DOMAIN; PROLIFERATION; ACETYLATION; INHIBITOR; STABILITY; COMPLEXES; DIFFERENTIATION; INFLAMMATION AB Unchecked epithelial cell death is fundamental to the pathogenesis of pneumonia. The recognition of unique signaling pathways that preserve epithelial cell viability may present new opportunities for interventional strategies. We describe that mortality factor 4 like 1 (Morf4l1), a protein involved in chromatin remodeling, is constitutively expressed at low levels in the lung because of its continuous degradation mediated by an orphan ubiquitin E3 ligase subunit, Fbxl18. Expression of Morf4l1 increases in humans with pneumonia and is up-regulated in lung epithelia after exposure to Pseudomonas aeruginosa or lipopolysaccharide. In a mouse model of pneumonia induced by P. aeruginosa, Morf4l1 is stabilized by acetylation that protects it from Fbxl18-mediated degradation. After P. aeruginosa infection of mice, overexpression of Morf4l1 resulted in lung epithelial cell death, whereas its depletion restored cell viability. Using in silico modeling and drug-target interaction studies, we identified that the U.S. Food and Drug Administration-approved thrombin inhibitor argatroban is a Morf4l1 antagonist. Argatroban inhibited Morf4l1-dependent histone acetylation, reduced its cytotoxicity, and improved survival of mice with experimental lung injury at doses that had no anticoagulant activity. These studies uncover a previously unrecognized biological mechanism where by pathogens subvert cell viability by extending the life span of a cytotoxic host protein. Morf4l1 may be a potential molecular target for non-antibiotic pharmacotherapy during severe pulmonary infection. C1 [Zou, Chunbin; Li, Jin; Xiong, Sheng; Chen, Yan; Wu, Qin; Li, Xiuying; Weathington, Nathaniel M.; Han, SeungHye; Snavely, Courtney; Chen, Bill B.; Mallampalli, Rama K.] Univ Pittsburgh, Acute Lung Injury Ctr Excellence, Dept Med, Pittsburgh, PA 15213 USA. [Weathington, Nathaniel M.; Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. RP Zou, CB (reprint author), Univ Pittsburgh, Acute Lung Injury Ctr Excellence, Dept Med, Pittsburgh, PA 15213 USA. EM zouc@upmc.edu; mallampallirk@upmc.edu FU NIH grants [HL096376, HL097376, HL098174, HL081784, P01 HL114453, HL116472, HL125435, P30 DK72506]; Office of Research and Development, Veterans Health Administration, U.S. Department of Veterans Affairs; Ministry of Science and Technology of China [2012ZX09103-301-033, 2012ZX09202-301-001]; Natural Science Foundation of China [30873082, 81070039, 81270100]; Major Biotech Industrialization Projects from Guangzhou Municipal Science and Technology Bureau [2010U1-E00541] FX This work was supported, in part, by NIH grants HL096376, HL097376, HL098174, HL081784, P01 HL114453 (to R.K.M.), HL116472 (to B.B.C.), HL125435 (to C.Z.), and P30 DK72506. This work was also supported by the Office of Research and Development, Veterans Health Administration, U.S. Department of Veterans Affairs, with a Merit Review Award. S.X. was supported by grants from the Ministry of Science and Technology of China (2012ZX09103-301-033 and 2012ZX09202-301-001), the Natural Science Foundation of China (30873082), and the Major Biotech Industrialization Projects from the Guangzhou Municipal Science and Technology Bureau (2010U1-E00541). Y.C. was supported by the Natural Science Foundation of China (81070039 and 81270100). NR 42 TC 1 Z9 1 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 28 PY 2015 VL 7 IS 311 AR 311ra171 DI 10.1126/scitranslmed.aac7793 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CW8GC UT WOS:000365236500003 PM 26511508 ER PT J AU Wang, Y Sahni, N Vidal, M AF Wang, Yang Sahni, Nidhi Vidal, Marc TI Global Edgetic Rewiring in Cancer Networks SO CELL SYSTEMS LA English DT Editorial Material C1 [Wang, Yang; Sahni, Nidhi; Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Wang, Yang; Sahni, Nidhi; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Wang, Yang; Sahni, Nidhi; Vidal, Marc] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. RP Vidal, M (reprint author), Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. EM marc_vidal@dfci.harvard.edu NR 11 TC 2 Z9 2 U1 0 U2 0 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 OCT 28 PY 2015 VL 1 IS 4 BP 251 EP 253 DI 10.1016/j.cels.2015.10.006 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA V47AZ UT WOS:000209926000004 PM 27136053 ER PT J AU Kinlay, S AF Kinlay, Scott TI Does This Study Make My Aorta Look Fat? SO CIRCULATION LA English DT Editorial Material DE Editorials; aneurysm; aortic diseases; endovascular procedures; surgery C1 [Kinlay, Scott] Vet Affairs Boston Healthcare Syst, Div Cardiovasc, Boston, MA USA. [Kinlay, Scott] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA USA. [Kinlay, Scott] Harvard Univ, Sch Med, Boston, MA USA. RP Kinlay, S (reprint author), VA Boston Healthcare Syst, Div Cardiovasc, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM scott.kinlay@va.gov FU CSRD VA [I01 CX000440, I21 CX000793]; Intramural VA [VA999999] NR 5 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 27 PY 2015 VL 132 IS 17 BP 1600 EP 1601 DI 10.1161/CIRCULATIONAHA.115.018958 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IU UT WOS:000369255500007 PM 26338954 ER PT J AU Kim, JB Kim, K Lindsay, ME MacGillivray, T Isselbacher, EM Cambria, RP Sundt, TM AF Kim, Joon Bum Kim, Kibeom Lindsay, Mark E. MacGillivray, Thomas Isselbacher, Eric M. Cambria, Richard P. Sundt, Thoralf M., III TI Risk of Rupture or Dissection in Descending Thoracic Aortic Aneurysm SO CIRCULATION LA English DT Article DE aneurysm; aorta; prognosis; risk factors; surgery ID OPEN SURGICAL REPAIR; NATURAL-HISTORY; SIZE; DIAMETER; DISEASE; SURVEILLANCE; MANAGEMENT; PREDICTOR; TRIAL; CM AB Background-Current practice guidelines recommend surgical repair of large thoracic aortic aneurysms to prevent fatal aortic dissection or rupture, but limited natural history data exist to support clinical criteria for timely intervention. Methods and Results-Of 3247 patients with thoracic aortic aneurysm registered in our institutional Thoracic Aortic Center Database, we identified and reviewed 257 nonsyndromic patients (age, 72.4 +/- 10.5 years; 143 female) with descending thoracic or thoracoabdominal aortic aneurysm without a history of aortic dissection in whom surgical intervention was not undertaken. The primary end point was a composite of aortic dissection/rupture and sudden death. Baseline mean maximal aortic diameter was 52.4 +/- 10.8 mm, with 103 patients having diameters >= 55 mm. During a median follow-up of 25.1 months (quartiles 1-3, 8.3-56.4 months), definite and possible aortic events occurred in 19 (7.4%) and 31 (12.1%) patients, respectively. On multivariable analyses, maximal aortic diameter at baseline emerged as the only significant predictor of aortic events (hazard ratio=1.12; 95% confidence interval, 1.08-1.15). Estimated rates of definite aortic events within 1 year were 5.5%, 7.2%, and 9.3% for aortic diameters of 50, 55, and 60 mm, respectively. Receiver-operating characteristic curves for discriminating aortic events were higher for indexed aortic sizes referenced by body size (area under the curve=0.832-0.889) but not significantly different from absolute maximal aortic diameter (area under the curve=0.805). Conclusions-Aortic size was the principal factor related to aortic events in unrepaired descending thoracic or thoracoabdominal aortic aneurysm. Although the risk of aortic events started to increase with a diameter >5.0 to 5.5 cm, it is uncertain whether repair of thoracic aortic aneurysms in this range leads to overall benefit, and the threshold for repair requires further evaluation. C1 [Kim, Joon Bum; MacGillivray, Thomas; Sundt, Thoralf M., III] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiac Surg, Boston, MA USA. [Kim, Joon Bum; Kim, Kibeom; MacGillivray, Thomas; Isselbacher, Eric M.; Cambria, Richard P.; Sundt, Thoralf M., III] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Thorac Aort Ctr, Boston, MA USA. [Lindsay, Mark E.; Isselbacher, Eric M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Lindsay, Mark E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Cardiol, Boston, MA USA. [Cambria, Richard P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vasc & Endovasc Surg, Boston, MA USA. [Kim, Joon Bum; Lindsay, Mark E.] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Thorac & Cardiovasc Surg, Seoul, South Korea. RP Sundt, TM (reprint author), Massachusetts Gen Hosp, Cox 652,55 Fruit St, Boston, MA 02114 USA. EM tsundt@partners.org OI Kim, Joon Bum/0000-0001-5801-2395 FU American Association for Thoracic Surgery's Evarts A. Graham Foundation FX This work was supported by the American Association for Thoracic Surgery's Evarts A. Graham Foundation. NR 26 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 27 PY 2015 VL 132 IS 17 BP 1620 EP 1629 DI 10.1161/CIRCULATIONAHA.114.015177 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IU UT WOS:000369255500011 PM 26338955 ER PT J AU White, JR Chang, CCH So-Armah, KA Stewart, JC Gupta, SK Butt, AA Gibert, CL Rimland, D Rodriguez-Barradas, MC Leaf, DA Bedimo, RJ Gottdiener, JS Kop, WJ Gottlieb, SS Budoff, MJ Khambaty, T Tindle, HA Justice, AC Freiberg, MS AF White, Jessica R. Chang, Chung-Chou H. So-Armah, Kaku A. Stewart, Jesse C. Gupta, Samir K. Butt, Adeel A. Gibert, Cynthia L. Rimland, David Rodriguez-Barradas, Maria C. Leaf, David A. Bedimo, Roger J. Gottdiener, John S. Kop, Willem J. Gottlieb, Stephen S. Budoff, Matthew J. Khambaty, Tasneem Tindle, Hilary A. Justice, Amy C. Freiberg, Matthew S. TI Depression and Human Immunodeficiency Virus Infection Are Risk Factors for Incident Heart Failure Among Veterans Veterans Aging Cohort Study SO CIRCULATION LA English DT Article DE depression; epidemiology; heart failure; HIV ID HIV-INFECTION; CARDIOVASCULAR EVENTS; DISEASE; HEALTH; ASSOCIATION; MECHANISMS; SYSTEM; CARE; ATHEROSCLEROSIS; COMORBIDITIES AB Background-Both HIV and depression are associated with increased heart failure (HF) risk. Depression, a common comorbidity, may further increase the risk of HF among adults with HIV infection (HIV+). We assessed the association between HIV, depression, and incident HF. Methods and Results-Veterans Aging Cohort Study (VACS) participants free from cardiovascular disease at baseline (n=81 427: 26 908 HIV+, 54 519 without HIV [HIV-]) were categorized into 4 groups: HIV- without major depressive disorder (MDD) [reference], HIV-with MDD, HIV+ without MDD, and HIV+ with MDD. International Classification of Diseases, Ninth Revision codes from medical records were used to determine MDD and the primary outcome, HF. After 5.8 years of follow-up, HF rates per 1000 person-years were highest among HIV+ participants with MDD (9.32; 95% confidence interval [CI], 8.20-10.6). In Cox proportional hazards models, HIV+ participants with MDD had a significantly higher risk of HF (adjusted hazard ratio, 1.68; 95% CI, 1.45-1.95) compared with HIV-participants without MDD. MDD was associated with HF in separate fully adjusted models for HIV- and HIV+ participants (adjusted hazard ratio, 1.21; 95% CI, 1.06-1.37; and adjusted hazard ratio, 1.29; 95% CI, 1.11-1.51, respectively). Among those with MDD, baseline antidepressant use was associated with lower risk of incident HF events (adjusted hazard ratio, 0.76; 95% CI, 0.58-0.99). Conclusions-Our study is the first to suggest that MDD is an independent risk factor for HF in HIV+ adults. These results reinforce the importance of identifying and managing MDD among HIV+ patients. Future studies must clarify mechanisms linking HIV, MDD, antidepressants, and HF and identify interventions to reduce HF morbidity and mortality in those with both HIV and MDD. C1 [White, Jessica R.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Chang, Chung-Chou H.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15260 USA. [So-Armah, Kaku A.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Stewart, Jesse C.; Khambaty, Tasneem] Indiana Univ Purdue Univ, Dept Psychol, Indianapolis, IN 46205 USA. [Gupta, Samir K.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Butt, Adeel A.] Hamad Healthcare Qual Inst, Doha, Qatar. [Butt, Adeel A.] Hamad Med Corp, Doha, Qatar. [Gibert, Cynthia L.] VA Med Ctr, Washington, DC USA. [Rimland, David] Emory Univ, Sch Med, Div Infect Dis, Atlanta, GA USA. [Rimland, David] Atlanta VA Med Ctr, Decatur, GA USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Infect Dis Sect, Michael E DeBakey VAMC, Houston, TX 77030 USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Leaf, David A.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. [Leaf, David A.] Greater Los Angeles VA Healthcare Syst, Div Gen Med, Los Angeles, CA USA. [Bedimo, Roger J.] VA North Texas Hlth Care Syst, Dept Med, Dallas, TX USA. [Gottdiener, John S.] Univ Maryland, Med Ctr, Div Cardiol, Baltimore, MD 21201 USA. [Kop, Willem J.] Tilburg Univ, Dept Med & Clin Psychol, NL-5000 LE Tilburg, Netherlands. [Gottlieb, Stephen S.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Budoff, Matthew J.] Los Angeles Biomed Res Inst, Torrance, CA USA. [Tindle, Hilary A.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37203 USA. [Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Justice, Amy C.] Vet Affairs Connecticut Hlth Care Syst, West Haven Vet Adm Med Ctr, West Haven, CT USA. [Freiberg, Matthew S.] Vanderbilt Univ, Sch Med, Div Cardiovasc Med, 2525 W End,Ste 300-A, Nashville, TN 37203 USA. [Freiberg, Matthew S.] Tennessee Valley Healthcare Syst, Nashville, TN USA. RP Freiberg, MS (reprint author), Vanderbilt Univ, Sch Med, Div Cardiovasc Med, 2525 W End,Ste 300-A, Nashville, TN 37203 USA. EM matthew.s.freiberg@vanderbilt.edu OI Justice, Amy/0000-0003-0139-5502 FU National Heart, Lung, and Blood Institute [HL095136, HL126557, HL083825]; National Institutes of Health on Alcohol Abuse and Alcoholism [AA013566, AA020790, AA020794] FX This work was supported by grants HL095136 and HL126557, and T32 Cardiovascular Epidemiology Training Program HL083825 from the National Heart, Lung, and Blood Institute, and grants AA013566, AA020790, and AA020794 from the National Institutes of Health on Alcohol Abuse and Alcoholism. NR 45 TC 6 Z9 6 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 27 PY 2015 VL 132 IS 17 BP 1630 EP 1638 DI 10.1161/CIRCULATIONAHA.114.014443 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IU UT WOS:000369255500012 PM 26358261 ER PT J AU Abraham, TM Pedley, A Massaro, JM Hoffmann, U Fox, CS AF Abraham, Tobin M. Pedley, Alison Massaro, Joseph M. Hoffmann, Udo Fox, Caroline S. TI Association Between Visceral and Subcutaneous Adipose Depots and Incident Cardiovascular Disease Risk Factors SO CIRCULATION LA English DT Article DE adipose tissue; epidemiology; population; risk factors ID INSULIN-RESISTANCE; JAPANESE-AMERICANS; TISSUE VOLUMES; HEART; FAT; FRAMINGHAM; INFLAMMATION; OBESITY; HYPERTENSION; ADIPOKINES AB Background-Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) vary in volume and quality. We evaluated whether fat volume or attenuation (indirect measure of quality) predicts metabolic risk factor changes. Methods and Results-Framingham Heart Study Multi-detector Computed Tomography Substudy participants (n=1730, 45% women) were followed up over a mean of 6.2 years. Baseline VAT and SAT volume (in cm(3)) and attenuation (in Hounsfield units) were assessed. Outcomes included blood pressure, lipids, and glucose. We constructed multivariable regression models predicting change from baseline to follow-up. Baseline VAT was associated with metabolic risk factors at follow-up. Per 500-cm(3) increase in baseline VAT, glucose was 2.34 mg/dL higher (95% confidence interval, 1.712.97) and high-density lipoprotein was 1.62 mg/dL lower (95% confidence interval, 0.97-2.28) in women (P<0.0001 for both). These findings remained significant after adjustment for body mass index. Results for SAT were similar although less striking. Lower (more negative) fat attenuation was associated with more adverse metabolic profiles at follow-up. For example, per 5-unit decrease in baseline VAT Hounsfield units, log triglycerides increased by 0.08 mg/dL (95% confidence interval, 0.05-0.12; P=0.005), which remained significant after adjustment for baseline VAT. Among men, VAT and SAT Hounsfield units were associated with changes in cardiovascular disease risk factors but were mostly attenuated after baseline volume adjustment. Conclusions-VAT volume and SAT volume are associated with incident metabolic risk factors beyond overall adiposity. Decreases in fat attenuation are also associated with incident risk factors. These findings suggest that both volume and quality of VAT and SAT contribute to metabolic risk. C1 [Abraham, Tobin M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Abraham, Tobin M.; Fox, Caroline S.] NHLBI, Bethesda, MD USA. [Abraham, Tobin M.; Pedley, Alison; Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol Hypertens & Diabet, Boston, MA USA. [Abraham, Tobin M.; Pedley, Alison; Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Fox, CS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Institutes of Health; [N01-HC-25195] FX The FHS of the National Heart, Lung, and Blood Institute is supported by contract N01-HC-25195. Dr Abraham is supported by an National Institutes of Health-sponsored T32 training grant. NR 27 TC 16 Z9 16 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 27 PY 2015 VL 132 IS 17 BP 1639 EP 1647 DI 10.1161/CIRCULATIONAHA.114.015000 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IU UT WOS:000369255500013 PM 26294660 ER PT J AU Lin, T Tong, W Chandra, A Hsu, SY Jia, HR Zhu, J Tseng, WJ Levine, MA Zhang, YJ Yan, SG Liu, XS Sun, DM Young, W Qin, L AF Lin, Tiao Tong, Wei Chandra, Abhishek Hsu, Shao-Yun Jia, Haoruo Zhu, Ji Tseng, Wei-Ju Levine, Michael A. Zhang, Yejia Yan, Shi-Gui Liu, X. Sherry Sun, Dongming Young, Wise Qin, Ling TI A comprehensive study of long-term skeletal changes after spinal cord injury in adult rats SO BONE RESEARCH LA English DT Article ID BONE-MINERAL DENSITY; X-RAY ABSORPTIOMETRY; MICRO-COMPUTED-TOMOGRAPHY; BIOMECHANICAL PROPERTIES; POSTMENOPAUSAL WOMEN; BIOCHEMICAL MARKERS; PARATHYROID-HORMONE; TRABECULAR BONE; PREVENTS BONE; GROWING RATS AB Spinal cord injury (SCI)-induced bone loss represents the most severe osteoporosis with no effective treatment. Past animal studies have focused primarily on long bones at the acute stage using adolescent rodents. To mimic chronic SCI inhuman patients, we performed a comprehensive analysis of long-term structural and mechanical changes in axial and appendicular bones in adult rats after SCI. In this experiment, 4-month-old Fischer 344 male rats received a clinically relevant T13 contusion injury. Sixteen weeks later, sublesional femurs, tibiae, and L4 vertebrae, supralesional humeri, and blood were collected from these rats and additional non-surgery rats for micro-computed tomography (mu CT), micro-finite element, histology, and serum biochemical analyses. At trabecular sites, extreme losses of bone structure and mechanical competence were detected in the metaphysis of sublesional long bones after SCI, while the subchondral part of the same bones showed much milder damage. Marked reductions in bone mass and strength were also observed in sublesional L4 vertebrae but not in supralesional humeri. At cortical sites, SCI induced structural and strength damage in both sub-and supralesional long bones. These changes were accompanied by diminished osteoblast number and activity and increased osteoclast number and activity. Taken together, our study revealed site-specific effects of SCI on bone and demonstrated sustained inhibition of bone formation and elevation of bone resorption at the chronic stage of SCI. C1 [Lin, Tiao; Tong, Wei; Chandra, Abhishek; Jia, Haoruo; Zhu, Ji; Tseng, Wei-Ju; Zhang, Yejia; Liu, X. Sherry; Qin, Ling] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. [Lin, Tiao] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Musculoskeletal Oncol, Guangzhou 510275, Guangdong, Peoples R China. [Tong, Wei] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Orthopaed, Wuhan 430074, Hubei, Peoples R China. [Hsu, Shao-Yun; Sun, Dongming; Young, Wise] Rutgers State Univ, WM Keck Ctr Collaborat Neurosci, Piscataway, NJ USA. [Jia, Haoruo] Shihezi Univ, Sch Med, Dept Orthopaed Surg, Shihezi, Xinjiang, Peoples R China. [Levine, Michael A.] Univ Penn, Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Levine, Michael A.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Zhang, Yejia] Univ Penn, Perelman Sch Med, Dept Phys Med & Rehabil, Philadelphia, PA 19104 USA. [Zhang, Yejia] Philadelphia Vet Affairs Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA USA. [Yan, Shi-Gui] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Orthopaed Surg, Hangzhou 310003, Zhejiang, Peoples R China. RP Qin, L (reprint author), Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. EM qinling@mail.med.upenn.edu OI Levine, Michael/0000-0003-0036-7809 FU National Institutes of Health [R01DK095803, 1K08HD049598]; Penn Center for Musculoskeletal Disorders (NIAMS/NIH) [P30AR050950]; ASBMR Junior Faculty Osteoporosis Basic Research Award; NIH/NIAMS [R03-AR065145]; Spinal Cord Injury Project FX This work was supported by the National Institutes of Health (R01DK095803 to LQ, 1K08HD049598 to YZ), Penn Center for Musculoskeletal Disorders P30AR050950 (NIAMS/NIH), ASBMR Junior Faculty Osteoporosis Basic Research Award (to LQ), and NIH/NIAMS R03-AR065145 (to XSL). We thank Mr. Sean O'Leary for his invaluable assistance and technical help in all the procedures and animal care. We are grateful to the donors of the Spinal Cord Injury Project for their generous support of spinal cord injury studies at the W. M. Keck Center for Collaborative Neuroscience at Rutgers University. The authors thank Dr. Martin Heyworth for critically editing the manuscript. NR 42 TC 3 Z9 3 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2095-4700 EI 2095-6231 J9 BONE RES JI Bone Res. PD OCT 27 PY 2015 VL 3 AR 15028 DI 10.1038/boneres.2015.28 PG 9 WC Cell & Tissue Engineering SC Cell Biology GA DA2RQ UT WOS:000367643900001 PM 26528401 ER PT J AU Zang, MR Zou, DH Yu, Z Li, F Yi, SH Ai, XF Qin, XQ Feng, XY Zhou, W Xu, Y Li, ZJ Hao, M Sui, WW Deng, SH Acharya, C Zhao, YZ Ru, K Qiu, LG An, G AF Zang, Meirong Zou, Dehui Yu, Zhen Li, Fei Yi, Shuhua Ai, Xiaofei Qin, Xiaoqi Feng, Xiaoyan Zhou, Wen Xu, Yan Li, Zengjun Hao, Mu Sui, Weiwei Deng, Shuhui Acharya, Chirag Zhao, Yaozhong Ru, Kun Qiu, Lugui An, Gang TI Detection of recurrent cytogenetic aberrations in multiple myeloma: A comparison between MLPA and iFISH SO ONCOTARGET LA English DT Article DE multiple myeloma; cytogenetic aberration; multiplex ligation-dependent probe amplification; interphase fluorescence in situ hybridization ID DEPENDENT PROBE AMPLIFICATION; IN-SITU HYBRIDIZATION; PROGNOSTIC VALUE; 12P DELETION; ABNORMALITIES; BORTEZOMIB; EXPERIENCE; THERAPY; IMPACT AB Multiple myeloma (MM) is a genetically heterogeneous disease with diverse clinical characteristics and outcomes. Recently, multiplex ligation-dependent probe amplification (MLPA) has emerged as an effective and robust method for the detection of cytogenetic aberrations in MM patients. In the present study, MLPA analysis was applied to analyze cytogenetics of CD138 tumor cells of 59 MM samples, and its result was compared, retrospectively, with the interphase fluorescence in situ hybridization (iFISH) data. We firstly established the normal range of each of the 42 diagnostic probes using healthy donor samples. A total of 151 aberrations were detected in 59 patient samples, and 49/59 cases (83.1%) harbored at least one copy number variation. Overall, 0-7 aberrations were detected per case using MLPA, indicating the heterogeneity and complexity of MM cytogenetics. We showed the high efficiency of MLPA and the high congruency of the two methods to assess cytogenetic aberrations. Considering that MLPA analysis is not reliable when the aberration only exits in a small population of tumor cells, it is essential to use both MLPA and iFISH as complementary techniques for the diagnosis of MM. C1 [Zang, Meirong; Zou, Dehui; Yu, Zhen; Yi, Shuhua; Ai, Xiaofei; Qin, Xiaoqi; Feng, Xiaoyan; Zhou, Wen; Xu, Yan; Li, Zengjun; Hao, Mu; Sui, Weiwei; Deng, Shuhui; Zhao, Yaozhong; Ru, Kun; Qiu, Lugui; An, Gang] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China. [Zang, Meirong; Zou, Dehui; Yu, Zhen; Yi, Shuhua; Ai, Xiaofei; Qin, Xiaoqi; Feng, Xiaoyan; Zhou, Wen; Xu, Yan; Li, Zengjun; Hao, Mu; Sui, Weiwei; Deng, Shuhui; Zhao, Yaozhong; Ru, Kun; Qiu, Lugui; An, Gang] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China. [Zang, Meirong; Zou, Dehui; Yu, Zhen; Yi, Shuhua; Ai, Xiaofei; Qin, Xiaoqi; Feng, Xiaoyan; Zhou, Wen; Xu, Yan; Li, Zengjun; Hao, Mu; Deng, Shuhui; Zhao, Yaozhong; Ru, Kun; Qiu, Lugui; An, Gang] Peking Union Med Coll, Tianjin, Peoples R China. [Zhou, Wen] Cent S Univ, Canc Res Inst, Key Lab Carcinogenesis, Minist Hlth, Changsha, Hunan, Peoples R China. [Zhou, Wen] Cent S Univ, Key Lab Carcinogenesis & Canc Invas, Minist Educ, Changsha, Hunan, Peoples R China. [Feng, Xiaoyan; Acharya, Chirag; An, Gang] Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Feng, Xiaoyan; Acharya, Chirag; An, Gang] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Ctr,Multiple Myeloma Ctr, Boston, MA 02115 USA. [Li, Fei] Nanchang Univ, Affiliated Hosp 1, Dept Hematol, Nanchang, Jiangxi, Peoples R China. RP An, G (reprint author), Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China. EM Gang_an@dfci.harvard.edu FU National Natural Science Fund [81400175, 81400174, 81172255, 81370632]; Special Key Anticancer Research and Development Program of Tianjin Municipality [12ZCDZSY17600]; Science and Technology Support Program of Jiangxi Province [20141BBG70028] FX The present study was supported by the National Natural Science Fund (81400175, 81400174, 81172255, 81370632), the Special Key Anticancer Research and Development Program of Tianjin Municipality (12ZCDZSY17600), the Science and Technology Support Program of Jiangxi Province (20141BBG70028). NR 28 TC 1 Z9 1 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 OCT 27 PY 2015 VL 6 IS 33 BP 34276 EP 34287 DI 10.18632/oncotarget.5371 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0PE UT WOS:000366107200031 PM 26416457 ER PT J AU Richards, EJ Permuth-Wey, J Li, YJ Chen, YA Coppola, D Reid, BM Lin, HY Teer, JK Berchuck, A Birrer, MJ Lawrenson, K Monteiro, ANA Schildkraut, JM Goode, EL Gayther, SA Sellers, TA Cheng, JQ AF Richards, Edward J. Permuth-Wey, Jennifer Li, Yajuan Chen, Y. Ann Coppola, Domenico Reid, Brett M. Lin, Hui-Yi Teer, Jamie K. Berchuck, Andrew Birrer, Michael J. Lawrenson, Kate Monteiro, Alvaro N. A. Schildkraut, Joellen M. Goode, Ellen L. Gayther, Simon A. Sellers, Thomas A. Cheng, Jin Q. TI A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer SO ONCOTARGET LA English DT Article DE ovarian cancer; genetic susceptibility; HOX cluster; long non-coding RNAs; single nucleotide polymorphisms ID GENOME-WIDE ASSOCIATION; HOX GENES; PROSTATE-CANCER; EXPRESSION; DIFFERENTIATION; SUSCEPTIBILITY; POLYMORPHISMS; RISK; IDENTIFICATION; EVOLUTION AB The homeobox A (HOXA) region of protein-coding genes impacts female reproductive system embryogenesis and ovarian carcinogenesis. The 5-prime end of HOXA includes three long non-coding RNAs (lncRNAs) (HOXA10-AS, HOXA11-AS, and HOTTIP) that are underexplored in epithelial ovarian cancer (EOC). We evaluated whether common genetic variants in these lncRNAs are associated with EOC risk and/or have functional roles in EOC development. Using genome-wide association study data from 1,201 serous EOC cases and 2,009 controls, an exonic variant within HOXA11-AS, rs17427875 (A>T), was marginally associated with reduced serous EOC risk (OR = 0.88 (95% CI: 0.78-1.01, p = 0.06). Functional studies of ectopic expression of HOXA11-AS minor allele T in EOC cells showed decreased survival, proliferation, migration, and invasion compared to common allele A expression. Additionally, stable expression of HOXA11-AS minor allele T reduced primary tumor growth in mouse xenograft models to a greater extent than common allele A. Furthermore, HOXA11-AS expression levels were significantly lower in human EOC tumors than normal ovarian tissues (p < 0.05), suggesting that HOXA11-AS has a tumor suppressor function in EOC which may be enhanced by the T allele. These findings demonstrate for the first time a role for HOXA11-AS in EOC with effects that could be modified by germline variants. C1 [Richards, Edward J.; Li, Yajuan; Cheng, Jin Q.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Mol Oncol, Tampa, FL 33682 USA. [Permuth-Wey, Jennifer; Reid, Brett M.; Monteiro, Alvaro N. A.; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Chen, Y. Ann; Lin, Hui-Yi; Teer, Jamie K.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Biostat & Bioinformat, Tampa, FL 33682 USA. [Coppola, Domenico] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Anat Pathol, Tampa, FL 33682 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lawrenson, Kate; Gayther, Simon A.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Schildkraut, Joellen M.] Univ Virginia, Sch Med, Publ Hlth Sci, Charlottesville, VA 22908 USA. [Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. RP Cheng, JQ (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr, Dept Mol Oncol, Tampa, FL 33682 USA. EM Thomas.sellers@moffitt.org; jin.cheng@moffitt.org FU Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative [U19-CA148112]; NIH/NCI [R01-CA160455, R01-CA137041]; Ovarian Cancer Research Fund [PPD/RPCI.07]; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred B. and Katherine B. Andersen Foundation; National Cancer Institute [P30-CA15083]; American Cancer Society [CRTG-00-196-01-CCE]; Department of Defense [DAMD-17-98-1-8659]; Celma Mastery Ovarian Cancer Foundation; Canadian Cancer Society; NIH [R01-CA63682, R01-CA63678]; Advanced Cancer Detection Center Grant; [R01-CA114343]; [R01-CA114343-S1]; [R01-CA122443]; [P50-CA136393]; [R01-CA76016]; [DAMD17-02-1-0666]; [R01-CA106414]; [R01-CA54419]; [P50-CA105009]; [P30-CA76292] FX This study was supported by funding from the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112). This study was also supported by NIH/NCI (R01-CA160455 and R01-CA137041) and the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The genotyping, bioinformatics, and biostatistical analysis for MAY, NCO, TBO, and TOR were supported by R01-CA114343 and R01-CA114343-S1. The MAY study is also supported by R01-CA122443, P50-CA136393, P30-CA15083 and funding from the Mayo Foundation, the Minnesota Ovarian Cancer Alliance, and the Fred B. and Katherine B. Andersen Foundation. The Mayo Clinic Genotyping Shared Resource was supported by the National Cancer Institute (P30-CA15083). The NCO study is supported by R01-CA76016 and DAMD17-02-1-0666. The TBO study is supported by R01-CA106414, the American Cancer Society (CRTG-00-196-01-CCE), the Advanced Cancer Detection Center Grant, Department of Defense (DAMD-17-98-1-8659), and the Celma Mastery Ovarian Cancer Foundation. The TOR study is supported by grants from the Canadian Cancer Society and the NIH (R01-CA63682 and R01-CA63678). The NEC study is supported by grants R01-CA54419 and P50-CA105009. Moffitt Cancer Center Biostatistics and Cancer Informatics Cores were supported in part by grant P30-CA76292. NR 42 TC 8 Z9 10 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 27 PY 2015 VL 6 IS 33 BP 34745 EP 34757 DI 10.18632/oncotarget.5784 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0PE UT WOS:000366107200067 PM 26430965 ER PT J AU Bollu, LR Katreddy, RR Blessing, AM Pham, N Zheng, BH Wu, X Zhang, WH AF Bollu, Lakshmi Reddy Katreddy, Rajashekhara Reddy Blessing, Alicia Marie Pham, Nguyen Zheng, Baohui Wu, Xu Zhang Weihua TI Intracellular activation of EGFR by fatty acid synthase dependent palmitoylation SO ONCOTARGET LA English DT Article DE EGFR; fatty acid synthase; palmitoylation; palmitoyl transferases; cancer ID GROWTH-FACTOR RECEPTOR; BREAST-CANCER CELLS; PROSTATE-CANCER; TARGETED THERAPIES; LUNG-CANCER; PHASE-II; OVEREXPRESSION; RESISTANCE; PALMITATE; GEFITINIB AB Epidermal growth factor receptor (EGFR) is an oncogenic receptor tyrosine kinase. Canonically, the tyrosine kinase activity of EGFR is regulated by its extracellular ligands. However, ligand-independent activation of EGFR exists in certain cancer cells, and the underlying mechanism remains to be defined. In this study, using PC3 and A549 cells as a model, we have found that, in the absence of extracellular ligands, a subpopulation of EGFR is constitutively active, which is needed for maintaining cell proliferation. Furthermore, we have found that fatty acid synthase (FASN)-dependent palmitoylation of EGFR is required for EGFR dimerization and kinase activation. Inhibition of FASN or palmitoyl acyltransferases reduced the activity and down-regulated the levels of EGFR, and sensitized cancer cells to EGFR tyrosine kinase inhibitors. It is concluded that EGFR can be activated intracellularly by FASN-dependent palmitoylation. This mechanism may serve as a new target for improving EGFR-based cancer therapy. C1 [Bollu, Lakshmi Reddy; Katreddy, Rajashekhara Reddy; Blessing, Alicia Marie; Pham, Nguyen; Zhang Weihua] Univ Houston, Coll Nat Sci & Math, Dept Biol & Biochem, Houston, TX 77004 USA. [Zheng, Baohui; Wu, Xu] Harvard Univ, Cutaneous Biol Res Ctr, Massachusetts Gen Hosp, Sch Med, Charlestown, MA USA. RP Zhang, WH (reprint author), Univ Houston, Coll Nat Sci & Math, Dept Biol & Biochem, Houston, TX 77004 USA. EM wzhang13@uh.edu RI Bollu, Lakshmi/O-4992-2015; OI Bollu, Lakshmi/0000-0001-9596-6251; Blessing, Alicia/0000-0002-3083-049X FU American Cancer Society [RSG-09-206-01]; Department of Defense Prostate Cancer Research Program [W91ZSQ8334N607]; National Institute of Health [1R21AG045382 - 01A1] FX Z. W. has been supported by grants from the American Cancer Society (RSG-09-206-01), the Department of Defense Prostate Cancer Research Program (W91ZSQ8334N607), and the National Institute of Health (1R21AG045382 - 01A1). We thank Dr. Masaki Fukata at the National Institutes of Natural Sciences, Okazaki, Japan, for sharing the HA-DHHC (PAT) plasmids. NR 36 TC 5 Z9 5 U1 2 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 27 PY 2015 VL 6 IS 33 BP 34992 EP 35003 DI 10.18632/oncotarget.5252 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0PE UT WOS:000366107200084 PM 26378037 ER PT J AU Edlow, BL Hinson, HE AF Edlow, Brian L. Hinson, Holly E. TI Blowing the whistle on sports concussions Will the risk of dementia change the game? SO NEUROLOGY LA English DT Editorial Material ID CHRONIC TRAUMATIC ENCEPHALOPATHY AB On March 13, 2015, Chris Borland, a star rookie linebacker on the San Francisco 49ers, announced his early retirement from professional football, citing concerns about chronic traumatic encephalopathy (CTE). Borland, who had a history of 2 diagnosed concussions, walked away from a multi-million-dollar contract and potential sports superstardom, explaining that from what I've researched and what I've experienced, I don't think it's worth the risk.(1) Perhaps just as surprising as Borland's announcement was the support he received from teammates and other athletessupport that reflects a growing recognition in the athletic community that repetitive head trauma may be associated with CTE and other forms of dementia.(2) Indeed, in a recent legal settlement, the National Football League estimated that approximately 30% of its former players will develop dementia. At the high school and college levels, state legislatures and universities have enacted limits to the number of full-contact practices, citing similar concerns about concussions. These developments have prompted a societal conversation about the risks of contact sports. C1 [Edlow, Brian L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Edlow, Brian L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Hinson, Holly E.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Hinson, Holly E.] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. RP Edlow, BL (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM bedlow@mgh.harvard.edu NR 10 TC 1 Z9 1 U1 2 U2 19 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 OCT 27 PY 2015 VL 85 IS 17 BP 1442 EP 1443 DI 10.1212/WNL.0000000000001902 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CV0UM UT WOS:000363968900004 PM 26253447 ER PT J AU Meehan, W Mannix, R Zafonte, R Pascual-Leone, A AF Meehan, William, III Mannix, Rebekah Zafonte, Ross Pascual-Leone, Alvaro TI Chronic traumatic encephalopathy and athletes SO NEUROLOGY LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; FOOTBALL-LEAGUE PLAYER; BRAIN-INJURY; PROFESSIONAL BOXERS; WHITE-MATTER; ALZHEIMERS-DISEASE; PHOSPHORYLATED TAU; SOCCER PLAYERS; AMYLOID-BETA; HEAD TRAUMA AB Recent case reports have described athletes previously exposed to repetitive head trauma while participating in contact sports who later in life developed mood disorders, headaches, cognitive difficulties, suicidal ideation, difficulties with speech, and aggressive behavior. Postmortem discoveries show that some of these athletes have pathologic findings that are collectively termed chronic traumatic encephalopathy (CTE). Current hypotheses suggest that concussions or perhaps blows to the head that do not cause the signs and symptoms necessary for making the diagnosis of concussion, so-called subconcussive blows, cause both the clinical and pathologic findings. There are, however, some athletes who participate in contact sports who do not develop the findings ascribed to CTE. Furthermore, there are people who have headaches, mood disorders, cognitive difficulties, suicidal ideation, and other clinical problems who have neither been exposed to repeated head trauma nor possessed the pathologic postmortem findings of those currently diagnosed with CTE. The current lack of prospective data and properly designed case-control studies limits the current understanding of CTE, leading to debate about the causes of the neuropathologic findings and the clinical observations. Given the potential for referral and recall bias in available studies, it remains unclear whether or not the pathologic findings made postmortem cause the presumed neurobehavioral sequela and whether the presumed risk factors, such as sports activity, cerebral concussions, and subconcussive blows, are solely causative of the clinical signs and symptoms. This article discusses the current evidence and the associated limitations. C1 [Meehan, William, III] Micheli Ctr Sports Injury Prevent, Waltham, MA 02453 USA. [Meehan, William, III; Mannix, Rebekah] Boston Childrens Hosp, Brain Injury Ctr, Boston, MA USA. [Meehan, William, III] Boston Childrens Hosp, Sports Concuss Clin, Div Sports Med, Boston, MA USA. [Meehan, William, III; Mannix, Rebekah] Boston Childrens Hosp, Div Emergency Med, Boston, MA USA. [Zafonte, Ross] Brigham & Womens Hosp, Massachusetts Gen Hosp, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, Boston, MA 02115 USA. [Pascual-Leone, Alvaro] Beth Israel Deaconess Med Ctr, Berenson Allen Ctr, Boston, MA 02215 USA. [Pascual-Leone, Alvaro] Beth Israel Deaconess Med Ctr, Dept Neurol, Div Intervent Cognit Neurosci, Boston, MA 02215 USA. [Pascual-Leone, Alvaro] Harvard Univ, Sch Med, Boston, MA USA. RP Meehan, W (reprint author), Micheli Ctr Sports Injury Prevent, Waltham, MA 02453 USA. EM william.meehan@childrens.harvard.edu FU National Football League Players Association; NIH [T32 HD40128-11A1, R01HD069776, R01NS073601, R21 MH099196, R21 NS082870, R21 NS085491, R21 HD07616]; Boston Children's Hospital Pilot Studies Grant; NIH/EKS-NICHD [R24 HD065688]; USAMRMC [W81XWH-08-2-0159]; DOD [W81XWH-11-2-0210]; Gordon Foundation to Treat Paralysis; Sidney R. Baer Jr Foundation; Harvard Catalyst/The Harvard Clinical and Translational Science Center (NCRR); Harvard Catalyst/The Harvard Clinical and Translational Science Center (NCATS NIH) [UL1 RR025758]; [NIDRR-H133A120085] FX W. Meehan receives royalties from ABC-Clio publishing for the sale of his book, Kids, Sports, and Concussion: A Guide for Coaches and Parents and royalties from Wolters Kluwer for working as an author for UpTo-Date. His research is funded, in part, by a grant from the National Football League Players Association and by philanthropic support from the National Hockey League Alumni Association through the Corey C. Griffin Pro-Am Tournament. R. Mannix is funded by the NIH (T32 HD40128-11A1) and a Boston Children's Hospital Pilot Studies Grant. R. Zafonte receives support from a grant from the National Football League Players Association and is also supported, in part, by NIH/EKS-NICHD R24 HD065688, USAMRMC W81XWH-08-2-0159, NIDRR-H133A120085, DOD W81XWH-11-2-0210, and the Gordon Foundation to Treat Paralysis. A. Pascual-Leone is also supported, in part, by grants from the Sidney R. Baer Jr Foundation, the NIH (R01HD069776, R01NS073601, R21 MH099196, R21 NS082870, R21 NS085491, R21 HD07616) and Harvard Catalyst/The Harvard Clinical and Translational Science Center (NCRR and the NCATS NIH, UL1 RR025758). Dr. Pascual-Leone serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neuroscience, Neuroelectrics, Axilum Robotics, Magstim Inc., and Neosync, and is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with EEG and MRI. His research is also funded, in part, by a grant from the National Football League Players Association. All funding sources provided salary support only; the content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the NIH, the National Football League Players Association, or the Sidney R. Baer Jr Foundation. None of the funding sources reviewed the data or manuscript. None was involved in data collection, analysis, interpretation, design, or recruitment. Go to Neurology.org for full disclosures. NR 58 TC 10 Z9 10 U1 10 U2 40 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 OCT 27 PY 2015 VL 85 IS 17 BP 1504 EP 1511 DI 10.1212/WNL.0000000000001893 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CV0UM UT WOS:000363968900013 PM 26253448 ER PT J AU Gill, SJ Travers, J Pshenichnaya, I Kogera, FA Barthorpe, S Mironenko, T Richardson, L Benes, CH Stratton, MR McDermott, U Jackson, SP Garnett, MJ AF Gill, Sonja J. Travers, Jon Pshenichnaya, Irina Kogera, Fiona A. Barthorpe, Syd Mironenko, Tatiana Richardson, Laura Benes, Cyril H. Stratton, Michael R. McDermott, Ultan Jackson, Stephen P. Garnett, Mathew J. TI Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma SO PLOS ONE LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE INHIBITOR; DNA-DAMAGE RESPONSE; CELL LUNG-CANCER; MUTANT-CELLS; REPAIR; TUMORS; SENSITIVITY; DEFICIENCY; STRATEGY; THERAPY AB Ewing's sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing's sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair. PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA. Here, we show that PARP inhibitor sensitivity in Ewing's sarcoma cells is not through an apparent defect in DNA repair by HR, but through hypersensitivity to trapped PARP1-DNA complexes. This drives accumulation of DNA damage during replication, ultimately leading to apoptosis. We also show that the activity of PARP inhibitors is potentiated by temozolomide in Ewing's sarcoma cells and is associated with enhanced trapping of PARP1-DNA complexes. Furthermore, through mining of large-scale drug sensitivity datasets, we identify a subset of glioma, neuroblastoma and melanoma cell lines as hypersensitive to the combination of temozolomide and PARP inhibition, potentially identifying new avenues for therapeutic intervention. These data provide insights into the anti-cancer activity of PARP inhibitors with implications for the design of treatment for Ewing's sarcoma patients with PARP inhibitors. C1 [Gill, Sonja J.; Pshenichnaya, Irina; Kogera, Fiona A.; Barthorpe, Syd; Mironenko, Tatiana; Richardson, Laura; Stratton, Michael R.; McDermott, Ultan; Jackson, Stephen P.; Garnett, Mathew J.] Wellcome Trust Sanger Inst, Hinxton, England. [Travers, Jon; Jackson, Stephen P.] Univ Cambridge, Gurdon Inst, Wellcome Trust Canc Res UK, Cambridge, England. [Travers, Jon; Jackson, Stephen P.] Univ Cambridge, Dept Biochem, Cambridge, England. [Benes, Cyril H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. RP Jackson, SP (reprint author), Wellcome Trust Sanger Inst, Hinxton, England. EM s.jackson@gurdon.cam.ac.uk; mg12@sanger.ac.uk OI McDermott, Ultan/0000-0001-9032-4700 FU Wellcome Trust [086357, 102696/Z/13/Z, WT092096]; Cancer Research UK [C6/A11224, C6946/A14492]; European Research Council; European Community Seventh Framework Program [HEALTH-F2-2010-259893]; University of Cambridge FX Research in the M.J.G. laboratory is supported by grants from the Wellcome Trust (086357 and 102696/Z/13/Z; http://www.wellcome.ac.uk/Funding). Research in the S.P.J. laboratory is funded by Cancer Research UK Program Grant C6/A11224 (http://www.cancerresearchuk.org/fundingfor-researchers/our-funding-sche mes), the European Research Council (http://erc.europa.eu/funding-andgrants)and the European Community Seventh Framework Program grant agreement no. HEALTH-F2-2010-259893 (DDResponse). Core infrastructure funding was provided by Cancer Research UK Grant C6946/A14492 and Wellcome Trust Grant WT092096. S.P.J. receives a salary from the University of Cambridge, supplemented by Cancer Research UK. J.T. was funded by the European Community Seventh Framework Program grant agreement no. HEALTH-F2-2010-259893 (DDResponse). U.M. is supported by a Cancer Research UK Clinician Scientist Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2015 VL 10 IS 10 AR e0140988 DI 10.1371/journal.pone.0140988 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU8PC UT WOS:000363804200024 PM 26505995 ER PT J AU Balastik, M Zhou, XZ Alberich-Jorda, M Weissova, R Ziak, J Pazyra-Murphy, MF Cosker, KE Machonova, O Kozmikova, I Chen, CH Pastorino, L Asara, JM Cole, A Sutherland, C Segal, RA Lu, KP AF Balastik, Martin Zhou, Xiao Zhen Alberich-Jorda, Meritxell Weissova, Romana Ziak, Jakub Pazyra-Murphy, Maria F. Cosker, Katharina E. Machonova, Olga Kozmikova, Iryna Chen, Chun-Hau Pastorino, Lucia Asara, John M. Cole, Adam Sutherland, Calum Segal, Rosalind A. Lu, Kun Ping TI Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons SO CELL REPORTS LA English DT Article ID RESPONSE MEDIATOR PROTEIN-2; ALZHEIMERS-DISEASE; NEURITE OUTGROWTH; GROWTH CONE; RHO-KINASE; PHOSPHORYLATION; SEMAPHORIN; ZEBRAFISH; MECHANISM; NEURONS AB Axon guidance relies on precise translation of extracellular signal gradients into local changes in cytoskeletal dynamics, but the molecular mechanisms regulating dose-dependent responses of growth cones are still poorly understood. Here, we show that during embryonic development in growing axons, a low level of Semaphorin3A stimulation is buffered by the prolyl isomerase Pin1. We demonstrate that Pin1 stabilizes CDK5-phosphorylated CRMP2A, the major isoform of CRMP2 in distal axons. Consequently, Pin1 knockdown or knockout reduces CRMP2A levels specifically in distal axons and inhibits axon growth, which can be fully rescued by Pin1 or CRMP2A expression. Moreover, Pin1 knockdown or knockout increases sensitivity to Sema3A-induced growth cone collapse in vitro and in vivo, leading to developmental abnormalities in axon guidance. These results identify an important isoform-specific function and regulation of CRMP2A in controlling axon growth and uncover Pin1-catalyzed prolyl isomerization as a regulatory mechanism in axon guidance. C1 [Balastik, Martin; Zhou, Xiao Zhen; Alberich-Jorda, Meritxell; Chen, Chun-Hau; Pastorino, Lucia; Asara, John M.; Lu, Kun Ping] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Balastik, Martin; Alberich-Jorda, Meritxell; Weissova, Romana; Ziak, Jakub; Machonova, Olga; Kozmikova, Iryna] Acad Sci Czech Republic, Inst Mol Genet, CR-14220 Prague 4, Czech Republic. [Balastik, Martin; Weissova, Romana; Ziak, Jakub] Acad Sci Czech Republic, Inst Physiol, CR-14220 Prague 4, Czech Republic. [Pazyra-Murphy, Maria F.; Cosker, Katharina E.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Pediat Oncol & Canc Biol, Boston, MA 02215 USA. [Pazyra-Murphy, Maria F.; Cosker, Katharina E.; Segal, Rosalind A.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02215 USA. [Cole, Adam; Sutherland, Calum] Univ Dundee, Biomed Res Inst, Ninewells Hosp, Dundee DD1 9SY, Scotland. [Lu, Kun Ping] Fujian Med Univ, Inst Translat Med, Fuzhou 350108, Peoples R China. RP Balastik, M (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, 330 Brookline Ave,CLS 0408, Boston, MA 02215 USA. EM martin.balastik@fgu.cas.cz; klu@bidmc.harvard.edu RI Balastik, Martin/C-4410-2014; OI Sutherland, Calum/0000-0003-4398-7434 FU NIH [S10 RR017927, R01AG039405, R01AG046319]; MSMT Navrat [LK11213, LK21307]; Marie Curie CIG [PCIG12-GA-2012-334431]; Czech Science Foundation (GACR) [15-03796S]; National Natural Science Foundation of China [U1205024]; MSMT [LO1419] FX We are grateful to G. Finn and M.-L. Luo for Pin1 KO mice, A. Kolodkin for AP-Sema3A plasmid, G. Alvarez-Bolado for comments on the manuscript, and O. Svoboda and Z. Kozmik for advice regarding the work with the zebrafish model. We also thank S. Hagen for Confocal Microscopy Core (NIH grant S10 RR017927). The work was supported by MSMT Navrat grant LK11213 and Marie Curie CIG grant PCIG12-GA-2012-334431 (to M.B.), MSMT Navrat grant LK21307 and the Czech Science Foundation (GACR, project 15-03796S) (to M.A.-J.), MSMT grant LO1419 (to O.M. and I.K.), and NIH grants R01AG039405 and R01AG046319 and National Natural Science Foundation of China grant U1205024 (to K.P.L.). NR 42 TC 3 Z9 3 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 27 PY 2015 VL 13 IS 4 BP 812 EP 828 DI 10.1016/j.celrep.2015.09.026 PG 17 WC Cell Biology SC Cell Biology GA CU8GY UT WOS:000363780900016 PM 26489457 ER PT J AU Tritos, NA Klibanski, A AF Tritos, Nicholas A. Klibanski, Anne TI Hyperprolactinemia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PROLACTIN; CABERGOLINE; DIAGNOSIS; SOCIETY C1 [Tritos, Nicholas A.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Tritos, Nicholas A.; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Zero Emerson Pl,Ste 112, Boston, MA 02114 USA. EM aklibanski@partners.org NR 10 TC 2 Z9 2 U1 1 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 OCT 27 PY 2015 VL 314 IS 16 BP 1742 EP 1743 DI 10.1001/jama.2015.7871 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CU7HC UT WOS:000363706300024 PM 26505599 ER PT J AU Yost, S Duran-Pinedo, AE Teles, R Krishnan, K Frias-Lopez, J AF Yost, Susan Duran-Pinedo, Ana E. Teles, Ricardo Krishnan, Keerthana Frias-Lopez, Jorge TI Functional signatures of oral dysbiosis during periodontitis progression revealed by microbial metatranscriptome analysis (vol 7, 27, 2015) SO GENOME MEDICINE LA English DT Correction C1 [Yost, Susan; Duran-Pinedo, Ana E.; Krishnan, Keerthana; Frias-Lopez, Jorge] Forsyth Inst, Cambridge, MA 02142 USA. [Frias-Lopez, Jorge] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Teles, Ricardo] Univ N Carolina, Sch Dent, Chapel Hill, NC 27599 USA. RP Frias-Lopez, J (reprint author), Forsyth Inst, 245 First St, Cambridge, MA 02142 USA. EM jfrias@forsyth.org NR 1 TC 1 Z9 1 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD OCT 27 PY 2015 VL 7 AR 111 DI 10.1186/s13073-015-0231-6 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA CU6CM UT WOS:000363619100001 PM 26507874 ER PT J AU van den Ham, HA Klungel, OH Singer, DE Leufkens, HGM van Staa, TP AF van den Ham, Hendrika A. Klungel, Olaf H. Singer, Daniel E. Leufkens, Hubert G. M. van Staa, Tjeerd P. TI Comparative Performance of ATRIA, CHADS(2), and CHA(2)DS(2)-VASc Risk Scores Predicting Stroke in Patients With Atrial Fibrillation Results From a National Primary Care Database SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE anticoagulants; atrial fibrillation; risk prediction; stroke; treatment decision ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; STRATIFICATION SCHEMES; GENERAL-PRACTICE; THROMBOEMBOLISM; ANTICOAGULATION; VALIDATION; GUIDELINES; COHORT AB BACKGROUND Previous studies report that CHADS(2) and CHA(2)DS(2)-VASc risk scores have similar discriminating ability (C statistic similar to 0.6). Recently a clinically based risk score, the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study risk score, was developed and validated. OBJECTIVES This study compared predictive ability of CHA(2)DS(2)-VASc and CHADS(2) ischemic stroke risk scores with ATRIA stroke risk score and their implications for anticoagulant treatment in patients with atrial fibrillation (AF). METHODS Patients with AF not using warfarin were included from the Clinical Practice Research Datalink database, 1998 to 2012. Patients were followed from AF diagnosis until occurrence of ischemic stroke, prescription of warfarin, death, or the study's end. Independent predictors of ischemic stroke were identified and the c-index and net reclassification improvement were calculated. RESULTS A total of 60,594 patients with AF were included. Annualized stroke rate was 2.99%. Event rates for moderate- and high-risk categories for CHA(2)DS(2)-VASc were lower than those of the ATRIA and CHADS(2). Age and previous stroke most strongly predicted ischemic stroke. C statistics for the full point scores were 0.70 (95% confidence interval [CI]: 0.69 to 0.71) for the ATRIA risk score, 0.68 (95% CI: 0.67 to 0.69) for CHADS2, and 0.68 (95% CI: 0.67 to 0.69) for CHA(2)DS(2)-VASc risk score. The net reclassification improvement was 0.23 (95% CI: 0.22 to 0.25) for ATRIA compared with CHA(2)DS(2)-VASc. CONCLUSIONS The ATRIA score performed better in the U.K. Clinical Practice Research Datalink AF cohort. It more accurately identified low-risk patients than the CHA(2)DS(2)-VASc score, which assigned these patients to higher-risk categories. Such reclassification of stroke risk could prevent overuse of anticoagulants in very low stroke risk patients with AF. (C) 2015 by the American College of Cardiology Foundation. C1 [van den Ham, Hendrika A.; Klungel, Olaf H.; Leufkens, Hubert G. M.; van Staa, Tjeerd P.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, NL-3508 TC Utrecht, Netherlands. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [van Staa, Tjeerd P.] Univ Manchester, Dept Hlth ERes, Manchester, Lancs, England. RP van Staa, TP (reprint author), Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, NL-3508 TC Utrecht, Netherlands. EM T.P.vanStaa@uu.nl RI Klungel, Olaf/I-9563-2016; CPRD, CPRD/B-9594-2017 FU Dutch private-public TI Pharma Mondriaan project; Boehringer Ingelheim; Bristol-Myers Squibb; Medtronic; IMI, TI Pharma; Netherlands Organisation for Health Research and Development; Dutch Health Care Insurance Board; EU 7th Framework Program; Dutch Medicines Evaluation Board; Dutch Ministry of Health FX Dr. Klungel has received unrestricted funding for pharmacoepidemiological research from the Dutch private-public TI Pharma Mondriaan project. Dr. Singer has served as a consultant to Boehringer Ingelheim, Bristol-Myers Squibb, CVS Health, Johnson and Johnson, Medtronic, and Merck; and has received research support from Boehringer Ingelheim, Bristol-Myers Squibb, and Medtronic. Dr. Leufkens is a researcher at the World Health Organization Collaborating Centre for Pharmaceutical Policy and Regulation, which receives no direct funding or donations from private parties, including pharmaceutical industry. Research funding from public-private partnerships (e.g., IMI, TI Pharma) is accepted under the condition that no company-specific product or company-related study is conducted. The Centre has received unrestricted research funding from public sources (e.g., Netherlands Organisation for Health Research and Development, the Dutch Health Care Insurance Board, EU 7th Framework Program, Dutch Medicines Evaluation Board, and Dutch Ministry of Health). Dr. Staa has participated in an expert meeting on simple trials for Boehringer Ingelheim. Mrs. van den Ham has reported that she has no relationships relevant to the contents of this paper to disclose. NR 30 TC 21 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 27 PY 2015 VL 66 IS 17 BP 1851 EP 1859 DI 10.1016/j.jacc.2015.08.03 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CK UT WOS:000363329500001 PM 26493655 ER PT J AU Cho, HS Seo, JH Wong, KHK Terasaki, Y Park, J Bong, K Arai, K Lo, EH Irimia, D AF Cho, Hansang Seo, Ji Hae Wong, Keith H. K. Terasaki, Yasukazu Park, Joseph Bong, Kiwan Arai, Ken Lo, Eng H. Irimia, Daniel TI Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology SO SCIENTIFIC REPORTS LA English DT Article ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA; TNF-ALPHA; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; EPITHELIAL-CELLS; ISCHEMIC-STROKE; DRUG-DELIVERY; PERMEABILITY; EXPRESSION AB Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases. C1 [Cho, Hansang; Wong, Keith H. K.; Bong, Kiwan; Irimia, Daniel] Harvard Univ, Sch Med, Massachusetts Gen Hosp, BioMEMS Resource Ctr, Boston, MA 02129 USA. [Seo, Ji Hae; Terasaki, Yasukazu; Arai, Ken; Lo, Eng H.] Harvard Univ, Sch Med, Mass Gen Hosp, Neuroprotect Res Lab Ctr, Charlestown, MA 02129 USA. [Cho, Hansang; Park, Joseph] Univ N Carolina, Ctr Biomed Engn & Sci, Mech Engn & Engn Sci, Charlotte, NC 28223 USA. RP Irimia, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, BioMEMS Resource Ctr, Boston, MA 02129 USA. EM dirimia@hms.harvard.edu RI Wong, Keith/J-6857-2012 OI Wong, Keith/0000-0002-6578-0373 FU National Institutes of Health [EB002503, GM092804]; National Institute of Neurological Disorders and Stroke [NS045776]; CRI (Charlotte Research Institute) Duke Energy Special Initiatives Funding FX All microfabrication procedures were performed at the BioMEMS Resource Center, supported by National Institutes of Health grant EB002503 and National Institute of Neurological Disorders and Stroke grant NS045776. Dr. Didier Dreau lab at UNC Charlotte provided access to equipment for running a hypoxia experiment and reading cytokine membrane. We gratefully acknowledge the support of National Institutes of Health grant GM092804 and CRI (Charlotte Research Institute) Duke Energy Special Initiatives Funding. NR 47 TC 13 Z9 15 U1 8 U2 39 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 OCT 27 PY 2015 VL 5 AR 15222 DI 10.1038/srep15222 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU3SU UT WOS:000363446400001 PM 26503597 ER PT J AU Doyle, JJ Doyle, AJ Wilson, NK Habashi, JP Bedja, D Whitworth, RE Lindsay, ME Schoenhoff, F Myers, L Huso, N Bachir, S Squires, O Rusholme, B Ehsan, H Huso, D Thomas, CJ Caulfield, MJ Van Eyk, JE Judge, DP Dietz, HC AF Doyle, Jefferson J. Doyle, Alexander J. Wilson, Nicole K. Habashi, Jennifer P. Bedja, Djahida Whitworth, Ryan E. Lindsay, Mark E. Schoenhoff, Florian Myers, Loretha Huso, Nick Bachir, Suha Squires, Oliver Rusholme, Benjamin Ehsan, Hamid Huso, David Thomas, Craig J. Caulfield, Mark J. Van Eyk, Jennifer E. Judge, Daniel P. Dietz, Harry C. CA GenTAC Registry Consortium MIBAVA Leducq Consortium TI A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome SO ELIFE LA English DT Article ID KINASE-C-DELTA; AORTIC-ANEURYSM PROGRESSION; ANGIOTENSIN-II; MOUSE MODEL; BETA; GROWTH; ACTIVATION; BLOCKADE; PATHWAY; CELLS AB Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKC beta) as a critical mediator of this pathway and demonstrate that the PKC beta inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKC beta and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. C1 [Doyle, Jefferson J.; Doyle, Alexander J.; Wilson, Nicole K.; Habashi, Jennifer P.; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Doyle, Jefferson J.; Doyle, Alexander J.; Wilson, Nicole K.; Habashi, Jennifer P.; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Doyle, Jefferson J.; Ehsan, Hamid] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Doyle, Alexander J.; Caulfield, Mark J.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med, London, England. [Habashi, Jennifer P.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Baltimore, MD 21205 USA. [Bedja, Djahida] Johns Hopkins Univ, Sch Med, Dept Cardiol, Baltimore, MD USA. [Bedja, Djahida] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW, Australia. [Whitworth, Ryan E.] Res Triangle Inst Int, Durham, NC USA. [Lindsay, Mark E.] Harvard Med Sch, Thorac Aort Ctr, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Lindsay, Mark E.] Harvard Med Sch, Thorac Aort Ctr, Massachusetts Gen Hosp, Dept Pediat, Boston, MA USA. [Schoenhoff, Florian] Inselspital Bern, Dept Cardiovasc Surg, Bern, Switzerland. [Schoenhoff, Florian; Van Eyk, Jennifer E.] Johns Hopkins Univ, Sch Med, Prote Innovat Ctr Heart Failure, Baltimore, MD USA. [Huso, David] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Thomas, Craig J.] Natl Ctr Adv Translat Sci, Div Preclin Innovat, Bethesda, MD USA. [Judge, Daniel P.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Doyle, JJ (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. EM doyle@jhmi.edu; hdietz@jhmi.edu FU National Institutes of Health [AR041135, AR049698]; Howard Hughes Medical Institute; National Marfan Foundation Bloomberg Fund; National Marfan Foundation Smilow Center for Marfan Syndrome Research; Fondation Leducq MIBAVA Leducq Consortium; National Heart, Lung, and Blood Institute GenTAC Consortium FX National Institutes of Health AR041135 Jennifer P Habashi, Harry C Dietz; Howard Hughes Medical Institute Alexander J Doyle, Harry C Dietz; National Marfan Foundation Bloomberg Fund Jefferson J Doyle, Jennifer P Habashi, Harry C Dietz; National Marfan Foundation Smilow Center for Marfan Syndrome Research Harry C Dietz; Fondation Leducq MIBAVA Leducq Consortium MIBAVA Members; National Heart, Lung, and Blood Institute GenTAC Consortium GenTAC Members; National Institute of Health AR049698 Jennifer P Habashi, Harry C Dietz NR 36 TC 0 Z9 0 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 27 PY 2015 VL 4 AR e08648 DI 10.7554/eLife.08648 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7RE UT WOS:000393419100001 ER PT J AU Doyle, JJ Doyle, AJ Wilson, NK Habashi, JP Bedja, D Whitworth, RE Lindsay, ME Schoenhoff, F Myers, L Huso, N Bachir, S Squires, O Rusholme, B Ehsan, H Huso, D Thomas, CJ Caulfield, MJ Van Eyk, JE Judge, DP Dietz, HC AF Doyle, Jefferson J. Doyle, Alexander J. Wilson, Nicole K. Habashi, Jennifer P. Bedja, Djahida Whitworth, Ryan E. Lindsay, Mark E. Schoenhoff, Florian Myers, Loretha Huso, Nick Bachir, Suha Squires, Oliver Rusholme, Benjamin Ehsan, Hamid Huso, David Thomas, Craig J. Caulfield, Mark J. Van Eyk, Jennifer E. Judge, Daniel P. Dietz, Harry C. CA GenTAC Registry Consortium MIBAVA Leducq Consortium TI A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome SO ELIFE LA English DT Article ID KINASE-C-DELTA; AORTIC-ANEURYSM PROGRESSION; ANGIOTENSIN-II; MOUSE MODEL; GROWTH; ACTIVATION; BLOCKADE; PATHWAY; CELLS; MICE AB Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKC beta) as a critical mediator of this pathway and demonstrate that the PKC beta inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCa and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. C1 [Doyle, Jefferson J.; Doyle, Alexander J.; Wilson, Nicole K.; Habashi, Jennifer P.; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Doyle, Jefferson J.; Doyle, Alexander J.; Wilson, Nicole K.; Habashi, Jennifer P.; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Doyle, Jefferson J.; Ehsan, Hamid] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Doyle, Alexander J.; Caulfield, Mark J.] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England. [Habashi, Jennifer P.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Baltimore, MD 21205 USA. [Bedja, Djahida] Johns Hopkins Univ, Sch Med, Dept Cardiol, Baltimore, MD USA. [Bedja, Djahida] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW 2109, Australia. [Whitworth, Ryan E.] Res Triangle Inst Int, Durham, NC USA. [Lindsay, Mark E.] Harvard Univ, Sch Med, Dept Med, Thorac Aort Ctr,Massachusetts Gen Hosp, Boston, MA USA. [Lindsay, Mark E.] Harvard Univ, Sch Med, Dept Pediat, Thorac Aort Ctr,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Schoenhoff, Florian] Univ Bern, Inselspital, Dept Cardiovasc Surg, CH-3010 Bern, Switzerland. [Schoenhoff, Florian; Van Eyk, Jennifer E.] Johns Hopkins Univ, Sch Med, Prote Innovat Ctr Heart Failure, Baltimore, MD USA. [Huso, David] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Thomas, Craig J.] Natl Ctr Adv Translat Sci, Div Preclin Innovat, Bethesda, MD USA. [Judge, Daniel P.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Doyle, JJ (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. EM jefferson.doyle@jhmi.edu; hdietz@jhmi.edu FU National Institutes of Health [AR041135, AR049698]; Howard Hughes Medical Institute; National Marfan Foundation; Fondation Leducq MIBAVA Leducq Consortium; National Heart, Lung, and Blood Institute GenTAC Consortium FX National Institutes of Health AR041135 Jennifer P Habashi, Harry C Dietz; Howard Hughes Medical Institute Alexander J Doyle, Harry C Dietz; National Marfan Foundation Bloomberg Fund Jefferson J Doyle, Jennifer P Habashi, Harry C Dietz; National Marfan Foundation Smilow Center for Marfan Syndrome Research Harry C Dietz; Fondation Leducq MIBAVA Leducq Consortium MIBAVA Members; National Heart, Lung, and Blood Institute GenTAC Consortium GenTAC Members; National Institute of Health AR049698 Jennifer P Habashi, Harry C Dietz NR 36 TC 10 Z9 10 U1 0 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 OCT 27 PY 2015 VL 4 AR e08648 DI 10.7554/eLife.08648 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CU8MS UT WOS:000363797700001 ER PT J AU Normandin, MD Yuan, HS Wilks, MQ Chen, HH Kinsella, JM Cho, H Guehl, NJ Absi-Halabi, N Hosseini, SM El Fakhri, G Sosnovik, DE Josephson, L AF Normandin, Marc D. Yuan, Hushan Wilks, Moses Q. Chen, Howard H. Kinsella, Joseph M. Cho, Hoonsung Guehl, Nicolas J. Absi-Halabi, Nader Hosseini, Seyed Mohammadreza El Fakhri, Georges Sosnovik, David E. Josephson, Lee TI Heat-Induced Radiolabeling of Nanoparticles for Monocyte Tracking by PET SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE heat-induced radiolabeling; imaging; monocyte trafficking; nanoparticles; positron emission tomography; pharmacokinetics ID IRON-OXIDE NANOPARTICLES; ENHANCED MRI; FERUMOXYTOL; PARAMETERS; CANCER; AGENT; CELLS; MICE AB Heat-induced radiolabeling (HIR) yielded Zr-89-Feraheme (FH) nanoparticles (NPs) that were used to determine NP pharmacokinetics (PK) by positron emission tomography (PET). Standard uptake values indicated a fast hepatic uptake that corresponded to blood clearance, and a second, slow uptake process by lymph nodes and spleen. By cytometry, NPs were internalized by circulating monocytes and monocytes invitro. Using an IV injection of HIR Zr-89-FH (rather than invitro cell labeling), PET/PK provided a view of monocyte trafficking, a key component of the immune response. C1 [Normandin, Marc D.; Yuan, Hushan; Wilks, Moses Q.; Guehl, Nicolas J.; Absi-Halabi, Nader; Hosseini, Seyed Mohammadreza; El Fakhri, Georges; Josephson, Lee] Massachusetts Gen Hosp, Ctr Adv Med Imaging Sci, Dept Radiol, Boston, MA 02114 USA. [Kinsella, Joseph M.] McGill Univ, Dept Bioengn, Montreal, PQ H3A 0C3, Canada. [Cho, Hoonsung] Chonnam Natl Univ, Sch Mat Sci & Engn, Gwangju 50075, South Korea. [Chen, Howard H.; Sosnovik, David E.; Josephson, Lee] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Josephson, L (reprint author), Massachusetts Gen Hosp, Ctr Adv Med Imaging Sci, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM ljosephson@mgh.harvard.edu FU R01 NIH [EB011996, EB009691, MH100350, CA165221, HL110241, HL112831]; NIH [K99L121152, T32EB013180] FX This work was supported by R01 NIH grants EB011996 (L.J.), EB009691 (L.J.), MH100350 (M.D.N.), CA165221 (G.E.F.), HL110241 (G.E.F.), HL112831 (D.E.S.) and NIH K99L121152 (H.H.C.), and T32EB013180 (G.E.F.). We thank K. Takahashi for assistance with animal handling procedures. The authors declare they have no conflict of interest. NR 26 TC 3 Z9 3 U1 10 U2 16 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD OCT 26 PY 2015 VL 54 IS 44 BP 13002 EP 13006 DI 10.1002/anie.201505525 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA CU3KM UT WOS:000363423900028 PM 26368132 ER PT J AU Feng, DD Cai, WJ Chen, XQ AF Feng, Danielle D. Cai, Waijiao Chen, Xiqun TI The associations between Parkinson's disease and cancer: the plot thickens SO TRANSLATIONAL NEURODEGENERATION LA English DT Review ID ALPHA-SYNUCLEIN OLIGOMERS; TUMOR-SUPPRESSOR GENE; REPEAT KINASE 2; AMYLOID PRECURSOR PROTEIN; REGULATES MITOCHONDRIAL DYNAMICS; RECESSIVE JUVENILE PARKINSONISM; HUMAN NEUROBLASTOMA SH-SY5Y; LHERMITTE-DUCLOS-DISEASE; GENOME-WIDE ASSOCIATION; LRRK2 G2019S MUTATION AB Epidemiological studies support a general inverse association between the risk of cancer development and Parkinson's disease (PD). In recent years however, increasing amount of eclectic evidence points to a positive association between PD and cancers through different temporal analyses and ethnic groups. This positive association has been supported by several common genetic mutations in SNCA, PARK2, PARK8, ATM, p53, PTEN, and MC1R resulting in cellular changes such as mitochondrial dysfunction, aberrant protein aggregation, and cell cycle dysregulation. Here, we review the epidemiological and biological advances of the past decade in the association between PD and cancers to offer insight on the recent and sometimes contradictory findings. C1 [Feng, Danielle D.; Cai, Waijiao; Chen, Xiqun] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Boston, MA 02138 USA. [Feng, Danielle D.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cai, Waijiao] Fudan Univ, Huashan Hosp, Key Lab Cellular & Mol Biol, Shanghai 200040, Peoples R China. RP Chen, XQ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Boston, MA 02138 USA. EM XCHEN17@mgh.harvard.edu NR 234 TC 9 Z9 9 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-9158 J9 TRANSL NEURODEGENER JI Transl. Neurodegener. PD OCT 26 PY 2015 VL 4 AR 20 DI 10.1186/s40035-015-0043-z PG 14 WC Neurosciences SC Neurosciences & Neurology GA CY3OE UT WOS:000366318300001 PM 26504519 ER PT J AU Liu, KKL Bartsch, RP Lin, AJ Mantegna, RN Ivanov, PC AF Liu, Kang K. L. Bartsch, Ronny P. Lin, Aijing Mantegna, Rosario N. Ivanov, Plamen Ch. TI Plasticity of brain wave network interactions and evolution across physiologic states SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE neural plasticity; network physiology; brain wave interactions; time delay stability; sleep ID PAIRED ASSOCIATIVE STIMULATION; SLEEP-WAKE TRANSITIONS; TEMPORAL CORRELATIONS; MEMORY CONSOLIDATION; SYNAPTIC PLASTICITY; SCALING BEHAVIOR; OSCILLATIONS; DYNAMICS; SYNCHRONY; NEUROMODULATION AB Neural plasticity transcends a range of spatio-temporal scales and serves as the basis of various brain activities and physiologic functions. At the microscopic level, it enables the emergence of brain waves with complex temporal dynamics. At the macroscopic level, presence and dominance of specific brain waves is associated with important brain functions. The role of neural plasticity at different levels in generating distinct brain rhythms and how brain rhythms communicate with each other across brain areas to generate physiologic states and functions remains not understood. Here we perform an empirical exploration of neural plasticity at the level of brain wave network interactions representing dynamical communications within and between different brain areas in the frequency domain. We introduce the concept of time delay stability (TDS) to quantify coordinated bursts in the activity of brain waves, and we employ a system-wide Network Physiology integrative approach to probe the network of coordinated brain wave activations and its evolution across physiologic states. We find an association between network structure and physiologic states. We uncover a hierarchical reorganization in the brain wave networks in response to changes in physiologic state, indicating new aspects of neural plasticity at the integrated level. Globally, we find that the entire brain network undergoes a pronounced transition from low connectivity in Deep Sleep and REM to high connectivity in Light Sleep and Wake. In contrast, we find that locally, different brain areas exhibit different network dynamics of brain wave interactions to achieve differentiation in function during different sleep stages. Moreover, our analyses indicate that plasticity also emerges in frequency-specific networks, which represent interactions across brain locations mediated through a specific frequency band. Comparing frequency-specific networks within the same physiologic state we find very different degree of network connectivity and link strength, while at the same time each frequency-specific network is characterized by a different signature pattern of sleep-stage stratification, reflecting a remarkable flexibility in response to change in physiologic state. These new aspects of neural plasticity demonstrate that in addition to dominant brain waves, the network of brain wave interactions is a previously unrecognized hallmark of physiologic state and function. C1 [Liu, Kang K. L.; Lin, Aijing; Ivanov, Plamen Ch.] Boston Univ, Dept Phys, Lab Network Physiol, Boston, MA 02215 USA. [Liu, Kang K. L.] Harvard Univ, Sch Med, Beth ISreal & Deaconess Med Ctr, Boston, MA 02115 USA. [Bartsch, Ronny P.] Bar Ilan Univ, Dept Phys, Ramat Gan, Israel. [Lin, Aijing] Beijing Jiaotong Univ, Dept Math, Sch Sci, Beijing, Peoples R China. [Mantegna, Rosario N.] Univ Palermo, Dipartimento Fis & Chim, Palermo, Italy. [Mantegna, Rosario N.] Cent European Univ, Ctr Network Sci, Budapest, Hungary. [Mantegna, Rosario N.] Cent European Univ, Dept Econ, Budapest, Hungary. [Ivanov, Plamen Ch.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Sleep Med, Boston, MA 02115 USA. [Ivanov, Plamen Ch.] Bulgarian Acad Sci, Inst Solid State Phys, Sofia, Bulgaria. RP Ivanov, PC (reprint author), Boston Univ, Dept Phys, Lab Network Physiol, Boston, MA 02215 USA. EM plamen@buphy.bu.edu RI Bartsch, Ronny/E-7117-2012 FU W M Keck Foundation; National Institutes of Health (NIH) [1R01- HL098437]; Office of Naval Research (ONR) [000141010078]; US-Israel Binational Science Foundation (BSF) [2012219]; EC- FP7 Marie Curie Fellowship (IIF) [628159]; National Natural Science Foundation of China [61304145]; Fundamental Research Funds for the Central Universities [2014RC014] FX We acknowledge support from the W M Keck Foundation, National Institutes of Health (NIH Grant 1R01- HL098437), the Office of Naval Research (ONR Grant 000141010078), the US-Israel Binational Science Foundation (BSF Grant 2012219). RB acknowledges support from EC- FP7 Marie Curie Fellowship (IIF 628159). AL acknowledges support from the National Natural Science Foundation of China (Grant no. 61304145) and the Fundamental Research Funds for the Central Universities (Grant no. 2014RC014). NR 60 TC 4 Z9 4 U1 0 U2 10 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD OCT 26 PY 2015 VL 9 AR 62 DI 10.3389/fncir.2015.00062 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CW3ZR UT WOS:000364931400001 PM 26578891 ER PT J AU Chiasson-MacKenzie, C Morris, ZS Baca, Q Morris, B Coker, JK Mirchev, R Jensen, AE Carey, T Stott, SL Golan, DE McClatchey, AI AF Chiasson-MacKenzie, Christine Morris, Zachary S. Baca, Quentin Morris, Breit Coker, Joanna K. Mirchev, Rossen Jensen, Anne E. Carey, Thomas Stott, Shannon L. Golan, David E. McClatchey, Andrea I. TI NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SINGLE-PARTICLE TRACKING; EPIDERMAL-GROWTH-FACTOR; EPITHELIAL ZONULA ADHERENS; APICAL CONSTRICTION; CELL-SHAPE; ERM PROTEINS; CYTOSKELETON; TENSION; JUNCTIONS; MEMBRANE AB The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR. We show that Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with the establishment of cell cell junctions are transduced across the cell cortex via the cortical actomyosin cytoskeleton to control the lateral mobility and activity of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact. C1 [Chiasson-MacKenzie, Christine; Morris, Zachary S.; Morris, Breit; Coker, Joanna K.; Jensen, Anne E.; Carey, Thomas; Stott, Shannon L.; McClatchey, Andrea I.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Chiasson-MacKenzie, Christine; Morris, Zachary S.; Morris, Breit; Coker, Joanna K.; McClatchey, Andrea I.] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. [Jensen, Anne E.; Carey, Thomas; Stott, Shannon L.] Massachusetts Gen Hosp, BioMEMs Resource Ctr, Charlestown, MA 02129 USA. [Chiasson-MacKenzie, Christine; Morris, Zachary S.; Morris, Breit; Coker, Joanna K.; McClatchey, Andrea I.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Baca, Quentin; Mirchev, Rossen; Golan, David E.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Stott, Shannon L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP McClatchey, AI (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. EM mcclatch@helix.mgh.harvard.edu OI Morris, Brett/0000-0003-4237-2796; Morris, Zachary/0000-0001-5558-3547 FU National Institutes of Health [R01 CA113733, R01 HL032854, F31 GM78720, T32 GM07306]; Children's Tumor Foundation FX This work was supported by grants from the National Institutes of Health (R01 CA113733 to A.I. McClatchey; R01 HL032854 to D.E. Golan; F31 GM78720 to Q. Baca; and T32 GM07306 to Z.S. Morris) and a fellowship from the Children's Tumor Foundation (to C. Chiasson-MacKenzie). A.I. McClatchey is the Patricia and Scott Eston MGH Reseach Scholar. NR 59 TC 5 Z9 5 U1 1 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 OCT 26 PY 2015 VL 211 IS 2 BP 391 EP 405 DI 10.1083/jcb.201503081 PG 15 WC Cell Biology SC Cell Biology GA CV4XN UT WOS:000364269900018 PM 26483553 ER PT J AU Chen, J Li, JL Chen, ZR Griffin, JD Wu, LZ AF Chen, Jie Li, Jian-Liang Chen, Zirong Griffin, James D. Wu, Lizi TI Gene expression profiling analysis of CRTC1-MAML2 fusion oncogene-induced transcriptional program in human mucoepidermoid carcinoma cells SO BMC CANCER LA English DT Article DE Oncogene; CRTC1-MAML2 fusion; CREB; Gene expression profiling; Mucoepidermoid carcinoma ID T(11/19) TRANSLOCATION; ACTIVATION; CREB; COACTIVATORS; PATHWAY; BIOLOGY; CLASSIFICATION; CANCER; TUMORS AB Background: Mucoepidermoid carcinoma (MEC) arises from multiple organs and accounts for the most common types of salivary gland malignancies. Currently, patients with unresectable and metastatic MEC have poor long-term clinical outcomes and no targeted therapies are available. The majority of MEC tumors contain a t(11; 19) chromosomal translocation that fuses two genes, CRTC1 and MAML2, to generate the chimeric protein CRTC1-MAML2. CRTC1-MAML2 displays transforming activity in vitro and is required for human MEC cell growth and survival, partially due to its ability to constitutively activate CREB-mediated transcription. Consequently, CRTC1-MAML2 is implicated as a major etiologic molecular event and a therapeutic target for MEC. However, the molecular mechanisms underlying CRTC1-MAML2 oncogenic action in MEC have not yet been systematically analyzed. Elucidation of the CRTC1-MAML2-regulated transcriptional program and its underlying mechanisms will provide important insights into MEC pathogenesis that are essential for the development of targeted therapeutics. Methods: Transcriptional profiling was performed on human MEC cells with the depletion of endogenous CRTC1-MAML2 fusion or its interacting partner CREB via shRNA-mediated gene knockdown. A subset of target genes was validated via real-time RT-PCR assays. CRTC1-MAML2-perturbed molecular pathways in MEC were identified through pathway analyses. Finally, comparative analysis of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles was carried out to assess the contribution of CREB in mediating CRTC1-MAML2-induced transcription. Results: A total of 808 differentially expressed genes were identified in human MEC cells after CRTC1-MAML2 knockdown and a subset of known and novel fusion target genes was confirmed by real-time RT-PCR. Pathway Analysis revealed that CRTC1-MAML2-regulated genes were associated with network functions that are important for cell growth, proliferation, survival, migration, and metabolism. Comparison of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles revealed common and distinct genes regulated by CRTC1-MAML2 and CREB, respectively. Conclusion: This study identified a specific CRTC1-MAML2-induced transcriptional program in human MEC cells and demonstrated that CRTC1-MAML2 regulates gene expression in CREB-dependent and independent manners. Our data provide the molecular basis underlying CRTC1-MAML2 oncogenic functions and lay a foundation for further functional investigation of CRTC1-MAML2-induced signaling in MEC initiation and maintenance. C1 [Chen, Jie; Griffin, James D.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Li, Jian-Liang] Sanford Burnham Prebys Med Discovery Inst Lake No, Orlando, FL 32827 USA. [Chen, Zirong; Wu, Lizi] Univ Florida, UF Hlth Canc Ctr, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. RP Wu, LZ (reprint author), Univ Florida, UF Hlth Canc Ctr, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. EM lzwu@ufl.edu RI chen, zirong/S-4042-2016 OI chen, zirong/0000-0002-0589-4619 FU National Institute of Dental & Craniofacial Research of the National Institutes of Health [R01DE023641] FX This study is supported by the National Institute of Dental & Craniofacial Research of the National Institutes of Health R01DE023641 (to L. Wu). NR 30 TC 0 Z9 0 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 26 PY 2015 VL 15 AR 803 DI 10.1186/s12885-015-1827-3 PG 13 WC Oncology SC Oncology GA CU2TX UT WOS:000363377600002 PM 26503699 ER PT J AU Hettmer, S Schinzel, AC Tchessalova, D Schneider, M Parker, CL Bronson, RT Richards, NGJ Hahn, WC Wagers, AJ AF Hettmer, Simone Schinzel, Anna C. Tchessalova, Daria Schneider, Michaela Parker, Christina L. Bronson, Roderick T. Richards, Nigel G. J. Hahn, William C. Wagers, Amy J. TI Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma SO ELIFE LA English DT Article ID CANCER; CELLS; SYNTHETASE; GLUTAMINE; RHABDOMYOSARCOMA; ONCOGENESIS; EXPRESSION; LEUKEMIA; PATHWAY; GROWTH AB Current therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets by selective targeting of the molecular networks that support sarcoma cell proliferation. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and disruption of Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Asparagine reliance of sarcoma cells may represent a metabolic vulnerability with potential anti-sarcoma therapeutic value. C1 [Hettmer, Simone; Tchessalova, Daria; Wagers, Amy J.] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Hettmer, Simone] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hettmer, Simone] Univ Hosp Berlin, Charite, Pediat Hematol Oncol, Berlin, Germany. [Hettmer, Simone; Schneider, Michaela] Univ Freiburg, Univ Med Ctr Freiburg, Div Pediat Hematol & Oncol, Dept Pediat & Adolescent Med, D-79106 Freiburg, Germany. [Hettmer, Simone; Tchessalova, Daria; Wagers, Amy J.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Schinzel, Anna C.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Schinzel, Anna C.; Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Parker, Christina L.] Harvard Univ, Sch Med, Summer Honors Undergrad Program, Boston, MA USA. [Parker, Christina L.] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Bronson, Roderick T.] Tufts Univ, Sch Vet, Dept Biomed Sci, North Grafton, MA USA. [Richards, Nigel G. J.] Indiana Univ Purdue Univ, Dept Chem & Chem Biol, Indianapolis, IN 46202 USA. RP Wagers, AJ (reprint author), Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM amy.wagers@joslin.harvard.edu FU American Association for Cancer Research [SU2C-AACR-IRG1111]; Sarcoma Foundation of America; St. Baldrick's Foundation; National Institute for Health [P01 CA050661, P01 CA142536, U01 CA176058] FX American Association for Cancer Research SU2C-AACR-IRG1111 Amy J Wagers; Sarcoma Foundation of America SARC-SPORE grant Simone Hettmer; St. Baldrick's Foundation Pediatric Research Grant Simone Hettmer; National Institute for Health Research P01 CA050661 William C Hahn; National Institute for Health Research P01 CA142536 William C Hahn; National Institute for Health Research U01 CA176058 William C Hahn NR 30 TC 6 Z9 6 U1 2 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 24 PY 2015 VL 4 AR e09436 DI 10.7554/eLife.09436 PG 17 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0LD UT WOS:000373893900001 ER PT J AU Cillo, AR Hilldorfer, BB Lalama, CM McKinnon, JE Coombs, RW Tenorio, AR Fox, L Gandhi, RT Ribaudo, H Currier, JS Gulick, RM Wilkin, TJ Mellors, JW AF Cillo, Anthony R. Hilldorfer, Benedict B. Lalama, Christina M. McKinnon, John E. Coombs, Robert W. Tenorio, Allan R. Fox, Lawrence Gandhi, Rajesh T. Ribaudo, Heather Currier, Judith S. Gulick, Roy M. Wilkin, Timothy J. Mellors, John W. TI Virologic and immunologic effects of adding maraviroc to suppressive antiretroviral therapy in individuals with suboptimal CD4(+) T-cell recovery SO AIDS LA English DT Article DE antiretroviral therapy intensification; HIV-1 immunotherapeutics; HIV-1 persistence; maraviroc; suboptimal T-cell recovery ID HIV-INFECTED PATIENTS; IMMUNE ACTIVATION; RALTEGRAVIR INTENSIFICATION; HIV-1-INFECTED PATIENTS; COMBINATION THERAPY; RANDOMIZED-TRIAL; DISEASE; BLOOD; APOPTOSIS; RESPONSES AB Background:Combination antiretroviral therapy (ART) suppresses HIV-1 replication, but does not restore CD4(+) T-cell counts in all individuals. To investigate the effects of maraviroc on HIV-1 persistence and the relations between virologic and immunologic parameters in individuals with incomplete CD4(+) T-cell recovery, we performed a prospective, open-label pilot trial in which maraviroc was added to a suppressive ART regimen for 24 weeks.Design:A5256 was a single-arm trial in which individuals on suppressive ART with incomplete CD4(+) T-cell recovery added maraviroc for 24 weeks.Methods:We quantified low-level, residual viremia in plasma and total HIV-1 DNA and 2-long terminal repeat (2-LTR) circles in peripheral blood mononuclear cells before and after maraviroc intensification. We also evaluated markers of CD4(+) and CD8(+) T-cell immune activation (%CD38(+)HLA-DR+) and apoptosis (%caspase3(+)/Bcl-2(-)).Results:No effect of maraviroc was found on the probability of detectable plasma viremia (1copy/ml; n=31, exact McNemar P=1.0) or detectable 2-LTR circles (n=28, P=0.25) or on total HIV-1 DNA (n=28, 90% confidence interval -0.1, +0.3 log(10)copies/10(6) CD4(+) T-cells). Premaraviroc HIV-1 DNA levels were inversely related to premaraviroc %CD38(+)HLA-DR+ CD4(+) T-cells (Spearman=-0.52, P=0.004), and lower premaraviroc HIV-1 DNA levels were associated with larger decreases in %CD38(+)HLA-DR+ CD4(+) T-cells during maraviroc intensification (Spearman=0.44, P=0.018).Conclusion:In individuals on suppressive ART with incomplete CD4(+) T-cell recovery, maraviroc intensification did not affect measures of HIV-1 persistence but did decrease persistent CD4(+) T-cell immune activation especially in individuals with low preintensification levels of HIV-1 DNA. C1 [Cillo, Anthony R.; Hilldorfer, Benedict B.; McKinnon, John E.; Mellors, John W.] Univ Pittsburgh, Sch Med, Div Infect Dis, Pittsburgh, PA 15261 USA. [Lalama, Christina M.; Ribaudo, Heather] Harvard Univ, TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [McKinnon, John E.] Henry Ford Hosp, Dept Med, Div Infect Dis, Detroit, MI 48202 USA. [Coombs, Robert W.] Univ Washington, Sch Med, Dept Lab Med & Med, Seattle, WA USA. [Tenorio, Allan R.] Rush Univ, Med Ctr, Dept Med, Chicago, IL 60612 USA. [Fox, Lawrence] NIAID, HIV Res Branch, Bethesda, MD 20892 USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Currier, Judith S.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Gulick, Roy M.; Wilkin, Timothy J.] Cornell Univ, Weill Med Coll, Div Infect Dis, New York, NY 10021 USA. RP Mellors, JW (reprint author), Univ Pittsburgh, Sch Med, Div Infect Dis, Scaife S818,3550 Terrace St, Pittsburgh, PA 15261 USA. EM jwm1@pitt.edu FU National Institute of Allergy and Infectious Diseases [UM1AI068636]; National Institute of Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); National Center for Research Resources [TR000457]; AIDS Clinical Trials Group to the Pittsburgh Virology Specialty Laboratory [AI068636]; Statistical and Data Management Center [AI068634, AAI38855]; University of Washington Center for AIDS Research (CFAR) [P30AI027757]; Pitt AIDS Research Training Grant [T32 AI065380-08]; [AI069412-08]; [AI069513]; [AI069419]; [AI069471]; [AI069472]; [AI069465]; [AI069532]; [AI069556]; [AI069424]; [AI069432]; [AI069496]; [AI069477]; [AI069494]; [AI069511]; [AI069484-07]; [AI069501]; [AI069471-08]; [AI069423-08]; [AI069439-08]; [AI069447]; [AI069452-08]; [AI69418-02]; [AI069534-08]; [AI069503-08]; [P30AI50410]; [P30AI050409]; [P30AI045008-15] FX The project described was supported by Award Number UM1AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). Participating clinical trials units were supported by the following grants: AI069412-08, AI069494, AI069513, AI069419, AI069471, AI069412-08, AI069472, AI069465, AI069532, AI069556, AI069424, AI069432, AI069496, AI069477, AI069494, AI069511, AI069484-07, AI069494, AI069501, AI069471-08, AI069423-08, AI069439-08, AI069447, AI069452-08, AI69418-02, AI069534-08, and AI069503-08. Centers for AIDS Research received support from the following grants: P30AI50410, P30AI050409 and P30AI045008-15. The National Center for Research Resources grant TR000457 supported the Clinical and Translational Science Center. This work was also supported by grants from the AIDS Clinical Trials Group to the Pittsburgh Virology Specialty Laboratory (AI068636) and the Statistical and Data Management Center (AI068634; AAI38855). R.W.C. received support from the University of Washington Center for AIDS Research (CFAR grant: P30AI027757). A.R.C. and B.B.H. received support from the Pitt AIDS Research Training Grant (T32 AI065380-08). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Allergy and Infectious Diseases or the National Institute of Health. NR 40 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD OCT 23 PY 2015 VL 29 IS 16 BP 2121 EP 2129 DI 10.1097/QAD.0000000000000810 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DB4IL UT WOS:000368476600001 PM 26544577 ER PT J AU Bui, HN Sluss, PM Hayes, FJ Blincko, S Knol, DL Blankenstein, MA Heijboer, AC AF Bui, H. N. Sluss, P. M. Hayes, F. J. Blincko, S. Knol, D. L. Blankenstein, M. A. Heijboer, A. C. TI Testosterone, free testosterone, and free androgen index in women: Reference intervals, biological variation, and diagnostic value in polycystic ovary syndrome SO CLINICA CHIMICA ACTA LA English DT Article DE Androgens; Liquid chromatography-tandem mass spectrometry, immunoassay; PCOS; Women ID TANDEM MASS-SPECTROMETRY; SERUM TESTOSTERONE; BLOOD-CONCENTRATIONS; QUALITY GOALS; SYNDROME PCOS; HEALTHY-MEN; CRITERIA; HIRSUTISM; CONSENSUS; MANAGEMENT AB Objective: The objective of our study was to determine reference intervals and biologic variation for testosterone (T), free testosterone (IT), and free androgen index (FAI) in women with accurate methods and to test the discriminative value of these parameters in a polycystic ovary syndrome (PCOS)-population. Methods: Serum was obtained daily during a normal menstrual cycle from 25 healthy women (677 data-points). A single serum sample was obtained from 44 PCOS-patients. T was measured by LC-MS/MS and by Architect 2nd generation T Immunoassay. Sex hormone-binding globulin was measured to calculate if and FAI. Results: Reference intervals which were established in healthy women with an ovulatory menstrual cycle were T = 0.3-1.6 nmol/L and 0.5-2.0 nmol/L, fT = 5.2-26 pmol/L and 7.2-33 pmol/L, and FAI = 0.4-2.9 and 0.6-4.4, by LC-MS/MS and immunoassay, respectively. T, ft and FAI were higher in PCOS patients than in controls (p <0.0001). The areas under the curve of receiver operator characteristic (ROC) plots were not different for T, if, or FAI when T was measured by LC-MS/MS versus immunoassay based on prediction of PCOS. FAI and fT were the strongest predictors of PCOS. Conclusions: When based upon the appropriate reference intervals and ROC analysis, LC-MS/MS and second generation immunoassay have equivalent clinical utility for the diagnosis of PCOS. (C) 2015 Elsevier B.V. All rights reserved. C1 [Bui, H. N.; Blankenstein, M. A.; Heijboer, A. C.] Vrije Univ Amsterdam, Med Ctr, Dept Clin Chem, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands. [Sluss, P. M.] Massachusetts Gen Hosp, Clin Pathol Core Lab, Boston, MA 02114 USA. [Hayes, F. J.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Blincko, S.] Abbott Diagnost, Wiesbaden, Germany. [Knol, D. L.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands. RP Heijboer, AC (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Clin Chem, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM a.heijboer@vumc.nl OI Heijboer, Annemieke/0000-0002-6712-9955; Blankenstein, Marinus/0000-0003-1186-0770 FU Abbott Diagnostics FX Funding for the analytical measurements was provided by Abbott Diagnostics. NR 35 TC 2 Z9 4 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 EI 1873-3492 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD OCT 23 PY 2015 VL 450 BP 227 EP 232 DI 10.1016/j.cca.2015.08.019 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CV4TN UT WOS:000364259500039 PM 26327459 ER PT J AU Iqbal, J Walsh, MT Hammad, SM Cuchel, M Tarugi, P Hegele, RA Davidson, NO Rader, DJ Klein, RL Hussain, MM AF Iqbal, Jahangir Walsh, Meghan T. Hammad, Samar M. Cuchel, Marina Tarugi, Patrizia Hegele, Robert A. Davidson, Nicholas O. Rader, Daniel J. Klein, Richard L. Hussain, M. Mahmood TI Microsomal Triglyceride Transfer Protein Transfers and Determines Plasma Concentrations of Ceramide and Sphingomyelin but Not Glycosylceramide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESTER TRANSFER PROTEIN; INSULIN-RESISTANCE; LIPID ABSORPTION; ABETALIPOPROTEINEMIA GENE; LIPOPROTEIN SECRETION; LIVER-MICROSOMES; APOLIPOPROTEIN-B; SPHINGOLIPIDS; MICE; INHIBITION AB Sphingolipids, a large family of bioactive lipids, are implicated in stress responses, differentiation, proliferation, apoptosis, and other physiological processes. Aberrant plasma levels of sphingolipids contribute to metabolic disease, atherosclerosis, and insulin resistance. They are fairly evenly distributed in high density and apoB-containing lipoproteins (B-lps). Mechanisms involved in the transport of sphingolipids to the plasma are unknown. Here, we investigated the role of microsomal triglyceride transfer protein (MTP), required for B-lp assembly and secretion, in sphingolipid transport to the plasma. Abetalipoproteinemia patients with deleterious mutations in MTP and absence of B-lps had significantly lower plasma ceramide and sphingomyelin but normal hexosylceramide, lactosylceramide, and different sphingosines compared with unaffected controls. Furthermore, similar differential effects on plasma sphingolipids were seen in liver-and intestine-specific MTP knock-out (L, I-Mttp(-/-)) mice, suggesting that MTP specifically plays a role in the regulation of plasma ceramide and sphingomyelin. We hypothesized that MTP deficiency may affect either their synthesis or secretion. MTP deficiency had no effect on ceramide and sphingomyelin synthesis but reduced secretion from primary hepatocytes and hepatoma cells. Therefore, MTP is involved in ceramide and sphingomyelin secretion but not in their synthesis. We also found that MTP transferred these lipids between vesicles in vitro. Therefore, we propose that MTP might regulate plasma ceramide and sphingomyelin levels by transferring these lipids to B-lps in the liver and intestine and facilitating their secretion. C1 [Iqbal, Jahangir; Walsh, Meghan T.; Hussain, M. Mahmood] Suny Downstate Med Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA. [Hussain, M. Mahmood] Suny Downstate Med Ctr, Dept Pediat, Brooklyn, NY 11203 USA. [Hammad, Samar M.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Cuchel, Marina; Rader, Daniel J.] Univ Penn, Cardiovasc Inst, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Tarugi, Patrizia] Univ Modena & Reggio Emilia, Dept Life Sci, I-41121 Modena, Italy. [Hegele, Robert A.] Robarts Res Inst, Blackburn Cardiovasc Genet Lab, London, ON N6A 5B7, Canada. [Davidson, Nicholas O.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Klein, Richard L.] Med Univ S Carolina, Dept Med, Div Endocrinol Metab & Med Genet, Charleston, SC 29425 USA. [Klein, Richard L.] Ralph H Johnson Dept Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. [Hussain, M. Mahmood] New York Harbor Healthcare Syst, Dept Vet Affairs, Brooklyn, NY 11209 USA. RP Hussain, MM (reprint author), Suny Downstate Med Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA. EM mahmood.hussain@downstate.edu RI Regan, Clinton/E-6250-2012; Hegele, Robert/G-3301-2011 FU National Institutes of Health [HL-95924, R56DK046900-17A1, HL-38180, DK-56260, DK-52574, P20 RR017677]; Veterans Affairs Merit Award [BX001728, BX000978]; American Heart Association; Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313] FX This work was supported, in whole or in part, by National Institutes of Health Grants HL-95924 and R56DK046900-17A1 (to M. M. H.) and Grants HL-38180, DK-56260, and DK-52574 (to N. O. D.). This work was also supported by Veterans Affairs Merit Award BX001728 (to M. M. H.), American Heart Association grant-in-aid (to J. I.), and Veterans Affairs Merit Award BX000978 (to R. L. K.).; Supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina Grant P30 CA138313 and National Institutes of Health Grant P20 RR017677 (to the Lipidomics Core, Lipidomics and Pathobiology COBRE, Medical University of South Carolina for sphingolipid analysis). NR 46 TC 5 Z9 5 U1 0 U2 2 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 OCT 23 PY 2015 VL 290 IS 43 BP 25863 EP 25875 DI 10.1074/jbc.M115.659110 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU4VA UT WOS:000363527300011 PM 26350457 ER PT J AU Hogan, MF Ravnskjaer, K Matsumura, S Huising, MO Hull, RL Kahn, SE Montminy, M AF Hogan, Meghan F. Ravnskjaer, Kim Matsumura, Shigenobu Huising, Mark O. Hull, Rebecca L. Kahn, Steven E. Montminy, Marc TI Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-CELL PROLIFERATION; FREE FATTY-ACIDS; GLUCOSE-METABOLISM; GENE-EXPRESSION; LIVER; TORC2; GLUCONEOGENESIS; OBESITY; MICE; ISLET AB Under fasting conditions, increases in circulating concentrations of glucagon maintain glucose homeostasis via the induction of hepatic gluconeogenesis. Triggering of the cAMP pathway in hepatocytes stimulates the gluconeogenic program via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2 and CRTC3. In parallel, decreases in circulating insulin also increase gluconeogenic gene expression via the de-phosphorylation and activation of the forkhead transcription factor FOXO1. Hepatic gluconeogenesis is increased in insulin resistance where it contributes to the attendant hyperglycemia. Whether selective activation of the hepatic CREB/CRTC pathway is sufficient to trigger metabolic changes in other tissues is unclear, however. Modest hepatic expression of a phosphorylation-defective and therefore constitutively active CRTC2S171,275A protein increased gluconeogenic gene expression under fasting as well as feeding conditions. Circulating glucose concentrations were constitutively elevated in CRTC2S(171,275)A-expressing mice, leading to compensatory increases in circulating insulin concentrations that enhance FOXO1 phosphorylation. Despite accompanying decreases in FOXO1 activity, hepatic gluconeogenic gene expression remained elevated in CRTC2S(171,275)A mice, demonstrating that chronic increases inCRTC2activity in the liver are indeed sufficient to promote hepatic insulin resistance and to disrupt glucose homeostasis. C1 [Hogan, Meghan F.; Ravnskjaer, Kim; Matsumura, Shigenobu; Huising, Mark O.; Montminy, Marc] Salk Inst Biol Studies, Peptide Biol Labs, La Jolla, CA 92037 USA. [Hogan, Meghan F.; Hull, Rebecca L.; Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98108 USA. [Hogan, Meghan F.; Hull, Rebecca L.; Kahn, Steven E.] Univ Washington, Seattle, WA 98108 USA. [Ravnskjaer, Kim] Univ Southern Denmark, Dept Biochem & Mol Biol, Odense, Denmark. [Matsumura, Shigenobu] Kyoto Univ, Grad Sch Agr, Div Food Sci & Biotechnol, Sakyo Ku, Kyoto 6068502, Japan. [Huising, Mark O.] Univ Calif Davis, Sch Med, Dept Physiol & Membrane Biol, Davis, CA 95616 USA. RP Montminy, M (reprint author), Salk Inst Biol Studies, Peptide Biol Labs, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM montminy@salk.edu RI Regan, Clinton/E-6250-2012; OI Kahn, Steven/0000-0001-7307-9002; Hull, Rebecca/0000-0001-9690-4087 FU National Institutes of Health [R37DK083834, 5T32GM007240, 5R01DK088082]; Clayton Foundation for Medical Research; Kieckhefer Foundation; Leona M. and Harry B. Helmsley Charitable Trust Grant [2012-PG-MED002]; Department of Veterans Affairs FX This work was supported by National Institutes of Health Grants R37DK083834 (to M. M., M. F. H.); 5T32GM007240 (to M. F. H.); 5R01DK088082 (to R. L. H.); The Clayton Foundation for Medical Research (to M. M.), the Kieckhefer Foundation (to M. M.), the Leona M. and Harry B. Helmsley Charitable Trust Grant # 2012-PG-MED002 (to M. M., M. F. H.); and the Department of Veterans Affairs (S. E. K.). The authors declare that they have no conflicts of interest with the contents of this article. NR 34 TC 2 Z9 2 U1 1 U2 4 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 OCT 23 PY 2015 VL 290 IS 43 BP 25997 EP 26006 DI 10.1074/jbc.M115.679266 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU4VA UT WOS:000363527300021 PM 26342077 ER PT J AU Ye, YX Calcagno, C Binderup, T Courties, G Keliher, EJ Wojtkiewicz, GR Iwamoto, Y Tang, J Perez-Medina, C Mani, V Ishino, S Johnbeck, CB Knigge, U Fayad, ZA Libby, P Weissleder, R Tawakol, A Dubey, S Belanger, AP Di Carli, MF Swirski, FK Kjaer, A Mulder, WJM Nahrendorf, M AF Ye, Yu-Xiang Calcagno, Claudia Binderup, Tina Courties, Gabriel Keliher, Edmund J. Wojtkiewicz, Gregory R. Iwamoto, Yoshiko Tang, Jun Perez-Medina, Carlos Mani, Venkatesh Ishino, Seigo Johnbeck, Camilla Bardram Knigge, Ulrich Fayad, Zahi A. Libby, Peter Weissleder, Ralph Tawakol, Ahmed Dubey, Shipra Belanger, Anthony P. Di Carli, Marcelo F. Swirski, Filip K. Kjaer, Andreas Mulder, Willem J. M. Nahrendorf, Matthias TI Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis SO CIRCULATION RESEARCH LA English DT Article DE atherosclerosis; 18F-fluorothymidine; imaging; inflammation; macrophage; positron emission tomography; proliferation ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; MYOCARDIAL-INFARCTION; CELL-PROLIFERATION; INFLAMMATION; PET; MONOCYTES; HEART AB Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention. Objective: To explore F-18-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis. Methods and Results: F-18-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased F-18-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.050.01 versus 0.17 +/- 0.01, P<0.05 in aorta; 0.13 +/- 0.01 versus 0.28 +/- 0.02, P<0.05 in bone marrow; 0.06 +/- 0.01 versus 0.22 +/- 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, F-18-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic F-18-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest F-18-fluorodeoxyglucose uptake enriched F-18-FLT. In patients with atherosclerosis, F-18-FLT signal significantly increased in the inflamed carotid artery and in the aorta. Conclusions: F-18-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis. C1 [Ye, Yu-Xiang; Courties, Gabriel; Keliher, Edmund J.; Wojtkiewicz, Gregory R.; Iwamoto, Yoshiko; Weissleder, Ralph; Swirski, Filip K.; Nahrendorf, Matthias] Massachusetts Gen Hosp, Dept Radiol, Ctr Syst Biol, Boston, MA 02114 USA. [Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Tawakol, Ahmed] Harvard Univ, Sch Med, Boston, MA USA. [Calcagno, Claudia; Tang, Jun; Perez-Medina, Carlos; Mani, Venkatesh; Ishino, Seigo; Fayad, Zahi A.; Mulder, Willem J. M.] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, Dept Radiol, New York, NY 10029 USA. [Binderup, Tina; Johnbeck, Camilla Bardram; Kjaer, Andreas] Natl Univ Hosp, Dept Clin Physiol Nucl Med & PET, Rigshosp, Copenhagen, Denmark. [Binderup, Tina; Johnbeck, Camilla Bardram; Kjaer, Andreas] Natl Univ Hosp, Rigshosp, Cluster Mol Imaging, Copenhagen, Denmark. [Knigge, Ulrich] Natl Univ Hosp, Rigshosp, Dept Clin Endocrinol PE, Copenhagen, Denmark. [Knigge, Ulrich] Natl Univ Hosp, Rigshosp, Dept Surg C, Copenhagen, Denmark. [Knigge, Ulrich] Univ Copenhagen, Copenhagen, Denmark. [Libby, Peter; Di Carli, Marcelo F.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Dubey, Shipra; Belanger, Anthony P.; Di Carli, Marcelo F.] Harvard Univ, Sch Med, Dept Radiol, Div Nucl Med & Mol Imaging,Brigham & Womens Hosp, Boston, MA 02115 USA. [Mulder, Willem J. M.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. RP Nahrendorf, M (reprint author), Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu OI Mani, Venkatesh/0000-0002-0432-2918; Tang, Jun/0000-0002-8285-5111; Kjaer, Andreas/0000-0002-2706-5547 FU National Institute of Health [HL114477, HL117829, HL096576, HL118440, HL125703, HL071021, EB009638]; Deutsche Herzstiftung [S/05/12]; MGH Research Scholar Award FX This work was funded by grants from the National Institute of Health HL114477, HL117829, HL096576, HL118440, HL125703, HL071021, EB009638, the Deutsche Herzstiftung (S/05/12), and the MGH Research Scholar Award. NR 25 TC 13 Z9 14 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD OCT 23 PY 2015 VL 117 IS 10 BP 835 EP 845 DI 10.1161/CIRCRESAHA.115.307024 PG 11 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA CU1YV UT WOS:000363319200004 PM 26394773 ER PT J AU Zhang, LM Chen, SB Ruan, JB Wu, JY Tong, AB Yin, Q Li, Y David, L Lu, A Wang, WL Marks, C Ouyang, Q Zhang, XZ Mao, YD Wu, H AF Zhang, Liman Chen, Shuobing Ruan, Jianbin Wu, Jiayi Tong, Alexander B. Yin, Qian Li, Yang David, Liron Lu, Alvin Wang, Wei Li Marks, Carolyn Ouyang, Qi Zhang, Xinzheng Mao, Youdong Wu, Hao TI Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization SO SCIENCE LA English DT Article ID CAUSES AUTOINFLAMMATION; LEGIONELLA-PNEUMOPHILA; SIGNAL-TRANSDUCTION; BACTERIAL LIGANDS; CRYSTAL-STRUCTURE; NLRC4 CAUSES; APOPTOSOME; SECRETION; MECHANISM; FLAGELLIN AB The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein PrgJ, and recruit NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. We found that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional adenosine triphosphatase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) reconstruction at subnanometer resolution revealed a similar to 90 degrees hinge rotation accompanying NLRC4 activation. Unlike in the related heptameric Apaf-1 apoptosome, in which each subunit needs to be conformationally activated by its ligand before assembly, a single PrgJ-activated NAIP2 initiates NLRC4 polymerization in a domino-like reaction to promote the disk assembly. These insights reveal the mechanism of signal amplification in NAIP-NLRC4 inflammasomes. C1 [Zhang, Liman; Ruan, Jianbin; Tong, Alexander B.; Yin, Qian; Li, Yang; David, Liron; Lu, Alvin; Wu, Hao] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zhang, Liman; Ruan, Jianbin; Tong, Alexander B.; Yin, Qian; Li, Yang; David, Liron; Lu, Alvin; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Chen, Shuobing; Wu, Jiayi; Ouyang, Qi; Mao, Youdong] Peking Univ, Peking Tsinghua Joint Ctr Life, State Key Lab Artificial Microstruct & Mesoscop,S, Ctr Quantitat Biol,Acad Adv Interdisciplinary Stu, Beijing 100871, Peoples R China. [Chen, Shuobing; Wu, Jiayi; Wang, Wei Li; Mao, Youdong] Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Dept Canc Immunol & Virol, Boston, MA 02215 USA. [Wang, Wei Li; Mao, Youdong] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Marks, Carolyn] Harvard Univ, Ctr Nanoscale Syst, Cambridge, MA 02138 USA. [Zhang, Xinzheng] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China. RP Wu, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM youdong_mao@dfci.harvard.edu; wu@crystal.harvard.edu RI Zhang , Xinzheng/E-6339-2013; Wang, Wei/B-8061-2009; OI Wang, Wei/0000-0002-5064-8097; Lu, Alvin/0000-0003-2353-848X FU NIH K99 grant [AI108793]; Cancer Research Institute; Intel academic grant; Peking University; NIH [1DP1HD087988]; NIH grant Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID) [AI100645]; NSF [ECS-0335765] FX We thank G. Bozkurt for technical assistance; H. Ploegh for providing engineered, Ca2+-independent sortase and the peptide-fluorophore conjugate Gly-Gly-Gly-TAMRA (GGG-TAMRA); and M. Ericsson for use of the Harvard Medical School EM facility. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Cryo-EM maps and atomic coordinates have been deposited in the Electron Microscopy Data Bank (EMDB IDs EMD-6458, EMD-6459, and EMD-6460 for C11, C12, and C10 reconstructions, respectively) and Protein Data Bank (PDB ID 3JBL for the C11 reconstruction). Supported by NIH K99 grant AI108793 (Q.Y.), a Cancer Research Institute postdoctoral fellowship (L.D.), an Intel academic grant, research funds at Peking University, and NIH grant 1DP1HD087988. The cryo-EMfacility was funded through the NIH grant AI100645 Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID). The experiments were performed in part at the Center for Nanoscale Systems at Harvard University, a member of the National Nanotechnology Infrastructure Network (NNIN), which is supported by NSF award ECS-0335765. NR 30 TC 36 Z9 37 U1 10 U2 36 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 OCT 23 PY 2015 VL 350 IS 6259 BP 404 EP 409 DI 10.1126/science.aac5789 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU0NG UT WOS:000363213400032 PM 26449474 ER PT J AU McMahon, GT Bennett, JA AF McMahon, Graham T. Bennett, Jennifer A. TI Case 33-2015: A 57-Year-Old Woman with Hair Loss and Deepening Voice SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 [McMahon, Graham T.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02138 USA. [McMahon, Graham T.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Bennett, Jennifer A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. RP McMahon, GT (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02138 USA. OI McMahon, Graham/0000-0003-4288-6535 FU Philips Healthcare Incubator FX Dr. Bennett reports receiving personal fees from Philips Healthcare Incubator. No other potential conflict of interest relevant to this article was reported. NR 6 TC 0 Z9 0 U1 0 U2 7 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 OCT 22 PY 2015 VL 373 IS 17 BP 1660 EP 1666 DI 10.1056/NEJMcpc1413304 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA CU1YH UT WOS:000363317800013 PM 26488697 ER PT J AU Won, JS Annamalai, B Choi, S Singh, I Singh, AK AF Won, Je-Seong Annamalai, Balasubramaniam Choi, Seungho Singh, Inderjit Singh, Autar K. TI S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion SO BRAIN RESEARCH LA English DT Article DE Calpain; Cdk5; Chronic cerebral hypoperfusion; S-nitrosoglutathione; p25, and tau ID NITRIC-OXIDE SYNTHASE; CHRONIC BRAIN HYPOPERFUSION; ALZHEIMERS-DISEASE; AMYLOID-BETA; BLOOD-FLOW; EXPERIMENTAL STROKE; SPATIAL MEMORY; PEROXYNITRITE FORMATION; NITROSO-GLUTATHIONE; BARRIER DISRUPTION AB We have previously reported that treatment of rats subjected to permanent bilateral common carotid artery occlusion (pBCCAO), a model of chronic cerebral hypoperfusion (CCH), with S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, improved cognitive functions and decreased amyloid-beta accumulation in the brains. Since CCH has been implicated in tau hyperphosphorylation induced neurodegeneration, we investigated the role of GSNO in regulation of tau hyperphosphorylation in rat pBCCAO model. The rats subjected to pBCCAO had a significant increase in tau hyperphosphoxylation with increased neuronal loss in hippocampal/cortical areas. GSNO treatment attenuated not only the tau hyperphosphorylation, but also the neurodegeneration in pBCCAO rat brains. The pBCCAO rat brains also showed increased activities of GSK-3 beta and Cdk5 (major tau kinases) and GSNO treatment significantly attenuated their activities. GSNO attenuated the increased calpain activities and calpain-mediated cleavage of p35 leading to production of p25 and aberrant Cdk5 activation. In in vitro studies using purified calpain protein, GSNO treatment inhibited calpain activities while 3-morpholinosydnonimine (a donor of peroxynitrite) treatment increased its activities, suggesting the opposing role of GSNO vs. peroxynitrite in regulation of calpain activities. In pBCCAO rat brains, GSNO treatment attenuated the expression of inducible nitric oxide synthase (iNOS) expression and also reduced the brain levels of nitro-tyrosine formation, thereby indicating the protective role of GSNO in iNOS/nitrosative-stress mediated calpain/tau pathologies under CCH conditions. Taken together with our previous report, these data support the therapeutic potential of GSNO, a biological NO carrier, as a neuro- and cognitive-protective agent under conditions of CCH. Published by Elsevier B.V. C1 [Won, Je-Seong; Annamalai, Balasubramaniam; Singh, Autar K.] Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. [Choi, Seungho; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Singh, Autar K.] Ralph H Johnson Vet Adm Med Ctr, Pathol & Lab Med Serv, Charleston, SC USA. RP Singh, AK (reprint author), Med Univ S Carolina, Charles P Darby Children Res Inst, Dept Pediat, 504D,173 Ashley Ave, Charleston, SC 29425 USA. EM avtar.singh@va.gov FU VA [BX001062, BX001072]; NIH [NS072511, NS 037766] FX Je-Seong Won and Balasubramaniam Annamalai both contributed equal effort and are co-first authors for this manuscript. This work was supported by Grants from VA (BX001062 and BX001072) and NIH (NS072511 and NS 037766). We also acknowledge Ms. Joyce Bryan for their help in procurement of animals and supplies. NR 86 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD OCT 22 PY 2015 VL 1624 BP 359 EP 369 DI 10.1016/j.brainres.2015.07.057 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CW5PY UT WOS:000365050100036 PM 26271717 ER PT J AU Kazak, L Chouchani, ET Jedrychowski, MP Erickson, BK Shinoda, K Cohen, P Vetrivelan, R Lu, GZ Laznik-Bogoslavski, D Hasenfuss, SC Kajimura, S Gygi, SP Spiegelman, BM AF Kazak, Lawrence Chouchani, Edward T. Jedrychowski, Mark P. Erickson, Brian K. Shinoda, Kosaku Cohen, Paul Vetrivelan, Ramalingam Lu, Gina Z. Laznik-Bogoslavski, Dina Hasenfuss, Sebastian C. Kajimura, Shingo Gygi, Steve P. Spiegelman, Bruce M. TI A Creatine-Driven Substrate Cycle Enhances Energy Expenditure and Thermogenesis in Beige Fat SO CELL LA English DT Article ID BROWN ADIPOSE-TISSUE; UCP1-INDEPENDENT THERMOGENESIS; WILD-TYPE; MICE; MITOCHONDRIA; COLD; ABLATION; OBESITY; MUSCLE; UCP1 AB Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a beta 3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis. C1 [Kazak, Lawrence; Chouchani, Edward T.; Cohen, Paul; Lu, Gina Z.; Laznik-Bogoslavski, Dina; Hasenfuss, Sebastian C.; Spiegelman, Bruce M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kazak, Lawrence; Chouchani, Edward T.; Jedrychowski, Mark P.; Erickson, Brian K.; Cohen, Paul; Hasenfuss, Sebastian C.; Gygi, Steve P.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Shinoda, Kosaku; Kajimura, Shingo] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Vetrivelan, Ramalingam] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Vetrivelan, Ramalingam] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Spiegelman, BM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu FU Canadian Institutes of Health Research postdoctoral fellowship; Human Frontier Science Program postdoctoral fellowship; NIH [DK031405]; JPB foundation FX We are grateful to Marc W. Kirschner, Mike P. Murphy, BeWieringa, and members of the Spiegelman lab for helpful discussions. pBAD-TOPO-TA/hPhospho1 was a kind gift from Colin Farquharson. The Biophysical Instrumentation Facility (NSF-0070319) is acknowledged for help with DSC. This work was supported by a Canadian Institutes of Health Research postdoctoral fellowship to L.K., by a Human Frontier Science Program postdoctoral fellowship to E.T.C., and by an NIH grant (DK031405) and the JPB foundation to B.M.S. NR 34 TC 47 Z9 48 U1 6 U2 36 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 OCT 22 PY 2015 VL 163 IS 3 BP 643 EP 655 DI 10.1016/j.cell.2015.09.035 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CW2NK UT WOS:000364828900018 PM 26496606 ER PT J AU Gibney, E Yetisen, A AF Gibney, Elizabeth Yetisen, Ali TI Q&A The nanomaterials designer SO NATURE LA English DT Editorial Material C1 [Yetisen, Ali] Harvard Univ, Cambridge, MA 02138 USA. [Yetisen, Ali] Massachusetts Gen Hosp, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 8 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 OCT 22 PY 2015 VL 526 IS 7574 BP 504 EP 504 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV1NX UT WOS:000364026100025 ER PT J AU Landau, DA Tausch, E Taylor-Weiner, AN Stewart, C Reiter, JG Bahlo, J Kluth, S Bozic, I Lawrence, M Bottcher, S Carter, SL Cibulskis, K Mertens, D Sougnez, CL Rosenberg, M Hess, JM Edelmann, J Kless, S Kneba, M Ritgen, M Fink, A Fischer, K Gabriel, S Lander, ES Nowak, MA Doehner, H Hallek, M Neuberg, D Getz, G Stilgenbauer, S Wu, CJ AF Landau, Dan A. Tausch, Eugen Taylor-Weiner, Amaro N. Stewart, Chip Reiter, Johannes G. Bahlo, Jasmin Kluth, Sandra Bozic, Ivana Lawrence, Mike Boettcher, Sebastian Carter, Scott L. Cibulskis, Kristian Mertens, Daniel Sougnez, Carrie L. Rosenberg, Mara Hess, Julian M. Edelmann, Jennifer Kless, Sabrina Kneba, Michael Ritgen, Matthias Fink, Anna Fischer, Kirsten Gabriel, Stacey Lander, Eric S. Nowak, Martin A. Doehner, Hartmut Hallek, Michael Neuberg, Donna Getz, Gad Stilgenbauer, Stephan Wu, Catherine J. TI Mutations driving CLL and their evolution in progression and relapse SO NATURE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; BRAF MUTATIONS; TUMOR PROGRESSION; GENOME; CANCER; HETEROGENEITY; LYMPHOMA; PATTERNS; REVEALS; DRIVER AB Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome. C1 [Landau, Dan A.; Taylor-Weiner, Amaro N.; Stewart, Chip; Reiter, Johannes G.; Lawrence, Mike; Carter, Scott L.; Cibulskis, Kristian; Sougnez, Carrie L.; Rosenberg, Mara; Hess, Julian M.; Gabriel, Stacey; Lander, Eric S.; Getz, Gad; Wu, Catherine J.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Landau, Dan A.; Reiter, Johannes G.; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Landau, Dan A.; Wu, Catherine J.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Landau, Dan A.; Wu, Catherine J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Tausch, Eugen; Mertens, Daniel; Edelmann, Jennifer; Kless, Sabrina; Doehner, Hartmut; Stilgenbauer, Stephan] Univ Ulm, Dept Internal Med 3, D-89081 Ulm, Germany. [Reiter, Johannes G.] IST Austria, A-3400 Klosterneuburg, Austria. [Reiter, Johannes G.; Bozic, Ivana; Nowak, Martin A.] Harvard Univ, Program Evolutionary Dynam, Cambridge, MA 02138 USA. [Bahlo, Jasmin; Kluth, Sandra; Fink, Anna; Fischer, Kirsten; Hallek, Michael] Univ Hosp, Dept Internal Med, D-50937 Cologne, Germany. [Bahlo, Jasmin; Kluth, Sandra; Fink, Anna; Fischer, Kirsten; Hallek, Michael] Univ Hosp, Ctr Integrated Oncol Cologne Bonn, D-50937 Cologne, Germany. [Bozic, Ivana; Nowak, Martin A.] Harvard Univ, Dept Math, Cambridge, MA 02138 USA. [Boettcher, Sebastian; Kneba, Michael; Ritgen, Matthias] Univ Hosp Schleswig Holstein, Dept Internal Med 2, D-24105 Kiel, Germany. [Carter, Scott L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Joint Ctr Canc Precis Med,Dana Farber Canc Inst, Boston, MA 02215 USA. [Mertens, Daniel] German Canc Res Ctr, Mechanisms Leukemogenesis, D-69121 Heidelberg, Germany. [Nowak, Martin A.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Hallek, Michael] Cologne Cluster Excellence Cellular Stress Respon, D-50931 Cologne, Germany. [Neuberg, Donna] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA. RP Wu, CJ (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM gadgetz@broadinstitute.org; Stephan.Stilgenbauer@uniklinik-ulm.de; cwu@partners.org RI Mertens, Daniel/F-4681-2011; Bozic, Ivana/C-5003-2008; OI Mertens, Daniel/0000-0003-0227-7188; Reiter, Johannes/0000-0002-0170-7353 FU ACS; ASH; Burroughs Wellcome Fund Career Award for Medical Scientists; NIH Big Data to Knowledge initiative (BD2K) [1K01ES025431-01]; European Research Council (ERC) [279307]; Austrian Science Fund (FWF) [P23499-N23]; FWF NFN [S11407-N23 RiSE]; German Jose Carreras Leukemia Foundation [R06/03v]; Deutsche Forschungsgemeinschaft [KFO 286, SFB 1074]; Else Kroner-Fresenius-Stiftung [2010_Kolleg24, 2012_A146]; Virtual Helmholtz Institute [VH-VI-404]; CLL Global Research Foundation (Alliance); Blavatnik Family Foundation; AACR; NIH/NCI [1R01CA182461-02, 1R01CA184922-01, 1U10CA180861-01] FX We thank all members of the Broad Institute's Biological Samples, Genetic Analysis and Genome Sequencing Platforms, who made this work possible (NHGRI-U54HG003067). We further thank all patients and their physicians for CLL8 trial participation and donation of samples; M. Mendila, N. Valente, S. Zurfluh, M. Wenger and J. Wingate for their support in conception and conduct of the CLL8 trial. D.A.L. is supported by an ACS Postdoctoral Fellowship, ASH Scholar Award, and the Burroughs Wellcome Fund Career Award for Medical Scientists and by the NIH Big Data to Knowledge initiative (BD2K, 1K01ES025431-01). J.G.R. was supported by the European Research Council (ERC) start grant 279307: Graph Games, Austrian Science Fund (FWF) grant no. P23499-N23, and FWF NFN grant no S11407-N23 RiSE. S.B. is supported by the German Jose Carreras Leukemia Foundation (project R06/03v). M.H. is supported by the Deutsche Forschungsgemeinschaft (KFO 286, Project 6). S. S. is supported by the Else Kroner-Fresenius-Stiftung (2010_Kolleg24, 2012_A146), Virtual Helmholtz Institute (VH-VI-404), CLL Global Research Foundation (Alliance), and Deutsche Forschungsgemeinschaft (SFB 1074 projects B1, B2). C.J.W. acknowledges support from the Blavatnik Family Foundation, AACR (SU2C Innovative Research Grant), and NIH/NCI (1R01CA182461-02, 1R01CA184922-01, 1U10CA180861-01). NR 38 TC 87 Z9 87 U1 7 U2 28 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 OCT 22 PY 2015 VL 526 IS 7574 BP 525 EP U132 DI 10.1038/nature15395 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV1NX UT WOS:000364026100040 PM 26466571 ER PT J AU Calderwood, SB Murray, BE Chambers, HF AF Calderwood, Stephen B. Murray, Barbara E. Chambers, Henry F. TI The 21st Century Cures Act SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Calderwood, Stephen B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Murray, Barbara E.] Univ Texas Houston, Sch Med, Houston, TX USA. [Chambers, Henry F.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Calderwood, SB (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 2 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 OCT 22 PY 2015 VL 373 IS 17 BP 1679 EP 1679 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CU1YH UT WOS:000363317800028 PM 26488713 ER PT J AU Shen, GM Upadhyay, C Zhang, J Pan, RM Zolla-Pazner, S Kong, XP Hioe, CE AF Shen, Guomiao Upadhyay, Chitra Zhang, Jing Pan, Ruimin Zolla-Pazner, Susan Kong, Xiang-Peng Hioe, Catarina E. TI Rationally Targeted Mutations at the V1V2 Domain of the HIV-1 Envelope to Augment Virus Neutralization by Anti-V1V2 Monoclonal Antibodies SO PLOS ONE LA English DT Article ID V3 LOOP; VACCINE TRIAL; CRYSTAL-STRUCTURE; TYPE-1; GP120; EPITOPES; GLYCOPROTEIN; PROTECTION; ENV; RECOGNITION AB HIV-1 envelope glycoproteins (Env) are the only viral antigens present on the virus surface and serve as the key targets for virus-neutralizing antibodies. However, HIV-1 deploys multiple strategies to shield the vulnerable sites on its Env from neutralizing antibodies. The V1V2 domain located at the apex of the HIV-1 Env spike is known to encompass highly variable loops, but V1V2 also contains immunogenic conserved elements recognized by cross-reactive antibodies. This study evaluates human monoclonal antibodies (mAbs) against V2 epitopes which overlap with the conserved integrin alpha 4 beta 7-binding LDV/I motif, designated as the V2i (integrin) epitopes. We postulate that the V2i Abs have weak or no neutralizing activities because the V2i epitopes are often occluded from antibody recognition. To gain insights into the mechanisms of the V2i occlusion, we evaluated three elements at the distal end of the V1V2 domain shown in the structure of V2i epitope complexed with mAb 830A to be important for antibody recognition of the V2i epitope. Amino-acid substitutions at position 179 that restore the LDV/I motif had minimal effects on virus sensitivity to neutralization by most V2i mAbs. However, a charge change at position 153 in the V1 region significantly increased sensitivity of subtype C virus ZM109 to most V2i mAbs. Separately, a disulfide bond introduced to stabilize the hypervariable region of V2 loop also enhanced virus neutralization by some V2i mAbs, but the effects varied depending on the virus. These data demonstrate that multiple elements within the V1V2 domain act independently and in a virus-dependent fashion to govern the antibody recognition and accessibility of V2i epitopes, suggesting the need for multi-pronged strategies to counter the escape and the shielding mechanisms obstructing the V2i Abs from neutralizing HIV-1. C1 [Shen, Guomiao; Upadhyay, Chitra; Zhang, Jing; Zolla-Pazner, Susan; Hioe, Catarina E.] Vet Affairs New York Harbor Healthcare Syst Manha, New York, NY USA. [Shen, Guomiao; Upadhyay, Chitra; Zhang, Jing; Zolla-Pazner, Susan; Hioe, Catarina E.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Pan, Ruimin; Kong, Xiang-Peng] NYU, Sch Med, Dept Biochem & Pharmacol, New York, NY USA. RP Hioe, CE (reprint author), James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. EM catarina.hioe@mssm.edu OI Kong, Xiang-Peng/0000-0001-5773-2681 FU NIH [R01 AI102740]; HIVRAD [P01 AI100151]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development FX This work was supported in part by NIH grants R01 AI102740 (CEH.) and HIVRAD P01 AI100151 (XPK, SZP) and by research funds from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (VA Merit Review and Research Career Scientist CEH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 0 Z9 0 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 22 PY 2015 VL 10 IS 10 AR e0141233 DI 10.1371/journal.pone.0141233 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU0ZU UT WOS:000363249300037 PM 26491873 ER PT J AU Frodermann, V van Duijn, J van Pel, M van Santbrink, PJ Bot, I Kuiper, J de Jager, SCA AF Frodermann, Vanessa van Duijn, Janine van Pel, Melissa van Santbrink, Peter J. Bot, Ilze Kuiper, Johan de Jager, Saskia C. A. TI Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development SO SCIENTIFIC REPORTS LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; RECEPTOR-DEFICIENT MICE; LIPOPROTEIN-LIPASE; STROMAL CELLS; DENSITY-LIPOPROTEIN; DENDRITIC CELLS; KNOCKOUT MICE; IN-VIVO; ADIPOSE-TISSUE; MOUSE MODEL AB Mesenchymal stem cells (MSCs) have regenerative properties, but recently they were also found to have immunomodulatory capacities. We therefore investigated whether MSCs could reduce atherosclerosis, which is determined by dyslipidaemia and chronic inflammation. We adoptively transferred MSCs into low-density lipoprotein-receptor knockout mice and put these on a Western-type diet to induce atherosclerosis. Initially after treatment, we found higher levels of circulating regulatory T cells. In the long-term, overall numbers of effector T cells were reduced by MSC treatment. Moreover, MSC-treated mice displayed a significant 33% reduction in circulating monocytes and a 77% reduction of serum CCL2 levels. Most strikingly, we found a previously unappreciated effect on lipid metabolism. Serum cholesterol was reduced by 33%, due to reduced very low-density lipoprotein levels, likely a result of reduced de novo hepatic lipogenesis as determined by a reduced expression of Stearoyl-CoA desaturase-1 and lipoprotein lipase. MSCs significantly affected lesion development, which was reduced by 33% in the aortic root. These lesions contained 56% less macrophages and showed a 61% reduction in T cell numbers. We show here for the first time that MSC treatment affects not only inflammatory responses but also significantly reduces dyslipidaemia in mice. This makes MSCs a potent candidate for atherosclerosis therapies. C1 [Frodermann, Vanessa; van Duijn, Janine; van Santbrink, Peter J.; Bot, Ilze; Kuiper, Johan; de Jager, Saskia C. A.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Biopharmaceut, Leiden, Netherlands. [van Pel, Melissa] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Leiden, Netherlands. [de Jager, Saskia C. A.] Univ Med Ctr Utrecht, Lab Expt Cardiol, Utrecht, Netherlands. RP Frodermann, V (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM vfrodermann@mgh.harvard.edu FU Dutch Heart Foundation [2009B093. 2012T083]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON2011-19] FX The authors would like to thank Edith Slot for technical assistance. This work was supported by the Dutch Heart Foundation (2009B093. 2012T083); and the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences, for the GENIUS project "Generating the best evidence-based pharmaceutical targets for atherosclerosis" (CVON2011-19). NR 59 TC 3 Z9 3 U1 4 U2 10 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 OCT 22 PY 2015 VL 5 AR 15559 DI 10.1038/srep15559 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT9MA UT WOS:000363140000001 PM 26490642 ER PT J AU Seco, J Spadea, MF AF Seco, Joao Spadea, Maria Francesca TI Imaging in particle therapy: State of the art and future perspective SO ACTA ONCOLOGICA LA English DT Editorial Material ID PROTON RANGE VERIFICATION; ENERGY COMPUTED-TOMOGRAPHY; GUIDED RADIATION-THERAPY; STOPPING POWER RATIOS; PROMPT GAMMA; QUALITY-ASSURANCE; MONTE-CARLO; PROSTATE-CANCER; LUNG-CANCER; SET-UP C1 [Seco, Joao] Massachusetts Gen Hosp, Radiat Oncol, Boston, MA 02114 USA. [Seco, Joao] Harvard Univ, Sch Med, Boston, MA USA. [Spadea, Maria Francesca] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy. RP Seco, J (reprint author), Massachusetts Gen Hosp, Radiat Oncol, Boston, MA 02114 USA. EM jseco@mgh.harvard.edu NR 49 TC 1 Z9 1 U1 3 U2 9 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0284-186X EI 1651-226X J9 ACTA ONCOL JI Acta Oncol. PD OCT 21 PY 2015 VL 54 IS 9 BP 1254 EP 1258 DI 10.3109/0284186X.2015.1075665 PG 5 WC Oncology SC Oncology GA CY8QZ UT WOS:000366674700003 PM 26329760 ER PT J AU Leijenaar, RTH Carvalho, S Hoebers, FJP Aerts, HJWL Van Elmpt, WJC Huang, SH Chan, B Waldron, JN O'Sullivan, B Lambin, P AF Leijenaar, Ralph T. H. Carvalho, Sara Hoebers, Frank J. P. Aerts, Hugo J. W. L. Van Elmpt, Wouter J. C. Huang, Shao Hui Chan, Biu Waldron, John N. O'Sullivan, Brian Lambin, Philippe TI External validation of a prognostic CT-based radiomic signature in oropharyngeal squamous cell carcinoma SO ACTA ONCOLOGICA LA English DT Article ID TEXTURE ANALYSIS; TEST-RETEST; CANCER; FEATURES; HEAD; REPRODUCIBILITY; RADIOTHERAPY; VARIABILITY; SURVIVAL; IMAGES AB Background. Oropharyngeal squamous cell carcinoma (OPSCC) is one of the fastest growing disease sites of head and neck cancers. A recently described radiomic signature, based exclusively on pre-treatment computed tomography (CT) imaging of the primary tumor volume, was found to be prognostic in independent cohorts of lung and head and neck cancer patients treated in the Netherlands. Here, we further validate this signature in a large and independent North American cohort of OPSCC patients, also considering CT artifacts.Methods. A total of 542 OPSCC patients were included for which we determined the prognostic index (PI) of the radiomic signature. We tested the signature model fit in a Cox regression and assessed model discrimination with Harrell's c-index. Kaplan-Meier survival curves between high and low signature predictions were compared with a log-rank test. Validation was performed in the complete cohort (PMH1) and in the subset of patients without (PMH2) and with (PMH3) visible CT artifacts within the delineated tumor region.Results. We identified 267 (49%) patients without and 275 (51%) with visible CT artifacts. The calibration slope () on the PI in a Cox proportional hazards model was 1.27 (H-0: = 1, p = 0.152) in the PMH1 (n = 542), 0.855 (H-0: = 1, p = 0.524) in the PMH2 (n = 267) and 1.99 (H-0: = 1, p = 0.002) in the PMH3 (n = 275) cohort. Harrell's c-index was 0.628 (p = 2.72e-9), 0.634 (p = 2.7e-6) and 0.647 (p = 5.35e-6) for the PMH1, PMH2 and PMH3 cohort, respectively. Kaplan-Meier survival curves were significantly different (p < 0.05) between high and low radiomic signature model predictions for all cohorts.Conclusion. Overall, the signature validated well using all CT images as-is, demonstrating a good model fit and preservation of discrimination. Even though CT artifacts were shown to be of influence, the signature had significant prognostic power regardless if patients with CT artifacts were included. C1 [Leijenaar, Ralph T. H.; Carvalho, Sara; Hoebers, Frank J. P.; Aerts, Hugo J. W. L.; Van Elmpt, Wouter J. C.; Lambin, Philippe] Maastricht Univ Med Ctr, GROW Sch Oncol & Dev Biol, Dept Radiat Oncol MAASTRO, Maastricht, Netherlands. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Radiat Oncol, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Radiol, Boston, MA 02115 USA. [Huang, Shao Hui; Chan, Biu; Waldron, John N.; O'Sullivan, Brian] Univ Toronto, Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. RP Leijenaar, RTH (reprint author), MAASTRO Clin, Dr Tanslaan 12, NL-6229 ET Maastricht, Netherlands. EM ralph.leijenaar@maastro.nl RI Aerts, Hugo/P-6350-2015 OI Aerts, Hugo/0000-0002-2122-2003 FU QuIC-ConCePT project - EFPIA companies [115151]; QuIC-ConCePT project - Innovative Medicine Initiative Joint Undertaking (IMI JU) [115151]; Dutch technology Foundation STW, which is the applied science division of NWO [10696 DuCAT]; Ministry of Economic Affairs; National Institute of Health [NIH-USA U01 CA 143062-01, NIH-USA U01 CA 190234-01]; EU; Kankeronderzoekfonds Limburg from the Health Foundation Limburg; Dutch Cancer Society [KWF UM 2011 - 5020, KWF UM 2009 - 4454]; Alpe d'HuZes-KWF (DESIGN) FX We acknowledge financial support from the QuIC-ConCePT project, which is partly funded by EFPIA companies and the Innovative Medicine Initiative Joint Undertaking (IMI JU) under Grant Agreement No. 115151. This research is also supported by the Dutch technology Foundation STW (grant No. 10696 DuCAT), which is the applied science division of NWO, and the Technology Programme of the Ministry of Economic Affairs. We also acknowledge financial support from the National Institute of Health (NIH-USA U01 CA 143062-01, and NIH-USA U01 CA 190234-01), EU 7th framework program (EURECA, ARTFORCE), Kankeronderzoekfonds Limburg from the Health Foundation Limburg and the Dutch Cancer Society (KWF UM 2011 - 5020, KWF UM 2009 - 4454), and Alpe d'HuZes-KWF (DESIGN). NR 34 TC 10 Z9 10 U1 0 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0284-186X EI 1651-226X J9 ACTA ONCOL JI Acta Oncol. PD OCT 21 PY 2015 VL 54 IS 9 BP 1423 EP 1429 DI 10.3109/0284186X.2015.1061214 PG 7 WC Oncology SC Oncology GA CY8QZ UT WOS:000366674700026 PM 26264429 ER PT J AU Edmund, JM Andreasen, D Mahmood, F Van Leemput, K AF Edmund, Jens M. Andreasen, Daniel Mahmood, Faisal Van Leemput, Koen TI Cone beam computed tomography guided treatment delivery and planning verification for magnetic resonance imaging only radiotherapy of the brain SO ACTA ONCOLOGICA LA English DT Article ID MRI-ONLY RADIOTHERAPY; PSEUDO-CT; NECK; HEAD AB Background. Radiotherapy based on MRI only (MRI-only RT) shows a promising potential for the brain. Much research focuses on creating a pseudo computed tomography (pCT) from MRI for treatment planning while little attention is often paid to the treatment delivery. Here, we investigate if cone beam CT (CBCT) can be used for MRI-only image-guided radiotherapy (IGRT) and for verifying the correctness of the corresponding pCT.Material and methods. Six patients receiving palliative cranial RT were included in the study. Each patient had three-dimensional (3D) T1W MRI, a CBCT and a CT for reference. Further, a pCT was generated using a patch-based approach. MRI, pCT and CT were placed in the same frame of reference, matched to CBCT and the differences noted. Paired pCT-CT and pCT-CBCT data were created in bins of 10 HU and the absolute difference calculated. The data were converted to relative electron densities (RED) using the CT or a CBCT calibration curve. The latter was either based on a CBCT phantom (phan) or a paired CT-CBCT population (pop) of the five other patients.Results. Non-significant (NS) differences in the pooled CT-CBCT, MRI-CBCT and pCT-CBCT transformations were noted. The largest deviations from the CT-CBCT reference were < 1 mm and 1 degrees. The average median absolute error (MeAE) in HU was 184 34 and 299 +/- 34 on average for pCT-CT and pCT-CBCT, respectively, and was significantly different (p < 0.01) in each patient. The average MeAE in RED was 0.108 +/- 0.025, 0.104 +/- 0.011 and 0.099 +/- 0.017 for pCT-CT, pCT-CBCT phan (p < 0.01 on 2 patients) and pCT-CBCT pop (NS), respectively.Conclusions. CBCT can be used for patient setup with either MRI or pCT as reference. The correctness of pCT can be verified from CBCT using a population-based calibration curve in the treatment geometry. C1 [Edmund, Jens M.; Andreasen, Daniel; Mahmood, Faisal] Univ Copenhagen, Gentofte & Herlev Hosp, Dept Oncol, Radiotherapy Res Unit, Herlev, Denmark. [Andreasen, Daniel; Van Leemput, Koen] Tech Univ Denmark, DTU Compute, DK-2800 Lyngby, Denmark. [Van Leemput, Koen] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Edmund, JM (reprint author), Univ Copenhagen, Gentofte & Herlev Hosp, Dept Oncol, Radiotherapy Res Unit, Herlev, Denmark. EM jens.edmund@regionh.dk RI Van Leemput, Koen/A-9197-2009; OI Van Leemput, Koen/0000-0001-6466-5309; Mahmood, Faisal/0000-0002-7270-7967 NR 16 TC 5 Z9 5 U1 2 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0284-186X EI 1651-226X J9 ACTA ONCOL JI Acta Oncol. PD OCT 21 PY 2015 VL 54 IS 9 BP 1496 EP 1500 DI 10.3109/0284186X.2015.1062546 PG 5 WC Oncology SC Oncology GA CY8QZ UT WOS:000366674700036 PM 26198652 ER PT J AU Hansen, DC Seco, J Sorensen, TS Petersen, JBB Wildberger, JE Verhaegen, F Landry, G AF Hansen, David C. Seco, Joao Sorensen, Thomas Sangild Petersen, Jorgen Breede Baltzer Wildberger, Joachim E. Verhaegen, Frank Landry, Guillaume TI A simulation study on proton computed tomography ( CT) stopping power accuracy using dual energy CT scans as benchmark SO ACTA ONCOLOGICA LA English DT Article ID MONTE-CARLO SIMULATIONS; MODEL-BASED APPROACH; EXPERIMENTAL-VERIFICATION; TISSUE SURROGATES; RADIOTHERAPY; CALIBRATION; NUMBERS; UNCERTAINTIES; PREDICTION; SELECTION AB Background. Accurate stopping power estimation is crucial for treatment planning in proton therapy, and the uncertainties in stopping power are currently the largest contributor to the employed dose margins. Dual energy x-ray computed tomography (CT) (clinically available) and proton CT (in development) have both been proposed as methods for obtaining patient stopping power maps. The purpose of this work was to assess the accuracy of proton CT using dual energy CT scans of phantoms to establish reference accuracy levels.Material and methods. A CT calibration phantom and an abdomen cross section phantom containing inserts were scanned with dual energy and single energy CT with a state-of-the-art dual energy CT scanner. Proton CT scans were simulated using Monte Carlo methods. The simulations followed the setup used in current prototype proton CT scanners and included realistic modeling of detectors and the corresponding noise characteristics. Stopping power maps were calculated for all three scans, and compared with the ground truth stopping power from the phantoms.Results. Proton CT gave slightly better stopping power estimates than the dual energy CT method, with root mean square errors of 0.2% and 0.5% (for each phantom) compared to 0.5% and 0.9%. Single energy CT root mean square errors were 2.7% and 1.6%. Maximal errors for proton, dual energy and single energy CT were 0.51%, 1.7% and 7.4%, respectively.Conclusion. Better stopping power estimates could significantly reduce the range errors in proton therapy, but requires a large improvement in current methods which may be achievable with proton CT. C1 [Hansen, David C.] Aarhus Univ Hosp, Dept Oncol, DK-8000 Aarhus, Denmark. [Seco, Joao] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Seco, Joao] Harvard Univ, Sch Med, Boston, MA USA. [Sorensen, Thomas Sangild] Aarhus Univ, Dept Clin Med, Aarhus, Denmark. [Petersen, Jorgen Breede Baltzer] Aarhus Univ Hosp, Dept Med Phys, Aarhus, Denmark. [Wildberger, Joachim E.] Maastricht Univ, Med Ctr MUMC, Dept Radiol, NL-6200 MD Maastricht, Netherlands. [Verhaegen, Frank; Landry, Guillaume] Maastricht Univ, Med Ctr MUMC, Dept Radiat Oncol MAASTRO, NL-6200 MD Maastricht, Netherlands. [Verhaegen, Frank] McGill Univ, Dept Oncol, Med Phys Unit, Montreal, PQ, Canada. [Landry, Guillaume] Univ Munich, Dept Med Phys, Fac Phys, Munich, Germany. RP Hansen, DC (reprint author), Norrebrogade 44,Bldg 5, DK-8000 Aarhus, Denmark. EM daviha@rm.dk OI Sorensen, Thomas Sangild/0000-0002-8482-7667 FU Lundbeck Centre for Interventional Research in Radiation Oncology (CIRRO) FX This work was sponsored by the Lundbeck Centre for Interventional Research in Radiation Oncology (CIRRO). Bjarne Thomsen, Department of Physics and Astronomy, Aarhus University is thanked for providing cluster computing time. NR 27 TC 6 Z9 6 U1 1 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0284-186X EI 1651-226X J9 ACTA ONCOL JI Acta Oncol. PD OCT 21 PY 2015 VL 54 IS 9 BP 1638 EP 1642 DI 10.3109/0284186X.2015.1061212 PG 5 WC Oncology SC Oncology GA CY8QZ UT WOS:000366674700055 PM 26219959 ER PT J AU Jablonski, AM Lamitina, T Liachko, NF Sabatella, M Lu, JY Zhang, L Ostrow, LW Gupta, P Wu, CY Doshi, S Mojsilovic-Petrovic, J Lans, H Wang, J Kraemer, B Kalb, RG AF Jablonski, Angela M. Lamitina, Todd Liachko, Nicole F. Sabatella, Mariangela Lu, Jiayin Zhang, Lei Ostrow, Lyle W. Gupta, Preetika Wu, Chia-Yen Doshi, Shachee Mojsilovic-Petrovic, Jelena Lans, Hannes Wang, Jiou Kraemer, Brian Kalb, Robert G. TI Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance SO JOURNAL OF NEUROSCIENCE LA English DT Article DE aging; ALS; motor neuron disease; neurodegeneration; proteotoxicity; RAD-23 ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; RETICULUM-ASSOCIATED DEGRADATION; UBIQUITIN-PROTEASOME SYSTEM; SELECTIVE ER STRESS; DNA-REPAIR; WILD-TYPE; CAENORHABDITIS-ELEGANS; TRANSGENIC MICE; SACCHAROMYCES-CEREVISIAE AB Misfolded proteins accumulate and aggregate in neurodegenerative disease. The existence of these deposits reflects a derangement in the protein homeostasis machinery. Using a candidate gene screen, we report that loss of RAD-23 protects against the toxicity of proteins known to aggregate in amyotrophic lateral sclerosis. Loss of RAD-23 suppresses the locomotor deficit of Caenorhabditis elegans engineered to express mutTDP-43 or mutSOD1 and also protects against aging and proteotoxic insults. Knockdown of RAD-23 is further neuroprotective against the toxicity of SOD1 and TDP-43 expression in mammalian neurons. Biochemical investigation indicates that RAD-23 modifies mutTDP-43 and mutSOD1 abundance, solubility, and turnover in association with altering the ubiquitination status of these substrates. In human amyotrophic lateral sclerosis spinal cord, we find that RAD-23 abundance is increased and RAD-23 is mislocalized within motor neurons. We propose a novel pathophysiological function for RAD-23 in the stabilization of mutated proteins that cause neurodegeneration. C1 [Jablonski, Angela M.; Gupta, Preetika; Doshi, Shachee] Univ Penn, Perelman Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA. [Zhang, Lei; Wu, Chia-Yen; Mojsilovic-Petrovic, Jelena; Kalb, Robert G.] Childrens Hosp Philadelphia, Res Inst, Div Neurol, Dept Pediat, Philadelphia, PA 19104 USA. [Kalb, Robert G.] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Lamitina, Todd] Univ Pittsburgh, Med Ctr, Dept Pediat & Cell Biol, Pittsburgh, PA 15213 USA. [Liachko, Nicole F.] Univ Washington, Dept Med, Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98195 USA. [Sabatella, Mariangela; Lans, Hannes; Kraemer, Brian] Erasmus MC, Canc Genom Inst, Dept Genet, NL-3015 CN Rotterdam, Netherlands. [Lu, Jiayin; Wang, Jiou] Johns Hopkins Univ, Sch Med, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. [Ostrow, Lyle W.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Kalb, RG (reprint author), Childrens Hosp Philadelphia, Res Inst, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM kalb@email.chop.edu RI Lans, Hannes/C-9902-2016 OI Lans, Hannes/0000-0003-4417-5358 FU NIH [R01-NS052325, R21-NS077909, F31-NS07726]; FP7 Marie Curie International Training Network Address [316390]; National Institutes of Health Office of Research Infrastructure Programs [P40-OD010440]; National Bioresource Project FX This work was supported by NIH Grants R01-NS052325 and R21-NS077909 to R.G.K., F31-NS07726 to A.M.J., and FP7 Marie Curie International Training Network Address 316390 to M.S. The RAD-23 fosmid was obtained from the C. elegans TransgeneOme project. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by National Institutes of Health Office of Research Infrastructure Programs P40-OD010440, and the National Bioresource Project for the Nematode. We thank Ulrich Hartl for the CPY*-GFP plasmid; Steven Grossman for the RAD-23 plasmids; Johns Ravits and Jeff Rothstein for providing human tissue; Maria Lim, Elizabeth Morton, Zissimos Mourelatos, and Predrag Krajacic for assistance; the Target ALS Human Postmortem Tissue Core for providing postmortem tissue samples; and Harry Ischiropolous, Kelly Jordan- Sciutto, Alice Chen-Plotkin, and Raymond Roos for guidance and helpful discussion. NR 91 TC 1 Z9 1 U1 3 U2 6 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 OCT 21 PY 2015 VL 35 IS 42 BP 14286 EP 14306 DI 10.1523/JNEUROSCI.0642-15.2015 PG 21 WC Neurosciences SC Neurosciences & Neurology GA CX9VB UT WOS:000366052700017 PM 26490867 ER PT J AU Pfeifer, CG Fisher, MB Carey, JL Mauck, RL AF Pfeifer, Christian G. Fisher, Matthew B. Carey, James L. Mauck, Robert L. TI Impact of guidance documents on translational large animal studies of cartilage repair SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID KNEE ARTHROSCOPIES; ENGINEERED CARTILAGE; DEFECTS; TISSUE; MODELS; TRANSPLANTATION; IMPLANTATION; OUTCOMES AB Promising therapies for cartilage repair are translated through large animal models toward human application. To guide this work, regulatory agencies publish recommendations ("guidance documents") to direct pivotal large animal studies. These are meant to aid in study design, outline metrics for judging efficacy, and facilitate comparisons between studies. To determine the penetrance of these documents in the field, we synthesized the recommendations of the American Society for Testing and Materials, U.S. Food and Drug Administration, and European Medicines Agency into a scoring system and performed a systematic review of the past 20 years of preclinical cartilage repair studies. Our hypothesis was that the guidance documents would have a significant impact on how large animal cartilage repair studies were performed. A total of 114 publications meeting our inclusion criteria were reviewed for adherence to 24 categories extracted from the guidance documents, including 11 related to study design and description and 13 related to study outcomes. Overall, a weak positive trend was observed over time (P = 0.004, R-2 = 0.07, slope = 0.63%/year), with overall adherence (the sum of study descriptors and outcomes) ranging from 32 +/- 16% to 58 +/- 14% in any individual year. There was no impact of the publication of the guidance documents on adherence (P = 0.264 to 0.50). Given that improved adherence would expedite translation, we discuss the reasons for poor adherence and outline approaches to increase and promote their more widespread adoption. C1 [Pfeifer, Christian G.; Fisher, Matthew B.; Carey, James L.; Mauck, Robert L.] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. [Pfeifer, Christian G.; Fisher, Matthew B.; Carey, James L.; Mauck, Robert L.] Philadelphia Vet Affairs Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA 19104 USA. [Pfeifer, Christian G.] Univ Regensburg, Med Ctr, Dept Trauma Surg, D-93053 Regensburg, Germany. [Fisher, Matthew B.] Univ N Carolina, Joint Dept Biomed Engn, Chapel Hill, NC 27599 USA. [Fisher, Matthew B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Mauck, Robert L.] AO Fdn, Acute Cartilage Injury Program, CH-7270 Davos, Switzerland. RP Mauck, RL (reprint author), Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. EM lemauck@mail.med.upenn.edu RI Fisher, Matthew/M-5809-2016 OI Fisher, Matthew/0000-0002-3212-0870 FU AO Foundation; U.S. NIH [R01 EB008722]; U.S. Department of Veterans Affairs [I01 RX000700]; Deutsche Forschungsgemeinschaft (DFG) FX This work was supported by the AO Foundation, the U.S. NIH (R01 EB008722), the U.S. Department of Veterans Affairs (I01 RX000700), and the Deutsche Forschungsgemeinschaft (DFG). NR 35 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 21 PY 2015 VL 7 IS 310 AR 310re9 DI 10.1126/scitranslmed.aac7019 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CY4BA UT WOS:000366352400006 PM 26491080 ER PT J AU Schoellhammer, CM Schroeder, A Maa, R Lauwers, GY Swiston, A Zervas, M Barman, R DiCiccio, AM Brugge, WR Anderson, DG Blankschtein, D Langer, R Traverso, G AF Schoellhammer, Carl M. Schroeder, Avi Maa, Ruby Lauwers, Gregory Yves Swiston, Albert Zervas, Michael Barman, Ross DiCiccio, Angela M. Brugge, William R. Anderson, Daniel G. Blankschtein, Daniel Langer, Robert Traverso, Giovanni TI Ultrasound-mediated gastrointestinal drug delivery SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; ULCERATIVE-COLITIS; 5-AMINOSALICYLIC ACID; CAVITATION; DIFFUSION; MEMBRANE; THERAPY; NANOPARTICLE; MOLECULES; BUBBLES AB There is a significant clinical need for rapid and efficient delivery of drugs directly to the site of diseased tissues for the treatment of gastrointestinal (GI) pathologies, in particular, Crohn's and ulcerative colitis. However, complex therapeutic molecules cannot easily be delivered through the GI tract because of physiologic and structural barriers. We report the use of ultrasound as a modality for enhanced drug delivery to the GI tract, with an emphasis on rectal delivery. Ultrasound increased the absorption of model therapeutics inulin, hydrocortisone, and mesalamine two-to tenfold in ex vivo tissue, depending on location in the GI tract. In pigs, ultrasound induced transient cavitation with negligible heating, leading to an order of magnitude enhancement in the delivery of mesalamine, as well as successful systemic delivery of a macromolecule, insulin, with the expected hypoglycemic response. In a rodent model of chemically induced acute colitis, the addition of ultrasound to a daily mesalamine enema (compared to enema alone) resulted in superior clinical and histological scores of disease activity. In both animal models, ultrasound treatment was well tolerated and resulted in minimal tissue disruption, and in mice, there was no significant effect on histology, fecal score, or tissue inflammatory cytokine levels. The use of ultrasound to enhance GI drug delivery is safe in animals and could augment the efficacy of GI therapies and broaden the scope of agents that could be delivered locally and systemically through the GI tract for chronic conditions such as inflammatory bowel disease. C1 [Schoellhammer, Carl M.; Schroeder, Avi; Maa, Ruby; Swiston, Albert; Anderson, Daniel G.; Blankschtein, Daniel; Langer, Robert; Traverso, Giovanni] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Schoellhammer, Carl M.; Schroeder, Avi; Barman, Ross; DiCiccio, Angela M.; Anderson, Daniel G.; Langer, Robert; Traverso, Giovanni] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Schroeder, Avi] Technion Israel Inst Technol, Fac Chem Engn, IL-32000 Haifa, Israel. [Lauwers, Gregory Yves] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zervas, Michael] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Brugge, William R.; Traverso, Giovanni] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Anderson, Daniel G.; Langer, Robert] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Anderson, Daniel G.; Langer, Robert] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Blankschtein, D (reprint author), MIT, Dept Chem Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM dblank@mit.edu; rlanger@mit.edu; ctraverso@partners.org OI Schoellhammer, Carl/0000-0001-6694-6761; Schroeder, Avi/0000-0003-2571-5937 FU NIH [EB-00351, EB-000244, CA014051, T32-DK007191-38-S1]; Max Planck Research Award; Alexander von Humboldt-Stiftung Foundation FX This work was funded by the NIH (grant nos. EB-00351, EB-000244, and CA014051) and the Max Planck Research Award, Award Ltr Dtd. 2/11/08, Alexander von Humboldt-Stiftung Foundation (to R.L.). G.T. was supported in part by NIH grant T32-DK007191-38-S1. NR 40 TC 10 Z9 10 U1 7 U2 24 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 21 PY 2015 VL 7 IS 310 AR 310ra168 DI 10.1126/scitranslmed.aaa5937 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CY4BA UT WOS:000366352400004 PM 26491078 ER PT J AU Santos, A Fernandez-Friera, L Villalba, M Lopez-Melgar, B Espana, S Mateo, J Mota, RA Jimenez-Borreguero, J Ruiz-Cabello, J AF Santos, Arnoldo Fernandez-Friera, Leticia Villalba, Maria Lopez-Melgar, Beatriz Espana, Samuel Mateo, Jesus Mota, Ruben A. Jimenez-Borreguero, Jesus Ruiz-Cabello, Jesus TI Cardiovascular imaging: what have we learned from animal models? SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE animal models; biomedical imaging; heart failure; myocardial infarction; pulmonary hypertension; atherosclerosis ID CARDIAC MAGNETIC-RESONANCE; ACUTE MYOCARDIAL-INFARCTION; PULMONARY ARTERIAL-HYPERTENSION; VENTRICULAR DIASTOLIC FUNCTION; POSITRON-EMISSION-TOMOGRAPHY; ISCHEMIA-REPERFUSION INJURY; IN-VIVO ASSESSMENT; HIGH-RESOLUTION ECHOCARDIOGRAPHY; AMERICAN-HEART-ASSOCIATION; ROW COMPUTED-TOMOGRAPHY AB Cardiovascular imaging has become an indispensable tool for patient diagnosis and follow up. Probably the wide clinical applications of imaging are due to the possibility of a detailed and high quality description and quantification of cardiovascular system structure and function. Also phenomena that involve complex physiological mechanisms and biochemical pathways, such as inflammation and ischemia, can be visualized in a non-destructive way. The widespread use and evolution of imaging would not have been possible without animal studies. Animal models have allowed for instance, (i) the technical development of different imaging tools, (ii) to test hypothesis generated from human studies and finally, (vi) to evaluate the translational relevance assessment of in vitro and ex-vivo results. In this review, we will critically describe the contribution of animal models to the use of biomedical imaging in cardiovascular medicine. We will discuss the characteristics of the most frequent models used in/for imaging studies. We will cover the major findings of animal studies focused in the cardiovascular use of the repeatedly used imaging techniques in clinical practice and experimental studies. We will also describe the physiological findings and/or learning processes for imaging applications coming from models of the most common cardiovascular diseases. In these diseases, imaging research using animals has allowed the study of aspects such as: ventricular size, shape, global function, and wall thickening, local myocardial function, myocardial perfusion, metabolism and energetic assessment, infarct quantification, vascular lesion characterization, myocardial fiber structure, and myocardial calcium uptake. Finally we will discuss the limitations and future of imaging research with animal models. C1 [Santos, Arnoldo; Fernandez-Friera, Leticia; Villalba, Maria; Lopez-Melgar, Beatriz; Espana, Samuel; Mateo, Jesus; Mota, Ruben A.; Jimenez-Borreguero, Jesus; Ruiz-Cabello, Jesus] Ctr Nacl Invest Cardiovasc Carlos III, Madrid, Spain. [Santos, Arnoldo; Espana, Samuel; Mateo, Jesus; Ruiz-Cabello, Jesus] CIBERES, Madrid, Spain. [Santos, Arnoldo; Espana, Samuel] Madrid MIT M Vis Consortium, Madrid, Spain. [Santos, Arnoldo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia, Boston, MA USA. [Fernandez-Friera, Leticia; Lopez-Melgar, Beatriz] Hosp Univ HM Monteprincipe, Madrid, Spain. [Mota, Ruben A.] Charles River, Barcelona, Spain. [Jimenez-Borreguero, Jesus] Hosp La Princesa, Cardiac Imagina Dept, Madrid, Spain. [Ruiz-Cabello, Jesus] Univ Complutense Madrid, Madrid, Spain. RP Ruiz-Cabello, J (reprint author), Ctr Nacl Invest Cardiovasc Carlos III, Madrid, Spain. EM ruizcabe@cnic.es RI Villalba-Orero, Maria/B-6765-2016; Ruiz-Cabello, Jesus/A-9570-2012; Espana, Samuel/E-9240-2010; OI Ruiz-Cabello, Jesus/0000-0001-8681-5056; Espana, Samuel/0000-0001-9092-4597; Villalba Orero, Maria/0000-0002-7680-3980 FU Consejeria de Educacion, juventud y Deporte of Comunidad de Madrid and the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7) under REA grant [291820] FX AS and SE are M+Vision COFUND Advanced Fellows and have received funding from Consejeria de Educacion, juventud y Deporte of Comunidad de Madrid and the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no 291820. NR 208 TC 1 Z9 1 U1 3 U2 14 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD OCT 21 PY 2015 VL 6 AR 227 DI 10.3389/fphar.2015.00227 PG 25 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CX9UI UT WOS:000366050800001 PM 26539113 ER PT J AU Kumar, S Fenwick, JD Underwood, TSA Deshpande, DD Scott, AJD Nahum, AE AF Kumar, Sudhir Fenwick, John D. Underwood, Tracy S. A. Deshpande, Deepak D. Scott, Alison J. D. Nahum, Alan E. TI Breakdown of Bragg-Gray behaviour for low-density detectors under electronic disequilibrium conditions in small megavoltage photon fields SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE Bragg-Gray breakdown; PinPoint and SCDDo detectors; electron fluence perturbation; non-equilibrium photon fields; Monte Carlo ID MONTE-CARLO CODE; STOPPING-POWER RATIOS; LINEAR ACCELERATORS; REFERENCE DOSIMETRY; DIAMOND DOSIMETER; SPOT SIZE; BEAMS; PERTURBATION; CHAMBER; RADIOTHERAPY AB In small photon fields ionisation chambers can exhibit large deviations from Bragg-Gray behaviour; the EGSnrc Monte Carlo (MC) code system has been employed to investigate this 'Bragg-Gray breakdown'. The total electron (+positron) fluence in small water and air cavities in a water phantom has been computed for a full linac beam model as well as for a point source spectrum for 6 MV and 15 MV qualities for field sizes from 0.25 x 0.25 cm(2) to 10 x 10 cm(2). A water-to-air perturbation factor has been derived as the ratio of total electron (+ positron) fluence, integrated over all energies, in a tiny water volume to that in a 'PinPoint 3D-chamber-like' air cavity; for the 0.25 x 0.25 cm(2) field size the perturbation factors are 1.323 and 2.139 for 6 MV and 15 MV full linac geometries respectively. For the 15 MV full linac geometry for field sizes of 1 x 1 cm(2) and smaller not only the absolute magnitude but also the 'shape' of the total electron fluence spectrum in the air cavity is significantly different to that in the water 'cavity'. The physics of this 'Bragg-Gray breakdown' is fully explained, making reference to the Fano theorem. For the 15 MV full linac geometry in the 0.25 x 0.25 cm(2) field the directly computed MC dose ratio, water-to-air, differs by 5% from the product of the Spencer-Attix stopping-power ratio (SPR) and the perturbation factor; this 'difference' is explained by the difference in the shapes of the fluence spectra and is also formulated theoretically. We show that the dimensions of an air-cavity with a perturbation factor within 5% of unity would have to be impractically small in these highly non-equilibrium photon fields. In contrast the dose to water in a 0.25 x 0.25 cm(2) field derived by multiplying the dose in the single-crystal diamond dosimeter (SCDDo) by the Spencer-Attix ratio is within 2.9% of the dose computed directly in the water voxel for full linac geometry at both 6 and 15 MV, thereby demonstrating that this detector exhibits quasi Bragg-Gray behaviour over a wide range of field sizes and beam qualities. C1 [Kumar, Sudhir; Nahum, Alan E.] Clatterbridge Canc Ctr, Dept Phys, Bebington CH63 4JY, England. [Kumar, Sudhir; Nahum, Alan E.] Univ Liverpool, Dept Phys, Liverpool L69 7ZE, Merseyside, England. [Kumar, Sudhir] Bhabha Atom Res Ctr, Radiol Phys & Advisory Div, Bombay 400094, Maharashtra, India. [Kumar, Sudhir; Deshpande, Deepak D.] Homi Bhabha Natl Inst, Bombay 400094, Maharashtra, India. [Deshpande, Deepak D.] Tata Mem Hosp, Dept Med Phys, Bombay 400012, Maharashtra, India. [Fenwick, John D.] Univ Oxford, Gray Inst Radiat Oncol & Biol, Dept Oncol, Oxford, England. [Underwood, Tracy S. A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Phys Res, Boston, MA 02116 USA. [Scott, Alison J. D.] Sir Charles Gairdner Hosp, Dept Radiat Oncol, Perth, WA 6009, Australia. RP Kumar, S (reprint author), Clatterbridge Canc Ctr, Dept Phys, Bebington CH63 4JY, England. EM sktomar1@yahoo.co.in; alan.nahum@clatterbridgecc.nhs.uk FU Commonwealth Scholarship - Commonwealth Scholarship Commission, UK [INCN-2010-42]; Clatterbridge Cancer Centre Charity FX We wish to thank the referees for their constructive and insightful criticisms which have resulted in significant improvements. The authors are grateful to Professor Philip Mayles, former head of the Department of Physics, Clatterbridge Cancer Centre (CCC) for his support during this work. We wish to thank Professor Frank Verhaegen, Maastro Clinic, Netherlands for insightful comments on the manuscript. The authors are also grateful to Professor Pedro Andreo, Stockholm University, Dr David Burns, BIPM, and Professor Jan Seuntjens, McGill University, Canada, for useful discussions during the development of this work. Thanks are also due to Dr Colin Baker, Dr Antony Carver, Dhvanil Karia and Georgios Georgiou for creating the friendly and helpful atmosphere of the CCC Physics research group and to the CCC IT section for their expertise. The authors are grateful to Varian Medical Systems for providing the geometrical details of the Varian linac used to create the Monte Carlo models. SK expresses his gratitude to Drs S D Sharma, D Datta, Pradeepkumar K S, Associate Director, HS & EG, Bhabha Atomic Research Centre (BARC), Mumbai, India, D N Sharma, former Director, HS & EG, BARC, H S Kushwaha, former Director, HS & EG, BARC and Raja Ramanna Fellow, Department of Atomic Energy, India and A N Nandakumar, former Head, RSD, AERB, Mumbai, India for their encouragement and support. SK was funded by Commonwealth Scholarship: INCN-2010-42 awarded by the Commonwealth Scholarship Commission, UK during 2010-11 and by funds awarded by 'Clatterbridge Cancer Centre Charity', for the period December 2014-February 2015. NR 56 TC 6 Z9 6 U1 1 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2015 VL 60 IS 20 BP 8187 EP 8212 DI 10.1088/0031-9155/60/20/8187 PG 26 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CW3SZ UT WOS:000364913500024 PM 26439724 ER PT J AU Huang, C Ouyang, J Reese, TG Wu, Y El Fakhri, G Ackerman, JL AF Huang, C. Ouyang, J. Reese, T. G. Wu, Y. El Fakhri, G. Ackerman, J. L. TI Continuous MR bone density measurement using water- and fat-suppressed projection imaging (WASPI) for PET attenuation correction in PET-MR SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE PET-MR; attenuation correction; bone imaging ID PARTIAL VOLUME CORRECTION; WHOLE-BODY; IN-VIVO; TIME; SEGMENTATION; TOMOGRAPHY; MATRIX; MOTION; CT; COMPENSATION AB Due to the lack of signal from solid bone in normal MR sequences for the purpose of MR-based attenuation correction, investigators have proposed using the ultrashort echo time (UTE) pulse sequence, which yields signal from bone. However, the UTE-based segmentation approach might not fully capture the intra-and inter-subject bone density variation, which will inevitably lead to bias in reconstructed PET images. In this work, we investigated using the water-and fat-suppressed proton projection imaging (WASPI) sequence to obtain accurate and continuous attenuation for bones. This approach is capable of accounting for intra-and inter-subject bone attenuation variations. Using data acquired from a phantom, we have found that that attenuation correction based on the WASPI sequence is more accurate and precise when compared to either conventional MR attenuation correction or UTE-based segmentation approaches. C1 [Huang, C.; Ouyang, J.; El Fakhri, G.] Massachusetts Gen Hosp, Dept Imaging, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. [Huang, C.; Ouyang, J.; Reese, T. G.; Wu, Y.; El Fakhri, G.; Ackerman, J. L.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Huang, C.] Stony Brook Med, Dept Radiol, Stony Brook, NY 11794 USA. [Huang, C.] Stony Brook Med, Dept Psychiat, Stony Brook, NY 11794 USA. [Reese, T. G.; Ackerman, J. L.] Massachusetts Gen Hosp, Dept Imaging, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Wu, Y.] Boston Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Huang, C (reprint author), Massachusetts Gen Hosp, Dept Imaging, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. EM chuan.huang@stonybrookmedicine.edu OI Ackerman, Jerome/0000-0001-5176-7496 FU NIH [R03-MH106994, R21-EB012326, R01-CA165221, R01-HL110241, R01-HL118261]; Athinoula A Martinos Center for Biomedical Imaging, the Imaging Sciences Training Program at the National Institutes of Health; Center for Functional Neuroimaging Technologies (NIH) [P41-EB015896] FX This research was supported in part by NIH grants R03-MH106994, R21-EB012326, R01-CA165221, R01-HL110241, R01-HL118261, the Athinoula A Martinos Center for Biomedical Imaging, the Imaging Sciences Training Program at the National Institutes of Health, and the Center for Functional Neuroimaging Technologies (funded by NIH grant P41-EB015896). NR 52 TC 1 Z9 1 U1 0 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2015 VL 60 IS 20 BP N369 EP N381 DI 10.1088/0031-9155/60/20/N369 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CW3SZ UT WOS:000364913500001 PM 26405761 ER PT J AU Miller, MA Gadde, S Pfirschke, C Engblom, C Sprachman, MM Kohler, RH Yang, KS Laughney, AM Wojtkiewicz, G La Kamaly, N Bhonagiri, S Pittet, MJ Farokhzad, OC Weissleder, R AF Miller, Miles A. Gadde, Suresh Pfirschke, Christina Engblom, Camilla Sprachman, Melissa M. Kohler, Rainer H. Yang, Katherine S. Laughney, Ashley M. Wojtkiewicz, Gregory La Kamaly, Nazi Bhonagiri, Sushma Pittet, Mikael J. Farokhzad, Omid C. Weissleder, Ralph TI Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID IN-VIVO; DRUG-DELIVERY; LIPOSOMAL DOXORUBICIN; VASCULAR-PERMEABILITY; LUNG-CANCER; CELL; TUMORS; SIZE; ACCUMULATION; FERUMOXYTOL AB Therapeutic nanoparticles (TNPs) have shown heterogeneous responses in human clinical trials, raising questions of whether imaging should be used to identify patients with a higher likelihood of NP accumulation and thus therapeutic response. Despite extensive debate about the enhanced permeability and retention (EPR) effect in tumors, it is increasingly clear that EPR is extremely variable; yet, little experimental data exist to predict the clinical utility of EPR and its influence on TNP efficacy. We hypothesized that a 30-nm magnetic NP (MNP) in clinical use could predict colocalization of TNPs by magnetic resonance imaging (MRI). To this end, we performed single-cell resolution imaging of fluorescently labeled MNPs and TNPs and studied their intratumoral distribution in mice. MNPs circulated in the tumor microvasculature and demonstrated sustained uptake into cells of the tumor microenvironment within minutes. MNPs could predictably demonstrate areas of colocalization for a model TNP, poly(D,L-lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG), within the tumor microenvironment with >85% accuracy and circulating within the microvasculature with >95% accuracy, despite their markedly different sizes and compositions. Computational analysis of NP transport enabled predictive modeling of TNP distribution based on imaging data and identified key parameters governing intratumoral NP accumulation and macrophage uptake. Finally, MRI accurately predicted initial treatment response and drug accumulation in a preclinical efficacy study using a paclitaxel-encapsulated NP in tumor-bearing mice. These approaches yield valuable insight into the in vivo kinetics of NP distribution and suggest that clinically relevant imaging modalities and agents can be used to select patients with high EPR for treatment with TNPs. C1 [Miller, Miles A.; Pfirschke, Christina; Engblom, Camilla; Sprachman, Melissa M.; Kohler, Rainer H.; Yang, Katherine S.; Laughney, Ashley M.; Wojtkiewicz, Gregory; Pittet, Mikael J.; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Miller, Miles A.; Kohler, Rainer H.; Pittet, Mikael J.; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gadde, Suresh; La Kamaly, Nazi; Bhonagiri, Sushma; Farokhzad, Omid C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Lab Nanomed & Biomat,Dept Anesthesiol, Boston, MA 02115 USA. [Farokhzad, Omid C.] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Farokhzad, OC (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Lab Nanomed & Biomat,Dept Anesthesiol, Boston, MA 02115 USA. EM ofarokhzad@bwh.harvard.edu; rweissleder@mgh.harvard.edu FU NIH [R01CA164448, U54-CA151884, 5P50CA086355, HL084312]; DoD [PC140318]; David H. Koch-Prostate Cancer Foundation Award in Nanotherapeutics; Deutsche Forschungsgemeinschaft (DFG) [PF809/1-1]; [T32 CA 79443] FX We thank A. Zaltsman, D. Pirovich, M. Sebas, O. Kister, N. Sergeyev, K. King, and Y. Iwamoto for technical assistance; S. Lippard and Y. Zheng for helpful discussions. Funding: This work was supported in part by the NIH (R01CA164448, U54-CA151884,5P50CA086355, and HL084312), DoD (PC140318), and the David H. Koch-Prostate Cancer Foundation Award in Nanotherapeutics. M.A.M. was supported by T32 CA 79443. C.P. is in part supported by Deutsche Forschungsgemeinschaft (DFG) PF809/1-1. NR 38 TC 0 Z9 0 U1 4 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 21 PY 2015 VL 7 IS 310 AR 314ra183 DI 10.1126/scitranslmed.aac6522 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CW8FV UT WOS:000365235800006 ER PT J AU Cai, HL Tan, QY Jiang, P Dang, RL Xue, Y Tang, MM Xu, P Deng, Y Li, HD Yao, JK AF Cai, H. L. Tan, Q. Y. Jiang, P. Dang, R. L. Xue, Y. Tang, M. M. Xu, P. Deng, Y. Li, H. D. Yao, J. K. TI A potential mechanism underlying atypical antipsychotics-induced lipid disturbances SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID INDUCED WEIGHT-GAIN; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; BODY-WEIGHT; METABOLIC SYNDROME; ANIMAL-MODEL; DOUBLE-BLIND; PROTEIN; RATS; SCHIZOPHRENIA; EXPRESSION AB Previous findings suggested that a four-protein complex, including sterol-regulatory element-binding protein (SREBP), SREBP-cleavage- activating protein (SCAP), insulin-induced gene (INSIG) and progesterone receptor membrane component 1 (PGRMC1), within the endoplasmic reticulum appears to be an important regulator responsible for atypical antipsychotic drug (AAPD)-induced lipid disturbances. In the present study, effects of typical antipsychotic drug and AAPDs as well as treatment outcome of steroid antagonist mifepristone (MIF) on the PGRMC1/INSIG/SCAP/SREBP pathway were investigated in rat liver using real-time quantitative polymerase chain reaction (qPCR) and western blot analysis. In addition, serum triacylglycerol, total cholesterol, free fatty acids and various hormones including progesterone, corticosterone and insulin were measured simultaneously. Following treatment with clozapine or risperidone, both lipogenesis and cholesterogenesis were enhanced via inhibition of PGRMC1/INSIG-2 and activation of SCAP/SREBP expressions. Such metabolic disturbances, however, were not demonstrated in rats treated with aripiprazole (ARI) or haloperidol (HAL). Moreover, the add-on treatment of MIF was effective in reversing the AAPD-induced lipid disturbances by upregulating the expression of PGRMC1/INSIG-2 and subsequent downregulation of SCAP/SREBP. Taken together, our findings suggest that disturbances in lipid metabolism can occur at an early stage of AAPD treatment before the presence of weight gain. Such metabolic defects can be modified by an add-on treatment of steroid antagonist MIF enhancing the PGRMC1 pathway. Thus, it is likely that PGRMC1/INSIG-2 signaling may be a therapeutic target for AAPD-induced weight gain. C1 [Cai, H. L.; Jiang, P.; Dang, R. L.; Xue, Y.; Tang, M. M.; Xu, P.; Deng, Y.; Li, H. D.] Cent S Univ, Xiangya Hosp 2, Dept Pharm, Changsha 410011, Hunan, Peoples R China. [Cai, H. L.; Jiang, P.; Dang, R. L.; Xue, Y.; Tang, M. M.; Xu, P.; Deng, Y.; Li, H. D.] Cent S Univ, Inst Clin Pharm, Changsha 410011, Hunan, Peoples R China. [Cai, H. L.; Yao, J. K.] Univ Pittsburgh, Dept Pharmaceut Sci, Sch Pharm, Pittsburgh, PA 15240 USA. [Cai, H. L.; Yao, J. K.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA 15240 USA. [Tan, Q. Y.] Guilin Med Univ, Sch Pharm, Guilin, Peoples R China. [Jiang, P.; Dang, R. L.; Xue, Y.; Tang, M. M.] Cent S Univ, Sch Pharm, Changsha 410011, Hunan, Peoples R China. [Yao, J. K.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15240 USA. RP Li, HD (reprint author), Cent S Univ, Xiangya Hosp 2, Dept Pharm, 139 Middle Renmin Rd, Changsha 410011, Hunan, Peoples R China. EM lihuande1953@126.com; jkyao@pitt.edu FU Nature Science Foundation of China [NSFC81401113, NSFC81101001, NSFC81360665]; Specialized Research Fund for the Doctoral Program of Higher Education of China [SRFDP20130162120060]; Chinese Scholarship Council; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory R&D (Senior Research Career Scientist Award); VA Pittsburgh Healthcare System FX This material is based on work supported in part by the grants from the Nature Science Foundation of China (NSFC81401113 (HLC), NSFC81101001 (PX) and NSFC81360665 (QYT)), the Specialized Research Fund for the Doctoral Program of Higher Education of China (SRFDP20130162120060 (HLC)), the Chinese Scholarship Council for oversea study program (HLC), the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory R&D (Senior Research Career Scientist Award (JKY)) and VA Pittsburgh Healthcare System (HLC and JKY). NR 49 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT 20 PY 2015 VL 5 AR e661 DI 10.1038/tp.2015.161 PG 8 WC Psychiatry SC Psychiatry GA DA2ZC UT WOS:000367664700002 PM 26485545 ER PT J AU D'Amico, AV AF D'Amico, Anthony V. TI Personalizing the Use of Active Surveillance As an Initial Approach for Men With Newly Diagnosed Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RADICAL PROSTATECTOMY; RISK; MORTALITY; OUTCOMES; TRIAL; AGE C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 13 TC 1 Z9 1 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 20 PY 2015 VL 33 IS 30 BP 3365 EP + DI 10.1200/JCO.2015.63.6118 PG 3 WC Oncology SC Oncology GA CX9IQ UT WOS:000366019300002 PM 26324374 ER PT J AU Atkins, MB Gravis, G Drosik, K Demkow, T Tomczak, P Wong, SS Michaelson, MD Choueiri, TK Wu, B Navale, L Warner, D Ravaud, A AF Atkins, Michael B. Gravis, Gwenaelle Drosik, Kazimierz Demkow, Tomasz Tomczak, Piotr Wong, Shirley S. Michaelson, M. Dror Choueiri, Toni K. Wu, Benjamin Navale, Lynn Warner, Douglas Ravaud, Alain TI Trebananib (AMG 386) in Combination With Sunitinib in Patients With Metastatic Renal Cell Cancer: An Open-Label, Multicenter, Phase II Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANGIOPOIETIN 1/2-NEUTRALIZING PEPTIBODY; RECURRENT OVARIAN-CANCER; ADVANCED SOLID TUMORS; DOUBLE-BLIND; ANTITUMOR-ACTIVITY; CARCINOMA; SORAFENIB; TRIAL; INHIBITOR; SURVIVAL AB Purpose Trebananib, an investigational recombinant peptide-Fc fusion protein, neutralizes the receptor-ligand interaction between Tie2 and angiopoietin-1/2. This phase II study was conducted to evaluate trebananib plus sunitinib, a vascular endothelial growth factor receptor inhibitor, in patients with metastatic clear cell renal cell carcinoma. Patients and Methods Adults with metastatic renal cell carcinoma were enrolled sequentially onto two cohorts that received sunitinib 50 mg once per day for 4 weeks on and 2 weeks off and intravenous trebananib once per week at a dose of 10 mg/kg in cohort A or 15 mg/kg in cohort B. The primary end points were incidences of adverse events (AEs) and dose interruptions of sunitinib during the first 12 weeks of treatment. Secondary end points included objective response rate and progression-free survival. Results Eighty-five patients were enrolled: 43 in cohort A, and 42 in cohort B. During the first 12 weeks of treatment, 58% and 57% of patients in cohorts A and B, respectively, had sunitinib dose interruptions (dose decrease, withholding, or withdrawal). The most frequent AEs were diarrhea (cohort A, 74%; cohort B, 67%), mucosal inflammation (cohort A, 49%; cohort B, 60%), and hypertension (cohort A, 52%; cohort B, 45%). AEs of grade 3 or greater occurred in 58% of patients in cohort A and in 69% of patients in cohort B. The objective response rate was 58% and 63% in cohorts A and B, respectively. The median progression-free survival time was 13.9 months (95% CI, 10.4 to 19.2) and 16.3 months (95% CI, 13.1 to 21.4) in cohorts A and B, respectively. The median overall survival time was 36 months (95% CI, 25.2 to not estimable) in cohort A and was not estimable (median follow-up, 25 months) in cohort B. Conclusion Trebananib plus sunitinib seemed to increase toxicity at the tested doses. Efficacy results suggest a potential benefit for the addition of trebananib to sunitinib. (C) 2015 by American Society of Clinical Oncology C1 [Atkins, Michael B.] Georgetown Univ, Washington, DC USA. [Gravis, Gwenaelle] Inst Paoli Calmettes, Marseille, France. [Ravaud, Alain] Ctr Hosp Univ Bordeaux, Hop St Andre, Bordeaux, France. [Drosik, Kazimierz] Reg Canc Ctr, Opole, Poland. [Demkow, Tomasz] Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Tomczak, Piotr] Univ Med Sci, Poznan, Poland. [Wong, Shirley S.] Western Hosp, Footscray, Vic, Australia. [Michaelson, M. Dror] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wu, Benjamin; Navale, Lynn; Warner, Douglas] Amgen Inc, Thousand Oaks, CA USA. RP Atkins, MB (reprint author), Georgetown Lombardi Comprehens Canc Ctr, Res Bldg Room E501,3970 Reservoir Rd,NW, Washington, DC 20057 USA. EM mba41@georgetown.edu OI Michaelson, Dror/0000-0001-9249-6338 FU Amgen FX We thank Erica Chevalier-Larsen, PhD (Complete Healthcare Communications), whose work was funded by Amgen, and Beate D. Quednau, PhD (Amgen), for assistance in the preparation of this article. NR 37 TC 8 Z9 9 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 20 PY 2015 VL 33 IS 30 BP 3431 EP + DI 10.1200/JCO.2014.60.6012 PG 10 WC Oncology SC Oncology GA CX9IQ UT WOS:000366019300014 PM 26304872 ER PT J AU Masters, GA Temin, S Azzoli, CG Giaccone, G Baker, S Brahmer, JR Ellis, PM Gajra, A Rackear, N Schiller, JH Smith, TJ Strawn, JR Trent, D Johnson, DH AF Masters, Gregory A. Temin, Sarah Azzoli, Christopher G. Giaccone, Giuseppe Baker, Sherman, Jr. Brahmer, Julie R. Ellis, Peter M. Gajra, Ajeet Rackear, Nancy Schiller, Joan H. Smith, Thomas J. Strawn, John R. Trent, David Johnson, David H. TI Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-III TRIAL; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; PACLITAXEL PLUS CARBOPLATIN; PLATINUM-BASED CHEMOTHERAPY; GROWTH-FACTOR RECEPTOR; EARLY PALLIATIVE CARE; TYROSINE KINASE INHIBITOR; TREATED JAPANESE PATIENTS; DOUBLE-BLIND AB Purpose To provide evidence-based recommendations to update the American Society of Clinical Oncology guideline on systemic therapy for stage IV non-small-cell lung cancer (NSCLC). Methods An Update Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of randomized controlled trials from January 2007 to February 2014. Results This guideline update reflects changes in evidence since the previous guideline. Recommendations There is no cure for patients with stage IV NSCLC. For patients with performance status (PS) 0 to 1 (and appropriate patient cases with PS 2) and without an EGFR-sensitizing mutation or ALK gene rearrangement, combination cytotoxic chemotherapy is recommended, guided by histology, with early concurrent palliative care. Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if no contraindications); combination or single-agent chemotherapy or palliative care alone for those with PS 2; afatinib, erlotinib, or gefitinib for those with sensitizing EGFR mutations; crizotinib for those with ALK or ROS1 gene rearrangement; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma. Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens, alternative chemotherapy, or a chemotherapy break. In the second-line setting, recommendations include docetaxel, erlotinib, gefitinib, or pemetrexed for patients with nonsquamous cell carcinoma; docetaxel, erlotinib, or gefitinib for those with squamous cell carcinoma; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib. In the third-line setting, for patients who have not received erlotinib or gefitinib, treatment with erlotinib is recommended. There are insufficient data to recommend routine third-line cytotoxic therapy. Decisions regarding systemic therapy should not be made based on age alone. Additional information can be found at http://www.asco.org/guidelines/nsclc and http://www.asco.org/guidelineswiki. (C) 2015 by American Society of Clinical Oncology C1 [Masters, Gregory A.] Helen F Graham Canc Ctr, Newark, DE USA. [Temin, Sarah] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Baker, Sherman, Jr.] Virginia Commonwealth Univ, Richmond, VA USA. [Trent, David] Virginia Canc Ctr, Richmond, VA USA. [Azzoli, Christopher G.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. [Brahmer, Julie R.; Smith, Thomas J.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Ellis, Peter M.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Gajra, Ajeet] Upstate Med Univ, Syracuse, NY USA. [Rackear, Nancy] Uniting Lung Canc, Ft Lauderdale, FL USA. [Schiller, Joan H.] Univ Texas Southwestern, Dallas, TX USA. [Johnson, David H.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Masters, GA (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU Bristol-Myers Squibb; Merck; AstraZeneca; Celgene; Synta; Astex Therapeutics; Sorono/EMD; Merrimack; Endocyte; Genentech; Novartis; Clovis Oncology; Johnson Johnson FX Bristol-Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Celgene (Inst); Celgene, Merck; Synta (Inst), Astex Therapeutics (Inst), Sorono/EMD (Inst), Merrimack (Inst), Endocyte (Inst), Synta (Inst), Astex Therapeutics (Inst), Genentech (Inst), Merrimack (Inst), Novartis (Inst), Synta (Inst), Clovis Oncology (Inst), Johnson & Johnson (Inst) NR 152 TC 78 Z9 81 U1 6 U2 11 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 20 PY 2015 VL 33 IS 30 BP 3488 EP + DI 10.1200/JCO.2015.62.1342 PG 30 WC Oncology SC Oncology GA CX9IQ UT WOS:000366019300022 PM 26324367 ER PT J AU Horowitz, N Miller, A Rungruang, B Richard, S Rodriguez, N Bookman, MA Hamilton, C Krivak, T Maxwell, GL AF Horowitz, Neil Miller, Austin Rungruang, Bunja Richard, Scott Rodriguez, Noah Bookman, Michael A. Hamilton, Chad Krivak, Thomas Maxwell, George Larry TI There Is Nothing New Under the Sun Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID PRIMARY DEBULKING SURGERY; ADVANCED-STAGE OVARIAN; NEOADJUVANT CHEMOTHERAPY; CANCER; TRIAL C1 [Horowitz, Neil] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Miller, Austin] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Rungruang, Bunja] Georgia Regents Univ, Augusta, GA USA. [Richard, Scott] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Rodriguez, Noah] Loma Linda Univ, Sch Med, Loma Linda, CA USA. [Bookman, Michael A.] Univ Arizona, Ctr Canc, Tucson, AZ USA. [Hamilton, Chad] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Krivak, Thomas] Western Penn Hosp, Pittsburgh, PA 15224 USA. [Maxwell, George Larry] Innova Fairfax Womens Hosp, Falls Church, VA USA. RP Horowitz, N (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 9 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 20 PY 2015 VL 33 IS 30 BP 3521 EP U224 DI 10.1200/JCO.2015.62.5707 PG 3 WC Oncology SC Oncology GA CX9IQ UT WOS:000366019300030 PM 26304879 ER PT J AU Rao, RC Gragoudas, ES AF Rao, Rajesh C. Gragoudas, Evangelos S. TI Choroidal Metastases From EML4-ALK-Positive Non-Small-Cell Lung Adenocarcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CANCER; CRIZOTINIB; MUTATIONS C1 [Rao, Rajesh C.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Gragoudas, Evangelos S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Rao, RC (reprint author), Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. OI Rao, Rajesh/0000-0002-5776-8366 NR 9 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 20 PY 2015 VL 33 IS 30 BP E112 EP E114 DI 10.1200/JCO.2013.50.2740 PG 3 WC Oncology SC Oncology GA CX9IQ UT WOS:000366019300001 PM 24733798 ER PT J AU Luo, LY Hahn, WC AF Luo, Leo Y. Hahn, William C. TI Oncogenic Signaling Adaptor Proteins SO JOURNAL OF GENETICS AND GENOMICS LA English DT Review DE Adaptor protein; Cancer; Oncogene ID CHRONIC MYELOGENOUS LEUKEMIA; RECEPTOR TYROSINE KINASES; GROWTH-FACTOR RECEPTORS; OVARIAN-CANCER; FRS2 FAMILY; SH3 DOMAIN; DOCKING PROTEINS; EPITHELIAL-CELLS; BINDING-SITE; MAP KINASE AB Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets. C1 [Luo, Leo Y.] Harvard Univ, Sch Med, Hlth Sci & Technol Program, Boston, MA 02115 USA. [Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Hahn, William C.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM William_Hahn@dfci.harvard.edu FU U.S. NIH [U01 CA176058]; H.L. Snyder Medical Research Foundation; HHMI Medical Student Fellowship FX This work was supported in part by grants from the U.S. NIH (U01 CA176058), the H.L. Snyder Medical Research Foundation and a HHMI Medical Student Fellowship. NR 67 TC 0 Z9 1 U1 1 U2 4 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1673-8527 EI 1873-5533 J9 J GENET GENOMICS JI J. Genet. Genomics PD OCT 20 PY 2015 VL 42 IS 10 BP 521 EP 529 DI 10.1016/j.jgg.2015.09.001 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CW7CU UT WOS:000365156300003 PM 26554907 ER PT J AU Basu, S Phillips, RS Bitton, A Song, ZR Landon, BE AF Basu, Sanjay Phillips, Russell S. Bitton, Asaf Song, Zirui Landon, Bruce E. TI Medicare Chronic Care Management Payments and Financial Returns to Primary Care Practices A Modeling Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HOSPITAL ADMISSIONS; GLOBAL PAYMENT; COMMUNITY CARE; HOME PILOT; PATIENT; HEALTH; COST; QUALITY; ORGANIZATIONS; IMPACT AB Background: Physicians have traditionally been reimbursed for face-to-face visits. A new non-visit-based payment for chronic care management (CCM) of Medicare patients took effect in January 2015. Objective: To estimate financial implications of CCM payment for primary care practices. Design: Microsimulation model incorporating national data on primary care use, staffing, expenditures, and reimbursements. Data Sources: National Ambulatory Medical Care Survey and other published sources. Target Population: Medicare patients. Time Horizon: 10 years. Perspective: Practice-level. Intervention: Comparison of CCM delivery approaches by staff and physicians. Outcome Measures: Net revenue per full-time equivalent (FTE) physician; time spent delivering CCM services. Results of Base-Case Analysis: If nonphysician staff were to deliver CCM services, net revenue to practices would increase despite opportunity and staffing costs. Practices could expect approximately $332 per enrolled patient per year (95% CI, $234 to $429) if CCM services were delivered by registered nurses RNs), approximately $372 (CI, $276 to $468) if services were delivered by licensed practical nurses, and approximately $385 (CI, $286 to $485) if services were delivered by medical assistants. For a typical practice, this equates to more than $75 000 of net annual revenue per FTE physician and 12 hours of nursing service time per week if 50% of eligible patients enroll. At a minimum, 131 Medicare patients (CI, 115 to 140 patients) must enroll for practices to recoup the salary and overhead costs of hiring a full-time RN to provide CCM services. Results of Sensitivity Analysis: If physicians were to deliver all CCM services, approximately 25% of practices nationwide could expect net revenue losses due to opportunity costs of face-to-face visit time. Limitation: The CCM program may alter long-term primary care use, which is difficult to predict. Conclusion: Practices that rely on nonphysician team members to deliver CCM services will probably experience substantial net revenue gains but must enroll a sufficient number of eligible patients to recoup costs. C1 [Basu, Sanjay] Stanford Univ, Sch Med, Stanford, CA 94305 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Basu, S (reprint author), Stanford Univ, Sch Med, Med Sch Off Build X322,1265 Welch Rd, Stanford, CA 94305 USA. FU Center for Medicare & Medicaid Innovation FX Dr. Bitton reports that he received personal fees from the Center for Medicare & Medicaid Innovation for serving as a part-time senior advisor to the Comprehensive Primary Care initiative at the Center for Medicare & Medicaid Innovation and that he participated in a technical expert panel convened by Mathematica Policy Research that advised the Assistant Secretary for Planning and Evaluation of Health and Human Services on the chronic care management fee. Dr. Landon reports personal fees from United Biosource and Research Triangle Institute outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-267 7. NR 55 TC 5 Z9 5 U1 3 U2 10 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 20 PY 2015 VL 163 IS 8 BP 580 EP + DI 10.7326/M14-2677 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA CU7QV UT WOS:000363737400016 PM 26389533 ER PT J AU Kugel, S Feldman, JL Klein, MA Silberman, DM Sebastian, C Mermel, C Dobersch, S Clark, AR Getz, G Denu, JM Mostoslavsky, R AF Kugel, Sita Feldman, Jessica L. Klein, Mark A. Silberman, Dafne M. Sebastian, Carlos Mermel, Craig Dobersch, Stephanie Clark, Abbe R. Getz, Gad Denu, John M. Mostoslavsky, Raul TI Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer SO CELL REPORTS LA English DT Article ID HISTONE DEACETYLASE SIRT6; DEACYLATION; CHROMATIN; SIRTUINS; LYSINE; CELLS AB Chromatin factors have emerged as the most frequently dysregulated family of proteins in cancer. We have previously identified the histone deacetylase SIRT6 as a key tumor suppressor, yet whether point mutations are selected for in cancer remains unclear. In this manuscript, we characterized naturally occurring patient-derived SIRT6 mutations. Strikingly, all the mutations significantly affected either stability or catalytic activity of SIRT6, indicating that these mutations were selected for in these tumors. Further, the mutant proteins failed to rescue sirt6 knockout (SIRT6 KO) cells, as measured by the levels of histone acetylation at glycolytic genes and their inability to rescue the tumorigenic potential of these cells. Notably, the main activity affected in the mutants was histone deacetylation rather than demyristoylation, pointing to the former as the main tumor-suppressive function for SIRT6. Our results identified cancer-associated point mutations in SIRT6, cementing its function as a tumor suppressor in human cancer. C1 [Kugel, Sita; Sebastian, Carlos; Mermel, Craig; Clark, Abbe R.; Getz, Gad; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Mostoslavsky, Raul] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Mermel, Craig; Getz, Gad; Mostoslavsky, Raul] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Feldman, Jessica L.; Klein, Mark A.; Denu, John M.] Univ Wisconsin, Dept Biomol Chem, Madison, WI 53715 USA. [Feldman, Jessica L.; Klein, Mark A.; Denu, John M.] Univ Wisconsin, Wisconsin Inst Discovery, Madison, WI 53715 USA. [Dobersch, Stephanie] Max Planck Inst Heart & Lung Res, D-61231 Bad Nauheim, Germany. [Silberman, Dafne M.] UBA, Fac Med, CONICET, Ctr Pharmacol & Bot Studies CEFYBO, RA-1121 Buenos Aires, DF, Argentina. RP Denu, JM (reprint author), Univ Wisconsin, Dept Biomol Chem, Madison, WI 53715 USA. EM jmdenu@wisc.edu; rmostoslavsky@mgh.harvard.edu FU NIH [1R01CA175727-01A1, DK088190-01A1, NIH GM065386]; Canadian Institutes of Health Research postdoctoral fellowship; Visionary postdoctoral fellowship from the Department of Defense FX We thank members of the R.M. and J.M.D. labs for invaluable discussions and advice. This work was supported in part by NIH grants 1R01CA175727-01A1, DK088190-01A1 (to R.M.), and NIH GM065386 (to J.M.D). R.M. is the Kristine and Bob Higgins MGH Research Scholar, the Warshaw Institute Fellow, and a Howard Goodman Awardee. S.K. is the recipient of a Canadian Institutes of Health Research postdoctoral fellowship. C.S. is supported by the Visionary postdoctoral fellowship from the Department of Defense. NR 21 TC 8 Z9 8 U1 1 U2 3 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 OCT 20 PY 2015 VL 13 IS 3 BP 479 EP 488 DI 10.1016/j.celrep.2015.09.022 PG 10 WC Cell Biology SC Cell Biology GA CU8GP UT WOS:000363780000004 PM 26456828 ER PT J AU Zhu, CL Xiao, F Lin, WY AF Zhu, Chuanlong Xiao, Fei Lin, Wenyu TI EFTUD2 on innate immunity SO ONCOTARGET LA English DT Editorial Material DE EFTUD2; HCV; RIG-I/MDA5; innate immunity; spliceosome; Immunology and Microbiology Section; Immune response; Immunity ID HEPATITIS-C VIRUS; REGULATOR C1 [Lin, Wenyu] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Liver Ctr, Boston, MA 02114 USA. [Lin, Wenyu] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Div, Boston, MA USA. RP Lin, WY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Liver Ctr, Boston, MA 02114 USA. EM wlin1@mgh.harvard.edu NR 7 TC 0 Z9 0 U1 0 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 OCT 20 PY 2015 VL 6 IS 32 BP 32313 EP 32314 DI 10.18632/oncotarget.5863 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CU0DQ UT WOS:000363186600018 PM 26427044 ER PT J AU Trombetta-Lima, M Winnischofer, SMB Demasi, MAA Astorino, R Carreira, ACO Wei, BY Ribas, TD Konig, MS Bowman-Colin, C Oba-Shinjo, SM Marie, SKN Stetler-Stevenson, W Sogayar, MC AF Trombetta-Lima, Marina Brochado Winnischofer, Sheila Maria Almeida Demasi, Marcos Angelo Astorino Filho, Renato Oliveira Carreira, Ana Claudia Wei, Beiyang Ribas, Thais de Assis Konig, Michelle Silberspitz Bowman-Colin, Christian Oba-Shinjo, Sueli Mieko Nagahashi Marie, Suely Kazue Stetler-Stevenson, William Sogayar, Mari Cleide TI Isolation and characterization of novel RECK tumor suppressor gene splice variants SO ONCOTARGET LA English DT Article DE RECK; GBM; splicing; isoforms; MMP ID CYSTEINE-RICH PROTEIN; MATRIX-METALLOPROTEINASE; KAZAL MOTIFS; DOWN-REGULATION; VEGF-A; CANCER; GLIOMA; INHIBITORS; INVASION; PATHWAY AB Glioblastoma multiforme is the most common and lethal of the central nervous system glial-derived tumors. RECK suppresses tumor invasion by negatively regulating at least three members of the matrix metalloproteinase family: MMP-9, MMP-2, and MT1-MMP. A positive correlation has been observed between the abundance of RECK expression in tumor samples and a more favorable prognosis for patients with several types of tumors. In the present study, novel alternatively spliced variants of the RECK gene: RECK-B and RECK-I were isolated by RT-PCR and sequenced. The expression levels and profiles of these alternative RECK transcripts, as well as canonical RECK were determined in tissue samples of malignant astrocytomas of different grades and in a normal tissue RNA panel by qRT-PCR. Our results show that higher canonical RECK expression, accompanied by a higher canonical to alternative transcript expression ratio, positively correlates with higher overall survival rate after chemotherapeutic treatment of GBM patients. U87MG and T98G cells over-expressing the RECK-B alternative variant display higher anchorage-independent clonal growth and do not display modulation of, respectively, MMP-2 and MMP-9 expression. Our findings suggest that RECK transcript variants might have opposite roles in GBM biology and the ratio of their expression levels may be informative for the prognostic outcome of GBM patients. C1 [Trombetta-Lima, Marina; Almeida Demasi, Marcos Angelo; Astorino Filho, Renato; Oliveira Carreira, Ana Claudia; Sogayar, Mari Cleide] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, SP, Brazil. [Trombetta-Lima, Marina; Almeida Demasi, Marcos Angelo; Astorino Filho, Renato; Oliveira Carreira, Ana Claudia; Ribas, Thais de Assis; Konig, Michelle Silberspitz; Bowman-Colin, Christian; Oba-Shinjo, Sueli Mieko; Nagahashi Marie, Suely Kazue; Sogayar, Mari Cleide] Univ Sao Paulo, NUCEL NETCEM Fac Med, BR-05360120 Sao Paulo, SP, Brazil. [Brochado Winnischofer, Sheila Maria] Univ Fed Parana, Dept Bioquim & Biol Mol, BR-81531990 Curitiba, Parana, Brazil. [Bowman-Colin, Christian] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. [Wei, Beiyang; Stetler-Stevenson, William] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Oba-Shinjo, Sueli Mieko; Nagahashi Marie, Suely Kazue] Univ Sao Paulo, Fac Med, Dept Neurol, BR-01246000 Sao Paulo, SP, Brazil. RP Sogayar, MC (reprint author), Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, SP, Brazil. EM mcsoga@iq.usp.br RI Trombetta Lima, Marina/P-1757-2015; Carreira, Ana Claudia/B-7655-2012; Marie, Suely/D-1870-2012; Oba-Shinjo, Sueli /C-4017-2012 OI Trombetta Lima, Marina/0000-0002-3687-6210; FU FAPESP-Fundacao de Apoio a Pesquisa do Estado de Sao Paulo [01/10707-7, 08/53971-5, 04/12133-6, 2010/51634-1]; CNPq-Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [457601/2013-2, 401828/2012-3, 401430/2013-8]; FINEP-Financiadora de Estudos e Projetos [01.06.0664.00, 01.08.0622.00]; BNDES-Banco Nacional de Desenvolvimento Economico e Social [09.2.1066.1]; CAPES-Coordenacao para o Aperfeicoamento do Ensino Superior [BEX 0518/11-5]; Fulbright Program [BEX 0518/11-5] FX This work was supported by FAPESP-Fundacao de Apoio a Pesquisa do Estado de Sao Paulo [grant numbers 01/10707-7, 08/53971-5, 04/12133-6, 2010/51634-1], CNPq-Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, [grants numbers 457601/2013-2; 401828/2012-3 and 401430/2013-8], FINEP-Financiadora de Estudos e Projetos [01.06.0664.00, 01.08.0622.00] and BNDES-Banco Nacional de Desenvolvimento Economico e Social [09.2.1066.1], joint CAPES-Coordenacao para o Aperfeicoamento do Ensino Superior and The Fulbright Program [BEX 0518/11-5]. NR 57 TC 2 Z9 2 U1 1 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 20 PY 2015 VL 6 IS 32 BP 33120 EP 33133 DI 10.18632/oncotarget.5305 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CU0DQ UT WOS:000363186600077 PM 26431549 ER PT J AU Yang, SZ Cho, YJ Jin, L Yuan, GD Datta, A Buckhaults, P Datta, PK AF Yang, Shanzhong Cho, Yong-Jig Jin, Lin Yuan, Guandou Datta, Arunima Buckhaults, Phillip Datta, Pran K. TI An epigenetic auto-feedback loop regulates TGF-beta type II receptor expression and function in NSCLC SO ONCOTARGET LA English DT Article DE c-Myc; miR-20a; TGF-b; TGF-b type II receptor; miR-145 ID CELL LUNG-CANCER; GROWTH-FACTOR-BETA; IN-VIVO ALTERATIONS; COLORECTAL-CANCER; DOWN-REGULATION; BREAST-CANCER; C-MYC; MIR-145; DISEASE; MICRORNAS AB The downregulation of transforming growth factor-beta (TGF-beta) type II receptor (T beta RII) expression and function plays a pivotal role in the loss of the TGF-beta-induced tumor suppressor function that contributes to lung cancer progression. The aberrant expression of miRNAs has been shown to be involved in the regulation of oncogenes and tumor suppressor genes. Our current study involving miRNA microarray, northern blot and QRT-PCR analysis shows an inverse correlation between miR-20a and T beta RII expression in non-small cell lung cancer (NSCLC) tissues and cell lines. Stable expression of miR-20a downregulates T beta RII in lung epithelial cells which results in an inhibition of TGF-beta signaling and attenuation of TGF-beta-induced cell growth suppression and apoptosis. Stable knock down of miR-20a increases T beta RII expression and inhibits tumorigenicity of lung cancer cells in vivo. Oncogene c-Myc promotes miR-20a expression by activating its promoter leading to downregulation of T beta RII expression and TGF-beta signaling. MiR-145, which is upregulated by TGF-beta, inhibits miR-20a expression by targeting c-Myc and upregulates T beta RII expression. These correlations among miRNAs and cellular proteins are supported by TCGA public database using NSCLC specimens. These results suggest a novel mechanism for the loss of T beta RII expression and TGF-beta-induced tumor suppressor functions in lung cancer through a complex auto-feedback loop TGF-beta/miR-145/c-Myc/miR-20a/T beta RII. C1 [Yang, Shanzhong; Jin, Lin; Yuan, Guandou; Datta, Arunima; Buckhaults, Phillip; Datta, Pran K.] Univ Alabama Birmingham, Dept Med, Div Hematol & Oncol, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Yang, Shanzhong; Jin, Lin; Datta, Pran K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Cho, Yong-Jig] Vanderbilt Univ, Dept Surg, Sch Med, Nashville, TN 37240 USA. RP Datta, PK (reprint author), Univ Alabama Birmingham, Dept Med, Div Hematol & Oncol, Ctr Comprehens Canc, Birmingham, AL 35294 USA. EM prandatta@uabmc.edu FU National Cancer Institute [R01 CA95195]; Veterans Affairs Merit Review Award; Faculty Development Award from UAB Comprehensive Cancer Center [P30 CA013148] FX This study was supported by National Cancer Institute R01 CA95195, Veterans Affairs Merit Review Award, and a Faculty Development Award from UAB Comprehensive Cancer Center, P30 CA013148 (to PK Datta). NR 48 TC 2 Z9 2 U1 0 U2 10 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 20 PY 2015 VL 6 IS 32 BP 33237 EP 33252 DI 10.18632/oncotarget.4893 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CU0DQ UT WOS:000363186600086 PM 26356817 ER PT J AU Alshami, J Guiot, MC Owen, S Kavan, P Gibson, N Solca, F Cseh, A Reardon, DA Muanza, T AF Alshami, Jad Guiot, Marie-Christine Owen, Scott Kavan, Petr Gibson, Neil Solca, Flavio Cseh, Agnieszka Reardon, David A. Muanza, Thierry TI Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: A case report SO ONCOTARGET LA English DT Article DE afatinib; temozolomide; glioblastoma; next-generation sequencing; epidermal growth factor receptor ID GROWTH-FACTOR-RECEPTOR; NEWLY-DIAGNOSED GLIOBLASTOMA; CELL LUNG-CANCER; NEURO-ONCOLOGIA GICNO; LONG-TERM SURVIVAL; PHASE-II; RANDOMIZED-TRIAL; EGFR MUTATIONS; MULTIFORME; GEFITINIB AB There are few effective treatments for recurrent glioblastoma multiforme (GBM). We present a patient with recurrent GBM who achieved a prolonged response to treatment with afatinib, an irreversible ErbB family blocker, plus temozolomide. A 58-year-old female patient was diagnosed with multifocal primary GBM. After surgical resection, first-line therapy comprised radiotherapy and temozolomide. Following disease progression after 3 temozolomide cycles, the patient entered a phase I/II clinical trial of afatinib (20-40 mg daily for 28 days) plus temozolomide (50 mg/m(2) every 21/28 days). Next-generation sequencing analysis of the brain tumor specimen was performed. At the last assessment, 63 treatment cycles had been completed and the patient had survived for similar to 5 years since recurrence. Significant disease regression was observed after 5 cycles and was maintained during long-term follow-up. Adverse events were consistent with the known tolerability profile of afatinib and were managed by treatment interruption/dose reduction. The patient had several epidermal growth factor receptor (EGFR) aberrations, including gene amplification and EGFRvIII positivity. Three somatic mutations were identified, including an unprecedented extracellular-domain substitution (D247Y). The patient has survived similar to 6-fold longer than normally expected in patients with recurrent GBM. The complex EGFR genotype may underlie sustained response to afatinib plus temozolomide. C1 [Alshami, Jad; Guiot, Marie-Christine; Owen, Scott; Kavan, Petr; Muanza, Thierry] McGill Univ, Ctr Hlth, Montreal Neurol Inst & Hosp, Clin Res Unit, Montreal, PQ, Canada. [Gibson, Neil] Boehringer Ingelheim Pharma GmbH & Co KG, Drug Metab & Pharmacokinet, Biberach, Germany. [Solca, Flavio; Cseh, Agnieszka] Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. [Reardon, David A.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Muanza, Thierry] McGill Univ, Jewish Gen Hosp, Radiat Oncol, Montreal, PQ H3T 1E2, Canada. RP Muanza, T (reprint author), McGill Univ, Ctr Hlth, Montreal Neurol Inst & Hosp, Clin Res Unit, Montreal, PQ, Canada. EM thierry.muanza@mcgill.ca FU Boehringer Ingelheim FX The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Lynn Pritchard, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this article. This study was supported by Boehringer Ingelheim. NR 33 TC 0 Z9 0 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 20 PY 2015 VL 6 IS 32 BP 34030 EP 34037 DI 10.18632/oncotarget.5297 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CU0DQ UT WOS:000363186600148 PM 26423602 ER PT J AU Cao, ZF Conway, KL Heath, RJ Rush, JS Leshchiner, ES Ramirez-Ortiz, ZG Nedelsky, NB Huang, HL Ng, A Gardet, A Cheng, SC Shamji, AF Rioux, JD Wijmenga, C Netea, MG Means, TK Daly, MJ Xavier, RJ AF Cao, Zhifang Conway, Kara L. Heath, Robert J. Rush, Jason S. Leshchiner, Elizaveta S. Ramirez-Ortiz, Zaida G. Nedelsky, Natalia B. Huang, Hailiang Ng, Aylwin Gardet, Agnes Cheng, Shih-Chin Shamji, Alykhan F. Rioux, John D. Wijmenga, Cisca Netea, Mihai G. Means, Terry K. Daly, Mark J. Xavier, Ramnik J. TI Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation SO IMMUNITY LA English DT Article ID INHERITED CARD9 DEFICIENCY; COLITIS SUSCEPTIBILITY LOCI; INNATE IMMUNITY; BOWEL-DISEASE; ANTIVIRAL RESPONSE; DEEP DERMATOPHYTOSIS; FUNGAL-INFECTIONS; CANDIDA-ALBICANS; DENDRITIC CELLS; CROHNS-DISEASE AB CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation. C1 [Cao, Zhifang; Conway, Kara L.; Heath, Robert J.; Nedelsky, Natalia B.; Ng, Aylwin; Gardet, Agnes; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Cao, Zhifang; Conway, Kara L.; Heath, Robert J.; Nedelsky, Natalia B.; Ng, Aylwin; Gardet, Agnes; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Cao, Zhifang; Conway, Kara L.; Heath, Robert J.; Nedelsky, Natalia B.; Huang, Hailiang; Ng, Aylwin; Gardet, Agnes; Daly, Mark J.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Cao, Zhifang; Conway, Kara L.; Heath, Robert J.; Nedelsky, Natalia B.; Ng, Aylwin; Gardet, Agnes; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Conway, Kara L.; Heath, Robert J.; Rush, Jason S.; Leshchiner, Elizaveta S.; Huang, Hailiang; Ng, Aylwin; Shamji, Alykhan F.; Daly, Mark J.; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Ramirez-Ortiz, Zaida G.; Means, Terry K.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Ramirez-Ortiz, Zaida G.; Means, Terry K.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. [Ramirez-Ortiz, Zaida G.; Means, Terry K.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Huang, Hailiang; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Cheng, Shih-Chin; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Cheng, Shih-Chin; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, NL-6525 GA Nijmegen, Netherlands. [Rioux, John D.] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Rioux, John D.] Univ Montreal, Montreal, PQ H1T 1C8, Canada. [Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. RP Xavier, RJ (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. EM xavier@molbio.mgh.harvard.edu RI Rioux, John/A-9599-2015; Wijmenga, Cisca/D-2173-2009; Cheng, Shih-Chin/H-4567-2015 OI Rioux, John/0000-0001-7560-8326; Cheng, Shih-Chin/0000-0003-1251-8774 FU Helmsley Trust; NIH [DK097485, DK062432, DK086502]; ERC [310372] FX We thank Drs. Hiromitsu Hara (Saga Medical School, Japan) for providing Card9-/- mice (Hara et al., 2007), Kara Lassen for guidance with manuscript preparation, and Petric Kuballa, Jakob Begun, and David Fei for assistance with experiments. This work was supported by funding from the Helmsley Trust and NIH grants DK097485, DK062432, and DK086502 to R.J.X. M.G.N. was supported by an ERC Consolidator Grant (no. 310372). T.K.M. NR 69 TC 8 Z9 8 U1 1 U2 6 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 OCT 20 PY 2015 VL 43 IS 4 BP 715 EP 726 DI 10.1016/j.immuni.2015.10.005 PG 12 WC Immunology SC Immunology GA CU4ED UT WOS:000363478700014 PM 26488816 ER PT J AU Virani, SS Maddox, TM Chan, PS Tang, FM Akeroyd, JM Risch, SA Oetgen, WJ Deswal, A Bozkurt, B Ballantyne, CM Petersen, LA AF Virani, Salim S. Maddox, Thomas M. Chan, Paul S. Tang, Fengming Akeroyd, Julia M. Risch, Samantha A. Oetgen, William J. Deswal, Anita Bozkurt, Biykem Ballantyne, Christie M. Petersen, Laura A. TI Provider Type and Quality of Outpatient Cardiovascular Disease Care Insights From the NCDR PINNACLE Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; chronic disease care; nurse practitioners; performance measures; physician assistants; physicians ID NURSE-PRACTITIONERS; PERFORMANCE-MEASURES; ATRIAL-FIBRILLATION; PHYSICIAN GENDER; DIABETES CARE; OUTCOMES; PROGRAM; RISKS AB BACKGROUND The current number of physicians will not be sufficient to accommodate 30 to 40 million Americans expected to secure health coverage with Affordable Care Act implementation. One proposed solution is to use advanced practice providers (APPs) (nurse practitioners and physician assistants). OBJECTIVES This study sought to determine whether there were clinically meaningful differences in the quality of care delivered by APPs versus physicians in a national sample of cardiology practices. METHODS Within the American College of Cardiology's PINNACLE Registry, we compared quality of coronary artery disease (CAD), heart failure, and atrial fibrillation care delivered by physicians and APPs for outpatient visits between January 1, 2012, and December 31, 2012. We performed hierarchical regression adjusting for provider sex; panel size; duration of participation in registry; and patient's age, sex, insurance, number of outpatient visits, history of hypertension, diabetes, myocardial infarction, and percutaneous coronary intervention or coronary artery bypass grafting in the preceding 12 months. RESULTS We included 883 providers (716 physicians and 167 APPs) in 41 practices who cared for 459,669 patients. Mean number of patients seen by APPs (260.7) was lower compared with that seen by physicians (581.2). Compliance with most CAD, heart failure, and atrial fibrillation measures was comparable, except for a higher rate of smoking cessation screening and intervention (adjusted rate ratio: 1.14; 95% confidence interval: 1.03 to 1.26) and cardiac rehabilitation referral (rate ratio: 1.40; 95% confidence interval: 1.16 to 1.70) among CAD patients receiving care from APPs. Compliance with all eligible CAD measures was low for both (12.1% and 12.2% for APPs and physicians, respectively) with no significant difference. Results were consistent when comparing practices with both physicians and APPs (n = 41) and physician-only practices (n = 49). CONCLUSIONS Apart from minor differences, a collaborative care delivery model, using both physicians and APPs, may deliver an overall comparable quality of outpatient cardiovascular care compared with a physician-only model. (C) 2015 by the American College of Cardiology Foundation. C1 [Virani, Salim S.; Akeroyd, Julia M.; Petersen, Laura A.] Baylor Coll Med, Hlth Policy Qual & Informat Program, Michael E DeBakey Vet Affairs Med Ctr, Hlth Serv Res & Dev Ctr Innovat, Houston, TX 77030 USA. [Virani, Salim S.; Akeroyd, Julia M.; Petersen, Laura A.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Virani, Salim S.; Deswal, Anita; Bozkurt, Biykem] Michael E DeBakey VA Med Ctr, Sect Cardiol, Houston, TX 77030 USA. [Virani, Salim S.; Bozkurt, Biykem; Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Cardiol Sect, Houston, TX 77030 USA. [Virani, Salim S.; Ballantyne, Christie M.] Houston Methodist DeBakey Heart & Vasc Ctr, Ctr Cardiovasc Dis Prevent, Houston, TX USA. [Maddox, Thomas M.] Vet Affairs Eastern Colorado Hlth Care Syst, Denver, CO USA. [Maddox, Thomas M.] Univ Colorado, Div Cardiol, Denver, CO 80202 USA. [Chan, Paul S.; Tang, Fengming] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Chan, Paul S.] Univ Missouri, Kansas City, MO 64110 USA. [Risch, Samantha A.; Oetgen, William J.] Amer Coll Cardiol, Washington, DC USA. RP Virani, SS (reprint author), Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM virani@bcm.edu OI Virani, Salim/0000-0001-9541-6954 FU Department of Veterans Affairs Health Services Research and Development (HSR&D) Service Career Development Award [09-028]; American Heart Association; American Diabetes Association Clinical Science and Epidemiology award; Department of Veterans Affairs HSR&D Service Career Development Award [08-021]; National Heart, Lung, and Blood Institute [1R01HL123980]; Novartis; Abbott Diagnostic; Amarin; Amgen; Bristol-Myers Squibb; Eli Lilly; Esperion; Merck; Pfizer; Regeneron; Roche Diagnostic; Sanofi-Synthelabo; Takeda Development Centers of America; National Institutes of Health; American Diabetes Association FX Dr. Virani is supported by a Department of Veterans Affairs Health Services Research and Development (HSR&D) Service Career Development Award (09-028); American Heart Association Beginning Grant-in-Aid; and the American Diabetes Association Clinical Science and Epidemiology award. Dr. Maddox is supported by a Department of Veterans Affairs HSR&D Service Career Development Award (08-021). Dr. Chan receives funding (1R01HL123980) from the National Heart, Lung, and Blood Institute. Dr. Deswal has received research support from Novartis as site PI of a multicenter clinical trial. Dr. Ballantyne has received grant/research support (all paid to the institution, not individual) from Abbott Diagnostic, Amarin, Amgen, Bristol-Myers Squibb, Eli Lilly, Esperion, Merck, Novartis, Pfizer, Regeneron, Roche Diagnostic, Sanofi-Synthelabo, and Takeda Development Centers of America, National Institutes of Health, American Diabetes Association, and American Heart Association; is a consultant to Abbott Diagnostic, Amarin, Amgen, AstraZeneca, Eli Lilly, Esperion, Genzyme, Matinas BioPharma Inc., Merck, Novartis, Pfizer, Regeneron, and Sanofi-Synthelabo; and has a provisional patent for "Biomarkers to Improve Prediction of Heart Failure Risk" (patent no. 61721475), filed by Baylor College of Medicine and Roche. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 31 TC 7 Z9 7 U1 1 U2 3 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 OCT 20 PY 2015 VL 66 IS 16 BP 1803 EP 1812 DI 10.1016/j.jacc.2015.08.017 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CI UT WOS:000363329300009 PM 26483105 ER PT J AU Rocco, P Gellad, WF Donohue, JM AF Rocco, Philip Gellad, Walid F. Donohue, Julie M. TI Modernizing Medicaid Managed Care Can States Meet the Data Challenges? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Rocco, Philip; Donohue, Julie M.] Univ Pittsburgh, Hlth Policy Inst, Sch Hlth Sci, Pittsburgh, PA 15261 USA. [Gellad, Walid F.] Vet Affairs Pittsburgh Hlth Care Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Gellad, Walid F.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA 15261 USA. [Donohue, Julie M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15261 USA. RP Rocco, P (reprint author), Univ Pittsburgh, Hlth Policy Inst, 3550 Terrace St,S310-1, Pittsburgh, PA 15261 USA. EM pbr8@pitt.edu OI Donohue, Julie/0000-0003-2418-6017 NR 9 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 20 PY 2015 VL 314 IS 15 BP 1559 EP 1560 DI 10.1001/jama.2015.10979 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CT7XK UT WOS:000363028500011 PM 26322564 ER PT J AU Oeffinger, KC Fontham, ETH Etzioni, R Herzig, A Michaelson, JS Shih, YCT Walter, LC Church, TR Flowers, CR LaMonte, SJ Wolf, AMD DeSantis, C Lortet-Tieulent, J Andrews, K Manassaram-Baptiste, D Saslow, D Smith, RA Brawley, OW Wender, R AF Oeffinger, Kevin C. Fontham, Elizabeth T. H. Etzioni, Ruth Herzig, Abbe Michaelson, James S. Shih, Ya-Chen Tina Walter, Louise C. Church, Timothy R. Flowers, Christopher R. LaMonte, Samuel J. Wolf, Andrew M. D. DeSantis, Carol Lortet-Tieulent, Joannie Andrews, Kimberly Manassaram-Baptiste, Deana Saslow, Debbie Smith, Robert A. Brawley, Otis W. Wender, Richard TI Breast Cancer Screening for Women at Average Risk 2015 Guideline Update From the American Cancer Society SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID SERVICES TASK-FORCE; YOUNG-ADULT CANCER; CARCINOMA IN-SITU; COST-EFFECTIVENESS; DIGITAL MAMMOGRAPHY; UNITED-STATES; OLDER WOMEN; QUANTITATIVE INTERPRETATION; TUMOR CHARACTERISTICS; MORTALITY REDUCTIONS AB IMPORTANCE Breast cancer is a leading cause of premature mortality among US women. Early detection has been shown to be associated with reduced breast cancer morbidity and mortality. OBJECTIVE To update the American Cancer Society (ACS) 2003 breast cancer screening guideline for women at average risk for breast cancer. PROCESS The ACS commissioned a systematic evidence review of the breast cancer screening literature to inform the update and a supplemental analysis of mammography registry data to address questions related to the screening interval. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. EVIDENCE SYNTHESIS Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health. Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages because of the greater number of mammograms, as well as the higher recall rate in younger women. The quality of the evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence. Analysis examining the screening interval demonstrates more favorable tumor characteristics when premenopausal women are screened annually vs biennially. Evidence does not support routine clinical breast examination as a screening method for women at average risk. RECOMMENDATIONS The ACS recommends that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years (strong recommendation). Women aged 45 to 54 years should be screened annually (qualified recommendation). Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation). Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation). Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation). The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age (qualified recommendation). CONCLUSIONS AND RELEVANCE These updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer screening. C1 [Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Fontham, Elizabeth T. H.] Louisiana State Univ, Sch Publ Hlth, New Orleans, LA USA. [Etzioni, Ruth] Univ Washington, Seattle, WA 98195 USA. [Etzioni, Ruth] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Michaelson, James S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Michaelson, James S.] Harvard Univ, Sch Med, Boston, MA USA. [Shih, Ya-Chen Tina] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Walter, Louise C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Walter, Louise C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Church, Timothy R.] Mason Canc Ctr, Minneapolis, MN USA. [Church, Timothy R.] Univ Minnesota, Minneapolis, MN USA. [Flowers, Christopher R.] Emory Univ, Sch Med, Atlanta, GA USA. [Flowers, Christopher R.] Winship Canc Inst, Atlanta, GA USA. [Wolf, Andrew M. D.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [DeSantis, Carol; Lortet-Tieulent, Joannie; Andrews, Kimberly; Manassaram-Baptiste, Deana; Saslow, Debbie; Smith, Robert A.; Brawley, Otis W.; Wender, Richard] Amer Canc Soc, Atlanta, GA 30303 USA. RP Smith, RA (reprint author), Amer Canc Soc, Canc Control Dept, 250 Williams St,Ste 600, Atlanta, GA 30303 USA. EM robert.smith@cancer.org RI Flowers, Christopher/F-1953-2010 OI Flowers, Christopher/0000-0002-9524-3990 FU American Cancer Society (ACS); Cancer Center Support Grant from the National Institutes of Health/National Cancer Institute [P30 CA008748] FX The American Cancer Society (ACS) supported the development of this guideline through the use of general funds. Dr Oeffinger was supported in part through a Cancer Center Support Grant from the National Institutes of Health/National Cancer Institute (P30 CA008748). NR 124 TC 109 Z9 112 U1 5 U2 29 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 OCT 20 PY 2015 VL 314 IS 15 BP 1599 EP 1614 DI 10.1001/jama.2015.12783 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA CT7XK UT WOS:000363028500020 PM 26501536 ER PT J AU Jain, NB Harris, MB Garshick, E AF Jain, Nitin B. Harris, Mitchel B. Garshick, Eric TI Trends in Traumatic Spinal Cord Injury Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Jain, Nitin B.] Vanderbilt Univ, Sch Med, Dept Phys Med & Rehabil, Nashville, TN 37202 USA. [Harris, Mitchel B.] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Garshick, Eric] VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, Boston, MA USA. RP Jain, NB (reprint author), Vanderbilt Univ, Sch Med, Dept Phys Med & Rehabil, 2201 Childrens Way, Nashville, TN 37202 USA. EM nitin.jain@vanderbilt.edu FU RRD VA [I01 RX000792] NR 6 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 20 PY 2015 VL 314 IS 15 BP 1643 EP 1644 DI 10.1001/jama.2015.11200 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CT7XK UT WOS:000363028500026 PM 26501542 ER PT J AU Patterson, HC Gerbeth, C Thiru, P Vogtle, NF Knoll, M Shahsafaei, A Samocha, KE Huang, CX Harden, MM Song, R Chen, C Kao, J Shi, J Salmon, W Shaul, YD Stokes, MP Silva, JC Bell, GW MacArthur, DG Ruland, J Meisinger, C Lodish, HF AF Patterson, Heide Christine Gerbeth, Carolin Thiru, Prathapan Voegtle, Nora F. Knoll, Marko Shahsafaei, Aliakbar Samocha, Kaitlin E. Huang, Cher X. Harden, Mark Michael Song, Rui Chen, Cynthia Kao, Jennifer Shi, Jiahai Salmon, Wendy Shaul, Yoav D. Stokesh, Matthew P. Silvah, Jeffrey C. Bell, George W. MacArthur, Daniel G. Ruland, Juergen Meisinger, Chris Lodish, Harvey F. TI A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fostamatinib; dasatinib; rotenone; Btk; PTPN6 ID PROTEIN-TYROSINE PHOSPHATASES; B-CELL ACTIVATION; MULTIPLE SEQUENCE ALIGNMENT; OXIDATIVE STRESS; IMMUNOAFFINITY ENRICHMENT; LYMPHOCYTE-ACTIVATION; DIVERGENCE TIMES; IN-VIVO; KINASE; SYK AB Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane spacelocalized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells. C1 [Patterson, Heide Christine; Thiru, Prathapan; Knoll, Marko; Huang, Cher X.; Harden, Mark Michael; Song, Rui; Chen, Cynthia; Shi, Jiahai; Salmon, Wendy; Shaul, Yoav D.; Bell, George W.; Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Patterson, Heide Christine; Shahsafaei, Aliakbar] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Patterson, Heide Christine] Partners HealthCare Personalized Med, Lab Mol Med, Cambridge, MA 02139 USA. [Patterson, Heide Christine; Ruland, Juergen] Tech Univ Munich, Klinikum Rechts Isar, Inst Klin Chem & Biochem, D-81675 Munich, Germany. [Gerbeth, Carolin; Voegtle, Nora F.; Meisinger, Chris] Univ Freiburg, Inst Biochem & Mol Biol, D-79104 Freiburg, Germany. [Gerbeth, Carolin; Voegtle, Nora F.; Meisinger, Chris] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany. [Samocha, Kaitlin E.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Samocha, Kaitlin E.; MacArthur, Daniel G.] Broad Inst, Cambridge, MA 02142 USA. [Stokesh, Matthew P.; Silvah, Jeffrey C.] Cell Signaling Technol, Danvers, MA 02142 USA. [Lodish, Harvey F.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Lodish, Harvey F.] MIT, Dept Biol Engn, Cambridge, MA 02142 USA. RP Patterson, HC (reprint author), Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. EM ckunst@partners.org; lodish@wi.mit.edu RI Meisinger, Chris/J-1110-2014; shi, jiahai/D-7650-2013 OI shi, jiahai/0000-0002-6467-8289 FU NIH [5 P30 CA06516]; Deutsche Forschungsgemeinschaft [Kn1106/1-1]; Ludwig Postdoctoral Fellowship; [KO8 GM102718]; [T32 HL007627]; [RO1 DK047618] FX We thank the imaging, bioinformatics, flow cytometry, and genome core facilities at the Whitehead and Koch Institute, the Dana-Farber/Harvard Cancer Center Specialized Histopathology Core (supported by NIH Grant 5 P30 CA06516), Tilman Brummer, Aftabul Haque, Elias Hobeika, and RIKEN for assistance or provision of reagents. This research was supported by Grants KO8 GM102718 and T32 HL007627 (to H.C.P.), Fellowship Kn1106/1-1 from the Deutsche Forschungsgemeinschaft (to M.K.), a Ludwig Postdoctoral Fellowship (to Y.D.S), and Grant RO1 DK047618 (to H.F.L.). NR 112 TC 10 Z9 10 U1 1 U2 6 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 OCT 20 PY 2015 VL 112 IS 42 BP E5679 EP E5688 DI 10.1073/pnas.1517932112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT9LN UT WOS:000363138600007 PM 26438848 ER PT J AU Brady, RE Constans, JI Marx, BP Spira, JL Gevirtz, R Kimbrell, TA Kramer, TL Pyne, JM AF Brady, Robert E. Constans, Joseph I. Marx, Brian P. Spira, James L. Gevirtz, Richard Kimbrell, Timothy A. Kramer, Teresa L. Pyne, Jeffrey M. TI Effect of Symptom Over-Reporting on Heart Rate Variability in Veterans With Posttraumatic Stress Disorder SO JOURNAL OF TRAUMA & DISSOCIATION LA English DT Article DE post-traumatic stress disorder; veterans; heart rate variability; over-reporting; assessment ID ADMINISTERED PTSD SCALE; POWER SPECTRAL-ANALYSIS; PSYCHOPHYSIOLOGICAL ASSESSMENT; VIETNAM VETERANS; COMBAT VETERANS; ASSOCIATIONS; AFGHANISTAN; UTILITY; DUTY; IRAQ AB Physiological assessment of posttraumatic stress disorder (PTSD) presents an additional avenue for evaluating the severity of PTSD symptoms. We investigated whether the presence of a high number of uncommon symptoms attenuated the relation between self-reported PTSD symptoms and heart rate variability (HRV). Participants were 115 veterans from Operation Iraqi Freedom and Operation Enduring Freedom with or without PTSD. Symptom over-report was assessed using the Miller Forensic Assessment of Symptoms Test (M-FAST). Participants completed the Clinician-Administered PTSD Scale and M-FAST and underwent physiological assessment to determine HRV. These data were then entered into a hierarchical linear regression equation to test the moderating effect of over-reporting on the relation between PTSD symptom severity and HRV. The result of this analysis failed to demonstrate a significant moderating effect of over-reporting on the PTSD and HRV relation. HRV was a significant predictor of PTSD symptom severity, and this relation did not differ across levels of over-reporting. These findings did not support the hypothesis that over-reporting would attenuate the relation between PTSD and HRV. Clinical and research implications and directions for future investigation are discussed. C1 [Brady, Robert E.; Kimbrell, Timothy A.; Pyne, Jeffrey M.] Cent Arkansas Vet Healthcare Syst, Hlth Serv Res & Dev, North Little Rock, AR USA. [Brady, Robert E.; Kimbrell, Timothy A.; Kramer, Teresa L.; Pyne, Jeffrey M.] Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. [Constans, Joseph I.] Southeast Louisiana Vet Hlth Care Syst, New Orleans, LA USA. [Constans, Joseph I.] Tulane Univ, Dept Psychiat, New Orleans, LA 70118 USA. [Marx, Brian P.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Marx, Brian P.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Spira, James L.] Natl Ctr PTSD Pacific Isl, Honolulu, HI USA. [Gevirtz, Richard] Alliant Int Univ, Dept Clin Psychol, San Diego, CA USA. RP Brady, RE (reprint author), Geisel Sch Med Dartmouth, Dept Psychiat, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM Robert.E.Brady@dartmouth.edu FU Veterans Affairs Clinical Science Research and Development Merit Review [06S-VANIMH-01]; South Central Veterans Affairs Mental Illness Research Education and Clinical Center; Veterans Affairs Health Services Research & Development Center for Mental Health Outcomes Research [HFP 09-155]; Center for Translational Neuroscience [GM103425] FX This work was supported by Veterans Affairs Clinical Science Research and Development Merit Review (06S-VANIMH-01), South Central Veterans Affairs Mental Illness Research Education and Clinical Center, Veterans Affairs Health Services Research & Development Center for Mental Health Outcomes Research (HFP 09-155), and Center for Translational Neuroscience (GM103425). This work does not represent the views of the Department of Veterans Affairs or the United States Government. NR 29 TC 2 Z9 2 U1 1 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1529-9732 EI 1529-9740 J9 J TRAUMA DISSOCIATIO JI J. Trauma Dissociation PD OCT 20 PY 2015 VL 16 IS 5 BP 551 EP 562 DI 10.1080/15299732.2015.1021505 PG 12 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CT2RL UT WOS:000362651100005 PM 26011249 ER PT J AU Viny, AD Ott, CJ Spitzer, B Rivas, M Meydan, C Papalexi, E Yelin, D Shank, K Reyes, J Chiu, A Romin, Y Boyko, V Thota, S Maciejewski, JP Melnick, A Bradner, JE Levine, RL AF Viny, Aaron D. Ott, Christopher J. Spitzer, Barbara Rivas, Martin Meydan, Cem Papalexi, Efthymia Yelin, Dana Shank, Kaitlyn Reyes, Jaime Chiu, April Romin, Yevgeniy Boyko, Vitaly Thota, Swapna Maciejewski, Jaroslaw P. Melnick, Ari Bradner, James E. Levine, Ross L. TI Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CELL IDENTITY GENES; SUPER-ENHANCERS; FLT3 MUTATIONS; IN-VIVO; CHROMATIN; CTCF; EXPRESSION; CANCER; STAT5 AB Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haplo-insufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function. C1 [Viny, Aaron D.; Spitzer, Barbara; Papalexi, Efthymia; Yelin, Dana; Shank, Kaitlyn; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Viny, Aaron D.; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Leukemia Serv, Dept Med, New York, NY 10065 USA. [Chiu, April] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Romin, Yevgeniy; Boyko, Vitaly] Mem Sloan Kettering Canc Ctr, Mol Cytol Core Facil, New York, NY 10065 USA. [Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Ctr Epigenet Res, New York, NY 10065 USA. [Ott, Christopher J.; Reyes, Jaime; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Ott, Christopher J.; Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Rivas, Martin; Meydan, Cem; Melnick, Ari] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Yelin, Dana] Rabin Med Ctr, Dept Med, IL-49100 Petah Tiqwa, Israel. [Thota, Swapna; Maciejewski, Jaroslaw P.] Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol Res, Cleveland, OH 44195 USA. RP Levine, RL (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. EM james_bradner@dfci.harvard.edu; leviner@mskcc.org OI Rivas, Martin/0000-0002-9603-6897; Viny, Aaron/0000-0001-7039-0110 FU Memorial Sloan Kettering Center Support Grant [P30 CA008748]; Pershing Square Sohn Prize for Cancer Research; Damon Runyon Cancer Research Foundation Postdoctoral Fellowship Award; American Society of Hematology Research Training Award; NCI Training Grant, Clinical Scholars Biomedical Research Training Program [T32 CA009512]; Leukemia and Lymphoma Society; NCI Pathway to Independence Award [K99CA190861] FX We would like to thank Dr. Katia Manova and the staff of the Molecular Cytology Core Facility for their assistance in imaging and processing of microscopy data and the Memorial Sloan Kettering Center Support Grant (P30 CA008748).; This work was supported by a grant from the Pershing Square Sohn Prize for Cancer Research (to R.L. Levine); a Damon Runyon Cancer Research Foundation Postdoctoral Fellowship Award, an American Society of Hematology Research Training Award for Fellows, an NCI Training Grant, Clinical Scholars Biomedical Research Training Program (T32 CA009512), and philanthropic support from the Dana Foundation and Lymphoma Foundation (to A.D. Viny); and a Research Fellow Award from the Leukemia and Lymphoma Society and an NCI Pathway to Independence Award (K99CA190861; to C.J. Ott). NR 42 TC 15 Z9 15 U1 1 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD OCT 19 PY 2015 VL 212 IS 11 BP 1819 EP 1832 DI 10.1084/jem.20151317 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CZ2HX UT WOS:000366926800012 PM 26438361 ER PT J AU Humar, M Gather, MC Yun, SH AF Humar, Matjaz Gather, Malte C. Yun, Seok-Hyun TI Cellular dye lasers: lasing thresholds and sensing in a planar resonator SO OPTICS EXPRESS LA English DT Article ID GREEN FLUORESCENT PROTEIN; BIOCAVITY LASER; MICROLASERS; MARKER; CELLS AB Biological cell lasers are promising novel building blocks of future biocompatible optical systems and offer new approaches to cellular sensing and cytometry in a microfluidic setting. Here, we demonstrate a simple method for providing optical gain by using a variety of standard fluorescent dyes. The dye gain medium can be located inside or outside a cell, or in both, which gives flexibility in experimental design and makes the method applicable to all cell types. Due to the higher refractive index of the cytoplasm compared to the surrounding medium, a cell acts as a convex lens in a planar Fabry-Perot cavity. Its effect on the stability of the laser cavity is analyzed and utilized to suppress lasing outside cells. The resonance modes depend on the shape and internal structure of the cell. As proof of concept, we show how the laser output modes are affected by the osmotic pressure. (C) 2015 Optical Society of America C1 [Humar, Matjaz; Gather, Malte C.; Yun, Seok-Hyun] Harvard Univ, Massachusetts Gen Hosp, Wellman Ctr Photomed, Sch Med, Cambridge, MA 02139 USA. [Humar, Matjaz] J Stefan Inst, Condensed Matter Dept, SI-1000 Ljubljana, Slovenia. [Gather, Malte C.] Univ St Andrews, Sch Phys & Astron, SUPA, St Andrews KY16 9SS, Fife, Scotland. [Yun, Seok-Hyun] Harvard Mit Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Yun, SH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Wellman Ctr Photomed, Sch Med, 65 Landsdowne St UP-5, Cambridge, MA 02139 USA. EM syun@hms.harvard.edu RI Humar, Matjaz/I-8862-2012; OI Humar, Matjaz/0000-0003-3338-6723; Gather, Malte/0000-0002-4857-5562 FU U.S. National Science Foundation [ECCS-1101947, ECCS-1505569]; National Institutes of Health [P41 EB015903]; Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme [627274]; European Community Framework Programme [640012] FX This research was supported in part by the U.S. National Science Foundation (ECCS-1101947, ECCS-1505569) and National Institutes of Health (P41 EB015903). M.H. was supported in part by the Marie Curie International Outgoing Fellowship No 627274 within the 7th European Community Framework Programme. M.C.G. was supported in part by the Starting Grant No 640012 within the H2020 European Community Framework Programme. NR 30 TC 4 Z9 4 U1 10 U2 22 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD OCT 19 PY 2015 VL 23 IS 21 BP 27865 EP 27879 AR UNSP 247953 DI 10.1364/OE.23.027865 PG 15 WC Optics SC Optics GA CY7FR UT WOS:000366574400097 PM 26480446 ER PT J AU Nambudiri, VE Nambudiri, NS Nazarian, RM Tsao, SS AF Nambudiri, Vinod E. Nambudiri, Navya S. Nazarian, Rosalynn M. Tsao, Sandy S. TI CASE REVIEW A rash starting on the palms and soles SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID GUTTATE PSORIASIS C1 [Nambudiri, Vinod E.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Nambudiri, Vinod E.; Tsao, Sandy S.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Nambudiri, Navya S.] Cooperat Med Coll, Cochin, Kerala, India. [Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Nambudiri, VE (reprint author), Brigham & Womens Hosp, Dept Internal Med, 75 Francis St, Boston, MA 02115 USA. EM vinod.nambudiri@gmail.com NR 4 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD OCT 19 PY 2015 VL 351 AR h5452 DI 10.1136/bmj.h5452 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CV3FF UT WOS:000364143300002 PM 26481515 ER PT J AU Wang, L Jacobson, O Avdic, D Rotstein, BH Weiss, ID Collier, L Chen, XY Vasdev, N Liang, SH AF Wang, Lu Jacobson, Orit Avdic, Din Rotstein, Benjamin H. Weiss, Ido D. Collier, Lee Chen, Xiaoyuan Vasdev, Neil Liang, Steven H. TI Ortho-Stabilized F-18-Azido Click Agents and their Application in PET Imaging with Single-Stranded DNA Aptamers SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE aptamers; bioconjugation; fluorine; PET imaging; radiopharmaceuticals ID POSITRON-EMISSION-TOMOGRAPHY; OLIGONUCLEOTIDE APTAMER; DERIVATIVES; PEPTIDES; PROBES; F-18; PTK7; 1,2,3-TRIAZOLES; CHEMISTRY; BOMBESIN AB Azido F-18-arenes are important and versatile building blocks for the radiolabeling of biomolecules via Huisgen cycloaddition ("click chemistry") for positron emission tomography (PET). However, routine access to such clickable agents is challenged by inefficient and/or poorly defined multistep radiochemical approaches. A high-yielding direct radiofluorination for azido F-18-arenes was achieved through the development of an ortho-oxygen-stabilized iodonium derivative (OID). This OID strategy addresses an unmet need for a reliable azido F-18-arene clickable agent for bioconjugation reactions. A ssDNA aptamer was radiolabeled with this agent and visualized in a xenograft mouse model of human colon cancer by PET, which demonstrates that this OID approach is a convenient and highly efficient way of labeling and tracking biomolecules. C1 [Wang, Lu; Avdic, Din; Rotstein, Benjamin H.; Collier, Lee; Vasdev, Neil; Liang, Steven H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Wang, Lu; Avdic, Din; Rotstein, Benjamin H.; Collier, Lee; Vasdev, Neil; Liang, Steven H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Jacobson, Orit; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Weiss, Ido D.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov; vasdev.neil@mgh.harvard.edu; liang.steven@mgh.harvard.edu FU Department of Radiology, MGH/HMS; NIBIB, NIH; NIH FX This work was supported by the Department of Radiology, MGH/HMS, and intramural research program of NIBIB, NIH. We thank Professor Lee Josephson for helpful discussion. S.H.L is a recipient of an NIH career development award. NR 48 TC 10 Z9 10 U1 15 U2 57 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD OCT 19 PY 2015 VL 54 IS 43 BP 12777 EP 12781 DI 10.1002/anie.201505927 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA CU3KB UT WOS:000363422700049 PM 26308650 ER PT J AU Germine, L Russell, R Bronstad, PM Blokland, GAM Smoller, JW Kwok, H Anthony, SE Nakayama, K Rhodes, G Wilmer, JB AF Germine, Laura Russell, Richard Bronstad, P. Matthew Blokland, Gabriella A. M. Smoller, Jordan W. Kwok, Holum Anthony, Samuel E. Nakayama, Ken Rhodes, Gillian Wilmer, Jeremy B. TI Individual Aesthetic Preferences for Faces Are Shaped Mostly by Environments, Not Genes SO CURRENT BIOLOGY LA English DT Article ID FACIAL ATTRACTIVENESS; SOCIAL TRANSMISSION; BEAUTY; BEHOLDER; AVERAGENESS; ADAPTATION; SYMMETRY; BEHAVIOR; HUMANS; PROSOPAGNOSIA AB Although certain characteristics of human faces are broadly considered more attractive (e.g., symmetry, averageness), people also routinely disagree with each other on the relative attractiveness of faces. That is, to some significant degree, beauty is in the "eye of the beholder." Here, we investigate the origins of these individual differences in face preferences using a twin design, allowing us to estimate the relative contributions of genetic and environmental variation to individual face attractiveness judgments or face preferences. We first show that individual face preferences (IP) can be reliably measured and are readily dissociable from other types of attractiveness judgments (e.g., judgments of scenes, objects). Next, we show that individual face preferences result primarily from environments that are unique to each individual. This is in striking contrast to individual differences in face identity recognition, which result primarily from variations in genes [1]. We thus complete an etiological double dissociation between two core domains of social perception (judgments of identity versus attractiveness) within the same visual stimulus (the face). At the same time, we provide an example, rare in behavioral genetics, of a reliably and objectively measured behavioral characteristic where variations are shaped mostly by the environment. The large impact of experience on individual face preferences provides a novel window into the evolution and architecture of the social brain, while lending new empirical support to the long-standing claim that environments shape individual notions of what is attractive. C1 [Germine, Laura; Blokland, Gabriella A. M.; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Germine, Laura; Anthony, Samuel E.; Nakayama, Ken] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Germine, Laura; Blokland, Gabriella A. M.; Smoller, Jordan W.] Harvard Univ, Dept Psychiat, Sch Med, Boston, MA 02115 USA. [Russell, Richard] Gettysburg Coll, Dept Psychol, Gettysburg, PA 17325 USA. [Bronstad, P. Matthew] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Kwok, Holum; Wilmer, Jeremy B.] Wellesley Coll, Dept Psychol, Wellesley, MA 02481 USA. [Rhodes, Gillian] Univ Western Australia, Sch Psychol, ARC Ctr Excellence Cognit & Its Disorders, Crawley, WA 6009, Australia. RP Germine, L (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. EM lgermine@gmail.com OI Blokland, Gabriella/0000-0003-0566-444X; Germine, Laura/0000-0001-8690-8412 FU Centre of Research Excellence Grant from the National Health and Medical Research Council; US National Institute of Mental Health [T32MH016259, F32MH102971, K24MH094614]; Australian Research Council Centre of Excellence in Cognition and Its Disorders [CE110001021]; ARC [DP0877379, DP130102300]; Brachman Hoffman Fellowship; Brachman Hoffman Small Grant FX This research was facilitated through access to the Australian Twin Registry, a national resource supported by a Centre of Research Excellence Grant from the National Health and Medical Research Council. This work was supported by US National Institute of Mental Health grants to L.G. (T32MH016259 and F32MH102971) and to J.W.S. (K24MH094614), the Australian Research Council Centre of Excellence in Cognition and Its Disorders (CE110001021), an ARC Professorial Fellowship to G.R. (DP0877379), an ARC Discovery Outstanding Researcher Award to G.R. (DP130102300), and a Brachman Hoffman Fellowship and Brachman Hoffman Small Grant to J.B.W. NR 48 TC 2 Z9 2 U1 6 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD OCT 19 PY 2015 VL 25 IS 20 BP 2684 EP 2689 DI 10.1016/j.cub.2015.08.048 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CU2NF UT WOS:000363359500026 PM 26441352 ER PT J AU Daley, GQ AF Daley, George Q. TI Stem cells and the evolving notion of cellular identity SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE embryonic stem cells; reprogramming; induced pluripotent stem cells; cellNet ID HUMAN SOMATIC-CELLS; BONE MARROW CELLS; DEFINED FACTORS; RADIATION SENSITIVITY; DIRECT CONVERSION; FIBROBLASTS; PLURIPOTENCY; FATE; TRANSPLANTATION; EXPRESSION AB Stem cells are but one class of the myriad types of cells within an organism. With potential to self-renew and capacity to differentiate, stem cells play essential roles at multiple stages of development. In the early embryo, pluripotent stem cells represent progenitors for all tissues while later in development, tissue-restricted stem cells give rise to cells with highly specialized functions. As best understood in the blood, skin and gut, stem cells are the seeds that sustain tissue homeostasis and regeneration, while in other tissues like the muscle, liver, kidney and lung, various stem or progenitor cells play facultative roles in tissue repair and response to injury. Here, I will provide a brief perspective on the evolving notion of cellular identity and how reprogramming and transcription factor-mediated conversions of one cell type into another have fundamentally altered our assumptions about the stability of cell identity, with profound long-term implications for biomedical research and regenerative medicine. C1 [Daley, George Q.] Boston Childrens Hosp, Howard Hughes Med Inst, Div Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Div Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu FU US National Institutes of Health, Progenitor Cell Biology Consortium [R24-DK092760, RC4-DK090913, UO1-HL100001]; Alex's Lemonade Stand; Doris Duke Medical Foundation; Ellison Medical Foundation FX The author is supported by grants from the US National Institutes of Health: R24-DK092760, RC4-DK090913, and UO1-HL100001 Progenitor Cell Biology Consortium; Alex's Lemonade Stand; Doris Duke Medical Foundation and Ellison Medical Foundation. NR 30 TC 1 Z9 1 U1 1 U2 10 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD OCT 19 PY 2015 VL 370 IS 1680 AR 20140376 DI 10.1098/rstb.2014.0376 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CT3PQ UT WOS:000362719500011 PM 26416685 ER PT J AU Ernst, M Romero, JM Buhk, JH Cheng, B Herrmann, J Fiehler, J Groth, M AF Ernst, Marielle Romero, Javier M. Buhk, Jan-Hendrik Cheng, Bastian Herrmann, Jochen Fiehler, Jens Groth, Michael TI Sensitivity of Hyperdense Basilar Artery Sign on Non-Enhanced Computed Tomography SO PLOS ONE LA English DT Article ID CT ANGIOGRAPHY; STATISTICAL-METHODS; OCCLUSION; AGREEMENT; DIAGNOSIS; THROMBUS; STROKE AB Purpose The hyperdense basilar artery sign (HBAS) is an indicator of vessel occlusion on non contrast-enhanced computer tomography (NECT) in acute stroke patients. Since basilar artery occlusion (BAO) is associated with a high mortality and morbidity, its early detection is of great clinical value. We sought to analyze the influence of density measurement as well as a normalized ratio of Hounsfield unit/hematocrit (HU/Hct) ratio on the detection of BAO on NECT in patients with suspected BAO. Materials and Methods 102 patients with clinically suspected BAO were examined with NECT followed immediately by Multidetector computed tomography Angiography. Two observers independently analyzed the images regarding the presence or absence of HBAS on NECT and performed HU measurements in the basilar artery. Receiver operating characteristic curve analysis was performed to determine the optimal density threshold for BAO using attenuation measurements or HU/Hct ratio. Results Sensitivity of visual detection of the HBAS on NECT was relatively low 81% (95%-CI, 54-95%) while specificity was high 91% (95%-CI, 82-96%). The highest sensitivity was achieved by the combination of visual assessment and additional quantitative attenuation measurements applying a cut-off value of 46.5 HU with 94% sensitivity and 81% specificity for BAO. A HU/Hct ratio >1.32 revealed sensitivity of 88% (95%-CI, 60-98%) and specificity of 84% (95%-CI, 74-90%). Conclusion In patients with clinically suspected acute BAO the combination of visual assessment and additional attenuation measurement with a cut-off value of 46.5 HU is a reliable approach with high sensitivity in the detection of BAO on NECT. C1 [Ernst, Marielle; Buhk, Jan-Hendrik; Fiehler, Jens; Groth, Michael] Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Neuroradiol, Ctr Radiol & Endoscopy, Hamburg, Germany. [Romero, Javier M.] Harvard Univ, Sch Med, Dept Radiol, Div Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Cheng, Bastian] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. [Herrmann, Jochen; Groth, Michael] Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Radiol, Ctr Radiol & Endoscopy, Div Pediat Radiol, Hamburg, Germany. RP Ernst, M (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Neuroradiol, Ctr Radiol & Endoscopy, Hamburg, Germany. EM m.ernst@uke.de NR 19 TC 0 Z9 0 U1 0 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 OCT 19 PY 2015 VL 10 IS 10 AR e0141096 DI 10.1371/journal.pone.0141096 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT7WW UT WOS:000363026600030 PM 26479718 ER PT J AU Liu, QL Krishnasamy, Y Rehman, H Lemasters, JJ Schnellmann, RG Zhong, Z AF Liu, Qinlong Krishnasamy, Yasodha Rehman, Hasibur Lemasters, John J. Schnellmann, Rick G. Zhong, Zhi TI Disrupted Renal Mitochondrial Homeostasis after Liver Transplantation in Rats SO PLOS ONE LA English DT Article ID ACUTE KIDNEY INJURY; PROLIFERATOR-ACTIVATED RECEPTOR; ACUTE TUBULAR-NECROSIS; CRITICAL ILLNESS; ISCHEMIA-REPERFUSION; HEPATORENAL-SYNDROME; MAMMALIAN-CELLS; PROTEIN-KINASE; RISK-FACTORS; BIOGENESIS AB Background Suppressed mitochondrial biogenesis (MB) contributes to acute kidney injury (AKI) after many insults. AKI occurs frequently after liver transplantation (LT) and increases mortality. This study investigated whether disrupted mitochondrial homeostasis plays a role in AKI after LT. Methods Livers were explanted from Lewis rats and implanted after 18 h cold storage. Kidney and blood were collected 18 h after LT. Results In the kidney, oxidative phosphorylation (OXPHOS) proteins ATP synthase-beta and NADH dehydrogenase-3 decreased 44% and 81%, respectively, with marked reduction in associated mRNAs. Renal PGC-1 alpha, the major regulator of MB, decreased 57% with lower mRNA and increased acetylation, indicating inhibited synthesis and suppressed activation. Mitochondrial transcription factor-A, which controls mtDNA replication and transcription, protein and mRNA decreased 66% and 68%, respectively, which was associated with 64% decreases in mtDNA. Mitochondrial fission proteins Drp-1 and Fis-1 and mitochondrial fusion protein mitofusin-1 all decreased markedly. In contrast, PTEN-induced putative kinase 1 and microtubule-associated protein 1A/1B-light chain 3 increased markedly after LT, indicating enhanced mitophagy. Concurrently, 18- and 13-fold increases in neutrophil gelatinase-associated lipocalin and cleaved caspase-3 occurred in renal tissue. Both serum creatinine and blood urea nitrogen increased >= 2 fold. Mild to moderate histological changes were observed in the kidney, including loss of brush border, vacuolization of tubular cells in the cortex, cast formation and necrosis in some proximal tubular cells. Finally, myeloperoxidase and ED-1 also increased, indicating inflammation. Conclusion Suppression of MB, inhibition of mitochondrial fission/fusion and enhancement of mitophagy occur in the kidneys of recipients of liver grafts after long cold storage, which may contribute to the occurrence of AKI and increased mortality after LT. C1 [Liu, Qinlong; Krishnasamy, Yasodha; Rehman, Hasibur; Lemasters, John J.; Schnellmann, Rick G.; Zhong, Zhi] Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. [Liu, Qinlong] Dalian Med Univ, Affiliated Hosp 2, Dalian, Liaoning Provin, Peoples R China. [Lemasters, John J.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Schnellmann, Rick G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Zhong, Z (reprint author), Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. EM zhong@musc.edu FU National Institutes of Health [DK70844, DK073336, DK037034]; Chinese National Natural Foundation [81470878] FX This study was supported, in part, by grants DK70844, DK073336 and DK037034 from the National Institutes of Health and grant #81470878 from Chinese National Natural Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 1 Z9 1 U1 0 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 OCT 19 PY 2015 VL 10 IS 10 AR e0140906 DI 10.1371/journal.pone.0140906 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT7WW UT WOS:000363026600025 PM 26480480 ER PT J AU Chatzi, C Schnell, E Westbrook, GL AF Chatzi, Christina Schnell, Eric Westbrook, Gary L. TI Localized hypoxia within the subgranular zone determines the early survival of newborn hippocampal granule cells SO ELIFE LA English DT Article ID NEURAL STEM-CELLS; ENDOTHELIAL GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; ADULT DENTATE GYRUS; VASCULAR NICHE; STIMULATES PROLIFERATION; PROGENITOR CELLS; OXYGEN-TENSION; IN-VITRO; NEUROGENESIS AB The majority of adult hippocampal newborn cells die during early differentiation from intermediate progenitors (IPCs) to immature neurons. Neural stem cells in vivo are located in a relative hypoxic environment, and hypoxia enhances their survival, proliferation and stemness in vitro. Thus, we hypothesized that migration of IPCs away from hypoxic zones within the SGZ might result in oxidative damage, thus triggering cell death. Hypoxic niches were observed along the SGZ, composed of adult NSCs and early IPCs, and oxidative byproducts were present in adjacent late IPCs and neuroblasts. Stabilizing hypoxia inducible factor-1 alpha with dimethyloxallyl glycine increased early survival, but not proliferation or differentiation, in neurospheres in vitro and in newly born SGZ cells in vivo. Rescue experiments in Bax(fl/fl) mutants supported these results. We propose that localized hypoxia within the SGZ contributes to the neurogenic microenvironment and determines the early, activity-independent survival of adult hippocampal newborn cells. C1 [Chatzi, Christina; Westbrook, Gary L.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Schnell, Eric] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR USA. [Schnell, Eric] VA Portland Hlth Care Syst, US Dept Vet Affairs, Portland, OR USA. RP Westbrook, GL (reprint author), Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. EM westbroo@ohsu.edu FU National Institutes of Health [NS R01 080979, NS P30 061800]; Ellison Medical Foundation; AXA Research Fund; U.S. Department of Veterans Affairs [CDA-2] FX National Institutes of Health NS R01 080979 Gary L Westbrook; Ellison Medical Foundation Gary L Westbrook; National Institutes of Health NS P30 061800 Gary L Westbrook; AXA Research Fund C Chatzi; U.S. Department of Veterans Affairs CDA-2 E Schnell NR 61 TC 3 Z9 3 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 17 PY 2015 VL 4 AR e08722 DI 10.7554/eLife.08722 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0JI UT WOS:000373887900001 PM 26476335 ER PT J AU Yeh, RW Elmariah, S Doros, G Kereiakes, DJ Mauri, L AF Yeh, Robert W. Elmariah, Sammy Doros, Gheorghe Kereiakes, Dean J. Mauri, Laura TI Mortality risk with dual antiplatelet therapy? SO LANCET LA English DT Letter ID METAANALYSIS C1 [Yeh, Robert W.; Elmariah, Sammy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA 02163 USA. [Yeh, Robert W.; Elmariah, Sammy; Doros, Gheorghe; Mauri, Laura] Harvard Clin Res Inst, Boston, MA USA. [Doros, Gheorghe] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Kereiakes, Dean J.] Christ Hosp, Heart & Vasc Ctr, Lindner Res Ctr, Cincinnati, OH 45219 USA. [Mauri, Laura] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, Boston, MA 02115 USA. RP Yeh, RW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA 02163 USA. EM ryeh@partners.org FU NHLBI NIH HHS [K23 HL118138] NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 17 PY 2015 VL 386 IS 10003 BP 1533 EP 1534 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CT5VC UT WOS:000362878200022 PM 26530618 ER PT J AU Tago, N Katolik, A Clark, NE Montemayor, EJ Seio, K Sekine, M Hart, PJ Damha, MJ AF Tago, Nobuhiro Katolik, Adam Clark, Nathaniel E. Montemayor, Eric J. Seio, Kohji Sekine, Mitsuo Hart, P. John Damha, Masad J. TI Design, Synthesis, and Properties of Phosphoramidate 2 ',5 '-Linked Branched RNA: Toward the Rational Design of Inhibitors of the RNA Lariat Debranching Enzyme SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID FRONTOTEMPORAL LOBAR DEGENERATION; TDP-43; OLIGORIBONUCLEOTIDES; SPLICEOSOME; DISEASE; ANALOGS AB Two RNA fragments linked by means of a 2',5' phosphodiester bridge (2' hydroxyl of one fragment connected to the 5' hydroxyl of the other) constitute a class of nucleic acids known as branched RNAs (bRNAs). In this report we show that bRNA analogues containing 2',5' phosphoramidate linkages (bN-RNAs) inhibit the lariat debranching enzyme, a 2',5'-phosphodiesterase that has recently been implicated in neurodegenerative diseases associated with aging. bN-RNAs were efficiently generated using automated solid-phase synthesis and suitably protected branchpoint building blocks. Two orthogonally removable groups, namely the 4-monomethoxytrityl (MMTr) group and the fluorenylmethyl-oxycarbonyl (Fmoc) groups, were evaluated as protecting groups of the 2' amino functionality. The 2'-N-Fmoc methodology was found to successfully produce bN-RNAs on solid-phase oligonucleotide synthesis. The synthesized bN-RNAs resisted hydrolysis by the lariat debranching enzyme (Dbr1) and, in addition, were shown to attenuate the Dbr1-mediated hydrolysis of native bRNA. C1 [Tago, Nobuhiro; Katolik, Adam; Damha, Masad J.] McGill Univ, Dept Chem, Montreal, PQ H3A 0B8, Canada. [Tago, Nobuhiro; Seio, Kohji; Sekine, Mitsuo] Tokyo Inst Technol, Dept Life Sci, Midori Ku, Yokohama, Kanagawa 2268501, Japan. [Clark, Nathaniel E.; Montemayor, Eric J.; Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX 78229 USA. [Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Montemayor, Eric J.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Montemayor, Eric J.] Univ Wisconsin, Dept Biomol Chem, Madison, WI 53706 USA. RP Damha, MJ (reprint author), McGill Univ, Dept Chem, 801 Sherbrooke St West, Montreal, PQ H3A 0B8, Canada. EM masad.damha@mcgill.ca FU National Science and Engineering Research Council; Department of Veterans Affairs [1 I01 BX002580]; Robert A. Welch Foundation [AQ-1399]; National Science Foundation [DBI-0905865]; Judith and Jean Pape Adams Charitable Foundation; Barshop Institute for Longevity and Aging Studies [5 T32 AG021890]; Japan Society for the Promotion of Science (JSPS) FX This work was supported in part by grants from the National Science and Engineering Research Council (to M.J.D.), Department of Veterans Affairs (1 I01 BX002580, to P.J.H.), the Robert A. Welch Foundation (AQ-1399, to P.J.H.), the National Science Foundation (DBI-0905865, to E.J.M.) the Judith and Jean Pape Adams Charitable Foundation (to P.J.H.), the Barshop Institute for Longevity and Aging Studies (5 T32 AG021890, to E.J.M. and N.E.C.), and a Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from a Japan Society for the Promotion of Science (JSPS). NR 28 TC 3 Z9 3 U1 2 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD OCT 16 PY 2015 VL 80 IS 20 BP 10108 EP 10118 DI 10.1021/acs.joc.5b01719 PG 11 WC Chemistry, Organic SC Chemistry GA CU0QU UT WOS:000363224600032 PM 26378468 ER PT J AU Gruss, S Treister, R Werner, P Traue, HC Crawcour, S Andrade, A Walter, S AF Gruss, Sascha Treister, Roi Werner, Philipp Traue, Harald C. Crawcour, Stephen Andrade, Adriano Walter, Steffen TI Pain Intensity Recognition Rates via Biopotential Feature Patterns with Support Vector Machines SO PLOS ONE LA English DT Article ID ELECTROMYOGRAPHIC SIGNALS; SKIN-CONDUCTANCE; STIMULATION AB Background The clinically used methods of pain diagnosis do not allow for objective and robust measurement, and physicians must rely on the patient's report on the pain sensation. Verbal scales, visual analog scales (VAS) or numeric rating scales (NRS) count among the most common tools, which are restricted to patients with normal mental abilities. There also exist instruments for pain assessment in people with verbal and / or cognitive impairments and instruments for pain assessment in people who are sedated and automated ventilated. However, all these diagnostic methods either have limited reliability and validity or are very time-consuming. In contrast, biopotentials can be automatically analyzed with machine learning algorithms to provide a surrogate measure of pain intensity. Methods In this context, we created a database of biopotentials to advance an automated pain recognition system, determine its theoretical testing quality, and optimize its performance. Eighty-five participants were subjected to painful heat stimuli (baseline, pain threshold, two intermediate thresholds, and pain tolerance threshold) under controlled conditions and the signals of electromyography, skin conductance level, and electrocardiography were collected. A total of 159 features were extracted from the mathematical groupings of amplitude, frequency, stationarity, entropy, linearity, variability, and similarity. Results We achieved classification rates of 90.94% for baseline vs. pain tolerance threshold and 79.29% for baseline vs. pain threshold. The most selected pain features stemmed from the amplitude and similarity group and were derived from facial electromyography. Conclusion The machine learning measurement of pain in patients could provide valuable information for a clinical team and thus support the treatment assessment. C1 [Gruss, Sascha; Traue, Harald C.; Walter, Steffen] Univ Ulm, Dept Psychosomat Med & Psychotherapy, Med Psychol, D-89069 Ulm, Germany. [Treister, Roi] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Treister, Roi] Harvard Univ, Sch Med, Dept Neurol, Nerve Injury Unit, Boston, MA 02115 USA. [Werner, Philipp] Univ Magdeburg, Inst Informat Technol & Commun, D-39106 Magdeburg, Germany. [Andrade, Adriano] Univ Fed Uberlandia, Biomed Engn Lab BioLab, BR-38400 Uberlandia, MG, Brazil. [Crawcour, Stephen] Tech Univ Dresden, Dept Clin Psychol & Psychotherapy, Dresden, Germany. RP Walter, S (reprint author), Univ Ulm, Dept Psychosomat Med & Psychotherapy, Med Psychol, D-89069 Ulm, Germany. EM steffen.walter@uni-ulm.de OI Andrade, Adriano/0000-0002-5689-6606 FU German Research Foundation [DFG/TR233/12]; Fundacao de Amparo a Pesquisa do Estado de Minas Gerais; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior; Brazilian government FX This research was part of the DFG/TR233/12 (http://www.dfg.de/) "Advancement and Systematic Validation of an Automated Pain Recognition System on the Basis of Facial Expression and Psychobiological Parameters" project, funded by the German Research Foundation, Fundacao de Amparo a Pesquisa do Estado de Minas Gerais, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior, and the Brazilian government funded travel, research stay and conference costs. NR 37 TC 6 Z9 6 U1 3 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 OCT 16 PY 2015 VL 10 IS 10 AR e0140330 DI 10.1371/journal.pone.0140330 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU0DF UT WOS:000363185500040 PM 26474183 ER PT J AU Liao, W Jordaan, G Nham, P Phan, RT Pelegrini, M Sharma, S AF Liao, Wei Jordaan, Gwen Nham, Phillipp Phan, Ryan T. Pelegrini, Matteo Sharma, Sanjai TI Gene expression and splicing alterations analyzed by high throughput RNA sequencing of chronic lymphocytic leukemia specimens SO BMC CANCER LA English DT Article DE CLL; RNA-sequencing; Differential gene expression; Alternative splicing ID COMPARATIVE GENOMIC HYBRIDIZATION; IDENTIFIES RECURRENT MUTATIONS; DIFFERENTIAL EXPRESSION; SIGNALING PATHWAY; CD38 EXPRESSION; SEQ EXPERIMENTS; BREAST CANCERS; B-CELLS; C-FOS; RECEPTOR AB Background: To determine differentially expressed and spliced RNA transcripts in chronic lymphocytic leukemia specimens a high throughput RNA-sequencing (HTS RNA-seq) analysis was performed. Methods: Ten CLL specimens and five normal peripheral blood CD19+ B cells were analyzed by HTS RNA-seq. The library preparation was performed with Illumina TrueSeq RNA kit and analyzed by Illumina HiSeq 2000 sequencing system. Results: An average of 48.5 million reads for B cells, and 50.6 million reads for CLL specimens were obtained with 10396 and 10448 assembled transcripts for normal B cells and primary CLL specimens respectively. With the Cuffdiff analysis, 2091 differentially expressed genes (DEG) between B cells and CLL specimens based on FPKM (fragments per kilobase of transcript per million reads and false discovery rate, FDR q < 0.05, fold change > 2) were identified. Expression of selected DEGs (n = 32) with up regulated and down regulated expression in CLL from RNA-seq data were also analyzed by qRT-PCR in a test cohort of CLL specimens. Even though there was a variation in fold expression of DEG genes between RNA-seq and qRT-PCR; more than 90 % of analyzed genes were validated by qRT-PCR analysis. Analysis of RNA-seq data for splicing alterations in CLL and B cells was performed by Multivariate Analysis of Transcript Splicing (MATS analysis). Skipped exon was the most frequent splicing alteration in CLL specimens with 128 significant events (P-value < 0.05, minimum inclusion level difference >0.1). Conclusion: The RNA-seq analysis of CLL specimens identifies novel DEG and alternatively spliced genes that are potential prognostic markers and therapeutic targets. High level of validation by qRT-PCR for a number of DEG genes supports the accuracy of this analysis. Global comparison of transcriptomes of B cells, IGVH non-mutated CLL (U-CLL) and mutated CLL specimens (M-CLL) with multidimensional scaling analysis was able to segregate CLL and B cell transcriptomes but the M-CLL and U-CLL transcriptomes were indistinguishable. The analysis of HTS RNA-seq data to identify alternative splicing events and other genetic abnormalities specific to CLL is an added advantage of RNA-seq that is not feasible with other genome wide analysis. C1 [Liao, Wei; Jordaan, Gwen; Sharma, Sanjai] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Div Hematol Oncol, Los Angeles, CA 90073 USA. [Nham, Phillipp; Phan, Ryan T.] VA Greater Los Angeles Healthcare Syst, Dept Pathol, Los Angeles, CA USA. [Pelegrini, Matteo] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90073 USA. [Sharma, Sanjai] Univ Calif Los Angeles, West Los Angeles VA Med Ctr, Los Angeles, CA 90073 USA. RP Sharma, S (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Div Hematol Oncol, Los Angeles, CA 90073 USA. EM sasharma@mednet.ucla.edu FU Flight Attendants Medical Research Institute (FAMRI); Veterans Administration Merit Research award FX SS is supported by a grant from Flight Attendants Medical Research Institute (FAMRI), and Veterans Administration Merit Research award. We thank the Broad Stem Cell Research Institute at UCLA for their help in high throughput RNA sequencing. NR 68 TC 2 Z9 2 U1 3 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 16 PY 2015 VL 15 AR 714 DI 10.1186/s12885-015-1708-9 PG 14 WC Oncology SC Oncology GA CT5QP UT WOS:000362865600002 PM 26474785 ER PT J AU Puliafito, A De Simone, A Seano, G Gagliardi, PA Di Blasio, L Chianale, F Gamba, A Primo, L Celani, A AF Puliafito, Alberto De Simone, Alessandro Seano, Giorgio Gagliardi, Paolo Armando Di Blasio, Laura Chianale, Federica Gamba, Andrea Primo, Luca Celani, Antonio TI Three-dimensional chemotaxis-driven aggregation of tumor cells SO SCIENTIFIC REPORTS LA English DT Article ID PROSTATE-CANCER CELLS; IN-VITRO; HOMOTYPIC AGGREGATION; LYSOPHOSPHATIDIC ACID; LUNG-CANCER; MIGRATION; INVASION; MORPHOGENESIS; METASTASIS; MECHANISMS AB One of the most important steps in tumor progression involves the transformation from a differentiated epithelial phenotype to an aggressive, highly motile phenotype, where tumor cells invade neighboring tissues. Invasion can occur either by isolated mesenchymal cells or by aggregates that migrate collectively and do not lose completely the epithelial phenotype. Here, we show that, in a three-dimensional cancer cell culture, collective migration of cells eventually leads to aggregation in large clusters. We present quantitative measurements of cluster velocity, coalescence rates, and proliferation rates. These results cannot be explained in terms of random aggregation. Instead, a model of chemotaxis-driven aggregation - mediated by a diffusible attractant - is able to capture several quantitative aspects of our results. Experimental assays of chemotaxis towards culture conditioned media confirm this hypothesis. Theoretical and numerical results further suggest an important role for chemotactic-driven aggregation in spreading and survival of tumor cells. C1 [Puliafito, Alberto; Seano, Giorgio; Gagliardi, Paolo Armando; Di Blasio, Laura; Chianale, Federica; Primo, Luca] Candiolo Canc Inst FPO IRCCS, Candiolo, Turin, Italy. [De Simone, Alessandro] Swiss Fed Inst Technol EPFL, Sch Life Sci, Swiss Inst Expt Canc Res ISREC, Lausanne, Switzerland. [Seano, Giorgio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Edwin L Steele Lab Tumor Biol, Boston, MA USA. [Gagliardi, Paolo Armando; Di Blasio, Laura; Primo, Luca] Univ Turin, Dept Oncol, I-10060 Turin, Italy. [Gamba, Andrea] Polytech Univ Turin, Dept Appl Sci & Technol, Inst Condensed Matter Phys & Complex Syst, I-10129 Turin, Italy. [Gamba, Andrea] Human Genet Fdn HuGeF, Turin, Italy. [Gamba, Andrea] Ist Nazl Fis Nucl INFN, I-10125 Turin, Italy. [Celani, Antonio] Abdus Salam Ctr Theoret Phys ICTP, Quantitat Life Sci Unit, I-34151 Trieste, Italy. RP Celani, A (reprint author), Abdus Salam Ctr Theoret Phys ICTP, Quantitat Life Sci Unit, Str Costiera 11, I-34151 Trieste, Italy. EM celani@ictp.it RI Seano, Giorgio/R-6611-2016; GAMBA, ANDREA ANTONIO/B-9097-2008; OI Seano, Giorgio/0000-0002-7294-302X; GAMBA, ANDREA ANTONIO/0000-0002-2591-2722; Gagliardi, Paolo Armando/0000-0002-4818-035X; di Blasio, Laura/0000-0002-1337-7654 FU Fondazione Piemontese per la Ricerca sul Cancro-Onlus; Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG 14635]; Fondo Investimenti per la Ricerca di Base (FIRB) RBAP11BYNP-Newton FX We are grateful to Stefano Di Talia, Livio Trusolino and Massimo Vergassola for their comments and critical reading on the manuscript. This study was supported by Fondazione Piemontese per la Ricerca sul Cancro-Onlus (Intramural Grant 5 x 1000 2008) and Systems Biology Start-up grant. Additional financial support came from Associazione Italiana per la Ricerca sul Cancro (AIRC) investigator grants IG 14635 to LP and Fondo Investimenti per la Ricerca di Base (FIRB) RBAP11BYNP-Newton to LP. NR 50 TC 5 Z9 5 U1 1 U2 17 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 OCT 16 PY 2015 VL 5 AR 15205 DI 10.1038/srep15205 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT5TC UT WOS:000362872800001 PM 26471876 ER PT J AU Li, CS Tian, HJ Zou, M Zhao, KW Li, YW Lao, LF Brochmann, EJ Duarte, MEL Daubs, MD Zhou, YH Murray, SS Wang, JC AF Li, Chen-Shuang Tian, Haijun Zou, Min Zhao, Ke-Wei Li, Yawei Lao, Lifeng Brochmann, Elsa J. Duarte, M. Eugenia L. Daubs, Michael D. Zhou, Yan-Heng Murray, Samuel S. Wang, Jeffrey C. TI Secreted phosphoprotein 24 kD (Spp24) inhibits growth of human pancreatic cancer cells caused by BMP-2 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Bone morphogenetic proteins-2; Secreted phosphoprotein 24 kD; Pancreatic cancer ID BONE MORPHOGENETIC PROTEIN-2; PROSTATE-CANCER; TUMOR-GROWTH; A549 CELLS; TGF-BETA; IN-VIVO; EXPRESSION; LESIONS; NOGGIN; OVEREXPRESSION AB The emerging role of bone morphogenetic proteins (BMPs) in the initiation and progression of multiple cancers has drawn great attention in cancer research. In this study, we report that BMP-2 can promote the proliferation of the pancreatic tumor cell line, PANC-1. Secreted phosphoprotein 24 kD (Spp24), a BMP binding protein, did not affect the proliferation of the cells but promoted the apoptosis of the cells in vitro. In a xeneograft tumor model using PANC-1 cells, BMP-2 dramatically promoted tumor growth, while Spp24 not only abolished the effect of BMP-2, but also dramatically induced tumor shrinking when used alone. Activation of Smad1/518 participated in this process as demonstrated by immunohistochemical staining of phosphorylated Smad 1/5/8. We conclude that Spp24 can be developed into a therapeutic agent that could be employed in clinical situations where the inhibition of BMPs and related proteins is advantageous. (C) 2015 Elsevier Inc. All rights reserved. C1 [Li, Chen-Shuang; Zhou, Yan-Heng] Peking Univ Sch & Hosp Stomatol, Dept Orthodont, Beijing 100081, Peoples R China. [Tian, Haijun] Second Mil Med Univ, Dept Orthopaed Surg, Changzheng Hosp, Shanghai, Peoples R China. [Tian, Haijun; Li, Yawei; Lao, Lifeng] Univ Calif Los Angeles, Dept Orthopaed Surg, Los Angeles, CA USA. [Tian, Haijun] Bethune Sch Med, Dept Surg, Shijiazhuang 050000, Peoples R China. [Zou, Min] Xi An Jiao Tong Univ, Sch & Hosp Stomatol, Dept Orthodont, Xian 710049, Peoples R China. [Zhao, Ke-Wei; Brochmann, Elsa J.; Murray, Samuel S.] VA Greater Angeles Healthcare Syst, Res Serv, North Hills, CA USA. [Brochmann, Elsa J.; Murray, Samuel S.] VA Greater Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr, North Hills, CA USA. [Brochmann, Elsa J.; Murray, Samuel S.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Duarte, M. Eugenia L.] Natl Inst Traumatol & Orthopaed, Rio De Janeiro, Brazil. [Daubs, Michael D.] Univ Nevada, Sch Med, Dept Surg, Div Orthopaed Surg, Las Vegas, NV 89154 USA. [Wang, Jeffrey C.] Univ So Calif, Dept Orthopaed Surg, Los Angeles, CA USA. RP Tian, HJ (reprint author), Bethune Sch Med, Dept Surg, 450 West Zhongshan Rd, Shijiazhuang 050000, Peoples R China. EM haijuntianmd@gmail.com; yanhengzhou@vip.163.com OI LI, Chenshuang/0000-0001-6331-6983 FU National Natural Science Foundation of China [81402229]; International S&T Cooperation Program of China [2013DFB30360]; Research Service of U.S. Department of Veterans Affairs [1IPBX000511, 1IORX000383] FX This work was supported by the National Natural Science Foundation of China (Grant No. 81402229), the International S&T Cooperation Program of China (Grant No. 2013DFB30360), and by the Research Service of the U.S. Department of Veterans Affairs (Grants No. 1IPBX000511 and 1IORX000383). NR 30 TC 3 Z9 3 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 16 PY 2015 VL 466 IS 2 BP 167 EP 172 DI 10.1016/j.bbrc.2015.08.124 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CT2CY UT WOS:000362610800004 PM 26334966 ER PT J AU Kim, HJ Barnitz, RA Kreslavsky, T Brown, FD Moffett, H Lemieux, ME Kaygusuz, Y Meissner, T Holderried, TAW Chan, S Kastner, P Haining, WN Cantor, H AF Kim, Hye-Jung Barnitz, R. Anthony Kreslavsky, Taras Brown, Flavian D. Moffett, Howell Lemieux, Madeleine E. Kaygusuz, Yasemin Meissner, Torsten Holderried, Tobias A. W. Chan, Susan Kastner, Philippe Haining, W. Nicholas Cantor, Harvey TI Stable inhibitory activity of regulatory T cells requires the transcription factor Helios SO SCIENCE LA English DT Article ID FOXP3 EXPRESSION; SELF-TOLERANCE; CIS-ELEMENT; DIFFERENTIATION; SURVIVAL; IDENTITY; STAT5 AB The maintenance of immune homeostasis requires regulatory T cells (T-regs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3(+) CD4 and Qa-1-restricted CD8 T-regs results in defective regulatory activity and autoimmunity in mice. Helios-deficient T-regs develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 T-regs also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. The definition of Helios as a key transcription factor that stabilizes T-regs in the face of inflammatory responses provides a genetic explanation for a core property of T-regs. C1 [Kim, Hye-Jung; Kreslavsky, Taras; Moffett, Howell; Kaygusuz, Yasemin; Meissner, Torsten; Holderried, Tobias A. W.; Cantor, Harvey] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. [Kim, Hye-Jung; Kreslavsky, Taras; Meissner, Torsten; Holderried, Tobias A. W.; Cantor, Harvey] Harvard Univ, Sch Med, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA USA. [Barnitz, R. Anthony; Brown, Flavian D.; Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Barnitz, R. Anthony; Haining, W. Nicholas] Boston Childrens Hosp, Dept Pediat, Boston, MA USA. [Lemieux, Madeleine E.] Bioinfo, Plantagenet, ON, Canada. [Chan, Susan; Kastner, Philippe] Univ Strasbourg, IGBMC, INSERM U964, CNRS UMR 7104, F-67404 Illkirch Graffenstaden, France. [Chan, Susan; Kastner, Philippe] Univ Strasbourg, Fac Med, Strasbourg, France. [Haining, W. Nicholas] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Cantor, H (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, 450 Brookline Ave, Boston, MA 02215 USA. EM harvey_cantor@dfci.harvard.edu OI Lemieux, Madeleine/0000-0001-6355-8691 FU LeRoy Schecter Research Foundation; Arthritis National Research Foundation; [NIH R01AI37562] FX We thank A. Thornton and E. Shevach (NIH) for provision of Heliosfl/fl.CD4-Cre mice, S. Crotty (La Jolla Institute for Allergy and Immunology) for provision of retroviral vector STAT5-CA, R. Bronson (DF/HCC Rodent Histopathology Core) for histology analysis, and A. Angel for manuscript and figure preparation. The data reported in this manuscript are tabulated in the main paper and in the supplementary materials. Raw data are archived in the Gene Expression Omnibus under accession numbers GSE72997 (ChIP-Sec) and GSE73015 (microarray). These studies were supported in part by research grants NIH R01AI37562 and the LeRoy Schecter Research Foundation to H.C. and the Arthritis National Research Foundation to H.-J.K. A provisional patent (U.S. patent application 62/170,379) has been filed pertaining to biological applications relating to the conversion of regulatory T cells into effector T cells for immunotherapy. NR 23 TC 31 Z9 31 U1 2 U2 22 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 OCT 16 PY 2015 VL 350 IS 6258 BP 334 EP + DI 10.1126/science.aad0616 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT5HD UT WOS:000362838700044 PM 26472910 ER PT J AU Masters, CL Bateman, R Blennow, K Rowe, CC Sperling, RA Cummings, JL AF Masters, Colin L. Bateman, Randall Blennow, Kaj Rowe, Christopher C. Sperling, Reisa A. Cummings, Jeffrey L. TI Alzheimer's disease SO NATURE REVIEWS DISEASE PRIMERS LA English DT Article ID QUALITY-OF-LIFE; MILD COGNITIVE IMPAIRMENT; RANDOMIZED CONTROLLED-TRIAL; POSITRON-EMISSION-TOMOGRAPHY; PHOSPHORYLATED TAU-PROTEIN; CREUTZFELDT-JAKOB-DISEASE; PLACEBO-CONTROLLED-TRIAL; AMYLOID-BETA DEPOSITION; AGE-SPECIFIC INCIDENCE; PITTSBURGH COMPOUND-B AB Alzheimer's disease is a chronic illness with long preclinical and prodromal phases (20 years) and an average clinical duration of 8-10 years. The disease has an estimated prevalence of 10-30% in the population >65 years of age with an incidence of 1-3%. Most patients with Alzheimer's disease (>95%) have the sporadic form, which is characterized by a late onset (80-90 years of age), and is the consequence of the failure to clear the amyloid-beta (A beta) peptide from the interstices of the brain. A large number of genetic risk factors for sporadic disease have been identified. A small proportion of patients (<1%) have inherited mutations in genes that affect processing of A beta and develop the disease at a much younger age (mean age of similar to 45 years). Detection of the accumulation of A beta is now possible in preclinical and prodromal phases using cerebrospinal fluid biomarkers and PET. Several approved drugs ameliorate some of the symptoms of Alzheimer's disease, but no current interventions can modify the underlying disease mechanisms. Management is focused on the support of the social networks surrounding the patient and the treatment of any co-morbid illnesses, such as cerebrovascular disease. C1 [Masters, Colin L.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, 30 Royal Parade, Parkville, Vic 3010, Australia. [Bateman, Randall] Washington Univ, Sch Med, St Louis, MO USA. [Blennow, Kaj] Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Neurosci & Physiol, Clin Neurochem Lab, Gothenburg, Sweden. [Rowe, Christopher C.] Austin Hlth, Mol Imaging Res, Melbourne, Vic, Australia. [Sperling, Reisa A.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Sperling, Reisa A.] Massachusetts Gen Hosp, Memory Disorders Unit, Boston, MA 02114 USA. [Cummings, Jeffrey L.] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Las Vegas, NV USA. RP Masters, CL (reprint author), Univ Melbourne, Florey Inst Neurosci & Mental Hlth, 30 Royal Parade, Parkville, Vic 3010, Australia. EM c.masters@unimelb.edu.au FU Eli Lilly; Roche; Merck; Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (Amgen); Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (Biogen Idec); Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (Eisai); Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (FORUM); Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (Genentech); Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (Janssen); Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (Lilly); Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (Roche); Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (Sanofi); GE Healthcare; Avid Radiopharmaceuticals; Primal; AstraZeneca; Navidea; Janssen FX C.L.M. has provided consultation to Eli Lilly, Actinogen and Prana Biotechnology. He has stock ownership in Prana Biotechnology. R.B. has provided consultation to FORUM, Merck, Roche, Sanofi, Boehringer Ingelheim and Eli Lilly. He currently consults and owns stock in C2N Diagnostics, which he co-founded. He also receives research support from Eli Lilly, Roche, Merck and the Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (comprising Amgen, Biogen Idec, Eisai, FORUM, Genentech, Janssen, Lilly, Roche and Sanofi). K.B. has served on advisory boards for Amgen, Eli Lilly, IBL International, Novartis, Roche Diagnostics and Sanofi-Aventis. C.C.R. has received research grants from GE Healthcare, Avid Radiopharmaceuticals, Primal, AstraZeneca and Navidea in the past 2 years. R.A.S. has served as a consultant for Janssen, Genentech, ISIS Pharmaceuticals and Roche. She receives research support from Eli Lilly and Janssen. J.L.C. has provided consultation to AbbVie, Acadia, Actinogen, ADAMAS, Alzheon, Anavex, Avanir, Biogen Idec, Biotie, Boehinger Ingelheim, Chase, Eisai, FORUM, Genentech, Grifols, Intracellular Therapies, Eli Lilly, Lundbeck, Merck, Neurotrope, Novartis, Nutricia, Otsuka, Pfizer, Resverlogix, Roche, Roivant, Suven, Takeda and Toyoma companies. NR 179 TC 7 Z9 7 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2056-676X J9 NAT REV DIS PRIMERS JI Nat. Rev. Dis. Primers PD OCT 15 PY 2015 VL 1 AR 15056 DI 10.1038/nrdp.2015.56 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA DT2WO UT WOS:000381342700001 PM 27188934 ER PT J AU Liu, N Wood, KB Schwab, JH Cha, TD Puhkan, RD Osler, PM Grottkau, BE AF Liu, Ning Wood, Kirkham B. Schwab, Joseph H. Cha, Thomas D. Puhkan, Rishabh D. Osler, Polina M. Grottkau, Brian E. TI Comparison of Intrawound Vancomycin Utility in Posterior Instrumented Spine Surgeries Between Patients With Tumor and Nontumor Patients SO SPINE LA English DT Article DE surgical site infection; vancomycin; spinal tumor; instrumented spine surgery; wound infection; seroma; antibiotics; radiotherapy; debridement; outcome ID ALLOGENEIC BLOOD-TRANSFUSIONS; SURGICAL SITE INFECTION; POSTOPERATIVE INFECTIONS; LOCAL APPLICATION; POWDER; EXPERIENCE; FUSION AB Study Design. Retrospective cohort study of consecutive patients. Objective. To compare the efficacy of intrawound vancomycin to prevent postoperative surgical site infection (SSI) between patients with spinal tumor and nontumor spine patients. Summary of Background Data. Recent studies have suggested that intrawound vancomycin is a promising method for reducing the SSI rate in spine surgery. However, the patient population in which it is most effective remains unknown. Methods. Medical records of a consecutive series of patients with tumor and nontumor spine patients who underwent open posterior instrumented surgeries at our institution between October 2011 and June 2014 were reviewed. 1 gram of vancomycin powder was evenly sprayed into the surgical site before drain placement. The SSI rates before and after vancomycin use were compared. Changes in SSI rates, which reflected the utility of vancomycin, were compared between patients with tumor and nontumor patients. Results. A total of 334 patients were enrolled including 25 patients with tumor and 129 nontumor patients in the "before" period, and 27 patients with tumor and 153 nontumor patients in the "after" period. Baseline characteristics in both patients with tumor and nontumor patients did not differ between periods. The SSI rate of nontumor patients was significantly reduced with intrawound vancomycin application (7.0% [9/129] vs. 0.7% [1/153], P = 0.011). However, the SSI rate in patients with tumor was not reduced (8.0% [2/25] vs. 14.8% [4/27], P = 0.442). 3 of the 4 patients with tumor who developed SSI after vancomycin use had previous radiotherapy, whereas only 1 SSI occurred in 14 patients with tumor without radiotherapy in the same period. Conclusion. Intrawound vancomycin may be beneficial for nontumor spine patients who undergo open posterior instrumented surgeries, but may not for those with spinal tumors. The poor physical health status, major surgical trauma, and tumor-related adjuvant treatments of patients with spinal tumor may contribute to this disparity. C1 [Liu, Ning; Wood, Kirkham B.; Schwab, Joseph H.; Cha, Thomas D.; Puhkan, Rishabh D.; Osler, Polina M.; Grottkau, Brian E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Spine Serv, Boston, MA 02114 USA. RP Wood, KB (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Orthopaed, Spine Serv,Yawkey Ctr, 55 Fruit St,Suite 3800, Boston, MA 02114 USA. EM KBwood@mgh.harvard.edu NR 13 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD OCT 15 PY 2015 VL 40 IS 20 BP 1586 EP 1592 DI 10.1097/BRS.0000000000001133 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DC4WH UT WOS:000369220500012 PM 26731703 ER PT J AU Elia, AEH Wang, DC Willis, NA Boardman, AP Hajdu, I Adeyemi, RO Lowry, E Gygi, SP Scully, R Elledge, SJ AF Elia, Andrew E. H. Wang, David C. Willis, Nicholas A. Boardman, Alexander P. Hajdu, Ildiko Adeyemi, Richard O. Lowry, Elizabeth Gygi, Steven P. Scully, Ralph Elledge, Stephen J. TI RFWD3-Dependent Ubiquitination of RPA Regulates Repair at Stalled Replication Forks SO MOLECULAR CELL LA English DT Article ID DNA-DAMAGE RESPONSE; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION REPAIR; PROTEIN-A; S-PHASE; CHECKPOINT; SUMO; COMPLEX; ACTIVATION; PATHWAY AB We have used quantitative proteomics to profile ubiquitination in the DNA damage response (DDR). We demonstrate that RPA, which functions as a protein scaffold in the replication stress response, is multiply ubiquitinated upon replication fork stalling. Ubiquitination of RPA occurs on chromatin, involves sites outside its DNA binding channel, does not cause proteasomal degradation, and increases under conditions of fork collapse, suggesting a role in repair at stalled forks. We demonstrate that the E3 ligase RFWD3 mediates RPA ubiquitination. RFWD3 is necessary for replication fork restart, normal repair kinetics during replication stress, and homologous recombination (HR) at stalled replication forks. Mutational analysis suggests that multisite ubiquitination of the entire RPA complex is responsible for repair at stalled forks. Multisite protein group sumoylation is known to promote HR in yeast. Our findings reveal a similar requirement for multisite protein group ubiquitination during HR at stalled forks in mammalian cells. C1 [Elia, Andrew E. H.; Wang, David C.; Boardman, Alexander P.; Hajdu, Ildiko; Adeyemi, Richard O.; Lowry, Elizabeth; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Elia, Andrew E. H.; Wang, David C.; Boardman, Alexander P.; Hajdu, Ildiko; Adeyemi, Richard O.; Lowry, Elizabeth; Elledge, Stephen J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Elia, Andrew E. H.; Wang, David C.; Boardman, Alexander P.; Hajdu, Ildiko; Adeyemi, Richard O.; Lowry, Elizabeth; Elledge, Stephen J.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Elia, Andrew E. H.; Wang, David C.; Boardman, Alexander P.; Lowry, Elizabeth] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Willis, Nicholas A.; Scully, Ralph] Harvard Univ, Dept Med, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Willis, Nicholas A.; Scully, Ralph] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Canc Res Inst, Boston, MA 02215 USA. [Gygi, Steven P.] Harvard Univ, Dept Cell Biol, Sch Med, Boston, MA 02115 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu RI Scully, Ralph/F-5008-2013 FU Burroughs Wellcome Fund CAMS Award; K12 Paul Calabresi Award for Oncology; EMBO long-term fellowship; NIH FX We thank members of the Elledge lab, L. Zou, and W. Harper for helpful discussions. We also thank L. Zou for the PRP19 stealth siRNA, J. Chen and Z. Gong for WT and siRNA-resistant RFWD3 clones, Y. Wang for the RFWD3 antibody, and M. Rape for WT, K63R, and K48R pCS2 His-ubiquitin plasmids. A.E.H.E. is supported by a Burroughs Wellcome Fund CAMS Award and K12 Paul Calabresi Award for Oncology. I.H. is a recipient of an EMBO long-term fellowship. R.O.A. is a HHMI fellow of the Life Sciences Research Foundation. This work was supported by NIH grants to S.J.E., R.S., and S.P.G. S.J.E. is an Investigator with the Howard Hughes Medical Institute. NR 50 TC 9 Z9 9 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD OCT 15 PY 2015 VL 60 IS 2 BP 280 EP 293 DI 10.1016/j.molcel.2015.09.011 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CY7JU UT WOS:000366585400010 PM 26474068 ER PT J AU Galli, GG Carrara, M Yuan, WC Valdes-Quezada, C Gurung, B Pepe-Mooney, B Zhang, TH Geeven, G Gray, NS de Laat, W Calogero, RA Camargo, FD AF Galli, Giorgio G. Carrara, Matteo Yuan, Wei-Chien Valdes-Quezada, Christian Gurung, Basanta Pepe-Mooney, Brian Zhang, Tinghu Geeven, Geert Gray, Nathanael S. de Laat, Wouter Calogero, Raffaele A. Camargo, Fernando D. TI YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers SO MOLECULAR CELL LA English DT Article ID CELL SELF-RENEWAL; GENE-EXPRESSION; SUPER-ENHANCERS; COACTIVATOR; CHROMATIN; MEDIATOR; COMPLEX; DIFFERENTIATION; TUMORIGENESIS; REQUIREMENT AB The Hippo/YAP signaling pathway is a crucial regulator of tissue growth, stem cell activity, and tumorigenesis. However, the mechanism by which YAP controls transcription remains to be fully elucidated. Here, we utilize global chromatin occupancy analyses to demonstrate that robust YAP binding is restricted to a relatively small number of distal regulatory elements in the genome. YAP occupancy defines a subset of enhancers and superenhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal polymerase II (Pol II) pause release. Mechanistically, YAP interacts and recruits the Mediator complex to enhancers, allowing the recruitment of the CDK9 elongating kinase. Genetic and chemical perturbation experiments demonstrate the requirement for Mediator and CDK9 in YAP-driven phenotypes of overgrowth and tumorigenesis. Our results here uncover the molecular mechanisms employed by YAP to exert its growth and oncogenic functions, and suggest strategies for intervention. C1 [Galli, Giorgio G.; Yuan, Wei-Chien; Gurung, Basanta; Pepe-Mooney, Brian; Camargo, Fernando D.] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Galli, Giorgio G.; Yuan, Wei-Chien; Pepe-Mooney, Brian; Camargo, Fernando D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Galli, Giorgio G.; Yuan, Wei-Chien; Gurung, Basanta; Camargo, Fernando D.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Carrara, Matteo; Calogero, Raffaele A.] Univ Turin, Dept Biotechnol & Hlth Sci, Ctr Mol Biotechnol, I-10126 Turin, Italy. [Valdes-Quezada, Christian; Geeven, Geert; de Laat, Wouter] Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands. [Valdes-Quezada, Christian; Geeven, Geert; de Laat, Wouter] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands. [Zhang, Tinghu; Gray, Nathanael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Camargo, FD (reprint author), Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. EM camargo@fas.harvard.edu RI Carrara, Matteo/J-8692-2016; OI Carrara, Matteo/0000-0002-8559-8296; Calogero, Raffaele/0000-0002-2848-628X FU National Institutes of Health [AR064036, DK099559]; American-Italian Cancer Foundation Post-Doctoral Research Fellowship FX We thank members of the Camargo lab for insightful discussion and support. This study was supported by grants from the National Institutes of Health (AR064036 and DK099559 to F.D.C.). FDC was a Pew Scholar in the Biomedical Sciences. GGG was supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship. NR 37 TC 21 Z9 21 U1 3 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD OCT 15 PY 2015 VL 60 IS 2 BP 328 EP 337 DI 10.1016/j.molcel.2015.09.001 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CY7JU UT WOS:000366585400014 PM 26439301 ER PT J AU Renneville, A Van Galen, P Canver, MC McConkey, M Krill-Burger, JM Dorfman, DM Holson, EB Bernstein, BE Orkin, SH Bauer, DE Ebert, BL AF Renneville, Aline Van Galen, Peter Canver, Matthew C. McConkey, Marie Krill-Burger, John M. Dorfman, David M. Holson, Edward B. Bernstein, Bradley E. Orkin, Stuart H. Bauer, Daniel E. Ebert, Benjamin L. TI EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression SO BLOOD LA English DT Article ID SICKLE-CELL-DISEASE; METHYLTRANSFERASE G9A; HISTONE METHYLTRANSFERASE; MAMMALIAN-CELLS; HUMAN GENOME; TRANSCRIPTION; METHYLATION; H3K9ME2; GLP; MAINTENANCE AB Fetal hemoglobin (HbF, alpha(2)gamma(2)) induction is a well-validated strategy for sickle cell disease (SCD) treatment. Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces gamma-globin expression. EHMT1/2 catalyze mono- and dimethylation of lysine 9 on histone 3 (H3K9), raising the possibility that H3K9Me2, a repressive chromatin mark, plays a role in silencing gamma-globin expression. In primary human adult erythroid cells, UNC0638 and EHMT1 or EHMT2 short hairpin RNA-mediated knockdown significantly increased gamma-globin expression, HbF synthesis, and the percentage of cells expressing HbF. At effective concentrations, UNC0638 did not alter cell morphology, proliferation, or erythroid differentiation of primary human CD34(+) hematopoietic stem and progenitor cells in culture ex vivo. In murine erythroleukemia cells, UNC0638 and Ehmt2 CRISPR/Cas9-mediated knockout both led to a marked increase in expression of embryonic beta-globin genes Hbb-epsilon y and Hbb-beta h1. In primary human adult erythroblasts, chromatin immunoprecipitation followed by sequencing analysis revealed that UNC0638 treatment leads to genome-wide depletion in H3K9Me2 and a concomitant increase in the activating mark H3K9Ac, which was especially pronounced at the gamma-globin gene region. In RNA-sequencing analysis of erythroblasts, gamma-globin genes were among the most significantly upregulated genes by UNC0638. Further increase in gamma-globin expression in primary human adult erythroid cells was achieved by combining EHMT1/2 inhibition with the histone deacetylase inhibitor entinostat or hypomethylating agent decitabine. Our data provide genetic and pharmacologic evidence that EHMT1 and EHMT2 are epigenetic regulators involved in gamma-globin repression and represent a novel therapeutic target for SCD. C1 [Renneville, Aline; McConkey, Marie; Ebert, Benjamin L.] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Renneville, Aline; Van Galen, Peter; Canver, Matthew C.; Orkin, Stuart H.; Bauer, Daniel E.; Ebert, Benjamin L.] Harvard Univ, Sch Med, Boston, MA USA. [Renneville, Aline] CHRU Lille, Biol & Pathol Ctr, Hematol Lab, F-59037 Lille, France. [Van Galen, Peter; Krill-Burger, John M.; Holson, Edward B.; Bernstein, Bradley E.; Ebert, Benjamin L.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Van Galen, Peter; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Van Galen, Peter; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Dorfman, David M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Orkin, Stuart H.; Bauer, Daniel E.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Orkin, Stuart H.; Bauer, Daniel E.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Ebert, BL (reprint author), 1 Blackfan Circle,Karp 5-210, Boston, MA 02115 USA. EM Benjamin_Ebert@dfci.harvard.edu FU Clinical Research Award from the Doris Duke Charitable Foundation; National Institutes of Health National Heart, Lung, and Blood Institute [1U01HL117720]; Leukemia and Lymphoma Society Scholar Award; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK56465]; French Society of Hematology (Societe Francaise d'Hematologie); NIDDK Award [F30DK103359-01A1] FX This work was supported by a Clinical Research Award from the Doris Duke Charitable Foundation; the National Institutes of Health National Heart, Lung, and Blood Institute (1U01HL117720); and a Leukemia and Lymphoma Society Scholar Award (B.L.E.). Enriched CD341 cells were obtained through the Core Center of Excellence program with partial funding support by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grant DK56465). A.R. received partial financial support from the French Society of Hematology (Societe Francaise d'Hematologie). M.C.C. was supported by a NIDDK Award (F30DK103359-01A1). NR 42 TC 14 Z9 14 U1 2 U2 15 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 OCT 15 PY 2015 VL 126 IS 16 BP 1930 EP 1939 DI 10.1182/blood-2015-06-649087 PG 10 WC Hematology SC Hematology GA CX1JH UT WOS:000365452000012 PM 26320100 ER PT J AU Heilmann, S Ratnakumar, K Langdon, EM Kansler, ER Kim, IS Campbell, NR Perry, EB McMahon, AJ Kaufman, CK van Rooijen, E Lee, W Iacobuzio-Donahue, CA Hynes, RO Zon, LI Xavier, JB White, RM AF Heilmann, Silja Ratnakumar, Kajan Langdon, Erin M. Kansler, Emily R. Kim, Isabella S. Campbell, Nathaniel R. Perry, Elizabeth B. McMahon, Amy J. Kaufman, Charles K. van Rooijen, Ellen Lee, William Iacobuzio-Donahue, Christine A. Hynes, Richard O. Zon, Leonard I. Xavier, Joao B. White, Richard M. TI A Quantitative System for Studying Metastasis Using Transparent Zebrafish SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER METASTASIS; ENDOTHELIN RECEPTOR-B; STEM-CELL; MALIGNANT-MELANOMA; BRAIN METASTASIS; ADULT ZEBRAFISH; NEURAL CREST; BONE-MARROW; RESISTANCE; EXPRESSION AB Metastasis is the defining feature of advanced malignancy, yet remains challenging to study in laboratory environments. Here, we describe a high-throughput zebrafish system for comprehensive, in vivo assessment of metastatic biology. First, we generated several stable cell lines from melanomas of transgenic mitfa-BRAFV600E; p53(-/-) fish. We then transplanted the melanoma cells into the transparent casper strain to enable highly quantitative measurement of the metastatic process at single-cell resolution. Using computational image analysis of the resulting metastases, we generated a metastasis score, m, that can be applied to quantitative comparison of metastatic capacity between experimental conditions. Furthermore, image analysis also provided estimates of the frequency of metastasis-initiating cells (similar to 1/120,000 cells). Finally, we determined that the degree of pigmentation is a key feature defining cells with metastatic capability. The small size and rapid generation of progeny combined with superior imaging tools make zebrafish ideal for unbiased high-throughput investigations of cell-intrinsic or microenvironmental modifiers of metastasis. The approaches described here are readily applicable to other tumor types and thus serve to complement studies also employing murine and human cell culture systems. (C) 2015 AACR. C1 [Heilmann, Silja; Lee, William; Xavier, Joao B.] Mem Sloan Kettering Canc Ctr, Computat Biol, New York, NY 10065 USA. [Ratnakumar, Kajan; Langdon, Erin M.; Kansler, Emily R.; Kim, Isabella S.; Perry, Elizabeth B.; White, Richard M.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet, New York, NY 10065 USA. [Campbell, Nathaniel R.] Weill Cornell Rockefeller Sloan Kettering Triinst, New York, NY USA. [McMahon, Amy J.; Hynes, Richard O.] MIT, David Koch Inst Integrated Canc Biol, Cambridge, MA 02139 USA. [McMahon, Amy J.; Kaufman, Charles K.; van Rooijen, Ellen; Hynes, Richard O.; Zon, Leonard I.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Kaufman, Charles K.; van Rooijen, Ellen; Zon, Leonard I.] Childrens Hosp Boston, Boston, MA USA. [Kaufman, Charles K.; van Rooijen, Ellen; Zon, Leonard I.] Harvard Univ, Sch Med, Boston, MA USA. [Kaufman, Charles K.; Zon, Leonard I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Iacobuzio-Donahue, Christine A.] Mem Sloan Kettering Canc Ctr, Pathol, New York, NY 10021 USA. [White, Richard M.] Weill Cornell Med Coll, New York, NY USA. RP White, RM (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave,MB 424, New York, NY 10065 USA. EM whiter@mskcc.org OI Kansler, Emily/0000-0001-9601-4084 FU NIH [DP2CA186572]; Melanoma Research Alliance Young Investigator Award; AACR/ASCO Young Investigator Award; Alan and Sandra Gerry Metastasis Research Initiative; Howard Hughes Medical Institute; Translational Research Oncology Training Program [5T32CA160001]; [K08AR055368] FX This work was supported by the NIH Directors New Innovator Award (DP2CA186572), K08AR055368, the Melanoma Research Alliance Young Investigator Award, an AACR/ASCO Young Investigator Award, the Alan and Sandra Gerry Metastasis Research Initiative, and the Howard Hughes Medical Institute, of which L.I. Zon and R.O. Hynes are Investigators. S. Heilmann is a James S. McDonnell postdoctoral fellow, E.B. Perry is a TROT Fellow (5T32CA160001-Translational Research Oncology Training Program), and A.J. McMahon was a Helen Hay Whitney Fellow. NR 43 TC 12 Z9 12 U1 2 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2015 VL 75 IS 20 BP 4272 EP 4282 DI 10.1158/0008-5472.CAN-14-3319 PG 11 WC Oncology SC Oncology GA CX3MA UT WOS:000365601900005 PM 26282170 ER PT J AU Soucheray, M Capelletti, M Pulido, I Kuang, YA Paweletz, CP Becker, JH Kikuchi, E Xu, CX Patel, TB Al-Shahrour, F Carretero, J Wong, KK Janne, PA Shapiro, GI Shimamura, T AF Soucheray, Margaret Capelletti, Marzia Pulido, Ines Kuang, Yanan Paweletz, Cloud P. Becker, Jeffrey H. Kikuchi, Eiki Xu, Chunxiao Patel, Tarun B. Al-Shahrour, Fatima Carretero, Julian Wong, Kwok-Kin Jaenne, Pasi A. Shapiro, Geoffrey I. Shimamura, Takeshi TI Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-RECEPTOR; EPITHELIAL-MESENCHYMAL TRANSITION; CELL LUNG-CANCER; ACQUIRED-RESISTANCE; MET AMPLIFICATION; T790M MUTATION; GEFITINIB; ERLOTINIB; SENSITIVITY; THERAPY AB Non-small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mousemodel of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGF beta secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFb was sufficient to induce EMT and resistance to EGFR TKI treatment. Furthermore, NSCLC HCC4006 cells with acquired resistance to gefitinib were characterized by a mesenchymal phenotype and displayed a higher prevalence of the EGFR T790M mutated allele. Notably, combined inhibition of EGFR and the TGF beta receptor in HCC4006 cells prevented EMT but was not sufficient to prevent acquired gefitinib resistance because of an increased emergence of the EGFR T790M allele compared with cells treated with gefitinib alone. Conversely, another independent NSCLC cell line, PC9, reproducibly developed EGFR T790M mutations as the primary mechanism underlying EGFR TKI resistance, even though the prevalence of the mutant allele was lower than that in HCC4006 cells. Thus, our findings underscore heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations that give rise to divergent resistance mechanisms in response to treatment and anticipate the complexity of EMT suppression as a therapeutic strategy. (C) 2015 AACR. C1 [Soucheray, Margaret; Becker, Jeffrey H.; Patel, Tarun B.; Shimamura, Takeshi] Loyola Univ Chicago, Stritch Sch Med, Oncol Res Inst, Dept Mol Pharmacol & Therapeut, Maywood, IL 60153 USA. [Capelletti, Marzia; Kuang, Yanan; Paweletz, Cloud P.; Xu, Chunxiao; Wong, Kwok-Kin; Jaenne, Pasi A.; Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Capelletti, Marzia; Kuang, Yanan; Paweletz, Cloud P.; Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Capelletti, Marzia; Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Pulido, Ines; Carretero, Julian] Univ Valencia, Fac Farm, Dept Fisiol, E-46100 Burjassot, Spain. [Kikuchi, Eiki] Hokkaido Univ Hosp, Dept Med 1, Sapporo, Hokkaido 060, Japan. [Al-Shahrour, Fatima] Spanish Natl Canc Res Ctr, Clin Res Programme, Translat Bioinformat Unit, Madrid, Spain. [Wong, Kwok-Kin] Dana Farber Canc Inst, Harvard Canc Ctr, Ludwig Ctr Dana Farber, Boston, MA 02115 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. RP Shimamura, T (reprint author), Loyola Univ Chicago, Stritch Sch Med, Oncol Res Inst, Dept Mol Pharmacol & Therapeut, 2160 S 1st Ave,Cardinal Bernardin Canc Ctr 205, Maywood, IL 60153 USA. EM tashimamura@luc.edu RI Carretero, Julian/N-5214-2014 OI Carretero, Julian/0000-0001-7269-8506 FU Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber Cancer Institute; American Cancer Society Illinois Division Basic Science [254563]; Loyola University Chicago Program Development Funding; Sumitomo Life Social Welfare Services Foundation; MINECO [SAF2010-21769]; ISCIII [RD12/0036/0045]; Generalitat Valenciana [ACOMP/2013/156, ACIF/2013/239]; NIH [CA140594, CA122794, CA163896, CA166480, CA114465, CA135257, CA154303] FX This work is initiated with the support from Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber Cancer Institute (T. Shimamura and G.I. Shapiro) and is supported by American Cancer Society Illinois Division Basic Science Grant #254563 and Loyola University Chicago Program Development Funding (T. Shimamura). This work is also supported by research fellowship from Sumitomo Life Social Welfare Services Foundation (E. Kikuchi), MINECO (SAF2010-21769), ISCIII (RD12/0036/0045) and Generalitat Valenciana (ACOMP/2013/156 and ACIF/2013/239; J. Carretero), NIH grants CA140594, CA122794, CA163896, CA166480 (K.-K. Wong), CA114465, CA135257, and CA154303 (P.A. Janne). NR 43 TC 18 Z9 19 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2015 VL 75 IS 20 BP 4372 EP 4383 DI 10.1158/0008-5472.CAN-15-0377 PG 12 WC Oncology SC Oncology GA CX3MA UT WOS:000365601900014 PM 26282169 ER PT J AU Zhao, JJ Chu, ZB Hu, Y Lin, JH Wang, ZQ Jiang, M Chen, M Wang, XJ Kang, Y Zhou, YS Chonghaile, TN Johncilla, ME Tai, YT Cheng, JQ Letai, A Munshi, NC Anderson, KC Carrasco, RD AF Zhao, Jian-Jun Chu, Zhang-Bo Hu, Yu Lin, Jianhong Wang, Zhongqiu Jiang, Meng Chen, Ming Wang, Xujun Kang, Yue Zhou, Yangsheng Chonghaile, Triona Ni Johncilla, Melanie E. Tai, Yu-Tzu Cheng, Jin Q. Letai, Antony Munshi, Nikhil C. Anderson, Kenneth C. Carrasco, Ruben D. TI Targeting the miR-221-222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma SO CANCER RESEARCH LA English DT Article ID CARCINOMA-CELL LINES; MICRORNA EXPRESSION; COLORECTAL-CANCER; PROGNOSTIC MARKER; INDUCED APOPTOSIS; TUMOR-SUPPRESSOR; LUNG-CANCER; IN-VITRO; MIR-221; PUMA AB Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma, intra-tumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. miRNAs are noncoding small RNAs that play important roles in the regulation of gene expression and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221-222 family in dexamethasone-induced drug resistance in multiple myeloma using the isogenic cell lines MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization data revealed gain of chromosome X regions at band p11.3, wherein the miR-221-222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221-222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely proapoptotic target. We confirmed PUMA mRNA as a direct target of miR-221-222 in MM1S and MM1R cells by both gain-of-function and loss-of-function studies. In addition, miR-221-222 treatment rendered MM1S cells resistant to dexamethasone, whereas anti-miR-221-222 partially restored the dexamethasone sensitivity of MM1R cells. These studies have uncovered a role for miR-221-222 in multiple myeloma drug resistance and suggest a potential therapeutic role for inhibitors of miR-221-222 binding to PUMA mRNA as a means of overcoming dexamethasone resistance in patients. The clinical utility of this approach is predicated on the ability of antisense miR-221-222 to increase survival while reducing tumor burden and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of multiple myeloma. Moreover, our observation of increased levels of miR-221-222 with decreased PUMA expression in multiple myeloma cells from patients at relapse versus untreated controls suggests an even broader role for miR-221-222 in drug resistance and provides a rationale for the targeting of miR-221-222 as a means of improving patient outcomes. (C) 2015 AACR. C1 [Zhao, Jian-Jun; Chu, Zhang-Bo; Lin, Jianhong; Wang, Zhongqiu; Jiang, Meng; Chen, Ming; Kang, Yue; Zhou, Yangsheng; Chonghaile, Triona Ni; Tai, Yu-Tzu; Letai, Antony; Munshi, Nikhil C.; Anderson, Kenneth C.; Carrasco, Ruben D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Chu, Zhang-Bo; Hu, Yu] Huazhong Univ Sci & Technol, Inst Hematol, Union Hosp, Tongji Med Coll, Wuhan 430074, Peoples R China. [Lin, Jianhong; Tai, Yu-Tzu; Munshi, Nikhil C.; Anderson, Kenneth C.; Carrasco, Ruben D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Lin, Jianhong; Tai, Yu-Tzu; Munshi, Nikhil C.; Anderson, Kenneth C.; Carrasco, Ruben D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Boston, MA 02115 USA. [Wang, Xujun] Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China. [Johncilla, Melanie E.; Carrasco, Ruben D.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Cheng, Jin Q.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Munshi, Nikhil C.] Boston VA Healthcare Syst, Boston, MA USA. RP Carrasco, RD (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02215 USA. EM jianjun_zhao@dfci.harvard.edu; ruben_carrasco@dfci.harvard.edu FU Multiple Myeloma Research Foundation (MMRF) research fellow award; Pathway to Independence Award from the NIH [1K99CA172292]; MMRF research fellow award; China Scholarship Council (CSC) award; Doctors Cancer Foundation; NIH [1R01CA151391] FX J.J. Zhao is supported by a Multiple Myeloma Research Foundation (MMRF) research fellow award and by a Pathway to Independence Award (1K99CA172292) from the NIH. T.N. Chonghaile is supported by an MMRF research fellow award. Z.B. Chu and Z. Wang are supported by a China Scholarship Council (CSC) award. D.R. Carrassco is supported by an MMRF senior award from the Doctors Cancer Foundation and a research grant (1R01CA151391) from the NIH. NR 49 TC 8 Z9 8 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2015 VL 75 IS 20 BP 4384 EP 4397 DI 10.1158/0008-5472.CAN-15-0457 PG 14 WC Oncology SC Oncology GA CX3MA UT WOS:000365601900015 PM 26249174 ER PT J AU Yoo, B Kavishwar, A Ross, A Wang, P Tabassum, DP Polyak, K Barteneva, N Petkova, V Pantazopoulos, P Tena, A Moore, A Medarova, Z AF Yoo, Byunghee Kavishwar, Amol Ross, Alana Wang, Ping Tabassum, Doris P. Polyak, Kornelia Barteneva, Natalia Petkova, Victoria Pantazopoulos, Pamela Tena, Aseda Moore, Anna Medarova, Zdravka TI Combining miR-10b-Targeted Nanotherapy with Low-Dose Doxorubicin Elicits Durable Regressions of Metastatic Breast Cancer SO CANCER RESEARCH LA English DT Article ID IRON-OXIDE NANOPARTICLES; INTERFERING RNA NANODRUG; MIR-B-10; CELLS; MODEL; MICRORNA-B-10; MIGRATION; INVASION; THERAPY AB The therapeutic promise of microRNA (miRNA) in cancer has yet to be realized. In this study, we identified and therapeutically exploited a new role for miR-10b at the metastatic site, which links its overexpression to tumor cell viability and proliferation. In the protocol developed, we combined a miR-10b-inhibitory nanodrug with low-dose anthracycline to achieve complete durable regressions of metastatic disease in a murine model of metastatic breast cancer. Mechanistic investigations suggested a potent antiproliferative, proapoptotic effect of the nanodrug in the metastatic cells, potentiated by a cell-cycle arrest produced by administration of the low-dose anthracycline. miR-10b was overexpressed specifically in cells with high metastatic potential, suggesting a role for this miRNA as a metastasis-specific therapeutic target. Taken together, our results implied the existence of pathways that regulate the viability and proliferation of tumor cells only after they have acquired the ability to grow at distant metastatic sites. As illustrated by miR-10b targeting, such metastasis-dependent apoptotic pathways would offer attractive targets for further therapeutic exploration. (C) 2015 AACR. C1 [Yoo, Byunghee; Kavishwar, Amol; Ross, Alana; Wang, Ping; Pantazopoulos, Pamela; Moore, Anna; Medarova, Zdravka] Massachusetts Gen Hosp, Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Dept Radiol, Boston, MA 02129 USA. [Yoo, Byunghee; Kavishwar, Amol; Ross, Alana; Wang, Ping; Pantazopoulos, Pamela; Moore, Anna; Medarova, Zdravka] Harvard Univ, Sch Med, Boston, MA USA. [Tabassum, Doris P.; Polyak, Kornelia] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Barteneva, Natalia] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Petkova, Victoria] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Mol Med Core, Boston, MA 02215 USA. [Tena, Aseda] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. RP Medarova, Z (reprint author), Massachusetts Gen Hosp, Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Dept Radiol, 13th St, Boston, MA 02129 USA. EM amoore@helix.mgh.harvard.edu; zmedarova@partners.org OI Kavishwar, Amol/0000-0001-8214-6625; Wang, Ping/0000-0001-6712-8939 FU National Cancer Institute [R00CA129070, R01CA16346101A1]; Breast Cancer Alliance [5T32CA009502] FX The study was supported under grants R00CA129070 and R01CA16346101A1 from the National Cancer Institute to Z. Medarova, the Young Investigator Award by the Breast Cancer Alliance to Z. Medarova, and 5T32CA009502 to A. Moore. NR 22 TC 10 Z9 10 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2015 VL 75 IS 20 BP 4407 EP 4415 DI 10.1158/0008-5472.CAN-15-0888 PG 9 WC Oncology SC Oncology GA CX3MA UT WOS:000365601900017 PM 26359455 ER PT J AU Kim, J Akbani, R Creighton, CJ Lerner, SP Weinstein, JN Getz, G Kwiatkowski, DJ AF Kim, Jaegil Akbani, Rehan Creighton, Chad J. Lerner, Seth P. Weinstein, John N. Getz, Gad Kwiatkowski, David J. TI Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise SO CLINICAL CANCER RESEARCH LA English DT Review ID UROTHELIAL CARCINOMA; BREAST-CANCER; MUTATIONS; GENE; SUBTYPES; FGFR3; SENSITIVITY; EXPRESSION; DISCOVERY; GRADE AB Invasive bladder cancer, for which there have been few therapeutic advances in the past 20 years, is a significant medical problem associated with metastatic disease and frequent mortality. Although previous studies had identified many genetic alterations in invasive bladder cancer, recent genome-wide studies have provided a more comprehensive view. Here, we review those recent findings and suggest therapeutic strategies. Bladder cancer has a high mutation rate, exceeded only by lung cancer and melanoma. About 65% of all mutations are due to APOBEC-mediated mutagenesis. There is a high frequency of mutations and/or genomic amplification or deletion events that affect many of the canonical signaling pathways involved in cancer development: cell cycle, receptor tyrosine kinase, RAS, and PI-3-kinase/mTOR. In addition, mutations in chromatin-modifying genes are unusually frequent in comparison with other cancers, and mutation or amplification of transcription factors is also common. Expression clustering analyses organize bladder cancers into four principal groups, which can be characterized as luminal, immune undifferentiated, luminal immune, and basal. The four groups show markedly different expression patterns for urothelial differentiation (keratins and uroplakins) and immunity genes (CD274 and CTLA4), among others. These observations suggest numerous therapeutic opportunities, including kinase inhibitors and antibody therapies for genes in the canonical signaling pathways, histone deacetylase inhibitors and novel molecules for chromatin gene mutations, and immune therapies, which should be targeted to specific patients based on genomic profiling of their cancers. (C) 2015 AACR. C1 [Kim, Jaegil; Getz, Gad; Kwiatkowski, David J.] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02139 USA. [Kim, Jaegil; Getz, Gad; Kwiatkowski, David J.] Harvard Univ, Cambridge, MA 02138 USA. [Akbani, Rehan; Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Creighton, Chad J.; Lerner, Seth P.] Baylor Coll Med, Houston, TX 77030 USA. [Getz, Gad] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kwiatkowski, David J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Kwiatkowski, DJ (reprint author), Brigham & Womens Hosp, 1 Blackfan Circle, Boston, MA 02115 USA. EM jaegil@broadinstitute.org; dk@rics.bwh.harvard.edu FU NCI of the NIH [CA143883, P30CA016672, CPRIT RP130397, P30CA125123, U24CA143843, P01CA120964]; Mary K. Chapman Foundation; Michael & Susan Dell Foundation FX R. Akbani and J.N. Weinstein are supported by the NCI of the NIH under award numbers CA143883 and P30CA016672, CPRIT RP130397, the Mary K. Chapman Foundation, and the Michael & Susan Dell Foundation. C.J. Creighton is supported by the NCI of the NIH under award numbers P30CA125123 and U24CA143843. D.J. Kwiatkowski is supported by the NCI of the NIH under award number P01CA120964. NR 34 TC 17 Z9 17 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2015 VL 21 IS 20 BP 4514 EP 4524 DI 10.1158/1078-0432.CCR-14-1215 PG 11 WC Oncology SC Oncology GA CV7WH UT WOS:000364486300005 PM 26473186 ER PT J AU Gorgun, G Samur, MK Cowens, KB Paula, S Bianchi, G Anderson, JE White, RE Singh, A Ohguchi, H Suzuki, R Kikuchi, S Harada, T Hideshima, T Tai, YT Laubach, JP Raje, N Magrangeas, F Minvielle, S Avet-Loiseau, H Munshi, NC Dorfman, DM Richardson, PG Anderson, KC AF Goerguen, Guellue Samur, Mehmet K. Cowens, Kristen B. Paula, Steven Bianchi, Giada Anderson, Julie E. White, Randie E. Singh, Ahaana Ohguchi, Hiroto Suzuki, Rikio Kikuchi, Shohei Harada, Takeshi Hideshima, Teru Tai, Yu-Tzu Laubach, Jacob P. Raje, Noopur Magrangeas, Florence Minvielle, Stephane Avet-Loiseau, Herve Munshi, Nikhil C. Dorfman, David M. Richardson, Paul G. Anderson, Kenneth C. TI Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID PROGRAMMED CELL-DEATH; SUPPRESSOR-CELLS; CLINICAL-SIGNIFICANCE; ANTI-PD-1 ANTIBODY; B7-H1 EXPRESSION; B7 FAMILY; LIGAND 1; THERAPEUTIC TARGET; IGH TRANSLOCATIONS; CARCINOMA PATIENTS AB Purpose: PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu. Experimental Design: Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138_multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti-multiple myeloma immune response and tumor cell growth. Results: Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFN gamma and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression. Conclusions: Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti-multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy. (C) 2015 AACR. C1 [Goerguen, Guellue; Samur, Mehmet K.; Cowens, Kristen B.; Paula, Steven; Bianchi, Giada; Anderson, Julie E.; White, Randie E.; Singh, Ahaana; Ohguchi, Hiroto; Suzuki, Rikio; Kikuchi, Shohei; Harada, Takeshi; Hideshima, Teru; Tai, Yu-Tzu; Laubach, Jacob P.; Munshi, Nikhil C.; Richardson, Paul G.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Raje, Noopur] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Magrangeas, Florence; Minvielle, Stephane] Univ Nantes, INSERM, UMR892, CNRS 6299, Nantes, France. [Magrangeas, Florence; Minvielle, Stephane] CHU Nantes, Unite Mixte Genom Canc, F-44035 Nantes 01, France. [Avet-Loiseau, Herve] CHU Rangueil, Unite Genom Myelome, F-31054 Toulouse, France. [Munshi, Nikhil C.] Boston VA Hlth Care Syst, Boston, MA USA. [Dorfman, David M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Gorgun, G (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M557, Boston, MA 02215 USA. EM gullu_gorgun@dfci.harvard.edu; kenneth_anderson@dfci.harvard.edu FU NIH/NCI Specialized Program of Research Excellence in Myeloma [P50 CA100707]; NIH/NCI Host-Tumor Cell Interactions in Myeloma: Therapeutic Applications [P01 CA78378]; NIH/NCI Molecular Sequelae of Myeloma-Bone Marrow Interactions: Therapeutic Applications [R01 CA50947] FX This work was supported by an NIH/NCI Specialized Program of Research Excellence in Myeloma P50 CA100707 (to K.C. Anderson); NIH/NCI Host-Tumor Cell Interactions in Myeloma: Therapeutic Applications P01 CA78378 (to K.C. Anderson), and NIH/NCI Molecular Sequelae of Myeloma-Bone Marrow Interactions: Therapeutic Applications R01 CA50947 (to K.C. Anderson) grants. NR 49 TC 28 Z9 28 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2015 VL 21 IS 20 BP 4607 EP 4618 DI 10.1158/1078-0432.CCR-15-0200 PG 12 WC Oncology SC Oncology GA CV7WH UT WOS:000364486300016 PM 25979485 ER PT J AU Fredenburgh, LE Kraft, BD Hess, DR Harris, RS Wolf, MA Suliman, HB Roggli, VL Davies, JD Winkler, T Stenzler, A Baron, RM Thompson, BT Choi, AM Welty-Wolf, KE Piantadosi, CA AF Fredenburgh, Laura E. Kraft, Bryan D. Hess, Dean R. Harris, R. Scott Wolf, Monroe A. Suliman, Hagir B. Roggli, Victor L. Davies, John D. Winkler, Tilo Stenzler, Alex Baron, Rebecca M. Thompson, B. Taylor Choi, Augustine M. Welty-Wolf, Karen E. Piantadosi, Claude A. TI Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE Streptococcus pneumoniae; pneumonia; carbon monoxide; drug delivery systems; Coburn-Forster-Kane equation ID CARBON-MONOXIDE INHALATION; STAPHYLOCOCCUS-AUREUS SEPSIS; ISCHEMIA-REPERFUSION INJURY; PROTEIN-KINASE PATHWAY; ACUTE KIDNEY INJURY; MITOCHONDRIAL BIOGENESIS; HEME OXYGENASE-1; CARBOXYHEMOGLOBIN LEVELS; CARDIOPULMONARY BYPASS; OXIDATIVE STRESS AB Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically relevant baboon model of Streptococcus pneumoniae pneumonia to 1) test a novel, ventilator-compatible CO delivery system; 2) establish a safe and effective CO dosing regimen; and 3) investigate the local and systemic effects of CO therapy on inflammation and acute lung injury (ALI). Animals were inoculated with S. pneumoniae (108-109 CFU) (n = 14) or saline vehicle (n = 5); in a subset with pneumonia (n = 5), we administered low-dose, inhaled CO gas (100-300 ppm X 60-90 min) at 0, 6, 24, and/or 48 h postinoculation and serially measured blood carboxyhemoglobin (COHb) levels. We found that CO inhalation at 200 ppm for 60 min is well tolerated and achieves a COHb of 6-8% with ambient CO levels <= 1 ppm. The COHb level measured at 20 min predicted the 60-min COHb level by the Coburn-Forster-Kane equation with high accuracy. Animals given inhaled CO + antibiotics displayed significantly less ALI at 8 days postinoculation compared with antibiotics alone. Inhaled CO was associated with activation of mitochondrial biogenesis in the lung and with augmentation of renal antioxidative programs. These data support the feasibility of safely delivering inhaled CO gas during mechanical ventilation and provide preliminary evidence that CO may accelerate the resolution of ALI in a clinically relevant nonhuman primate pneumonia model. C1 [Fredenburgh, Laura E.; Baron, Rebecca M.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Dept Med, Boston, MA 02115 USA. [Kraft, Bryan D.; Welty-Wolf, Karen E.; Piantadosi, Claude A.] Duke Univ, Med Ctr, Dept Med, Div Pulm Allergy & Crit Care Med, Durham, NC 27710 USA. [Hess, Dean R.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Hess, Dean R.; Winkler, Tilo] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Harris, R. Scott; Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Wolf, Monroe A.; Suliman, Hagir B.; Piantadosi, Claude A.] Duke Univ, Med Ctr, Dept Anesthesiol, Durham, NC 27710 USA. [Roggli, Victor L.; Piantadosi, Claude A.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Davies, John D.] Duke Univ, Med Ctr, Dept Resp Care, Durham, NC USA. [Stenzler, Alex] 12th Man Technol, Garden Grove, CA USA. [Choi, Augustine M.] Weill Cornell Med Coll, Dept Med, Div Pulm & Crit Care Med, New York, NY USA. RP Fredenburgh, LE (reprint author), Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. EM lfredenburgh@rics.bwh.harvard.edu RI Winkler, Tilo/B-5337-2009 OI Winkler, Tilo/0000-0002-7276-5550 FU Gates Foundation Global Health Institute; National Institutes of Health [P01 HL108801] FX This work was supported by the Gates Foundation Global Health Institute and the National Institutes of Health grant P01 HL108801. NR 65 TC 2 Z9 2 U1 2 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD OCT 15 PY 2015 VL 309 IS 8 BP L834 EP L846 DI 10.1152/ajplung.00240.2015 PG 13 WC Physiology; Respiratory System SC Physiology; Respiratory System GA CV2OH UT WOS:000364095600009 PM 26320156 ER PT J AU Arthur, J Huang, JM Nomura, N Jin, WW Li, W Cheng, X Brown, D Lu, HJ AF Arthur, Julian Huang, Jianmin Nomura, Naohiro Jin, William W. Li, Wei Cheng, Xiang Brown, Dennis Lu, Hua Jenny TI Characterization of the putative phosphorylation sites of the AQP2 C terminus and their role in AQP2 trafficking in LLC-PK1 cells SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aquaporin-2; phosphorylation; vasopressin; LLC-PK1; endocytosis ID AQUAPORIN-2 WATER CHANNEL; RENAL EPITHELIAL-CELLS; COLLECTING DUCT; MEMBRANE; VASOPRESSIN; ENDOCYTOSIS; EXPRESSION; TEMPERATURE; SERINE-261; SURFACE AB Vasopressin (VP) stimulates a signaling cascade that results in phosphorylation and apical membrane accumulation of aquaporin-2 (AQP2), leading to water reabsorption by kidney collecting ducts. However, the roles of most C-terminal phosphorylation events in stimulated and constitutive AQP2 recycling are incompletely understood. Here, we generated LLC-PK1 cells containing point mutations of all potential phosphorylation sites in the AQP2 C terminus: S226, S229, T244, S256, S261, S264, and S269, to determine their impact on AQP2 trafficking. We produced an All Null AQP2 construct in which these serine (S) or threonine (T) residues were mutated to alanine (A) or glycine (G), and we then reintroduced the phosphorylation mimic aspartic acid (D) individually to each site in the All Null mutant. As expected, the All Null mutant does not accumulate at the plasma membrane in response to VP but still undergoes constitutive recycling, as shown by its membrane accumulation when endocytosis is blocked by methyl-beta-cyclodextrin (M beta CD), and accumulation in a perinuclear patch at low temperature (20 degrees C). Single phosphorylation mimics S226D, S229D, T244D, S261D, S264D, and S269D were insufficient to cause membrane accumulation of AQP2 alone or after VP treatment. However, AQP2 S256 reintroduced into the All Null mutant maintains its trafficking response to VP. We conclude that 1) constitutive recycling of AQP2 does not require phosphorylation at any C-terminal sites; 2) forced "phosphorylation" of sites in the AQP2 C terminus is insufficient to stimulate membrane accumulation in the absence of S256 phosphorylation; and 3) phosphorylation of S256 alone is necessary and sufficient to cause membrane accumulation of AQP2. C1 Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lu, HJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, CPZN 8150,185 Cambridge St, Boston, MA 02114 USA. EM Halu@partners.org RI cheng, xiang/C-9987-2016 OI cheng, xiang/0000-0001-5315-9830 FU National Institutes of Health (NIH) [DK096586]; NIH [DK096586, DK-096586-01, DK092619, DK096015]; Nephcure Foundation; MGH/ECOR; Boston Area Diabetes and Endocrinology Research Center [DK57521]; MGH Center for the Study of Inflammatory Bowel Disease [DK43351] FX This work was supported by National Institutes of Health (NIH) Grant DK096586 (D. Brown) and NIH grant minority supplement DK-096586-01 (J. Arthur). H. A. Lu is supported by NIH Grants DK092619, DK096586, and DK096015, the Nephcure Foundation, and MGH/ECOR. Additional support for the Program in Membrane Biology Microscopy Core comes from the Boston Area Diabetes and Endocrinology Research Center (DK57521) and the MGH Center for the Study of Inflammatory Bowel Disease (DK43351). NR 24 TC 2 Z9 2 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD OCT 15 PY 2015 VL 309 IS 8 BP F673 EP F679 DI 10.1152/ajprenal.00152.2015 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA CV2QH UT WOS:000364100900001 PM 26290367 ER PT J AU Wells, JM Jackson, PL Viera, L Bhatt, SP Gautney, J Handley, G King, RW Xu, X Gaggar, A Bailey, WC Dransfield, MT Blalock, JE AF Wells, J. Michael Jackson, Patricia L. Viera, Liliana Bhatt, Surya P. Gautney, Joshua Handley, Guy King, R. Wilson Xu, Xin Gaggar, Amit Bailey, William C. Dransfield, Mark T. Blalock, J. Edwin TI A Randomized, Placebo-controlled Trial of Roflumilast Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE COPD; roflumilast; neutrophil; proline-glycine-proline; prolyl endopeptidase ID PDE4 INHIBITOR ROFLUMILAST; AIRWAY INFLAMMATION; CLINICAL-TRIALS; COPD; EMPHYSEMA; THERAPY; CHEMOATTRACTANT; EXACERBATIONS; AZITHROMYCIN; PATHOGENESIS AB Rationale: Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease (COPD). It has antiinflammatory effects; however, it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression. The self-propagating acetyl-proline-glycine-proline (AcPGP) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD. AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A(4) hydrolase serving as the enzymes responsible for its production and degradation, respectively. Objectives: We hypothesized that roflumilast would decrease AcPGP, halting the feed-forward cycle of inflammation Methods: We conducted a single-center, placebo-controlled, randomized study investigating 12 weeks of roflumilast treatment added to current therapy in moderate-to-severe COPD with chronic bronchitis. Subjects underwent sputum and blood analyses, pulmonary function testing, exercise tolerance, and quality-of-life assessment at 0, 4, and 12 weeks. Measurements and Main Results: Twenty-seven patients were enrolled in the intention-to-treat analysis. Roflumilast treatment decreased sputum AcPGP by more than 50% (P < 0.01) and prolyl endopeptidase by 46% (P = 0.02), without significant improvement in leukotriene A(4) hydrolase activity compared with placebo. Roflumilast also reduces other inflammatory markers. There were no significant changes in lung function, quality of life, or exercise tolerance between roflumilast- and placebo-treated groups. Conclusions: Roflumilast reduces pulmonary inflammation through decreasing prolyl endopeptidase activity and AcPGP. As expected for lower AcPGP levels, markers of neutrophilic inflammation are blunted. Inhibiting this self-propagating pathway lessens the overall inflammatory burden, which may alter the natural history of COPD, including the risk of exacerbation. C1 [Wells, J. Michael; Jackson, Patricia L.; Viera, Liliana; Bhatt, Surya P.; King, R. Wilson; Xu, Xin; Gaggar, Amit; Bailey, William C.; Dransfield, Mark T.; Blalock, J. Edwin] Univ Alabama Birmingham, Dept Med, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Wells, J. Michael; Jackson, Patricia L.; Viera, Liliana; Bhatt, Surya P.; Bailey, William C.; Dransfield, Mark T.; Blalock, J. Edwin] Univ Alabama Birmingham, UAB Lung Hlth Ctr, Birmingham, AL USA. [Wells, J. Michael; Jackson, Patricia L.; Viera, Liliana; King, R. Wilson; Xu, Xin; Gaggar, Amit; Blalock, J. Edwin] Univ Alabama Birmingham, UAB Program Protease & Matrix Biol, Birmingham, AL USA. [Gautney, Joshua; Handley, Guy] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Wells, J. Michael; Gaggar, Amit; Dransfield, Mark T.] Birmingham VA Med Ctr, Dept Med, Birmingham, AL USA. RP Wells, JM (reprint author), 1900 Univ Blvd,MCLM 894, Birmingham, AL 35294 USA. EM jmwells@uab.edu OI Blalock, J. Edwin/0000-0001-5303-8123 FU Forest Laboratories, Inc.; The University of Alabama at Birmingham Targeted Metabolomics and Proteomics Laboratory [S10 RR17261, P30 DK079337-07, R01 AG043076-03, 4R00 HL111322-03] FX Supported by Forest Laboratories, Inc. The University of Alabama at Birmingham Targeted Metabolomics and Proteomics Laboratory receives key support from S10 RR17261, P30 DK079337-07, R01 AG043076-03, and 4R00 HL111322-03. NR 44 TC 8 Z9 8 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD OCT 15 PY 2015 VL 192 IS 8 BP 934 EP 942 DI 10.1164/rccm.201503-0543OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CU2NE UT WOS:000363359400008 PM 26151090 ER PT J AU Vaughn, JE Sorror, ML Storer, BE Chauncey, TR Pulsipher, MA Maziarz, RT Maris, MB Hari, P Laport, GG Franke, GN Agura, ED Langston, AA Rezvani, AR Storb, R Sandmaier, BM Maloney, DG AF Vaughn, Jennifer E. Sorror, Mohamed L. Storer, Barry E. Chauncey, Thomas R. Pulsipher, Michael A. Maziarz, Richard T. Maris, Michael B. Hari, Parameswaran Laport, Ginna G. Franke, Georg N. Agura, Edward D. Langston, Amelia A. Rezvani, Andrew R. Storb, Rainer Sandmaier, Brenda M. Maloney, David G. TI Long-Term Sustained Disease Control in Patients With Mantle Cell Lymphoma With or Without Active Disease After Treatment With Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning SO CANCER LA English DT Article DE conditioning regimen; long-term follow-up; mantle cell lymphoma; nonmyeloablative conditioning; stem cell transplantation ID NON-HODGKINS-LYMPHOMA; VERSUS-HOST-DISEASE; REDUCED-INTENSITY; MARROW TRANSPLANTATION; MOLECULAR REMISSIONS; CLINICAL-TRIAL; FOLLOW-UP; BLOOD; GRAFT; MALIGNANCY AB BACKGROUND: Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL). METHODS: This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%). RESULTS: The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P =.05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P =.02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P =.03). CONCLUSIONS: Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses. (c) 2015 American Cancer Society. C1 [Vaughn, Jennifer E.; Sorror, Mohamed L.; Chauncey, Thomas R.; Storb, Rainer; Sandmaier, Brenda M.; Maloney, David G.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Vaughn, Jennifer E.; Sorror, Mohamed L.; Chauncey, Thomas R.; Storb, Rainer; Sandmaier, Brenda M.; Maloney, David G.] Univ Washington, Sch Med, Dept Med, Div Med Oncol, Seattle, WA 98195 USA. [Storer, Barry E.] Fred Hutchinson Canc Res Ctr, Clin Stat Program, Div Clin Res, Seattle, WA 98109 USA. [Storer, Barry E.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Chauncey, Thomas R.] VA Puget Sound Hlth Care Syst, Marrow Transplant Unit, Seattle, WA USA. [Pulsipher, Michael A.] Primary Childrens Med Ctr, Pediat Blood & Marrow Transplant Program, Salt Lake City, UT USA. [Pulsipher, Michael A.] Univ Utah, Sch Med, Div Hematol Hematol Malignancies, Huntsman Canc Inst, Salt Lake City, UT USA. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Ctr Hematol Malignancies, Knight Canc Inst, Portland, OR 97201 USA. [Maris, Michael B.] Colorado Blood Canc Inst, Denver, CO USA. [Hari, Parameswaran] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Laport, Ginna G.; Rezvani, Andrew R.] Stanford Sch Med, Div Blood & Marrow Transplantat, Dept Med, Stanford, CA USA. [Franke, Georg N.; Storb, Rainer] Univ Leipzig, Div Hematol Oncol & Hemostaseol, Dept Med, D-04109 Leipzig, Germany. [Agura, Edward D.] Baylor Univ, Sch Med, Hematopoiet Stem Cell Program, Dallas, TX USA. [Langston, Amelia A.] Emory Univ, Sch Med, Div Hematol Oncol, Atlanta, GA 30322 USA. [Langston, Amelia A.] Emory Univ, Bone Marrow & Stem Cell Transplant Ctr, Winship Canc Inst, Atlanta, GA 30322 USA. RP Sorror, ML (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave North,D1-100, Seattle, WA 98109 USA. EM msorror@fredhutch.org OI Hari, Parameswaran/0000-0002-8800-297X FU National Heart, Lung, and Blood Institute of the National Institutes of Health [CA018029, CA15704, CA078902, HL088021, 5T32HL007093-38]; American Cancer Society [RSG-13-084-01-CPHPS]; Patient-Centered Outcomes Research Institute [CE-1304-7451]; American Cancer Society FX This study was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grants CA018029, CA15704, CA078902, HL088021, and 5T32HL007093-38). Mohamed L. Sorror is also supported by a Research Scholar Grant from the American Cancer Society (RSG-13-084-01-CPHPS) and by a contract from the Patient-Centered Outcomes Research Institute (CE-1304-7451). Andrew Rezvani reports a Mentored Research Scholar Grant from the American Cancer Society. NR 38 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2015 VL 121 IS 20 BP 3709 EP 3716 DI 10.1002/cncr.29498 PG 8 WC Oncology SC Oncology GA CU1EN UT WOS:000363262700020 PM 26207349 ER PT J AU Dawes, AJ Maggard-Gibbons, M AF Dawes, Aaron J. Maggard-Gibbons, Melinda TI Reply to The Long and Winding Road in Cancer Survivorship Care SO CANCER LA English DT Letter C1 [Dawes, Aaron J.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Dept Surg,Robert Wood Johnson Fdn Clin Scholars P, Los Angeles, CA 90095 USA. [Maggard-Gibbons, Melinda] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA 90095 USA. [Maggard-Gibbons, Melinda] Olive View Univ Calif Los Angeles, Dept Surg, Med Ctr, Los Angeles, CA USA. RP Dawes, AJ (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Dept Surg,Robert Wood Johnson Fdn Clin Scholars P, Los Angeles, CA 90095 USA. OI Dawes, Aaron/0000-0003-4574-6765 FU NCI NIH HHS [U54 CA143931] NR 3 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2015 VL 121 IS 20 BP 3750 EP 3750 DI 10.1002/cncr.29546 PG 1 WC Oncology SC Oncology GA CU1EN UT WOS:000363262700027 PM 26138082 ER PT J AU Li-ChunHsieh, K Schob, S Zeller, MWG Pulli, B Ali, M Wang, CH Chiou, TTY Tsang, YM Lee, PS Stossel, TP Chen, JW AF Li-ChunHsieh, Kevin Schob, Stefan Zeller, Matthias W. G. Pulli, Benjamin Ali, Muhammad Wang, Cuihua Chiou, Terry Ting-Yu Tsang, Yuk-Ming Lee, Po-Shun Stossel, Thomas P. Chen, John W. TI Gelsolin decreases actin toxicity and inflammation in murine multiple sclerosis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Gelsolin; Experimental autoimmune encephalomyelitis (EAE); Actin; Inflammation; Myeloperoxidase; Magnetic resonance imaging ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PLASMA GELSOLIN; SCAVENGER SYSTEM; MEDICAL PROGRESS; MYELOPEROXIDASE; DISEASE; PROTEINS; CELLS; PATHOGENESIS; MECHANISMS AB Gelsolin is the fourth most abundant protein in the body and its depletion in the blood has been found in multiple sclerosis (MS) patients. How gelsolin affects the MS brain has not been studied. We found that while the secreted form of gelsolin (pGSN) decreased in the blood of experimental autoimmune encephalomyelitis (EAE) mice, pGSN concentration increased in the EAE brain. Recombinant human pGSN (rhp-GSN) decreased extracellular actin and myeloperoxidase activity in the brain, resulting in reduced disease activity and less severe clinical disease, suggesting that gelsolin could be a potential therapeutic target for MS. (C) 2015 Elsevier B.V. All rights reserved. C1 [Li-ChunHsieh, Kevin; Schob, Stefan; Zeller, Matthias W. G.; Pulli, Benjamin; Ali, Muhammad; Wang, Cuihua; Chen, John W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol,Dept Radiol, Cambridge, MA 02138 USA. [Chiou, Terry Ting-Yu; Lee, Po-Shun; Stossel, Thomas P.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Translat Med Div, Cambridge, MA 02138 USA. [Tsang, Yuk-Ming] Far Eastern Mem Hosp, Dept Radiol, Div Med Imaging, New Taipei City, Taiwan. RP Chen, JW (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol,Dept Radiol, Cambridge, MA 02138 USA. EM jwchen@mgh.harvard.edu FU National Institute of Health [R01NS070835, R01NS072167] FX This work is supported by grants from the National Institute of Health (R01NS070835 and R01NS072167). NR 36 TC 2 Z9 2 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 15 PY 2015 VL 287 BP 36 EP 42 DI 10.1016/j.jneuroim.2015.08.006 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CU2IN UT WOS:000363347300008 PM 26439960 ER PT J AU Singh, B Owens, KM Bajpai, P Desouki, MM Srinivasasainagendra, V Tiwari, HK Singh, KK AF Singh, Bhupendra Owens, Kjerstin M. Bajpai, Prachi Desouki, Mohamed Mokhtar Srinivasasainagendra, Vinodh Tiwari, Hemant K. Singh, Keshav K. TI Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties SO PLOS ONE LA English DT Article ID COPY-NUMBER; HUMAN CANCERS; SYNONYMOUS MUTATIONS; DRIVER MUTATIONS; MTDNA DEPLETION; ALPERS-SYNDROME; BREAST-CANCER; KINASE GENE; CROSS-TALK; GAMMA AB Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of POLG1, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic properties. C1 [Singh, Bhupendra; Bajpai, Prachi; Singh, Keshav K.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA. [Owens, Kjerstin M.] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. [Desouki, Mohamed Mokhtar] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Nashville, TN 37235 USA. [Srinivasasainagendra, Vinodh; Tiwari, Hemant K.] Univ Alabama Birmingham, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. [Singh, Keshav K.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Singh, Keshav K.] Univ Alabama Birmingham, Dept Environm Hlth, Birmingham, AL USA. [Singh, Keshav K.] Univ Alabama Birmingham, Ctr Free Rad Biol, Birmingham, AL USA. [Singh, Keshav K.] Univ Alabama Birmingham, Ctr Aging, Birmingham, AL USA. [Singh, Keshav K.] Univ Alabama Birmingham, UAB Comprehens Canc Ctr, Birmingham, AL USA. [Singh, Keshav K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. RP Singh, KK (reprint author), Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA. EM kksingh@uab.edu FU Veterans Administration [1I01BX001716]; NIH [R21 5R21CA176054] FX This study was supported by grants from Veterans Administration 1I01BX001716 and NIH R21 5R21CA176054. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 1 Z9 1 U1 0 U2 4 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 OCT 15 PY 2015 VL 10 IS 10 AR e0139846 DI 10.1371/journal.pone.0139846 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU0CX UT WOS:000363184600020 PM 26468652 ER PT J AU Martin, JT Milby, AH Ikuta, K Poudel, S Pfeifer, CG Elliott, DM Smith, HE Mauck, RL AF Martin, John T. Milby, Andrew H. Ikuta, Kensuke Poudel, Subash Pfeifer, Christian G. Elliott, Dawn M. Smith, Harvey E. Mauck, Robert L. TI A radiopaque electrospun scaffold for engineering fibrous musculoskeletal tissues: Scaffold characterization and in vivo applications SO ACTA BIOMATERIALIA LA English DT Article DE Tissue engineering; Electrospinning; Intervertebral disc; Imaging; Radiography ID INTERVERTEBRAL DISC REPLACEMENT; NANOFIBROUS SCAFFOLDS; EXTRACELLULAR-MATRIX; PARTIAL MENISCECTOMY; POLYMER SCAFFOLDS; MODEL; REPAIR; CELLS; MENISCUS; VITRO AB Tissue engineering strategies have emerged in response to the growing prevalence of chronic musculoskeletal conditions, with many of these regenerative methods currently being evaluated in translational animal models. Engineered replacements for fibrous tissues such as the meniscus, annulus fibrosus, tendons, and ligaments are subjected to challenging physiologic loads, and are difficult to track in vivo using standard techniques. The diagnosis and treatment of musculoskeletal conditions depends heavily on radiographic assessment, and a number of currently available implants utilize radiopaque markers to facilitate in vivo imaging. In this study, we developed a nanofibrous scaffold in which individual fibers included radiopaque nanoparticles. Inclusion of radiopaque particles increased the tensile modulus of the scaffold and imparted radiation attenuation within the range of cortical bone. When scaffolds were seeded with bovine mesenchymal stem cells in vitro, there was no change in cell proliferation and no evidence of promiscuous conversion to an osteogenic phenotype. Scaffolds were implanted ex vivo in a model of a meniscal tear in a bovine joint and in vivo in a model of total disc replacement in the rat coccygeal spine (tail), and were visualized via fluoroscopy and microcomputed tomography. In the disc replacement model, histological analysis at 4 weeks showed that the scaffold was biocompatible and supported the deposition of fibrous tissue in vivo. Nanofibrous scaffolds that include radiopaque nanoparticles provide a biocompatible template with sufficient radiopacity for in vivo visualization in both small and large animal models. This radiopacity may facilitate image-guided implantation and non-invasive long-term evaluation of scaffold location and performance. Statement of Significance The healing capacity of fibrous musculoskeletal tissues is limited, and injury or degeneration of these tissues compromises the standard of living of millions in the US. Tissue engineering repair strategies for the intervertebral disc, meniscus, tendon and ligament have progressed from in vitro to in vivo evaluation using a variety of animal models, and the clinical application of these technologies is imminent. The composition of most scaffold materials however does not allow for visualization by methods available to clinicians (e.g., radiography), and thus it is not possible to assess their performance in situ. In this work, we describe a radiopaque nanofibrous scaffold that can be visualized radiographically in both small and large animal models and serve as a framework for the development of an engineered fibrous tissue. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 [Martin, John T.; Milby, Andrew H.; Ikuta, Kensuke; Poudel, Subash; Pfeifer, Christian G.; Smith, Harvey E.; Mauck, Robert L.] Univ Penn, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. [Martin, John T.; Milby, Andrew H.; Ikuta, Kensuke; Pfeifer, Christian G.; Smith, Harvey E.; Mauck, Robert L.] Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA USA. [Martin, John T.; Poudel, Subash; Mauck, Robert L.] Univ Penn, Dept Mech Engn & Appl Mech, Philadelphia, PA 19104 USA. [Pfeifer, Christian G.] Univ Regensburg, Med Ctr, Dept Trauma Surg, D-93053 Regensburg, Germany. [Elliott, Dawn M.] Univ Delaware, Dept Biomed Engn, Newark, DE USA. [Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. RP Martin, JT (reprint author), Univ Penn, McKay Orthopaed Res Lab, Orthopaed Surg & Bioengn, 36th St & Hamilton Walk,424 Stemmler Hall, Philadelphia, PA 19104 USA. EM johnma@mail.med.upenn.edu; andrew.milby@uphs.upenn.edu; ken.ikuta.hto@gmail.com; spoudel@seas.upenn.edu; dr.christianpfeifer@gmail.com; delliott@udel.edu; harvey.smith@uphs.upenn.edu; lemauck@mail.med.upenn.edu FU Department of Defense [OR090090]; National Institutes of Health [R01 EB02425]; Penn Center for Musculoskeletal Disorders [P30 AR050950]; Department of Veterans' Affairs [IK2 RX001476] FX This study was supported by the Department of Defense (OR090090), the National Institutes of Health (R01 EB02425), the Penn Center for Musculoskeletal Disorders (P30 AR050950), and the Department of Veterans' Affairs (IK2 RX001476, H.E.S.). NR 35 TC 2 Z9 2 U1 9 U2 38 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 EI 1878-7568 J9 ACTA BIOMATER JI Acta Biomater. PD OCT 15 PY 2015 VL 26 BP 97 EP 104 DI 10.1016/j.actbio.2015.08.001 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CT6IR UT WOS:000362917200010 PM 26248165 ER PT J AU Beack, S Kong, WH Jung, HS Do, IH Han, S Kim, H Kim, KS Yun, SH Hahn, SK AF Beack, Songeun Kong, Won Ho Jung, Ho Sang Do, In Hwan Han, Seulgi Kim, Hyemin Kim, Ki Su Yun, Seok Hyun Hahn, Sei Kwang TI Photodynamic therapy of melanoma skin cancer using carbon dot - chlorin e6-hyaluronate conjugate SO ACTA BIOMATERIALIA LA English DT Article DE Carbon dot; Chlorin e6; Hyaluronate; Transdermal delivery; Photodynamic therapy ID HYALURONIC-ACID; SINGLET OXYGEN; LIVING CELLS; IN-VIVO; PHOTOSENSITIZER; NANOPARTICLES; APOPTOSIS; DELIVERY; TISSUES AB Despite wide application of photodynamic therapy (PDT) for the treatment of melanoma skin cancers, there are strong biomedical unmet needs for the effective generation of singlet oxygen after targeted delivery of photosensitizers. Here, we investigated a facile PDT of melanoma skin cancer using transdermal carbon dot - chlorine e6 - hyaluronate (Cdot-Ce6-HA) conjugates. The Cdot-Ce6-HA conjugate was synthesized by the coupling reaction of diaminohexane modified HA (DAH-HA) with the carboxylic group of Ce6. The singlet oxygen generation of Cdot-Ce6-HA conjugates in aqueous solution was more significant than that of free Ce6. The enhanced transdermal and intracellular delivery of Cdot-Ce6-HA conjugates to B16F10 melanoma cells in tumor model mice were corroborated by confocal microscopy and two-photon microscopy. The laser irradiation after topical treatment with Cdot-Ce6-HA conjugates resulted in complete suppression of melanoma skin cancers. The antitumor effect was confirmed by histological analysis with H&E staining and TUNEL assay for tumor apoptosis. Taken together, we could confirm the feasibility of Cdot-Ce6-HA conjugate for transdermal PDT of melanoma skin cancers. Statement of Significance To our knowledge, this is the first report on a facile transdermal photodynamic therapy (PDT) of melanoma skin cancer using carbon dot - chlorine e6 - hyaluronate (Cdot-Ce6-HA) conjugates. We found that the singlet oxygen generation of Cdot-Ce6-HA conjugates in aqueous solution was more significant than that of free Ce6. Confocal microscopy and two-photon microscopy clearly confirmed the enhanced transdermal and intracellular delivery of Cdot-Ce6-HA conjugates to B16F10 melanoma cells in tumor model mice. Taken together, we could confirm the feasibility of Cdot-Ce6-HA conjugate for transdermal PDT of melanoma skin cancers. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 [Beack, Songeun; Kong, Won Ho; Jung, Ho Sang; Do, In Hwan; Han, Seulgi; Kim, Hyemin; Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, Pohang 790784, South Korea. [Kim, Ki Su; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Kim, Ki Su; Yun, Seok Hyun] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Hahn, SK (reprint author), Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, 77 Cheongam Ro, Pohang 790784, South Korea. EM skhanb@postech.ac.kr FU NRF - MEST [2012R1A2A2A06045773]; Korean Health Technology R&D Project, Ministry of Health and Welfare, Korea [HI14C1658]; MSIP (Ministry of Science, ICT and Future Planning), Korea [NIPA-2014-H0201-14-1001]; Pohang Center for Evaluation of Biomaterials (Pohang Technopark) FX This study was supported by Mid-career Researcher Program through NRF Grant funded by the MEST (No. 2012R1A2A2A06045773). This research was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Korea (HI14C1658). This research was supported by the MSIP (Ministry of Science, ICT and Future Planning), Korea, under the "IT Consilience Creative Program" (NIPA-2014-H0201-14-1001) supervised by the NIPA (National IT Industry Promotion Agency). We appreciate the technical assistance of Hoe-Yune Jung with the use of the IVIS spectrum facility supported by the Pohang Center for Evaluation of Biomaterials (Pohang Technopark). NR 33 TC 9 Z9 9 U1 16 U2 98 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 EI 1878-7568 J9 ACTA BIOMATER JI Acta Biomater. PD OCT 15 PY 2015 VL 26 BP 295 EP 305 DI 10.1016/j.actbio.2015.08.027 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CT6IR UT WOS:000362917200028 PM 26297888 ER PT J AU White, PL Wingard, JR Bretagne, S Loffler, J Patterson, TF Slavin, MA Barnes, RA Pappas, PG Donnelly, JP AF White, P. Lewis Wingard, John R. Bretagne, Stephane Loeffler, Juergen Patterson, Thomas F. Slavin, Monica A. Barnes, Rosemary A. Pappas, Peter G. Donnelly, J. Peter TI Aspergillus Polymerase Chain Reaction: Systematic Review of Evidence for Clinical Use in Comparison With Antigen Testing SO CLINICAL INFECTIOUS DISEASES LA English DT Review DE Aspergillus; PCR; galactomannan; beta-D-glucan; aspergillosis ID LINKED-IMMUNOSORBENT-ASSAY; INVASIVE PULMONARY ASPERGILLOSIS; BRONCHOALVEOLAR LAVAGE FLUID; REAL-TIME PCR; LATEX AGGLUTINATION-TEST; BETA-D-GLUCAN; MARROW TRANSPLANT RECIPIENTS; GALACTOMANNAN ENZYME-IMMUNOASSAY; HIGH-RISK PATIENTS; FUNGAL-INFECTIONS AB Background. Aspergillus polymerase chain reaction (PCR) was excluded from the European Organisation for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions of invasive fungal disease because of limited standardization and validation. The definitions are being revised. Methods. A systematic literature review was performed to identify analytical and clinical information available on inclusion of galactomannan enzyme immunoassay (GM-EIA) (2002) and beta-D-glucan (2008), providing a minimal threshold when considering PCR. Categorical parameters and statistical performance were compared. Results. When incorporated, GM-EIA and beta-D-glucan sensitivities and specificities for diagnosing invasive aspergillosis were 81.6% and 91.6%, and 76.9% and 89.4%, respectively. Aspergillus PCR has similar sensitivity and specificity (76.8%-88.0% and 75.0%-94.5%, respectively) and comparable utility. Methodological recommendations and commercial PCR assays assist standardization. Although all tests have limitations, currently, PCR is the only test with independent quality control. Conclusions. We propose that there is sufficient evidence that is at least equivalent to that used to include GM-EIA and beta-D-glucan testing, and that PCR is now mature enough for inclusion in the EORTC/MSG definitions. C1 [White, P. Lewis] Univ Wales Hosp, Publ Hlth Wales, Microbiol Cardiff, Cardiff CF14 4XN, S Glam, Wales. [Wingard, John R.] Univ Florida Hlth, Gainesville, FL USA. [Bretagne, Stephane] Paris Diderot Univ, AP HP, St Louis Hosp, Paris, France. [Loeffler, Juergen] Univ Wurzburg, Wurzburg, Germany. [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Slavin, Monica A.] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic 3010, Australia. [Barnes, Rosemary A.] Cardiff Univ, Infect Immun & Biochem, Cardiff CF10 3AX, S Glam, Wales. [Pappas, Peter G.] Univ Alabama Birmingham, Birmingham, AL USA. [Donnelly, J. Peter] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. RP White, PL (reprint author), Univ Wales Hosp, Publ Hlth Wales, Microbiol Cardiff, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM lewis.white@wales.nhs.uk OI Patterson, Thomas /0000-0002-9513-7127; Bretagne, Stephane/0000-0001-6870-3800; Slavin, Monica/0000-0002-8443-314X FU Myconostica; Luminex; Renishaw Diagnostics; MSD; Gilead Sciences; Pfizer; Astellas; Merck; Schering- Plough; MSD Australia; Pfizer Australia; Scynexis; T2 Biosystems; Viamet FX P. L. W. is a founding member of the European Aspergillus PCR Initiative (EAPCRI); received project funding from Myconostica, Luminex, and Renishaw Diagnostics; was sponsored by Myconostica, MSD, and Gilead Sciences to attend international meetings; and provided consultancy for Renishaw Diagnostics Limited. J. R. W. has received speaker fees from Pfizer and has provided consultancy for Merck, Astellas, Ansun and Gilead. S. B. is a founding member of the EAPCRI, received project funding from Renishaw Diagnostics, was sponsored by Pfizer and MSD to attend international meetings, and provided consultancy for Gilead. J. L. is a founding member of the EAPCRI, received an educational grant and scientific fellowship award from Pfizer, and was sponsored by Astellas to attend international meetings. T. F. P. has received research grants from Astellas and Merck, and has been a consultant or scientific advisory board member for Astellas, Merck, Scynexis, Toyoma, and Viamet. M. A. S. has been a member of advisory boards for and received research funding from Pfizer, MSD, Schering- Plough, and Gilead Sciences; serves on the Antifungal Advisory Boards of Gilead Sciences Inc, MSD, and Pfizer; and has received funding in the form of untied grants from Gilead Sciences Inc, MSD Australia, and Pfizer Australia. R. A. B. is a founding member of the EAPCRI, received an educational grant and scientific fellowship award from Gilead Sciences and Pfizer, is a member of the advisory board and speakers' bureau for Gilead Sciences, MSD, Astellas, and Pfizer, and was sponsored by Gilead Sciences and Pfizer to attend international meetings. P. G. P. has received research support from Astellas, Merck, Gilead, Scynexis, and T2 Biosystems; and has served as an ad hoc scientific advisor for Astellas, Merck, Gilead, Scynexis, T2 Biosystems, and Viamet. J. P. D. is a founding member of the EAPCRI, is a member of the advisory board for Gilead Sciences and Pfizer, and has been on speakers' bureaus for Gilead Sciences, MSD, and Pfizer. NR 93 TC 21 Z9 21 U1 1 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2015 VL 61 IS 8 BP 1293 EP 1303 DI 10.1093/cid/civ507 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT6WN UT WOS:000362953800011 PM 26113653 ER PT J AU Linkin, DR Richardson, DM AF Linkin, Darren R. Richardson, Diane M. TI Regarding Primary Care Patients Who Received Influenza Vaccine at Veteran Health Administration Medical Centers Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID OLDER-ADULTS; HOSPITALIZATIONS C1 [Linkin, Darren R.] Univ Penn, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Linkin, Darren R.] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Linkin, Darren R.] Philadelphia Vet Affairs Med Ctr, Dept Med, Div Infect Dis, Philadelphia, PA USA. [Richardson, Diane M.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. RP Linkin, DR (reprint author), Philadelphia VA Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM linkin@mail.med.upenn.edu NR 6 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2015 VL 61 IS 8 BP 1345 EP 1345 DI 10.1093/cid/civ549 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT6WN UT WOS:000362953800021 PM 26157051 ER PT J AU Winston, DJ Busuttil, RW Singh, N AF Winston, Drew J. Busuttil, Ronald W. Singh, Nina TI Antifungal Prophylaxis in Liver Transplant Recipients SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID INVASIVE FUNGAL-INFECTIONS; DOUBLE-BLIND; TRIAL; FLUCONAZOLE; PREVENTION; MICAFUNGIN C1 [Winston, Drew J.; Busuttil, Ronald W.] Univ Calif Los Angeles, Med Ctr, Dept Surg, Liver Transplant Program, Los Angeles, CA 90095 USA. [Winston, Drew J.] Univ Calif Los Angeles, Med Ctr, Dept Med, Los Angeles, CA 90095 USA. [Singh, Nina] Univ Pittsburgh, Vet Affairs Pittsburgh Healthcare Syst, Dept Med, Pittsburgh, PA 15260 USA. RP Winston, DJ (reprint author), Univ Calif Los Angeles, Med Ctr, Dept Med, 10833 LeConte Ave,CHS,Rm 42-121, Los Angeles, CA 90095 USA. EM dwinston@mednet.ucla.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2015 VL 61 IS 8 BP 1349 EP U162 DI 10.1093/cid/civ565 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT6WN UT WOS:000362953800024 PM 26261207 ER PT J AU Goroll, AH AF Goroll, Allan H. TI Toward Trusting Therapeutic Relationships - In Favor of the Annual Physical SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. RP Goroll, AH (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. NR 4 TC 4 Z9 4 U1 0 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 OCT 15 PY 2015 VL 373 IS 16 BP 1487 EP 1489 DI 10.1056/NEJMp1508270 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CT5VX UT WOS:000362880300003 PM 26465982 ER PT J AU Mansour, MK Ackman, JB Branda, JA Kradin, RL AF Mansour, Michael K. Ackman, Jeanne B. Branda, John A. Kradin, Richard L. TI Case 32-2015: A 57-Year-Old Man with Severe Pneumonia and Hypoxemic Respiratory Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PULMONARY BLASTOMYCOSIS; GATA2 DEFICIENCY; INFECTIONS; HISTOPLASMOSIS; DIAGNOSIS; DISEASE; STATES; TESTS C1 [Mansour, Michael K.; Kradin, Richard L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ackman, Jeanne B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ackman, Jeanne B.; Kradin, Richard L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mansour, Michael K.; Kradin, Richard L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ackman, Jeanne B.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Ackman, Jeanne B.; Kradin, Richard L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Mansour, MK (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 25 TC 0 Z9 0 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 15 PY 2015 VL 373 IS 16 BP 1554 EP 1564 DI 10.1056/NEJMcpc1503830 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CT5VX UT WOS:000362880300012 PM 26465989 ER PT J AU Vodopivec, I Venna, N Rizzo, JF Prasad, S AF Vodopivec, Ivana Venna, Nagagopal Rizzo, Joseph F., III Prasad, Sashank TI Clinical features, diagnostic findings, and treatment of Susac syndrome: A case series SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Susac syndrome; Encephalopathy; Hearing loss; Visual impairment; Branch retinal artery occlusion; MRI; Fluorescein angiography ID ANTIENDOTHELIAL CELL ANTIBODIES; MULTIPLE-SCLEROSIS; CORPUS-CALLOSUM; LESIONS; MR AB Background: Susac syndrome (SS) is a rare, presumed autoimmune condition characterized by the clinical triad of branch retinal artery occlusions (BRAOs), encephalopathy, and sensorineural hearing loss. The aim of this study was to evaluate clinical features, diagnostic results, treatment, and outcomes in SS. Methods: Five patients with SS were referred to three tertiary care centers in Boston. The observation period across these patients was 7-57 months. Results: At initial presentation, none of the patients demonstrated the complete triad of BRAO, sensorineural hearing loss, and encephalopathy. The interval between symptom onset and diagnosis of SS was 4-30 weeks. Brain MRI findings thought to be characteristic of SS (including callosal fluid-attenuated inversion recovery (FLAIR) hyperintense and T1 hypointense lesions) were frequently absent. Microinfarcts noted on diffusion-weighted imaging (DWI), BRAOs and vessel wall hyperfluorescence on fluorescein angiography (FA) were present in all cases in the acute encephalopathic phase. All patients treated with glucocorticoids and intravenous immunoglobulins (IVIg) alone experienced further clinical progression until additional immunosuppressive therapy was instituted. Conclusions: The rarity of SS, its incomplete and variable presentation, and the nonspecific imaging findings invariably led to delayed diagnosis. DWI and FA should be used to identify the acute microvascular injury and monitor treatment response. Immunomodulatory agents more potent than glucocorticoids and IVIg might be required to control the disease. (C) 2015 Elsevier B.V. All rights reserved. C1 [Vodopivec, Ivana; Venna, Nagagopal; Rizzo, Joseph F., III; Prasad, Sashank] Harvard Univ, Sch Med, Boston, MA USA. [Vodopivec, Ivana] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Vodopivec, Ivana; Rizzo, Joseph F., III] Massachusetts Eye & Ear Infirm, Neuroophthalmol Serv, Boston, MA 02114 USA. [Venna, Nagagopal; Prasad, Sashank] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Vodopivec, I (reprint author), Massachusetts Gen Hosp, Dept Neurol, 15 Parkman St, Boston, MA 02114 USA. EM ivodopivec@partners.org NR 25 TC 5 Z9 6 U1 3 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2015 VL 357 IS 1-2 BP 50 EP 57 DI 10.1016/j.jns.2015.06.063 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CS5SQ UT WOS:000362138800008 PM 26148931 ER PT J AU Charidimou, A Song, M AF Charidimou, Andreas Song, Min TI Evolving trends in cerebral amyloid angiopathy research themes: Insights from medical subject heading analysis SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Letter DE Intracerebral hemorrhage; Cerebral amyloid angiopathy; Informetrics; Bibliometrics; MeSH C1 [Charidimou, Andreas] UCL Inst Neurol, London WC1N 3BG, England. [Charidimou, Andreas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hemorrhag Stroke Res Program,Dept Neurol,Stroke R, Boston, MA 02114 USA. [Song, Min] Yonsei Univ, Dept Lib & Informat Sci, Seoul 120749, South Korea. RP Charidimou, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, J Kistler Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM andreas.charidimou.09@ucl.ac.uk NR 7 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2015 VL 357 IS 1-2 BP 341 EP 342 DI 10.1016/j.jns.2015.08.001 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CS5SQ UT WOS:000362138800069 PM 26265474 ER PT J AU Klein, MM Downs, HM Oaklander, AL AF Klein, M. M. Downs, H. M. Oaklander, A. L. TI Diagnostic performance of a multivariate model of normal epidermal nerve fiber (enf) density for skin-biopsy diagnosis of small-fiber polyneuropathy (sfpn) SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Meeting Abstract CT 22nd World Congress of Neurology (WCN) CY OCT 31-NOV 05, 2015 CL Santiago, CHILE C1 [Klein, M. M.; Downs, H. M.] Harvard Med Sch, Massachusetts Gen Hosp, Neurol, Boston, MA USA. [Oaklander, A. L.] Harvard Med Sch, Massachusetts Gen Hosp, Neurol & Pathol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2015 VL 357 SU 1 MA 1147 BP E337 EP E338 DI 10.1016/j.jns.2015.08.1202 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DX8JV UT WOS:000384634802052 ER PT J AU Koudriavtseva, T Plantone, D Renna, R Mandoj, C Mainero, C AF Koudriavtseva, T. Plantone, D. Renna, R. Mandoj, C. Mainero, C. TI Interferon-beta therapy and risk of thrombocytopenia in multiple sclerosis patients SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Meeting Abstract CT 22nd World Congress of Neurology (WCN) CY OCT 31-NOV 05, 2015 CL Santiago, CHILE C1 [Koudriavtseva, T.; Plantone, D.; Renna, R.] Regina Elena Natl Canc Inst IFO, Neurol Unit, Rome, Italy. [Mandoj, C.] Regina Elena Natl Canc Inst IFO, Clin Pathol, Rome, Italy. [Mainero, C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2015 VL 357 SU 1 MA 1021 BP E309 EP E309 DI 10.1016/j.jns.2015.08.1088 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DX8JV UT WOS:000384634801378 ER PT J AU Martins, S Norrving, B Salinas, J Sprinkhuizen, S Schwamm, L AF Martins, S. Norrving, B. Salinas, J. Sprinkhuizen, S. Schwamm, L. TI Defining an international standard set of patient-centered outcome measures after stroke SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Meeting Abstract CT 22nd World Congress of Neurology (WCN) CY OCT 31-NOV 05, 2015 CL Santiago, CHILE C1 [Martins, S.] Hosp Moinhos Vento, Neurol & Neurosurg, Porto Alegre, RS, Brazil. [Norrving, B.] Lund Univ, Neurol, Lund, Sweden. [Salinas, J.; Schwamm, L.] Harvard Med Sch, Massachusetts Gen Hosp, Neurol, Boston, MA USA. [Sprinkhuizen, S.] Int Consortium Hlth Outcomes Measurement, Neurol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2015 VL 357 SU 1 MA 1354 BP E394 EP E394 DI 10.1016/j.jns.2015.08.1397 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DX8JV UT WOS:000384634802215 ER PT J AU Treister, R Liu, X Lang, M O'Neil, K Oaklander, AL AF Treister, R. Liu, X. Lang, M. O'Neil, K. Oaklander, A. L. TI First evaluation of efficacy and safety of intravenous immunoglobulin (ivig) treatment of dysimmune small-fiber predominant polyneuropathy (sfpn) SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Meeting Abstract CT 22nd World Congress of Neurology (WCN) CY OCT 31-NOV 05, 2015 CL Santiago, CHILE C1 [Treister, R.; Liu, X.; Lang, M.; O'Neil, K.] Harvard Med Sch, Massachusetts Gen Hosp, Neurol, Boston, MA USA. [Oaklander, A. L.] Harvard Med Sch, Massachusetts Gen Hosp, Neurol Neuropathol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2015 VL 357 SU 1 MA 1160 BP E341 EP E342 DI 10.1016/j.jns.2015.08.1213 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DX8JV UT WOS:000384634802063 ER PT J AU Landeck, L Gonzalez, E Koch, OM AF Landeck, Lilla Gonzalez, Ernesto Koch, Olaf Manfred TI Handling chemotherapy drugsDo medical gloves really protect? SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE chemotherapy drugs; speciality patient examination gloves; prevention in health care workers; basic glove materials: latex; nitrile; vinyl ID HEALTH-CARE WORKERS; OCCUPATIONAL-EXPOSURE; ANTINEOPLASTIC DRUGS; CYTOSTATIC DRUGS; LATEX ALLERGY; NURSES; AGENTS; INFORMATION; INTEGRITY; HAZARDS AB Due to their potential mutagenic, carcinogenic and teratogenic effects occupational exposure to chemotherapy drugs should be kept to a minimum. Utilization of personnel protective devices, especially the use of protective medical gloves, is a mainstay to avoid skin contact. The choice of appropriate gloves is of outstanding importance. For optimal protection in the oncology setting it is essential to establish general guidelines evaluating appropriate materials and defining quality standards. Establishing these guidelines can facilitate better handling and avoid potential hazards and late sequelae. In Europe there are no specific requirements or test methodologies for medical gloves used in the oncology environment. The implementation of uniform standards for gloves used while handling chemotherapy drugs would be desirable. In contrast, in the US medical gloves used to handle chemotherapy drugs have to fulfill requirements according to the ASTM International (American Society of Testing and Materials) standard D 6978-05. Nitrile or natural rubber latex is a preferred basic glove material, while vinyl is considered inappropriate because of its generally increased permeability. For extended exposure to chemotherapy drugs, double gloving, the use of thicker gloves and the frequent change of gloves increases their protective power. C1 [Landeck, Lilla] Ernst von Bergmann Gen Hosp, Dept Dermatol, D-14467 Potsdam, Germany. [Gonzalez, Ernesto] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Koch, Olaf Manfred] Klinikum Osnabruck, Dept Oncol, Osnabruck, Germany. RP Landeck, L (reprint author), Ernst von Bergmann Gen Hosp, Dept Dermatol, Charlottenstr 67, D-14467 Potsdam, Germany. EM llandeck@klinikumevb.de NR 42 TC 0 Z9 0 U1 5 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2015 VL 137 IS 8 BP 1800 EP 1805 DI 10.1002/ijc.29058 PG 6 WC Oncology SC Oncology GA CO7OV UT WOS:000359350600008 PM 24978061 ER PT J AU Gaykalova, DA Manola, JB Ozawa, H Zizkova, V Morton, K Bishop, JA Sharma, R Zhang, C Michailidi, C Considine, M Tan, M Fertig, EJ Hennessey, PT Ahn, J Koch, WM Westra, WH Khan, Z Chung, CH Ochs, MF Califano, JA AF Gaykalova, Daria A. Manola, Judith B. Ozawa, Hiroyuki Zizkova, Veronika Morton, Kathryn Bishop, Justin A. Sharma, Rajni Zhang, Chi Michailidi, Christina Considine, Michael Tan, Marietta Fertig, Elana J. Hennessey, Patrick T. Ahn, Julie Koch, Wayne M. Westra, William H. Khan, Zubair Chung, Christine H. Ochs, Michael F. Califano, Joseph A. TI NF-B and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HNSCC; HPV; STAT3; NF-B; transcription factor ID KAPPA-B; HUMAN-PAPILLOMAVIRUS; MOLECULAR CLASSIFICATION; DECOY OLIGONUCLEOTIDE; SIGNAL TRANSDUCER; GENE-EXPRESSION; CANCER-THERAPY; COPY NUMBER; ACTIVATION; P53 AB Using high-throughput analyses and the TRANSFAC database, we characterized TF signatures of head and neck squamous cell carcinoma (HNSCC) subgroups by inferential analysis of target gene expression, correcting for the effects of DNA methylation and copy number. Using this discovery pipeline, we determined that human papillomavirus-related (HPV+) and HPV- HNSCC differed significantly based on the activity levels of key TFs including AP1, STATs, NF-B and p53. Immunohistochemical analysis confirmed that HPV- HNSCC is characterized by co-activated STAT3 and NF-B pathways and functional studies demonstrate that this phenotype can be effectively targeted with combined anti-NF-B and anti-STAT therapies. These discoveries correlate strongly with previous findings connecting STATs, NF-B and AP1 in HNSCC. We identified five top-scoring pair biomarkers from STATs, NF-B and AP1 pathways that distinguish HPV+ from HPV- HNSCC based on TF activity and validated these biomarkers on TCGA and on independent validation cohorts. We conclude that a novel approach to TF pathway analysis can provide insight into therapeutic targeting of patient subgroup for heterogeneous disease such as HNSCC. C1 [Gaykalova, Daria A.; Zizkova, Veronika; Morton, Kathryn; Bishop, Justin A.; Zhang, Chi; Michailidi, Christina; Tan, Marietta; Hennessey, Patrick T.; Ahn, Julie; Koch, Wayne M.; Westra, William H.; Khan, Zubair; Chung, Christine H.; Califano, Joseph A.] Johns Hopkins Med Inst, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21231 USA. [Manola, Judith B.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ozawa, Hiroyuki; Considine, Michael; Fertig, Elana J.; Chung, Christine H.; Ochs, Michael F.] Johns Hopkins Med Inst, Dept Oncol, Baltimore, MD 21231 USA. [Zizkova, Veronika] Palacky Univ, Lab Mol Pathol, Inst Mol & Translat Med, CR-77147 Olomouc, Czech Republic. [Bishop, Justin A.; Sharma, Rajni; Westra, William H.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA. [Zhang, Chi] Univ Virginia, Charlottesville, VA USA. [Considine, Michael; Fertig, Elana J.; Ochs, Michael F.] Johns Hopkins Med Inst, Div Oncol Biostat, Baltimore, MD 21231 USA. [Ochs, Michael F.] Coll New Jersey, Dept Math & Stat, Ewing, NJ USA. [Califano, Joseph A.] Greater Baltimore Med Ctr, Milton J Dance Head & Neck Ctr, Baltimore, MD USA. [Hennessey, Patrick T.] Mid Michigan Ear Nose & Throat, E Lansing, MI USA. RP Califano, JA (reprint author), Johns Hopkins Med Inst, Dept Otolaryngol Head & Neck Surg, 1550 Orleans St,Room 5N 04, Baltimore, MD 21231 USA. EM jcalifa@jhmi.edu FU American Head and Neck Society (AHNS) [306481]; NIDCR/NIH Challenge Grant [RC1DE020324, R01 DE013152]; NIDCR/NCI [P50DE019032]; NIH/NLM [R01 LM011000] FX Grant sponsor: American Head and Neck Society (AHNS); Grant number: 306481; Grant sponsor: NIDCR/NIH Challenge Grant; Grant numbers: RC1DE020324, R01 DE013152; Grant sponsor: NIDCR/NCI; Grant number: P50DE019032; Grant sponsor: NIH/NLM; Grant number: R01 LM011000 NR 51 TC 13 Z9 13 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2015 VL 137 IS 8 BP 1879 EP 1889 DI 10.1002/ijc.29558 PG 11 WC Oncology SC Oncology GA CO7OV UT WOS:000359350600015 PM 25857630 ER PT J AU Yang, XQ Shen, J Gao, Y Feng, Y Guan, YC Zhang, Z Mankin, H Hornicek, FJ Duan, ZF AF Yang, Xiaoqian Shen, Jacson Gao, Yan Feng, Yong Guan, Yichun Zhang, Zhan Mankin, Henry Hornicek, Francis J. Duan, Zhenfeng TI Nsc23925 prevents the development of paclitaxel resistance by inhibiting the introduction of P-glycoprotein and enhancing apoptosis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ovarian cancer; paclitaxel resistance; NSC23925; Pgp; apoptosis ID X-RECEPTOR AGONIST; EPITHELIAL OVARIAN-CANCER; ADVANCED BREAST-CARCINOMA; CELL LUNG-CANCER; MULTIDRUG-RESISTANCE; PHASE-II; GENE AMPLIFICATION; BEXAROTENE LGD1069; TARGRETIN PREVENTS; VALSPODAR PSC-833 AB Strategies to prevent the emergence of drug resistance will increase the effectiveness of chemotherapy treatment and prolong survival of women with ovarian cancer. The aim of our study is to determine the effects of NSC23925 on preventing the development of paclitaxel resistance in ovarian cancer both in cultured cells in vitro and in mouse xenograft models in vivo, and to further elucidate these underlying mechanisms. We first developed a paclitaxel-resistant ovarian cancer cell line, and demonstrated that NSC23925 could prevent the introduction of paclitaxel resistance by specifically inhibiting the overexpression of P-glycoprotein (Pgp) in vitro. The paclitaxel-resistant ovarian cancer cells were then established in a mouse model by continuous paclitaxel treatment in combination with or without NSC23925 administration in the mice. The majority of mice continuously treated with paclitaxel alone eventually developed paclitaxel resistance with overexpression of Pgp and antiapoptotic proteins, whereas mice remained sensitivity to paclitaxel and displayed lower expression levels of Pgp and antiapoptotic proteins after administered continuously with combination of paclitaxel-NSC23925. Paclitaxel-NSC23925-treated mice experienced significantly longer overall survival time than paclitaxel-treated mice. Furthermore, the combination of paclitaxel and NSC23925 therapy did not induce obvious toxicity as measured by mice body weight changes, blood cell counts and histology of internal organs. Collectively, our observations provide evidence that NSC23925 in combination with paclitaxel may prevent the onset of Pgp or antiapoptotic-mediated paclitaxel resistance, and improve the long-term clinical outcome in patients with ovarian cancer. What's New Finding ways to thwart drug resistance may be as important as identifying new chemotherapeutics. In ovarian cancer, paclitaxel works well initially, but the cancer often returns, no longer susceptible to paclitaxel. Could this resistance be prevented? This study targeted the P-glycoprotein (Pgp), known for pumping chemotherapeutic agents out of the cell. The authors showed that inhibiting the overexpression of Pgp in cultured ovarian cancer cells thwarts the onset of paclitaxel resistance. Mice bearing ovarian cancers who were treated with paclitaxel and a Pgp inhibitor remained sensitive to paclitaxel, and survived longer than mice treated with paclitaxel alone. C1 [Yang, Xiaoqian; Shen, Jacson; Gao, Yan; Feng, Yong; Guan, Yichun; Mankin, Henry; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Yang, Xiaoqian; Shen, Jacson; Gao, Yan; Feng, Yong; Guan, Yichun; Mankin, Henry; Hornicek, Francis J.; Duan, Zhenfeng] Harvard Univ, Sch Med, Boston, MA USA. [Yang, Xiaoqian; Guan, Yichun; Zhang, Zhan] Zhengzhou Univ, Affiliated Hosp 3, Dept Obstet & Gynaecol, Zhengzhou 450052, Henan Province, Peoples R China. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, 100 Blossom St,Jackson 1115, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu FU Gattegno and Wechsler Funds, Sarcoma Foundation of America; China Scholarship Council; National Cancer Institute/National Institutes of Health [UOI-CA 151452] FX Grant sponsors: Gattegno and Wechsler Funds, Sarcoma Foundation of America (Dr. Duan), and Scholarship from China Scholarship Council (Dr. Yang); Grant sponsor: National Cancer Institute/National Institutes of Health; Grant number: UOI-CA 151452 NR 48 TC 5 Z9 7 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2015 VL 137 IS 8 BP 2029 EP 2039 DI 10.1002/ijc.29574 PG 11 WC Oncology SC Oncology GA CO7OV UT WOS:000359350600030 PM 25904021 ER PT J AU Lucia, U Ponzetto, A Deisboeck, TS AF Lucia, Umberto Ponzetto, Antonio Deisboeck, Thomas S. TI A thermodynamic approach to the 'mitosis/apoptosis' ratio in cancer SO PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS LA English DT Article DE Apoptosis; Mitosis; Entropy; Irreversibility; Apoptosis/mitosis ratio ID MODULATED ELECTROMAGNETIC-FIELDS; TUMOR-GROWTH INHIBITION; STATIC MAGNETIC-FIELDS; CELLS IN-VITRO; ENTROPY GENERATION; ELECTRIC-FIELDS; OPEN SYSTEMS; EXPOSURE; PROLIFERATION; STIMULATION AB Cancer can be considered as an open, complex, (bio-thermo)dynamic and self-organizing system. Consequently, an entropy generation approach has been employed to analyze its mitosis/apoptosis ratio. Specifically, a novel thermodynamic anticancer strategy is suggested, based on the variation of entropy generation caused by the application of external fields, for example electro-magnetic fields, for therapeutic purposes. Eventually, this innovative approach could support conventional therapies, particularly for inoperable tumors or advanced stages of cancer, when larger tumor burden is diagnosed, and therapeutic options are often limited. (C) 2015 Elsevier B.V. All rights reserved. C1 [Lucia, Umberto] Politecn Torino, Dipartimento Energia, I-10129 Turin, Italy. [Ponzetto, Antonio] Univ Turin, Dept Med Sci, I-10126 Turin, Italy. [Deisboeck, Thomas S.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Deisboeck, Thomas S.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Lucia, U (reprint author), Politecn Torino, Dipartimento Energia, Corso Duca Abruzzi 24, I-10129 Turin, Italy. EM umberto.lucia@polito.it; antonio.ponzetto@unito.it; deisboec@helix.mgh.harvard.edu OI Lucia, Umberto/0000-0002-3123-2133; ponzetto, antonio/0000-0002-1551-3664 NR 69 TC 10 Z9 10 U1 2 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 EI 1873-2119 J9 PHYSICA A JI Physica A PD OCT 15 PY 2015 VL 436 BP 246 EP 255 DI 10.1016/j.physa.2015.05.046 PG 10 WC Physics, Multidisciplinary SC Physics GA CM5CN UT WOS:000357704500022 ER PT J AU Gomperts, SN Kloosterman, F Wilson, MA AF Gomperts, Stephen N. Kloosterman, Fabian Wilson, Matthew A. TI VTA neurons coordinate with the hippocampal reactivation of spatial experience SO ELIFE LA English DT Article ID VENTRAL TEGMENTAL AREA; PLACE-CELL SEQUENCES; DOPAMINE NEURONS; AWAKE STATE; MEMORY; SLEEP; REPLAY; RIPPLES; STRIATUM; REWARD AB Spatial learning requires the hippocampus, and the replay of spatial sequences during hippocampal sharp wave-ripple (SPW-R) events of quiet wakefulness and sleep is believed to play a crucial role. To test whether the coordination of VTA reward prediction error signals with these replayed spatial sequences could contribute to this process, we recorded from neuronal ensembles of the hippocampus and VTA as rats performed appetitive spatial tasks and subsequently slept. We found that many reward responsive (RR) VTA neurons coordinated with quiet wakefulness associated hippocampal SPW-R events that replayed recent experience. In contrast, coordination between RR neurons and SPW-R events in subsequent slow wave sleep was diminished. Together, these results indicate distinct contributions of VTA reinforcement activity associated with hippocampal spatial replay to the processing of wake and SWS-associated spatial memory. C1 [Gomperts, Stephen N.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA USA. [Gomperts, Stephen N.; Wilson, Matthew A.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Gomperts, Stephen N.; Wilson, Matthew A.] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Kloosterman, Fabian] NERF, Leuven, Belgium. [Kloosterman, Fabian] IMEC, Leuven, Belgium. [Kloosterman, Fabian] Lab Biol Psychol, Dept Psychol, Leuven, Belgium. RP Gomperts, SN (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA USA. EM sgomperts@partners.org FU National Institutes of Health [K08-MH-81207-01A1, R01-MH061976]; Office of Naval Research [N00014-10-1-0936] FX National Institutes of Health K08-MH-81207-01A1 Stephen N Gomperts; National Institutes of Health R01-MH061976 Matthew A Wilson; Office of Naval Research N00014-10-1-0936 Matthew A Wilson NR 42 TC 6 Z9 6 U1 1 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 14 PY 2015 VL 4 AR e05360 DI 10.7554/eLife.05360 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0IB UT WOS:000373884600001 ER PT J AU van den Heuvel, MP Scholtens, LH Barrett, LF Hilgetag, CC de Reus, MA AF van den Heuvel, Martijn P. Scholtens, Lianne H. Barrett, Lisa Feldman Hilgetag, Claus C. de Reus, Marcel A. TI Bridging Cytoarchitectonics and Connectomics in Human Cerebral Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE connectivity; connectomics; cytoarchitectonics; diffusion MRI; MRI; pyramidal neuron ID CORTICAL STRUCTURE; CONNECTIONS; COGNITION; BRAIN; ORGANIZATION; PRINCIPLES; WORKSPACE; NETWORK; CELL; MRI AB The rich variation in cytoarchitectonics of the human cortex is well known to play an important role in the differentiation of cortical information processing, with functional multimodal areas noted to display more branched, more spinous, and an overall more complex cytoarchitecture. In parallel, connectome studies have suggested that also the macroscale wiring profile of brain areas may have an important contribution in shaping neural processes; for example, multimodal areas have been noted to display an elaborate macroscale connectivity profile. However, how these two scales of brain connectivity are related-and perhaps interact-remains poorly understood. In this communication, we combined data from the detailed mappings of early twentieth century cytoarchitectonic pioneers Von Economo and Koskinas (1925) on the microscale cellular structure of the human cortex with data on macroscale connectome wiring as derived from high-resolution diffusion imaging data from the Human Connectome Project. In a cross-scale examination, we show evidence of a significant association between cytoarchitectonic features of human cortical organization-in particular the size of layer 3 neurons-and whole-brain corticocortical connectivity. Our findings suggest that aspects of microscale cytoarchitectonics and macroscale connectomics are related. C1 [van den Heuvel, Martijn P.; Scholtens, Lianne H.; de Reus, Marcel A.] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3508 GA Utrecht, Netherlands. [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02129 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Hilgetag, Claus C.] Univ Med Ctr Hamburg Eppendorf, Dept Computat Neurosci, D-20246 Hamburg, Germany. RP van den Heuvel, MP (reprint author), Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, Heidelberglaan 100,POB 85500,Room A01-126, NL-3508 GA Utrecht, Netherlands. EM M.P.vandenheuvel@umcutrecht.nl OI Hilgetag, Claus C/0000-0003-2129-8910 FU National Institutes of Health (NIH) [1U54MH091657]; Netherlands Organization for Scientific Research (VENI) [451-12-001] FX Human neuroimaging data were kindly provided by the Washington University, University of Minnesota, and Oxford University (WU-Minn HCP consortium; Principal Investigators: David Van Essen and Kamil Ugurbil; Grant 1U54MH091657) funded by the 16 National Institutes of Health (NIH) institutes and centers that support the NIH Blueprint for Neuroscience Research and by the McDonnell Center for Systems Neuroscience at Washington University. M.P.v.d.H. is supported by the Netherlands Organization for Scientific Research (VENI Grant 451-12-001). NR 36 TC 14 Z9 14 U1 2 U2 7 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 OCT 14 PY 2015 VL 35 IS 41 BP 13943 EP 13948 DI 10.1523/JNEUROSCI.2630-15.2015 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CX9US UT WOS:000366051800015 PM 26468195 ER PT J AU Miyamoto, N Maki, T Shindo, A Liang, AC Maeda, M Egawa, N Itoh, K Lo, EK Lok, J Ihara, M Arai, K AF Miyamoto, Nobukazu Maki, Takakuni Shindo, Akihiro Liang, Anna C. Maeda, Mitsuyo Egawa, Naohiro Itoh, Kanako Lo, Evan K. Lok, Josephine Ihara, Masafumi Arai, Ken TI Astrocytes Promote Oligodendrogenesis after White Matter Damage via Brain-Derived Neurotrophic Factor SO JOURNAL OF NEUROSCIENCE LA English DT Article DE astrocyte; BDNF; oligodendrogenesis; prolonged cerebral hypoperfusion; white matter injury ID CHRONIC CEREBRAL HYPOPERFUSION; BASAL FOREBRAIN; MOUSE MODEL; CELLS; MICE; OLIGODENDROCYTES; DIFFERENTIATION; PROLIFERATION; MYELINATION; ISCHEMIA AB Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAP(cre)/BDNFwt/fl) in which BDNF expression is downregulated specifically in GFAP(+) astrocytes. Both wild-type (GFAP(wt)/BDNFwt/fl mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF. C1 [Miyamoto, Nobukazu; Maki, Takakuni; Shindo, Akihiro; Liang, Anna C.; Egawa, Naohiro; Itoh, Kanako; Lo, Evan K.; Lok, Josephine; Arai, Ken] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Boston, MA 02114 USA. [Miyamoto, Nobukazu; Maki, Takakuni; Shindo, Akihiro; Liang, Anna C.; Egawa, Naohiro; Itoh, Kanako; Lo, Evan K.; Lok, Josephine; Arai, Ken] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Boston, MA 02114 USA. [Lok, Josephine] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Maeda, Mitsuyo] RIKEN Ctr Life Sci Technol, RIKEN CLST JEOL Collaborat Ctr, Multimodal Microstruct Anal Unit, Kobe, Hyogo 6500047, Japan. [Ihara, Masafumi] Natl Cerebral & Cardiovasc Ctr, Dept Stroke & Cerebrovasc Dis, Suita, Osaka 5658565, Japan. RP Arai, K (reprint author), Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA. EM karai@partners.org OI Ihara, Masafumi/0000-0002-7102-4048 FU National Institutes of Health Research Abroad Grant from the Uehara Memorial Foundation FX This work was supported in part by a National Institutes of Health Research Abroad Grant from the Uehara Memorial Foundation. NR 19 TC 11 Z9 11 U1 1 U2 6 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 OCT 14 PY 2015 VL 35 IS 41 BP 14002 EP 14008 DI 10.1523/JNEUROSCI.1592-15.2015 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CX9US UT WOS:000366051800020 PM 26468200 ER PT J AU Ji, MB Lewis, S Camelo-Piragua, S Ramkissoon, SH Snuderl, M Venneti, S Fisher-Hubbard, A Garrard, M Fu, D Wang, AC Heth, JA Maher, CO Sanai, N Johnson, TD Freudiger, CW Sagher, O Xie, XS Orringer, DA AF Ji, Minbiao Lewis, Spencer Camelo-Piragua, Sandra Ramkissoon, Shakti H. Snuderl, Matija Venneti, Sriram Fisher-Hubbard, Amanda Garrard, Mia Fu, Dan Wang, Anthony C. Heth, Jason A. Maher, Cormac O. Sanai, Nader Johnson, Timothy D. Freudiger, Christian W. Sagher, Oren Xie, Xiaoliang Sunney Orringer, Daniel A. TI Detection of human brain tumor infiltration with quantitative stimulated Raman scattering microscopy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID 5-AMINOLEVULINIC ACID; CLINICAL ARTICLE; MALIGNANT GLIOMA; CONTROLLED-TRIAL; RESECTION; FLUORESCENCE; EXTENT; GLIOBLASTOMA; SURGERY; HISTOPATHOLOGY AB Differentiating tumor from normal brain is a major barrier to achieving optimal outcome in brain tumor surgery. New imaging techniques for visualizing tumor margins during surgery are needed to improve surgical results. We recently demonstrated the ability of stimulated Raman scattering (SRS) microscopy, a nondestructive, label-free optical method, to reveal glioma infiltration in animal models. We show that SRS reveals human brain tumor infiltration in fresh, unprocessed surgical specimens from 22 neurosurgical patients. SRS detects tumor infiltration in near-perfect agreement with standard hematoxylin and eosin light microscopy (kappa = 0.86). The unique chemical contrast specific to SRS microscopy enables tumor detection by revealing quantifiable alterations in tissue cellularity, axonal density, and protein/lipid ratio in tumor-infiltrated tissues. To ensure that SRS microscopic data can be easily used in brain tumor surgery, without the need for expert interpretation, we created a classifier based on cellularity, axonal density, and protein/lipid ratio in SRS images capable of detecting tumor infiltration with 97.5% sensitivity and 98.5% specificity. Quantitative SRS microscopy detects the spread of tumor cells, even in brain tissue surrounding a tumor that appears grossly normal. By accurately revealing tumor infiltration, quantitative SRS microscopy holds potential for improving the accuracy of brain tumor surgery. C1 [Ji, Minbiao; Fu, Dan; Xie, Xiaoliang Sunney; Orringer, Daniel A.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Lewis, Spencer; Garrard, Mia; Wang, Anthony C.; Heth, Jason A.; Maher, Cormac O.; Sagher, Oren] Univ Michigan, Dept Neurosurg, Ann Arbor, MI 48109 USA. [Camelo-Piragua, Sandra; Venneti, Sriram; Fisher-Hubbard, Amanda] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Ramkissoon, Shakti H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ramkissoon, Shakti H.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Snuderl, Matija] NYU, Dept Pathol, New York, NY 10016 USA. [Snuderl, Matija] NYU, Dept Neurol, New York, NY 10016 USA. [Sanai, Nader] St Josephs Hosp, Barrow Neurol Inst, Div Neurosurg Oncol, Barrow Brain Tumor Res Ctr, Phoenix, AZ 85013 USA. [Johnson, Timothy D.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Freudiger, Christian W.] Invenio Imaging Inc, Menlo Pk, CA 94025 USA. RP Xie, XS (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM xie@chemistry.harvard.edu; dorringe@med.umich.edu RI Ji, Minbiao/C-7793-2011; OI Ji, Minbiao/0000-0002-9066-4008; Snuderl, Matija/0000-0003-0752-0917 FU National Institute of Biomedical Imaging and Bioengineering [R01EB017254]; National Cancer Institute [R01CA175391]; National Institute of Neurologic Disorders and Stroke [K08NS087118, F32NS074744]; NIH Director's Transformative Research Award Program T-R01 [R01EB010244-01]; American Association of Neurological Surgeons NREF (Neurosurgery Research and Education Foundation) Young Clinician Investigator Award; Michigan Institute for Clinical and Health Research [2UL1TR000433] FX Funding: Research reported in this publication was supported by the National Institute of Biomedical Imaging and Bioengineering (R01EB017254 to X.S.X. and D.A.O.), National Cancer Institute (R01CA175391 to N.S.), National Institute of Neurologic Disorders and Stroke (K08NS087118 to S.H.R.; F32NS074744 to A.C.W.), and the NIH Director's Transformative Research Award Program T-R01 (R01EB010244-01 to X.S.X.). This work was also supported by the 2013-2014 American Association of Neurological Surgeons NREF (Neurosurgery Research and Education Foundation) Young Clinician Investigator Award and the Michigan Institute for Clinical and Health Research 2UL1TR000433 (D.A.O.). NR 46 TC 18 Z9 18 U1 6 U2 34 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 14 PY 2015 VL 7 IS 309 AR 309ra163 DI 10.1126/scitranslmed.aab0195 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CW8FO UT WOS:000365235100005 PM 26468325 ER PT J AU Samuel, R Duda, DG Fukumura, D Jain, RK AF Samuel, Rekha Duda, Dan G. Fukumura, Dai Jain, Rakesh K. TI Vascular diseases await translation of blood vessels engineered from stem cells SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Review ID SMOOTH-MUSCLE-CELLS; ENDOTHELIAL PROGENITOR CELLS; ATTENUATE LIMB ISCHEMIA; UMBILICAL-CORD BLOOD; IN-VIVO; HEART-DISEASE; IPS CELLS; SOMATIC-CELLS; MOUSE MODEL; PLURIPOTENCY AB The discovery of human induced pluripotent stem cells (hiPSCs) might pave the way toward a long-sought solution for obtaining sufficient numbers of autologous cells for tissue engineering. Several methods exist for generating endothelial cells or perivascular cells from hiPSCs in vitro for use in the building of vascular tissue. We discuss current developments in the generation of vascular progenitor cells from hiPSCs and the assessment of their functional capacity in vivo, opportunities and challenges for the clinical translation of engineered vascular tissue, and modeling of vascular diseases using hiPSC-derived vascular progenitor cells. C1 [Samuel, Rekha; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. [Samuel, Rekha; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Samuel, Rekha] Christian Med Coll & Hosp, Ctr Stem Cell Res, Vellore 632002, Tamil Nadu, India. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu FU NCI NIH HHS [R01 CA115767, R01 CA085140, R01 CA159258, P01 CA080124, R01 CA096915, R01 CA126642] NR 87 TC 1 Z9 2 U1 3 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 14 PY 2015 VL 7 IS 309 AR 309rv6 DI 10.1126/scitranslmed.aaa1805 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CW8FO UT WOS:000365235100002 PM 26468328 ER PT J AU Dendup, T Richter, JM Yamaoka, Y Wangchuk, K Malaty, HM AF Dendup, Tashi Richter, James M. Yamaoka, Yoshio Wangchuk, Kinley Malaty, Hoda M. TI Geographical distribution of the incidence of gastric cancer in Bhutan SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Gastric cancer; Mortality; Epidemiology; Bhutan ID HELICOBACTER-PYLORI INFECTION; HIGH PREVALENCE; INTESTINAL METAPLASIA; ERADICATION; EPIDEMIOLOGY; METAANALYSIS; PROGRESSION; GUIDELINES; MANAGEMENT; MORTALITY AB AIM: to estimate the prevalence of gastric cancer (GC) in a cohort of patients diagnosed with GC and to compare it with patients diagnosed with all other types of gastro-intestinal (GI) cancer during the same period. METHODS: Between 2008 and 2013, five-year period, the medical records of all GI cancer patients who underwent medical care and confirm diagnosis of cancer were reviewed at the National Referral Hospital, Thimphu which is the only hospital in the country where surgical and cancer diagnosis can be made. Demographic information, type of cancer, and the year of diagnosis were collected. RESULTS: There were a total of 767 GI related cancer records reviewed during the study period of which 354 (46%) patients were diagnosed with GC. There were 413 patients with other GI cancer including; esophagus, colon, liver, rectum, pancreas, gall bladder, cholangio-carcinoma and other GI tract cancers. The GC incidence rate is approximately 0.9/10000 per year (367 cases/5 years per 800000 people). The geographic distribution of GC was the lowest in the south region of Bhutan 0.3/10000 per year compared to the central region 1.4/10000 per year, Eastern region 1.2/10000 per year, and the Western region 1.1/10000 per year. Moreover, GC in the South part was significantly lower than the other GI cancer in the same region (8% vs 15%; OR = 1.8, 95% CI: 1.3-3.1, P = 0.05). Among GC patients, 38% were under the age of 60 years, mean age at diagnosis was 62.3 (+/- 12.1) years with male-to-female ratio 1:0.5. The mean age among patients with all other type GI cancer was 60 years (+/- 13.2) and male-to-female ratio of 1:0.7. At time of diagnosis of GC, 342 (93%) were at stage 3 and 4 of and by the year 2013; 80 (23%) GC patients died compared to 31% death among patients with the all other GI cancer (P = 0.08). CONCLUSION: The incidence rate of GC in Bhutan is twice as high in the United States but is likely an underestimate rate because of unreported and undiagnosed cases in the villages. The high incidence of GC in Bhutan could be attributed to the high prevalence of Helicobacter pylori infection that we previously reported. The lowest incidence of GC in Southern part of the country could be due to the difference in the ethnicity as most of its population is of Indian and Nepal origin. Our current study emphasizes on the importance for developing surveillance and prevention strategies for GC in Bhutan. C1 [Dendup, Tashi] Jigme Dorji Wangchuck Natl Referral Hosp, Dept Surg, Thimphu, Bhutan. [Richter, James M.] Harvard Univ, Sch Med, MGH Gastroenterol Associates, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yamaoka, Yoshio] Oita Univ, Fac Med, Dept Environm & Prevent Med, Yufu 8795593, Japan. [Wangchuk, Kinley] Jigme Dorji Wangchuck Natl Referral Hosp, Dept Lab Med, Microbiol Unit, Thimphu, Bhutan. [Malaty, Hoda M.] Dept Med, Baylor Coll Med, Houston, TX 77030 USA. RP Malaty, HM (reprint author), Baylor Coll Med, Dept Med, Vet Affairs Med Ctr 111D, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hmalaty@bcm.edu FU Center for Eye Research and Education, Boston Massachusetts FX Supported by The Center for Eye Research and Education, Boston Massachusetts (partly). NR 36 TC 0 Z9 0 U1 0 U2 1 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD OCT 14 PY 2015 VL 21 IS 38 BP 10883 EP 10889 DI 10.3748/wjg.v21.i38.10883 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CU1GA UT WOS:000363267200018 PM 26478679 ER PT J AU Lee, H Shin, TH Cheon, J Weissleder, R AF Lee, Hakho Shin, Tae-Hyun Cheon, Jinwoo Weissleder, Ralph TI Recent Developments in Magnetic Diagnostic Systems SO CHEMICAL REVIEWS LA English DT Review ID IRON-OXIDE NANOPARTICLES; IMMUNOMAGNETIC CELL-SEPARATION; IMAGING CONTRAST AGENTS; HISTIDINE-TAGGED PROTEINS; CIRCULATING TUMOR-CELLS; ONE-POT SYNTHESIS; FEPT NANOPARTICLES; IN-VIVO; CANCER-CELLS; BIOLOGICAL APPLICATIONS C1 [Lee, Hakho; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. [Shin, Tae-Hyun; Cheon, Jinwoo] Yonsei Univ, Dept Chem, Seoul 120749, South Korea. RP Weissleder, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu FU NIH [R01EB004626, R01EB010011, HHSN268201000044C, R01HL113156, U54-CA119349, K12CA087723-09]; DoD OCRP Award [W81XWH-14-1-0279]; National Creative Research Initiative [2010-0018286]; Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs [HI08C2149] FX The authors thank Dr. Huilin Shao (MGH) for reviewing the manuscript. This work was supported in part by NIH Grants R01EB004626, R01EB010011, HHSN268201000044C, R01HL113156, U54-CA119349, and K12CA087723-09; DoD OCRP Award W81XWH-14-1-0279; the National Creative Research Initiative (2010-0018286 J.C.), and the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs (HI08C2149 J.C.). NR 350 TC 34 Z9 34 U1 23 U2 123 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD OCT 14 PY 2015 VL 115 IS 19 SI SI BP 10690 EP 10724 DI 10.1021/cr500698d PG 35 WC Chemistry, Multidisciplinary SC Chemistry GA CT7NR UT WOS:000363002300007 PM 26258867 ER PT J AU Jiang, YH Fan, X Yu, ZY Liao, ZB Wang, XS van Leyen, K Sun, XC Lo, EH Wang, XY AF Jiang, Yinghua Fan, Xiang Yu, Zhanyang Liao, Zhengbu Wang, Xiao-Shu van Leyen, Klaus Sun, Xiaochuan Lo, Eng H. Wang, Xiaoying TI Combination low-dose tissue-type plasminogen activator plus annexin A2 for improving thrombolytic stroke therapy SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE cerebral ischemia; tissue-type plasminogen activator; annexin A2; thrombolysis; combination therapy; focal embolic stroke model; rats ID ACUTE ISCHEMIC-STROKE; FOCAL EMBOLIC STROKE; BLOOD-BRAIN-BARRIER; CELL-SURFACE; IN-VITRO; TPA; RECEPTOR; ASSOCIATION; INJURY; FIBRINOLYSIS AB Risk of hemorrhagic transformation, incomplete reperfusion, neurotoxicity, and a short treatment time window comprises major challenges for tissue plasminogen activator (tPA) thrombolytic stroke therapy. Improving tPA therapy has become one of the highest priorities in the stroke field. This mini review article focuses on our recent efforts aimed at evaluating a novel combination approach of low-dose tPA plus recombinant annexin A2 (rA2, a tPA, and plasminogen co-receptor), which might enhance tPA thrombolytic efficacy, while reducing its associated complications related to intracerebral hemorrhagic transformation. Results of our experimental studies using a focal embolic stroke model in rats support the feasibility of the combination approach and suggest the potential for successful clinical translation. C1 [Jiang, Yinghua; Liao, Zhengbu; Wang, Xiao-Shu; Sun, Xiaochuan] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Chongqing, Peoples R China. [Jiang, Yinghua; Fan, Xiang; Yu, Zhanyang; Liao, Zhengbu; Wang, Xiao-Shu; van Leyen, Klaus; Lo, Eng H.; Wang, Xiaoying] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Program,Neuroprotect Res Lab,Dept Neurol, Boston, MA 02163 USA. [Fan, Xiang] Tianjin Univ Tradit Chinese Med, Res Inst Tradit Chinese Med, Tianjin, Peoples R China. RP Wang, XY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Program,Neuroprotect Res Lab,Dept Neurol, Boston, MA 02163 USA. EM wangxi@helix.mgh.harvard.edu FU National Institute of Health [R01-NS065998, UO1-NS072324] FX This work was supported in part by the National Institute of Health grants R01-NS065998 and UO1-NS072324 (to XW). NR 43 TC 2 Z9 2 U1 0 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD OCT 14 PY 2015 VL 9 AR 397 DI 10.3389/fncel.2015.00397 PG 5 WC Neurosciences SC Neurosciences & Neurology GA CT3DX UT WOS:000362688500001 PM 26528130 ER PT J AU van Leyen, K Arai, K Wang, XY Lo, EH AF van Leyen, Klaus Arai, Ken Wang, Xiaoying Lo, Eng H. TI From cell to cell: The breakdown of intercellular connectivity after stroke and how to regain contact SO BRAIN RESEARCH LA English DT Editorial Material C1 [van Leyen, Klaus; Arai, Ken; Wang, Xiaoying; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroprotect Res Lab,Dept Radiol, Charlestown, MA 02129 USA. RP van Leyen, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroprotect Res Lab,Dept Radiol, Charlestown, MA 02129 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD OCT 14 PY 2015 VL 1623 SI SI BP 1 EP 2 DI 10.1016/j.brainres.2015.08.036 PG 2 WC Neurosciences SC Neurosciences & Neurology GA CS5UU UT WOS:000362144600001 PM 26363519 ER PT J AU Dalkara, T Alarcon-Martinez, L AF Dalkara, Turgay Alarcon-Martinez, Luis TI Cerebral microvascular pericytes and neurogliovascular signaling in health and disease SO BRAIN RESEARCH LA English DT Review DE Neurovascular unit; Neurovascular coupling; Pericyte; Angiogenesis; Inflammation; Recanalization; Retinopathy; Dementia ID BLOOD-BRAIN-BARRIER; ENDOTHELIAL NITRIC-OXIDE; INDUCED CA2+ RESPONSES; ACUTE ISCHEMIC-STROKE; STEM-CELL ACTIVITY; ALZHEIMERS-DISEASE; IN-VIVO; CNS PERICYTES; NEUROVASCULAR UNIT; AMYLOID-BETA AB Increases in neuronal activity cause an enhanced blood flow to the active brain area. This neurovascular coupling is regulated by multiple mechanisms: Adenosine and lactate produced as metabolic end-products couple activity with flow by inducing vasodilation. As a specific mechanism to the brain, synaptic activity-induced Ca2+ increases in astrocytes, intemeurons and neurons translate neuronal activity to vasoactive signals such as arachidonic acid metabolites and NO. K+ released onto smooth muscle cells through Ca2+-activated K+ channels on end-feet can also induce vasodilation during neuronal activity. An intense communication between the endothelia, pericytes and astrocytes is required for development and functioning of the neurovascular unit as well as the BBB. The ratio of pericytes to endothelial cells is higher in the cerebral microcirculation than other tissues. Pericytes play a role in distribution of microvascular blood flow in response to the local demand as a final regulatory step after arterioles, which feed a larger cohort of cells. Pericyte endothelial communication is essential for vasculogenesis. Pericyte also take part in leukocyte infiltration and immune responses. The microvascular injury induced by ischemia/reperfusion plays a critical role in tissue survival after recanalization by inducing sustained pericyte contraction and microcirculatory clogging (noreflow) and by disrupting BBB integrity. Suppression of oxidative/nitrative stress or sustained adenosine delivery during re-opening of an occluded artery improves the outcome of recanalization by promoting microcirculatory reflow. Pericyte dysfunction in retinal microvessels is the main cause of diabetic retinopathy. Recent findings suggest that the age-related microvascular dysfunction may initiate the neurodegenerative changes seen Alzheimer's dementia. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. (C) 2015 Elsevier B.V. All rights reserved. C1 [Dalkara, Turgay] Hacettepe Univ, Fac Med, Dept Neurol, TR-06100 Ankara, Turkey. [Dalkara, Turgay; Alarcon-Martinez, Luis] Hacettepe Univ, Inst Neurol Sci & Psychiat, TR-06100 Ankara, Turkey. [Dalkara, Turgay] Harvard Univ, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Dalkara, Turgay] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Dalkara, T (reprint author), Hacettepe Univ, Inst Neurol Sci & Psychiat, TR-06100 Ankara, Turkey. EM tdalkara@hacettepe.edu.tr FU Turkish Academy of Sciences; Brain Circulation Scheme of Marie Curie Actions into the 7th Framework Program of European Union FX Dr. Turgay Dalkara's research is supported by The Turkish Academy of Sciences. Dr. Luis Alarcon-Martinez's research is supported by the Co-funded Brain Circulation Scheme of Marie Curie Actions into the 7th Framework Program of European Union. Dr. Luis Alarcon-Martinez prepared Figs. 3 and 5. NR 163 TC 19 Z9 19 U1 9 U2 39 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD OCT 14 PY 2015 VL 1623 SI SI BP 3 EP 17 DI 10.1016/j.brainres.2015.03.047 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CS5UU UT WOS:000362144600002 PM 25862573 ER PT J AU Itoh, K Maki, T Lok, J Arai, K AF Itoh, Kanako Maki, Takakuni Lok, Josephine Arai, Ken TI Mechanisms of cell-cell interaction in oligodendrogenesis and remyelination after stroke SO BRAIN RESEARCH LA English DT Review DE White matter; Stroke; Oligodendrocyte precursor cell; Cell-cell interaction ID FOCAL CEREBRAL-ISCHEMIA; CENTRAL-NERVOUS-SYSTEM; CUPRIZONE-INDUCED DEMYELINATION; LEUKEMIA INHIBITORY FACTOR; ENDOTHELIAL GROWTH-FACTOR; DIMINISHES AUTOIMMUNE DEMYELINATION; SPINAL-CORD DEMYELINATION; PROSTAGLANDIN-D SYNTHASE; NEUROTROPHIC FACTOR CNTF; MYELIN BASIC-PROTEIN AB White matter damage is a clinically important aspect of several central nervous system diseases, including stroke. Cerebral white matter primarily consists of axonal bundles ensheathed with myelin secreted by mature oligodendrocytes, which play an important role in neurotransmission between different areas of gray matter. During the acute phase of stroke, damage to oligodendrocytes leads to white matter dysfunction through the loss of myelin. On the contrary, during the chronic phase, white matter components promote an environment, which is favorable for neural repair, vascular remodeling, and remyelination. For effective remyelination to take place, oligodendrocyte precursor cells (OPCs) play critical roles by proliferating and differentiating into mature oligodendrocytes, which help to decrease the burden of axonal injury. Notably, other types of cells contribute to these OPC responses under the ischemic conditions. This mini-review summarizes the non-cell autonomous mechanisms in oligodendrogenesis and remyelination after white matter damage, focusing on how OPCs receive support from their neighboring cells. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. (C) 2015 Elsevier B.V. All rights reserved. C1 [Itoh, Kanako; Maki, Takakuni; Lok, Josephine; Arai, Ken] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. [Itoh, Kanako; Maki, Takakuni; Lok, Josephine; Arai, Ken] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Itoh, Kanako; Maki, Takakuni; Lok, Josephine; Arai, Ken] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Lok, Josephine] Massachusetts Gen Hosp, Dept Pediat, Charlestown, MA 02129 USA. RP Arai, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA. EM karai@partners.org FU National Institutes of Health [P01 NS055104, R01 NS065089] FX Supported by National Institutes of Health (P01 NS055104 and R01 NS065089). NR 178 TC 2 Z9 2 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD OCT 14 PY 2015 VL 1623 SI SI BP 135 EP 149 DI 10.1016/j.brainres.2015.04.039 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CS5UU UT WOS:000362144600013 PM 25960351 ER PT J AU Sakadzic, S Lee, J Boas, DA Ayata, C AF Sakadzic, Sava Lee, Jonghwan Boas, David A. Ayata, Cenk TI High-resolution in vivo optical imaging of stroke injury and repair SO BRAIN RESEARCH LA English DT Review DE High-resolution; Optical imaging; Stroke; Cellular imaging; Multi-photon microscopy; Optical coherence tomography; Photoacoustic imaging ID CEREBRAL-BLOOD-FLOW; ENCODED FLUORESCENT INDICATOR; NADH-NAD(+) REDOX STATE; COHERENCE TOMOGRAPHY; LIVING CELLS; PHOTOACOUSTIC MICROSCOPY; SPREADING DEPRESSION; 2-PHOTON MICROSCOPY; LIVE CELLS; ASTROCYTE RESPONSES AB Central nervous system (CNS) function and dysfunction are best understood within a framework of interactions between neuronal, glial and vascular compartments comprising the neurovascular unit (NVU), all of which contribute to stroke-induced CNS injury, plasticity, repair, and recovery. Recent advances in in vivo optical microscopy have enabled us to observe and interrogate cells and their processes with high spatial resolution in real time and in their natural environment deep in the brain tissue. Here, we review some of these state-of-the-art imaging techniques with an emphasis on imaging the interactions among the constituents of the NVU during ischemic injury and repair in small animal models. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. (C) 2015 Elsevier B.V. All rights reserved. C1 [Sakadzic, Sava; Lee, Jonghwan; Boas, David A.] Massachusetts Gen Hosp, Dept Radiol, Opt Div, MHG MIT HMS Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sakadzic, Sava; Lee, Jonghwan; Boas, David A.; Ayata, Cenk] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Ayata, Cenk] Massachusetts Gen Hosp, Dept Radiol, Neurovasc Res Lab, Charlestown, MA 02129 USA. [Ayata, Cenk] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. [Ayata, Cenk] Massachusetts Gen Hosp, Dept Neurol, Neurosci Intens Care Unit, Boston, MA 02114 USA. [Ayata, Cenk] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Sakadzic, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, Opt Div, MHG MIT HMS Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM sava.sakadzic@mgh.harvard.edu FU National Institute of Health [EB018464, EB000790, NS055104, NS061505, K99EB014879]; Foundation Leducq [FLQ12CVD01]; Heitman Foundation; Ellison Medical Foundation FX The authors would like to thank Kassandra Kisler for useful discussion. We would also like to thank support from the National Institute of Health (Grants EB018464, EB000790, NS055104, NS061505 and K99EB014879), Foundation Leducq (grant number FLQ12CVD01), the Heitman Foundation, and the Ellison Medical Foundation. NR 187 TC 5 Z9 5 U1 7 U2 50 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD OCT 14 PY 2015 VL 1623 SI SI BP 174 EP 192 DI 10.1016/j.brainres.2015.04.044 PG 19 WC Neurosciences SC Neurosciences & Neurology GA CS5UU UT WOS:000362144600017 PM 25960347 ER PT J AU Lewis, LD Voigts, J Flores, FJ Schmitt, LL Wilson, MA Halassa, MM Brown, EN AF Lewis, Laura D. Voigts, Jakob Flores, Francisco J. Schmitt, L. Lan Wilson, Matthew A. Halassa, Michael M. Brown, Emery N. TI Thalamic reticular nucleus induces fast and local modulation of arousal state SO ELIFE LA English DT Article ID FREELY-MOVING RAT; SLEEP DELTA-WAVES; HIGH-DENSITY EEG; NEURONS IN-VIVO; SLOW WAVES; INDUCED UNCONSCIOUSNESS; INTRINSIC OSCILLATION; NEOCORTICAL NEURONS; GENERAL-ANESTHESIA; NETWORK STATE AB During low arousal states such as drowsiness and sleep, cortical neurons exhibit rhythmic slow wave activity associated with periods of neuronal silence. Slow waves are locally regulated, and local slow wave dynamics are important for memory, cognition, and behaviour. While several brainstem structures for controlling global sleep states have now been well characterized, a mechanism underlying fast and local modulation of cortical slow waves has not been identified. Here, using optogenetics and whole cortex electrophysiology, we show that local tonic activation of thalamic reticular nucleus (TRN) rapidly induces slow wave activity in a spatially restricted region of cortex. These slow waves resemble those seen in sleep, as cortical units undergo periods of silence phase-locked to the slow wave. Furthermore, animals exhibit behavioural changes consistent with a decrease in arousal state during TRN stimulation. We conclude that TRN can induce rapid modulation of local cortical state. C1 [Lewis, Laura D.] Harvard Univ, Soc Fellows, Cambridge, MA 02138 USA. [Lewis, Laura D.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Lewis, Laura D.; Voigts, Jakob; Flores, Francisco J.; Wilson, Matthew A.; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Flores, Francisco J.; Brown, Emery N.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA USA. [Flores, Francisco J.; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. [Schmitt, L. Lan; Halassa, Michael M.] NYU, Inst Neurosci, New York, NY USA. [Wilson, Matthew A.] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard MIT Hlth Sci & Technol, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Halassa, MM (reprint author), NYU, Inst Neurosci, New York, NY USA. EM halassa@nyumc.org; enb@neurostat.mit.edu OI Flores, Francisco/0000-0002-8974-9717 FU National Institutes of Health (NIH) [TR01 GM104948, K99 N5078115]; Canadian Institutes of Health Research (CIHR); Society of Fellows, Harvard University FX National Institutes of Health (NIH) TR01 GM104948 Emery N Brown; Canadian Institutes of Health Research (CIHR) Doctoral Research Award Laura D Lewis; Society of Fellows, Harvard University Junior Fellowship Laura D Lewis; National Institutes of Health (NIH) K99 N5078115 Michael M Halassa NR 75 TC 10 Z9 10 U1 1 U2 9 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 13 PY 2015 VL 4 AR e08760 DI 10.7554/eLife.08760 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0JJ UT WOS:000373888000001 PM 26460547 ER PT J AU Ingason, A Giegling, I Hartmann, AM Genius, J Konte, B Friedl, M Ripke, S Sullivan, PF St Clair, D Collier, DA O'Donovan, MC Mirnics, K Rujescu, D AF Ingason, A. Giegling, I. Hartmann, A. M. Genius, J. Konte, B. Friedl, M. Ripke, S. Sullivan, P. F. St Clair, D. Collier, D. A. O'Donovan, M. C. Mirnics, K. Rujescu, D. CA PGC TI Expression analysis in a rat psychosis model identifies novel candidate genes validated in a large case-control sample of schizophrenia SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID NMDA RECEPTOR ANTAGONISM; DE-NOVO MUTATIONS; COMMON VARIANTS; GLUTAMATERGIC TRANSMISSION; INTELLECTUAL DISABILITY; CONFERRING RISK; LANGUAGE; KETAMINE; SUSCEPTIBILITY; MICRODELETIONS AB Antagonists of the N-methyl-D-aspartate (NMDA)-type glutamate receptor induce psychosis in healthy individuals and exacerbate schizophrenia symptoms in patients. In this study we have produced an animal model of NMDA receptor hypofunction by chronically treating rats with low doses of the NMDA receptor antagonist MK-801. Subsequently, we performed an expression study and identified 20 genes showing altered expression in the brain of these rats compared with untreated animals. We then explored whether the human orthologs of these genes are associated with schizophrenia in the largest schizophrenia genome-wide association study published to date, and found evidence for association for 4 out of the 20 genes: SF3B1, FOXP1, DLG2 and VGLL4. Interestingly, three of these genes, FOXP1, SF3B1 and DLG2, have previously been implicated in neurodevelopmental disorders. C1 [Ingason, A.; Giegling, I.; Hartmann, A. M.; Konte, B.; Friedl, M.; Rujescu, D.] Univ Halle Wittenberg, Dept Psychiat, D-06112 Halle, Germany. [Genius, J.] Univ Munich, Dept Psychiat, D-80539 Munich, Germany. [Ripke, S.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [St Clair, D.] Univ Aberdeen, Dept Mental Hlth, Aberdeen, Scotland. [Collier, D. A.] Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. [O'Donovan, M. C.] Cardiff Univ, Ctr Neuropsychiat Genet & Genom, MRC, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Mirnics, K.] Vanderbilt Univ, Dept Psychiat, Nashville, TN 37235 USA. RP Rujescu, D (reprint author), Univ Halle Wittenberg, Dept Psychiat Psychotherapy & Psychosomat, Julius Kuhn Str 7, D-06112 Halle, Germany. EM dan.rujescu@uk-halle.de RI Hansen, Thomas Folkmann/O-5965-2014 OI Hansen, Thomas Folkmann/0000-0001-6703-7762 FU German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the e:Med Programme [01ZX1314] FX We thank the participating subjects for making this study possible. Parts of this study were supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314). NR 53 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT 13 PY 2015 VL 5 AR e656 DI 10.1038/tp.2015.151 PG 6 WC Psychiatry SC Psychiatry GA DA2YV UT WOS:000367664000002 PM 26460480 ER PT J AU Smith, T Hutchison, P Schror, K Claria, J Lanas, A Patrignani, P Chan, AT Din, F Langley, R Elwood, P Freedman, A Eccles, R AF Smith, Tom Hutchison, Pippa Schroer, Karsten Claria, Joan Lanas, Angel Patrignani, Paola Chan, Andrew T. Din, Farhat Langley, Ruth Elwood, Peter Freedman, Andrew Eccles, Ron TI Aspirin in the 21st century-common mechanisms of disease and their modulation by aspirin: a report from the 2015 scientific conference of the international aspirin foundation, 28 August, London, UK SO ECANCERMEDICALSCIENCE LA English DT Article DE aspirin; cancer; Lynch syndrome; Hughes syndrome; diabetes; HIV ID PLATELET-FUNCTION; CANCER AB Professor Peter Rothwell of Oxford University chaired the annual Scientific Conference of the International Aspirin Foundation in London on 28 August 2015. It took the form of four sessions. Aspirin has more than one action in its effects on disease. Its acetylation of cyclooxygenase 2 (COX-2) in platelets leads to the blockade of pro-inflammatory chemicals and generation of anti-inflammatory mediators and increase in nitrous oxide (NO) production, which helps to preserve arterial endothelium. But platelets are not its only target. There is now evidence that aspirin has a direct antitumour effect on intestinal mucosal cells that block their potential transformation into cancer cells. Randomised placebo-controlled trials (RCTs) in people with histories of colorectal neoplasia have shown that aspirin reduces the risk of recurrent adenomas and reduces long-term cancer incidence in patients with Lynch syndrome. Among women given aspirin for cardiovascular disease, there were fewer cancers than in those given placebo. Epidemiological evidence has suggested that aspirin treatment after cancer is diagnosed reduces the incidence of metastases and prolongs survival, and long-term studies of anticancer treatment with aspirin are under way to confirm this. Apart from cancer studies, aspirin use is now firmly established as treatment for antiphospholipid syndrome (Hughes syndrome) and is being used to prevent and treat the heightened risk of cardiovascular disease in diabetes mellitus and in patients with HIV. C1 [Smith, Tom] The Croft, Girvan KA26 0RU, Ayr, Scotland. [Hutchison, Pippa] Int Aspirin Fdn, Maidstone ME16 8AU, Kent, England. [Schroer, Karsten] Univ Dusseldorf, Inst Pharmakol & Klin Pharmakol, D-40225 Dusseldorf, Germany. [Claria, Joan] Univ Barcelona, Hosp Clin, E-08036 Barcelona, Spain. [Lanas, Angel] Univ Zaragoza, Univ Hosp, Serv Digest Dis, IIS Aragon,CIBERehd, Zaragoza, Spain. [Patrignani, Paola] Univ G DAnnunzio, Dept Neurosci Imaging & Clin Sci, I-66100 Chieti, Italy. [Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Din, Farhat] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Langley, Ruth] UCL, MRC, Clin Trials Unit, Inst Clin Trials & Methodol, London, England. [Elwood, Peter] Cardiff Univ, Dept Primary Care & Publ Hlth, Cochrane Inst, Cardiff CF10 3AX, S Glam, Wales. [Freedman, Andrew] Cardiff Univ, Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Eccles, Ron] Cardiff Univ, Common Cold Ctr, Cardiff CF10 3AX, S Glam, Wales. RP Smith, T (reprint author), The Croft, Girvan KA26 0RU, Ayr, Scotland. EM doctom.smith@outlook.com OI Eccles, Ronald/0000-0001-9492-2062 NR 17 TC 1 Z9 1 U1 2 U2 6 PU CANCER INTELLIGENCE LTD PI BRISTOL PA 11 ALMA VALE RD,, BRISTOL, BS8 2HL, ENGLAND SN 1754-6605 J9 ECANCERMEDICALSCIENC JI eCancerMedicalScience PD OCT 13 PY 2015 VL 9 AR 581 DI 10.3332/ecancer.2015.581 PG 5 WC Oncology SC Oncology GA CV1HI UT WOS:000364003900001 PM 26557879 ER PT J AU Bonaca, MP Bhatt, DL Steg, PG Budaj, A Bansilal, S Storey, RF Im, K Magnani, G Ophuis, TO Ruda, M Hamm, C Spinar, J Kiss, RG Diaz, R Van de Werf, FJ Montalescot, G Jensen, EC Held, P Braunwald, E Sabatine, MS AF Bonaca, Marc P. Bhatt, Deepak L. Steg, Philippe G. Budaj, Andrej Bansilal, Sameer Storey, Robert F. Im, KyungAh Magnani, Giulia Ophuis, T. Oude Ruda, Michael Hamm, Christian Spinar, Jindrich Kiss, Robert Gabor Diaz, Rafael Van de Werf, Frans J. Montalescot, Gilles Jensen, Eva C. Held, Peter Braunwald, Eugene Sabatine, Marc S. TI Efficacy of Long-Term Ticagrelor in Stented Patients in PEGASUS-TIMI 54 SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Antiplatelet therapy C1 [Bonaca, Marc P.; Bhatt, Deepak L.; Im, KyungAh; Magnani, Giulia; Braunwald, Eugene; Sabatine, Marc S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp, Boston, MA 02115 USA. [Steg, Philippe G.] Hop Bichat Claude Bernard, F-75877 Paris, France. [Budaj, Andrej] Grochowski Hosp, Warsaw, Poland. [Bansilal, Sameer] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Storey, Robert F.] Univ Sheffield, Sheffield, S Yorkshire, England. [Ophuis, T. Oude] CWZ, Nijmegen, Netherlands. [Ruda, Michael] Russian Cardiol Res Ctr, Moscow, Russia. [Hamm, Christian] Kerckhoff Heart Ctr, Bad Nauheim, Germany. [Spinar, Jindrich] Masaryk Univ, Fac Med, Brno, Czech Republic. [Spinar, Jindrich] Univ Hosp Brno, Brno, Czech Republic. [Kiss, Robert Gabor] State Hlth Ctr, Budapest, Hungary. [Diaz, Rafael] ECLA, Rosario, Argentina. [Van de Werf, Frans J.] Katholieke Univ Leuven Hosp, Leuven, Belgium. [Montalescot, Gilles] Hop La Pitie Salpetriere, Paris, France. [Jensen, Eva C.; Held, Peter] AstraZeneca, Molndal, Sweden. NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-78 BP B36 EP B36 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000079 ER PT J AU Christopoulos, G Kandzari, D Yeh, R Jaffer, F Karmpaliotis, D Wyman, RM Alaswad, K Lombardi, W Grantham, JA Moses, JW Christakopoulos, GE Tarar, MNJ Rangan, BV Lembo, N Garcia, S Cipher, D Thompson, C Banerjee, S Brilakis, E AF Christopoulos, Georgios Kandzari, David Yeh, Robert Jaffer, Farouc Karmpaliotis, Dimitri Wyman, R. Michael Alaswad, Khaldoon Lombardi, William Grantham, J. Aaron Moses, Jeffrey W. Christakopoulos, Georgios E. Tarar, Muhammad Nauman J. Rangan, Bavana V. Lembo, Nicholas Garcia, Santiago Cipher, Daisha Thompson, Craig Banerjee, Subhash Brilakis, Emmanouil TI Development of a new prediction rule for chronic total occlusion recanalization failure: The Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS CTO) score SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Chronic total occlusion; PCI; Scoring system C1 [Christopoulos, Georgios] Mayo Clin, Rochester, MN USA. [Kandzari, David; Lembo, Nicholas] Piedmont Heart Inst, Atlanta, GA USA. [Yeh, Robert; Jaffer, Farouc] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Karmpaliotis, Dimitri; Moses, Jeffrey W.] Columbia Univ, New York, NY USA. [Wyman, R. Michael] Torrance Mem Med Ctr, Torrance, CA USA. [Alaswad, Khaldoon] Henry Ford Hosp, Detroit, MI 48202 USA. [Lombardi, William] Univ Washington, Seattle, WA 98195 USA. [Grantham, J. Aaron] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Christakopoulos, Georgios E.; Tarar, Muhammad Nauman J.; Rangan, Bavana V.; Cipher, Daisha; Banerjee, Subhash; Brilakis, Emmanouil] VA North Texas Healthcare Syst, Dallas, TX USA. [Christakopoulos, Georgios E.; Tarar, Muhammad Nauman J.; Rangan, Bavana V.; Cipher, Daisha; Banerjee, Subhash; Brilakis, Emmanouil] UT Southwestern Med Ctr, Dallas, TX USA. [Garcia, Santiago] Univ Minnesota, Minneapolis, MN USA. [Garcia, Santiago] Minneapolis VA Med Ctr, Minneapolis, MN USA. [Thompson, Craig] Boston Sci, Natick, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-161 BP B58 EP B59 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000125 ER PT J AU Cohen, MG Matthews, RV Maini, B Dixon, S Vetrovec, GW Wohns, DH Palacios, IF Popma, J Ohman, EM Schreiber, T O'Neill, WW AF Cohen, Mauricio G. Matthews, Ray V. Maini, Brij Dixon, Simon Vetrovec, George W. Wohns, David H. Palacios, Igor F. Popma, Jeffrey Ohman, E. Magnus Schreiber, Theodore O'Neill, William W. TI Use of a Percutaneous Left Ventricular Assist Device for High Risk Percutaneous Coronary Interventions. Clinical Trial versus Real World Experience SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE High-risk PCI; Impella; Left ventricular assist device C1 [Cohen, Mauricio G.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Matthews, Ray V.] Univ So Calif, Los Angeles, CA USA. [Maini, Brij] PinnacleHlth Cardiovasc Inst, Wormleysburg, PA USA. [Dixon, Simon] Beaumont Hosp, Royal Oak, MI USA. [Vetrovec, George W.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Wohns, David H.] Frederik Meijer Heart & Vasc Inst Spectrum Hlth, Grand Rapids, MI USA. [Palacios, Igor F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Popma, Jeffrey] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ohman, E. Magnus] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Schreiber, Theodore] Detroit Med Ctr, Cardiovasc Inst, Detroit, MI USA. [O'Neill, William W.] Henry Ford Hosp, Detroit, MI 48202 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-20 BP B8 EP B9 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000021 ER PT J AU Garg, A Mennuni, MG Theodoropoulos, K Sharma, A Kostis, J Stefanini, GG AF Garg, Aakash Mennuni, Marco G. Theodoropoulos, Kleanthis Sharma, Abhishek Kostis, John Stefanini, Giulio G. TI Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting In Left Main Coronary Artery Disease: Long-Term Follow-Up Meta-Analysis Of 6156 Patients SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE PCI outcomes C1 [Garg, Aakash] St Peters Univ Hosp Rutgers RWJMS, New Brunswick, NJ USA. [Mennuni, Marco G.; Stefanini, Giulio G.] Humanitas Res Hosp, Milan, Italy. [Theodoropoulos, Kleanthis] James J Peters VA Hosp, Icahn Sch Med Mt Sinai, Bronx, NY USA. [Sharma, Abhishek] SUNY Downstate Univ, Brooklyn, NY USA. [Kostis, John] UMDNJ, CVI, New Brunswick, NJ USA. [Kostis, John] UMDNJ, RWJMS, New Brunswick, NJ USA. NR 0 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 OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-463 BP B189 EP B190 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000412 ER PT J AU Herrera, JE Cubeddu, R Torres, W Velasco, L Finizola, B D'Empaire, G Octavio, JA Garcia, E Herrera, JA Levine, R Palacios, IF AF Herrera, Jose E. Cubeddu, Roberto Torres, William Velasco, Luis Finizola, Bartolome D'Empaire, Gabriel Octavio, Jose A. Garcia, Eleazar Herrera, Jose A. Levine, Robert Palacios, Igor F. TI Acute Hemodynamic Effects of Percutaneous Transluminal Caval Flow Intermittent Restriction with Balloon, in Ischemic and Non Ischemic Heart Failure Patients SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Balloon; Device therapy; Innovation C1 [Herrera, Jose E.; Garcia, Eleazar; Herrera, Jose A.] Ascardio, Barquisimeto, Venezuela. [Cubeddu, Roberto] Adventure Hosp, Miami, FL USA. [Torres, William; Velasco, Luis; Finizola, Bartolome] Ascardio, Barquisimeto, Lara, Venezuela. [D'Empaire, Gabriel; Octavio, Jose A.] Hosp Clin Caracas, Caracas, Venezuela. [Levine, Robert; Palacios, Igor F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-733 BP B299 EP B299 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000674 ER PT J AU Krishnan, K Dvir, D Ye, J Ge, L Tseng, E AF Krishnan, Kapil Dvir, Danny Ye, Jian (James) Ge, Liang Tseng, Elaine TI Impact of Balloon-Expandable Transcatheter Aortic Valve Size on Stent and Leaflet Stresses SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Computational Modeling; Computed tomography; Transcatheter aortic valve replacement C1 [Krishnan, Kapil; Ge, Liang] UCSF Med Ctr, San Francisco, CA USA. [Dvir, Danny] St Pauls Hosp, Vancouver, BC V6Z 1Y6, Canada. [Ye, Jian (James)] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Tseng, Elaine] Univ Calif San Francisco, Med Ctr, San Francisco, CA USA. [Tseng, Elaine] San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-659 BP B270 EP B270 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000601 ER PT J AU Meelu, OA Sartori, S Theodoropoulos, K Roy, S Thapi, R Baber, U Moreno, PR Krishnan, P Dangas, G Kini, A Sharma, SK Mehran, R AF Meelu, Omar A. Sartori, Samantha Theodoropoulos, Kleanthis Roy, Swathi Thapi, Roja Baber, Usman Moreno, Pedro R. Krishnan, Prakash Dangas, George Kini, Annapoorna Sharma, Samin K. Mehran, Roxana TI Outcomes Among Patients Enrolled Versus Not Enrolled In Interventional Cardiovascular Clinical Trials: Insights From A Single-center Analysis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Clinical outcomes; Clinical Trial C1 [Meelu, Omar A.] Mt Sinai Heart, New York, NY USA. [Sartori, Samantha; Krishnan, Prakash; Sharma, Samin K.] Mt Sinai Sch Med, New York, NY USA. [Theodoropoulos, Kleanthis] James J Peters VA Med Ctr, Icahn Sch Med Mt Sinai Bronx, Bronx, NY USA. [Roy, Swathi; Thapi, Roja; Moreno, Pedro R.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Baber, Usman] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dangas, George; Kini, Annapoorna] Mt Sinai, New York, NY USA. [Mehran, Roxana] Mt Sinai Hosp, New York, NY 10029 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-446 BP B182 EP B183 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000396 ER PT J AU Meelu, OA Sartori, S Theodoropoulos, K Roy, S Thapi, R Baber, U Dangas, G Moreno, PR Krishnan, P Kini, A Sharma, SK Mehran, R AF Meelu, Omar A. Sartori, Samantha Theodoropoulos, Kleanthis Roy, Swathi Thapi, Roja Baber, Usman Dangas, George Moreno, Pedro R. Krishnan, Prakash Kini, Annapoorna Sharma, Samin K. Mehran, Roxana TI Real World Generalizability Of Patients Enrolled In Clinical Trials Versus Those Not Enrolled SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Clinical Trial C1 [Meelu, Omar A.] Mt Sinai Heart, New York, NY USA. [Sartori, Samantha; Krishnan, Prakash; Sharma, Samin K.] Mt Sinai Sch Med, New York, NY USA. [Theodoropoulos, Kleanthis] James J Peters VA Med Ctr, Icahn Sch Med Mt Sinai Bronx, Bronx, NY USA. [Roy, Swathi; Thapi, Roja; Moreno, Pedro R.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Baber, Usman; Mehran, Roxana] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dangas, George; Kini, Annapoorna] Mt Sinai, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-447 BP B183 EP B183 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000397 ER PT J AU Shah, R Jones, WS Kohl, LP Hoffmann, U Douglas, PS Yow, E Lee, KL Fordyce, CB Mark, DB Lowe, AL Kosinski, AS Patel, M AF Shah, Rohan Jones, William S. Kohl, Louis P. Hoffmann, Udo Douglas, Pamela S. Yow, Eric Lee, Kerry L. Fordyce, Christopher B. Mark, Daniel B. Lowe, Alicia L. Kosinski, Andrzej S. Patel, Manesh TI Comparison of Visual Assessment of Coronary Stenosis with Independent Quantitative Coronary Angiography: Findings from the PROMISE Trial (PROspective Multicenter Imaging Study for Evaluation of chest pain) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Angiography; Coronary artery disease; Quantitative coronary angiography C1 [Shah, Rohan; Jones, William S.; Kohl, Louis P.; Douglas, Pamela S.; Yow, Eric; Lee, Kerry L.; Fordyce, Christopher B.; Mark, Daniel B.; Lowe, Alicia L.; Kosinski, Andrzej S.] Duke Univ, Durham, NC USA. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Patel, Manesh] Duke, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-284 BP B111 EP B112 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000244 ER PT J AU Sharma, A Sharma, SK Garg, A Vallakati, A Marmur, JD Mukherjee, D Stone, GW AF Sharma, Abhishek Sharma, Samin K. Garg, Aakash Vallakati, Ajay Marmur, Jonathan D. Mukherjee, Debabrata Stone, Gregg W. TI Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation in Patients with ACS vs. non-ACS: A Systematic Review and Meta-Analysis of Randomized Controlled Trials SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Acute coronary syndromes; Double anti-platelet therapy; Drug-eluting stent C1 [Sharma, Abhishek; Marmur, Jonathan D.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Sharma, Samin K.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Garg, Aakash] Icahn Sch Med Mt Sinai, James J Peters VA Hosp, Bronx, NY USA. [Vallakati, Ajay] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Mukherjee, Debabrata] Texas Tech Univ, Div Cardiol, El Paso, TX USA. [Stone, Gregg W.] Columbia Univ, Med Ctr, New York, NY USA. [Stone, Gregg W.] Cardiovasc Res Fdn, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-184 BP B68 EP B69 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000148 ER PT J AU Szerlip, M Arsalan, M Holper, EM Arnold, SV Vemulapalli, S Rumsfeld, JS Brown, D Li, ZK Mack, M AF Szerlip, Molly Arsalan, Mani Holper, Elizabeth M. Arnold, Suzanne V. Vemulapalli, Sreekanth Rumsfeld, John S. Brown, David Li, Zhuokai Mack, Michael TI Outcomes of TAVR in Nonagenarians in the US: Insights from the STS/ACC TVT Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Nonagenarians; Quality of life; TAVR C1 [Szerlip, Molly; Arsalan, Mani; Brown, David] Heart Hosp Baylor Plano, Plano, TX USA. [Holper, Elizabeth M.] Cardiopulm Res Sci & Technol Inst, Dallas, TX USA. [Arnold, Suzanne V.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Vemulapalli, Sreekanth] Duke Univ, Med Ctr, Durham, NC USA. [Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. [Li, Zhuokai] Duke Clin Res Inst, Durham, NC USA. [Mack, Michael] Baylor Healthcare Syst, Plano, TX USA. RI Li, Zhuokai/F-4681-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-618 BP B252 EP B252 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000561 ER PT J AU Theodoropoulos, K Mennuni, MG Garg, A Sharma, A Stefanini, GG AF Theodoropoulos, Kleanthis Mennuni, Marco G. Garg, Aakash Sharma, Abhishek Stefanini, Giulio G. TI Long-Term Mortality Of Percutaneous Coronary Intervention With Drug-Eluting Stents Compared To Bypass Surgery In Patients With Left Main Disease Stratified By The SYNTAX Score: Comprehensive Systematic Review And Meta-Analysis Of 3372 Patients SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Left main coronary artery disease; Meta-analysis; Syntax score C1 [Theodoropoulos, Kleanthis] James J Peters VA Med Ctr, Icahn Sch Med Mt Sinai Bronx, Bronx, NY USA. [Mennuni, Marco G.; Stefanini, Giulio G.] Humanitas Res Hosp, Milan, Italy. [Garg, Aakash] James J Peters VA Hosp, Icahn Sch Med Mt Sinai, Bronx, NY USA. [Sharma, Abhishek] SUNY Downstate Univ, Brooklyn, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-464 BP B190 EP B190 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000413 ER PT J AU Pigott, K Rick, J Xie, SRX Hurtig, H Chen-Plotkin, A Duda, JE Morley, JF Chahine, LM Dahodwala, N Akhtar, RS Siderowf, A Trojanowski, JQ Weintraub, D AF Pigott, Kara Rick, Jacqueline Xie, Sharon X. Hurtig, Howard Chen-Plotkin, Alice Duda, John E. Morley, James F. Chahine, Lama M. Dahodwala, Nabila Akhtar, Rizwan S. Siderowf, Andrew Trojanowski, John Q. Weintraub, Daniel TI Longitudinal study of normal cognition in Parkinson disease SO NEUROLOGY LA English DT Article ID 5-YEAR FOLLOW-UP; DIAGNOSTIC-CRITERIA; MOTOR SUBTYPE; LEWY BODIES; DEMENTIA; IMPAIRMENT; COHORT; PROGRESSION; DISORDER; CAMPAIGN AB Objective:To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods.Methods:A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors.Results:We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinson's Disease Rating Scale motor score (p 0.001), and worse global cognitive score (p < 0.001).Conclusions:Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD. C1 [Pigott, Kara; Rick, Jacqueline; Hurtig, Howard; Chen-Plotkin, Alice; Duda, John E.; Morley, James F.; Chahine, Lama M.; Dahodwala, Nabila; Akhtar, Rizwan S.; Weintraub, Daniel] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Trojanowski, John Q.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Xie, Sharon X.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Duda, John E.; Morley, James F.; Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Siderowf, Andrew] Avid Radiopharmaceut, Philadelphia, PA USA. RP Weintraub, D (reprint author), Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. EM daniel.weintraub@uphs.upenn.edu FU National Institute of Neurological Disorders and Stroke [P50 NS053488] FX National Institute of Neurological Disorders and Stroke P50 NS053488. NR 34 TC 20 Z9 20 U1 6 U2 13 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 OCT 13 PY 2015 VL 85 IS 15 BP 1276 EP 1282 DI 10.1212/WNL.0000000000002001 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CT7QO UT WOS:000363009800004 PM 26362285 ER PT J AU Lee, HG Kim, H Kim, EJ Park, PG Dong, SM Choi, TH Kim, H Chong, CR Liu, JO Chen, J Ambinder, RF Hayward, SD Park, JH Lee, JM AF Lee, Hyun Gyu Kim, Hyemi Kim, Eun Jung Park, Pil-Gu Dong, Seung Myung Choi, Tae Hyun Kim, Hyunki Chong, Curtis R. Liu, Jun O. Chen, Jianmeng Ambinder, Richard F. Hayward, S. Diane Park, Jeon Han Lee, Jae Myun TI Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation SO ONCOTARGET LA English DT Article DE Epstein-Barr virus-associated gastric carcinoma; gemcitabine; ataxia telangiectasia-mutated; p53; EBVaGC mouse model ID KINASE-EXPRESSING CELLS; VIRAL GENE-EXPRESSION; IN-VIVO; TUMOR-CELLS; GANCICLOVIR; CANCER; MALIGNANCIES; INDUCTION; ESTABLISHMENT; CHEMOTHERAPY AB The constant presence of the viral genome in Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) suggests the applicability of novel EBV-targeted therapies. The antiviral nucleoside drug, ganciclovir (GCV), is effective only in the context of the viral lytic cycle in the presence of EBV-encoded thymidine kinase (TK)/protein kinase (PK) expression. In this study, screening of the Johns Hopkins Drug Library identified gemcitabine as a candidate for combination treatment with GCV. Pharmacological induction of EBV-TK or PK in EBVaGC-originated tumor cells were used to study combination treatment with GCV in vitro and in vivo. Gemcitabine was found to be a lytic inducer via activation of the ataxia telangiectasia-mutated (ATM)/p53 genotoxic stress pathway in EBVaGC. Using an EBVaGC mouse model and a [I-125] fialuridine (FIAU)-based lytic activation imaging system, we evaluated gemcitabine-induced lytic activation in an in vivo system and confirmed the efficacy of gemcitabine-GCV combination treatment. This viral enzyme-targeted anti-tumor strategy may provide a new therapeutic approach for EBVaGCs. C1 [Lee, Hyun Gyu; Kim, Hyemi; Park, Pil-Gu; Park, Jeon Han; Lee, Jae Myun] Yonsei Univ, Coll Med, Dept Microbiol & Immunol, Seoul, South Korea. [Kim, Hyemi; Lee, Jae Myun] Yonsei Univ, Coll Med, Brain Korea PLUS Project Med Sci 21, Seoul, South Korea. [Kim, Eun Jung; Choi, Tae Hyun] Korea Inst Radiol & Med Sci, Radiopharmaceut Res Team, Seoul, South Korea. [Dong, Seung Myung] Natl Canc Ctr, Res Inst, Goyang, Gyeonggi Do, South Korea. [Kim, Hyunki] Yonsei Univ, Coll Med, Dept Pathol, Seoul, South Korea. [Chong, Curtis R.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Chong, Curtis R.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Liu, Jun O.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Liu, Jun O.; Chen, Jianmeng; Ambinder, Richard F.; Hayward, S. Diane] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Lee, JM (reprint author), Yonsei Univ, Coll Med, Dept Microbiol & Immunol, Seoul, South Korea. EM jaemyun@yuhs.ac RI rchnds, rchnds/D-7595-2016 FU National Research Foundation of Korea (NRF) - Korea government [NRF-2007-0056423, NRF-2015R1A2A2A01005412]; Korea Healthcare Technology R&D Project, Ministry of Health, Welfare, Republic of Korea [HI13C0826] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2007-0056423 and NRF-2015R1A2A2A01005412), and the Korea Healthcare Technology R&D Project, Ministry of Health, Welfare, Republic of Korea (HI13C0826). NR 48 TC 1 Z9 1 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 13 PY 2015 VL 6 IS 31 BP 31018 EP 31029 DI 10.18632/oncotarget.5041 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CU0DD UT WOS:000363185200058 PM 26427042 ER PT J AU Lamming, DW Cummings, NE Rastelli, AL Gao, F Cava, E Bertozzi, B Spelta, F Pili, R Fontana, L AF Lamming, Dudley W. Cummings, Nicole E. Rastelli, Antonella L. Gao, Feng Cava, Edda Bertozzi, Beatrice Spelta, Francesco Pili, Roberto Fontana, Luigi TI Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model SO ONCOTARGET LA English DT Article DE protein restriction; mTOR; mice; cancer; aging ID INDUCED INSULIN-RESISTANCE; LIFE-SPAN; COMPLEX 2; CANCER; LONGEVITY; MICE; HEALTH; GROWTH; IGF-1; PROSTATE AB Reduced dietary protein intake and intermittent fasting (IF) are both linked to healthy longevity in rodents, and are effective in inhibiting cancer growth. The molecular mechanisms underlying the beneficial effects of chronic protein restriction (PR) and IF are unclear, but may be mediated in part by a down-regulation of the IGF/mTOR pathway. In this study we compared the effects of PR and IF on tumor growth in a xenograft mouse model of breast cancer. We also investigated the effects of PR and IF on the mechanistic Target Of Rapamycin (mTOR) pathway, inhibition of which extends lifespan in model organisms including mice. The mTOR protein kinase is found in two distinct complexes, of which mTOR complex 1 (mTORC1) is responsive to acute treatment with amino acids in cell culture and in vivo. We found that both PR and IF inhibit tumor growth and mTORC1 phosphorylation in tumor xenografts. In somatic tissues, we found that PR, but not IF, selectively inhibits the activity of the amino acid sensitive mTORC1, while the activity of the second mTOR complex, mTORC2, was relatively unaffected by PR. In contrast, IF resulted in increased S6 phosphorylation in multiple metabolic tissues. Our work represents the first finding that PR may reduce mTORC1 activity in tumors and multiple somatic tissues, and suggest that PR may represent a highly translatable option for the treatment not only of cancer, but also other age-related diseases. C1 [Lamming, Dudley W.; Cummings, Nicole E.] Univ Wisconsin, Dept Med, Madison, WI USA. [Lamming, Dudley W.; Cummings, Nicole E.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Lamming, Dudley W.; Cummings, Nicole E.] Univ Wisconsin, Endocrinol & Reprod Physiol Grad Training Program, Madison, WI USA. [Rastelli, Antonella L.] Washington Univ, Div Oncol, St Louis, MO USA. [Gao, Feng] Washington Univ, Div Biostat, St Louis, MO USA. [Cava, Edda; Bertozzi, Beatrice; Spelta, Francesco; Fontana, Luigi] Washington Univ, Div Geriatr & Nutr Sci, St Louis, MO 63130 USA. [Cava, Edda] Univ Roma La Sapienza, Dept Expt Med, Rome, Italy. [Spelta, Francesco] Univ Verona, Dept Med, I-37100 Verona, Italy. [Pili, Roberto] Indiana Univ Sch Med, Dept Med, Div Hematol Oncol, Indianapolis, IN 46202 USA. [Fontana, Luigi] Univ Brescia, Sch Med, Dept Clin & Expt Sci, Brescia, Italy. [Fontana, Luigi] CEINGE Biotecnol Avanzate, Naples, Italy. RP Fontana, L (reprint author), Washington Univ, Div Geriatr & Nutr Sci, St Louis, MO 63130 USA. EM dlamming@medicine.wisc.edu; fontana.luigi@gmail.com OI Cava, Edda/0000-0002-8186-039X FU Bakewell Foundation; National Institute of Health; UW-Madison School of Medicine and Public Health; UW-Madison Department of Medicine; K99/R00 Pathway to Independence Award from the NIH/NIA [AG041765] FX The Fontana lab is supported by grants from the Bakewell Foundation. The Lamming lab is supported in part by a grant from the National Institute of Health and startup funds from the UW-Madison School of Medicine and Public Health and the UW-Madison Department of Medicine. D.W.L is supported in part by a K99/R00 Pathway to Independence Award from the NIH/NIA (AG041765). This work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government. NR 34 TC 5 Z9 6 U1 2 U2 8 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 13 PY 2015 VL 6 IS 31 BP 31233 EP 31240 DI 10.18632/oncotarget.5180 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CU0DD UT WOS:000363185200073 PM 26378060 ER PT J AU Wu, H Wang, AL Zhang, W Wang, BL Chen, C Wang, WC Hu, C Ye, Z Zhao, Z Wang, L Li, XX Yu, KL Liu, J Wu, JX Yan, XE Zhao, P Wang, JH Wang, C Weisberg, EL Gray, NS Yun, CH Liu, J Chen, L Liu, QS AF Wu, Hong Wang, Aoli Zhang, Wei Wang, Beilei Chen, Cheng Wang, Wenchao Hu, Chen Ye, Zi Zhao, Zheng Wang, Li Li, Xixiang Yu, Kailin Liu, Juan Wu, Jiaxin Yan, Xiao-E Zhao, Peng Wang, Jinhua Wang, Chu Weisberg, Ellen L. Gray, Nathanael S. Yun, Cai-Hong Liu, Jing Chen, Liang Liu, Qingsong TI Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells SO ONCOTARGET LA English DT Article DE ibrutinib; NSCLC; EGFR mutation; drug resistance; drug combination ID GROWTH-FACTOR RECEPTOR; BRUTONS TYROSINE KINASE; CHRONIC LYMPHOCYTIC-LEUKEMIA; LUNG-CANCER; ACQUIRED-RESISTANCE; INHIBITORS; BTK; MUTATION; GEFITINIB; LYMPHOMA AB Through comprehensive comparison study, we found that ibrutinib, a clinically approved covalent BTK kinase inhibitor, was highly active against EGFR (L858R, del19) mutant driven NSCLC cells, but moderately active to the T790M 'gatekeeper' mutant cells and not active to wild-type EGFR NSCLC cells. Ibrutinib strongly affected EGFR mediated signaling pathways and induced apoptosis and cell cycle arrest (G0/G1) in mutant EGFR but not wt EGFR cells. However, ibrutinib only slowed down tumor progression in PC-9 and H1975 xenograft models. MEK kinase inhibitor, GSK1120212, could potentiate ibrutinib's effect against the EGFR (L858R/T790M) mutation in vitro but not in vivo. These results suggest that special drug administration might be required to achieve best clinical response in the ongoing phase I/II clinical trial with ibrutinib for NSCLC. C1 [Wu, Hong; Wang, Aoli; Wang, Beilei; Chen, Cheng; Wang, Wenchao; Hu, Chen; Zhao, Zheng; Wang, Li; Li, Xixiang; Yu, Kailin; Liu, Juan; Wu, Jiaxin; Liu, Jing; Liu, Qingsong] Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China. [Wu, Hong; Wang, Aoli; Wu, Jiaxin; Liu, Qingsong] Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China. [Zhang, Wei; Chen, Liang] Natl Inst Biol Sci, Collaborat Innovat Ctr Canc Med, Beijing 102206, Peoples R China. [Ye, Zi; Wang, Chu] Peking Univ, Peking Tsinghua Ctr Life Sci, Coll Chem & Mol Engn,Synthet & Funct Biomol Ctr, Key Lab Bioorgan Chem & Mol Engn,Minist Educ,Beij, Beijing 100871, Peoples R China. [Yan, Xiao-E; Zhao, Peng; Yun, Cai-Hong] Peking Univ, Hlth Sci Ctr, Beijing Key Lab Tumor Syst Biol, Inst Syst Biomed,Dept Biophys, Beijing 100191, Peoples R China. [Yan, Xiao-E; Zhao, Peng; Yun, Cai-Hong] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Mol & Translat Med, Beijing 100191, Peoples R China. [Wang, Jinhua; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Wang, Jinhua; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Weisberg, Ellen L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Liu, Qingsong] Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. RP Liu, J (reprint author), Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China. EM jingliu@hmfl.ac.cn; chenliang@nibs.ac.cn; qsliu97@hmfl.ac.cn OI liu, jing/0000-0001-9513-3591 FU grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences; NIH [P01 CA154303-03]; China "Thousand Talents Program"; "Hundred Talents Program" of The Chinese Academy of Sciences; Anhui Province Natural Science Foundation Annual Key Program [1301023011]; National Science Foundation of China [31270769]; National Basic Research Program of China (973 Program) [2012CB917202]; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC) [2015SRG-HSC022] FX J. Liu, Q. Liu, W. Wang and L. Cheng are supported by the grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014-2016)" from Chinese Academy of Sciences. N. Gray is supported by NIH grant P01 CA154303-03. We want to thank China "Thousand Talents Program" support for Q. Liu and C. Wang; "Hundred Talents Program" of The Chinese Academy of Sciences support for J. Liu, and W. Wang. Z. Zhao is supported by Anhui Province Natural Science Foundation Annual Key Program (grant number: 1301023011), C.-H.Y. is funded by the National Science Foundation of China (No. 31270769) and the National Basic Research Program of China (973 Program, No. 2012CB917202). Q. Liu is also supported by Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC # 2015SRG-HSC022). The authors thank the mass spectrometry facility of National Center for Protein Sciences at Peking University for assistance with data collection and Dr. Rong Meng for technical support. NR 29 TC 5 Z9 5 U1 7 U2 18 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 13 PY 2015 VL 6 IS 31 BP 31313 EP 31322 DI 10.18632/oncotarget.5182 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CU0DD UT WOS:000363185200080 PM 26375053 ER PT J AU Tong, T Yang, Z Chen, JW Zhu, JM Yao, ZW AF Tong, Tong Yang, Zhong Chen, John W. Zhu, Jianming Yao, Zhenwei TI Dynamic H-1-MRS assessment of brain tumors: A novel approach for differential diagnosis of glioma SO ONCOTARGET LA English DT Article DE clinical paper; magnetic resonance imaging; magnetic resonance spectroscopy; glioma; differential diagnosis ID MAGNETIC-RESONANCE-SPECTROSCOPY; PROTON MR SPECTROSCOPY; CEREBRAL GLIOMAS; GD-CONTRAST; PERFUSION AB Purpose: To determine whether the changes of [Cho/NAA] ratio in patients with glioma, measured by dynamic H-1-MRS can be used to differentiate between high-grade and low-grade gliomas. Materials and Methods: This prospective study was approved by the institutional ethics committee. Written informed consent was obtained. Forty-nine patients with biopsy-proven glioma and 20 normal control subjects were recruited in this study. The maximum [Cho/NAA] ratios, acquired at 0 min, and at 6 min, were calculated and assessed from volume of interests (VOI) in the tumor areas and in the surrounding normal tissue for each patient. Absolute difference in the [Cho/NAA] ratios, from MRS acquired at 0 and 6 min, in high-grade glioma, low-grade glioma, and control subjects were compared. Results: The maximum [Cho/NAA] ratio acquired from the tumor area at the 0 min is 6.08 +/- 2.02, which was significantly different (p = .017) from that acquired after 6 min, 4.87 +/- 2.13. The [Cho/NAA] ratio from the surrounding normal tissue area did not change significantly from spectra acquired at different times (0 min, 6 min). Absolute difference in [Cho/NAA] ratios acquired at 0 and 6 min time points were significantly higher (P < 0.001) in high-grade glioma (= 3.86 +/- 3.31) than in low-grade glioma (= 0.81 +/- 0.90), and control subjects (0.061 +/- 0.026, P = 0.000), while there was no significantly difference in low-grade glioma and control subjects. Conclusions: Dynamic H-1-MRS can be useful for differential diagnosis between high-grade and low-grade gliomas as well as insight into the heterogeneity within the tumor. C1 [Tong, Tong] Fudan Univ, Shanghai Canc Ctr, Dept Radiol, Shanghai 200433, Peoples R China. [Yang, Zhong; Yao, Zhenwei] Fudan Univ, Huashan Hosp, Dept Radiol, Shanghai 200433, Peoples R China. [Chen, John W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Innovat Imaging, Boston, MA USA. [Zhu, Jianming] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC USA. RP Yao, ZW (reprint author), Fudan Univ, Huashan Hosp, Dept Radiol, Shanghai 200433, Peoples R China. EM jwchen@mgh.harvard.edu; aocnhnr@126.com FU NSFC (natural science foundation of china) [81271633] FX This study was supported by NSFC (natural science foundation of china) 81271633. NR 14 TC 0 Z9 2 U1 0 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 13 PY 2015 VL 6 IS 31 BP 32257 EP 32265 DI 10.18632/oncotarget.4899 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CU0DD UT WOS:000363185200148 PM 26337080 ER PT J AU Fumagalli, D Gacquer, D Rothe, F Lefort, A Libert, F Brown, D Kheddoumi, N Shlien, A Konopka, T Salgado, R Larsimont, D Polyak, K Willard-Gallo, K Desmedt, C Piccart, M Abramowicz, M Campbell, PJ Sotiriou, C Detours, V AF Fumagalli, Debora Gacquer, David Rothe, Francoise Lefort, Anne Libert, Frederick Brown, David Kheddoumi, Naima Shlien, Adam Konopka, Tomasz Salgado, Roberto Larsimont, Denis Polyak, Kornelia Willard-Gallo, Karen Desmedt, Christine Piccart, Martine Abramowicz, Marc Campbell, Peter J. Sotiriou, Christos Detours, Vincent TI Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome SO CELL REPORTS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; MUTATIONAL PROCESSES; ADENOSINE-DEAMINASE; ADAR DEAMINASES; WIDESPREAD RNA; PARALLEL DNA; SEQ DATA; GENE; SITES; IDENTIFICATION AB Little is known about how RNA editing operates in cancer. Transcriptome analysis of 68 normal and cancerous breast tissues revealed that the editing enzyme ADAR acts uniformly, on the same loci, across tissues. In controlled ADAR expression experiments, the editing frequency increased at all loci with ADAR expression levels according to the logistic model. Loci-specific "editabilities,'' i.e., propensities to be edited by ADAR, were quantifiable by fitting the logistic function to dose-response data. The editing frequency was increased in tumor cells in comparison to normal controls. Type I interferon response and ADAR DNA copy number together explained 53% of ADAR expression variance in breast cancers. ADAR silencing using small hairpin RNA lentivirus transduction in breast cancer cell lines led to less cell proliferation and more apoptosis. A-to-I editing is a pervasive, yet reproducible, source of variation that is globally controlled by 1q amplification and inflammation, both of which are highly prevalent among human cancers. C1 [Fumagalli, Debora; Rothe, Francoise; Brown, David; Kheddoumi, Naima; Salgado, Roberto; Desmedt, Christine; Sotiriou, Christos] Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab, B-1000 Brussels, Belgium. [Gacquer, David; Lefort, Anne; Libert, Frederick; Konopka, Tomasz; Detours, Vincent] Univ Libre Bruxelles, IRIBHM, B-1070 Brussels, Belgium. [Detours, Vincent] WELBIO, B-1070 Brussels, Belgium. [Shlien, Adam; Campbell, Peter J.] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, Cambs, England. [Larsimont, Denis] Univ Libre Bruxelles, Inst Jules Bordet, Dept Pathol, B-1000 Brussels, Belgium. [Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Willard-Gallo, Karen] Univ Libre Bruxelles, Inst Jules Bordet, Mol Immunol Unit, B-1000 Brussels, Belgium. [Piccart, Martine; Sotiriou, Christos] Univ Libre Bruxelles, Inst Jules Bordet, Dept Med, B-1000 Brussels, Belgium. [Abramowicz, Marc] Free Univ Brussels, Hop Erasme, Dept Genet, B-1070 Brussels, Belgium. RP Sotiriou, C (reprint author), Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab, Blvd Waterloo 125, B-1000 Brussels, Belgium. EM christos.sotiriou@bordet.be; vdetours@ulb.ac.be OI Desmedt, Christine/0000-0002-5223-5579 FU Belgian National Cancer Plan [PNC29]; WELBIO; FNRS; National Research Council Canada; EMBO; Brussels Region; ULB Computing Center FX This work was supported by a grant of the Belgian National Cancer Plan PNC29. D.G. and T.K. have been supported by a WELBIO grant. M.A., D.B., V.D., and C.S. were supported by the FNRS. A.S. is funded by the H.L. Holmes Award from the National Research Council Canada and an EMBO fellowship. C.D. has been supported by the Brussels Region. The authors thank Raphael Leplae and the ULB Computing Center for their support, Roland De Wind for pathology support, Cedric Blanpain, Sabine Costagliola, Jacques E. Dumont, Pierre Vanderhaeghen, and Gilbert Vassart for helpful discussions. NR 55 TC 14 Z9 14 U1 1 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 OCT 13 PY 2015 VL 13 IS 2 BP 277 EP 289 DI 10.1016/j.celrep.2015.09.032 PG 13 WC Cell Biology SC Cell Biology GA CT6VU UT WOS:000362951500007 PM 26440892 ER PT J AU O'Brien, EC Greiner, MA Xian, Y Fonarow, GC Olson, DM Schwamm, LH Bhatt, DL Smith, EE Maisch, L Hannah, D Lindholm, B Peterson, ED Pencina, MJ Hernandez, AF AF O'Brien, Emily C. Greiner, Melissa A. Xian, Ying Fonarow, Gregg C. Olson, DaiWai M. Schwamm, Lee H. Bhatt, Deepak L. Smith, Eric E. Maisch, Lesley Hannah, Deidre Lindholm, Brianna Peterson, Eric D. Pencina, Michael J. Hernandez, Adrian F. TI Clinical Effectiveness of Statin Therapy After Ischemic Stroke: Primary Results From the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study SO CIRCULATION LA English DT Article DE hydroxymethylglutaryl-CoA reductase inhibitors; lipids; patient-centered outcomes research; stroke ID INTRACEREBRAL HEMORRHAGE; PATIENTS PERSPECTIVE; GUIDELINES-STROKE; UNCERTAINTY LIFE; HEART-FAILURE; TRIALS; CARE; ATTACK; RISK; REPRESENTATION AB Background-In patients with ischemic stroke, data on the real-world effectiveness of statin therapy for clinical and patient-centered outcomes are needed to better inform shared decision making. Methods and Results-Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) is a Patient-Centered Outcomes Research Institute-funded research program designed with stroke survivors to evaluate the effectiveness of poststroke therapies. We linked data on patients 65 years of age enrolled in the Get With The Guidelines-Stroke Registry to Medicare claims. Two-year to postdischarge outcomes of those discharged on a statin versus not on a statin were adjusted through inverse probability weighting. Our coprimary outcomes were major adverse cardiovascular events and home time (days alive and out of a hospital or skilled nursing facility). Secondary outcomes included all-cause mortality, all-cause readmission, cardiovascular readmission, and hemorrhagic stroke. From 2007 to 2011, 77468 patients who were not taking statins at the time of admission were hospitalized with ischemic stroke; of these, 71% were discharged on statin therapy. After adjustment, statin therapy at discharge was associated with a lower hazard of major adverse cardiovascular events (hazard ratio, 0.91; 95% confidence interval, 0.87-0.94), 28 more home-time days after discharge (P<0.001), and lower all-cause mortality and readmission. Statin therapy at discharge was not associated with increased risk of hemorrhagic stroke (hazard ratio, 0.94; 95% confidence interval, 0.72-1.23). Among statin-treated patients, 31% received a high-intensity dose; after risk adjustment, these patients had outcomes similar to those of recipients of moderate-intensity statin. Conclusion-In older ischemic stroke patients who were not taking statins at the time of admission, discharge statin therapy was associated with lower risk of major adverse cardiovascular events and nearly 1 month more home time during the 2-year period after hospitalization. C1 [O'Brien, Emily C.; Greiner, Melissa A.; Xian, Ying; Peterson, Eric D.; Pencina, Michael J.; Hernandez, Adrian F.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. [Olson, DaiWai M.] Univ Texas Southwestern, Dallas, TX USA. [Schwamm, Lee H.] Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Smith, Eric E.] Brigham & Womens Hosp, Heart & Vasc Ctr, Boston, MA 02115 USA. [Smith, Eric E.] Harvard Univ, Sch Med, Boston, MA USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. RP O'Brien, EC (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM emily.obrien@duke.edu RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU Patient-Centered Outcomes Research Institute [CE-1304-7073] FX This work was supported by an award (CE-1304-7073) from the Patient-Centered Outcomes Research Institute. NR 31 TC 5 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 13 PY 2015 VL 132 IS 15 BP 1404 EP 1413 DI 10.1161/CIRCULATIONAHA.115.016183 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CT1MY UT WOS:000362563800006 PM 26246175 ER PT J AU Friedman, AA Amzallag, A Pruteanu-Malinici, I Baniya, S Cooper, ZA Piris, A Hargreaves, L Igras, V Frederick, DT Lawrence, DP Haber, DA Flaherty, KT Wargo, JA Ramaswamy, S Benes, CH Fisher, DE AF Friedman, Adam A. Amzallag, Arnaud Pruteanu-Malinici, Iulian Baniya, Subash Cooper, Zachary A. Piris, Adriano Hargreaves, Leeza Igras, Vivien Frederick, Dennie T. Lawrence, Donald P. Haber, Daniel A. Flaherty, Keith T. Wargo, Jennifer A. Ramaswamy, Sridhar Benes, Cyril H. Fisher, David E. TI Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment SO PLOS ONE LA English DT Article ID TYROSINE KINASE INHIBITOR; MUTANT COLORECTAL CANCERS; RAF INHIBITION; METASTATIC MELANOMA; ACQUIRED-RESISTANCE; CONFERS RESISTANCE; PATHWAY; MEK; REACTIVATION; VEMURAFENIB AB A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1) transporter inhibition. We identified drugs sensitizing cell lines that are BRAF(V600E) mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR) and platelet derived growth factor receptor (PDGFR) family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs), demonstrating the potential of drug-rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK) kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations. C1 [Friedman, Adam A.; Amzallag, Arnaud; Pruteanu-Malinici, Iulian; Baniya, Subash; Hargreaves, Leeza; Igras, Vivien; Frederick, Dennie T.; Lawrence, Donald P.; Haber, Daniel A.; Flaherty, Keith T.; Ramaswamy, Sridhar; Benes, Cyril H.; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02163 USA. [Friedman, Adam A.; Baniya, Subash; Hargreaves, Leeza; Igras, Vivien; Fisher, David E.] Massachusetts Gen Hosp, Dermatol & Cutaneous Biol Res Ctr, Charlestown, MA USA. [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Piris, Adriano] Massachusetts Gen Hosp, Div Dermatopathol, Boston, MA 02114 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Friedman, AA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02163 USA. EM aafriedman@partners.org; cbenes@partners.org; dfisher3@partners.org OI Cooper, Zachary/0000-0003-1059-0940 FU National Institutes of Health [P01CA163222, R21CA175907, 1K08CA160692-01A1, U54CA163125, 1U54HG006097-01]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Doris Duke Medical Foundation; Elsa U. Pardee Foundation grant; Fred Lovejoy Resident Research and Education Award; Brigham and Women's Hospital Department of Dermatology NIH Training Grant [T32AR007098-38]; Wellcome Trust [086357, 102696] FX This work was supported by the National Institutes of Health (P01CA163222 and R21CA175907 to D.E.F.; 1K08CA160692-01A1 and U54CA163125 to J.A.W., 1U54HG006097-01 to C.H.B.), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.E.F.), the Doris Duke Medical Foundation (D.E.F.), an Elsa U. Pardee Foundation grant (D.E.F.), a Fred Lovejoy Resident Research and Education Award (A.A.F.), a Brigham and Women's Hospital Department of Dermatology NIH Training Grant T32AR007098-38 (A.A.F.), and grants from the Wellcome Trust (086357 and 102696; C.H.B., D.A.H.). NR 45 TC 5 Z9 5 U1 0 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 OCT 13 PY 2015 VL 10 IS 10 AR e0140310 DI 10.1371/journal.pone.0140310 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT6ZJ UT WOS:000362962300078 PM 26461489 ER PT J AU Kochupurakkal, BS Wang, ZGC Hua, T Culhane, AC Rodig, SJ Rajkovic-Molek, K Lazaro, JB Richardson, AL Biswas, DK Iglehart, JD AF Kochupurakkal, Bose S. Wang, Zhigang C. Hua, Tony Culhane, Aedin C. Rodig, Scott J. Rajkovic-Molek, Koraljka Lazaro, Jean-Bernard Richardson, Andrea L. Biswas, Debajit K. Iglehart, J. Dirk TI RelA-Induced Interferon Response Negatively Regulates Proliferation SO PLOS ONE LA English DT Article ID NF-KAPPA-B; HUMAN BREAST-CANCER; MAMMARY EPITHELIAL-CELLS; KINASE 4/6 INHIBITOR; FACTOR-I; CYCLE ARREST; PHOSPHATIDYLINOSITOL 3-KINASE; EXPRESSION PATTERNS; SECRETORY PHENOTYPE; THERAPEUTIC TARGET AB Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-gamma elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-gamma converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2-breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2-breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors. C1 [Kochupurakkal, Bose S.; Wang, Zhigang C.; Hua, Tony; Lazaro, Jean-Bernard; Richardson, Andrea L.; Biswas, Debajit K.; Iglehart, J. Dirk] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Culhane, Aedin C.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Rodig, Scott J.; Richardson, Andrea L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Iglehart, J. Dirk] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Rajkovic-Molek, Koraljka] Clin Hosp Ctr Rijeka, Dept Cytol, Rijeka, Croatia. RP Kochupurakkal, BS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM bose_kochupurakkal@dfci.harvard.edu; jiglehart@partners.org FU DF/HCC SPORE [CA89393]; Women's Cancer Program at Dana-Farber Cancer Institute; Teri Brodeur Fellowship; Hale Family Fellowship FX The research was supported by the DF/HCC SPORE (CA89393) and the Women's Cancer Program at Dana-Farber Cancer Institute. BSK is a recipient of the Teri Brodeur and Hale Family Fellowships. NR 97 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 13 PY 2015 VL 10 IS 10 AR e0140243 DI 10.1371/journal.pone.0140243 PG 33 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT6ZJ UT WOS:000362962300071 PM 26460486 ER PT J AU Singh, B Li, XR Owens, KM Vanniarajan, A Liang, P Singh, KK AF Singh, Bhupendra Li, Xiurong Owens, Kjerstin M. Vanniarajan, Ayyasamy Liang, Ping Singh, Keshav K. TI Human REV3 DNA Polymerase Zeta Localizes to Mitochondria and Protects the Mitochondrial Genome SO PLOS ONE LA English DT Article ID CATALYTIC SUBUNIT; POL-ZETA; CANCER-CELLS; EMBRYONIC LETHALITY; INDUCED MUTAGENESIS; MAMMALIAN-CELLS; BREAST-CANCER; ERROR-FREE; DAMAGE; GENE AB To date, mitochondrial DNA polymerase. (POLG) is the only polymerase known to be present in mammalian mitochondria. A dogma in the mitochondria field is that there is no other polymerase present in the mitochondria of mammalian cells. Here we demonstrate localization of REV3 DNA polymerase in the mammalian mitochondria. We demonstrate localization of REV3 in the mitochondria of mammalian tissue as well as cell lines. REV3 associates with POLG and mitochondrial DNA and protects the mitochondrial genome from DNA damage. Inactivation of Rev3 leads to reduced mitochondrial membrane potential, reduced OXPHOS activity, and increased glucose consumption. Conversely, inhibition of the OXPHOS increases expression of Rev3. Rev3 expression is increased in human primary breast tumors and breast cancer cell lines. Inactivation of Rev3 decreases cell migration and invasion, and localization of Rev3 in mitochondria increases survival and the invasive potential of cancer cells. Taken together, we demonstrate that REV3 functions in mammalian mitochondria and that mitochondrial REV3 is associated with the tumorigenic potential of cells. C1 [Singh, Bhupendra] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Li, Xiurong; Owens, Kjerstin M.; Vanniarajan, Ayyasamy] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. [Liang, Ping] Brock Univ, Dept Biol Sci, St Catharines, ON L2S 3A1, Canada. [Singh, Keshav K.] Univ Alabama Birmingham, Dept Genet Pathol, Ctr Free Rad Biol, Environm Hlth,Ctr Aging, Birmingham, AL 35294 USA. [Singh, Keshav K.] Univ Alabama Birmingham, UAB Comprehens Canc Ctr, Birmingham, AL USA. [Singh, Keshav K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Singh, KK (reprint author), Univ Alabama Birmingham, Dept Genet Pathol, Ctr Free Rad Biol, Environm Hlth,Ctr Aging, Birmingham, AL 35294 USA. EM kksingh@uab.edu FU Veterans Administration [1I01BX001716] FX This study was supported by grant from Veterans Administration (1I01BX001716) to KKS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 3 Z9 3 U1 0 U2 4 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 OCT 13 PY 2015 VL 10 IS 10 AR e0140409 DI 10.1371/journal.pone.0140409 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT6ZJ UT WOS:000362962300091 PM 26462070 ER PT J AU Stahl, JE Dossett, ML LaJoie, AS Denninger, JW Mehta, DH Goldman, R Fricchione, GL Benson, H AF Stahl, James E. Dossett, Michelle L. LaJoie, A. Scott Denninger, John W. Mehta, Darshan H. Goldman, Roberta Fricchione, Gregory L. Benson, Herbert TI Relaxation Response and Resiliency Training and Its Effect on Healthcare Resource Utilization SO PLOS ONE LA English DT Article ID BEHAVIORAL MEDICINE INTERVENTION; DECREASED BLOOD-PRESSURE; PROPENSITY-SCORE METHODS; MIND-BODY INTERVENTION; NF-KAPPA-B; COST-EFFECTIVENESS; SYMPTOM REDUCTION; MEDITATION; MINDFULNESS; STRESS AB Background Poor psychological and physical resilience in response to stress drives a great deal of health care utilization. Mind-body interventions can reduce stress and build resiliency. The rationale for this study is therefore to estimate the effect of mind-body interventions on healthcare utilization. Objective Estimate the effect of mind body training, specifically, the Relaxation Response Resiliency Program (3RP) on healthcare utilization. Design Retrospective controlled cohort observational study. Setting: Major US Academic Health Network. Sample: All patients receiving 3RP at the MGH Benson-Henry Institute from 1/12/2006 to 7/1/2014 (n = 4452), controls (n = 13149) followed for a median of 4.2 years (.85-8.4 yrs). Measurements: Utilization as measured by billable encounters/year (be/yr) stratified by encounter type: clinical, imaging, laboratory and procedural, by class of chief complaint: e.g., Cardiovascular, and by site of care delivery, e.g., Emergency Department. Subgroup analysis by propensity score matched pre-intervention utilization rate. Results At one year, total utilization for the intervention group decreased by 43% [53.5 to 30.5 be/yr] (p < 0.0001). Clinical encounters decreased by 41.9% [40 to 23.2 be/yr], imaging by 50.3% [11.5 to 5.7 be/yr], lab encounters by 43.5%[9.8 to 5.6], and procedures by 21.4%[2.2 to 1.7 be/yr], all p < 0.01. The intervention group's Emergency department (ED) visits decreased from 3.6 to 1.7/year (p<0.0001) and Hospital and Urgent care visits converged with the controls. Subgroup analysis (identically matched initial utilization rates-Intervention group: high utilizing controls) showed the intervention group significantly reduced utilization relative to the control group by: 18.3% across all functional categories, 24.7% across all site categories and 25.3% across all clinical categories. Conclusion Mind body interventions such as 3RP have the potential to substantially reduce healthcare utilization at relatively low cost and thus can serve as key components in any population health and health care delivery system. C1 [Stahl, James E.; Dossett, Michelle L.; Denninger, John W.; Mehta, Darshan H.; Goldman, Roberta; Fricchione, Gregory L.; Benson, Herbert] Massachusetts Gen Hosp, MGH Benson Henry Inst, Boston, MA 02114 USA. [Stahl, James E.] Dartmouth Hitchcock Med Ctr, Gen Internal Med Sect, Lebanon, NH 03766 USA. [Stahl, James E.; Mehta, Darshan H.] Massachusetts Gen Hosp, MGH Inst Technol Assessment, Boston, MA 02114 USA. [Dossett, Michelle L.] Massachusetts Gen Hosp, MGH Div Gen Med, Boston, MA 02114 USA. [Denninger, John W.; Fricchione, Gregory L.] Massachusetts Gen Hosp, MGH Dept Psychiat, Boston, MA 02114 USA. [LaJoie, A. Scott] Univ Louisville, Hlth Promot & Behav Sci, MGH Dept Psychiat, Louisville, KY 40292 USA. RP Stahl, JE (reprint author), Massachusetts Gen Hosp, MGH Benson Henry Inst, Boston, MA 02114 USA. EM james.e.stahl@dartmouth.edu OI Mehta, Darshan/0000-0003-0457-4717 FU NCCIH NIH HHS [T32 AT000051] NR 47 TC 5 Z9 5 U1 5 U2 18 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 OCT 13 PY 2015 VL 10 IS 10 AR e0140212 DI 10.1371/journal.pone.0140212 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT6ZJ UT WOS:000362962300065 PM 26461184 ER PT J AU Wu, YJ Shi, ZY Wang, MJ Zhu, YB Li, C Li, GD Marcantonio, ER Xie, ZC Shen, Y AF Wu, Yujie Shi, Zhongyong Wang, Meijuan Zhu, Yingbo Li, Cheng Li, Guodong Marcantonio, Edward R. Xie, Zhongcong Shen, Yuan TI Different MMSE Score Is Associated with Postoperative Delirium in Young-Old and Old-Old Adults SO PLOS ONE LA English DT Article ID CARDIAC-SURGERY; RISK-FACTORS; ELDERLY-PATIENTS; ASSESSMENT SCALE; PREDICTION RULE; CHINESE VERSION; HIP-SURGERY; DEMENTIA; VALIDATION; SHANGHAI AB Background Postoperative delirium is one of the most common postoperative complications in geriatric patients. Mini-mental state examination (MMSE) assesses cognitive function in patients and is associated with postoperative delirium. However, whether there is an age-dependent relationship between preoperative MMSE score and postoperative delirium remains unknown. Methods We therefore set out to investigate the association between preoperative MMSE score and postoperative delirium in young-old (<= 80 year-old, 75.46 +/- 4.69 years, 27.0% male, n = 63) and old-old (>80 year-old, 84.51 +/- 3.46 years, 20.9% male, n = 67) participants, who had repairs of hip fractures under general anesthesia. The Confusion Assessment Method and Memorial Delirium Assessment Scale were administrated before surgery, and on the first, second and fourth days after surgery, to assess the incidence and severity of the delirium, respectively. A receiver operating characteristic curve analysis was used to calculate the optimal cutoff score of MMSE in predicting postoperative delirium. Results Thirty-four (26.2%) of 130 patients (80.12 +/- 6.12 years, 23.8% male) developed postoperative delirium. Preoperative MMSE scores were negatively associated with higher incidences and greater severity of postoperative delirium. The optimal cutoff scores of MMSE associated with postoperative delirium for young-old and old-old participants were 18.4 and 21.4, with a sensitivity of 60% and 83.8%, and a specificity of 92.5% and 62.8%, respectively. Conclusion The data demonstrated the optimal cutoff score of MMSE associated with postoperative delirium in young-old adults might be lower than that in old-old adults. Pending further investigation, these findings suggest that the association between preoperative MMSE score and postoperative delirium is age-dependent. C1 [Wu, Yujie; Shi, Zhongyong; Wang, Meijuan; Zhu, Yingbo; Shen, Yuan] Tongji Univ, Peoples Hosp 10, Dept Psychiat, Shanghai 200072, Peoples R China. [Li, Cheng] Tongji Univ, Peoples Hosp 10, Dept Anesthesiol, Shanghai 200072, Peoples R China. [Li, Guodong] Tongji Univ, Peoples Hosp 10, Dept Orthoped Surg, Shanghai 200072, Peoples R China. [Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med, Boston, MA 02215 USA. [Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Primary Care & Gerontol, Boston, MA 02215 USA. [Marcantonio, Edward R.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA. [Xie, Zhongcong] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Xie, ZC (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA. EM zxie@mgh.harvard.edu; kmshy@sina.com FU National Natural Science Foundation of China [81200833, 81571034]; Shanghai Natural Science Foundation [12ZR1428600]; National Institutes of Health, Bethesda, Maryland [R21AG038994]; Alzheimer's Association, Chicago, Illinois; Mid-Career Investigator Award from the National Institute on Aging [K24AG035075] FX This research was supported by research grants 81200833 and 81571034 from the National Natural Science Foundation of China and 12ZR1428600 from the Shanghai Natural Science Foundation to Dr. Yuan Shen; and also supported by R21AG038994 from National Institutes of Health, Bethesda, Maryland and Investigator-initiated Research grant from Alzheimer's Association, Chicago, Illinois to Zhongcong Xie; Dr. Marcantonio was funded in part by a Mid-Career Investigator Award (K24AG035075) from the National Institute on Aging. NR 31 TC 0 Z9 0 U1 3 U2 8 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 OCT 13 PY 2015 VL 10 IS 10 AR e0139879 DI 10.1371/journal.pone.0139879 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT6ZJ UT WOS:000362962300029 PM 26460750 ER PT J AU Hoon, M Sinha, R Okawa, H Suzuki, SC Hirano, AA Brecha, N Rieke, F Wong, ROL AF Hoon, Mrinalini Sinha, Raunak Okawa, Haruhisa Suzuki, Sachihiro C. Hirano, Arlene A. Brecha, Nicholas Rieke, Fred Wong, Rachel O. L. TI Neurotransmission plays contrasting roles in the maturation of inhibitory synapses on axons and dendrites of retinal bipolar cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE GABA receptor; retina; synaptic inhibition; axon-dendrite ID GABA(A) RECEPTORS; RAT RETINA; PRESYNAPTIC INHIBITION; HOMEOSTATIC PLASTICITY; MOUSE RETINA; GLYCINE; CIRCUITS; TRANSMISSION; PHARMACOLOGY; TRANSPORTER AB Neuronal output is modulated by inhibition onto both dendrites and axons. It is unknown whether inhibitory synapses at these two cellular compartments of an individual neuron are regulated coordinately or separately during in vivo development. Because neurotransmission influences synapse maturation and circuit development, we determined how loss of inhibition affects the expression of diverse types of inhibitory receptors on the axon and dendrites of mouse retinal bipolar cells. We found that axonal GABA but not glycine receptor expression depends on neurotransmission. Importantly, axonal and dendritic GABAA receptors comprise distinct subunit compositions that are regulated differentially by GABA release: Axonal GABAA receptors are down-regulated but dendritic receptors are up-regulated in the absence of inhibition. The homeostatic increase in GABAA receptors on bipolar cell dendrites is pathway-specific: Cone but not rod bipolar cell dendrites maintain an up-regulation of receptors in the transmission deficient mutants. Furthermore, the bipolar cell GABAA receptor alterations are a consequence of impaired vesicular GABA release from amacrine but not horizontal interneurons. Thus, inhibitory neurotransmission regulates in vivo postsynaptic maturation of inhibitory synapses with contrasting modes of action specific to synapse type and location. C1 [Hoon, Mrinalini; Okawa, Haruhisa; Suzuki, Sachihiro C.; Wong, Rachel O. L.] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Sinha, Raunak; Rieke, Fred] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Sinha, Raunak; Rieke, Fred] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Hirano, Arlene A.; Brecha, Nicholas] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Hirano, Arlene A.; Brecha, Nicholas] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Brecha, Nicholas] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Brecha, Nicholas] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Hoon, M (reprint author), Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. EM mhoon@uw.edu; wongr2@uw.edu FU Knights Templar Eye Foundation; Human Frontier Science Foundation; VA Career Scientist Award; Howard Hughes Medical Institute; NIH [EY10699, EY11850, EY01730, EY15573] FX We thank J. M. Fritschy, R. Enz, H. Wassle and S. Haverkamp for their generous gifts of GABA receptor antibodies, and B. Luscher for GABA gamma 2lox mice. We also thank R. Lewis for assistance with generating Grm6-Cre mice and C. Gamlin and P. Mardoum for helpful comments on the manuscript. This work was supported by Knights Templar Eye Foundation (career starter grant to M. H.), Human Frontier Science Foundation (long-term fellowship to R. S.), VA Career Scientist Award (to N.B.), the Howard Hughes Medical Institute (F.R.), and NIH Grants EY10699 (to R.O.L.W.), EY11850 (to F.R.), Vision Core Grant EY01730 (to M. Neitz), and EY15573 (to N.B.). NR 41 TC 2 Z9 2 U1 1 U2 3 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 OCT 13 PY 2015 VL 112 IS 41 BP 12840 EP 12845 DI 10.1073/pnas.1510483112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT9IQ UT WOS:000363130900068 PM 26420868 ER PT J AU Sheppard, NG Jarl, L Mahadessian, D Strittmatter, L Schmidt, A Madhusudan, N Tegner, J Lundberg, EK Asplund, A Jain, M Nilsson, R AF Sheppard, Nina Gustafsson Jarl, Lisa Mahadessian, Diana Strittmatter, Laura Schmidt, Angelika Madhusudan, Nikhil Tegner, Jesper Lundberg, Emma K. Asplund, Anna Jain, Mohit Nilsson, Roland TI The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation SO SCIENTIFIC REPORTS LA English DT Article ID DEHYDROGENASE-METHENYLTETRAHYDROFOLATE CYCLOHYDROLASE; DEPENDENT METHYLENETETRAHYDROFOLATE DEHYDROGENASE; NOVO THYMIDYLATE BIOSYNTHESIS; ONE-CARBON METABOLISM; CANCER-CELLS; IDENTIFICATION; FIBROBLASTS; INHIBITION; BINDING AB Folate metabolism is central to cell proliferation and a target of commonly used cancer chemotherapeutics. In particular, the mitochondrial folate-coupled metabolism is thought to be important for proliferating cancer cells. The enzyme MTHFD2 in this pathway is highly expressed in human tumors and broadly required for survival of cancer cells. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in cancer cell biology. We here report that MTHFD2 is co-expressed with two distinct gene sets, representing amino acid metabolism and cell proliferation, respectively. Consistent with a role for MTHFD2 in cell proliferation, MTHFD2 expression was repressed in cells rendered quiescent by deprivation of growth signals (serum) and rapidly re-induced by serum stimulation. Overexpression of MTHFD2 alone was sufficient to promote cell proliferation independent of its dehydrogenase activity, even during growth restriction. In addition to its known mitochondrial localization, we found MTHFD2 to have a nuclear localization and co-localize with DNA replication sites. These findings suggest a previously unknown role for MTHFD2 in cancer cell proliferation, adding to its known function in mitochondrial folate metabolism. C1 [Sheppard, Nina Gustafsson; Jarl, Lisa; Schmidt, Angelika; Tegner, Jesper; Nilsson, Roland] Karolinska Inst, Dept Med, Unit Computat Med, Stockholm, Sweden. [Sheppard, Nina Gustafsson; Jarl, Lisa; Schmidt, Angelika; Tegner, Jesper; Nilsson, Roland] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden. [Sheppard, Nina Gustafsson] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden. [Mahadessian, Diana; Lundberg, Emma K.] Royal Inst Technol, Sci Life Lab, Solna, Sweden. [Strittmatter, Laura; Madhusudan, Nikhil] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Strittmatter, Laura; Madhusudan, Nikhil] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Asplund, Anna] Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Jain, Mohit] Univ Calif San Diego, Dept Med, Inst Metabol Med, San Diego, CA 92103 USA. RP Nilsson, R (reprint author), Karolinska Inst, Dept Med, Unit Computat Med, Stockholm, Sweden. EM roland.nilsson@ki.se RI Schmidt, Angelika/E-1909-2016 OI Schmidt, Angelika/0000-0002-1185-3012 FU Swedish Society for Medical Research; Marie Curie Intra European Fellowship within the 7th European Community Framework Programme; VR Medicine grant [B0326401, B0305901]; Stockholm County Council [01626-2009]; Mary Kay Foundation; Strategic Programme in Cancer Research at Karolinska Institutet; Jeanssons Stiftelser grant [JS2012-0137]; Cancerfonden grant [CAN2013/822]; Stiftelsen for Strategisk Forskning [ICA10-0023] FX The authors would like to thank Vamsi K Mootha for providing overexpression constructs for MTHFD2 and MTHFD2-dead. This research was supported by the Swedish Society for Medical Research and VR Medicine grant no. B0305901 (NGS), Marie Curie Intra European Fellowship within the 7th European Community Framework Programme (to AS.), VR Medicine grant no. B0326401 (JT, AS), Stockholm County Council no. 01626-2009 (JT, AS), Mary Kay Foundation (MJ), the Strategic Programme in Cancer Research at Karolinska Institutet and Stiftelsen for Strategisk Forskning grant no. ICA10-0023 (RN), Jeanssons Stiftelser grant no. JS2012-0137 (LJ) and Cancerfonden grant no. CAN2013/822. NR 31 TC 6 Z9 6 U1 3 U2 15 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 OCT 13 PY 2015 VL 5 AR 15029 DI 10.1038/srep15029 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT2OJ UT WOS:000362641800003 ER PT J AU Zhao, XS Sega, RA AF Zhao, Xuesong Sega, Rosalind A. TI A Polyamine Twist on Hedgehog Signaling SO DEVELOPMENTAL CELL LA English DT Editorial Material ID MEDULLOBLASTOMA; RESISTANCE; TUMORS AB The Hedgehog pathway plays important roles in embryonic development and oncogenesis, but how it affects metabolism is less clear. D'Amico et al. (2015) now demonstrate that the Hedgehog pathway regulates translation of ornithine decarboxylase, thereby enhancing polyamine biosynthesis and cell proliferation in neural precursor cells and in brain tumors. C1 [Zhao, Xuesong; Sega, Rosalind A.] Dana Farber Canc Inst, Canc Biol & Pediat Oncol, Boston, MA 02115 USA. [Zhao, Xuesong; Sega, Rosalind A.] Harvard Univ, Sch Med, Neurobiol, Boston, MA 02115 USA. RP Sega, RA (reprint author), Dana Farber Canc Inst, Canc Biol & Pediat Oncol, Boston, MA 02115 USA. EM rosalind_segal@dfci.harvard.edu NR 9 TC 0 Z9 0 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD OCT 12 PY 2015 VL 35 IS 1 BP 1 EP 2 DI 10.1016/j.devcel.2015.09.024 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CT8ON UT WOS:000363076000001 PM 26460938 ER PT J AU Filbin, MG Stiles, CD AF Filbin, Mariella G. Stiles, Charles D. TI Of Brains and Blood: Developmental Origins of Glioma Diversity? SO CANCER CELL LA English DT Editorial Material ID GLIOBLASTOMA; CELLS AB The multiple cell types of brain and blood arise from pluripotent stem cells via progressively more committed downstream progenitors. In this issue of Cancer Cell, Alcantara Llaguno and colleagues show that identical genetic drivers give rise to distinct glioma subtypes within differentially committed neural progenitors-a paradigm well established for leukemias. C1 [Filbin, Mariella G.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Stiles, Charles D.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. RP Stiles, CD (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM charles_stiles@dfci.harvard.edu NR 10 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD OCT 12 PY 2015 VL 28 IS 4 BP 403 EP 404 DI 10.1016/j.ccell.2015.09.013 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CT5KO UT WOS:000362848800002 PM 26461085 ER PT J AU Mez, J Solomon, TM Daneshvar, DH Murphy, L Kiernan, PT Montenigro, PH Kriegel, J Abdolmohammadi, B Fry, B Babcock, KJ Adams, JW Bourlas, AP Papadopoulos, Z McHale, L Ardaugh, BM Martin, BR Dixon, D Nowinski, CJ Chaisson, C Alvarez, VE Tripodis, Y Stein, TD Goldstein, LE Katz, DI Kowall, NW Cantu, RC Stern, RA McKee, AC AF Mez, Jesse Solomon, Todd M. Daneshvar, Daniel H. Murphy, Lauren Kiernan, Patrick T. Montenigro, Philip H. Kriegel, Joshua Abdolmohammadi, Bobak Fry, Brian Babcock, Katharine J. Adams, Jason W. Bourlas, Alexandra P. Papadopoulos, Zachary McHale, Lisa Ardaugh, Brent M. Martin, Brett R. Dixon, Diane Nowinski, Christopher J. Chaisson, Christine Alvarez, Victor E. Tripodis, Yorghos Stein, Thor D. Goldstein, Lee E. Katz, Douglas I. Kowall, Neil W. Cantu, Robert C. Stern, Robert A. McKee, Ann C. TI Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study SO ALZHEIMERS RESEARCH & THERAPY LA English DT Article ID FRONTOTEMPORAL LOBAR DEGENERATION; ALZHEIMERS ASSOCIATION WORKGROUPS; RESEARCH DIAGNOSTIC-CRITERIA; 21ST-CENTURY BRAIN BANKING; MILD COGNITIVE IMPAIRMENT; FOOTBALL-LEAGUE PLAYER; NATIONAL-INSTITUTE; NEUROPATHOLOGIC ASSESSMENT; COLUMBIA-UNIVERSITY; PARKINSON-DISEASE AB Introduction: Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as "at risk" for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE. Methods: Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE. Results: We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology. Conclusions: The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria. C1 [Mez, Jesse; Solomon, Todd M.; Daneshvar, Daniel H.; Murphy, Lauren; Kiernan, Patrick T.; Montenigro, Philip H.; Kriegel, Joshua; Abdolmohammadi, Bobak; Fry, Brian; Babcock, Katharine J.; Adams, Jason W.; Bourlas, Alexandra P.; Papadopoulos, Zachary; Alvarez, Victor E.; Stein, Thor D.; Goldstein, Lee E.; Kowall, Neil W.; Cantu, Robert C.; Stern, Robert A.; McKee, Ann C.] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Mez, Jesse; Murphy, Lauren; Kiernan, Patrick T.; Kriegel, Joshua; Abdolmohammadi, Bobak; Fry, Brian; Babcock, Katharine J.; Adams, Jason W.; Bourlas, Alexandra P.; Papadopoulos, Zachary; Goldstein, Lee E.; Katz, Douglas I.; Cantu, Robert C.; Stern, Robert A.; McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Daneshvar, Daniel H.; McHale, Lisa; Nowinski, Christopher J.; Cantu, Robert C.] Sports Legacy Inst, Waltham, MA 02451 USA. [Montenigro, Philip H.; Stern, Robert A.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Ardaugh, Brent M.; Martin, Brett R.; Dixon, Diane; Chaisson, Christine] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02118 USA. [Alvarez, Victor E.; Stein, Thor D.; Kowall, Neil W.; McKee, Ann C.] VA Boston Healthcare Syst, US Dept Vet Affairs, Jamaica Plain, MA 02130 USA. [Alvarez, Victor E.; Stein, Thor D.; McKee, Ann C.] Dept Vet Affairs Med Ctr, Bedford, MA 01730 USA. [Alvarez, Victor E.; Stein, Thor D.; Kowall, Neil W.; McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [Tripodis, Yorghos] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Katz, Douglas I.] Braintree Rehabil Hosp, Braintree, MA 02184 USA. [Kowall, Neil W.; McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. [Cantu, Robert C.; Stern, Robert A.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [Cantu, Robert C.] Emerson Hosp, Dept Neurosurg, Concord, MA 01742 USA. RP McKee, AC (reprint author), Boston Univ, Sch Med, Alzheimers Dis Ctr, 72 East Concord St,B-7800, Boston, MA 02118 USA. EM amckee@bu.edu RI Kowall, Neil/G-6364-2012; OI Kowall, Neil/0000-0002-6624-0213; Stein, Thor/0000-0001-6954-4477; Daneshvar, Daniel/0000-0003-3691-9513; Tripodis, Yorghos/0000-0003-2190-7608; Montenigro, Philip/0000-0003-4442-9207 FU National Institute of Neurological Disorders and Stroke [1UO1NS086659-01, R01 NS078337, R56 NS078337]; U.S. Department of Defense [W81XWH-13-2-0064]; U.S. Department of Veterans Affairs, the Veterans Affairs Biorepository [CSP 501]; Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS); Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence [B6796-C]; National Institute on Aging Boston University Alzheimer's Disease Center [P30AG13846]; Department of Defense Peer Reviewed Alzheimer's Research Program (DoD-PRARP grant) [13267017]; National Institute on Aging Boston University Framingham Heart Study [R01 AG1649]; National Operating Committee on Standards for Athletic Equipment; Sports Legacy Institute FX The authors gratefully acknowledge the use of the resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA, USA). We also gratefully acknowledge the help of all members of the Chronic Traumatic Encephalopathy Program at Boston University School of Medicine, the VA Boston Healthcare System, and the individuals and families whose participation and contributions made this work possible. This work was supported by the National Institute of Neurological Disorders and Stroke (grants 1UO1NS086659-01, R01 NS078337, R56 NS078337), the U.S. Department of Defense (grant W81XWH-13-2-0064), the U.S. Department of Veterans Affairs, the Veterans Affairs Biorepository (CSP 501), the Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS), the Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (grant B6796-C), the National Institute on Aging Boston University Alzheimer's Disease Center (grant P30AG13846; supplement 0572063345-5), the Department of Defense Peer Reviewed Alzheimer's Research Program (DoD-PRARP grant 13267017), the National Institute on Aging Boston University Framingham Heart Study (grant R01 AG1649), the National Operating Committee on Standards for Athletic Equipment, and the Sports Legacy Institute. This work was also supported by unrestricted gifts from the Andlinger Family Foundation, the WWE, and the NFL. NR 78 TC 8 Z9 8 U1 2 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PD OCT 12 PY 2015 VL 7 AR 62 DI 10.1186/s13195-015-0148-8 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT2KD UT WOS:000362629500001 PM 26455775 ER PT J AU Acquisto, S Iyer, RV Driskill, KM Pinheiro, N Weatherly, J Musto, KR Lowitzer, H McCallum, L Drapek, L AF Acquisto, Susan Iyer, Renuka V. Driskill, Karen M. Pinheiro, Natasha Weatherly, Jacqueline Musto, Kaitlyn R. 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Clin. Oncol. PD OCT 10 PY 2015 VL 33 IS 29 SU S MA 39 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000038 ER PT J AU Bickel, KE McNiff, KK Buss, MK Kamal, A Lupu, D Abernethy, AP Broder, MS Shapiro, CL Acheson, AK Malin, J Evans, TL Krzyzanowska, MK AF Bickel, Kathleen Elizabeth McNiff, Kristen K. Buss, Mary K. Kamal, Arif Lupu, Dale Abernethy, Amy Pickar Broder, Michael S. Shapiro, Charles L. Acheson, Anupama Kurup Malin, Jennifer Evans, Tracey L. Krzyzanowska, Monika K. TI Defining high-quality palliative care in oncology practice: An ASCO/AAHPM Guidance Statement SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Geisel Sch Medcine Dartmouth, White River Junct VA Med Ctr, Woodstock, VT USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Newton, MA USA. Duke Univ, Med Ctr, Durham, NC USA. Amer Acad Hosp & Palliat Med, Glenview, IL USA. Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. Partnership Hlth Analyt Res LLC, Beverly Hills, CA USA. Ohio State Univ, Columbus, OH 43210 USA. Providence Oncol & Hematol Care Clin, Portland, OR USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Penn, Wynnewood, PA USA. Princess Margaret Canc Ctr, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2015 VL 33 IS 29 SU S MA 108 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000106 ER PT J AU Carr, AL Traeger, L Cashavelly, BJ Pirl, WF AF Carr, Alaina L. Traeger, Lara Cashavelly, Barbara J. Pirl, William F. TI Resiliency among nursing staff in an inpatient medical oncology unit. 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PD OCT 10 PY 2015 VL 33 IS 29 SU S MA 24 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000025 ER PT J AU Dawson, GA Glushko, I Hagan, MP AF Dawson, George Anthony Glushko, Ignat Hagan, Michael Philip TI A cross-sectional view of radiation fractionation schemes used for painful bone metastases (PBM) cases within the Veterans Health Administration Radiation Oncology Centers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 James J Peters VA Med Ctr, New York, NY USA. James J Peters VA Med Ctr, Bronx, NY USA. Virginia Commonwealth Univ, Mineral, VA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 177 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000172 ER PT J AU El-Jawahri, A VanDusen, H Traeger, L Fishbein, J Keenan, T Greer, JA Pirl, WF Jackson, VA Eusebio, J Gallagher, ER Spitzer, TR Ballen, KK McAfee, SL Dey, B Chen, YB Temel, JS AF El-Jawahri, Areej VanDusen, Harry Traeger, Lara Fishbein, Joel Keenan, Tanya Greer, Joseph A. Pirl, William F. Jackson, Vicki A. Eusebio, Justin Gallagher, Emily R. Spitzer, Thomas R. Ballen, Karen K. McAfee, Steven L. Dey, Bimalangshu Chen, Yi-Bin Albert Temel, Jennifer S. TI Quality of life and depression during hospitalization for hematopoietic stem cell transplantation to predict quality of life and post-traumatic stress disorder symptoms at 6 months post-transplant. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Massachusetts Gen Hosp, Brookline, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Needham, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 215 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000207 ER PT J AU El-Jawahri, A Keenan, T Abel, GA Steensma, DP LeBlanc, TW Traeger, L Fathi, AT DeAngelo, DJ Wadleigh, M Hobbs, G Amrein, PC Stone, RM Ballen, KK Chen, YB Temel, JS AF El-Jawahri, Areej Keenan, Tanya Abel, Gregory Alan Steensma, David P. LeBlanc, Thomas William Traeger, Lara Fathi, Amir Tahmasb DeAngelo, Daniel J. Wadleigh, Martha Hobbs, Gabriela Amrein, Philip C. Stone, Richard M. Ballen, Karen K. Chen, Yi-Bin Albert Temel, Jennifer S. TI Potentially avoidable hospitalizations in older patients with acute myeloid leukemia (AML) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Duke Univ, Med Ctr, Durham, NC USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Massachusetts Gen Hosp, Needham, MA USA. NR 0 TC 1 Z9 1 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. 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PD OCT 10 PY 2015 VL 33 IS 29 SU S MA 124 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000120 ER PT J AU Kumar, P Hatfield, L Wright, AA Temel, JS Keating, NL AF Kumar, Pallavi Hatfield, Laura Wright, Alexi A. Temel, Jennifer S. Keating, Nancy Lynn TI Associations between hospice use and end-of-life (EOL) care outcomes in patients with advanced cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Univ Penn, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Dept Healthcare Policy, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 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. 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NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 155 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000151 ER PT J AU LeBaron, VT Quinones, R Nibecker, C White-Hammond, G Smith, PT Balboni, TA Balboni, M AF LeBaron, Virginia T. Quinones, Rebecca Nibecker, Callie White-Hammond, Gloria Smith, Patrick T. Balboni, Tracy A. Balboni, Michael TI Developing a conceptual framework of optimal spiritual care: Clergy perspectives. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Univ Virginia, Sch Nursing, Charlottesville, VA 22903 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Gordon Conwell Theol Seminary, Boston, MA USA. Harvard Univ, Sch Med, Ctr Bioeth, Boston, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 234 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000226 ER PT J AU LeBlanc, TW Wolf, SP Davis, DM Samsa, G Locke, SC El-Jawahri, A Tulsky, JA Abernethy, AP AF LeBlanc, Thomas William Wolf, Steven Paul Davis, Debra M. Samsa, Greg Locke, Susan C. El-Jawahri, Areej Tulsky, James A. Abernethy, Amy P. TI Severity of and contributors to distress in patients with acute myeloid leukemia (AML) receiving induction chemotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Duke Univ, Med Ctr, Durham, NC USA. Duke Univ, Sch Med, Durham, NC USA. Duke Clin Res Inst, Ctr Learning Hlth Care, Durham, NC USA. Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. Duke Canc Care Res Program, Durham, NC USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Flatiron Hlth, New York, NY USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 83 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000082 ER PT J AU MacDonald, J Amoyal, N Nisotel, L Perez, GK Traeger, L Temel, JS Pirl, WF Safren, SA Greer, JA AF MacDonald, James Amoyal, Nicole Nisotel, Lauren Perez, Giselle Katiria Traeger, Lara Temel, Jennifer S. Pirl, William F. Safren, Steven A. Greer, Joseph A. TI Mobile application of cognitive behavioral therapy for anxiety and advanced cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Brookline, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 220 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000212 ER PT J AU Marron, JM Kang, TI Cronin, A Mack, JW AF Marron, Jonathan Michael Kang, Tammy I. Cronin, Angel Mack, Jennifer W. TI Intended and unintended consequences: Ethics, communication, and prognostic disclosure in pediatric oncology. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Boston Childrens Canc & Blood Disorder Ctr, Dana Farber Canc Inst, Boston, MA USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 10 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000011 ER PT J AU Moran, SMC El-Jawahri, A Pirl, WF Traeger, L Kumar, P Ryan, DP Lennes, IT Cashavelly, BJ Martinson, HS VanDusen, H Hochberg, EP Jackson, VA Greer, JA Temel, JS Nipp, RD AF Moran, Samantha M. C. El-Jawahri, Areej Pirl, William F. Traeger, Lara Kumar, Pallavi Ryan, David P. Lennes, Inga Tolin Cashavelly, Barbara J. Martinson, Holly S. VanDusen, Harry Hochberg, Ephraim P. Jackson, Vicki A. Greer, Joseph A. Temel, Jennifer S. Nipp, Ryan David TI Symptom burden in hospitalized patients with advanced cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Brookline, MA USA. Univ Penn Hlth Syst, Philadelphia, PA USA. Harvard Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 100 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000099 ER PT J AU Nipp, RD Kirchhoff, AC Fair, DB Kuhlthau, K Hyland, K Perez, GK Armstrong, GT Nathan, PC Oeffinger, KC Leisenring, WM Park, ER AF Nipp, Ryan David Kirchhoff, Anne C. Fair, Douglas Beaty Kuhlthau, Karen Hyland, Kelly Perez, Giselle Katiria Armstrong, Gregory T. Nathan, Paul C. Oeffinger, Kevin C. Leisenring, Wendy M. Park, Elyse R. TI Financial burden among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Dana Farber Canc Inst, Harvard Canc Ctr, Boston, MA 02115 USA. Univ Utah, Dept Pediat, Salt Lake City, UT USA. Primary Childrens Med Ctr, Salt Lake City, UT USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2015 VL 33 IS 29 SU S MA 233 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000225 ER PT J AU Nipp, RD Fishbein, J El-Jawahri, A Pirl, WF Moran, SMC McCarty, C Eusebio, J Gallagher, ER Park, ER Jackson, VA Greer, JA Temel, JS AF Nipp, Ryan David Fishbein, Joel El-Jawahri, Areej Pirl, William F. Moran, Samantha M. C. McCarty, Caitlin Eusebio, Justin Gallagher, Emily R. Park, Elyse R. Jackson, Vicki A. Greer, Joseph A. Temel, Jennifer S. TI Depression and anxiety among family caregivers of patients with advanced cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Dana Farber Canc Inst, Harvard Canc Ctr, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Brookline, MA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 224 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000216 ER PT J AU Nipp, RD Powell, E Moy, B AF Nipp, Ryan David Powell, Elizabeth Moy, Beverly TI Hospitalizations and emergency department use in cancer clinical trial patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Harvard Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 160 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000156 ER PT J AU Nipp, RD Betof, AS Rubin, KM Blackmon, SM Flaherty, K Lawrence, DP Sullivan, RJ AF Nipp, Ryan David Betof, Allison Shayna Rubin, Krista M. Blackmon, Shauna M. Flaherty, Keith Lawrence, Donald P. Sullivan, Ryan J. TI Palliative care and hospice use among melanoma patients treated with immunotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Harvard Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 116 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000112 ER PT J AU Nipp, RD Powell, E Moy, B AF Nipp, Ryan David Powell, Elizabeth Moy, Beverly TI Palliative care consultation for patients enrolled in cancer clinical trials. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Harvard Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 139 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000135 ER PT J AU Nipp, RD El-Jawahri, A Pirl, WF Fishbein, J Moran, SMC McCarty, C Eusebio, J Gallagher, ER Park, ER Jackson, VA Greer, JA Temel, JS AF Nipp, Ryan David El-Jawahri, Areej Pirl, William F. Fishbein, Joel Moran, Samantha M. C. McCarty, Caitlin Eusebio, Justin Gallagher, Emily R. Park, Elyse R. Jackson, Vicki A. Greer, Joseph A. Temel, Jennifer S. TI Quality of life and mood in patients with advanced cancer: Associations with prognostic understanding and coping style SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Harvard Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Brookline, MA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 76 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000075 ER PT J AU Nisotel, L Amoyal, N Fishbein, J MacDonald, J Pirl, WF Temel, JS Lennes, IT Safren, SA Buzaglo, JS Jethwani, K Greer, JA AF Nisotel, Lauren Amoyal, Nicole Fishbein, Joel MacDonald, James Pirl, William F. Temel, Jennifer S. Lennes, Inga Tolin Safren, Steven A. Buzaglo, Joanne S. Jethwani, Kamal Greer, Joseph A. TI Development of a mobile application (app) for improving symptoms and adherence to oral chemotherapy in patients with cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Brookline, MA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Res & Training Inst, Canc Support Community, Philadelphia, PA USA. Partners HealthCare Ctr Connected Hlth, Boston, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 189 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000184 ER PT J AU Odejide, OO Cronin, A Condron, N Earle, C Wolfe, J Abel, GA AF Odejide, Oreofe Olukemi Cronin, Angel Condron, Nolan Earle, Craig Wolfe, Joanne Abel, Gregory Alan TI Timeliness of end-of-life (EOL) discussions for blood cancers: A national survey of hematologic oncologists. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Inst Clin Evaluat Sci, Toronto, ON, Canada. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 13 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000014 ER PT J AU Paladino, J Bernacki, R Hutchings, M Lipsitz, SR Neville, BA Gawande, A Block, S AF Paladino, Joanna Bernacki, Rachelle Hutchings, Mathilde Lipsitz, Stuart R. Neville, Bridget A. Gawande, Atul Block, Susan TI Effect of conversations about values and goals on anxiety in patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Dana Farber Canc Inst, Ariadne Labs, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Ariadne Labs, Boston, MA USA. Dana Farber Canc Inst, Cambridge, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 9 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000010 ER PT J AU Pirl, WF Lerner, J Eusebio, J Traeger, L Fields, L El-Jawahri, A Greer, JA Temel, JS AF Pirl, William F. Lerner, Jennifer Eusebio, Justin Traeger, Lara Fields, Lauren El-Jawahri, Areej Greer, Joseph A. Temel, Jennifer S. TI Association between oncologists' dispositional affect and depressive symptoms in their patients with metastatic cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Massachusetts Gen Hosp, Brookline, MA USA. Harvard Univ, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 214 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000206 ER PT J AU Pirl, WF Fujisawa, D Stagl, J Eusebio, J Traeger, L El-Jawahri, A Greer, JA Temel, JS AF Pirl, William F. Fujisawa, Daisuke Stagl, Jamie Eusebio, Justin Traeger, Lara El-Jawahri, Areej Greer, Joseph A. Temel, Jennifer S. TI Actigraphy as an objective measure of performance status in patients with advanced cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Massachusetts Gen Hosp, Brookline, MA USA. Keio Univ, Tokyo, Japan. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 62 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000061 ER PT J AU Sanders, JJ Sterba, KW Ford, D Block, S AF Sanders, Justin J. Sterba, Katherine W. Ford, Dee Block, Susan TI The acceptability to African-Americans of a structured conversation guide to improve advance care planning in the setting of cancer: A focus-group study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Dana Farber Canc Inst, Cambridge, MA USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 11 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000012 ER PT J AU Slater, S Doyle, K AF Slater, Sarah Doyle, Kathleen TI Long-term collaboration for building sustainable palliative care in Belarus. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Mt Auburn Hosp, Cambridge, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 142 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000138 ER PT J AU Solis, RM Cronin, A Watts, CD Steensma, DP Stone, RM DeAngelo, DJ Owens, RL Wadleigh, M Abel, GA AF Solis, Roxanne M. Cronin, Angel Watts, Corey D. Steensma, David P. Stone, Richard M. DeAngelo, Daniel J. Owens, Robert L. Wadleigh, Martha Abel, Gregory Alan TI Impact of sleep disturbance in myelodysplastic syndromes (MDS) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 99 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000098 ER PT J AU Temel, JS Currow, DC Fearon, K Yan, Y Friend, J Abernethy, AP AF Temel, Jennifer S. Currow, David Christopher Fearon, Kenneth Yan, Ying Friend, John Abernethy, Amy Pickar TI Anamorelin in patients with advanced non-small cell lung cancer and cachexia: Results from the phase III studies ROMANA 1 and 2 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Flinders Univ S Australia, Adelaide, SA 5001, Australia. Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. Helsinn Therapeut Inc, Iselin, NJ USA. Duke Univ, Durham, NC USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 175 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000170 ER PT J AU Vick, JB Pertsch, N Hutchings, M Neville, BA Lipsitz, S Gawande, A Block, S Bernacki, R AF Vick, Judith B. Pertsch, Nate Hutchings, Mathilde Neville, Bridget A. Lipsitz, Stu Gawande, Atul Block, Susan Bernacki, Rachelle TI The utility of the surprise question in identifying patients most at risk of death. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Johns Hopkins Univ, Sch Med, Ariadne Labs, Dana Farber Canc Inst, Baltimore, MD USA. Dana Farber Canc Inst, Ariadne Labs, Boston, MA 02115 USA. Ariadne Labs, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2015 VL 33 IS 29 SU S MA 8 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000009 ER PT J AU Walling, AM D'Ambruoso, S Pietras, C Malin, J Hurvitz, SA Watts, F Ferrell, B Zisser, A Wenger, N AF Walling, Anne M. D'Ambruoso, Sarah Pietras, Christopher Malin, Jennifer Hurvitz, Sara A. Watts, Frances Ferrell, Bruce Zisser, Ann Wenger, Neil TI Evaluation of the efficiency of an embedded palliative nurse practitioner in an oncology clinic. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Univ Calif Los Angeles, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Healthcare Hematol Oncol Breast Oncol Program, Santa Monica, CA USA. Anthem, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 146 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000142 ER PT J AU Zhang, HP Rickerson, E Barysauskas, C Catalano, PJ Jacobson, JO Dalby, CK Lindvall, C Selvaggi, KJ AF Zhang, Haipeng Rickerson, Elizabeth Barysauskas, Constance Catalano, Paul J. Jacobson, Joseph O. Dalby, Carole Kathleen Lindvall, Charlotta Selvaggi, Kathy J. TI The Intensive Palliative Care Unit (IPCU): Changing outcomes for hospitalized cancer patients in an academic medical center. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Palliative Care in Oncology Symposium CY OCT 09-10, 2015 CL Boston, MA C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Dana Farber Canc Inst, Waban, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 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 10 PY 2015 VL 33 IS 29 SU S MA 135 PG 1 WC Oncology SC Oncology GA DO9LD UT WOS:000378107000131 ER PT J AU Irie, T Sips, PY Kai, S Kida, K Ikeda, K Hirai, S Moazzami, K Jiramongkolchai, P Bloch, DB Doulias, PT Armoundas, AA Kaneki, M Ischiropoulos, H Kranias, E Bloch, KD Stamler, JS Ichinose, F AF Irie, Tomoya Sips, Patrick Y. Kai, Shinichi Kida, Kotaro Ikeda, Kohei Hirai, Shuichi Moazzami, Kasra Jiramongkolchai, Pawina Bloch, Donald B. Doulias, Paschalis-Thomas Armoundas, Antonis A. Kaneki, Masao Ischiropoulos, Harry Kranias, Evangelia Bloch, Kenneth D. Stamler, Jonathan S. Ichinose, Fumito TI Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy SO CIRCULATION RESEARCH LA English DT Article DE beta adrenergic; calcium; heart failure; myocardial contraction; nitric oxide; receptors ID BRIDGE CYCLING KINETICS; TROPONIN-C MUTATIONS; S-NITROSYLATION; MYOCARDIAL-CONTRACTILITY; MOUSE HEARTS; PHOSPHOLAMBAN; PHOSPHORYLATION; TEMPERATURE; MYOCYTES; DENITROSYLATION AB Rationale: The regulation of calcium (Ca2+) homeostasis by -adrenergic receptor (AR) activation provides the essential underpinnings of sympathetic regulation of myocardial function, as well as a basis for understanding molecular events that result in hypertrophic signaling and heart failure. Sympathetic stimulation of the AR not only induces protein phosphorylation but also activates nitric oxide-dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in AR-dependent regulation of Ca2+ handling has not yet been explicated fully. Objective: To elucidate the role of protein S-nitrosylation, a major transducer of nitric oxide bioactivity, on AR-dependent alterations in cardiomyocyte Ca2+ handling and hypertrophy. Methods and Results: Using transgenic mice to titrate the levels of protein S-nitrosylation, we uncovered major roles for protein S-nitrosylation, in general, and for phospholamban and cardiac troponin C S-nitrosylation, in particular, in AR-dependent regulation of Ca2+ homeostasis. Notably, S-nitrosylation of phospholamban consequent upon AR stimulation is necessary for the inhibitory pentamerization of phospholamban, which activates sarcoplasmic reticulum Ca2+-ATPase and increases cytosolic Ca2+ transients. Coincident S-nitrosylation of cardiac troponin C decreases myocardial sensitivity to Ca2+. During chronic adrene